The Use of Neuromodulation for Symptom Management.
Pain and other symptoms of autonomic dysregulation such as hypertension, dyspnoea and bladder instability can lead to intractable suffering. Incorporation of neuromodulation into symptom management, including palliative care treatment protocols, is becoming a viable option scientifically, ethically, and economically in order to relieve suffering. It provides further opportunity for symptom control that cannot otherwise be provided by pharmacology and other conventional methods.


Synthesis, spectroscopic, and structural studies on transition metal complexes involving homoleptic tripodal selenoether and telluroether coordination.
The reaction of [MCl2(NCMe)2] (M = Pd or Pt) with 2 molar equiv of MeC(CH2ER)3 (E = Se, R = Me; E = Te, R = Me or Ph) and 2 molar equiv of TlPF6 affords the bis ligand complexes [M(MeC(CH2ER)3)2][PF6]2. The crystal structure of [Pt(MeC(CH2SeMe)3)2][PF6]2 (C16H36F12P2PtSe6, a = 12.272(10) A, b = 18.563(9) A, c = 15.285(7) A, beta = 113.18(3) degrees, monoclinic, P2(1)/n, Z = 4) confirms distorted square planar Se4 coordination at Pt(II), derived from two bidentate tripod selenoethers with the remaining arm not coordinated and directed away from the metal center. Solution NMR studies indicate that these species are fluxional and that the telluroether complexes are rather unstable in solution. The octahedral bis tripod complexes [Ru(MeC(CH2SMe)3)2][CF3-SO3]2 and [Ru(MeC(CH2TePh)3)2][CF3SO3]2 are obtained from [Ru(dmf)6][CF3SO3]3 and tripod ligand in EtOH solution. The thioether complex (C18H36F6O6RuS8, a = 8.658(3) A, b = 11.533(3) A, c = 8.659(2) A, alpha = 108.33(2) degrees, beta = 91.53(3) degrees, gamma = 106.01(2) degrees, triclinic, P1, Z = 1) is isostructural with its selenoether analogue, involving two facially coordinated trithioether ligands in the syn configuration. NMR spectroscopy confirms that this configuration is retained in solution for all of the bis tripod Ru(II) complexes. These low-spin d6 complexes show unusually high ligand field splittings. The hexaselenoether Rh(III) complex [Rh(MeC(CH2SeMe)3)2][PF6]3 was obtained by treatment of [Rh(H2O)6]3+ with 2 molar equiv of MeC(CH2SeMe)3 in aqueous MeOH in the presence of excess PF6- anion, while the iridium(III) analogue [Ir(MeC(CH2SeMe)3)2][PF6]3 was obtained via the reaction of the Ir(I) precursor [IrCl(C8H14)2]2 with the selenoether tripod in MeOH/aqueous HBF4. NMR studies reveal different invertomers in solution for both the Rh and Ir species. The Cu(I) complexes [Cu(MeC(CH2ER)3)2]PF6 were obtained from [Cu(NCMe)4]PF6 and tripod ligand in CH2Cl2 solution. The corresponding Ag(I) species [Ag(MeC(CH2TeR)3)2]CF3SO3 (R = Me or Ph) were obtained from Ag[CF3SO3] and tripod telluroether. In contrast, a similar reaction with 2 molar equiv of MeC(CH2SeMe)3 afforded only the 1:1 complex [Ag(MeC(CH2SeMe)3)]CF3SO3. The structure of this species (C9H18AgF3O3SSe3, a = 8.120(3) A, b = 15.374(3) A, c = 14.071(2) A, beta = 93.86(2) degrees, monoclinic, P2(1)/n, Z = 4) reveals a distorted trigonal planar geometry at Ag(I) derived from one bidentate selenoether and one monodentate selenoether. These units are then linked to adjacent Ag(I) ions to give a one-dimensional linear chain cation.


Potential Clinical Implications of miR-1 and miR-21 in Heart Disease and Cardioprotection.
The interest in non-coding RNAs, which started more than a decade ago, has still not weakened. A wealth of experimental and clinical studies has suggested the potential of non-coding RNAs, especially the short-sized microRNAs (miRs), to be used as the new generation of therapeutic targets and biomarkers of cardiovascular disease, an ever-growing public health issue in the modern world. Among the hundreds of miRs characterized so far, microRNA-1 (miR-1) and microRNA-21 (miR-21) have received some attention and have been associated with cardiac injury and cardioprotection. In this review article, we summarize the current knowledge of the function of these two miRs in the heart, their association with cardiac injury, and their potential cardioprotective roles and biomarker value. While this field has already been extensively studied, much remains to be done before research findings can be translated into clinical application for patient's benefit.


The Cochrane review of physiotherapy interventions for ankylosing spondylitis.
To update the Cochrane review on the effectiveness of physiotherapy interventions in the management of ankylosing spondylitis (AS). All randomized studies available in systematic searches (electronic databases, contact with authors, reference lists) up to February 2004 were included. Two reviewers independently selected trials for inclusion, assessed the validity of included trials, and extracted data. Investigators were contacted to obtain missing information. Six trials with a total of 561 participants were included. Two trials compared individualized home exercise programs with no intervention. Low quality evidence for effects in favor of the home exercise program was found in physical function and spinal mobility [absolute benefit 10.3 cm on fingertip to floor distance; relative percentage difference (RPD) 37%)]. Further, the trials showed low quality evidence for no group differences in pain. Three trials compared supervised group physiotherapy with an individualized home exercise program. Moderate quality evidence for effectiveness was found in patient global assessment and spinal mobility in favor of the supervised group. The trials showed moderate quality evidence for no differences in pain intensity between the groups. One trial compared a 3-week inpatient spa-exercise therapy followed by weekly outpatient group physiotherapy with weekly outpatient group physiotherapy alone. Moderate quality evidence was found for effects in pain (absolute benefit 0.9 cm on visual analog scale; RPD 19%), physical function (absolute benefit 1 cm; RPD 24%), and patient global assessment (absolute benefit 1.3 cm; RPD 27%), in favor of the combined spa-exercise therapy. The current best available evidence suggests that physiotherapy is beneficial for people with AS. However, it is still not clear which treatment protocol should be recommended in the management of AS.


An investigation of models of illness in carers of schizophrenia patients using the Illness Perception Questionnaire.
Although carers' reactions to schizophrenic illness in a close family member may have important implications for the patient and for themselves, little is known of factors that influence the way carers respond. In the area of physical health problems, people's models of their illness or illness representations have been found to be related to the ways they react and cope with their illness. This study examines the use of a modified form of the Illness Perception Questionnaire (IPQ) to investigate illness models in a sample of carers of schizophrenia patients. Forty-seven carers participated. The psychometric properties of the modified IPQ were examined, and a number of carer and patient outcomes were investigated in relation to carer scores on the illness identity, consequences, control-cure and timeline subscales of the modified IPQ. These outcomes included measures of carer distress and burden, expressed emotion dimensions, and patient functioning. The modified IPQ was found to be a reliable measure of carers' perceptions of schizophrenia. Carer functioning, the patient-carer relationship and patient illness characteristics were associated with different dimensions of illness perceptions. The findings support the proposal that carer cognitive representations of the illness may have important implications for both carer and patient outcomes in schizophrenia.


The impact of endotracheal suctioning on gas exchange and hemodynamics during lung-protective ventilation in acute respiratory distress syndrome.
To evaluate the respiratory and hemodynamic effects of open suctioning (OS) versus closed suctioning (CS) during pressure-control (PC) and volume-control (VC) ventilation, using a lung-protective ventilation strategy in an animal model of acute respiratory distress syndrome (ARDS). Animal laboratory in a university hospital. Randomized cross-over evaluation. Eight female Dorset sheep. Lung lavage was used to simulate ARDS. We applied VC and PC mechanical ventilation with a tidal volume of 6 mL/kg and positive end-expiratory pressure (PEEP), adjusted based on a table of PEEP versus fraction of inspired oxygen (FIO2). Suctioning was performed for 10 s with a suction pressure of -100 mm Hg, during both OS and CS. OS and CS were randomly performed with each animal. Hemodynamics and arterial blood gases were recorded before, during, and after endotracheal suctioning. The PaO2/FIO2 ratios before suctioning were similar in all groups, as were the PEEP and FIO2. PaO2/FIO2 was lower after OS than after CS/VC or CS/PC. There was no post-suctioning difference in oxygenation between CS/VC and CS/PC. PaCO2 recorded 10 min after suctioning was greater than the presuctioning value, in all groups. Intrapulmonary shunt fraction increased between baseline and 10 min post-suctioning with OS and CS/VC, but did not significantly increase with CS/PC. There were no significant changes in hemodynamics pre-suctioning versus post-suctioning with OS, CS/VC, or CS/PC. PaO2/FIO2) was better maintained during CS with both VC and PC modes during lung-protective ventilation for ARDS, as compared with OS, and shunt fraction post-suctioning changed least with PC.


Chaos and unpredictability in evolution.
The possibility of complicated dynamic behavior driven by nonlinear feedbacks in dynamical systems has revolutionized science in the latter part of the last century. Yet despite examples of complicated frequency dynamics, the possibility of long-term evolutionary chaos is rarely considered. The concept of "survival of the fittest" is central to much evolutionary thinking and embodies a perspective of evolution as a directional optimization process exhibiting simple, predictable dynamics. This perspective is adequate for simple scenarios, when frequency-independent selection acts on scalar phenotypes. However, in most organisms many phenotypic properties combine in complicated ways to determine ecological interactions, and hence frequency-dependent selection. Therefore, it is natural to consider models for evolutionary dynamics generated by frequency-dependent selection acting simultaneously on many different phenotypes. Here we show that complicated, chaotic dynamics of long-term evolutionary trajectories in phenotype space is very common in a large class of such models when the dimension of phenotype space is large, and when there are selective interactions between the phenotypic components. Our results suggest that the perspective of evolution as a process with simple, predictable dynamics covers only a small fragment of long-term evolution.


