Could neonatal disseminated herpes simplex virus infections be treated earlier?
Neonatal disseminated herpes simplex virus (HSV) infection can cause rapidly progressive multiple organ failure with an 85% mortality if untreated. Early recognition and treatment may improve outcome [N Engl J Med 324(1991)450]. (i) To determine the number and presentation of neonates with disseminated HSV admitted to an intensive care unit. (ii) To determine paediatric Specialist Registrar (SpR) awareness of the diagnosis and management of a typical potential case of neonatal disseminated HSV. (i) A 10-year review of case notes of neonates admitted to the intensive care unit (ICU) at Great Ormond Street Hospital. (ii) A telephone questionnaire of 'on-call' Paediatric SpR's in the London area. Eight cases of confirmed disseminated HSV infection were identified. All died. Each case followed a similar clinical course with presentation between days 5-9 of life (median day 7). A short prodrome preceded the rapid development of disseminated intravascular coagulopathy (DIC), hepatitis and multiple organ failure. Only three cases received antiviral treatment in the first 24 h after hospital admission. None of the 30 registrars who were interviewed initially considered disseminated HSV in the differential diagnosis of a 7-day-old baby presenting with non-specific signs of sepsis. Only 4/30 referring unit protocols included disseminated HSV in the differential diagnosis of neonatal sepsis. HSV infection should be considered in the differential diagnosis of the acutely unwell neonate. This condition is rare but well documented in the literature. Effective antiviral therapies exist but are often not started early in the clinical course. Awareness of this condition needs to be increased.


Effects of cone adaptation on variability in S-cone increment thresholds.
Short-wavelength automated perimetry (SWAP) has gained popularity as a clinical tool for the assessment of short-wavelength-sensitive (S)-cone visual function, but has also been shown to have higher threshold variability than conventional achromatic perimetry, possibly due to an imbalance between S-cone adaptation and long (L)- and medium (M)-wavelength-sensitive cone adaptation. To investigate potential causes for this relatively high variability, we studied the effects of luminance and S-cone adaptation on variability in S-cone increment thresholds. Foveal S-cone increment thresholds were measured on adapting backgrounds ranging from 1.17 to 4.17 log troland (Td) and from -0.16 to 3.66 log S-cone trolands (Td(S)). Within-session variability (slope of the psychometric function) was evaluated in 2 trained and 15 inexperienced normal observers. Test-retest variability was evaluated in the 2 trained observers, and interobserver variability in the group of 15 observers. Multiple linear regression was used to model the effects of log luminance, log S-cone adaptation, and second-site polarization (ratio of luminance and S-cone adaptation; log [Td/Td(S)]). Test-retest variability was lower for conditions with higher levels of S-cone adaptation (F = 9.04, P = 0.013, for the trained observers). Adaptation conditions with lower levels of polarization were associated with lower within-session variability (F = 6.9, P = 0.011; trained observers) and interobserver variability (F = 33.7, P = 0.004; group of 15 observers). Variability of S-cone increment thresholds can be reduced by using adaptation conditions with a higher level of S-cone adaptation and/or a more balanced ratio between luminance and S-cone adaptation than is used for SWAP.


Polyaniline nanofibers: broadening applications for conducting polymers.
Polyaniline is a conducting polymer with incredible promise, but it has had limited use due to poor reaction control and processability associated with conventional morphologies. Polyaniline nanofibers, on the other hand, have demonstrated, through manufacturing techniques discovered during the past decade, increased processability, higher surface area, and improved consistency and stability in aqueous dispersions, which are finally allowing for expanded commercial development of this promising polymer. This review explores some intriguing applications of polyaniline nanofibers, as well as the advantages and remaining challenges in developing better products using polyaniline in this new morphology.


Are there rapid feedback effects on Approximate Number System acuity?
Humans are believed to be equipped with an Approximate Number System (ANS) that supports non-symbolic representations of numerical magnitude. Correlations between individual measures of the precision of the ANS and mathematical ability have raised the question of whether the precision can be improved by feedback training. A study (DeWind and Brannon, 2012) reported improvement in discrimination precision occurring within 600-700 trials of feedback, suggesting ANS malleability with rapidly improving acuity in response to feedback. We tried to replicate the rapid improvement in a control group design, while controlling for the use of perceptual cues. The results indicate no learning effects, but a minor constant advantage for the feedback group. The measures of motivation suggest that feedback has a positive effect on motivation and that the difference in discrimination is due to the greater motivation of participants with feedback. These results suggest that at least for adults the number sense may not respond to feedback in the short-term.


[The influence of the social net of lactating mothers in the breastfeeding: the strategic role of the relatives and professionals of health].
The objective was to raise and classify scientific works on the influence of the social net of lactating mothers in the context of the breastfeeding. A bibliographical review was done in the main databases (MEDLINE, LILACS, SciELO), using as keywords: breastfeeding, weaning and family (and their versions in English and Spanish). Books, thesis, dissertations, and publications in international and national institutions were consulted (WHO, UNICEF, Ministry of Health). It could be observed that the actors that compose the social net of the lactating mothers can interfere in the decision of breastfeeding, through different extents, such as the encouragement/support to the initiative; reviewing the knowledge and cultural values; family tradition; and the cultivation of the indifference/discourage and the pressure exercised on the lactating mothers in relation to the form of feeding the child. In this way, it can infer on the need of the implementation of new health practices regarding to the care of this group. It is worth to highlight, the importance of the professionals to be qualified for the sensitive listening on the meaning of the nursing under the glance of the lactating mothers . Finally, it stands out the importance role of the social net of the lactating mothers, especially the family, for a successful breastfeeding.


Estimating the prevalence of breast cancer using a disease model: data problems and trends.
BACKGROUND: Health policy and planning depend on quantitative data of disease epidemiology. However, empirical data are often incomplete or are of questionable validity. Disease models describing the relationship between incidence, prevalence and mortality are used to detect data problems or supplement missing data. Because time trends in the data affect their outcome, we compared the extent to which trends and known data problems affected model outcome for breast cancer. METHODS: We calculated breast cancer prevalence from Dutch incidence and mortality data (the Netherlands Cancer Registry and Statistics Netherlands) and compared this to regionally available prevalence data (Eindhoven Cancer Registry, IKZ). Subsequently, we recalculated the model adjusting for 1) limitations of the prevalence data, 2) a trend in incidence, 3) secondary primaries, and 4) excess mortality due to non-breast cancer deaths. RESULTS: There was a large discrepancy between calculated and IKZ prevalence, which could be explained for 60% by the limitations of the prevalence data plus the trend in incidence. Secondary primaries and excess mortality had relatively small effects only (explaining 17% and 6%, respectively), leaving a smaller part of the difference unexplained. CONCLUSION: IPM models can be useful both for checking data inconsistencies and for supplementing incomplete data, but their results should be interpreted with caution. Unknown data problems and trends may affect the outcome and in the absence of additional data, expert opinion is the only available judge.


Public policy governing organ and tissue procurement in the United States. Results from the National Organ and Tissue Procurement Study.
To determine why Required Request policies, which mandate that hospitals request donation from donor-eligible families, have not resulted in increased organ procurement. Stratified sample of 23 acute-care general hospitals in two metropolitan areas. Chart review identified all eligible donors in study hospitals during a 20-month period. Health care professionals who spoke with the families of eligible donors after death were interviewed to determine families' and health care providers' behaviors after patients' deaths with reference to the donation process. All patient deaths (n = 10,681) were reviewed, and 841 donor-eligible cases were chosen for in-depth study; 1809 health care professionals who provided care to these patients were interviewed. The ability of health care providers to identify donor-eligible patients, approach families about donation, and obtain families' consent to donation. 83% of health care professionals correctly identified donor-eligible patients. The families of donor-eligible patients were approached about donation in 73.0% of the cases. Families were more likely to be approached about organ (86.6%) donation than either tissue (69.5%) or cornea (67.3%) donation (P < 0.001). The families of organ-eligible patients were less likely to be approached if the patient was female, was on a general medical or surgical floor, or was being cared for by internists. Only 46.5% of families of eligible donors agreed to donate organs, 34.5% agreed to donate tissues, and 23.5% agreed to donate corneas. Although health care professionals do request that families donate, families consent to donation less frequently than was previously assumed. Empirically based education campaigns are needed so that health care professionals can improve their communication skills and so that discussion about this important issue can be stimulated among family members.


Prefrontal neuronal assemblies temporally control fear behaviour.
Precise spike timing through the coordination and synchronization of neuronal assemblies is an efficient and flexible coding mechanism for sensory and cognitive processing. In cortical and subcortical areas, the formation of cell assemblies critically depends on neuronal oscillations, which can precisely control the timing of spiking activity. Whereas this form of coding has been described for sensory processing and spatial learning, its role in encoding emotional behaviour remains unknown. Fear behaviour relies on the activation of distributed structures, among which the dorsal medial prefrontal cortex (dmPFC) is known to be critical for fear memory expression. In the dmPFC, the phasic activation of neurons to threat-predicting cues, a spike-rate coding mechanism, correlates with conditioned fear responses and supports the discrimination between aversive and neutral stimuli. However, this mechanism does not account for freezing observed outside stimuli presentations, and the contribution of a general spike-time coding mechanism for freezing in the dmPFC remains to be established. Here we use a combination of single-unit and local field potential recordings along with optogenetic manipulations to show that, in the dmPFC, expression of conditioned fear is causally related to the organization of neurons into functional assemblies. During fear behaviour, the development of 4 Hz oscillations coincides with the activation of assemblies nested in the ascending phase of the oscillation. The selective optogenetic inhibition of dmPFC neurons during the ascending or descending phases of this oscillation blocks and promotes conditioned fear responses, respectively. These results identify a novel phase-specific coding mechanism, which dynamically regulates the development of dmPFC assemblies to control the precise timing of fear responses.


