RT1.P, rat class Ib genes related to mouse TL: evidence that CD1 molecules but not authentic TL antigens are expressed by rat thymus.
CD1 and TL were once thought to be genetic homologues because of their thymus-specific expression. We investigated their equivalents in the rat to clarify whether their structure and pattern of expression are conserved in rodents. Two rat class Ib genes, containing 3' sequences very similar to mouse TL, were identified and designated RT1.P. Neither of them, however, can encode ordinary class I molecules due to the accumulation of harmful mutations in the 5' regions that are unique to RT1.P, while the 3' TL-like regions still retain protein-coding capacity. Comparison of the structural organization of three types of TL family genes, which include mouse T3/T18-encoding TL antigens, mouse T1/T16, and rat RT1. P1/P2 pseudogenes, revealed the presence of a clear demarcation between the type-specific and TL-specific sequences at intron 3. This finding suggests that recombination plays an important role in creating the TL family genes in rodents. Characteristic features of TL, such as a low level of polymorphism and linkage to the major histocompatibility complex, were also observed in the rat. On the other hand, rat CD1 molecules were expressed at a high level on the surface of thymocytes. Absence of authentic TL antigens and thymic expression of CD1d molecules in the rat suggest the plasticity and conservation of class Ib genes in rodent evolution. Functions of TL may be substituted with CD1 or other class Ib molecules expressed by rat thymus.


Stem cells and vascular dementia: from basic science to the clinic.
Vascular dementia (VD) is the second most common cause of dementia following Alzheimer's disease (AD). The major symptoms of VD including memory loss, language deficits and impairment of executive functions. Its specific etiology and pathogenesis remain unknown. Currently, treatment options of VD are still limited. The therapeutic strategies aim to control the vascular risk factors and improve the cognitive function. In recent years, cell therapy for neurodegenerative diseases has attracted a great deal of attention. Evidence suggested that stem cell transplantation could improve the symptoms of cerebral infarction and AD. Therefore, it may serve as a potential therapy for VD. We summarized the latest research results both in vitro and in vivo. Further, the clinical trial of stem cell transplantation in VD patients was also reviewed. Finally, the limitations and future directions of cell therapy in VD treatment were discussed.


Bringing Feedback in From the Outback via a Generic and Preference-Sensitive Instrument for Course Quality Assessment.
Much effort and many resources have been put into developing ways of eliciting valid and informative student feedback on courses in medical, nursing, and other health professional schools. Whatever their motivation, items, and setting, the response rates have usually been disappointingly low, and there seems to be an acceptance that the results are potentially biased. The objective of the study was to look at an innovative approach to course assessment by students in the health professions. This approach was designed to make it an integral part of their educational experience, rather than a marginal, terminal, and optional add-on as "feedback". It becomes a weighted, but ungraded, part of the course assignment requirements. A ten-item, two-part Internet instrument, MyCourseQuality (MCQ-10D), was developed following a purposive review of previous instruments. Shorthand labels for the criteria are: Content, Organization, Perspective, Presentations, Materials, Relevance, Workload, Support, Interactivity, and Assessment. The assessment is unique in being dually personalized. In part 1, at the beginning of the course, the student enters their importance weights for the ten criteria. In part 2, at its completion, they rate the course on the same criteria. Their ratings and weightings are combined in a simple expected-value calculation to produce their dually personalized and decomposable MCQ score. Satisfactory (technical) completion of both parts contributes 10% of the marks available in the course. Providers are required to make the relevant characteristics of the course fully transparent at enrollment, and the course is to be rated as offered. A separate item appended to the survey allows students to suggest changes to what is offered. Students also complete (anonymously) the standard feedback form in the setting concerned. Piloting in a medical school and health professional school will establish the organizational feasibility and acceptability of the approach (a version of which has been employed in one medical school previously), as well as its impact on provider behavior and intentions, and on student engagement and responsiveness. The priorities for future improvements in terms of the specified criteria are identified at both individual and group level. The group results from MCQ will be compared with those from the standard feedback questionnaire, which will also be completed anonymously by the same students (or some percentage of them). We present a protocol for the piloting of a student-centered, dually personalized course quality instrument that forms part of the assignment requirements and is therefore an integral part of the course. If, and how, such an essentially formative Student-Reported Outcome or Experience Measure can be used summatively, at unit or program level, remains to be determined, and is not our concern here.