[Intimate partner sexual violence among men and women in urban Brazil, 2005].
To estimate the prevalence of intimate partner sexual violence among men and women of the Brazilian urban population and factors associated to it. The data analyzed is part of the study conducted between 1998 and 2005 among urban populations in Brazil. The data was obtained by means of a questionnaire applied to a representative sample of 5.040 individuals, men and women 16 to 65 years of age. Descriptive analysis was undertaken with weighted data, utilizing F design-based tests, with 5% significance. The global prevalence of intimate partner sexual violence was 8.6%, being predominant among women (11.8% versus 5.1%). Women consistently reported higher rates of violence then men, except in cases involving homo/bisexual partners. The rate verified for male homo/bisexuals was significantly greater than that found among male heterosexuals, but this difference in rates was not significant among women. The black population, irrespective of sex, referred more violence than the white population. The lower the income and years of formal education, the greater the rates of violence. However, men from poorer regions referred more violence, but this did not occur with respect to women. Diverse situations with respect to work, use of condoms, lower age at first intercourse and number of partners during the last five years differed significantly among women, but not among men. For both men and women sexual violence was associated with being separated or divorced, having had STDs, self -evaluation of being at risk for HIV, but was not associated with testing positive for HIV. The high magnitude of sexual violence as well as female surtax is confirmed. Violence as a result of gender conflicts, that pervades social stratification and ethnic groups is reiterated. As to the Aids epidemic, sexual violence is an important factor to be taken into consideration when discussing the feminization of the population affected by the disease.


Discharge destination and repeat hospitalizations.
Is discharge destination a determinant of readmission? Studies to date have been inconclusive. The primary purpose of this study was to identify the role of discharge destination in the occurrence of repeat hospitalizations for a national sample of patients discharged from Veterans Health Administration (VHA) hospitals. The authors studied a 20% random sample of individual patients, 65 years of age or older, with either chronic obstructive pulmonary disease, stroke, or dementia who were discharged from a Veterans Health Administration hospital in 1988. All data for the study were obtained from secondary administrative sources. Multiple sources were used to determine discharge destination. The authors focused on personal home versus nursing home discharge destination. Both VHA and Medicare discharge data were used to track hospital readmissions. Proportional hazards regression models were used to examine the independent association of discharge destination with time to readmission within 30 days, 6 months, 1 year, and 2 years of discharge, adjusting for severity, other clinical and demographic characteristics, and censoring deaths. After adjustment and including out-of-system (Medicare) use, we found that patients with chronic obstructive pulmonary disease and patients with dementia who were discharged to nursing homes (community and Veterans Health Administration, respectively) were less likely to be readmitted within 30 days after discharge than patients discharged to personal homes. These findings have important implications for adjusting hospital performance profiles based on discharge destination and for focussing efforts to reduce the frequency and associated costs of hospital readmissions.


Idelalisib Impacts Cell Growth through Inhibiting Translation-Regulatory Mechanisms in Mantle Cell Lymphoma.
PI3K is a critical node in the B-cell receptor pathway, which is responsible for survival and proliferation of B-cell malignancies. Idelalisib, a PI3Kδ-isoform-specific inhibitor, has been approved to treat B-cell malignancies. Although biological activity of the drug has been evaluated, molecular mechanisms and signaling pathway disruption leading to the biological effects of idelalisib are not yet well defined. Prior laboratory reports have identified transcription and translation as the primary events for attenuation of PI3Kα isoform. We hypothesized that PI3Kδ-isoform inhibition by idelalisib should also affect gene transcription and protein translation. Using three mantle cell lymphoma cell lines and primary cells from patients, biological consequences such as apoptosis/cell-cycle analysis, as well as RNA/protein synthesis were evaluated. Proteomics analyses (RPPA and immunoblot assays) defined molecular events downstream of PI3K/AKT cassette. Idelalisib treatment resulted in inhibition of protein synthesis, which correlated with reduction in cell size and cell growth. A moderate loss of viability without any change in cell-cycle profile was observed. Idelalisib treatment inhibited AKT activation, an immediate downstream PI3K effector, and also reduced phosphorylation levels of downstream AKT/mTOR pathway proteins such as PRAS40. In addition, idelalisib treatment impeded activation of the MAPK pathway, and MEK, ERK and p90RSK phosphorylation levels were reduced. Reduction in AKT, PDK1, and MEK phosphorylation correlated with protein synthesis inhibition. Collectively, these results clarify the molecular mechanisms of actions and may provide biomarkers and targets for combination with idelalisib in B-cell malignancies. Clin Cancer Res; 23(1); 181-92. ©2016 AACR.


Adaptation of HIV-1 to human leukocyte antigen class I.
The rapid and extensive spread of the human immunodeficiency virus (HIV) epidemic provides a rare opportunity to witness host-pathogen co-evolution involving humans. A focal point is the interaction between genes encoding human leukocyte antigen (HLA) and those encoding HIV proteins. HLA molecules present fragments (epitopes) of HIV proteins on the surface of infected cells to enable immune recognition and killing by CD8(+) T cells; particular HLA molecules, such as HLA-B*57, HLA-B*27 and HLA-B*51, are more likely to mediate successful control of HIV infection. Mutation within these epitopes can allow viral escape from CD8(+) T-cell recognition. Here we analysed viral sequences and HLA alleles from >2,800 subjects, drawn from 9 distinct study cohorts spanning 5 continents. Initial analysis of the HLA-B*51-restricted epitope, TAFTIPSI (reverse transcriptase residues 128-135), showed a strong correlation between the frequency of the escape mutation I135X and HLA-B*51 prevalence in the 9 study cohorts (P = 0.0001). Extending these analyses to incorporate other well-defined CD8(+) T-cell epitopes, including those restricted by HLA-B*57 and HLA-B*27, showed that the frequency of these epitope variants (n = 14) was consistently correlated with the prevalence of the restricting HLA allele in the different cohorts (together, P < 0.0001), demonstrating strong evidence of HIV adaptation to HLA at a population level. This process of viral adaptation may dismantle the well-established HLA associations with control of HIV infection that are linked to the availability of key epitopes, and highlights the challenge for a vaccine to keep pace with the changing immunological landscape presented by HIV.


Role of Calcium-Sensing Receptor in Mechanotransducer-Channel-Mediated Ca2+ Influx in Hair Cells of Zebrafish Larvae.
The calcium-sensing receptor (CaSR) is an extracellular Ca2+ sensor that plays a critical role in maintaining Ca2+ homeostasis in several organs, including the parathyroid gland and kidneys. In this study, through in situ hybridization, the expression of CaSR mRNA was found in the neuromasts of zebrafish larvae. Immunohistochemistry further demonstrated that the CaSR protein was present in neuromast hair cell stereocilia and basolateral membranes. Based on the expression and subcellular localization of the CaSR in hair cells, we hypothesized that the CaSR is expressed in zebrafish lateral-line hair cells to regulate mechanotransducer (MET)-channel-mediated Ca2+ entry. Using the scanning ion-selective electrode technique, MET-channel-mediated Ca2+ influx at the stereocilia of hair cells was measured in intact larvae. Ca2+ influx was suppressed after larvae were pretreated with a CaSR activator (R-568) or high-Ca2+ (HCa) medium. Gene knockdown by using morpholino oligonucleotides decreased CaSR expression in hair cells and eliminated the effects of R-568 and HCa on Ca2+ influx. In addition, we found that treatment with R-568 attenuated neomycin-induced hair cell death. This study is the first to demonstrate that the CaSR is involved in mechanotransduction in zebrafish hair cells.


Association of lifelong occupation and educational level with subclinical atherosclerosis in different European regions. Results from the IMPROVE study.
We aimed to examine the association between socioeconomic status (SES) and subclinical atherosclerosis, as assessed by carotid intima-media-thickness (C-IMT) and to investigate whether the effect of social inequality on C-IMT is mediated by cardiovascular (CV) risk factors and whether it is dissimilar in men and women, and in different European countries. We assessed the association of lifelong occupation and educational level with C-IMT in the IMPROVE study cohort including 3703 subjects (median age 64.4 years; 48% men) from Southern (Italy), Western (France and the Netherlands) and Northern Europe (Finland and Sweden). Three summary measures of C-IMT (IMTmean, IMTmax, IMTmean-max), obtained from four segments of both carotids, were considered. After adjusting for conventional CV risk factors, current employment status and diet, C-IMT was higher in manual workers than in white collars (+7.7%, +5.3%, +4.6% for IMTmax, IMTmean-max and IMTmean, respectively; all p<.0001). Similar results were obtained by stratification for educational level. The effect of occupation on C-IMT was comparable in men and women and in different age groups, and was only partially mediated by differences in CV risk factors. Of note, the association of C-IMT with occupation was significant in Western and Northern Europe but not in Italy, with a significant statistical interaction (p = .0005). Low SES was associated with subclinical atherosclerosis in subjects with at least three CV risk factors. Such association was stronger in Northern and Western Europe than in Italy. This difference was not completely explained by inequalities in CV risk factors and behavioural variables.


The ecocultural context and child behavior problems: A qualitative analysis in rural Nepal.
Commonly used paradigms for studying child psychopathology emphasize individual-level factors and often neglect the role of context in shaping risk and protective factors among children, families, and communities. To address this gap, we evaluated influences of ecocultural contextual factors on definitions, development of, and responses to child behavior problems and examined how contextual knowledge can inform culturally responsive interventions. We drew on Super and Harkness' "developmental niche" framework to evaluate the influences of physical and social settings, childcare customs and practices, and parental ethnotheories on the definitions, development of, and responses to child behavior problems in a community in rural Nepal. Data were collected between February and October 2014 through in-depth interviews with a purposive sampling strategy targeting parents (N = 10), teachers (N = 6), and community leaders (N = 8) familiar with child-rearing. Results were supplemented by focus group discussions with children (N = 9) and teachers (N = 8), pile-sort interviews with mothers (N = 8) of school-aged children, and direct observations in homes, schools, and community spaces. Behavior problems were largely defined in light of parents' socialization goals and role expectations for children. Certain physical settings and times were seen to carry greater risk for problematic behavior when children were unsupervised. Parents and other adults attempted to mitigate behavior problems by supervising them and their social interactions, providing for their physical needs, educating them, and through a shared verbal reminding strategy (samjhaune). The findings of our study illustrate the transactional nature of behavior problem development that involves context-specific goals, roles, and concerns that are likely to affect adults' interpretations and responses to children's behavior. Ultimately, employing a developmental niche framework will elucidate setting-specific risk and protective factors for culturally compelling intervention strategies.


