Neuronal variability of Resting State activity in Eating Disorders: increase and decoupling in Ventral Attention Network and relation with clinical symptoms.
Despite the great number of resting state functional connectivity studies on Eating Disorders (ED), no biomarkers could be detected yet. Therefore, we here focus on a different measure of resting state activity that is neuronal variability. The objective of this study was to investigate neuronal variability in the resting state of women with ED and to correlate possible differences with clinical and psychopathological indices. 58 women respectively 25 with Anorexia Nervosa (AN), 16 with Bulimia Nervosa (BN) and 17 matched healthy controls (CN) were enrolled for the study. All participants were tested with a battery of psychometric tests and underwent a functional Magnetic Resonance Imaging (fMRI) resting state scanning. We investigated topographical patterns of variability measured by the Standard Deviation (SD) of the Blood-Oxygen-Level-Dependent (BOLD) signal (as a measure of neuronal variability) in the resting-state and their relationship to clinical and psychopathological indices. Neuronal variability was increased in both anorectic and bulimic subjects specifically in the Ventral Attention Network (VAN) compared to healthy controls. No significant differences were found in the other networks. Significant correlations were found between neuronal variability of VAN and various clinical and psychopathological indices. We here show increased neuronal variability of VAN in ED patients. As the VAN is relevant for switching between endogenous and exogenous stimuli, our results showing increased neuronal variability suggest unstable balance between body attention and attention to external world. These results offer new perspective on the neurobiological basis of ED. Clinical and therapeutic implication will be discussed.


Outcomes of Triceps Rupture in the US Military: Minimum 2-Year Follow-up.
The objective of this study was to examine the subjective and objective midterm functional clinical outcomes of surgically repaired triceps injuries in a moderate- to high-demand population. The US Military Health System was queried to identify all surgically treated triceps tendon ruptures between 2008 and 2013. Primary endpoints included rates of rerupture, perioperative complications, or significant persistent elbow dysfunction; Disability of the Arm, Shoulder and Hand (DASH) score, Mayo Elbow score, and ability to do push-ups were also extracted. Thirty-seven patients underwent triceps tendon repair with a mean follow-up of 49.8 ± 17.3 months (range: 26.8-80.2). The most common mechanisms of injury were military duties (27%), sporting activity (24%), or fall-related (21.6%), with most injuries occurring during an eccentric movement (54%). While 45% experienced occasional elbow pain postoperatively, only 1 patient (2.7%) had a rerupture. Despite this, at 2 years, 31 patients (84%) were able to return to full military duty. While 6 patients were discharged from military service, only 1 underwent medical separation while 5 retired for reasons unrelated to their triceps tendon rupture. Patient-reported outcomes were available for 14 patients at final follow-up. The average DASH and Mayo Elbow scores were 4.7 (SD ± 4.7, range: 0-15.9) and 85.4 (SD ± 11.7, range: 60-100), respectively. The cohort could perform mean 54.2 (range: 9-90) push-ups. In additional, 12 of 14 (85.7%) were satisfied with their elbow function. The active duty cohort experienced excellent postoperative results with a high rate of return to military duty, despite nearly half of the patients recognizing some degree of activity-related, elbow pain.


A pilot study on pharmacokinetic/pharmacodynamic target attainment in critically ill patients receiving piperacillin/tazobactam.
In critically ill patients, multi-trauma and intensive therapy can influence the pharmacokinetics (PK) and pharmacodynamics (PD) of antibiotics with time-dependent bacterial killing. Consequently, PK/PD targets (%fT>MIC) - crucial for antimicrobial effects -may not be attained. Two patients admitted to the surgical ICU of the University Hospital in Hradec Králove for multiple-trauma were given piperacillin/tazobactam by 1-hour IV infusion 4/0.5 g every 8h. PK variables: total and renal clearance (CLtot, CLR), volume of distribution (Vd), and elimination half-life (T1/2) were calculated, followed by glomerular filtration rate (MDRD) and cumulative fluid balance (CFB-total fluid volume based on 24-h registered fluid intake minus output). The PK/PD target attainment (100%fT>MIC) was defined as free (f) piperacillin plasma concentrations that remain, during the entire dosing interval (T), above the minimum inhibitory concentration (100%fT>MIC) within days 4-8 (when CFB culminates and disappears). Piperacillin concentrations were determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS) and corrected for unbound fraction (22%). CFB culminated over days 2-5 reaching 15-30 L and was associated with a large Vd (29-42 L). While MDRD in patient 1 was low (0.3-0.4 mL s⁻¹ 1.7 m⁻²), that of patient 2 was increasing (> 3.1 mL s⁻¹ 1.7 m⁻²), which was associated with augmented CLR. In patient 2, the fT reached only 62, 52, and 44% on days 4, 6, and 8, respectively. In patient 1, the %fT was much higher, attaining values four to fivefold greater than that targeted. Critically ill patients are at risk of drug under- or overdosing without dose up-titration with regard to covariate effects and individual drug pharmacokinetics.


Elevated serum pesticide levels and risk for Alzheimer disease.
The causes of late-onset Alzheimer disease (AD) are not yet understood but likely include a combination of genetic, environmental, and lifestyle factors. Limited epidemiological studies suggest that occupational pesticide exposures are associated with AD. Previously, we reported that serum levels of dichlorodiphenyldichloroethylene (DDE), the metabolite of the pesticide dichlorodiphenyltrichloroethane (DDT), were elevated in a small number of patients with AD (n=20). To evaluate the association between serum levels of DDE and AD and whether the apolipoprotein E (APOE) genotype modifies the association. A case-control study consisting of existing samples from patients with AD and control participants from the Emory University Alzheimer's Disease Research Center and the University of Texas Southwestern Medical School's Alzheimer's Disease Center. Serum levels of DDE were measured in 79 control and 86 AD cases. Serum DDE levels, AD diagnosis, severity of AD measured by the Mini-Mental State Examination score, and interaction with APOE4 status. Levels of DDE were 3.8-fold higher in the serum of those with AD (mean [SEM], 2.64 [0.35] ng/mg cholesterol) when compared with control participants (mean [SEM], 0.69 [0.1] ng/mg cholesterol; P < .001). The highest tertile of DDE levels was associated with an odds ratio of 4.18 for increased risk for AD (95% CI, 2.54-5.82; P < .001) and lower Mini-Mental State Examination scores (-1.605; range, -3.095 to -0.114; P < .0001). The Mini-Mental State Examination scores in the highest tertile of DDE were -1.753 points lower in the subpopulation carrying an APOE ε4 allele compared with those carrying an APOE ε3 allele (P interaction = .04). Serum levels of DDE were highly correlated with brain levels of DDE (ρ = 0.95). Exposure of human neuroblastoma cells to DDT or DDE increased levels of amyloid precursor protein. Elevated serum DDE levels are associated with an increased risk for AD and carriers of an APOE4 ε4 allele may be more susceptible to the effects of DDE. Both DDT and DDE increase amyloid precursor protein levels, providing mechanistic plausibility for the association of DDE exposure with AD. Identifying people who have elevated levels of DDE and carry an APOE ε4 allele may lead to early identification of some cases of AD.


Genetic Diversity and Physiological Performance of Portuguese Wild Beet (Beta vulgaris spp. maritima) from Three Contrasting Habitats.
The establishment of stress resilient sugar beets (Beta vulgaris spp. vulgaris) is an important breeding goal since this cash crop is susceptible to drought and salinity. The genetic diversity in cultivated sugar beets is low and the beet wild relatives are useful genetic resources for tolerance traits. Three wild beet populations (Beta vulgaris spp. maritima) from contrasting environments, Vaiamonte (VMT, dry inland hill), Comporta (CMP, marsh) and Oeiras (OEI, coastland), and one commercial sugar beet (Isella variety, SB), are compared. At the genetic level, the use of six microsatellite allowed to detect a total of seventy six alleles. It was observed that CMP population has the highest value concerning the effective number of alleles and of expected heterozygosity. By contrast, sugar beet has the lowest values for all the parameters considered. Loci analysis with STRUCTURE allows defining three genetic clusters, the sea beet (OEI and CMP), the inland ruderal beet (VMT) and the sugar beet (SB). A screening test for progressive drought and salinity effects demonstrated that: all populations were able to recover from severe stress; drought impact was higher than that from salinity; the impact on biomass (total, shoot, root) was population specific. The distinct strategies were also visible at physiological level. We evaluated the physiological responses of the populations under drought and salt stress, namely at initial stress stages, late stress stages, and early stress recovery. Multivariate analysis showed that the physiological performance can be used to discriminate between genotypes, with a strong contribution of leaf temperature and leaf osmotic adjustment. However, the separation achieved and the groups formed are dependent on the stress type, stress intensity and duration. Each of the wild beet populations evaluated is very rich in genetic terms (allelic richness) and exhibited physiological plasticity, i.e., the capacity to physiologically adjust to changing environments. These characteristics emphasize the importance of the wild beet ecotypes for beet improvement programs. Two striking ecotypes are VMT, which is the best to cope with drought and salinity, and CMP which has the highest root to shoot ratio. These genotypes can supply breeding programs with distinct goals.


The Early Positive Approaches to Support (E-PAtS) study: study protocol for a feasibility cluster randomised controlled trial of a group programme (E-PAtS) for family caregivers of young children with intellectual disability.
Children with intellectual disability have an IQ < 70, associated deficits in adaptive skills and are at increased risk of having clinically concerning levels of behaviour problems. In addition, parents of children with intellectual disability are likely to report high levels of mental health and other psychological problems. The Early Positive Approaches to Support (E-PAtS) programme for family caregivers of young children (5 years and under) with intellectual and developmental disabilities is a group-based intervention which aims to enhance parental psychosocial wellbeing and service access and support positive development for children. The aim of this study is to assess the feasibility of delivering E-PAtS to family caregivers of children with intellectual disability by community parenting support service provider organisations. The study will inform a potential, definitive RCT of the effectiveness and cost-effectiveness of E-PAtS. This study is a feasibility cluster randomised controlled trial, with embedded process evaluation. Up to 2 family caregivers will be recruited from 64 families with a child (18 months to 5 years) with intellectual disability at research sites in the UK. Participating families will be allocated to intervention: control on a 1:1 basis; intervention families will be offered the E-PAtS programme immediately, continuing to receive usual practice, and control participants will be offered the opportunity to attend the E-PAtS programme at the end of the follow-up period and will continue to receive usual practice. Data will be collected at baseline, 3 months post-randomisation and 12 months post-randomisation. The primary aim is to assess feasibility via the assessment of: recruitment of service provider organisations; participant recruitment; randomisation; retention; intervention adherence; intervention fidelity and the views of participants, intervention facilitators and service provider organisations regarding intervention delivery and study processes. The secondary aim is preliminary evaluation of a range of established outcome measures for individual family members, subsystem relationships and overall family functioning, plus additional health economic outcomes for inclusion in a future definitive trial. The results of this study will inform a potential future definitive trial, to evaluate the effectiveness and cost-effectiveness of the E-PAtS intervention to improve parental psychosocial wellbeing. Such a trial would have significant scientific impact internationally in the intellectual disability field. ISRCTN70419473.