Distribution and genetic structure of Aedes japonicus japonicus populations (Diptera: Culicidae) in Germany.
In recent years, the number of imported cases of arthropod-borne diseases in Europe, such as dengue fever, has increased steadily, as did the emergence and distribution of invasive insect vectors. Consequently, the risk of disease spreading into previously unaffected regions through invasive mosquitoes is also increasing. One example of an invasive mosquito is Aedes japonicus japonicus (A. j. japonicus), which spread from its original habitat in Japan to North America and Europe. This species has been shown to act as a vector for Japanese encephalitis and West Nile viruses. In Europe, A. j. japonicus has been detected in Switzerland, Belgium, Slovenia, and Germany, where it has become a resident species. Here, we describe the recent spread and genetic structure of A. j. japonicus populations in Germany. By monitoring the species in Baden-Württemberg in 2011 and 2012, we observed a considerable enlargement of the infested area from 54 municipalities in 2011 to 124 municipalities in 2012. To elucidate the colonization of Europe by A. j. japonicus, seven microsatellite loci were studied in 106 individuals sampled in Germany and Switzerland in 2012. The same markers were genotyped in 31 North American and 26 Japanese specimens. Population genetic analyses indicated that A. j. japonicus in Baden-Württemberg and North Rhine-Westphalia represented two genetically distinct populations with FST-values of 0.073-0.152, suggesting that they originated from two independent introduction events in the past. These results are of particular interest in light of vectorial variability for the transmission of viruses and other pathogens in Europe.


Composite cavity fiber laser sensors based on weak feedback.
A novel composite cavity optical fiber laser (CCFL) sensor, based on weak feedback of the optical fiber end face, is proved theoretically and experimentally. The application of the vibration measurement based on the CCFL sensor is demonstrated to prove its feasibility.


Recent insights into the immunopathogenesis of psoriasis provide new therapeutic opportunities.
Chronic and excessive inflammation in skin and joints causes significant morbidity in psoriasis patients. As a prevalent T lymphocyte-mediated disorder, psoriasis, as well as the side effects associated with its treatment, affects patients globally. In this review, recent progress is discussed in the areas of genetics, the immunological synapse, the untangling of the cytokine web and signaling pathways, xenotransplantation models, and the growing use of selectively targeted therapies. Since psoriasis is currently incurable, new management strategies are proposed to replace previous serendipitous approaches. Such strategic transition from serendipity to the use of novel selective agents aimed at defined targets in psoriatic lesions is moving rapidly from research benches to the bedsides of patients with this chronic and debilitating disease.


HEREDITARY ENDOCRINE TUMOURS: CURRENT STATE-OF-THE-ART AND RESEARCH OPPORTUNITIES: MEN1-related pancreatic NETs: identification of unmet clinical needs and future directives.
The PanNET Working Group of the 16th International Multiple Endocrine Neoplasia Workshop (MEN2019) convened in Houston, TX, USA, 27-29 March 2019 to discuss key unmet clinical needs related to PanNET in the context of MEN1, with a special focus on non-functioning (nf)-PanNETs. The participants represented a broad range of medical scientists as well as representatives from patient organizations, pharmaceutical industry and research societies. In a case-based approach, participants addressed early detection, surveillance, prognostic factors and management of localized and advanced disease. For each topic, after a review of current evidence, key unmet clinical needs and future research directives to make meaningful progress for MEN1 patients with nf-PanNETs were identified. International multi-institutional collaboration is needed for adequately sized studies and validation of findings in independent datasets. Collaboration between basic, translational and clinical scientists is paramount to establishing a translational science approach. In addition, bringing clinicians, scientists and patients together improves the prioritization of research goals, assures a patient-centered approach and maximizes patient involvement. It was concluded that collaboration, research infrastructure, methodologic and reporting rigor are essential to any translational science effort. The highest priority for nf-PanNETs in MEN1 syndrome are (1) the development of a data and biospecimen collection architecture that is uniform across all MEN1 centers, (2) unified strategies for diagnosis and follow-up of incident and prevalent nf-PanNETs, (3) non-invasive detection of individual nf-PanNETs that have an increased risk of metastasis, (4) chemoprevention clinical trials driven by basic research studies and (5) therapeutic targets for advanced disease based on biologically plausible mechanisms.


Orchard Sports Injury Classification System 10.1 Plus: An End-User Study.
The purpose of this study was to establish the level of ease of use and effectiveness of the Orchard Sport Injury Classification System (OSICS) 10.1 Plus for recording injuries and interventions. Three hundred and forty-two (males=148, females=192, no response=2; age=30.9±9.5y; experience=9.1±10.5y) athletic trainers (ATs) in the United States completed the survey. Participants were primarily employed in the secondary school (n=135) or collegiate setting (n=171). Participants entered system includes the OSICS 10.1 to catalog injuries and Current Procedural Terminology (CPT) codes to document interventions. Participants completed an 18-item end-user evaluation to assess the ease of use and effectiveness of the OSICS 10.1 Plus (5-point Likert scale). Participants indicated that the OSICS 10.1 Plus is overall easy to use (4.1±0.7pts), easy to enter an injury (4.1±0.8pts), and easy to enter the associated interventions (3.9±0.8pts). Respondents were neutral about whether the OSICS 10.1 Plus matched their current injury (3.5±1.0pts) or intervention (3.5±0.9pts) records. A majority of participants indicated that they could find the injury (281/342, 82.2%) and interventions (225/342, 65.8%) of interest. A majority of respondents (205/342, 60.0%) indicated they would consider using OSICS 10.1 Plus for injury surveillance in clinical practice. The OSICS 10.1 Plus could serve as an effective and useful mechanism for injury surveillance with minor modifications; however, we, as professionals in sports healthcare, need to improve regular medical documentation first so that we are better able to conduct injury surveillance among our patients.


Enhanced discriminability for nonbiological motion violating the two-thirds power law.
The two-thirds power law describes the relationship between velocity and curvature in human motor movements. Interestingly, this motor law also affects visual motion perception, in which stimuli moving according to the two-thirds power law are perceived to have a constant velocity compared to stimuli actually moving at constant velocity. Thus, visual motion adhering to biological motion principles causes a kinematic illusion of smooth and velocity-invariant motion. However, it is yet unclear how this motion law affects the discrimination of visual stimuli and if its encoding requires attention. Here we tested the perceptual discrimination of stimuli following biological (two-thirds power law) or nonbiological movement under conditions in which the stimuli were degraded or masked through continuous flash suppression. Additionally, we tested subjective perception of naturalness and velocity consistency. Our results show that the discriminability of a visual target is inversely related to the perceived "naturalness" of its movement. Discrimination of stimuli following the two-thirds power law required more time than the same stimuli moving at constant velocity or nonecological variants of the two-thirds power law and was present for both masked and degraded stimuli.


Cortisol dynamics are associated with electrocardiographic abnormalities following the aneurysmal subarachnoid hemorrhage.
Electrocardiographic (ECG) abnormalities are common following subarachnoid hemorrhage (SAH). It probably represents cardiovascular stress after SAH. The purpose of this study was to assess cortisol dynamics in relation to the ECG abnormality and disease course of SAH. The study follows a consecutive cohort of aneurysmal SAH patients, who underwent surgery within 72 hours of onset, and they were followed up for 10 days. Serum cortisols, cortisol-binding globulin (CGB), adenocorticotropic hormone were measured (between 08.00-09.00 hours) preoperatively and then on postoperative days (PODs) 2, 4, 7, and 10. Electrocardiographs (ECG) were recorded on initial assessment and after surgery on daily basis in ICU. ECG abnormalities will be followed up by measurement of cardiac troponin T to quantify the myocyte necrosis. Logistic regression analysis using commercial available software STATA 9. A total of 44 patients (20 M and 24 F) were eligible for the cohort analysis. Average patient age is 52.02 years (52.02 ± 11.23), and 86% (6/44) arrived with World Federation of Neurosurgical Society Scale grade 3 or better. The ECG abnormality was found in 10 cases (22.7%), but the abnormal TnT (>1 μg/l) were found in eight cases, and two cases contribute to the mortality. The ECG abnormalities are significantly associated with total cortisol on day 4 (P < 0.05) and free cortisol on day 2 (P = 0.0065). Elevated levels of morning cortisol within the first four days after surgery are associated with the ECG abnormality.


The MED7 subunit paralogs of Mediator function redundantly in development of etiolated seedlings in Arabidopsis.
MED7 is a subunit of the Mediator middle module and is encoded by two paralogs in Arabidopsis. We generated MED7 silenced lines using RNAi to study its impact on Arabidopsis growth and development. Compared with wild type, etiolated seedlings of the MED7 silenced lines exhibited reduced hypocotyl length caused by reduced cell elongation when grown in the dark. The hypocotyl length phenotype was rescued by exogenously supplied brassinosteroid. In addition, MED7 silenced seedlings exhibited defective hook opening in the dark as well as defective cotyledon expansion in the presence of the brassinosteroid inhibitor brassinazole. Whole transcriptome analysis on etiolated seedlings using RNA sequencing revealed several genes known to be regulated by auxin and brassinosteroids, and a broad range of cell wall-related genes that were differentially expressed in the MED7 silenced lines. This was especially evident for genes involved in cell wall extension and remodeling, such as EXPANSINs and XTHs. Conditional complementation with each MED7 paralog individually restored the hypocotyl phenotype as well as the gene expression defects. Additionally, conditional expression of MED7 had no effects that were independent of the Mediator complex on the observed phenotypes. We concluded that the MED7 paralogs function redundantly in regulating genes required for the normal development of etiolated Arabidopsis seedlings.


Baseline staging of newly diagnosed prostate cancer: a summary of the literature.
Staging for prostate cancer often includes bone scanning and computerized tomography (CT). We systematically reviewed the published evidence for these tests. We searched MEDLINE for articles on these investigations in newly diagnosed cases of prostate cancer. Data were pooled based on prostate specific antigen (PSA), grade and tumor stage. Among 23 studies examining the role of bone scan metastases were detected in 2.3%, 5.3% and 16.2% of patients with PSA levels less than 10, 10.1 to 19.9 and 20 to 49.9 ng/ml, respectively. Scanning detected metastases in 6.4% of men with organ confined cancer and 49.5% with locally advanced disease. Detection rates were 5.6% and 29.9% for Gleason scores 7 or less and 8 or greater, respectively. Among 25 studies CT documented lymphadenopathy in 0 and 1.1% of patients with PSA less than 20 and 20 ng/ml or greater, respectively. CT detection rate was 0.7% and 19.6% in patients with localized and locally advanced disease, respectively. Detection rates in patients with Gleason scores 7 or less and 8 or greater were 1.2% and 12.5%, respectively. These risks were typically much greater on pathological evaluation. Patients with low risk prostate cancer are unlikely to have metastatic disease documented by bone scan or CT. Therefore, these investigations should not be standard practice. However, patients with PSA 20 ng/ml or greater, locally advanced disease, or Gleason score 8 or greater are at higher risk for bone metastases and should be considered for bone scan. CT may be useful in patients with locally advanced disease or Gleason score 8 or greater but appears not to be of benefit in patients with increased PSA alone.