Using geometric constraints through parallelepipeds for calibration and 3D modeling.
This paper concerns the incorporation of geometric information in camera calibration and 3D modeling. Using geometric constraints enables more stable results and allows us to perform tasks with fewer images. Our approach is motivated and developed within a framework of semi-automatic 3D modeling, where the user defines geometric primitives and constraints between them. It is based on the observation that constraints, such as coplanarity, parallelism, or orthogonality, are often embedded intuitively in parallelepipeds. Moreover, parallelepipeds are easy to delineate by a user and are well adapted to model the main structure of, e.g., architectural scenes. In this paper, first a duality that exists between the shape parameters of a parallelepiped and the intrinsic parameters of a camera is described. Then, a factorization-based algorithm exploiting this relation is developed. Using images of parallelepipeds, it allows us to simultaneously calibrate cameras, recover shapes of parallelepipeds, and estimate the relative pose of all entities. Besides geometric constraints expressed via parallelepipeds, our approach simultaneously takes into account the usual self-calibration constraints on cameras. The proposed algorithm is completed by a study of the singular cases of the calibration method. A complete method for the reconstruction of scene primitives that are not modeled by parallelepipeds is also briefly described. The proposed methods are validated by various experiments with real and simulated data, for single-view as well as multiview cases.


Inter-observer agreement in reporting HER 2 Neu protein over expression by immunohistochemistry.
HER 2 Neu protein overexpression and its detection by immunohistochemistry (IHC) has become quiet critical because of its relevance in regards to Herceptin treatment. This peer review was done at a tertiary care center, which aimed at determining the inter-observer variation among five pathologists and evaluating the degree of agreement between them. The aim of our study was to determine the reproducibility of HER 2 Neu system of reporting in breast cancer cases and determine inter-observer variability among five pathologists at a tertiary care center. To compare the results with similar studies done at other centers. Retrospective descriptive study. Hematoxylin and Eosin (H and E) and IHC stained slides of 104 cases of carcinoma breast, on which HER 2 Neu status had been reported were reviewed. The time period for selection was from January 2010 to December 2011 (2 year period). Five pathologists reviewed the H and E and IHC slides independently and scored the results on a specially designed work sheet. Kappa values for inter-observer variation and Cornbach's alpha for internal consistency were calculated. SPSS 20.0 (IBM). not known. Complete agreement was seen between all five pathologists in 70 cases (70/104) = 67%. Agreement between four pathologists was seen in 78 cases (78/104) = 75%. Agreement between three pathologists was seen in 92 cases (92/104) = 88%. The global value for kappa co efficient for agreement between two pathologists was 0.706 and Cornbach alpha for internal consistency of reporting in the department was 0.987. CONCLUSION/KEY MESSAGES: Our departmental peer review indicated that there is good inter-observer concordance (agreement between two pathologists) and there is strong overall internal consistency of reporting for HER 2 Neu reporting by IHC. Our results are comparable to International reported data of similar studies.


Predictors of Opioid and Alcohol Pharmacotherapy Initiation at Hospital Discharge Among Patients Seen by an Inpatient Addiction Consult Service.
Medications for opioid use disorder (MOUD) and alcohol use disorder (MAUD) are effective and under-prescribed. Hospital-based addiction consult services can engage out-of-treatment adults in addictions care. Understanding which patients are most likely to initiate MOUD and MAUD can inform interventions and deepen understanding of hospitals' role in addressing substance use disorders (SUD). Determine patient- and consult-service level characteristics associated with MOUD/MAUD initiation during hospitalization. We analyzed data from a study of the Improving Addiction Care Team (IMPACT), an interprofessional hospital-based addiction consult service at an academic medical center. Researchers collected patient surveys and clinical data from September 2015 to May 2018. We used logistic regression to identify characteristics associated with medication initiation among participants with OUD, AUD, or both. Candidate variables included patient demographics, social determinants, and treatment-related factors. Three hundred thirty-nine participants had moderate to severe OUD, AUD, or both and were not engaged in MOUD/MAUD care at admission. Past methadone maintenance treatment (aOR 2.07, 95%CI (1.17, 3.66)), homelessness (aOR 2.63, 95%CI (1.52, 4.53)), and partner substance use (aOR 2.05, 95%CI (1.12, 3.76) were associated with MOUD/MAUD initiation. Concurrent methamphetamine use disorder (aOR 0.32, 95%CI (0.18, 0.56)) was negatively associated with MOUD/MAUD initiation. The association of MOUD/MAUD initiation with homelessness and partner substance use suggests that hospitalization may be an opportunity to reach highly-vulnerable people, further underscoring the need to provide hospital-based addictions care as a health-system strategy. Methamphetamine's negative association with MOUD/MAUD warrants further study.


Molecular mechanisms of cigarette smoke-induced proliferation of lung cells and prevention by vitamin C.
Lung cancer is the leading cause of cancer dearth. Cigarette smoking is the strongest risk factor for developing lung cancer, which is conceivably initiated by proliferation. Here, we show that low concentration of aqueous extract of cigarette smoke (AECS) causes excessive proliferation of human lung epithelial cells (A549) without any apoptotic cell death. The causative factor responsible for AECS-induced proliferation has been identified as p-benzoquinone (p-BQ). Coimmunoprecipitation and immunoblot experiments indicate that p-BQ binds with epidermal growth factor receptor (EGFR). However, in contrast to EGF, it causes aberrant phosphorylation of EGFR that lacks c-Cbl-mediated ubiquitination and degradation resulting in persistent activation of EGFR. This is followed by activation of Hras + Kras and the downstream survival and proliferative signaling molecules Akt and ERK1/2, as well as the nuclear transcription factors c-Myc and c-Fos. Vitamin C and/or antibody to p-BQ prevents AECS/p-BQ-induced proliferation of lung cells apparently by inactivating p-BQ and thereby preventing activation of EGFR and the downstream signaling molecules. The results suggest that vitamin C and/or antibody to p-BQ may provide a novel intervention for preventing initiation of lung cancer in smokers.


Addressing the policy cacophony does not require more evidence: an argument for reframing obesity as caloric overconsumption.
Numerous policies have been proposed to address the public health problem of obesity, resulting in a policy cacophony. The noise of so many policy options renders it difficult for policymakers to determine which policies warrant implementation. This has resulted in calls for more and better evidence to support obesity policy. However, it is not clear that evidence is the solution. This paper argues that to address the policy cacophony it is necessary to rethink the problem of obesity, and more specifically, how the problem of obesity is framed. This paper argues that the frame "obesity" be replaced by the frame "caloric overconsumption", concluding that the frame caloric overconsumption can overcome the obesity policy cacophony. Frames are important because they influence public policy. Understood as packages that define issues, frames influence how best to approach a problem. Consequently, debates over public policy are considered battles over framing, with small shifts in how an issue is framed resulting in significant changes to the policy environment. This paper presents a rationale for reframing the problem of obesity as caloric overconsumption. The frame "obesity" contributes to the policy cacophony by including policies aimed at both energy output and energy input. However, research increasingly demonstrates that energy input is the primary cause of obesity, and that increases in energy input are largely attributable to the food environment. By focusing on policies that aim to prevent increases in energy input, the frame caloric overconsumption will reduce the noise of the obesity policy cacophony. While the proposed frame will face some challenges, particularly industry opposition, policies aimed at preventing caloric overconsumption have a clearer focus, and can be more politically palatable if caloric overconsumption is seen as an involuntary risk resulting from the food environment. The paper concludes that policymakers will be able to make better sense of the obesity policy cacophony if the problem of obesity is reframed as caloric overconsumption. By focusing on a specific cause of obesity, energy input, the frame caloric overconsumption allows policymakers to focus on the most promising obesity prevention policies.


Diabetes and depression comorbidity and socio-economic status in low and middle income countries (LMICs): a mapping of the evidence.
Non-communicable diseases account for more than 50% of deaths in adults aged 15-59 years in most low income countries. Depression and diabetes carry an enormous public health burden, making the identification of risk factors for these disorders an important strategy. While socio-economic inequalities in chronic diseases and their risk factors have been studied extensively in high-income countries, very few studies have investigated social inequalities in chronic disease risk factors in low or middle-income countries. Documenting chronic disease risk factors is important for understanding disease burdens in poorer countries and for targeting specific populations for the most effective interventions. The aim of this review is to systematically map the evidence for the association of socio-economic status with diabetes and depression comorbidity in low and middle income countries. The objective is to identify whether there is any evidence on the direction of the relationship: do co-morbidities have an impact on socio-economic status or vice versa and whether the prevalence of diabetes combined with depression is associated with socio-economic status factors within the general population. To date no other study has reviewed the evidence for the extent and nature of this relationship. By systematically mapping the evidence in the broader sense we can identify the policy and interventions implications of existing research, highlight the gaps in knowledge and suggest future research. Only 14 studies were found to analyse the associations between depression and diabetes comorbidity and socio-economic status. Studies show some evidence that the occurrence of depression among people with diabetes is associated with lower socio-economic status. The small evidence base that considers diabetes and depression in low and middle income countries is out of step with the scale of the burden of disease.


Differential expression of nitric oxide in serotonergic projection neurons: neurochemical identification of dorsal raphe inputs to rodent trigeminal somatosensory targets.
The dorsal raphe (DR) is invested with nitric oxide synthase (NOS)-expressing profiles. To characterize the connections of NO-containing cells and further assess neurochemical relationships maintained by DR, the transmitter identity of the raphe projection to the trigeminal somatosensory system was examined. Rats were injected with retrograde tracer into vibrissae-related target areas or with anterograde tracer into DR. NADPH-diaphorase (NADPHd) histochemistry or NOS-immunostaining was combined with serotonin (5HT)- or serotonin transporter (SERT)-immunolabeling to examine: 1) the presence of NO in 5HT-containing axons from DR; 2) the distribution of NO-containing fibers with respect to other nitrergic profiles in the somatosensory system; and 3) the propensity for individual projection neurons in specific subdivisions of DR to colocalize 5HT and NO. Results confirm that "barrel-like" patches can be identified in several adult trigeminal relay nuclei by NADPHd histochemistry and demonstrate that fibers from DR contain 5HT and NO. Observations include a high percentage of cortical midline projection neurons which contained NADPHd (70-80%) and coexpressed 5HT. In contrast, approximately 40% of retrogradely labeled DR-thalamus cells in the lateral wing demonstrated NADPHd or 5HT expression, but not both in the same neuron. Colocalization of NADPHd and 5HT within individual DR projection neurons indicates that: i) DR is a source of nitrergic input to trigeminal structures, and ii) NO and 5HT may be simultaneously released to influence information-processing within somatosensory targets. Disparities in NADPHd expression between retrogradely labeled DR neuronal subpopulations further suggest functional differences in the impact of NO on cortical and subcortical targets.