Comparison of the effects of preoperative melatonin or vitamin C administration on postoperative analgesia.
The analgesic benefit of melatonin and vitamin C as primary or adjuvant agents has been reported in various studies; however, their analgesic effects in the treatment of postoperative pain remain unclear. Thus, we aimed to evaluate the effect of single preoperative dose of oral melatonin or vitamin C administration on postoperative analgesia. In this study, we recruited 165 adult patients undergoing elective major abdominal surgery under general anesthesia. Patients were randomly divided into three equal (n = 55) groups. One hour before surgery, patients received orally melatonin (6 mg) in group M, vitamin C (2 g) in group C, or a placebo tablet in group P. Pain, sedation, patient satisfaction, total morphine consumption from a patient-controlled analgesia device, supplemental analgesic requirement, and the incidence of nausea and vomiting were recorded throughout 24 h after surgery. The mean pain score and total morphine consumption were found significantly lower in both M and C groups compared with group P (p < 0.001). There were no significant differences between group M and C with respect to pain scores (p = 0.117) and total morphine consumption (p = 0.090). Patients requested less supplemental analgesic and experienced less nausea and vomiting in groups M and C compared with group P. In conclusion, preoperative oral administration of 6 mg melatonin or 2 g vitamin C led to a reduction in pain scores, total morphine consumption, supplemental analgesic requirement, and the incidence of nausea and vomiting compared with placebo.


The serological properties of the cell surface proteins of Vibrio cholerae.
The serological properties of cell surface proteins of Vibrio cholerae belonging to both the biotypes (classical and El Tor) and the serotypes (Ogawa and Inaba) were investigated. Proteins were isolated by extracting V. cholerae with EDTA in the presence of sodium chloride. The surface localization of these proteins was confirmed with (a) radioiodinated protein A as an immunoprobe and (b) antiserum absorption studies with whole bacteria. There were similarities among the polypeptides of cell surface proteins isolated from various V. cholerae types. Antisera to these proteins agglutinated several V. cholerae strains, irrespective of biotype, serotype and antibiotic sensitivity. The antisera did not agglutinate pathogenic enteric bacteria such as enterotoxigenic Escherichia coli, Salmonella typhi, Shigella spp., Aeromonas hydrophila and Yersinia enterocolitica. The cell surface proteins of V. cholerae were immunogenic in rabbits as high titres of anti-protein specific antibodies were detected by the ELISA technique in the immune sera. These results suggest that the cell surface proteins are common antigens of V. cholerae and can be developed as a potential vaccine candidate against cholera.


Light-regulated interactions with SPA proteins underlie cryptochrome-mediated gene expression.
Cryptochromes are a class of photosensory receptors that control important processes in animals and plants primarily by regulating gene expression. How photon absorption by cryptochromes leads to changes in gene expression has remained largely elusive. Three recent studies, including Lian and colleagues (pp. 1023-1028) and Liu and colleagues (pp. 1029-1034) in this issue of Genes & Development, demonstrate that the interaction of light-activated Arabidopsis cryptochromes with a class of regulatory components of E3 ubiquitin ligase complexes leads to environmentally controlled abundance of transcriptional regulators.


Non-frequency-shifted, high-fidelity phase conjugation with aberrated pump waves by Brillouin-enhanced four-wave mixing.
The results of an experimental investigation of a new geometry for producing phase conjugation by Brillouin-enhanced four-wave mixing are presented. In this geometry, the four-wave mixing medium is carbon disulfide, and the backward-going pump wave is created from the transmitted forward-going pump wave by stimulated Brillouin scattering (SBS) in glycerol. The two pump waves are hence phase conjugates of each other, and the quality of the phase-conjugation process is not degraded even by the use of an aberrated pump wave. The probe wave is created by SBS in carbon disulfide, which has a Brillouin frequency half that of glycerol, and the conjugate wave is therefore generated at the same frequency as the probe. Since the pump and signal waves differ in frequency by the Brillouin frequency of the carbon disulfide four-wave mixing medium, high reflectivities (approximately 2000%) are obtained as a result of Brillouin resonance enhancement.


Ontogeny of the spheno-occipital synchondrosis in a modern Queensland, Australian population using computed tomography.
Due to disparity regarding the age at which skeletal maturation of the spheno-occipital synchondrosis occurs in forensic and biological literature, this study provides recalibrated multislice computed tomography (MSCT) age standards for the Australian (Queensland) population, using a Bayesian statistical approach. The sample comprises retrospective cranial/cervical MSCT scans obtained from 448 males and 416 females aged birth to 20 years from the Skeletal Biology and Forensic Anthropology Research Osteological Database. Fusion status of the synchondrosis was scored using a modified six-stage scoring tier on an MSCT platform, with negligible observer error (κ = 0.911 ± 0.04, intraclass correlation coefficient = 0.994). Bayesian transition analysis indicates that females are most likely to transition to complete fusion at 13.1 years and males at 15.6 years. Posterior densities were derived for each morphological stage, with complete fusion of the synchondrosis attained in all Queensland males over 16.3 years of age and females aged 13.8 years and older. The results demonstrate significant sexual dimorphism in synchondrosis fusion and are suggestive of intrapopulation variation between major geographic regions in Australia. This study contributes to the growing repository of contemporary anthropological standards calibrated for the Queensland milieu to improve the efficacy of the coronial process for medicolegal death investigation. As a stand-alone age indicator, the basicranial synchondrosis may be consulted as an exclusion criterion when determining the age of majority that constitutes 17 years in Queensland forensic practice.


Parasitoid wasp affects metabolism of cockroach host to favor food preservation for its offspring.
Unlike predators, which immediately consume their prey, parasitoid wasps incapacitate their prey to provide a food supply for their offspring. We have examined the effects of the venom of the parasitoid wasp Ampulex compressa on the metabolism of its cockroach prey. This wasp stings into the brain of the cockroach causing hypokinesia. We first established that larval development, from egg laying to pupation, lasts about 8 days. During this period, the metabolism of the stung cockroach slows down, as measured by a decrease in oxygen consumption. Similar decreases in oxygen consumption occurred after pharmacologically induced paralysis or after removing descending input from the head ganglia by severing the neck connectives. However, neither of these two groups of cockroaches survived more than six days, while 90% of stung cockroaches survived at least this long. In addition, cockroaches with severed neck connectives lost significantly more body mass, mainly due to dehydration. Hence, the sting of A. compressa not only renders the cockroach prey helplessly submissive, but also changes its metabolism to sustain more nutrients for the developing larva. This metabolic manipulation is subtler than the complete removal of descending input from the head ganglia, since it leaves some physiological processes, such as water retention, intact.


Comparison of Persistent Symptoms After COVID-19 and Other Non-SARS-CoV-2 Infections in Children.
Introduction: The data on long COVID in children is scarce since children and adolescents are typically less severely affected by acute COVID-19. This study aimed to identify the long-term consequences of SARS-CoV-2 infection in children, and to compare the persistent symptom spectrum between COVID-19 and community-acquired infections of other etiologies. Methods: This was an ambidirectional cohort study conducted at the Children's Clinical University Hospital in Latvia. The study population of pediatric COVID-19 patients and children with other non-SARS-CoV-2-community-acquired infections were invited to participate between July 1, 2020, and April 30, 2021. Results: In total, 236 pediatric COVID-19 patients were enrolled in the study. Additionally, 142 comparison group patients were also enrolled. Median follow-up time from acute symptom onset was 73.5 days (IQR; 43-110 days) in the COVID-19 patient group and 69 days (IQR, 58-84 days) in the comparison group. Most pediatric COVID-19 survivors (70%, N = 152) reported at least one persistent symptom, but more than half of the patients (53%, N = 117) noted two or more long-lasting symptoms. The most commonly reported complaints among COVID-19 patients included persistent fatigue (25.2%), cognitive sequelae, such as irritability (24.3%), and mood changes (23.3%), as well as headaches (16.9%), rhinorrhea (16.1%), coughing (14.4%), and anosmia/dysgeusia (12.3%). In addition, 105 (44.5%) COVID patients had persistent symptoms after the 12-week cut-off point, with irritability (27.6%, N = 29), mood changes (26.7%, N = 28), and fatigue (19.2%, N = 20) being the most commonly reported ones. Differences in symptom spectrum among the various age groups were seen. Logistic regression analysis showed that long-term persistent symptoms as fever, fatigue, rhinorrhea, loss of taste and/or smell, headaches, cognitive sequelae, and nocturnal sweating were significantly associated with the COVID-19 experience when compared with the controls. Conclusions: We found that at the time of interview almost three-quarters of children reported at least one persistent symptom, but the majority of patients (53%) had two or more concurrent symptoms. The comparison group's inclusion in the study allowed us to identify that symptom persistence is more apparent with COVID-19 than any other non-SARS-CoV-2 infection. More research is needed to distinguish the symptoms of long COVID from pandemic-associated complaints. Each persistent symptom is important in terms of child well-being during COVID-19 recovery.