Efficacy of an intensive outpatient rehabilitation program in alcoholism: predictors of outcome 6 months after treatment.
Treatment of alcohol-dependent patients was primarily focused on inpatient settings in the past decades. The efficacy of these treatment programs has been evaluated in several studies and proven to be sufficient. However, with regard to the increasing costs in public healthcare systems, questions about alternative treatment strategies have been raised. Meanwhile, there is growing evidence that outpatient treatment might be comparably effective as inpatient treatment, at least for subgroups of alcohol dependents. On that background, the present study aimed to evaluate the efficacy of a high-structured outpatient treatment program in 103 alcohol-dependent patients. 74 patients (72%) terminated the outpatient treatment regularly. At 6 months' follow-up, 95% patients were successfully located and personally re-interviewed. Analyses revealed that 65 patients (64%) were abstinent at the 6-month follow-up evaluation and 37 patients (36%) were judged to be non-abstinent. Pre-treatment variables which were found to have a negative impact (non-abstinence) on the 6-month outcome after treatment were a higher severity of alcohol dependence measured by a longer duration of alcohol dependence, a higher number of prior treatments and a stronger alcohol craving (measured by the Obsessive Compulsive Drinking Scale). Further patients with a higher degree of psychopathology measured by the Beck Depression Inventory (depression) and State-Trait Anxiety Inventory (anxiety) relapsed more often. In summary, results of this study indicate a favorable outcome of socially stable alcohol-dependent patients and patients with a lower degree of depression, anxiety and craving in an intensive outpatient rehabilitation program.


Pulmonary capillary hemangiomatosis: the role of invasive cardiopulmonary exercise testing.
Pulmonary capillary hemangiomatosis (PCH) is a rare form of pulmonary arterial hypertension (PAH) characterized by pulmonary capillary proliferation and pseudoinvasion of collagenous septal structures. PCH is often accompanied by veno-occlusive changes and pulmonary hypertensive arterial remodeling. The clinical and pathological diagnosis of PCH can be subtle and easily missed. Most reported cases of PCH have been associated with resting PAH. We report the cases of 3 patients who initially presented with exertional dyspnea with normal to mildly elevated resting pulmonary arterial pressures and marked intrapulmonary shunting. In all 3 patients, invasive cardiopulmonary exercise testing was suggestive of pulmonary vascular disease. Owing to abnormalities on invasive exercise testing, lung biopsies were performed; these were diagnostic of PCH, and the patients were referred for lung transplantation. We describe unique features of these 3 cases-including novel pathological findings and the presence of intrapulmonary shunting in all 3 patients-and we discuss the role of cardiopulmonary exercise testing in the evaluation of PCH.


Plant dynamin-related protein families DRP1 and DRP2 in plant development.
Two separate families of Arabidopsis dynamin-related proteins, DRP1 and DRP2, have been implicated in clathrin-mediated endocytosis and cell plate maturation during cytokinesis. The present review summarizes the current genetic, biochemical and cell biological knowledge about these two protein families, and suggests key directions for more fully understanding their roles and untangling their function in membrane trafficking. We focus particularly on comparing and contrasting these two protein families, which have very distinct domain structures and are independently essential for Arabidopsis development, yet which have been implicated in very similar cellular processes during cytokinesis and cell expansion.


Validation of a SARS-CoV-2 spike protein ELISA for use in contact investigations and serosurveillance.
Since emergence of SARS-CoV-2 in late 2019, there has been a critical need to understand prevalence, transmission patterns, to calculate the burden of disease and case fatality rates. Molecular diagnostics, the gold standard for identifying viremic cases, are not ideal for determining true case counts and rates of asymptomatic infection. Serological detection of SARS-CoV-2 specific antibodies can contribute to filling these knowledge gaps. In this study, we describe optimization and validation of a SARS-CoV-2-specific-enzyme linked immunosorbent assay (ELISA) using the prefusion-stabilized form of the spike protein [1]. We performed receiver operator characteristic (ROC) analyses to define the specificities and sensitivities of the optimized assay and examined cross reactivity with immune sera from persons confirmed tohave had infections with other coronaviruses. These assays will be used to perform contact investigations and to conduct large-scale, cross sectional surveillance to define disease burden in the population.