Tn6188 - a novel transposon in Listeria monocytogenes responsible for tolerance to benzalkonium chloride.
Controlling the food-borne pathogen Listeria (L.) monocytogenes is of great importance from a food safety perspective, and thus for human health. The consequences of failures in this regard have been exemplified by recent large listeriosis outbreaks in the USA and Europe. It is thus particularly notable that tolerance to quaternary ammonium compounds such as benzalkonium chloride (BC) has been observed in many L. monocytogenes strains. However, the molecular determinants and mechanisms of BC tolerance of L. monocytogenes are still largely unknown. Here we describe Tn6188, a novel transposon in L. monocytogenes conferring tolerance to BC. Tn6188 is related to Tn554 from Staphylococcus (S.) aureus and other Tn554-like transposons such as Tn558, Tn559 and Tn5406 found in various Firmicutes. Tn6188 comprises 5117 bp, is integrated chromosomally within the radC gene and consists of three transposase genes (tnpABC) as well as genes encoding a putative transcriptional regulator and QacH, a small multidrug resistance protein family (SMR) transporter putatively associated with export of BC that shows high amino acid identity to Smr/QacC from S. aureus and to EmrE from Escherichia coli. We screened 91 L. monocytogenes strains for the presence of Tn6188 by PCR and found Tn6188 in 10 of the analyzed strains. These isolates were from food and food processing environments and predominantly from serovar 1/2a. L. monocytogenes strains harboring Tn6188 had significantly higher BC minimum inhibitory concentrations (MICs) (28.5 ± 4.7 mg/l) than strains without Tn6188 (14 ± 3.2 mg/l). Using quantitative reverse transcriptase PCR we could show a significant increase in qacH expression in the presence of BC. QacH deletion mutants were generated in two L. monocytogenes strains and growth analysis revealed that ΔqacH strains had lower BC MICs than wildtype strains. In conclusion, our results provide evidence that Tn6188 is responsible for BC tolerance in various L. monocytogenes strains.


Construction of an antigenic map of the haemagglutinin-esterase protein of influenza C virus.
Four different antigenic sites (A-1, A-2, B-1, B-2) have been identified previously on the haemagglutinin-esterase (HE) glycoprotein of influenza C/Ann Arbor/1/50 virus with seven monoclonal antibodies (MAbs). In this study we produced 30 additional anti-HE MAbs, nine of which demonstrated at least one of the following activities: haemagglutination inhibition, receptor-destroying enzyme inhibition, haemolysis inhibition, and neutralization (group A). The remaining had none of these activities (group B). These antibodies, and those previously isolated, were used to construct a more complete antigenic map of the HE molecule. Operational and topological analyses showed that a minimum of nine non-overlapping or partially overlapping antigenic sites were present on the HE protein, five recognized by group A MAbs (A-1 to A-5) and four by group B (B-1 to B-4). Among these antigenic sites, site A-5 was unique in that MAbs to this site inhibited the receptor-destroying activity without influencing the receptor-binding activity, which supports the idea that the sites responsible for these two functions are separate. It was also found that several group B MAbs were cross-reactive with host cell antigens.


Correction to: Prevalence of colorectal cancer in acute uncomplicated diverticulitis and the role of the interval colonoscopy.
The original version of this article, unfortunately, contained errors. The first and family names of the authors were interchanged. The correct author names are now correctly presented in this article. The original article has been corrected.].


The woodchuck as an animal model for pathogenesis and therapy of chronic hepatitis B virus infection.
This review describes the woodchuck and the woodchuck hepatitis virus (WHV) as an animal model for pathogenesis and therapy of chronic hepatitis B virus (HBV) infection and disease in humans. The establishment of woodchuck breeding colonies, and use of laboratory-reared woodchucks infected with defined WHV inocula, have enhanced our understanding of the virology and immunology of HBV infection and disease pathogenesis, including major sequelae like chronic hepatitis and hepatocellular carcinoma. The role of persistent WHV infection and of viral load on the natural history of infection and disease progression has been firmly established along the way. More recently, the model has shed new light on the role of host immune responses in these natural processes, and on how the immune system of the chronic carrier can be manipulated therapeutically to reduce or delay serious disease sequelae through induction of the recovery phenotype. The woodchuck is an outbred species and is not well defined immunologically due to a limitation of available host markers. However, the recent development of several key host response assays for woodchucks provides experimental opportunities for further mechanistic studies of outcome predictors in neonatal- and adult-acquired infections. Understanding the virological and immunological mechanisms responsible for resolution of self-limited infection, and for the onset and maintenance of chronic infection, will greatly facilitate the development of successful strategies for the therapeutic eradication of established chronic HBV infection. Likewise, the results of drug efficacy and toxicity studies in the chronic carrier woodchucks are predictive for responses of patients chronically infected with HBV. Therefore, chronic WHV carrier woodchucks provide a well-characterized mammalian model for preclinical evaluation of the safety and efficacy of drug candidates, experimental therapeutic vaccines, and immunomodulators for the treatment and prevention of HBV disease sequelae.


Analysis of Lung Flute-collected Sputum for Lung Cancer Diagnosis.
Molecular analysis of sputum can help diagnose lung cancer. We have demonstrated that Lung Flute can be used to collect sputum from individuals who cannot spontaneously expectorate sputum. The objective of this study is to further evaluate the performance of the Lung Flute by comparing the characteristics of parallel samples collected with and without the Lung Flute and the usefulness for diagnosis of lung cancer. Fifty-six early-stage lung cancer patients (40 current smokers and 16 former smokers) and 73 cancer-free individuals (52 current smokers and 21 former smokers) were instructed to spontaneously cough and use Lung Flute for sputum sampling. Sputum cytology and polymerase chain reaction analysis of three miRNAs (miRs-21, 31, and 210) were performed in the specimens. All 92 current smokers and 11 (28.7%) of 37 former smokers spontaneously expectorated sputum and also produced sputum when using the Lung Flute. Twenty-seven former smokers (70.3%) who could not spontaneously expectorate sputum, however, were able to produce sputum when using the Lung Flute. The specimens were of low respiratory origin without contamination from other sources, eg, saliva. There was no difference of sputum volume and cell populations, diagnostic efficiency of cytology, and analysis of the miRNAs in the specimens collected by the two approaches. Analysis of the sputum miRNAs produced 83.93% sensitivity and 87.67% specificity for identifying lung cancer. Therefore, sputum collected by the Lung Flute has comparable features as spontaneously expectorated sputum. Using the Lung Flute enables former smokers who cannot spontaneously expectorate to provide adequate sputum to improve sputum collection for lung cancer diagnosis.


Simple allele-discriminating PCR for cost-effective and rapid genotyping and mapping.
Single nucleotide polymorphisms (SNPs) are widely observed between individuals, ecotypes, and species, serving as an invaluable molecular marker for genetic, genomic, ecological and evolutionary studies. Although, a large number of SNP-discriminating methods are currently available, few are suited for low-throughput and low-cost applications. Here, we describe a genotyping method named Simple Allele-discriminating PCR (SAP), which is ideally suited for the small-scale genotyping and gene mapping routinely performed in small to medium research or teaching laboratories. We demonstrate the feasibility and application of SAP to discriminate wild type alleles from their respective mutant alleles in Arabidopsis thaliana. Although the design principle was previously described, it is unclear if the method is technically robust, reliable, and applicable. Three primers were designed for each individual SNP or allele with two allele-discriminating forward primers (one for wild type and one for the mutant allele) and a common reverse primer. The two allele-discriminating forward primers are designed so that each incorporates one additional mismatch at the adjacent (penultimate) site from the SNP, resulting in two mismatches between the primer and its non-target template and one mismatch between the primer and its target template. The presence or absence of the wild type or the mutant allele correlates with the presence or absence of respective PCR product. The presence of both wild type-specific and mutant-specific PCR products would indicate heterozygosity. SAP is shown here to discriminate three mutant alleles (lug-3, lug-16, and luh-1) from their respective wild type alleles. In addition, the SAP principle is shown to work in conjunction with fluorophore-labeled primers, demonstrating the feasibility of applying SAP to high throughput SNP analyses. SAP offers an excellent alternative to existing SNP-discrimination methods such as Cleaved Amplified Polymorphic Sequence (CAPS) or derived CAPS (dCAPS). It can also be adapted for high throughput SNP analyses by incorporating fluorophore-labeled primers. SAP is reliable, cost-effective, fast, and simple, and can be applied to all organisms not limited to Arabidopsis thaliana.


Responses of neurons in the rat's ventral nucleus of the lateral lemniscus to amplitude-modulated tones.
Recordings were made from single neurons in the rat's ventral nucleus of the lateral lemniscus (VNLL) to determine responses to amplitude-modulated (AM) tones. The neurons were first characterized on the basis of their response to tone bursts presented to the contralateral ear and a distinction was made between those with transient onset responses and those with sustained responses. Sinusoidal AM tones were then presented to the contralateral ear with a carrier that matched the neuron's characteristic frequency (CF). Modulation transfer functions were generated on the basis of firing rate (MTF(FR)) and vector strength (MTF(VS)). Ninety-two percent of onset neurons that responded continuously to AM tones had band-pass MTF(FR)s with best modulation frequencies from 10 to 300 Hz. Fifty-four percent of sustained neurons had band-pass MTF(FR)s with best modulation frequencies from 10 to 500 Hz; other neurons had band-suppressed, all-pass, low-pass, or high-pass functions. Most neurons showed either band-pass or low-pass MTF(VS). Responses were well synchronized to the modulation cycle with maximum vector strengths ranging from 0.37 to 0.98 for sustained neurons and 0.78 to 0.99 for onset neurons. The upper frequency limit for response synchrony was higher than that reported for inferior colliculus, but lower than that seen in more peripheral structures. Results suggest that VNLL neurons, especially those with onset responses to tone bursts, are sensitive to temporal features of sounds and narrowly tuned to different modulation rates. However, there was no evidence of a topographic relation between dorsoventral position along the length of VNLL and best modulation frequency as determined by either firing rate or vector strength.