Geometry as a catalyst: how vapor cavities nucleate from defects.
The onset of cavitation is strongly enhanced by the presence of rough surfaces or impurities in the liquid. Despite decades of research, the way the geometry of these defects promote the nucleation of bubbles and its effect on the kinetics of the process remains largely unclear. We present here a comprehensive explanation of the catalytic action that roughness elements exert on the nucleation process for both pure vapor cavities and gas ones. This approach highlights that nucleation may follow nontrivial paths connected with a sharp decrease of the free energy barriers as compared to flat surfaces. Furthermore, we demonstrate the existence of intermediate metastable states that break the nucleation process in multiple steps; these states correspond to what is commonly known as cavitation nuclei. A single dimensionless parameter, the nucleation number, is found to control this rich phenomenology. The devised theory allows one to quantify the effect of the geometry and hydrophobicity of surface asperities on nucleation. Within the same framework, it is possible to treat both vapor cavitation, which is relevant, e.g., for organic liquids, and gas-promoted cavitation, which is commonly encountered in water. The theory is shown to be valid from the nano- to the macroscale.


Multivariate Higher-Order IRT Model and MCMC Algorithm for Linking Individual Participant Data From Multiple Studies.
Many clinical and psychological constructs are conceptualized to have multivariate higher-order constructs that give rise to multidimensional lower-order traits. Although recent measurement models and computing algorithms can accommodate item response data with a higher-order structure, there are few measurement models and computing techniques that can be employed in the context of complex research synthesis, such as meta-analysis of individual participant data or integrative data analysis. The current study was aimed at modeling complex item responses that can arise when underlying domain-specific, lower-order traits are hierarchically related to multiple higher-order traits for individual participant data from multiple studies. We formulated a multi-group, multivariate higher-order item response theory (HO-IRT) model from a Bayesian perspective and developed a new Markov chain Monte Carlo (MCMC) algorithm to simultaneously estimate the (a) structural parameters of the first- and second-order latent traits across multiple groups and (b) item parameters of the model. Results from a simulation study support the feasibility of the MCMC algorithm. From the analysis of real data, we found that a bivariate HO-IRT model with different correlation/covariance structures for different studies fit the data best, compared to a univariate HO-IRT model or other alternate models with unreasonable assumptions (i.e., the same means and covariances across studies). Although more work is needed to further develop the method and to disseminate it, the multi-group multivariate HO-IRT model holds promise to derive a common metric for individual participant data from multiple studies in research synthesis studies for robust inference and for new discoveries.


Inhaled drug delivery for tuberculosis therapy.
One third of the world population is infected with tuberculosis (TB), and new infections occur at a rate of one per second. The recent increase in the emergence of drug-resistant strains of Mycobacterium tuberculosis and the dearth of anti-TB drugs is threatening the future containment of TB. New drugs or delivery systems that will stop the spread of TB and slow down or prevent the development of drug-resistant strains are urgently required. One of the reasons for the emergence of drug-resistant strains is the exposure of mycobacteria to sub-therapeutic levels of one or more antibiotics. Lung lesions containing large numbers of bacteria are poorly vascularized and are fortified with thick fibrous tissue; conventional therapy by the oral and parenteral routes may provide sub-therapeutic levels of anti-TB drugs to these highly sequestered organisms. Administering drugs by the pulmonary route to the lungs allows higher drug concentrations in the vicinity of these lesions. Supplementing conventional therapy with inhaled anti-TB therapy may allow therapeutic concentrations of drug to penetrate effectively into lung lesions and treat the resident mycobacteria.


Visual Performance of Daily-disposable Multifocal Soft Contact Lenses: A Randomized, Double-blind Clinical Trial.
The present study highlights the differences between modern daily-disposable multifocal soft contact lenses to assist eye care practitioners in fitting presbyopic contact lens wearers. The purpose of this study was to compare visual performance of three daily-disposable multifocal contact lenses. Presbyopes (n = 72) wore 1-Day Acuvue Moist Multifocal, BioTrue ONEday for Presbyopia, and Dailies AquaComfort Plus Multifocal for 1 week in a prospective, randomized, double-blind, crossover clinical trial. After 1 week, high- and low-contrast visual acuities (HCVA, LCVA) were measured between 6 m and 40 cm and stereopsis at 40 cm. Subjective performance was assessed with 1- to 10-point rating scales for clarity, ghosting, driving vision, vision stability, ease of focusing, overall vision satisfaction, and ocular comfort. Willingness to purchase was reported with categorical responses. Linear mixed models and χ tests were used for analysis, and level of significance was set at 5%. BioTrue provided better HCVA and LCVA at distance than did Acuvue Moist (P ≤ .03). Subjectively, Acuvue Moist was rated lowest for distance clarity, distance ghosting, and driving vision (P ≤ .05). Acuvue Moist provided better HCVA at 70 to 40 cm and LCVA at 1 m to 40 cm than did BioTrue (P ≤ .01) and better LCVA at 1 m to 50 cm than did AquaComfort Plus (P ≤ .02). AquaComfort Plus also provided better HCVA and LCVA at 50 and 40 cm than did BioTrue (P ≤ .03). Acuvue Moist provided better stereopsis than did BioTrue (P = .02). Subjectively, BioTrue was rated lowest for near clarity (P ≤ .007) and lower than Acuvue Moist for intermediate clarity and near ghosting (P ≤ .04). No other differences were found between lenses (P > .05). BioTrue had better distance performance compared with near, whereas Acuvue Moist performed conversely. AquaComfort Plus performed reasonably overall.


Magnetic Resonance Arthrographic Demonstration of Association of Superior Labrum Anterior and Posterior Lesions With Extended Anterior Labral Tears.
The objective of this study was to evaluate retrospectively the full extent of anterior labral tear and associated other labral tears on magnetic resonance arthrographic images in patients with anterior shoulder instability. One hundred ten magnetic resonance arthrography images with anterior labral tear were retrieved from the database of the Radiology Department. Two skeletal radiologists, one with 15 years of experience and the other with 5 years of experience analyzed the images in random order. Approval for the study was granted by the Ethics Committee. Statistical analyses were performed using SPSS software. The most common localization of the labral lesions was at the anterior-inferior part of the glenoid labrum (22.7%). The anterior labral tears were commonly associate with superior labrum anterior and posterior (SLAP) lesions (45%). The most common type of SLAP lesion was type V (23.6%). Superior Labrum Anterior and Posterior type V lesion was more often detected in patients with Bankart lesion (27.7%, P = 0.043). Isolated anterior labral tears are less than expected. In majority of the cases, a distinct tear at a different site of the labrum accompanies the anterior labral tear. Massive anterior labral tears are mostly seen together with SLAP lesions.


Early Maladaptive Schemas among patients diagnosed with bipolar disorder.
Bipolar disorder is associated with a variety of cognitive features that seem to play a role in affective symptoms. Schema theory may serve as a unifying theory that would explain many of these features. This study is an exploratory investigation of schema theory's Early Maladaptive Schemas (EMSs) among individuals diagnosed with bipolar disorder. A sample of 74 participants with bipolar disorder and 99 mixed clinical controls (46 with unipolar depression and 53 with anxiety disorders) completed the Young Schema Questionnaire and comparison measures. Associations were investigated using univariate and multivariate analyses. Mean scores were compared with previously established benchmarks. Participants with bipolar disorder demonstrate elevated scores on most EMSs, many at an intermediate position between nonclinical and mixed clinical control groups. When controlling for depression, participants with bipolar disorder exceed those with unipolar depression on Approval-Seeking/Recognition-Seeking and Entitlement/Grandiosity. Bipolar group membership is predicted by high scores on Approval-Seeking/Recognition-Seeking and low scores on Emotional Inhibition and Abandonment. Women were overrepresented. Axis II traits were not assessed, nor were manic symptoms in the mixed clinical sample. Bipolar disorder is associated with a general activation of the EMSs. Approval-Seeking/Recognition-Seeking and Entitlement/Grandiosity seem to be particularly high, while Emotional Inhibition and Abandonment seem to be typically low. These EMS are highly consistent with characteristics of the bipolar spectrum. By demonstrating the activation of the EMSs, this study suggests that the EMS component of schema theory may be applied to bipolar disorder. Future research should explore how EMSs might interact with life events to trigger affective symptoms and, ultimately, the applicability of schema therapy to bipolar disorder.


Impacts of land use, restoration, and climate change on tropical peat carbon stocks in the twenty-first century: implications for climate mitigation.
The climate mitigation potential of tropical peatlands has gained increased attention as Southeast Asian peatlands are being deforested, drained and burned at very high rates, causing globally significant carbon dioxide (CO2) emissions to the atmosphere. We used a process-based dynamic tropical peatland model to explore peat carbon (C) dynamics of several management scenarios within the context of simulated twenty-first century climate change. Simulations of all scenarios with land use, including restoration, indicated net C losses over the twenty-first century ranging from 10 to 100 % of pre-disturbance values. Fire can be the dominant C-loss pathway, particularly in the drier climate scenario we tested. Simulated 100 years of oil palm (Elaeis guineensis) cultivation with an initial prescribed burn resulted in 2400-3000 Mg CO2 ha-1 total emissions. Simulated restoration following one 25-year oil palm rotation reduced total emissions to 440-1200 Mg CO2 ha-1, depending on climate. These results suggest that even under a very optimistic scenario of hydrological and forest restoration and the wettest climate regime, only about one third of the peat C lost to the atmosphere from 25 years of oil palm cultivation can be recovered in the following 75 years if the site is restored. Emissions from a simulated land degradation scenario were most sensitive to climate, with total emissions ranging from 230 to 10,600 Mg CO2 ha-1 over 100 years for the wettest and driest dry season scenarios, respectively. The large difference was driven by increased fire probability. Therefore, peat fire suppression is an effective management tool to maintain tropical peatland C stocks in the near term and should be a high priority for climate mitigation efforts. In total, we estimate emissions from current cleared peatlands and peatlands converted to oil palm in Southeast Asia to be 8.7 Gt CO2 over 100 years with a moderate twenty-first century climate. These emissions could be minimized by effective fire suppression and hydrological restoration.