Consensus-based perioperative protocols during the COVID-19 pandemic.
During the COVID-19 pandemic, quaternary-care facilities continue to provide care for patients in need of urgent and emergent invasive procedures. Perioperative protocols are needed to streamline care for these patients notwithstanding capacity and resource constraints. A multidisciplinary panel was assembled at the University of California, San Francisco, with 26 leaders across 10 academic departments, including 7 department chairpersons, the chief medical officer, the chief operating officer, infection control officers, nursing leaders, and resident house staff champions. An epidemiologist, an ethicist, and a statistician were also consulted. A modified two-round, blinded Delphi method based on 18 agree/disagree statements was used to build consensus. Significant disagreement for each statement was tested using a one-sided exact binomial test against an expected outcome of 95% consensus using a significance threshold of p < 0.05. Final triage protocols were developed with unblinded group-level discussion. Overall, 15 of 18 statements achieved consensus in the first round of the Delphi method; the 3 statements with significant disagreement (p < 0.01) were modified and iteratively resubmitted to the expert panel to achieve consensus. Consensus-based protocols were developed using unblinded multidisciplinary panel discussions. The final algorithms 1) quantified outbreak level, 2) triaged patients based on acuity, 3) provided a checklist for urgent/emergent invasive procedures, and 4) created a novel scoring system for the allocation of personal protective equipment. In particular, the authors modified the American College of Surgeons three-tiered triage system to incorporate more urgent cases, as are often encountered in neurosurgery and spine surgery. Urgent and emergent invasive procedures need to be performed during the COVID-19 pandemic. The consensus-based protocols in this study may assist healthcare providers to optimize perioperative care during the pandemic.


Atrial Fibrillation Recurrence and Peri-Procedural Complication Rates in nMARQ vs. Conventional Ablation Techniques: A Systematic Review and Meta-Analysis.
Background and Objectives: Atrial fibrillation is a common abnormal cardiac rhythm caused by disorganized electrical impulses. AF which is refractory to antiarrhythmic management is often treated with catheter ablation. Recently a novel ablation system (nMARQ) was introduced for PV isolation. However, there has not been a systematic review of its efficacy or safety compared to traditional ablation techniques. Therefore, we conducted this meta-analysis on the nMARQ ablation system. Methods: PubMed and EMBASE were searched up until 1st of September 2017 for articles on nMARQ. A total of 136 studies were found, and after screening, 12 studies were included in this meta-analysis. Results: Our meta-analysis shows that the use of nMARQ was associated with higher odds of AF non-recurrence (n = 1123, odds ratio = 6.79, 95% confidence interval 4.01-11.50; P < 0.05; I2 took a value of 83%). Moreover, the recurrence rate of AF using nMARQ was not significantly different from that of traditional ablation procedures (n = 158 vs. 196; OR = 0.97, 95% confidence interval:0.59-1.61). No significant difference in complication rates was observed between these groups (RR: 0.86; 95% CI: 0.37-1.99; P > 0.05). There were four reported mortalities in the nMARQ group compared to none in the conventional ablation group (relative risk: 1.58; 95% CI: 0.09-29.24; P > 0.05). Conclusions: AF recurrence rates are comparable between nMARQ and conventional ablation techniques. Although general complication rates are similar for both groups, the higher mortality with nMARQ suggests that conventional techniques should be used for resistant AF until improved safety profiles of nMARQ can be demonstrated.


Dissociative anesthesia for safety's sake: ketamine and diazepam--a 35-year personal experience.
Recent discussions and proposed rules and regulations regarding outpatient surgery facilities have raised the question of the appropriateness of general anesthesia versus heavy sedation. The controversy is based mostly on anecdotal information and the prejudice of the authors. A recent article that describes the improved platelet function induced by ketamine adds patient safety to the rationale for sedation. Most of us have trained in university settings where an entire department was devoted to general anesthesia and little true outpatient surgery was performed. When ambulatory facilities were available, they were usually staffed by anesthesiologists. Indeed, the first free-standing outpatient surgery center in Phoenix, Arizona, was owned and operated by a local group of anesthesiologists. Properly administered, diazepam and ketamine dissociative sedation is safe and effective for every aesthetic procedure, regardless of size or duration, and it should be available for all aesthetic surgeons. In the author's experience, more than 30,000 procedures have been performed with this method since 1966 without a single case of deep vein thrombosis or pulmonary embolus. In contrast, a former associate, because of his lack of experience, chose to use general anesthesia for a few larger cases in another facility. One of those cases, an abdominoplasty, resulted in a serious case of deep vein thrombosis with subsequent alleged disability and litigation. Therefore, the author is writing to share his extensive experience with his colleagues in hopes that these safe systems will become more widespread and to spare future patients the attendant unnecessary increased morbidity and mortality associated with general anesthesia.