Functional inhibition of retinal pigment epithelial cell-substrate adhesion with a monoclonal antibody against the beta 1 subunit of integrin.
In the preceding report, experiments were described which identify the 2A10 antigen of retinal pigment epithelial (RPE) cells as a beta 1 subunit of the cell-surface extracellular matrix receptor protein integrin. In this article, experiments are presented which use the 2A10 and CSAT antibodies, both directed against the beta 1 subunit, to investigate the role of integrin in RPE and fibroblast (FB) cell-substrate adhesion. When added to cultures simultaneously with cells, either the 2A10 or CSAT antibodies inhibit both FB and RPE cell adhesion and spreading on laminin (LM). However, although the 2A10 antibody blocks adhesion and spreading of FB and RPE cells on fibronectin (FN), the CSAT antibody has no effect. The inhibition of the 2A10 antibody is specific for integrin-mediated adhesion; it does not affect FB or RPE cell adhesion and spreading on tissue-culture plastic. When RPE cells are first allowed to attach to and spread on FN and LM and then the 2A10 or CSAT antibody is added to the cultures, both cause detachment and rounding of RPE cells from LM, but neither has any effect on the cells already spread on FN. These results indicate that there are differences in the way FB and RPE cells interact with LM and FN. Furthermore, these results provide the first direct functional demonstration that RPE cell-substrate adhesion is mediated by integrin.


Toxicological comments to the discussion about REACH.
It is the ultimate goal of the intended REACH process (Registration, Evaluation and Authorization of Chemicals) of the European Union to identify substances of hazardous properties and to evaluate the risks of human and environmental exposure. During the last few months there has been a controversial discussion as to what extent in vitro studies and consideration of structure activity relationship provide sufficient information to waive repeated exposure studies. Industry as well as certain regulatory agencies or NGOs support this approach and propose that repeated dose studies may only be required beyond 100 t/a. From a toxicological point of view it has to be stressed that this discussion primarily considers the cost reduction and protection of animals, whereas protection of human health and the environment are secondary. In vitro studies only allow identification of specific hazardous properties which can be detected by the specific test system. Moreover, appropriate information on the dose response of adverse effects, identification of thresholds and NOELs that are essential for risk characterization cannot be obtained from these studies. Consequently, identification of all relevant hazardous properties and endpoints of adverse effects can only be determined in the intact animal by repeated dose studies such as 28-day or 90-day studies. In the absence of such information the hazard identification is incomplete and there is no basis for appropriate risk assessment of human exposure. Thus, any waiving of repeated dose studies in animals bears the probability of unforeseen effects in case of acute or continuous human exposure. From this the undersigning European Toxicologists conclude: 1. The intention of REACH is to identify hazardous properties in order that a reliable risk assessment can be made and measures taken to deal with chemicals posing a significant risk. 2. The recent debate has centered on ways in which the well established in vivo methods for risk assessment can be bypassed. 3. The evidence that the available alternatives would support such replacement is weak. Progress to improve their value for risk assessment purposes is bound to be slow because the issues are very complex. As a group of European Toxicologists we strongly support the need for more research support in these areas, but we believe that over claims for progress is damaging their development. 4. Under the circumstances only two options are available: to reduce very substantially the estimation of hazard and risk with inevitable adverse consequences for human health and environmental protection, or to continue the existing methods until properly validated new methods are available.


Performance of Pediatrics' residents as clinical teachers: A student-based assessment.
To assess the clinical teaching skills of Pediatrics' residents as rated by final year MBBS students by using augmented Stanford Faculty Development Program questionnaire (SFDPQ) in a teaching hospital, Lahore. This cross- sectional survey was conducted in the Department of Pediatrics, King Edward Medical University, Lahore in six months in 2016.Total of 265 students of final year MBBS, attending the teaching sessions organized by residents during their four weeks rotation in Pediatrics were included by non-probability purposive sampling. The augmented SFDPQ was emailed to the study participants after the completion of the clinical rotation, following several encounters with the resident. The data was entered in SPSS 22 for statistical analysis. Scores for each domain (learning climate, control of session, communication of goals, promoting understanding and retention, evaluation, promoting self-directed learning, teacher's knowledge and teacher's attitude) were also presented as mean and standard deviation. One-sample Kolmogorov-Smirnov test was applied to observe the normality of data. Where normality of data was observed, independent sample t-test was applied and where normality of data was not observed, Mann-Whitney U test was applied to compare the score between genders. Score of four was considered as cut off score for satisfactory results. Out of 265 students, 250 responded with response rate of 94.3%. Out of 250 medical students, 105 (42.0%) were male and 145(58.0%) were female. The internal consistency (Cronbach's alpha) of this score was excellent (0.973). The mean score for all SFDPQ domains was also sub-optimal (2.90±0.611). The mean total score was sub-optimal for learning climate (3.39±0.69), control of session (3.25±0.77), communication of goals (3.26±0.86), promoting understanding and retention (3.26±0.77), evaluation (2.25±0.67), promoting self-directed learning (3.17±0.90), teacher's knowledge (3.14±0.93) and teacher's attitude (3.31±0.89), while it was good only for feedback (4.03±0.11). The mean total score for all SFDPQ domains in males and females was 3.05±0.54 and 2.79±0.64 respectively. Although sub-optimal in both the genders, the score was significantly higher in males with p-value 0.001. We found suboptimal clinical teaching skills of Pediatrics' residents as rated by final year MBBS medical students.


An Out-of-Pocket Cost Removal Intervention on Fecal Occult Blood Test Attendance.
To date, no comparative study has assessed the impact of a cost-removal intervention on fecal occult blood testing (FOBT). In 2012, the Japanese government introduced a nationwide project to remove out-of-pocket costs for FOBT. The study objective was to evaluate the differential impact of the intervention on FOBT attendance in the total population and various subgroups. This study analyzed 309,103 people in national, repeated cross-sectional studies, observed pre- and post-intervention (2010 and 2013), using covariate-adjusted difference-in-differences estimates to compare intervention and no-intervention groups. The outcome measure was uptake of FOBT attendance resulting from the intervention. Stratified analyses were conducted according to sociodemographic and health-related characteristics. The intervention was associated with significantly positive uptake of FOBT in both genders, but the impact was greater in women than men: 6.7% (95% CI=5.2, 8.1) for women and 2.7% (95% CI=1.1, 4.3) for men in the covariate-adjusted models. Post-intervention, attendance increased in almost all subgroups in women. However, among men, some socially advantaged subgroups, such as high expenditure, high education, and public officers, showed no effect. Some subgroups such as current smokers and less than high school education were identified as hard-to-reach populations that may be less sensitive to the intervention, irrespective of gender. This is the first comparative study of cost-removal intervention for uptake of FOBT. The intervention may increase FOBT attendance. However, the size of the effect is not great, especially in men, and differential effects occurred across subgroups including gender and socioeconomic differences.


Zyxin stabilizes RIG-I and MAVS interactions and promotes type I interferon response.
RIG-I and MDA5 are cytoplasmic viral RNA sensors that belong to the RIG-I-like receptors (RLRs), which induce antiviral innate immune responses, including the production of type I interferon and other pro-inflammatory cytokines. After recognition of viral RNA, the N-terminal caspase activation and recruitment domains (CARDs) of RIG-I and MDA5 bind to a CARD in the MAVS adaptor molecule, resulting in MAVS oligomerization and downstream signaling. To reveal the molecular mechanism of MAVS-dependent signaling, we performed a yeast two-hybrid screening and identified zyxin as a protein that binds to MAVS. Zyxin co-immunoprecipitated with MAVS in human cells. A proximity ligation assay showed that zyxin and MAVS partly co-localized on mitochondria. Ectopic expression of zyxin augmented MAVS-mediated IFN-β promoter activation, and knockdown of zyxin (ZYX) attenuated the IFN-β promoter activation. Moreover, ZYX knockdown reduced the expression of type I IFN and an interferon-inducible gene after stimulation with polyI:C or influenza A virus RNA. Interestingly, physical interactions between RLRs and MAVS were abrogated by ZYX knockdown. These observations indicate that zyxin serves as a scaffold for the interactions between RLRs and MAVS.


Long-term results of a phase 2 trial of nilotinib 400 mg twice daily in newly diagnosed patients with chronic-phase chronic myeloid leukemia.
Nilotinib is a potent, second-generation inhibitor of BCR-ABL1 tyrosine kinase and has been approved as frontline and salvage therapy for patients with chronic-phase chronic myeloid leukemia (CP-CML). In this single-institution, phase 2 study, 122 patients with newly diagnosed CP-CML received nilotinib 400 mg twice daily. The median follow-up on study was 78.3 months (interquartile range, 58.4-96.5 months). Fifty-six percent of patients remained on therapy at the last follow-up. Both the complete cytogenetic response rate and the major molecular response (MR) rate were 91%. Seventy-five percent and 59% of patients achieved a ≥4.5-log reduction in BCR-ABL1 transcripts (MR4.5) and a sustained MR4.5 beyond 2 years, respectively. The estimated event-free survival and overall survival rates at 5 years were 89% and 93%, respectively, and the corresponding rates at 10 years were 85% and 88%, respectively. Treatment discontinuation due to toxicity occurred in 19% of patients, mostly because of cardiovascular events (10%) and biochemical abnormalities (6%). The top 3 nonhematologic toxicities were rash (55%), elevated bilirubin (57%), and elevated aminotransferases (48%). Hematologic toxicity was transient and mild. Ischemic cardiovascular adverse events occurred in 8% of patients. Four patients (3%) progressed to accelerated or blast phase while on therapy, and 7 patients (6%) died on study. The current data confirm the long-term efficacy of nilotinib 400 mg twice daily in patients with CP-CML. A majority of patients can achieve sustained MR4.5.