A model of motion transparency processing with local center-surround interactions and feedback.
Motion transparency occurs when multiple coherent motions are perceived in one spatial location. Imagine, for instance, looking out of the window of a bus on a bright day, where the world outside the window is passing by and movements of passengers inside the bus are reflected in the window. The overlay of both motions at the window leads to motion transparency, which is challenging to process. Noisy and ambiguous motion signals can be reduced using a competition mechanism for all encoded motions in one spatial location. Such a competition, however, leads to the suppression of multiple peak responses that encode different motions, as only the strongest response tends to survive. As a solution, we suggest a local center-surround competition for population-encoded motion directions and speeds. Similar motions are supported, and dissimilar ones are separated, by representing them as multiple activations, which occurs in the case of motion transparency. Psychophysical findings, such as motion attraction and repulsion for motion transparency displays, can be explained by this local competition. Besides this local competition mechanism, we show that feedback signals improve the processing of motion transparency. A discrimination task for transparent versus opaque motion is simulated, where motion transparency is generated by superimposing large field motion patterns of either varying size or varying coherence of motion. The model's perceptual thresholds with and without feedback are calculated. We demonstrate that initially weak peak responses can be enhanced and stabilized through modulatory feedback signals from higher stages of processing.


Cost-effectiveness of antiretroviral therapy for prevention.
Recent empirical studies and analyses have heightened interest in the use of expanded antiretroviral therapy (ART) for prevention of HIV transmission. However, ART is expensive, approximately $600 per person per year, raising issues of the cost and cost-effectiveness of ambitious ART expansion. The goal of this review is to equip the reader with the conceptual tools and substantive background needed to understand and evaluate the policy and programmatic implications of cost-effectiveness assessments of ART for prevention. We provide this review in six sections. We start by introducing and explaining basic concepts of health economics as they relate to this issue, including resources, costs, health metrics (such as Disability-Adjusted Life Years), and different types of economic analysis. We then review research on the cost and cost-effectiveness of ART as treatment, and on the cost-effectiveness of traditional HIV prevention. We describe critical issues in the epidemic impact of ART, such as suppression of transmission and the role of the acute phase of infection. We then present a conceptual model for conducting and interpreting cost-effectiveness analyses of ART as prevention, and review the existing preliminary estimates in this area. We end with a discussion of future directions for programmatic demonstrations and evaluation.


Microsurgical salvage of the intractable oral vestibule.
The significance of the oral vestibule is often underappreciated in composite craniomaxillofacial reconstruction, and its deficiency results in considerable incompetence. Results of traditional vestibuloplasty techniques are unpredictable when the recipient bed is compromised in the setting of trauma or irradiation. The authors present an alternative approach for restoring the intractable oral vestibule with free tissue transfer. An institutional review board-approved retrospective review of patients who underwent oral vestibular reconstruction was conducted at R Adams Cowley Shock Trauma Center and Johns Hopkins Hospital from 2002 to 2007. Thirteen patients were identified: six defects resulted from tumor extirpation, six resulted from traumatic injury, and one resulted from infection. There were eight men and five women, with a mean age of 46 years. Thirteen free tissue transfers of the oral vestibule were conducted: six ulnar forearm and seven anterolateral thigh perforator flaps. The average follow-up was 17 months. There were no flap failures and only one complication noted, which did not result in negative sequelae. The functional results were good, with all patients experiencing increased labial excursion and subjective improvement in the handling of food bolus and saliva. Preservation of oral vestibular height, width, and volume is essential for aesthetic appearance and functional competence. Free tissue transfer provides an innovative alternative in the management of the intractable and obliterated oral vestibule. It can be performed successfully, providing excellent results predictably.


Incomplete factorial and response surface methods in experimental design: yield optimization of tRNA(Trp) from in vitro T7 RNA polymerase transcription.
We have studied the yield of Escherichia coli tRNA(Trp) obtained from in vitro T7 RNA polymerase transcription using incomplete factorial and response surface methods. Incomplete factorial experiments were first used to estimate the relative impact of six variables on the yield of tRNA(Trp). Fifteen trials were performed according to a balanced and randomized design. The correlation between observed yield and all experimental variables was identified by stepwise multiple linear regression analysis. The concentrations of T7 RNA polymerase, DNA template, NTP and MgCl2 proved to be significantly correlated with the yield of tRNA(Trp). We then optimized the yield with respect to each of these four variables simultaneously with a designed, response surface experiment based on the Hardin-Sloane minimum prediction variance algorithm. Twenty experiments were performed, in duplicate, to sample the quadratic surface relating the yield to the four significant variables. Coefficients of the quadratic function with all two-factor interactions were evaluated by stepwise regression using least squares, and significant coefficients were retained. Partial differentiation of the resulting quadratic model showed it to possess an optimum. Transcription performed at the corresponding conditions yielded 6-fold more tRNA(Trp) than the initial conditions, confirming the predictive value of the experimentally determined response surface.


Mandibular molar uprighting using orthodontic miniscrew implants: a systematic review.
The purpose of this systematic review was to identify studies and present the use of miniscrew implants (MIs) as an alternative treatment to mandibular molar uprighting. An electronic search and handsearching were conducted by two independent reviewers to identify relevant articles, published up to January 27, 2017. In order to methodologically assess the eligible studies, a pilot checklist consisting of 22 items was also implemented. After exclusion of all the irrelevant papers, only 17 studies were included, presenting 27 cases of mandibular molar uprighting in all planes using both direct and indirect force traction by MIs. Regarding the quality evaluation, the mean score of the included studies was 13.2, indicating a rather poor methodology implemented in the majority of the included cases. Due to many advantages, MIs provide a unique treatment alternative and constitute a reliable solution for treating tipped or impacted molars. Regarding the force application, a direct method is simpler, as it requires one MI and a single bracket or button, minimizing the patient's discomfort and also reducing chair time compared to more complex indirect anchorage. It also eliminates the possibility of unwanted movement of the anchorage unit, which can occur even with indirect anchorage as a result of technical errors. However, direct anchorage has limitations in cases of lingually tipped or rotated molars because a single force may be insufficient to upright the tooth.


Epithelial eotaxin-2 and eotaxin-3 expression: relation to asthma severity, luminal eosinophilia and age at onset.
Eosinophilic inflammation is implicated in asthma. Eotaxin 1-3 regulate eosinophil trafficking into the airways along with other chemotactic factors. However, the epithelial and bronchoalveolar lavage (BAL) cell expression of these chemokines in relation to asthma severity and eosinophilic phenotypes has not been addressed. To measure the expression of the three eotaxin isoforms in bronchoscopically obtained samples and compare them with clinically relevant parameters between normal subjects and patients with asthma. Normal subjects and patients with asthma of varying severity recruited through the Severe Asthma Research Program underwent clinical assessment and bronchoscopy with airway brushing and BAL. Eotaxin 1-3 mRNA/protein were measured in epithelial and BAL cells and compared with asthma severity, control and eosinophilic inflammation. Eotaxin-2 and eotaxin-3 mRNA and eotaxin-2 protein were increased in airway epithelial brushings from patients with asthma and were highest in cases of severe asthma (p values 0.0155, 0.0033 and 0.0006, respectively), with eotaxin-2 protein increased with age at onset. BAL cells normally expressed high levels of eotaxin-2 mRNA/protein but BAL fluid levels of eotaxin-2 were lowest in severe asthma. Epithelial eotaxin-2 and eotaxin-3 mRNA/protein was associated with sputum eosinophilia, lower forced expiratory volume in 1 s and more asthma exacerbations. Airway epithelial cell eotaxin-2 protein differed by asthma severity only in those with late onset disease, and tended to be highest in those with late onset eosinophilic asthma. Epithelial eotaxin-2 and 3 are increased in asthma and severe asthma. Their expression may contribute to luminal migration of eosinophils, especially in later onset disease, asthma control and severity.


Substantia nigra activity level predicts trial-to-trial adjustments in cognitive control.
Effective adaptation to the demands of a changing environment requires flexible cognitive control. The medial and the lateral frontal cortices are involved in such control processes, putatively in close interplay with the BG. In particular, dopaminergic projections from the midbrain (i.e., from the substantia nigra [SN] and the ventral tegmental area) have been proposed to play a pivotal role in modulating the activity in these areas for cognitive control purposes. In that dopaminergic involvement has been strongly implicated in reinforcement learning, these ideas suggest functional links between reinforcement learning, where the outcome of actions shapes behavior over time, and cognitive control in a more general context, where no direct reward is involved. Here, we provide evidence from functional MRI in humans that activity in the SN predicts systematic subsequent trial-to-trial RT prolongations that are thought to reflect cognitive control in a stop-signal paradigm. In particular, variations in the activity level of the SN in one trial predicted the degree of RT prolongation on the subsequent trial, consistent with a modulating output signal from the SN being involved in enhancing cognitive control. This link between SN activity and subsequent behavioral adjustments lends support to theoretical accounts that propose dopaminergic control signals that shape behavior both in the presence and in the absence of direct reward. This SN-based modulatory mechanism is presumably mediated via a wider network that determines response speed in this task, including frontal and parietal control regions, along with the BG and the associated subthalamic nucleus.


Linear Fitted-Q Iteration with Multiple Reward Functions.
We present a general and detailed development of an algorithm for finite-horizon fitted-Q iteration with an arbitrary number of reward signals and linear value function approximation using an arbitrary number of state features. This includes a detailed treatment of the 3-reward function case using triangulation primitives from computational geometry and a method for identifying globally dominated actions. We also present an example of how our methods can be used to construct a real-world decision aid by considering symptom reduction, weight gain, and quality of life in sequential treatments for schizophrenia. Finally, we discuss future directions in which to take this work that will further enable our methods to make a positive impact on the field of evidence-based clinical decision support.