Craniosynostosis.
Skull deformity in infants continues to be a diagnostic and therapeutic challenge. Deformational plagiocephaly is a common and somewhat benign cause of skull deformity in infants that must be distinguished from the more serious craniosynostosis, which occurs alone or as a syndrome. Examining an infant's head from above can help the physician distinguish true lambdoid synostosis from deformational plagiocephaly. In infants with lambdoid synostosis, the posterior bossing is in the parietal area contralateral to the flat part of the head. Deformational plagiocephaly causes frontal bossing ipsilateral to the flat part of the head. In infants with lambdoid synostosis, the ear is displaced posteriorly toward the fused suture. In infants with deformational plagiocephaly, the ear is displaced anteriorly. Isolated sagittal synostosis is the most common type of craniosynostosis. Of the more than 150 craniosynostosis syndromes, Crouzon's disease and Apert's syndrome account for the majority of cases. The diagnosis of craniosynostosis relies on physical examination, plain radiography, and computed tomography. Untreated progressive craniosynostosis leads to inhibition of brain growth, and an increase in intracranial and intraorbital pressure. Infants should be evaluated as soon as they are diagnosed.


Serenoa repens extract additionally to quinolones in the treatment of chronic bacterial prostatitis. The preliminary results of a long term observational study.
Chronic prostatitis displays a variety of symptoms (mainly local pain exhibiting variability in origin and intensity). The purpose of this article is to briefly present the preliminary results of our study examining the role of phytotherapeutic agents in the treatment of chronic prostatitis patients. The study included in total fifty-six consecutive patients who visited the outpatient department. Subjects were randomized into two groups. Subjects in the first group (28 patients) received prulifloxacin 600 mg for 15 days, while subjects in the second group (28 patients) received prulifloxacin 600 mg for 15 days and Serenoa repens extract for 8 weeks. The response was tested using laboratory and clinical criteria. We found statistically significant differences between the two groups regarding pain regression and no statistically significant regarding bacterial eradication. Moreover however while sexual dysfunction improvement was equally achieved in both groups, improvement of urinary symptoms was more evident in the 2nd group especially after the completion of the antibiotic treatment. Serenoa repens extract for 8 weeks seems to improve prostatitis related pain. Further randomized, placebo-controlled studies are needed to substantiate safer conclusions.


Impact of alfuzosin on sexual function in Taiwanese men with benign prostatic hyperplasia.
To assess the effect of alfuzosin (XATRAL) 10 mg once daily on sexual function in men with moderate to severe lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH), patients with suggestive symptomatic BPH, an International Prostate Symptom Score (IPSS) >8 (range of scores, 0-35), and sexual attempts at least once per month were enrolled. All patients received alfuzosin 10 mg once daily for 24 weeks and were asked to complete the IPSS test and Male Sexual Health Questionnaire at weeks 0 (baseline), 1, 4, 12, and 24. Other assessments included the International Index of Erectile Function-five-item version (range of scores: 5-25), as well as onset of action and peak urinary flow rate (Q(max)). From September 2006 to May 2008, 279 patients were enrolled from nine centers in Taiwan. At 24 weeks, alfuzosin effectively improved LUTS and quality of life, as demonstrated by a reduction in the IPSS total score (17.3 vs. 9.9, p < 0.001) and the IPSS bother score (3.8 vs. 2.5, p < 0.001). The majority (85%) of patients perceived an improvement of urinary symptoms within 1 month of administration. In patients with an International Index of Erectile Function-five-item version score of ≤16, alfuzosin significantly improved erectile disorder and satisfaction subscores at each time point (p ≤ 0.02). Prolonged-release alfuzosin effectively improved LUTS, quality of life, erectile function, and sexual satisfaction in men with BPH and mild to severe erectile dysfunction. Alfuzosin is an effective treatment option for the management of patients with BPH/LUTS and concomitant sexual dysfunction.


17α-Ethinyl estradiol affects anxiety and shoaling behavior in adult male zebra fish (Danio rerio).
Ethinyl estradiol is a potent endocrine disrupting compound in fish and ubiquitously present in the aquatic environment. In this study, we exposed adult zebra fish (Danio rerio) males to 0, 5 or 25 ng Ethinyl estradiol/L for 14 days and analyzed the effects on non-reproductive behavior. Effects of treatment of the exposed males was shown by vitellogenin induction, while brain aromatase (CYP 19B) activity was not significantly altered. Both concentrations of Ethinyl estradiol significantly altered the behavior in the Novel tank test, where anxiety is determined as the tendency to stay at the bottom when introduced into an unfamiliar environment. The effects were, however, opposite for the two concentrations. Fish that were exposed to 5 ng/L had longer latency before upswim, fewer transitions to the upper half and shorter total time spent in the upper half compared with control fish, while 25 ng Ethinyl estradiol treatment resulted in shorter latency and more and longer visits to the upper half. The swimming activity of 25, but not 5 ng-exposed fish were slightly but significantly reduced, and these fish tended to spend a lot of time at the surface. We also studied the shoaling behavior as the tendency to leave a shoal of littermates trapped behind a Plexiglas barrier at one end of the test tank. The fish treated with Ethinyl estradiol had significantly longer latency before leaving shoal mates and left the shoal fewer times. Further, the fish exposed to 5 ng/L also spent significantly less time away from shoal than control fish. Fertilization frequency was higher in males exposed to 5 ng/L Ethinyl estradiol when compared with control males, while no spawning was observed after treatment with 25 ng/L. The testes from both treatment groups contained a normal distribution of spermatogenesis stages, and no abnormality in testis morphology could be observed. In conclusion, we have observed effects on two behaviors not related to reproduction in zebra fish males after treatment with Ethinyl estradiol, adding to the ecological consequences of contamination of aquatic environments with estrogenic substances.


Function of alternative splicing.
Alternative splicing is one of the most important mechanisms to generate a large number of mRNA and protein isoforms from the surprisingly low number of human genes. Unlike promoter activity, which primarily regulates the amount of transcripts, alternative splicing changes the structure of transcripts and their encoded proteins. Together with nonsense-mediated decay (NMD), at least 25% of all alternative exons are predicted to regulate transcript abundance. Molecular analyses during the last decade demonstrate that alternative splicing determines the binding properties, intracellular localization, enzymatic activity, protein stability and posttranslational modifications of a large number of proteins. The magnitude of the effects range from a complete loss of function or acquisition of a new function to very subtle modulations, which are observed in the majority of cases reported. Alternative splicing factors regulate multiple pre-mRNAs and recent identification of physiological targets shows that a specific splicing factor regulates pre-mRNAs with coherent biological functions. Therefore, evidence is now accumulating that alternative splicing coordinates physiologically meaningful changes in protein isoform expression and is a key mechanism to generate the complex proteome of multicellular organisms.


Evaluation of a Warning System for Early-Season Control of Grapevine Powdery Mildew.
In several grape-growing areas of the world, including northern Italy, powdery mildew epidemics, caused by Erysiphe necator, are mainly triggered by the ascospores produced in overwintered chasmothecia. Growers in northern Italy usually control the disease with fixed-interval fungicide applications. A warning system was developed for early-season powdery mildew control based on (i) short-term weather forecasts, (ii) a model that simulates the severity of each E. necator ascosporic infection, and (iii) a mobile phone short-message system. This warning system was evaluated in six vineyards in northern Italy from 2006 to 2008, between bud break of vines and early berry development; an unsprayed control was compared with "low-risk" and "high-risk" model-driven sprays and a calendar-based "grower" spray program. Use of the warning system reduced disease severity on leaves and bunches compared with the unsprayed control and resulted in the same level of control of powdery mildew as the grower's spray program, with reduced fungicide applications and costs. On average, 5.7 sprays were applied following the grower's spray program (with an average cost of 221 €/ha/year); use of the warning system reduced fungicide applications by 36% (low-risk program, saving of 56 €/ha/year) or 75% (high-risk program, saving of 161 €/ha/year).


Phylogenetic analysis of Bolivian bat trypanosomes of the subgenus schizotrypanum based on cytochrome B sequence and minicircle analyses.
The aim of this study was to establish the phylogenetic relationships of trypanosomes present in blood samples of Bolivian Carollia bats. Eighteen cloned stocks were isolated from 115 bats belonging to Carollia perspicillata (Phyllostomidae) from three Amazonian areas of the Chapare Province of Bolivia and studied by xenodiagnosis using the vectors Rhodnius robustus and Triatoma infestans (Trypanosoma cruzi marenkellei) or haemoculture (Trypanosoma dionisii). The PCR DNA amplified was analyzed by nucleotide sequences of maxicircles encoding cytochrome b and by means of the molecular size of hyper variable regions of minicircles. Ten samples were classified as Trypanosoma cruzi marinkellei and 8 samples as Trypanosoma dionisii. The two species have a different molecular size profile with respect to the amplified regions of minicircles and also with respect to Trypanosoma cruzi and Trypanosoma rangeli used for comparative purpose. We conclude the presence of two species of bat trypanosomes in these samples, which can clearly be identified by the methods used in this study. The presence of these trypanosomes in Amazonian bats is discussed.