Rapid Motion Adaptation Reveals the Temporal Dynamics of Spatiotemporal Correlation between ON and OFF Pathways.
At the early stages of visual processing, information is processed by two major thalamic pathways encoding brightness increments (ON) and decrements (OFF). Accumulating evidence suggests that these pathways interact and merge as early as in primary visual cortex. Using regular and reverse-phi motion in a rapid adaptation paradigm, we investigated the temporal dynamics of within and across pathway mechanisms for motion processing. When the adaptation duration was short (188 ms), reverse-phi and regular motion led to similar adaptation effects, suggesting that the information from the two pathways are combined efficiently at early-stages of motion processing. However, as the adaption duration was increased to 752 ms, reverse-phi and regular motion showed distinct adaptation effects depending on the test pattern used, either engaging spatiotemporal correlation between the same or opposite contrast polarities. Overall, these findings indicate that spatiotemporal correlation within and across ON-OFF pathways for motion processing can be selectively adapted, and support those models that integrate within and across pathway mechanisms for motion processing.


Clockophagy is a novel selective autophagy process favoring ferroptosis.
Ferroptosis is a form of nonapoptotic regulated cell death driven by iron-dependent lipid peroxidation. Autophagy involves a lysosomal degradation pathway that can either promote or impede cell death. A high level of autophagy has been associated with ferroptosis, but the mechanisms underpinning this relationship are largely elusive. We characterize the contribution of autophagy to ferroptosis in human cancer cell lines and mouse tumor models. We show that "clockophagy," the selective degradation of the core circadian clock protein ARNTL by autophagy, is critical for ferroptosis. We identify SQSTM1 as a cargo receptor responsible for autophagic ARNTL degradation. ARNTL inhibits ferroptosis by repressing the transcription of Egln2, thus activating the prosurvival transcription factor HIF1A. Genetic or pharmacological interventions blocking ARNTL degradation or inhibiting EGLN2 activation diminished, whereas destabilizing HIF1A facilitated, ferroptotic tumor cell death. Thus, our findings reveal a new pathway, initiated by the autophagic removal of ARNTL, that facilitates ferroptosis induction.


Evaluating approaches to find exon chains based on long reads.
Transcript prediction can be modeled as a graph problem where exons are modeled as nodes and reads spanning two or more exons are modeled as exon chains. Pacific Biosciences third-generation sequencing technology produces significantly longer reads than earlier second-generation sequencing technologies, which gives valuable information about longer exon chains in a graph. However, with the high error rates of third-generation sequencing, aligning long reads correctly around the splice sites is a challenging task. Incorrect alignments lead to spurious nodes and arcs in the graph, which in turn lead to incorrect transcript predictions. We survey several approaches to find the exon chains corresponding to long reads in a splicing graph, and experimentally study the performance of these methods using simulated data to allow for sensitivity/precision analysis. Our experiments show that short reads from second-generation sequencing can be used to significantly improve exon chain correctness either by error-correcting the long reads before splicing graph creation, or by using them to create a splicing graph on which the long-read alignments are then projected. We also study the memory and time consumption of various modules, and show that accurate exon chains lead to significantly increased transcript prediction accuracy. The simulated data and in-house scripts used for this article are available at http://www.cs.helsinki.fi/group/gsa/exon-chains/exon-chains-bib.tar.bz2.


Bayesian hierarchical meta-analytic methods for modeling surrogate relationships that vary across treatment classes using aggregate data.
Surrogate endpoints play an important role in drug development when they can be used to measure treatment effect early compared to the final clinical outcome and to predict clinical benefit or harm. Such endpoints are assessed for their predictive value of clinical benefit by investigating the surrogate relationship between treatment effects on the surrogate and final outcomes using meta-analytic methods. When surrogate relationships vary across treatment classes, such validation may fail due to limited data within each treatment class. In this paper, two alternative Bayesian meta-analytic methods are introduced which allow for borrowing of information from other treatment classes when exploring the surrogacy in a particular class. The first approach extends a standard model for the evaluation of surrogate endpoints to a hierarchical meta-analysis model assuming full exchangeability of surrogate relationships across all the treatment classes, thus facilitating borrowing of information across the classes. The second method is able to relax this assumption by allowing for partial exchangeability of surrogate relationships across treatment classes to avoid excessive borrowing of information from distinctly different classes. We carried out a simulation study to assess the proposed methods in nine data scenarios and compared them with subgroup analysis using the standard model within each treatment class. We also applied the methods to an illustrative example in colorectal cancer which led to obtaining the parameters describing the surrogate relationships with higher precision.


Determinants of FIV and HIV Vif sensitivity of feline APOBEC3 restriction factors.
Feline immunodeficiency virus (FIV) is a global pathogen of Felidae species and a model system for Human immunodeficiency virus (HIV)-induced AIDS. In felids such as the domestic cat (Felis catus), APOBEC3 (A3) genes encode for single-domain A3Z2s, A3Z3 and double-domain A3Z2Z3 anti-viral cytidine deaminases. The feline A3Z2Z3 is expressed following read-through transcription and alternative splicing, introducing a previously untranslated exon in frame, encoding a domain insertion called linker. Only A3Z3 and A3Z2Z3 inhibit Vif-deficient FIV. Feline A3s also are restriction factors for HIV and Simian immunodeficiency viruses (SIV). Surprisingly, HIV-2/SIV Vifs can counteract feline A3Z2Z3. To identify residues in feline A3s that Vifs need for interaction and degradation, chimeric human-feline A3s were tested. Here we describe the molecular direct interaction of feline A3s with Vif proteins from cat FIV and present the first structural A3 model locating these interaction regions. In the Z3 domain we have identified residues involved in binding of FIV Vif, and their mutation blocked Vif-induced A3Z3 degradation. We further identified additional essential residues for FIV Vif interaction in the A3Z2 domain, allowing the generation of FIV Vif resistant A3Z2Z3. Mutated feline A3s also showed resistance to the Vif of a lion-specific FIV, indicating an evolutionary conserved Vif-A3 binding. Comparative modelling of feline A3Z2Z3 suggests that the residues interacting with FIV Vif have, unlike Vif-interacting residues in human A3s, a unique location at the domain interface of Z2 and Z3 and that the linker forms a homeobox-like domain protruding of the Z2Z3 core. HIV-2/SIV Vifs efficiently degrade feline A3Z2Z3 by possible targeting the linker stretch connecting both Z-domains. Here we identified in feline A3s residues important for binding of FIV Vif and a unique protein domain insertion (linker). To understand Vif evolution, a structural model of the feline A3 was developed. Our results show that HIV Vif binds human A3s differently than FIV Vif feline A3s. The linker insertion is suggested to form a homeo-box domain, which is unique to A3s of cats and related species, and not found in human and mouse A3s. Together, these findings indicate a specific and different A3 evolution in cats and human.


Cell cycle-dependent differentiation dynamics balances growth and endocrine differentiation in the pancreas.
Organogenesis relies on the spatiotemporal balancing of differentiation and proliferation driven by an expanding pool of progenitor cells. In the mouse pancreas, lineage tracing at the population level has shown that the expanding pancreas progenitors can initially give rise to all endocrine, ductal, and acinar cells but become bipotent by embryonic day 13.5, giving rise to endocrine cells and ductal cells. However, the dynamics of individual progenitors balancing self-renewal and lineage-specific differentiation has never been described. Using three-dimensional live imaging and in vivo clonal analysis, we reveal the contribution of individual cells to the global behaviour and demonstrate three modes of progenitor divisions: symmetric renewing, symmetric endocrinogenic, and asymmetric generating a progenitor and an endocrine progenitor. Quantitative analysis shows that the endocrine differentiation process is consistent with a simple model of cell cycle-dependent stochastic priming of progenitors to endocrine fate. The findings provide insights to define control parameters to optimize the generation of β-cells in vitro.


Effect of highly active antiretroviral therapy on the natural history of anal squamous intraepithelial lesions and anal human papillomavirus infection.
The effect of highly active antiretroviral therapy (HAART) on the natural history of anal squamous intraepithelial lesions (ASIL)-the likely anal cancer precursor-and anal human papillomavirus (HPV) infection is unknown. ASIL severity and level of anal HPV DNA were evaluated among HIV-positive men who have sex with men (MSM) for at least 6 months before initiation of HAART. The results were compared with those from a 6-month period after initiation of HAART. Anal swabs for cytology and HPV studies were obtained, followed by high-resolution anoscopy and biopsy. Among men whose most severe pre-HAART diagnosis was atypical squamous cells of undetermined significance or low-grade ASIL, 18% (confidence interval [CI], 6-31%, 7 of 38) progressed and 21% (CI, 8-34%, 8 of 38) regressed 6 months after starting HAART. Seventeen percent (CI, 0-38%, 2 of 12) of study subjects who began with a normal diagnosis developed ASIL. Only 4% (CI, 0-10%, 1 of 28) of study subjects with high-grade ASIL regressed to normal. There was no reduction in the proportion of study subjects who tested positive for HPV DNA or HPV DNA levels after HAART initiation. The ASIL and HPV data were similar to those of the pre-HAART comparison period. These results indicate that HAART has little effect on either ASIL or HPV in the first 6 months after HAART initiation.