To asses inter- and intra-observer variability for breast density and BIRADS assessment categories in mammographic reporting.
To evaluate the inter- and intra-observer variability among radiologists in the characterisation of mammograms according to Breast Imaging Reporting and Data System assessment and breast density categories. The descriptive cross-sectional study was conducted at Aga Khan University Hospital, Karachi, from January 2014 to June 2014. Using non-probability purposive sampling, all mammograms in the study were interpreted by three radiologists on the basis of Breast Imaging Reporting and Data System categories and by assessing the breast density composition. The inter-observer variability was recorded by comparing the difference in the interpretation and categorisation of each case. Intra-observer variability was noted by comparing the differences in the two sets of results from reading the same mammogram three months apart. A total of 254 mammograms were reviewed and the mean age of patients was 55.2±11.6 years. In the first round of diagnostic imaging, there was moderate agreement among all three possible pairs of observers regarding breast density (k= 0.50-0.41), but for Breast Imaging Reporting and Data System categories the agreement was less (k=0.27-0.13). After 3 months, variability of observer 1 showed substantial agreement (k=0.65).Variability between observer 2 and observer 3 showed moderate agreement (k=0.13).In terms of categories, intra-observer differences were variable: observer 1 (?=0.61; observer 2(?=0.17); observer 3 (k=0.45). Despite standardised guidelines for reporting density and assessment categories, observer variability continues to exist.


Is tree loss associated with cardiovascular-disease risk in the Women's Health Initiative? A natural experiment.
Data from the Women's Health Initiative were used to quantify the relationship between the loss of trees to an invasive forest pest-the emerald ash borer-and cardiovascular disease. We estimated a semi-parametric Cox proportional hazards model of time to cardiovascular disease, adjusting for confounders. We defined the incidence of cardiovascular disease as acute myocardial infarction requiring overnight hospitalization, silent MI determined from serial electrocardiograms, ischemic or hemorrhagic stroke, or death from coronary heart disease. Women living in a county infested with emerald ash borer had an increased risk of cardiovascular disease (HR=1.25, 95% CI: 1.20-1.31).


Perireceptor events in taste.
The microenvironment at chemical receptor sites is important for ligand-receptor interaction as it can influence the entry, residence time or exit of odorant and sapid molecules. The perireceptor milieu at apical taste cell microvilli consists of taste pore mucus and secretions from salivary glands. The majority of taste buds are sheltered in epithelial folds of the foliate and circumvallate papillae where saliva is provided predominantly by the lingual von Ebner's glands (VEGs). To investigate possible saliva-tastant interactions, we have characterized a prominent 18 kDa secretory protein expressed in human, rat and pig VEGs. The human and rat VEG proteins share 60% sequence identity and, by virtue of their protein and gene structure, can be assigned to the lipocalin superfamily of lipophilic ligand carrier proteins. VEG proteins might function as transporters of hydrophobic molecules, for example bitter substances, like the nasal odorant-binding proteins that belong to the same protein family. Because binding experiments using various bitter substances have so far failed, and in light of the species-specific expression, other functions for VEG proteins must be considered. These include the protection of taste epithelia, pheromone transport and lipid binding.


Reinforcement-Sensitive Personality Traits Associated With Passion in Heterosexual Intimate Relationships: An fNIRS Investigation.
According to the triangular theory of love, passion is an indispensable component of romantic love. Some brain imaging studies have shown that passionate arousal in intimate relationships is associated with the reward circuits in the brain. We hypothesized that the individual reward sensitivity trait is also related to passion in intimate relationships, and two separate studies were conducted in the present research. In the first study, 558 college students who were currently in love were selected as participants. The correlation between intimacy and reinforcement sensitivity in individuals identifying as heterosexual was explored using the Sensitivity to Punishment and Sensitivity to Reward Questionnaire, the Passionate Love Scale, and the Triangular Love Scale. In the second study, participants were 42 college students who were also currently in love. Functional near-infrared spectroscopy (fNIRS) was adopted to explore the neurophysiological interaction between reward sensitivity and emotional arousal induced in participants when presented a photograph of their partner, a friend, or a stranger. The results showed that reward sensitivity was positively correlated with passion, and punishment sensitivity was negatively correlated with intimacy and commitment. Significant interactions between reward sensitivity and photograph type were found, and the triangular part of the inferior frontal gyrus showed a particular relevance to the reward-sensitive personality trait toward partners. Overall, the findings support reinforcement sensitivity theory and suggest that reinforcement-sensitive personality traits (personality traits of reward and punishment sensitivity) are associated with all three components of love, with only reward sensitivity being related to passion.


Antibiotic-associated Manipulation of the Gut Microbiota and Phenotypic Restoration in NOD Mice.
Segmented filamentous bacterium (SFB) a gram-positive, anaerobic, and intestinal commensal organism directly influences the development of Th17 helper cells in the small intestine of mice. In NOD mice, SFB colonization interferes with the development of type 1 diabetes (T1D), a T-cell-mediated autoimmune disease, suggesting that SFB may influence Th17 cells to inhibit Th1 populations associated with the anti-β-cell immune response. This effect is a serious concern for investigators who use NOD mice for diabetes research because the expected incidence of disease decreases markedly when they are colonized by SFB. A room housing mice for T1D studies at The Jackson Laboratory was determined by fecal PCR testing to have widespread SFB colonization of multiple NOD strains after a steady decline in the incidence of T1D was noted. Rederivation of all NOD-related mouse strains was not feasible; therefore an alternative treatment using antibiotics to eliminate SFB from colonized mice was undertaken. After antibiotic treatment, soiled bedding from NOD mouse strains housed in SFB-free high-health-status production barrier rooms was used to reintroduce the gastrointestinal microbiota. Over the past 16 mo since treating the mice and disinfecting the mouse room, regular PCR testing has shown that no additional SFB colonization of mice has occurred, and the expected incidence of T1D has been reestablished in the offspring of treated mice.


Assessment of the impact of implementing the Baby-Friendly Hospital Initiative.
To evaluate the impact of the Baby-Friendly Hospital Initiative on the breastfeeding practices of mothers from the urban area of Montes Claros, MG, Brazil. A comparative analysis was performed of two cross-sectional breastfeeding indicator studies with randomized samples of children under 2 years of age. One study was carried out before and the other after the Baby-Friendly Hospital Initiative had been implemented throughout all public pregnancy and childbirth care services in the city. Kaplan-Meyer survival curves were constructed for different breastfeeding patterns. Log rank testing was used to calculate the level of significance of differences between curves for before and after the Initiative. The survival curves demonstrate that breastfeeding rates increased during the study period. The log rank test detected significance for increases in all patterns of breastfeeding (p < 0.000). Median overall breastfeeding duration increased from 8.9 to 11.6 months and median duration of exclusive breastfeeding rose from 27 days to 3.5 months. Implementation of the Baby-Friendly Hospital Initiative in all public maternity units in Montes Claros significantly increased breastfeeding rates in the city. Since the ideal state of affairs has not yet been reached, further strategies must be implemented to promote and support breastfeeding practices.


Spider poisoning: a report of six cases from the Central Anatolian region, Turkey.
Spiders exist in every place and ecosystem. Spiders in tropical regions are particularly poisonous and can be dangerous to humans. Nearly 20,000 spider species are known, and almost all are venomous, although only 60 species worldwide are poisonous in humans. In our area, eight species are reported as poisonous in humans. Although most cases of spider bite are benign and require no intervention, severe local and systemic reactions may occur sometimes in the pediatric population, resulting in admission to the pediatric intensive care unit. In this report, we present the cases of six children from the Central Anatolian region in Turkey who were seriously affected by spider bites, and we review the literature on spider envenomation.


Origin of Spectral Band Patterns in the Cosmic Unidentified Infrared Emission.
The cosmic unidentified infrared emission (UIE) band phenomenon is generally considered as indicative of free-flying polycyclic aromatic hydrocarbon molecules in space. However, a coherent explanation of emission spectral band patterns depending on astrophysical source is yet to be resolved under this attribution. Meanwhile astronomers have restored the alternative origin as due to amorphous carbon particles, but assigning spectral patterns to specific structural elements of particles is equally challenging. Here we report a physical principle in which inclusion of nonplanar structural defects in aromatic core molecular structures (π domains) induces spectral patterns typical of the phenomenon. We show that defects in model π domains modulate the electronic-vibration coupling that activates the delocalized π-electron contribution to aromatic vibrational modes. The modulation naturally disperses C=C stretch modes in band patterns that readily resemble the UIE bands in the elusive 6-9 μm range. The electron-vibration interaction mechanics governing the defect-induced band patterns underscores the importance of π delocalization in the emergence of UIE bands. We discuss the global UIE band regularity of this range as compatible with an emission from the delocalized sp^{2} phase, as π domains, confined in disordered carbon mixed-phase aggregates.


Genetic diversity of the African malaria vector Anopheles gambiae.
The sustainability of malaria control in Africa is threatened by the rise of insecticide resistance in Anopheles mosquitoes, which transmit the disease. To gain a deeper understanding of how mosquito populations are evolving, here we sequenced the genomes of 765 specimens of Anopheles gambiae and Anopheles coluzzii sampled from 15 locations across Africa, and identified over 50 million single nucleotide polymorphisms within the accessible genome. These data revealed complex population structure and patterns of gene flow, with evidence of ancient expansions, recent bottlenecks, and local variation in effective population size. Strong signals of recent selection were observed in insecticide-resistance genes, with several sweeps spreading over large geographical distances and between species. The design of new tools for mosquito control using gene-drive systems will need to take account of high levels of genetic diversity in natural mosquito populations.


Risk factors for stroke in middle aged British men.
To determine the risk factors for stroke in a cohort representative of middle aged British men. Prospective study of a cohort of men followed up for eight years. General practices in 24 towns in England, Wales, and Scotland (the British regional heart study). 7735 men aged 40-59 at screening, selected at random from one general practice in each town. Fatal and non-fatal strokes. 110 of the men had at least one stroke; there were four times as many non-fatal as fatal strokes. The relative risk of stroke was 12.1 in men who had high blood pressure (systolic blood pressure greater than or equal to 160 mm Hg) and were current smokers compared with normotensive, non-smoking men. Diastolic blood pressure yielded no additional information, and former cigarette smokers had the same risk as men who had never smoked. Heavy alcohol intake was associated with a relative risk of stroke of 3.8 in men without previously diagnosed cardiovascular disease. Men with pre-existing ischaemic heart disease had an increased risk of stroke, but only when left ventricular hypertrophy on electrocardiography was also present. Systolic blood pressure, cigarette smoking, and left ventricular hypertrophy on electrocardiography in men with pre-existing ischaemic heart disease were found to be the major risk factors for stroke in middle aged British men. Heavy alcohol intake seemed to increase the risk of stroke in men without previously diagnosed cardiovascular disease. A large proportion of strokes should be preventable by controlling blood pressure and stopping smoking.