[Immaturity of brain as an endophenotype of neuropsychiatric disorders].
Schizophrenia and bipolar disorder are severe neuropsychiatric disorders, affecting about 1% of the population. Identifying endophenotypes in the brains of neuropsychiatric patients is now considered the way to understand the underlying mechanisms and to improve therapeutic outcomes. However, the endophenotypes and brain mechanisms of the disorders remain unknown. We have previously reported that alpha-CaMKII heterozygous knockout mice show abnormal behaviors related to neuropsychiatric disorders. In these mutant mice, almost all neurons in the hippocampal dentate gyrus stay at a pseudo-immature state, which we refer to as "immature dentate gyrus (iDG)." So far, the iDG phenotype and similar behavioral abnormalities have been found in Schnurri-2 knockout, SNAP-25 mutant, and forebrain-specific calcineurin knockout mice. In addition, we found that both chronic fluoxetine treatment and pilocarpine-induced seizures can reverse the maturation state of the mature neurons, resulting in the iDG phenotype in wild-type mice. Such an iDG-like phenomenon was observed in the post-mortem brains from patients with schizophrenia/bipolar disorder. Recent studies suggest that cortex and amygdala of schizophrenia patients are also at a pseudo-immature state. Based on the findings, we proposed that immaturity of certain types of cells in the brain is a potential endophenotype of neuropsychiatric disorders.


Using Mobile Health Tools to Engage Rural Underserved Individuals in a Diabetes Education Program in South Texas: Feasibility Study.
Access to diabetes education and resources for diabetes self-management is limited in rural communities, despite higher rates of diabetes in rural populations compared with urban populations. Technology and mobile health (mHealth) interventions can reduce barriers and improve access to diabetes education in rural communities. Screening, Brief Intervention, and Referral to Treatment (SBIRT) and financial incentives can be used with mHealth interventions to increase the uptake of diabetes education; however, studies have not examined their combined use for diabetes self-management in rural settings. This two-phase Stage 1 feasibility study aimed to use a mixed methods design to examine the feasibility and acceptability of an mHealth diabetes education program combining SBIRT and financial incentives to engage rural individuals. In Phase 1, we aimed to develop, adapt, and refine the intervention protocol. In Phase 2, a 3-month quasi-experimental study was conducted with individuals from 2 rural communities in South Texas. Study participants were individuals who attended free diabetes screening events in their community. Those with low or medium risk received health education material, whereas those with high risk or those with a previous diagnosis of diabetes participated in motivational interviewing and enrolled in the 6-week mHealth Diabetes Self-Management Education Program under either an unconditional or aversion incentive contract. The participants returned for a 3-month follow-up. Feasibility and acceptability of the intervention were determined by the rate of participant recruitment and retention, the fidelity of program delivery and compliance, and the participant's satisfaction with the intervention program. Of the 98 screened rural community members in South Texas, 72 individuals met the study eligibility and 62 individuals agreed to enroll in the study. The sample was predominately female and Hispanic, with an average age of 52.6 years. The feedback from study participants indicated high levels of satisfaction with the mHealth diabetes education program. In the poststudy survey, the participants reported high levels of confidence to continue lifestyle modifications, that is, weight loss, physical activity, and diet. The retention rate was 50% at the 3-month follow-up. Participation in the intervention was high at the beginning and dissipated in the later weeks regardless of the incentive contract type. Positive changes were observed in weight (mean -2.64, SD 6.01; P<.05) and glycemic control index (-.30; P<.05) in all participants from baseline to follow-up. The finding showed strong feasibility and acceptability of study recruitment and enrollment. The participants' participation and retention were reasonable given the unforeseen events that impacted the study communities during the study period. Combining mHealth with SBIRT has the potential to reach individuals with need to participate in diabetes education in rural communities.


Angular and polarization response of multimode sensors with resistive-grid absorbers.
High-sensitivity receiver systems with near-ideal polarization sensitivity are highly desirable for development of millimeter and submillimeter radio astronomy. Multimoded bolometers provide a unique solution to achieve such sensitivity, for which hundreds of single-mode sensors would otherwise be required. The primary concern in employing such multimoded sensors for polarimetery is the control of the polarization systematics. In this work, we examine the angular- and polarization-dependent absorption pattern of a thin resistive grid or membrane, which models an absorber used for a multimoded bolometer. The result shows that a freestanding thin resistive absorber with a surface resistivity of η/2, where η is the impedance of free space, attains a beam pattern with equal E- and H-plane responses, leading to zero cross-polarization. For a resistive-grid absorber, the condition is met when a pair of grids is positioned orthogonal to each other and both have a resistivity of η/2. When a reflective backshort termination is employed to improve absorption efficiency, the cross-polar level can be suppressed below -30 dB if acceptance angle of the sensor is limited to ≲60°. The small cross-polar systematics have even-parity patterns and do not contaminate the measurements of odd-parity polarization patterns, for which many of the recent instruments for cosmic microwave background are designed. Underlying symmetry that suppresses these cross-polar systematics is discussed in detail. The estimates and formalism provided in this work offer key tools in the design consideration of the instruments using the multimoded polarimeters.


Discordant phylogeographic patterns between the Y chromosome and mitochondrial DNA in the house mouse: selection on the Y chromosome?
We have compared patterns of geographic variation and molecular divergence of mitochondrial DNA (mtDNA) and Y chromosome over the range of the different subspecies of Mus musculus. MtDNA was typed for 305 nucleotides in the control region, the Y chromosome for 834 base pairs (bp) in Zfy introns and 242 bp in Sry, a Zfy2 18-bp deletion, and two microsatellites. Apparent discrepancies exist between the distributions of the lineages of mtDNA and of the two major Y-chromosome lineages thus defined: some subspecies share the same mtDNA lineage but have different Y-chromosome lineages or vice versa. One microsatellite reveals a geographically clustered variation inside the distribution of each Y-chromosome lineage, showing that new Y-chromosome variants can rapidly spread locally. The two major Y-chromosome lineages have a divergence time only about one fourth of that between mtDNA lineages. Although this recent coalescence of the Y chromosomes between subspecies could partly be due to a lower ancestral polymorphism of the Y chromosome, it suggests that secondary introgression after the radiation of the subspecies might have occurred. There is evidence that the differentiation of the Y-chromosome lineages contributes to partial reproductive isolation between subspecies, and patterns of molecular evolution suggest that selection has played a role in the rapid spread across subspecies.


Acceptance of rapid HIV screening in a southeastern emergency department.
The objective was to assess the acceptance of an emergency department (ED) human immunodeficiency virus (HIV) screening program based on the Centers for Disease Control and Prevention (CDC) recommendations for routine HIV screening in health care settings. Rapid HIV screening was offered on an opt-out basis to patients aged 13 to 64 years presenting to the ED by trained HIV counselors. Patients were excluded if they had a history of HIV, were physically or mentally incapacitated, did not understand their right to opt-out, or did not speak English or Spanish. Statistical analyses, including logistic regression, were performed to assess the associations between the demographics of patients offered testing and their test acceptance or refusal. From March 2008 to January 2009, a total of 5,080 (91%) of the 5,585 patients offered the HIV test accepted, and 506 (9%) refused. White and married patients were less likely to accept testing than those who were African American and unmarried (p < 0.001). Adult patients were almost twice as likely to accept testing as pediatric patients (odds ratio [OR] = 1.95; 95% confidence interval [CI] = 1.50 to 2.53). As age increased among pediatric patients, testing refusal decreased (OR = 0.71; 95% CI = 0.59 to 0.85), and as age increased among adult patients, testing refusal increased (OR = 1.17; 95% CI = 1.12 to 1.22). Two percent of persons accepting the test were considered high risk. Males were more likely to report high-risk behavior than females (OR = 1.83; 95% CI = 1.23 to 2.72). The opt-out approach results in high acceptance of routine HIV screening. Widespread adoption of the CDC's recommendations, although feasible, will require significant increases in resources.


Frequency of bone mineral density testing in adult kidney transplant recipients from Ontario, Canada: a population-based cohort study.
We lack consensus on the clinical value, frequency, and timing of bone mineral density (BMD) testing in kidney transplant recipients. This study sought to determine practice patterns in BMD testing across kidney transplant centres in Ontario, Canada, and to compare the frequency of testing in kidney transplant recipients to non-transplant reference groups. Using healthcare databases from Ontario, Canada we conducted a population-based cohort study of adult kidney transplant recipients who received a transplant from 1994-2009. We used logistic regression to determine if there was a statistically significant difference across transplant centres in the decision to perform at least one BMD test after transplantation, adjusting for covariates that may influence a physician's decision to order a BMD test. We used the McNemar's test to compare the number of recipients who had at least one BMD test to non-transplant reference groups (matching on age, sex, and date of cohort entry). In the first 3 years after transplant, 4821 kidney transplant recipients underwent 4802 BMD tests (median 1 test per recipient, range 0 to 6 tests), costing $600,000 (2014 CAD equivalent dollars). Across the six centres, the proportion of recipients receiving at least one BMD test varied widely (ranging from 15.6 to 92.1 %; P < 0.001). Over half (58 %) of the recipients received at least one BMD test post-transplant, a value higher than two non-transplant reference groups (general population with a previous non-vertebral fracture [hip, forearm, proximal humerus], 13.8 %; general population with no previous non-vertebral fracture, 8.5 %; P value <0.001 for each of the comparisons). There is substantial practice variability in BMD testing after transplant. New high-quality information is needed to inform the utility, optimal timing, and frequency of BMD testing in kidney transplant recipients.


Cell competition corrects noisy Wnt morphogen gradients to achieve robust patterning in the zebrafish embryo.
Morphogen signalling forms an activity gradient and instructs cell identities in a signalling strength-dependent manner to pattern developing tissues. However, developing tissues also undergo dynamic morphogenesis, which may produce cells with unfit morphogen signalling and consequent noisy morphogen gradients. Here we show that a cell competition-related system corrects such noisy morphogen gradients. Zebrafish imaging analyses of the Wnt/β-catenin signalling gradient, which acts as a morphogen to establish embryonic anterior-posterior patterning, identify that unfit cells with abnormal Wnt/β-catenin activity spontaneously appear and produce noise in the gradient. Communication between unfit and neighbouring fit cells via cadherin proteins stimulates apoptosis of the unfit cells by activating Smad signalling and reactive oxygen species production. This unfit cell elimination is required for proper Wnt/β-catenin gradient formation and consequent anterior-posterior patterning. Because this gradient controls patterning not only in the embryo but also in adult tissues, this system may support tissue robustness and disease prevention.