Cannabis education needs assessment among Canadian physicians-in-training.
Since 1999, the Canadian courts have recognized the rights of patients to access cannabis for therapeutic purposes (CTP). Due to the increasing interest in the use of CTP, competency with the topic among health care providers is essential. As concerns mount around the role of industry involvement in cannabis education, it has become increasingly important for medical schools to provide physicians-in-training balanced evidence regarding the harms and benefits of CTP. In the present study, we surveyed Canadian physicians-in-training regarding their knowledge, experience, attitudes, and barriers surrounding CTP. Survey questions were adapted from extant physician and nurse practitioner education needs assessments. We invited representatives from all 17 Canadian universities with a Faculty of Medicine to electronically distribute the survey to physicians-in-training. The survey was accessed by 93 physicians-in-training of whom 76 provided responses (46 % female; Mage = 28, SD = 3.03). Physicians-in-training reported receiving significantly less instruction on CTP than they desired. Responses demonstrated differences between current and desired knowledge across all domains queried. More education was the factor identified as most likely to increase comfort authorizing and discussing CTP with patients. Findings from this study demonstrate an expressed desire for more education surrounding CTP among a self-selected sample of Canadian physicians-in-training. There was a substantial divergence between current and desired levels of knowledge, and the largest gaps related to creating effective treatment plans and understanding the risks and benefits of CTP. Improving the educational opportunities of students will improve standard-of-care for patients.


Loss of switch/sucrose non-fermenting complex protein expression in undifferentiated gastrointestinal and pancreatic carcinomas.
Undifferentiated carcinoma refers to an epithelial malignancy that lacks morphological evidence of differentiation. Recent studies have implicated the loss of constitutively expressed switch/sucrose non-fermenting (SWI/SNF) complex subunits in undifferentiated carcinomas of the gastrointestinal tract and other sites. In this study we examine the expression of SWI/SNF and mismatch repair (MMR) proteins in a series of undifferentiated carcinomas from the gastrointestinal tract and the pancreas. We searched pathology databases from four Canadian health centres for primary undifferentiated carcinoma from gastrointestinal and pancreatic resection specimens. Upon review of 31 cases, 19 were confirmed to be undifferentiated carcinomas (eight colonic, six gastric, three pancreatic, one appendiceal and one duodenal). Immunohistochemical analysis of SMARCA4, SMARCA2, SMARCB1, ARID1A, ARID1B, MSH2, MSH6, MLH1 and PMS2 was performed on whole sections. Five of 19 (26%) showed loss of core SWI/SNF proteins (two loss of SMARCA4, one loss of SMARCB1 and two concurrent loss of ARID1A and ARID1B). SMARCA4, SMARCB1, or ARID1A/ARID1B-deficient undifferentiated carcinoma consistently exhibited sheet-like growth pattern, with cellular discohesion and rhabdoid morphology. Nine of 17 undifferentiated carcinomas tested were MMR-deficient by immunohistochemistry. In comparison, none of the 12 poorly differentiated carcinomas that were originally diagnosed as undifferentiated carcinomas showed loss of SMARCA4, SMARCA2, SMARCB1 or ARID1B. Undifferentiated gastrointestinal/pancreatic carcinomas show frequent loss of expression of SWI/SNF complex proteins. The loss of these core components of SWI/SNF complex may contribute to the arrest of cellular differentiation, resulting in the undifferentiated histology and aggressive clinical behaviour.


Real-Time Monitoring of Yersinia pestis Promoter Activity by Bioluminescence Imaging.
Bioluminescence imaging (BLI) has become a major strategy for real-time analysis of dynamic biological processes. In particular, bioluminescent reporter microorganisms have been designed to advance our understanding of infectious diseases. Non-invasive monitoring of light-emitting pathogenic bacteria has revealed novel features of pathogenesis and enabled quantitative and qualitative analysis of antibacterial therapies. Transcriptional gene fusions using the bacterial luciferase operon luxCDABE as a reporter have been successfully used to monitor gene expression in vitro and in vivo, leading to valuable applications and major findings. In this chapter, we describe the construction of Yersinia pestis strains bearing a chromosomal copy of the luxCDABE operon under the control of promoters regulated by temperature and their application to quantify gene expression in real-time in bacteria growing in vitro and in a murine bubonic plague model.