Radiation Therapy Oncology Group (RTOG) 88-08 and Eastern Cooperative Oncology Group (ECOG) 4588: preliminary results of a phase III trial in regionally advanced, unresectable non-small-cell lung cancer.
Regionally advanced, surgically unresectable non-small-cell lung cancer represents a disease with an extremely poor prognosis. External-beam irradiation to the primary tumor and regional lymphatics is generally accepted as standard therapy. The use of more aggressive radiation regimens and the addition of cytotoxic chemotherapy to radiotherapy have yielded conflicting results. Recently, however, results from clinical trials using innovative irradiation delivery techniques or chemotherapy before irradiation have indicated that patients treated with protocols that incorporate these modifications may have higher survival rates than patients receiving standard radiation therapy. On the basis of these results, the Radiation Therapy Oncology Group (RTOG)-Eastern Cooperative Oncology Group (ECOG) elected to conduct a phase III trial comparing the following regimens: 1) standard radiation therapy, 2) induction chemotherapy followed by standard radiation therapy, and 3) twice-daily radiation therapy. Patients with surgically unresectable stage II, IIIA, or IIIB non-small-cell lung cancer were potential candidates. Staging was nonsurgical. Patients were required to have a Karnofsky performance status of 70 or more and weight loss less than 5% for 3 months prior to entry into the trial, to be older than 18 years of age, and to have no metastatic disease. Of the 490 patients registered in the trial, 452 were eligible. The disease in 95% of the patients was stage IIIA or IIIB. More than two thirds of the patients had a Karnofsky performance status of more than 80. Patients were randomly assigned to receive either 60 Gy of radiation therapy delivered at 2 Gy per fraction, 5 days a week, over a 6-week period (standard radiation therapy); induction chemotherapy consisting of cisplatin (100 mg/m2) on days 1 and 29 and 5 mg/m2 vinblastine per week for 5 consecutive weeks beginning on day 1 with cisplatin, followed by standard radiation therapy starting on day 50; or 69.6 Gy delivered at 1.2 Gy per fraction twice daily (hyperfractionated radiation therapy). Toxicity was acceptable, with four treatment-related deaths. Three patients subsequently died of chronic pulmonary complications. Compliance with protocol treatment was acceptable. One-year survival (%) and median survival (months) were as follows: standard radiation therapy--46%, 11.4 months; chemotherapy plus radiotherapy--60%, 13.8 months; and hyperfractionated radiation therapy--51%, 12.3 months. The chemotherapy plus radiotherapy arm was statistically superior to the other two treatment arms (logrank P = .03). In "good-risk" patients with surgically unresectable non-small-cell lung cancer, induction chemotherapy followed by irradiation was superior to hyperfractionated radiation therapy or standard radiation therapy alone, yielding a statistically significant short-term survival advantage.


Effects of sample handling and storage on quantitative lipid analysis in human serum.
There is sparse information about specific storage and handling protocols that minimize analytical error and variability in samples evaluated by targeted metabolomics. Variance components that affect quantitative lipid analysis in a set of human serum samples were determined. The effects of freeze-thaw, extraction state, storage temperature, and freeze-thaw prior to density-based lipoprotein fractionation were quantified. The quantification of high abundance metabolites, representing the biologically relevant lipid species in humans, was highly repeatable (with coefficients of variation as low as 0.01 and 0.02) and largely unaffected by 1-3 freeze-thaw cycles (with 0-8% of metabolites affected in each lipid class). Extraction state had effects on total lipid class amounts, including decreased diacylglycerol and increased phosphatidylethanolamine in thawed compared with frozen samples. The effects of storage temperature over 1 week were minimal, with 0-4% of metabolites affected by storage at 4 degrees C, -20 degrees C, or -80 degrees C in most lipid classes, and 19% of metabolites in diacylglycerol affected by storage at -20 degrees C. Freezing prior to lipoprotein fractionation by density ultracentrifugation decreased HDL free cholesterol by 37% and VLDL free fatty acid by 36%, and increased LDL cholesterol ester by 35% compared with fresh samples. These findings suggest that density-based fractionation should preferably be undertaken in fresh serum samples because up to 37% variability in HDL and LDL cholesterol could result from a single freeze-thaw cycle. Conversely, quantitative lipid analysis within unfractionated serum is minimally affected even with repeated freeze-thaw cycles.


Telerehabilitation and recovery of motor function: a systematic review and meta-analysis.
Recent advances in telecommunication technologies have boosted the possibility to deliver rehabilitation via the internet (i.e. telerehabilitation). Several studies have shown that telerehabilitation is effective to improve clinical outcomes in disabling conditions. The aim of this review was to determine whether telerehabilitation was more effective than other modes of delivering rehabilitation to regain motor function, in different populations of patients.We searched PubMed, Embase and the Cochrane library retrieving 2360 records. Twelve studies were included involving different populations (i.e. neurological, total knee arthroplasty (TKA), cardiac) of patients. Inconclusive finding were found on the effect of telerehabilitation for neurological patients (SMD = 0.08, CI 95% = -0.13, 0.29), while both for cardiac (SMD = 0.24, CI 95% = 0.04, 0.43) and TKA patients (Timed Up and Go test: MD = -5.17, CI 95% = -9.79, -0.55) the results were in favour of telerehabilitation.Conclusive evidence on the efficacy of telerehabilitation for treatment of motor function, regardless of pathology, was not reached. Nevertheless, a strong positive effect was found for patients following orthopaedic surgery, suggesting that the increased intensity provided by telerehabilitation is a promising option to be offered to patients. More and higher quality research is needed in this field especially with neurological patients.


Impact of a centralized osteoporosis coordinator on post-fracture osteoporosis management: a cluster randomized trial.
We conducted a cluster randomized trial evaluating the effect of a centralized coordinator who identifies and follows up with fracture patients and their primary care physicians about osteoporosis. Compared with controls, intervention patients were five times more likely to receive BMD testing and two times more likely to receive appropriate management. To determine if a centralized coordinator who follows up with fracture patients and their primary care physicians by telephone and mail (intervention) will increase the proportion of patients who receive appropriate post-fracture osteoporosis management, compared to simple fall prevention advice (attention control). A cluster randomized controlled trial was conducted in small community hospitals in the province of Ontario, Canada. Hospitals that treated between 60 and 340 fracture patients per year were eligible. Patients 40 years and older presenting with a low trauma fracture were identified from Emergency Department records and enrolled in the trial. The primary outcome was 'appropriate' management, defined as a normal bone mineral density (BMD) test or taking osteoporosis medications. Thirty-six hospitals were randomized to either intervention or control and 130 intervention and 137 control subjects completed the study. The mean age of participants was 65 ± 12 years and 69% were female. The intervention increased the proportion of patients who received appropriate management within 6 months of fracture; 45% in the intervention group compared with 26% in the control group (absolute difference of 19%; adjusted OR, 2.3; 95% CI, 1.3-4.1). The proportion who had a BMD test scheduled or performed was much higher with 57% of intervention patients compared with 21% of controls (absolute difference of 36%; adjusted OR, 4.8; 95% CI, 3.0-7.0). A centralized osteoporosis coordinator is effective in improving the quality of osteoporosis care in smaller communities that do not have on-site coordinators or direct access to osteoporosis specialists.


Elemental composition of particulate matter and the association with lung function.
Negative effects of long-term exposure to particulate matter (PM) on lung function have been shown repeatedly. Spatial differences in the composition and toxicity of PM may explain differences in observed effect sizes between studies. We conducted a multicenter study in 5 European birth cohorts-BAMSE (Sweden), GINIplus and LISAplus (Germany), MAAS (United Kingdom), and PIAMA (The Netherlands)-for which lung function measurements were available for study subjects at the age of 6 or 8 years. Individual annual average residential exposure to copper, iron, potassium, nickel, sulfur, silicon, vanadium, and zinc within PM smaller than 2.5 μm (PM2.5) and smaller than 10 μm (PM10) was estimated using land-use regression models. Associations between air pollution and lung function were analyzed by linear regression within cohorts, adjusting for potential confounders, and then combined by random effects meta-analysis. We observed small reductions in forced expiratory volume in the first second, forced vital capacity, and peak expiratory flow related to exposure to most elemental pollutants, with the most substantial negative associations found for nickel and sulfur. PM10 nickel and PM10 sulfur were associated with decreases in forced expiratory volume in the first second of 1.6% (95% confidence interval = 0.4% to 2.7%) and 2.3% (-0.1% to 4.6%) per increase in exposure of 2 and 200 ng/m, respectively. Associations remained after adjusting for PM mass. However, associations with these elements were not evident in all cohorts, and heterogeneity of associations with exposure to various components was larger than for exposure to PM mass. Although we detected small adverse effects on lung function associated with annual average levels of some of the evaluated elements (particularly nickel and sulfur), lower lung function was more consistently associated with increased PM mass.


Common variants in maturity-onset diabetes of the young genes and future risk of type 2 diabetes.
Mutations in the hepatocyte nuclear factor (HNF)-1alpha, HNF-4alpha, glucokinase (GCK), and HNF-1beta genes cause maturity-onset diabetes of the young (MODY), but it is not known whether common variants in these genes predict future type 2 diabetes. We tested 14 previously associated polymorphisms in HNF-1alpha, HNF-4alpha, GCK, and HNF-1beta for association with type 2 diabetes-related traits and future risk of type 2 diabetes in 2,293 individuals from the Botnia study (Finland) and in 15,538 individuals from the Malmö Preventive Project (Sweden) with a total follow-up >360,000 years. The polymorphism rs1169288 in HNF-1alpha strongly predicted future type 2 diabetes (hazard ratio [HR] 1.2, P = 0.0002). Also, SNPs rs4810424 and rs3212198 in HNF-4alpha nominally predicted future type 2 diabetes (HR 1.3 [95% CI 1.0-1.6], P = 0.03; and 1.1 [1.0-1.2], P = 0.04). The rs2144908 polymorphism in HNF-4alpha was associated with elevated rate of hepatic glucose production during a hyperinsulinemic-euglycemic clamp (P = 0.03) but not with deterioration of insulin secretion over time. The SNP rs1799884 in the GCK promoter was associated with elevated fasting plasma glucose (fPG) concentrations that remained unchanged during the follow-up period (P = 0.4; SE 0.004 [-0.003-0.007]) but did not predict future type 2 diabetes (HR 0.9 [0.8-1.0], P = 0.1). Polymorphisms in HNF-1beta (transcription factor 2 [TCF2]) did not significantly influence insulin or glucose values nor did they predict future type 2 diabetes. In conclusion, genetic variation in both HNF-1alpha and HNF-4alpha predict future type 2 diabetes, whereas variation in the GCK promoter results in a sustained but subtle elevation of fPG that is not sufficient to increase risk for future type 2 diabetes.