Selective demineralisation of dentine extrafibrillar minerals-A potential method to eliminate water-wet bonding in the etch-and-rinse technique.
The present study tested the central hypothesis that selective demineralisation of dentine extrafibrillar minerals by lowering the phosphoric acid concentration improves the quality of the resin-dentine interface. Dentine surfaces were etched with different concentrations of phosphoric acid (1, 5, 10, 20, 30 or 40wt%). Scanning electron microscopy was used to observe the micromorphology of the etched dentine surfaces. Energy dispersive X-ray analysis was performed to determine the residual Ca-content of the demineralised dentine matrix. Atomic force microscopy-based nanoindentation was used to analyse the nanomechanical properties of the treated dentine surfaces. The influence of H3PO4 concentration on resin-dentine bond strength was evaluated by microtensile bond strength testing. One-way ANOVA was used to compare the residual Ca-content ratio, reduced elastic modulus (Er) of the treated dentine surfaces and microtensile bond strength among groups. Collagen fibrils appeared to be wider in diameter after etching with 5% and 10% H3PO4. The partially-demineralized collagen scaffold retained part of its rigidity to maintain an uncollapsed three-dimensional structure. Etching with 1% H3PO4 resulted in the highest residual Ca-content ratio and Er of demineralised dentine matrix, followed by 5% H3PO4. Those values were all significantly higher than values derived from the other groups. Etching with 30% H3PO4 resulted in the lowest Ca-content ratio and Er. Using 5% H3PO4 as etchant resulted in the highest resin-dentine bond strength. Selective demineralisation of the dentine matrix may be achieved by lowering the H3PO4 concentration to 5wt%, to achieve better bonding performance. By retaining intrafibrillar minerals, more through air-drying of the partially demineralised collagen matrix may be accomplished without the need to worry about collapsing a mineral-free collagen matrix during air-drying. This may result in the elimination of water-wet bonding during the application of etch-and-rinse adhesives.


Monte Carlo modeling of spatial coherence: free-space diffraction.
We present a Monte Carlo method for propagating partially coherent fields through complex deterministic optical systems. A Gaussian copula is used to synthesize a random source with an arbitrary spatial coherence function. Physical optics and Monte Carlo predictions of the first- and second-order statistics of the field are shown for coherent and partially coherent sources for free-space propagation, imaging using a binary Fresnel zone plate, and propagation through a limiting aperture. Excellent agreement between the physical optics and Monte Carlo predictions is demonstrated in all cases. Convergence criteria are presented for judging the quality of the Monte Carlo predictions.


Associations among depression severity, painful physical symptoms, and social and occupational functioning impairment in patients with major depressive disorder: a 3-month, prospective, observational study.
To investigate associations among depression severity, painful physical symptoms (PPS), and social and occupational functioning impairment in patients with major depressive disorder (MDD) who had achieved complete remission (CR) or partial remission (PR) after acute treatment. This was a 12-week, multicenter, prospective, observational study. Patients with MDD treated with an antidepressant medication for the previous 12 weeks (±3 weeks) who had achieved CR (defined as a 17-item Hamilton Rating Scale for Depression [HAM-D17] score ≤7) or PR (HAM-D17 score ≥8 and ≤18) were enrolled. Depression severity, PPS, and impairment in social and occupational functioning were assessed using the HAM-D17, the Brief Pain Inventory (Short Form) (BPI-SF), and the Social and Occupational Functioning Assessment Scale (SOFAS), respectively, at enrollment (Week 12) and after 12 weeks (Week 24). Overall, 323 Japanese patients with MDD were enrolled (CR n=158, PR n=165) and 288 patients completed the study (CR n=139, PR n=149). HAM-D17 and SOFAS scores were strongly and negatively correlated at enrollment (Week 12; P<0.0001) and Week 24 (P<0.0001). A weak negative correlation between the BPI-SF and SOFAS was observed at Week 24 (P=0.0011), but not at enrollment (P=0.164). Remission status at enrollment (CR or PR) was associated with achieving normal social and occupational functioning (SOFAS score ≥80) at Week 24 in patients who had not achieved normal social and occupational functioning (SOFAS score <80) at enrollment (CR vs PR, OR=0.05 [95% CIs 0.01-0.18], P<0.0001). A greater proportion of patients with CR and no PPS at enrollment achieved SOFAS scores ≥80 at Week 24 than those with CR and PPS. Our results suggest that treating both depressive symptoms and PPS is important for achieving a normal level of functioning on a long-term basis in patients with MDD.


The impact of developmental biology on cancer research: an overview.
In recent years developmental biology has contributed a great deal to cancer research. This is in part because both fields address the question of how genes control the three-dimensional organisation of tissues, and how mutation of genes alters this. But also in recent years, the discovery that signalling pathways are conserved from worms to man, combined with the power of developmental biology's model organisms, principally Drosophila and C. elegans, to reveal signalling pathways that control tissue growth and organisation, has had a huge impact. Examples of this are the subject of the reviews in this issue, including the EGF-receptor, Wnt/APC/catenin, TGF-beta/Smad and hedgehog/patched/smoothened pathways, all of which were discovered and/or pieced together in model organisms, and all of which are disrupted by mutation in human cancer. Other topics considered are the control and execution of apoptosis; the search for tumour-suppressor-like genes in Drosophila; and genes of the Polycomb and Trithorax Groups that regulate the commitment of cells to patterns of differentiation, and that are among the targets for chromosome translocations. These stories illustrate how developmental biology has shown that there are many more signalling pathways relevant to neoplasia than the receptor tyrosine kinase pathways that first dominated the field; and that the signalling is more than just mitogenic or anti-mitogenic, and should be viewed as providing cells with information about their position and neighbours, that determines their role, differentiation and behaviour.


Mitochondrial transplantation: applications for pediatric patients with congenital heart disease.
Mitochondrial transplantation refers to transplantation of respiratory competent mitochondria from healthy tissue into tissues injured by ischemia and reperfusion. This technique has been utilized for recovery of myocardial dysfunction in pediatric patients. The preclinical experience and initial patient experience with this technique are reviewed in this article. Initial experience is with pediatric patients undergoing extracorporeal membrane oxygenation support following myocardial ischemia and reperfusion. The initial pediatric experience suggests low side effect profile with favorable efficacy in a small group of patients.


T1 bladder cancer in Norway: treatment and survival.
Evaluation of treatment and survival of pT1 stage (T1) bladder cancer (BC) patients diagnosed with transitional cell carcinoma of the urinary bladder in Norway. According to the Cancer Registry of Norway, 1,108 patients were diagnosed with T1 BC between 2008-2012. Information on surgical and medical procedures was provided by the Norwegian Patients Registry. Regression and survival models were applied to characterize patients receiving bacillus Calmette-Guerin (BCG) and radical cystectomy (RC) as early and delayed treatment and to estimate overall and cause specific survival rates (OS; CSS). Adjustments for sex, age, WHO grade and concomitant cis were made. In total, 449 (41%) patients received BCG treatment, 162 (15%) as early treatment. RC represented the early treatment in 96 (9%) patients and the delayed treatment in 84 (8%). Overall, 850 (77%) patients received neither BCG nor RC as early treatment, of whom 287 (26%) were treated with BCG and 66 (6%) with RC during follow-up. Patients <75 years and patients with high grade tumors or concomitant cis were more likely to receive BCG and RC as early treatment. 5-year survival rates for all T1 BC patients were 84% (CSS) and 65% (OS). Delayed RC was associated with the lowest 5-year CSS (70%). After adjustment, gender did not impact treatment choice and CSS. The use of BCG as early treatment indicates low adherence to existing guidelines. Delayed RC was associated with low survival rates. An increased focus on the management of T1 patients is needed in Norway.