Specific heat measurement of thin suspended SiN membrane from 8 K to 300 K using the 3ω-Völklein method.
We present a specific heat measurement technique adapted to thin or very thin suspended membranes from low temperature (8 K) to 300 K. The presented device allows the measurement of the heat capacity of a 70 ng silicon nitride membrane (50 or 100 nm thick), corresponding to a heat capacity of 1.4 × 10(-10) J/K at 8 K and 5.1 × 10(-8) J/K at 300 K. Measurements are performed using the 3ω method coupled to the Völklein geometry. This configuration allows the measurement of both specific heat and thermal conductivity within the same experiment. A transducer (heater/thermometer) is used to create an oscillation of the heat flux on the membrane; the voltage oscillation appearing at the third harmonic which contains the thermal information is measured using a Wheatstone bridge set-up. The heat capacity measurement is performed by measuring the variation of the 3ω voltage over a wide frequency range and by fitting the experimental data using a thermal model adapted to the heat transfer across the membrane. The experimental data are compared to a regular Debye model; the specific heat exhibits features commonly seen for glasses at low temperature.


Effectiveness of strategies for reducing risky alcohol consumption among youth living in rural or remote areas: a systematic review protocol.
The aim of this review is to evaluate the effectiveness of strategies for reducing risky alcohol consumption among youth living in rural and remote areas. Youth living in rural and remote areas are more likely to drink alcohol and are at higher risk of experiencing alcohol-related harm than youth living in urban locations. However, a review has not yet been conducted evaluating the effectiveness of strategies for reducing young people's risky alcohol consumption in rural and remote locations. This systematic review will consider papers that include youth (aged 12 to 24 years) who are identified as living in rural, remote, regional, non-urban or non-metropolitan locations. Any intervention or strategy with the purpose of reducing or preventing alcohol consumption or alcohol-related harms among this population will be considered. The primary outcome is frequency of short-term risky alcohol consumption, as measured by self-reported incidents of drinking five or more standard drinks. Secondary outcomes will also be included. Sources of published studies, unpublished studies and gray literature will be searched. Only studies in English published from 1999 will be included. Titles and abstracts of all search results will be screened. The full text of potentially relevant studies will then be assessed in detail. Studies will be stratified by methodological quality. The data extracted will include specific details about the populations, study methods, interventions and outcomes. Studies will be pooled in statistical meta-analysis, where possible, and where statistical pooling is not possible, the findings will be presented in narrative form.


A novel fluorescent retrograde neural tracer: cholera toxin B conjugated carbon dots.
The retrograde neuroanatomical tracing method is a key technique to study the complex interconnections of the nervous system. Traditional tracers have several drawbacks, including time-consuming immunohistochemical or immunofluorescent staining procedures, rapid fluorescence quenching and low fluorescence intensity. Carbon dots (CDs) have been widely used as a fluorescent bio-probe due to their ultrasmall size, excellent optical properties, chemical stability, biocompatibility and low toxicity. Herein, we develop a novel fluorescent neural tracer: cholera toxin B-carbon dot conjugates (CTB-CDs). It can be taken up and retrogradely transported by neurons in the peripheral nervous system of rats. Our results show that CTB-CDs possess high photoluminescence intensity, good optical stability, a long shelf-life and non-toxicity. Tracing with CTB-CDs is a direct and more economical way of performing retrograde labelling experiments. Therefore, CTB-CDs are reliable fluorescent retrograde tracers.