Offset-free broadband Yb:fiber optical frequency comb for optical clocks.
We demonstrate a passively offset-frequency stabilized optical frequency comb centered at 1060 nm. The offset-free comb was achieved through difference frequency generation (DFG) between two portions of a supercontinuum based on a Yb:fiber laser. As the DFG comb had only one degree of freedom, repetition frequency, full stabilization was achieved via locking one of the modes to an ultra-stable continuous wave (CW) laser. The DFG comb provided sufficient average power to enable further amplification, using Yb-doped fiber amplifier, and spectral broadening. The spectrum spanned from 690 nm to 1300 nm and the average power was of several hundred mW, which could be ideal for the comparison of optical clocks, such as optical lattice clocks operated with Sr (698 nm) and Hg (1063 nm) reference atoms.


The landscape of nucleotide polymorphism among 13,500 genes of the conifer picea glauca, relationships with functions, and comparison with medicago truncatula.
Gene families differ in composition, expression, and chromosomal organization between conifers and angiosperms, but little is known regarding nucleotide polymorphism. Using various sequencing strategies, an atlas of 212k high-confidence single nucleotide polymorphisms (SNPs) with a validation rate of more than 92% was developed for the conifer white spruce (Picea glauca). Nonsynonymous and synonymous SNPs were annotated over the corresponding 13,498 white spruce genes representative of 2,457 known gene families. Patterns of nucleotide polymorphisms were analyzed by estimating the ratio of nonsynonymous to synonymous numbers of substitutions per site (A/S). A general excess of synonymous SNPs was expected and observed. However, the analysis from several perspectives enabled to identify groups of genes harboring an excess of nonsynonymous SNPs, thus potentially under positive selection. Four known gene families harbored such an excess: dehydrins, ankyrin-repeats, AP2/DREB, and leucine-rich repeat. Conifer-specific sequences were also generally associated with the highest A/S ratios. A/S values were also distributed asymmetrically across genes specifically expressed in megagametophytes, roots, or in both, harboring on average an excess of nonsynonymous SNPs. These patterns confirm that the breadth of gene expression is a contributing factor to the evolution of nucleotide polymorphism. The A/S ratios of Medicago truncatula genes were also analyzed: several gene families shared between P. glauca and M. truncatula data sets had similar excess of synonymous or nonsynonymous SNPs. However, a number of families with high A/S ratios were found specific to P. glauca, suggesting cases of divergent evolution at the functional level.


Analysis of balloon dilatation of human vein graft stenoses.
Controversy continues as to whether percutaneous transluminal angioplasty (PTA) or surgical revision is the ideal modality for the treatment of failing grafts. This prompted a histopathologic analysis of failing human vein graft segments subjected to ex vivo balloon dilatation to define variables responsible for the discrepant results. Fifteen vein graft lesions from 14 patients with failing infrainguinal bypasses were recovered after surgical excision. Each graft lesion was focal and uniform in length (2.1 +/- 0.3 cm). Rings sectioned from adjacent regions of each vein graft lesion before and after balloon inflation were processed for histologic study, photomicrography, and image analysis. Angioplasty balloon size was selected on the basis of preoperative arteriograms. Graft lesions were divided into three groups based on lesion thickness and the degree of fibrosis and cellularity seen on sections stained with Masson's trichrome. The luminal area before angioplasty was not significantly different for the three groups (p > 0.2). Vein grafts with thick intimas (group 1) had significantly less luminal dilatation after angioplasty as compared with less thick intimal lesions (groups 2 and 3; p < 0.001). Those lesions with varying degrees of cellularity (groups 2 and 3) showed no significant differences in luminal diameter after angioplasty. However, the cellular lesions in group 2 consistently formed multiple intimal flaps that could produce PTA failures even with good luminal restoration. The varying histology of vein graft lesions and associated differences in intimal thickness and cellularity may be responsible for the inconsistent results following PTA. Estimates of wall thickness before angioplasty, particularly in the intimal area, may be helpful in evaluating which lesions might benefit most from PTA.


Test-retest repeatability and relative validity of the Global Physical Activity Questionnaire in a developing country context.
The increasing prevalence of chronic lifestyle diseases in developing countries warrants reliable and valid surveillance of physical activity levels in the population. This study assesses the test-retest repeatability and criterion validity of the WHO-recommended Global Physical Activity Questionnaire (GPAQ) in Vietnamese adults during the dry and wet seasons. In 2007 a representative sample of 169 adults (25-64 years) was recruited to determine the GPAQ reliability and validity. GPAQ assesses time and intensity of physical activities spent during a usual week. To assess short and long term reliability, participants completed the GPAQ twice during the dry season 2 weeks apart and again 2 months later during the wet season. For validation purposes, participants wore an accelerometer during the 7 days before the first and last GPAQ assessments. The total GPAQ score showed repeatability correlations of 0.69 after 2 weeks and of 0.55 after 2 months. Total GPAQ score and accelerometer data showed validity correlations of 0.34 and 0.20 in the dry and wet season, respectively. There was a difference in physical activity patterns between the dry and wet seasons. GPAQ is suitable for surveillance of physical activity among adults in Vietnam.


This is the day your life must surely change : Prioritising behavioural change in musculoskeletal practice.
Behavioural change is the modification or transformation of behaviour. Health behaviour has been defined as, 'any activity undertaken for the purpose of preventing or detecting disease or for improving health and wellbeing' (Bennell et al., 2019 [1]). For a smoker it is acting on the decision to stop or reduce the number of cigarettes smoked, for someone with a higher than ideal body mass index, it is acting to reduce weight and for someone who isn't achieving ideal levels of exercise (Briggs et al., 2020 [2]) it is the decision and action to increase metabolic activity. With increased understanding of the importance of self-management and impact of lifestyle, clinicians supporting people presenting with musculoskeletal symptoms have recognized that behavioural change is an essential component of the care we need to prioritize. It is about sharing the benefits of lifestyle choices that promote health, discussing how to introduce and maintain them, and supporting people through their journey of change, so the change becomes the new normal. Behavioural change science assumes that (i) morbidity and mortality are due in part to certain behaviours and (ii) these behaviours are modifiable. The aim of this debate article is to discuss reasons why clinicians must include long term behavioural change into their management plan and methods they may use to facilitate the change ensuring recipients are empowered to act and make today the day their 'lives will surely change'.


A systems approach to analyze transcription factors in mammalian cells.
Transcription factors (TFs) play a central role in the development of multicellular organisms. The sequential actions of critical TFs direct cells to adopt defined differentiation pathways leading to functional, fully differentiated tissues. Here, we describe a generic experimental pipeline that integrates biochemistry, genetics and next generation sequencing with bioinformatics to characterize TF complexes composition, function and target genes at a genome-wide scale. We show an application of this experimental pipeline which aims to unravel the molecular events taking place during hematopoietic cell differentiation.


Proteomic profiling of intestinal prechylomicron transport vesicle (PCTV)-associated proteins in an animal model of insulin resistance (94 char).
Intestinal overproduction of apolipoprotein B (apoB)-48-containing chylomicrons is increasingly recognized as an underlying factor in metabolic dyslipidemia commonly observed in insulin-resistant states. Enhanced chylomicron assembly and secretion has been documented in animal models of insulin resistance, but the underlying mechanistic factors are unknown. Chylomicron assembly occurs through a series of complex vesicular interactions involving prechylomicron transport vesicles (PCTVs), which transport lipids from the endoplasmic reticulum (ER) to the Golgi. We report proteomic profiles of PCTVs isolated from the enteric ER in the small intestine of the fructose-fed hamster, an established model of diet-induced insulin resistance. Using 2D gel electrophoresis and tandem mass spectrometry, PCTVs were characterized and proteomic profiles of PCTV-associated proteins from insulin-resistant and control enterocytes were developed, with the intention of identifying proteins involved in insulin signaling attenuation and lipoprotein overproduction. A number of PCTV-associated proteins were found to be differentially expressed including microsomal triglyceride transfer protein (MTP), apoB-48, Sar1 and VAMP7. We postulate that altered expression of Sar1 and MTP may contribute to increased chylomicron assembly in the fructose-fed hamster. These findings have increased our understanding of the intracellular assembly and transport of nascent chylomicrons and potential cellular factors responsible for lipoprotein overproduction in insulin-resistant states.


Reporting of preclinical tumor-graft cancer therapeutic studies.
Characterize the parameters of reporting tumor-graft experiments for oncologic drug development. Using Institute of Scientific Information impact factors, we identified the most-cited medical and oncology journals with tumor-graft experiments in murine models. For each article, the characteristics of the experimental design, outcome measurements, and statistical analysis were examined. We examined 145 articles describing tumor-graft experiments from October through December 2008. The articles spanned a range of disease types, animal models, treatments and delivery methods. One hundred (69%) articles were missing information needed to replicate the experiments. Outcome measurements included: tumor size (83%), biological changes (57%), and survival or cure-rate outcomes (28%). Thirty-three percent did not specify how tumor size was measured and 30% were missing the formula for evaluating volume. Only 14% utilized appropriate statistical methods. Ninety-one percent of studies were reported as positive and 7% reported with mixed positive-negative results; only 2% of studies were reported negative or inconclusive. Twenty-two articles from 2012 showed improvement in the utilization of statistical methods (35% optimal, p = 0.05) but had a similar fraction with experimental design issues (82%; p = 0.32) limiting reproducibility and 91% had positive results. Tumor-graft studies are reported without a set standard, often without the methodological information necessary to reproduce the experiments. The high percentage of positive trials suggests possible publication bias. Considering the widespread use of such experiments for oncologic drug development, scientists and publishers should develop experimental and publication guidelines for such experiments to ensure continued improvements in reporting.