Stimulation of the wrist acupuncture point PC6 for preventing postoperative nausea and vomiting.
Postoperative nausea and vomiting (PONV) are common complications following surgery and anaesthesia. Antiemetic drugs are only partially effective in preventing PONV. An alternative approach is to stimulate the PC6 acupoint on the wrist. This is an update of a Cochrane review first published in 2004, updated in 2009 and now in 2015. To determine the effectiveness and safety of PC6 acupoint stimulation with or without antiemetic drug versus sham or antiemetic drug for the prevention of PONV in people undergoing surgery. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (Cochrane Library, Issue 12, 2014), MEDLINE (January 2008 to December 2014), EMBASE (January 2008 to December 2014), ISI Web of Science (January 2008 to December 2014), World Health Organization Clinical Trials Registry, ClinicalTrials.gov, and reference lists of articles to identify additional studies. We applied no language restrictions. All randomized trials of techniques that stimulated the PC6 acupoint compared with sham treatment or drug therapy, or combined PC6 acupoint and drug therapy compared to drug therapy, for the prevention of PONV. Interventions used in these trials included acupuncture, electro-acupuncture, transcutaneous electrical acupoint stimulation, transcutaneous nerve stimulation, laser stimulation, capsicum plaster, acu-stimulation device, and acupressure in people undergoing surgery. Primary outcomes were the incidences of nausea and vomiting after surgery. Secondary outcomes were the need for rescue antiemetic therapy and adverse effects. Two review authors independently extracted the data and assessed the risk of bias domains for each trial. We used a random-effects model and reported risk ratio (RR) with associated 95% confidence interval (95% CI). We used trial sequential analyses to help provide information on when we had reached firm evidence in cumulative meta-analyses of the primary outcomes, based on a 30% risk ratio reduction in PONV. We included 59 trials involving 7667 participants. We rated two trials at low risk of bias in all domains (selection, attrition, reporting, blinding and other). We rated 25 trials at high risk in one or more risk-of-bias domains. Compared with sham treatment, PC6 acupoint stimulation significantly reduced the incidence of nausea (RR 0.68, 95% CI 0.60 to 0.77; 40 trials, 4742 participants), vomiting (RR 0.60, 95% CI 0.51 to 0.71; 45 trials, 5147 participants) and the need for rescue antiemetics (RR 0.64, 95% CI 0.55 to 0.73; 39 trials, 4622 participants). As heterogeneity among trials was substantial and there were study limitations, we rated the quality of evidence as low. Using trial sequential analysis, the required information size and boundary for benefit were reached for both primary outcomes.PC6 acupoint stimulation was compared with six different types of antiemetic drugs (metoclopramide, cyclizine, prochlorperazine, droperidol. ondansetron and dexamethasone). There was no difference between PC6 acupoint stimulation and antiemetic drugs in the incidence of nausea (RR 0.91, 95% CI 0.75 to 1.10; 14 trials, 1332 participants), vomiting (RR 0.93, 95% CI 0.74 to 1.17; 19 trials, 1708 participants), or the need for rescue antiemetics (RR 0.87, 95% CI 0.65 to 1.16; 9 trials, 895 participants). We rated the quality of evidence as moderate, due to the study limitations. Using trial sequential analyses, the futility boundary was crossed before the required information size was surpassed for both primary outcomes.Compared to antiemetic drugs, the combination of PC6 acupoint stimulation and antiemetic therapy reduced the incidence of vomiting (RR 0.56, 95% CI 0.35 to 0.91; 9 trials, 687 participants) but not nausea (RR 0.79, 95% CI 0.55 to 1.13; 8 trials, 642 participants). We rated the quality of evidence as very low, due to substantial heterogeneity among trials, study limitations and imprecision. Using trial sequential analysis, none of the boundaries for benefit, harm or futility were crossed for PONV. The need for rescue antiemetic was lower in the combination PC6 acupoint stimulation and antiemetic group than the antiemetic group (RR 0.61, 95% CI 0.44 to 0.86; 5 trials, 419 participants).The side effects associated with PC6 acupoint stimulation were minor, transient and self-limiting (e.g. skin irritation, blistering, redness and pain) in 14 trials. Publication bias was not apparent in the contour-enhanced funnel plots. There is low-quality evidence supporting the use of PC6 acupoint stimulation over sham. Compared to the last update in 2009, no further sham comparison trials are needed. We found that there is moderate-quality evidence showing no difference between PC6 acupoint stimulation and antiemetic drugs to prevent PONV. Further PC6 acupoint stimulation versus antiemetic trials are futile in showing a significant difference, which is a new finding in this update. There is inconclusive evidence supporting the use of a combined strategy of PC6 acupoint stimulation and antiemetic drug over drug prophylaxis, and further high-quality trials are needed.


Sequence evidence for common ancestry of eukaryotic endomembrane coatomers.
Eukaryotic cells are defined by compartments through which the trafficking of macromolecules is mediated by large complexes, such as the nuclear pore, transport vesicles and intraflagellar transport. The assembly and maintenance of these complexes is facilitated by endomembrane coatomers, long suspected to be divergently related on the basis of structural and more recently phylogenomic analysis. By performing supervised walks in sequence space across coatomer superfamilies, we uncover subtle sequence patterns that have remained elusive to date, ultimately unifying eukaryotic coatomers by divergent evolution. The conserved residues shared by 3,502 endomembrane coatomer components are mapped onto the solenoid superhelix of nucleoporin and COPII protein structures, thus determining the invariant elements of coatomer architecture. This ancient structural motif can be considered as a universal signature connecting eukaryotic coatomers involved in multiple cellular processes across cell physiology and human disease.


Loss of heterozygosity at the mannose 6-phosphate insulin-like growth factor 2 receptor (M6P/IGF2R) locus predisposes patients to radiation-induced lung injury.
To investigate the relationship between loss of heterozygosity (LOH) at the mannose 6-phosphate/insulin-like growth factor 2 receptor (M6P/IGF2R) gene locus and the development of radiation-induced lung injury. Thirty-five lung cancer patients with both stored plasma for Transforming Growth Factor beta1 (TGFbeta1) analysis and sufficient quantities of archival pathology tissue to screen for LOH were studied. All patients had been treated with thoracic radiotherapy for their malignancy and had radiographically detectable tumor present before beginning radiotherapy. Tumor and normal cells were microdissected from archival lung cancer pathology specimens. Two polymorphisms in the 3' untranslated region of the M6P/IGF2R were used to screen for LOH. Plasma TGFbeta1 levels were measured using acid-ethanol extraction and an ELISA. TGFbeta1 and M6P/IGF2R protein expression was estimated by immunofluorescence and immunohistochemical staining. Symptomatic radiation pneumonitis was scored according to National Cancer Institute Common Toxicity Criteria without knowledge of the results of TGFbeta or LOH analyses. Of the 35 patients, 10 were homozygous for this polymorphism (noninformative) and were excluded. Of the 25 informative patients, 13 had LOH. Twelve of 13 patients with LOH had increased pretreatment plasma TGFbeta1 levels, vs. 3/12 patients without LOH (p < 0.01). A decrease or loss of M6P/IGF2R protein in the malignant cell accompanied by increased latent TGFbeta1 protein in extracellular matrix and tumor stroma was found in tumors with LOH, suggesting that this mutation resulted in loss of function of the receptor. Seven of 13 (54%) LOH patients developed symptomatic radiation-induced lung injury vs. 1/12 (8%) of patients without LOH (p = 0.05). Loss of the M6P/IGF2R gene strongly correlates with the development of radiation pneumonitis after thoracic radiotherapy (RT). Furthermore, patients with LOH (in the setting of measurable tumor) are much more likely to have elevated plasma TGFbeta, suggesting an inability to normally process this cytokine. Thus, loss of the M6P/IGF2R gene may predispose patients to the development of radiation-induced lung injury.


In vivo histology of the myelin g-ratio with magnetic resonance imaging.
The myelin g-ratio, defined as the ratio between the inner and the outer diameter of the myelin sheath, is a fundamental property of white matter that can be computed from a simple formula relating the myelin volume fraction to the fiber volume fraction or the axon volume fraction. In this paper, a unique combination of magnetization transfer, diffusion imaging and histology is presented, providing a novel method for in vivo magnetic resonance imaging of the axon volume fraction and the myelin g-ratio. Our method was demonstrated in the corpus callosum of one cynomolgus macaque, and applied to obtain full-brain g-ratio maps in one healthy human subject and one multiple sclerosis patient. In the macaque, the g-ratio was relatively constant across the corpus callosum, as measured by both MRI and electron microscopy. In the human subjects, the g-ratio in multiple sclerosis lesions was higher than in normal appearing white matter, which was in turn higher than in healthy white matter. Measuring the g-ratio brings us one step closer to fully characterizing white matter non-invasively, making it possible to perform in vivo histology of the human brain during development, aging, disease and treatment.


Comparative genomic and methylome analysis of non-virulent D74 and virulent Nagasaki Haemophilus parasuis isolates.
Haemophilus parasuis is a respiratory pathogen of swine and the etiological agent of Glässer's disease. H. parasuis isolates can exhibit different virulence capabilities ranging from lethal systemic disease to subclinical carriage. To identify genomic differences between phenotypically distinct strains, we obtained the closed whole-genome sequence annotation and genome-wide methylation patterns for the highly virulent Nagasaki strain and for the non-virulent D74 strain. Evaluation of the virulence-associated genes contained within the genomes of D74 and Nagasaki led to the discovery of a large number of toxin-antitoxin (TA) systems within both genomes. Five predicted hemolysins were identified as unique to Nagasaki and seven putative contact-dependent growth inhibition toxin proteins were identified only in strain D74. Assessment of all potential vtaA genes revealed thirteen present in the Nagasaki genome and three in the D74 genome. Subsequent evaluation of the predicted protein structure revealed that none of the D74 VtaA proteins contain a collagen triple helix repeat domain. Additionally, the predicted protein sequence for two D74 VtaA proteins is substantially longer than any predicted Nagasaki VtaA proteins. Fifteen methylation sequence motifs were identified in D74 and fourteen methylation sequence motifs were identified in Nagasaki using SMRT sequencing analysis. Only one of the methylation sequence motifs was observed in both strains indicative of the diversity between D74 and Nagasaki. Subsequent analysis also revealed diversity in the restriction-modification systems harbored by D74 and Nagasaki. The collective information reported in this study will aid in the development of vaccines and intervention strategies to decrease the prevalence and disease burden caused by H. parasuis.


Why Are Obstetric Units in Rural Hospitals Closing Their Doors?
To understand hospital- and county-level factors for rural obstetric unit closures, using mixed methods. Hospital discharge data from Healthcare Cost and Utilization Project's Statewide Inpatient Databases, American Hospital Association Annual Survey, and Area Resource File for 2010, as well as 2013-2014 telephone interviews of all 306 rural hospitals in nine states with at least 10 births in 2010. Via interview, we ascertained obstetric unit status, reasons for closures, and postclosure community capacity for prenatal care. Multivariate logistic regression and qualitative analysis were used to identify factors associated with unit closures between 2010 and 2014. Exactly 7.2 percent of rural hospitals in the study closed their obstetric units. These units were smaller in size, more likely to be privately owned, and located in communities with lower family income, fewer obstetricians, and fewer family physicians. Prenatal care was still available in 17 of 19 communities, but local women would need to travel an average of 29 additional miles to access intrapartum care. Rural obstetric unit closures are more common in smaller hospitals and communities with a limited obstetric workforce. Concerns about continuity of rural maternity care arise for women with local prenatal care but distant intrapartum care.


Higher-order statistics of input ensembles and the response of simple model neurons.
Pairwise correlations among spike trains recorded in vivo have been frequently reported. It has been argued that correlated activity could play an important role in the brain, because it efficiently modulates the response of a postsynaptic neuron. We show here that a neuron's output firing rate critically depends on the higher-order statistics of the input ensemble. We constructed two statistical models of populations of spiking neurons that fired with the same rates and had identical pairwise correlations, but differed with regard to the higher-order interactions within the population. The first ensemble was characterized by clusters of spikes synchronized over the whole population. In the second ensemble, the size of spike clusters was, on average, proportional to the pairwise correlation. For both input models, we assessed the role of the size of the population, the firing rate, and the pairwise correlation on the output rate of two simple model neurons: a continuous firing-rate model and a conductance-based leaky integrate-and-fire neuron. An approximation to the mean output rate of the firing-rate neuron could be derived analytically with the help of shot noise theory. Interestingly, the essential features of the mean response of the two neuron models were similar. For both neuron models, the three input parameters played radically different roles with respect to the postsynaptic firing rate, depending on the interaction structure of the input. For instance, in the case of an ensemble with small and distributed spike clusters, the output firing rate was efficiently controlled by the size of the input population. In addition to the interaction structure, the ratio of inhibition to excitation was found to strongly modulate the effect of correlation on the postsynaptic firing rate.