[Effects of oxidative stress and NF-kappaB levels in peripheral blood mononuclear cells on development of silicosis].
To investigate the change of indicators of oxidative stress in serum and NF-kappaB in peripheral blood mononuclear cells of patients with silicosis, and explore the mechanism of the development of silicosis. The subjects were divided into (1) 200 workers exposed to SiO2 for at least 1 years in a foundry served as the dust-exposure group; (2) 130 cases with silicosis (I phase silicosis 64 cases, II phase 46 cases III phase 20 cases) served as the silicosis group; (3) 32 cases with 0+ phase silicosis in the foundry served as the observed group,(4)100 subjects from a hotel served as the control group. The serum including superoxide dismutase (SOD), nitric oxide (NO), serum glutathione peroxidase (GSH-Px), total antioxidant capacity (T-AOC), nitric oxide synthase (NOS), lipid malondialdehyde (MDA) and NF-kappaB protein levels in peripheral blood mononuclear cells were determined, respectively. Compared with the control group, NO levels in dust-exposed group and silicosis group significantly increased, and SOD decreased significantly (P < 0.05 or P < 0.01). Compared with the control group and dust-exposed group, T-AOC, NOS, MDA levels in silicosis group significantly increased (P < 0.05 or P < 0.01). GSH-Px in dust-exposed group and silicosis group were (231.164 +/- 36.484) and (270.469 +/- 39.228)U/ml, respectively which were significantly than that [(223.360 +/- 46.838) U/ml] in control group (P < 0.05 or P < 0.01), and there was significant difference of GSHPx between the silicosis group and the dust-exposed group significantly (P < 0.01) . GSH-Px level [(290.750 +/- 39.129) U/ml] in III phase silicosis group were significantly higher than those [(256.906 +/- 21.41) and (259.594 +/- 34.79) U/ml] in observation group and I phase silicosis group (P < 0.05). NF-kappaB levels [(72.06 +/- 9.12) and (85.25 +/- 11.64) ng/L] in dust-exposed group and silicosis group were significantly higher than that [(59.71 +/- 9.27) ng/L] in control group (P < 0.01), and there was significant difference of between the silicosis group and the dust-exposed group (P < 0.01). There was a positive correlation between serum GSH-Px level and the silicosis stages (r = 0.507, P < 0.01). Also there was a positive correlation between NF-kappaB level and silicosis stages, age, GSH-Px or NO levels (r = 0.376, 0.243, 0.233, 0.221, P < 0.01). The imbalance of oxidative and anti-oxidation system and the activation of NF-kappaB are related with the occurrence and development of silicosis. The monitoring of oxidative stress indicators and NF-kappaB is beneficial to the prediction and prognosis assessment of silicosis.


Taste preference and psychopathology.
Excessive food intake has been linked to many factors including taste preference and the presence of psychopathology. The purpose of this study was to investigate the association between sweet and salty taste preference and psychopathology in patients with severe obesity. A consecutive series of patients applying for bariatric surgery was recruited for the study. Taste preference was self-reported. Psychopathology was assessed using the revised version of the Minnesota Multiphasic Personality Inventory-2 (MMPI-2). 190 patients were included in the study. In comparison with patients who had salty taste preference, patients with sweet taste preference had significantly higher elevations on the depression (OD: 4.090, p = 0.010) and the hysteria (OD: 2.951, p = 0.026) clinical scales of the MMPI-2. The results suggest the presence of an association between taste preference and psychopathology. The findings may be of interest for clinicians who are involved in the treatment of obesity. In particular, they may wish to pay increased attention to patients with sweet taste preference or who have a strong attraction for both sweet and salty foods, in order to detect psychopathology and to adapt the treatment.


Optical effects of energetic copper-ion irradiation on copper mirrors.
The optical effects of radiation damage to metal mirrors have been examined using copper-ion beams incident on copper mirrors. Incident ion energies of 2, 5, and 8 MeV were used and dose levels were examined up to 4 x 10(16) ions/cm(2). Both crystalline and OFHC copper mirrors were studied. In situ ellipsometric data were recorded (lambda = 633 nm) during the irradiations to determine the dose-dependent behavior of the radiation effects. Spectral reflectivity and optical scattering were evaluated for samples before and after the irradiations. Complementary analysis of the samples was performed with scanning electron microscopy, Auger electron spectroscopy, and electron spectroscopy for chemical analysis. Significant changes in ellipsometric parameters were noted during the irradiations. After exposure to large dose values, the optical properties of crystalline mirrors were consistent with the optical properties of bare copper. The ellipsometric changes have been attributed to alteration of the surface oxide film. Dose-dependent data have been used to determine the important damage mechanisms.


An overview of machine learning methods for monotherapy drug response prediction.
For an increasing number of preclinical samples, both detailed molecular profiles and their responses to various drugs are becoming available. Efforts to understand, and predict, drug responses in a data-driven manner have led to a proliferation of machine learning (ML) methods, with the longer term ambition of predicting clinical drug responses. Here, we provide a uniquely wide and deep systematic review of the rapidly evolving literature on monotherapy drug response prediction, with a systematic characterization and classification that comprises more than 70 ML methods in 13 subclasses, their input and output data types, modes of evaluation, and code and software availability. ML experts are provided with a fundamental understanding of the biological problem, and how ML methods are configured for it. Biologists and biomedical researchers are introduced to the basic principles of applicable ML methods, and their application to the problem of drug response prediction. We also provide systematic overviews of commonly used data sources used for training and evaluation methods.