Hospitalization for gastrointestinal and liver diseases: the effect of socioeconomic and medical supply factors.
A growing body of research has documented significant variation in health care use between communities. As the health care system is transformed, providers and payers should understand the interaction between a community, its sociodemographic characteristics, and its use of health resources. We describe the association between a population's demographic, socioeconomic, and medical resources and hospital use related to gastrointestinal and liver diseases. We used an all-payer hospital discharge database for Michigan from 1986 to 1988. We identified all medical and surgical hospital admissions during this period from two of the Diagnostic Related Group, Major Diagnostic Categories: No. 6, Diseases and Disorders of the Digestive System; and No. 7, Diseases and Disorders of the Hepatobiliary System and Pancreas. We analyzed age- and sex-specific use rates. Finally, we analyzed the influence of sociodemographic variables from the Area Resource File at the county level, on hospital use, using a Poisson regression model. We noted a significant association between increased hospitalizations and increased age in a community. Hospital beds per capita did not influence admission rates overall, although more hospital beds were associated with more medical admissions. Overall, the total physician supply was associated with more admissions. Finally, the most important socioeconomic variable was education. As the level of education of a county increased, hospital admissions decreased dramatically. The transformation of the health care delivery system presents opportunities and challenges. Understanding the underlying epidemiology of disease and how it interacts with a community's socioeconomic and medical resources or medical supply characteristics will be necessary to meet the community's health needs and to ensure the financial viability of providers. This is especially true when payers use a standard payment in a region, such as Medicare's managed care payment, without adjustments for the underlying population characteristics known to influence use.


Preliminary Results of Caregiver Speaks: A Storytelling Intervention for Bereaved Family Caregivers.
When bereaved cancer caregivers have the opportunity to tell stories about their caregiving and bereavement journey, they are better able to make meaning of these experiences. Creating a space where they can share stories with other bereaved caregivers increases social validation, facilitates the meaning-making process, and reduces distress and risk for complicated grief. This study explored the feasibility and acceptability of an innovative storytelling intervention for bereaved family caregivers of cancer patients. Twenty-one participants engaged in the intervention, and eleven were interviewed about their experience. Results indicated study feasibility and intervention acceptability. Suggestions for future intervention were also provided.


Endoscopic management of Barrett's esophagus: European Society of Gastrointestinal Endoscopy (ESGE) Position Statement.
Current practices for the management of Barrett's esophagus (BE) vary across Europe, as several national European guidelines exist. This Position Statement from the European Society of Gastrointestinal Endoscopy (ESGE) is an attempt to homogenize recommendations and, hence, patient management according to the best scientific evidence and other considerations (e.g. health policy). A Working Group developed consensus statements, using the existing national guidelines as a starting point and considering new evidence in the literature. The Position Statement wishes to contribute to a more cost-effective approach to the care of patients with BE by reducing the number of surveillance endoscopies for patients with a low risk of malignant progression and centralizing care in expert centers for those with high progression rates.Main statements MS1 The diagnosis of BE is made if the distal esophagus is lined with columnar epithelium with a minimum length of 1 cm (tongues or circular) containing specialized intestinal metaplasia at histopathological examination. MS2 The ESGE recommends varying surveillance intervals for different BE lengths. For patients with an irregular Z-line/columnar-lined esophagus of < 1 cm, no routine biopsies or endoscopic surveillance is advised. For BE ≥ 1 cm and < 3 cm, BE surveillance should be repeated every 5 years. For BE ≥ 3 cm and < 10 cm, the interval for endoscopic surveillance should be 3 years. Patients with BE with a maximum extent ≥ 10 cm should be referred to a BE expert center for surveillance endoscopies. Patients with limited life expectancy and advanced age should be discharged from endoscopic surveillance. MS3 The diagnosis of any degree of dysplasia (including "indefinite for dysplasia") in BE requires confirmation by an expert gastrointestinal pathologist. MS4 Patients with visible lesions in BE diagnosed as dysplasia or early cancer should be referred to a BE expert center. All visible abnormalities, regardless of the degree of dysplasia, should be removed by means of endoscopic resection techniques in order to obtain optimal histopathological staging MS5 All patients with a BE ≥ 10 cm, a confirmed diagnosis of low grade dysplasia, high grade dysplasia (HGD), or early cancer should be referred to a BE expert center for surveillance and/or treatment. BE expert centers should meet the following criteria: annual case load of ≥10 new patients undergoing endoscopic treatment for HGD or early carcinoma per BE expert endoscopist; endoscopic and histological care provided by endoscopists and pathologists who have followed additional training; at least 30 supervised endoscopic resection and 30 endoscopic ablation procedures to acquire competence in technical skills, management pathways, and complications; multidisciplinary meetings with gastroenterologists, surgeons, oncologists, and pathologists to discuss patients with Barrett's neoplasia; access to experienced esophageal surgery; and all BE patients registered prospectively in a database.


Decellularized tendon extracellular matrix-a valuable approach for tendon reconstruction?
Tendon healing is generally a time-consuming process and often leads to a functionally altered reparative tissue. Using degradable scaffolds for tendon reconstruction still remains a compromise in view of the required high mechanical strength of tendons. Regenerative approaches based on natural decellularized allo- or xenogenic tendon extracellular matrix (ECM) have recently started to attract interest. This ECM combines the advantages of its intrinsic mechanical competence with that of providing tenogenic stimuli for immigrating cells mediated, for example, by the growth factors and other mediators entrapped within the natural ECM. A major restriction for their therapeutic application is the mainly cell-associated immunogenicity of xenogenic or allogenic tissues and, in the case of allogenic tissues, also the risk of disease transmission. A survey of approaches for tendon reconstruction using cell-free tendon ECM is presented here, whereby the problems associated with the decellularization procedures, the success of various recellularization strategies, and the applicable cell types will be thoroughly discussed. Encouraging in vivo results using cell-free ECM, as, for instance, in rabbit models, have already been reported. However, in comparison to native tendon, cells remain mostly inhomogeneously distributed in the reseeded ECM and do not align. Hence, future work should focus on the optimization of tendon ECM decellularization and recolonization strategies to restore tendon functionality.


Induction and regulation of tumor necrosis factor-related apoptosis-inducing ligand/Apo-2 ligand-mediated apoptosis in renal cell carcinoma.
The lack of effective therapy for disseminated renal cell carcinoma (RCC) has stimulated the search for novel treatments including immunotherapeutic strategies. However, poor therapeutic responses and marked toxicity associated with immunological agents has limited their use. The tumor necrosis factor family member tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)/Apo-2 ligand induces apoptosis in a variety of tumor cell types, while having little cytotoxic activity against normal cells. In this study the activation and regulation of TRAIL-induced apoptosis and TRAIL receptor expression in human RCC cell lines and pathologic specimens was examined. TRAIL induced caspase-mediated apoptotic death of RCC cells with variable sensitivities among the cell lines tested. Compared with TRAIL-sensitive RCC cell lines (A-498, ACHN, and 769-P), the TRAIL-resistant RCC cell line (786-O) expressed lesser amounts of the death-inducing TRAIL receptors, and greater amounts of survivin, an inhibitor of apoptosis. Incubation of 786-O with actinomycin D increased the expression of the death-inducing TRAIL receptors and, concomitantly, decreased the intracellular levels of survivin, resulting in TRAIL-induced apoptotic death. The link between survivin and TRAIL regulation was confirmed when an increase in TRAIL resistance was observed after overexpression of survivin in the TRAIL-sensitive, survivin-negative RCC line A-498. These findings, along with our observation that TRAIL receptors are expressed in RCC tumor tissue, suggest that TRAIL may be useful as a therapeutic agent for RCC and that survivin may partially regulate TRAIL-induced cell death.


Circulating endothelial progenitors in vascular repair.
Endothelial Colony Forming Cells (ECFCs) are obtained in culture from Circulating Endothelial Progenitor Cells. They display all characteristics of endothelial cells and they display stem cells features. Cord blood-derived ECFCs (CB-ECFCs) have a high clonogenic and proliferative potentials, and exhibit vascular repair capabilities useful for the treatment of ischemic diseases. However, the link between immaturity and functional properties of CB-ECFCs is still poorly defined. We showed that these cells have a high clonogenic potential and are capable to be efficiently reprogrammed into induced pluripotent stem cells. Moreover, we analyzed the expression of a broad panel of genes involved in embryonic stem cell properties. We define a novel stem cell transcriptional signature for CB-ECFCs fora better characterization and stratification according to their stem cell profile. We then improved the yield of CB-ECFC production for obtaining cells more functional in fewer passages. We used Glycosaminoglycans (GAG), components from the extracellular matrix which potentiate heparin binding growth factor activities. GAG mimetics were designed, having the capacity to increase the yield of ECFC during the isolation process, to increase the number of colonies, improve adhesion, proliferation, migration and self-renewal. GAG mimetics have thus great interest for vascular regeneration in combination with ECFC. Our results show that CB-ECFC are immature cells harboring specific functions such as formation of colonies, proliferation and formation of vascular structures in vitro and in vivo.


Cancer control problems in the Lynch syndromes.
The Lynch syndromes account for about 4 to 6 percent of the total colorectal cancer (CRC) burden. Despite more than two decades of documentation in the literature, many physicians fail to recognize the clinical features of these syndromes. The lack of premonitory physical stigmata, coupled with the absence of a biomarker of cancer susceptibility, mandates full reliance on a well-orchestrated family history for diagnosis. These deficiencies impede cancer control. Even if the diagnosis is made, proper surveillance and management measures that are responsive to the Lynch syndromes' natural history may fail to be implemented. We describe CRC occurrences in patients from four extended Lynch syndrome kindreds. Failures in cancer control were attributable to poor patient compliance and/or to limited physician knowledge about the natural history and surveillance recommendations for the Lynch syndromes. Physicians need to more effectively educate their high-risk patients about the significance of genetic risk, the natural history of CRC, and the appropriate surveillance strategies in the Lynch syndromes.