Impact of renin-angiotensin-aldosterone system inhibition on mortality in critically ill COVID-19 patients with pre-existing hypertension: a prospective cohort study.
The influence of renin-angiotensin-aldosterone system (RAAS) inhibitors on the critically ill COVID-19 patients with pre-existing hypertension remains uncertain. This study examined the impact of previous use of angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB) on the critically ill COVID-19 patients. Data from an international, prospective, observational cohort study involving 354 hospitals spanning 54 countries were included. A cohort of 737 COVID-19 patients with pre-existing hypertension admitted to intensive care units (ICUs) in 2020 were targeted. Multi-state survival analysis was performed to evaluate in-hospital mortality and hospital length of stay up to 90 days following ICU admission. A total of 737 patients were included-538 (73%) with pre-existing hypertension had received ACEi/ARBs before ICU admission, while 199 (27%) had not. Cox proportional hazards model showed that previous ACEi/ARB use was associated with a decreased hazard of in-hospital death (HR, 0.74, 95% CI 0.58-0.94). Sensitivity analysis adjusted for propensity scores showed similar results for hazards of death. The average length of hospital stay was longer in ACEi/ARB group with 21.2 days (95% CI 19.7-22.8 days) in ICU and 6.7 days (5.9-7.6 days) in general ward compared to non-ACEi/ARB group with 16.2 days (14.1-18.6 days) and 6.4 days (5.1-7.9 days), respectively. When analysed separately, results for ACEi or ARB patient groups were similar for both death and discharge. In critically ill COVID-19 patients with comorbid hypertension, use of ACEi/ARBs prior to ICU admission was associated with a reduced risk of in-hospital mortality following adjustment for baseline characteristics although patients with ACEi/ARB showed longer length of hospital stay. Clinical trial registration The registration number: ACTRN12620000421932; The date of registration: 30, March 2020; The URL of the registration: https://www.australianclinicaltrials.gov.au/anzctr/trial/ACTRN12620000421932 .


The link between mental rotation ability and basic numerical representations.
Mental rotation and number representation have both been studied widely, but although mental rotation has been linked to higher-level mathematical skills, to date it has not been shown whether mental rotation ability is linked to the most basic mental representation and processing of numbers. To investigate the possible connection between mental rotation abilities and numerical representation, 43 participants completed four tasks: 1) a standard pen-and-paper mental rotation task; 2) a multi-digit number magnitude comparison task assessing the compatibility effect, which indicates separate processing of decade and unit digits; 3) a number-line mapping task, which measures precision of number magnitude representation; and 4) a random number generation task, which yields measures both of executive control and of spatial number representations. Results show that mental rotation ability correlated significantly with both size of the compatibility effect and with number mapping accuracy, but not with any measures from the random number generation task. Together, these results suggest that higher mental rotation abilities are linked to more developed number representation, and also provide further evidence for the connection between spatial and numerical abilities.


Conservation of protein abundance patterns reveals the regulatory architecture of the EGFR-MAPK pathway.
Various genetic mutations associated with cancer are known to alter cell signaling, but it is not clear whether they dysregulate signaling pathways by altering the abundance of pathway proteins. Using a combination of RNA sequencing and ultrasensitive targeted proteomics, we defined the primary components-16 core proteins and 10 feedback regulators-of the epidermal growth factor receptor (EGFR)-mitogen-activated protein kinase (MAPK) pathway in normal human mammary epithelial cells and then quantified their absolute abundance across a panel of normal and breast cancer cell lines as well as fibroblasts. We found that core pathway proteins were present at very similar concentrations across all cell types, with a variance similar to that of proteins previously shown to display conserved abundances across species. In contrast, EGFR and transcriptionally controlled feedback regulators were present at highly variable concentrations. The absolute abundance of most core proteins was between 50,000 and 70,000 copies per cell, but the adaptors SOS1, SOS2, and GAB1 were found at far lower amounts (2000 to 5000 copies per cell). MAPK signaling showed saturation in all cells between 3000 and 10,000 occupied EGFRs, consistent with the idea that adaptors limit signaling. Our results suggest that the relative stoichiometry of core MAPK pathway proteins is very similar across different cell types, with cell-specific differences mostly restricted to variable amounts of feedback regulators and receptors. The low abundance of adaptors relative to EGFR could be responsible for previous observations that only a fraction of total cell surface EGFR is capable of rapid endocytosis, high-affinity binding, and mitogenic signaling.


Executive functions and prefrontal cortex: a matter of persistence?
Executive function is thought to originates from the dynamics of frontal cortical networks. We examined the dynamic properties of the blood oxygen level dependent time-series measured with functional MRI (fMRI) within the prefrontal cortex (PFC) to test the hypothesis that temporally persistent neural activity underlies performance in three tasks of executive function. A numerical estimate of signal persistence, the Hurst exponent, postulated to represent the coherent firing of cortical networks, was determined and correlated with task performance. Increasing persistence in the lateral PFC was shown to correlate with improved performance during an n-back task. Conversely, we observed a correlation between persistence and increasing commission error - indicating a failure to inhibit a prepotent response - during a Go/No-Go task. We propose that persistence within the PFC reflects dynamic network formation and these findings underline the importance of frequency analysis of fMRI time-series in the study of executive functions.


[The management of nephropathic patients during the Covid-19 pandemic: the experience of Ragusa].
The public emergency caused by Covid-19 has forced health services to reorganize in order to separate positive patients from negative ones. In nephrology, this reorganization involves several levels of assistance concerning hospitalizations, ambulatory care and haemodialysis. Within the Complex Unit of Nephrology in Ragusa, the distribution of nephro-dialytic resources has involved four different hospitals, hence ensuring haemodialysis services for asymptomatic and pauci-symptomatic Covid-19 patients as well as for patients in Covid-Unit, Sub-Intensive Therapy and Intensive Care Unit. In this complex context, we had to create a common protocol involving all the professionals who provide assistance in our Unit, across the different structures. We also report some encouraging data that seem to indicate the effectiveness of the protocols put in place.


Monitoring the newly qualified nurses in Sweden: the Longitudinal Analysis of Nursing Education (LANE) study.
The Longitudinal Analysis of Nursing Education (LANE) study was initiated in 2002, with the aim of longitudinally examining a wide variety of individual and work-related variables related to psychological and physical health, as well as rates of employee and occupational turnover, and professional development among nursing students in the process of becoming registered nurses and entering working life. The aim of this paper is to present the LANE study, to estimate representativeness and analyse response rates over time, and also to describe common career pathways and life transitions during the first years of working life. Three Swedish national cohorts of nursing students on university degree programmes were recruited to constitute the cohorts. Of 6138 students who were eligible for participation, a total of 4316 consented to participate and responded at baseline (response rate 70%). The cohorts will be followed prospectively for at least three years of their working life. Sociodemographic data in the cohorts were found to be close to population data, as point estimates only differed by 0-3% from population values. Response rates were found to decline somewhat across time, and this decrease was present in all analysed subgroups. During the first year after graduation, nearly all participants had qualified as nurses and had later also held nursing positions. The most common reason for not working was due to maternity leave. About 10% of the cohorts who graduated in 2002 and 2004 intended to leave the profession one year after graduating, and among those who graduated in 2006 the figure was almost twice as high. Intention to leave the profession was more common among young nurses. In the cohort who graduated in 2002, nearly every fifth registered nurse continued to further higher educational training within the health professions. Moreover, in this cohort, about 2% of the participants had left the nursing profession five years after graduating. Both high response rates and professional retention imply a potential for a thorough analysis of professional practice and occupational health.


Performance based financing and job satisfaction in a semiurban health district in Cameroon.
The performance based financing approach is being tested in four regions of Cameroon, including the Littoral region. Our study aimed to study the effects associated with the implementation of the performance based financing approach within the health facilities based in the health district of Edea in the Littoral region in Cameroon. We've carried out a crosssectional analytical study among 178 health personnel from 21 health facilities under PBF-contract within the health district of Edea. We have studied their sociodemographic characteristics, the individual and collective effects resulting from the performance based financing subsidies and the level of job satisfaction. Participants' job satisfaction was measured with the French version of the Minnesota satisfaction scale. The results were presented in a descriptive and analytical form at the alpha = 5% and the P-value 5%. We recruited 113 women and 65 men. The mean age was 39.19 ± 8.95 years. The individual results of the performance based financing were the regular collection of subsidies between F CFA 20-40.000 (42.1%), the improvement of working conditions (74.2%) and living conditions (67.4%) and the acquisition of new skills (69.7%). Collectively, participants confirmed the increase of the users attendance (65.7%), the improvement of the internal organization (79.8%), the purchase of new equipment (84.3%) and the improved quality of health care (86%). Satisfaction is influenced by age (P=0.016), gender (P=0.01), occupational category (P=0.04), type of health facility (P=0.02) and the amount of subsidies (P=0.03). The healthcare personnel's were satisfied with the improvement of their social conditions (66.67%), working conditions (62.88%), the transparency in health centers management (69%) and their involvement in the health centers' functioning (76.6%). Participants were dissatisfied with their salaries (70.2%) and the lack of opportunities for advancement (47.8%). The positive effects of the performance based financing approach contributed to the job satisfaction of the healthcare workers in the Edea health district. These results should prompt the government to extend the performance based financing approach to communities and other health districts in Cameroon.


European population substructure correlates with systemic lupus erythematosus endophenotypes in North Americans of European descent.
Previous work has demonstrated that Northern and Southern European ancestries are associated with specific systemic lupus erythematosus (SLE) manifestations. In this study, 1855 SLE cases of European descent were genotyped for 4965 single-nucleotide polymorphisms and principal components analysis of genotype information was used to define population substructure. The first principal component (PC1) distinguished Northern from Southern European ancestry, PC2 differentiated Eastern from Western European ancestry and PC3 delineated Ashkenazi Jewish ancestry. Compared with Northern European ancestry, Southern European ancestry was associated with autoantibody production (odds ratio (OR)=1.40, 95% confidence interval (CI) 1.07-1.83) and renal involvement (OR 1.41, 95% CI 1.06-1.87), and was protective for discoid rash (OR=0.51, 95% CI 0.32-0.82) and photosensitivity (OR=0.74, 95% CI 0.56-0.97). Both serositis (OR=1.46, 95% CI 1.12-1.89) and autoantibody production (OR=1.38, 95% CI 1.06-1.80) were associated with Western compared to Eastern European ancestry. Ashkenazi Jewish ancestry was protective against neurologic manifestations of SLE (OR=0.62, 95% CI 0.40-0.94). Homogeneous clusters of cases defined by multiple PCs demonstrated stronger phenotypic associations. Genetic ancestry may contribute to the development of SLE endophenotypes and should be accounted for in genetic studies of disease characteristics.