Brazilian propolis extract increases leptin expression in mouse adipocytes.
We investigated the anti-obesity effects of Brazilian green propolis ethanol extract using a mouse model of obesity. Repeated intraperitoneal injection of propolis (100 mg/kg twice a week) caused feeding suppression in C57BL/6 mice, whereas this treatment had negligible effects on C57BL/6 ob/ob mice. Since C57BL/6 ob/ob mice have a missense mutation in the Lep gene, leptin is likely to contribute to the propolis-induced feeding suppression. We found that propolis treatment indeed clearly increased leptin mRNA production in the visceral adipose tissues. Moreover, propolis extract directly elevated leptin expression in differentiated 3T3-L1 adipocytes. Artepillin C, an important organic compound found in Brazilian green propolis, failed to induce leptin mRNA in 3T3-L1 cells. Compounds other than artepillin C in Brazilian propolis must thus cause leptin induction in adipocytes, possibly resulting in the suppression of feeding and obesity.


The portfolio effect cushions mosquito populations and malaria transmission against vector control interventions.
Portfolio effects were first described as a basis for mitigating against financial risk by diversifying investments. Distributing investment across several different assets can stabilize returns and reduce risks by statistical averaging of individual asset dynamics that often correlate weakly or negatively with each other. The same simple probability theory is equally applicable to complex ecosystems, in which biological and environmental diversity stabilizes ecosystems against natural and human-mediated perturbations. Given the fundamental limitations to how well the full complexity of ecosystem dynamics can be understood or anticipated, the portfolio effect concept provides a simple framework for more critical data interpretation and pro-active conservation management. Applied to conservation ecology purposes, the portfolio effect concept informs management strategies emphasizing identification and maintenance of key ecological processes that generate complexity, diversity and resilience against inevitable, often unpredictable perturbations. Applied to the reciprocal goal of eliminating the least valued elements of global biodiversity, specifically lethal malaria parasites and their vector mosquitoes, simply understanding the portfolio effect concept informs more cautious interpretation of surveillance data and simulation model predictions. Malaria transmission mediated by guilds of multiple vectors in complex landscapes, with highly variable climatic and meteorological conditions, as well as changing patterns of land use and other human behaviours, will systematically tend to be more resilient to attack with vector control than it appears based on even the highest quality surveillance data or predictive models. Malaria vector control programmes may need to be more ambitious, interpret their short-to-medium term assessments of intervention impact more cautiously, and manage stakeholder expectations more conservatively than has often been the case thus far.


Population-based differences in the outcome and presentation of lung cancer patients based upon racial, histologic, and economic factors in all lung patients and those with metastatic disease.
To investigate the interrelation between economic, marital, and known histopathologic/therapeutic prognostic factors in presentation and survival of patients with lung cancer in nine different ethnic groups. A retrospective review of the SEER database was conducted through the years 2007-2012. Population differences were assessed via chi-square testing. Multivariable analyses (MVA) were used to detect overall survival (OS) differences in the total population (TP, N = 153,027) and for those patients presenting with Stage IV (N = 70,968). Compared to Whites, Blacks were more likely to present with younger age, male sex, lower income, no insurance, single/widowed partnership, less squamous cell carcinomas, and advanced stage; and experience less definitive surgery, lower OS, and lung cancer-specific (LCSS) survival. White Hispanics presented with younger age, higher income, lower rates of insurance, single/widowed partnership status, advanced stage, more adenocarcinomas, and lower rates of definitive surgery, but no difference in OS and LCSS than Whites. In the TP and Stage IV populations, MVAs revealed that OS was better or equivalent to Whites for all other ethnic groups and was positively associated with insurance, marriage, and higher income. Blacks presented with more advanced disease and were more likely to succumb to lung cancer, but when adjusted for prognostic factors, they had a better OS in the TP compared to Whites. Disparities in income, marital status, and insurance rather than race affect OS of patients with lung cancer. Because of their presentation with advanced disease, Black and Hispanics are likely to have increased benefit from lung cancer screening.


Gray matter is targeted in first-attack multiple sclerosis.
The cause of multiple sclerosis (MS), its driving pathogenesis at the earliest stages, and what factors allow the first clinical attack to manifest remain unknown. Some imaging studies suggest gray rather than white matter may be involved early, and some postulate this may be predictive of developing MS. Other imaging studies are in conflict. To determine if there was objective molecular evidence of gray matter involvement in early MS we used high-resolution mass spectrometry to identify proteins in the cerebrospinal fluid (CSF) of first-attack MS patients (two independent groups) compared to established relapsing remitting (RR) MS and controls. We found that the CSF proteins in first-attack patients were differentially enriched for gray matter components (axon, neuron, synapse). Myelin components did not distinguish these groups. The results support that gray matter dysfunction is involved early in MS, and also may be integral for the initial clinical presentation.


Bayesian structural inference for hidden processes.
We introduce a Bayesian approach to discovering patterns in structurally complex processes. The proposed method of Bayesian structural inference (BSI) relies on a set of candidate unifilar hidden Markov model (uHMM) topologies for inference of process structure from a data series. We employ a recently developed exact enumeration of topological ε-machines. (A sequel then removes the topological restriction.) This subset of the uHMM topologies has the added benefit that inferred models are guaranteed to be ε-machines, irrespective of estimated transition probabilities. Properties of ε-machines and uHMMs allow for the derivation of analytic expressions for estimating transition probabilities, inferring start states, and comparing the posterior probability of candidate model topologies, despite process internal structure being only indirectly present in data. We demonstrate BSI's effectiveness in estimating a process's randomness, as reflected by the Shannon entropy rate, and its structure, as quantified by the statistical complexity. We also compare using the posterior distribution over candidate models and the single, maximum a posteriori model for point estimation and show that the former more accurately reflects uncertainty in estimated values. We apply BSI to in-class examples of finite- and infinite-order Markov processes, as well to an out-of-class, infinite-state hidden process.


Four events of host switching in Aspidoderidae (Nematoda) involve convergent lineages of mammals.
The Great American Interchange resulted in the mixing of faunistic groups with different origins and evolutionary trajectories that underwent rapid diversification in North and South America. As a result, groups of animals of recent arrival converged into similar habits and formed ecological guilds with some of the endemics. We present a reconstruction of the evolutionary events in Aspidoderidae, a family of nematodes that infect mammals that are part of this interchange, i.e., dasypodids, opossums, and sigmodontine, geomyid, and hystricognath rodents. By treating hosts as discrete states of character and using parsimony and Bayesian inferences to optimize these traits into the phylogeny of Aspidoderidae, we reconstructed Dasypodidae (armadillos) as the synapomorphic host for the family. In addition, 4 events of host switching were detected. One consisted of the switch from dasypodids to hystricognath rodents, and subsequently to geomyid rodents. The remaining set of events consisted of a switch from dasypodids to didelphid marsupials and then to sigmodontine rodents. The reconstruction of the ancestral distribution suggests 3 events of dispersal into the Nearctic. Two of these invasions would suggest that 2 different lineages of dasypodid parasites entered the Northern Hemisphere at different times, which is consistent with the presence of 2 lineages of armadillos in Mexico.


Conception to ongoing pregnancy: the 'black box' of early pregnancy loss.
Even when conditions are optimal, the maximum chance of a clinically recognized pregnancy occurring in a given menstrual cycle is 30-40%. Increasing evidence points to preclinical pregnancy loss rather than failure of conception as the principal cause for the relatively low fecundity observed in humans. While sensitive assays for hCG have provided a glimpse of the events occurring between implantation and the missed menstrual period, new cytogenetic techniques have further opened this 'black box', providing novel insights into the causes of early pregnancy wastage. In this article, the evidence and causes of preclinical or 'occult' pregnancy are reviewed, and the implications for the infertile patient are addressed.


Immunogenicity and safety of inactivated influenza vaccines in primed populations: a systematic literature review and meta-analysis.
Several inactivated influenza vaccine formulations for systemic administration in man are currently available for annual (seasonal) immunization: split virus and subunit (either plain-aqueous, or virosomal, or adjuvanted by MF59). From a literature search covering the period 1978-2009, 33 articles could be identified, which described randomized clinical trials comparing at least two of the four vaccine formulations with respect to serum hemagglutination inhibition (HI) antibody response, local and systemic vaccine reactions and serious adverse events after vaccination, and employing seasonal vaccine components and doses. In total, 9121 vaccinees of all ages, either healthy or with underlying diseases, were involved. Most vaccinees were primed or had been vaccinated in previous years. For immunogenicity, homologous post-vaccination geometric mean HI titers (GMTs) were analyzed by a random effects model for continuous data. Unreported standard deviations (SD) were addressed by imputing assumed SD-values. Age and health state of the vaccinees appeared to have little influence on the outcome. The immunogenicity of split, aqueous and virosomal subunit formulations were similar, with geometric mean ratio values (GMR, quotient of paired GMT-values) varying around one (0.93-1.24). The MF59-adjuvanted subunit vaccine induced, on average, larger antibody titers than the non-adjuvanted vaccine formulations, but the absolute increase was small (GMR-values varying between 1.25 and 1.40). Vaccine reactions were analyzed using a random effects model for binary data. Local and systemic reactogenicity was similar among non-adjuvanted formulations. The adjuvanted subunit formulation was more frequently associated with local reactions than the non-adjuvanted formulations (rate ratio: 2.12, significant). Systemic reactions were similar among all vaccine formulations. The original articles emphasized the mild and transient character of the vaccine reactions and the absence of serious vaccine-related adverse events. This adequate amount of evidence led to the conclusion that all the currently available inactivated influenza vaccine formulations are safe, well tolerated and similarly effective to control seasonal influenza outbreaks across primed populations and age ranges.