Communication About Microbicide Use Between Couples in KwaZulu-Natal, South Africa.
The ways in which couples communicate about microbicides is likely to influence microbicide uptake and usage. We collected quantitative data about whether women in a microbicide trial discussed microbicides with their partners and explored communication about microbicides during 79 in-depth-interviews with women enrolled in the trial and 17 focus-group discussions with community members. After 4 weeks in the trial, 60 % of 1092 women had discussed microbicides with their partners; in multivariate analysis, this was associated with younger age, clinic of enrolment and not living in households that owned cattle. After 52 weeks, 84 % of women had discussed microbicides; in multivariate analysis, this was associated with not living in households that owned cattle, not living in a household that relied on the cheapest water source, allocation to 0.5 % PRO2000 gel and consistent gel adherence. Qualitative findings highlighted that women in committed relationships were expected to discuss microbicides with their partners and preferred to use microbicides with their partner's knowledge. Women had different reasons for, and ways of, discussing microbicides and these were influenced by the couple's decision-making roles. Although there was tolerance for the use of microbicides without a partner's knowledge, the women who used microbicides secretly appeared to be women who were least able to discuss microbicides. In KwaZulu-Natal, socio-cultural norms informing sexual communication are amenable to microbicide introduction.


Long-term adverse effects after retropubic and robot-assisted radical prostatectomy. Nationwide, population-based study.
Surgery for prostate cancer is associated with adverse effects. We studied long-term risk of adverse effects after retropubic (RRP) and robot-assisted radical prostatectomy (RARP). In the National Prostate Cancer Register of Sweden, men who had undergone radical prostatectomy (RP) between 2004 and 2014 were identified. Diagnoses and procedures indicating adverse postoperative effects were retrieved from the National Patient Register. Relative risk (RR) of adverse effects after RARP versus RRP was calculated in multivariable analyses adjusting for year of surgery, hospital surgical volume, T stage, Gleason grade, PSA level at diagnosis, patient age, comorbidity, and educational level. A total of 11 212 men underwent RRP and 8500 RARP. Risk of anastomotic stricture was lower after RARP than RRP, RR for diagnoses 0.51 (95%CI = 0.42-0.63) and RR for procedures 0.46 (95%CI = 0.38-0.55). Risk of inguinal hernia was similar after RARP and RRP but risk of incisional hernia was higher after RARP, RR for diagnoses 1.48 (95%CI = 1.01-2.16), and RR for procedures 1.52 (95%CI = 1.02-2.26). The postoperative risk profile for RARP and RRP was quite similar. However, risk of anastomotic stricture was lower and risk of incisional hernia higher after RARP.


Gamete intrafallopian transfer as treatment for infertility associated with endometriosis.
Forty-six patients with endometriosis-associated infertility underwent 59 GIFT cycles. The pregnancy rate per cycle was 30.5%. The presence of endometriomas in 11 patients did not affect this rate adversely. We conclude that, provided at least one fallopian tube is patent, GIFT compensates effectively for the possible causes of infertility in these patients.


Reward sharpens orientation coding independently of attention.
It has long been known that rewarding improves performance. However it is unclear whether this is due to high level modulations in the output modules of associated neural systems or due to low level mechanisms favoring more "generous" inputs? Some recent studies suggest that primary sensory areas, including V1 and A1, may form part of the circuitry of reward-based modulations, but there is no data indicating whether reward can be dissociated from attention or cross-trial forms of perceptual learning. Here we address this issue with a psychophysical dual task, to control attention, while perceptual performance on oriented targets associated with different levels of reward is assessed by measuring both orientation discrimination thresholds and behavioral tuning functions for tilt values near threshold. We found that reward, at any rate, improved performance. However, higher reward rates showed an improvement of orientation discrimination thresholds by about 50% across conditions and sharpened behavioral tuning functions. Data were unaffected by changing the attentional load and by dissociating the feature of the reward cue from the task-relevant feature. These results suggest that reward may act within the span of a single trial independently of attention by modulating the activity of early sensory stages through a improvement of the signal-to-noise ratio of task-relevant channels.


Assessment of the Association of Cannabis on Female Sexual Function With the Female Sexual Function Index.
Cannabis use has increased in the last decade, and the impact of cannabis on female sexual function remains unclear. To assess the impact of frequency of use, chemovar (tetrahydrocannabinol, cannabinol, or both) type, and method of consumption on female sexual function among cannabis users. Adults who visited a single-partner cannabis dispensary's locations were invited to participate in an uncompensated, anonymous online survey October 20, 2019 and March 12, 2020. The survey assessed baseline demographics, health status, cannabis use habits as well as used the validated Female Sexual Function Index (FSFI) to assess sexual function. The main outcomes of this study are the total FSFI score (sexual dysfunction cutoff <26.55) and subdomain scores including desire, arousal, lubrication, orgasm, satisfaction, and pain. A total of 452 women responded with the majority between the ages of 30-49 years (54.7%) and in a relationship or married (81.6%). Of them,72.8% reported using cannabis more than 6 times per week, usually through smoking flower (46.7%). Women who reported more cannabis use, reported higher FSFI scores (29.0 vs 26.7 for lowest vs highest frequencies of reported use, P = .003). Moreover, an increase in cannabis use frequency by one additional use per week was associated with an increase in total FSFI (β = 0.61, P = .0004) and subdomains including desire domain (P = .02), arousal domain (P = .0002), orgasm domain (P = .002), and satisfaction domain (P = .003). For each additional step of cannabis use intensity (ie, times per week), the odds of reporting female sexual dysfunction declined by 21% (odds ratio: 0.79, 95% confidence interval: 0.68-0.92, P = .002). Method of consumption of cannabis and chemovar type did not consistently impact FSFI scores or odds of sexual dysfunction. Increased frequency of marijuana use is associated with improved sexual function among female users, whereas chemovar type, method of consumption, and reason for use does not impact outcomes. Kasman AM, Bhambhvani HP, Wilson-King G, et al. Assessment of the Association of Cannabis on Female Sexual Function With the Female Sexual Function Index. Sex Med 2020;8:699-708.


Work-related musculoskeletal disorders among physical therapists.
Increasing evidence suggests that musculoskeletal disorders are common in workers in the United States health care industry. Physical therapists, who commonly treat patients with these disorders, are also at risk for work-related musculoskeletal disorders (WMD) in the upper limbs and low back. The purpose of this study was to determine the prevalence of WMD during a 12-month period and the job factors that may be associated with these disorders in physical therapists. A four-page questionnaire was mailed to physical therapists (N = 1,160) who attended The University of Iowa between 1943 and 1993. Nine hundred twenty-eight questionnaires were returned (80% response rate) from physical therapists in 46 states. Based on a literature review and pilot study of physical therapists, a survey instrument was constructed consisting of a symptom survey, a job-factor survey, and various demographic information. The highest prevalences of WMD among physical therapists were in the following anatomical areas: low back (45%), wrist/hand (29.6%), upper back (28.7%), and neck (24.7%). The job factor rated most likely to contribute to job-related musculoskeletal disorders was "lifting or transferring dependent patients." The prevalence of WMD in physical therapists also was affected by work setting, practice specialty, age of patient, and gender of therapist. Specific strategies should be developed to reduce WMD in the practice of physical therapy.


Nucleotide sequence of the 3' terminal region of belladonna mottle virus-Iowa (renamed Physalis mottle virus) RNA and an analysis of the relationships of tymoviral coat proteins.
The 3' terminal 1255 nt sequence of Physalis mottle virus (PhMV) genomic RNA has been determined from a set of overlapping cDNA clones. The open reading frame (ORF) at the 3' terminus corresponds to the amino acid sequence of the coat protein (CP) determined earlier except for the absence of the dipeptide, Lys-Leu, at position 110-111. In addition, the sequence upstream of the CP gene contains the message coding for 178 amino acid residues of the C-terminus of the putative replicase protein (RP). The sequence downstream of the CP gene contains an untranslated region whose terminal 80 nucleotides can be folded into a characteristic tRNA-like structure. A phylogenetic tree constructed after aligning separately the sequence of the CP, the replicase protein (RP) and the tRNA-like structure determined in this study with the corresponding sequences of other tymoviruses shows that PhMV wrongly named belladonna mottle virus [BDMV(I)] is a separate tymovirus and not another strain of BDMV(E) as originally envisaged. The phylogenetic tree in all the three cases is identical showing that any subset of genomic sequence of sufficient length can be used for establishing evolutionary relationships among tymoviruses.


Can mitomycin facilitate endoscopic dilatation treatment of benign oesophageal stricture?
A best evidence topic in cardiothoracic surgery was written according to a structured protocol. The question addressed was 'Can mitomycin facilitate endoscopic dilatation treatment of benign esophageal stricture (mainly including caustic and anastomotic esophageal stricture)?' Altogether, 115 papers were found using the reported search, of which 6 represented the best evidence to answer the clinical question, which included 1 randomized controlled trial, 1 systematic review and 4 cohort studies. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results of these papers are tabulated. Mytomicin was topically applied as an adjunct to endoscopic dilatation with a concentration of 0.1-1 mg/ml in those included studies. Most of the studies reported that topical application of mitomycin could augment the effect of endoscopic dilatation treatment to achieve less dilatation number and significant improvement of dysphagia in patients suffering benign oesophageal stricture, and would not increase the risk of complications. These satisfying adjunct effects were observed in both child patients and adult patients. Therefore, we conclude that mitomycin can serve as a useful adjunct to endoscopic dilatation for benign oesophageal stricture. On the basis of our evidence, we strongly believe that topical application of mitomycin would augment the efficacy of endoscopic dilatation of benign oesophageal stricture.


The calculation of thermodynamic properties of molecules.
Thermodynamic data are key in the understanding and design of chemical processes. Next to the experimental evaluation of such data, computational methods are valuable and sometimes indispensable tools in obtaining heats of formation and Gibbs free energies. The major toolboxes to obtain such quantities by computation are quantum mechanical methods and group contribution methods. Although a lot of progress was made over the last decade, for the majority of chemical species we are still quite a bit away from what is often referred to as chemical accuracy, i.e.'1 kcal mol(-1)'. Currently, for larger molecules the combination of group contribution methods with group additive values that are determined with the best available computational ab initio methods seems to be a viable alternative to obtain thermodynamic properties near chemical accuracy. New developments and full use of existing tools may lead to further improvements (critical review, 83 references).


Intergenic variants of HBS1L-MYB are responsible for a major quantitative trait locus on chromosome 6q23 influencing fetal hemoglobin levels in adults.
Individual variation in fetal hemoglobin (HbF, alpha(2)gamma(2)) response underlies the remarkable diversity in phenotypic severity of sickle cell disease and beta thalassemia. HbF levels and HbF-associated quantitative traits (e.g., F cell levels) are highly heritable. We have previously mapped a major quantitative trait locus (QTL) controlling F cell levels in an extended Asian-Indian kindred with beta thalassemia to a 1.5-Mb interval on chromosome 6q23, but the causative gene(s) are not known. The QTL encompasses several genes including HBS1L, a member of the GTP-binding protein family that is expressed in erythroid progenitor cells. In this high-resolution association study, we have identified multiple genetic variants within and 5' to HBS1L at 6q23 that are strongly associated with F cell levels in families of Northern European ancestry (P = 10(-75)). The region accounts for 17.6% of the F cell variance in northern Europeans. Although mRNA levels of HBS1L and MYB in erythroid precursors grown in vitro are positively correlated, only HBS1L expression correlates with high F cell alleles. The results support a key role for the HBS1L-related genetic variants in HbF control and illustrate the biological complexity of the mechanism of 6q QTL as a modifier of fetal hemoglobin levels in the beta hemoglobinopathies.


Translocation products in acute myeloid leukemia activate the Wnt signaling pathway in hematopoietic cells.
The acute myeloid leukemia (AML)-associated translocation products AML1-ETO, PML-retinoic acid receptor alpha (RARalpha), and PLZF-RARalpha encode aberrant transcription factors. Several lines of evidence suggest similar pathogenetic mechanisms for these fusion proteins. We used high-density oligonucleotide arrays to identify shared target genes in inducibly transfected U937 cells expressing AML1-ETO, PML-RARalpha, or PLZF-RARalpha. All three fusion proteins significantly repressed the expression of 38 genes and induced the expression of 14 genes. Several of the regulated genes were associated with Wnt signaling. One of these, plakoglobin (gamma-catenin), was induced on the mRNA and protein level by all three fusion proteins. In addition, primary AML blasts carrying one of the fusion proteins significantly overexpressed plakoglobin. The plakoglobin promoter was cloned and shown to be induced by AML1-ETO, with promoter activation depending on the corepressor and histone deacetylase binding domains. The induction of plakoglobin by AML fusion proteins led to downstream signaling and transactivation of TCF- and LEF-dependent promoters, including the c-myc promoter, which was found to be bound by plakoglobin in vivo after AML1-ETO expression. beta-Catenin protein levels and TCF and LEF target genes such as c-myc and cyclin D1 were found to be induced by the fusion proteins. On the functional level, a dominant negative TCF inhibited colony growth of AML1-ETO-positive Kasumi cells, whereas plakoglobin transfection into myeloid 32D cells enhanced proliferation and clonal growth. Injection of plakoglobin-expressing 32D cells into syngeneic mice accelerated the development of leukemia. Transduction of plakoglobin into primitive murine hematopoietic progenitor cells preserved the immature phenotype during colony growth, suggesting enhanced self-renewal. These data provide evidence that activation of Wnt signaling is a common feature of several balanced translocations in AML.


New paradigms in cell death in human diabetic nephropathy.
Cell death is thought to contribute to progressive renal cell depletion in diabetic nephropathy. Unbiased gene expression profiling identified novel cell death molecules in human diabetic nephropathy. The expression of TNF-related apoptosis-inducing ligand (TRAIL), its decoy receptor osteoprotegerin, and receptors Fas (a Fas ligand receptor) and CD74 (a migration inhibitory factor (MIF) receptor) were induced in human diabetic nephropathy. Cell culture studies supported the functional relevance of this observation and the relationship to a high glucose environment. To define novel proapoptotic proteins upregulated in diabetic nephropathy, functional genomic screens for novel apoptosis mediators were integrated with genome-wide expression profiling and identified candidates for further functional analysis, including brain acid-soluble protein 1 (BASP1). Several lines of evidence point toward induction of endoplasmic reticulum stress response in human diabetic nephropathy. Functional studies defining an unequivocal contribution of endoplasmic reticulum stress to cell death in this setting are still needed. Further comparative studies will be required to define whether there is a specific aspect of apoptosis in progressive human diabetic nephropathy or whether the mechanisms are shared among all patients with chronic kidney disease. The next challenge will be to define the consequence of therapeutic interference of the apoptosis pathways in diabetic nephropathy and chronic kidney disease.


Estimating PMTCT's Impact on Heterosexual HIV Transmission: A Mathematical Modeling Analysis.
Prevention of mother-to-child HIV transmission (PMTCT) strategies include combined short-course antiretrovirals during pregnancy (Option A), triple-drug antiretroviral treament (ART) during pregnancy and breastfeeding (Option B), or lifelong ART (Option B+). The WHO also recommends ART for HIV treatment and prevention of sexual transmission of HIV. The impact of PMTCT strategies on prevention of sexual HIV transmission of HIV is not known. We estimated the population-level impact of PMTCT interventions on heterosexual HIV transmission in southwestern Uganda and KwaZulu-Natal, South Africa, two regions with different HIV prevalence and fertility rates. We constructed and validated dynamic, stochastic, network-based HIV transmission models for each region. PMTCT Options A, B, and B+ were simulated over ten years under three scenarios: 1) current ART and PMTCT coverage, 2) current ART and high PMTCT coverage, and 3) high ART and PMTCT coverage. We compared adult HIV incidence after ten years of each intervention to Option A (and current ART) at current coverage. At current coverage, Options B and B+ reduced heterosexual HIV incidence by about 5% and 15%, respectively, in both countries. With current ART and high PMTCT coverage, Option B+ reduced HIV incidence by 35% in Uganda and 19% in South Africa, while Option B had smaller, but meaningful, reductions. The greatest reductions in HIV incidence were achieved with high ART and PMTCT coverage. In this scenario, all PMTCT strategies yielded similar results. Implementation of Options B/B+ reduces adult HIV incidence, with greater effect (relative to Option A at current levels) in Uganda than South Africa. These results are likely driven by Uganda's higher fertility rates.


Developmental course of ADHD symptomatology during the transition from childhood to adolescence: a review with recommendations.
Although historically conceptualized as a disorder that was limited to males during middle childhood, ADHD is currently conceptualized as a chronic disorder that persists into adolescence and adulthood for both sexes. Nonetheless, the veracity of adult ADHD continues to be the source of debate. In order to frame this debate, research leading to the conceptualization of ADHD as a chronic disorder is reviewed. A distinction is made between the developmental outcomes versus the developmental course of ADHD. It is concluded that although childhood ADHD is associated with negative developmental outcomes in adolescence and adulthood, questions about the developmental course of ADHD remain. Although it appears that ADHD diminishes with advancing age, a number of methodological limitations prohibit firm conclusions. Recommendations for future studies are made with an emphasis on 1) overcoming extant methodological limitations in the literature and 2) the need for theoretically derived hypotheses regarding continuity and change in ADHD symptomatology over time.


Llama immunization with full-length VAR2CSA generates cross-reactive and inhibitory single-domain antibodies against the DBL1X domain.
VAR2CSA stands today as the leading vaccine candidate aiming to protect future pregnant women living in malaria endemic areas against the severe clinical outcomes of pregnancy associated malaria (PAM). The rational design of an efficient VAR2CSA-based vaccine relies on a profound understanding of the molecular interactions associated with P. falciparum infected erythrocyte sequestration in the placenta. Following immunization of a llama with the full-length VAR2CSA recombinant protein, we have expressed and characterized a panel of 19 nanobodies able to recognize the recombinant VAR2CSA as well as the surface of erythrocytes infected with parasites originating from different parts of the world. Domain mapping revealed that a large majority of nanobodies targeted DBL1X whereas a few of them were directed towards DBL4ε, DBL5ε and DBL6ε. One nanobody targeting the DBL1X was able to recognize the native VAR2CSA protein of the three parasite lines tested. Furthermore, four nanobodies targeting DBL1X reproducibly inhibited CSA adhesion of erythrocytes infected with the homologous NF54-CSA parasite strain, providing evidences that DBL1X domain is part or close to the CSA binding site. These nanobodies could serve as useful tools to identify conserved epitopes shared between different variants and to characterize the interactions between VAR2CSA and CSA.


Automaticity of online control processes in manual aiming.
Experiments that manipulated the visual feedback of the moving limb have suggested the existence of efficient and automatic online correction processes. We wanted to determine whether the latency/gain of the correction for a cursor jump are only influenced by the size of the cursor jump or whether they are also influenced by the need of a correction for the target to be reached. In Experiment 1, we used two target sizes (5 and 30 mm) and three cursor-jump amplitudes (5, 15, and 25 mm), so that for some target size/cursor-jump combinations, no correction would be needed to reach the target. Participants were not aware of the cursor jump, but we observed a 65% correction regardless of target size. In Experiment 2, participants pointed at a large target for which a 15-mm cursor jump never impeded target attainment. Participants modified the trajectory of their movement in the direction opposite to the cursor jump (42% of the cursor jump). Our results indicate that the latency of the correction for a cursor jump was not influenced by the size of the cursor jump or that of the target. However, the correction tailored the movement's initial impulse according to the target's characteristics.


Combining alcohol and energy drinks: An examination of psychosocial constructs and alcohol outcomes among college students using a longitudinal design.
Combining alcohol and energy drinks (e.g., Red Bull and vodka) is a significant problem on college campuses. To date, few studies have examined psychosocial constructs specific to alcohol-energy drink cocktail (AmED) consumption that could be amenable to change via prevention efforts targeting this population. The aim of the current study was to examine differences in AmED-specific attitudes, beliefs, normative perceptions among students who report AmED use compared to college student drinkers who consume alcohol only. In addition, these two groups were compared on their intentions to consume AmEDs, actual AmED use, and other drinking outcomes using a longitudinal design. Participants (N = 386, 59% female) completed a web-based survey in the spring of their first year of college and fall of their second year assessing alcohol-energy drink cocktail use, psychosocial decision-making constructs, heavy drinking, and alcohol-related consequences. Findings revealed that combiners of alcohol and energy drinks had more positive attitudes and beliefs about AmED use, higher perceived peer norms, and stronger intentions toward future use. Accordingly, at Time 2, this group reported significantly higher AmED use, along with high-risk drinking and related consequences. The findings reinforce that AmED use is associated with risky drinking practices, and suggest potential targets for change for future prevention efforts.