Quick fixes to improve workers' health: Results using engineering assessment technology.
Personal respirable dust sampling and the evaluation of control technologies have been providing exposure information to the mining industry but not necessarily in a way that shows how technology can be integrated to provide organizational support and resources for workers to mitigate dust sources on site. In response, the U.S. National Institute for Occupational Safety and Health (NIOSH) used previously developed Helmet-CAM technology to design and engage in a behavioral/engineering cooperative intervention to initiate and enhance mine site conversations about the risks and potential occurrences of respirable silica dust exposures on the job as well as provide impetus and solutions for mitigating higher sources of dust. The study involved 48 workers from five mine sites, who agreed to participate between April 2015 and September 2016. Using the Helmet-CAM in this series of longitudinal interventions revealed several exposure trends in respirable silica dust sources and, in many cases, simple quick-fix strategies to reduce their sources. This paper focuses on several specific identified sources of dust that were elevated but could be reduced through basic engineering fixes, low-cost resources, and supportive communication from management to remind and engage workers in protective work practices.


Endoscopic corpus callosotomy and hemispherotomy.
Corpus callosotomy and hemispherotomy are conventionally performed via a large craniotomy with the aid of a microscope for children with intractable epilepsy. Primary technical considerations include completeness of disconnection and blood loss. The authors describe an endoscopic technique performed through a microcraniotomy for these procedures. Four patients with drop attacks and 2 with intractable seizures related to a neonatal stroke underwent endoscopic complete corpus callosotomy and hemispherotomy, respectively. The surgeries were performed through a 2- to 3-cm precoronal microcraniotomy. Interhemispheric dissection to the corpus callosum was done using the standard technique. Subsequently, the bimanual technique with a suction device mounted on an endoscope was used to perform a complete corpus callosotomy, including interforniceal and anterior commissure disconnection. In patients who had hemispherotomy, the fornix was resected posteriorly and lateral disconnection was done by unroofing the temporal horn. Anteriorly, endoscopic corticectomy was done along the ipsilateral anterior cerebral artery to reach the bifurcation of the internal carotid artery to complete the anterior disconnection. Postoperative MRI and diffusion tensor imaging (DTI) of the brain were performed to confirm complete disconnection. The procedure was accomplished successfully in all patients, with excellent visualization secured. None of the patients required a blood transfusion. Postoperative MRI and DTI confirmed completeness of the disconnection. Patients who underwent corpus callosotomy had complete resolution of drop attacks at a mean follow-up of 6 months, and patients who underwent hemispherotomy became seizure free. Endoscopic corpus callosotomy and hemispherotomy are surgically feasible procedures associated with minimal blood loss, minimal risk, and excellent visualization.


Claudin-3 regulates bile canalicular paracellular barrier and cholesterol gallstone core formation in mice.
Most cholesterol gallstones have a core consisting of inorganic and/or organic calcium salts, although the mechanisms of core formation are poorly understood. We examined whether the paracellular permeability of ions at hepatic tight junctions is involved in the core formation of cholesterol gallstones, with particular interest in the role of phosphate ion, a common food additive and preservative. We focused on claudin-3 (Cldn3), a paracellular barrier-forming tight junction protein whose expression in mouse liver decreases with age. Since Cldn3-knockout mice exhibited gallstone diseases, we used them to assess the causal relationship between paracellular phosphate ion permeability and the core formation of cholesterol gallstones. In the liver of Cldn3-knockout mice, the paracellular phosphate ion permeability through hepatic tight junctions was significantly increased, resulting in calcium phosphate core formation. Cholesterol overdose caused cholesterol gallstone disease in these mice. We revealed that in the hepatobiliary system, Cldn3 functions as a paracellular barrier for phosphate ions, to help maintain biliary ion homeostasis. We provide in vivo evidence that elevated phosphate ion concentrations play a major role in the lifestyle- and age-related risks of developing cholesterol gallstone disease under cholesterol overdose. Herein, we reveal a new mechanism for cholesterol gallstone formation, in which increased paracellular phosphate ion permeability across hepatobiliary epithelia causes calcium phosphate core formation and cholesterol gallstones. Thus, altered phosphate ion metabolism under cholesterol overdose plays a major role in the lifestyle- and age-related risks of developing cholesterol gallstone disease.


Design and characterization of a metal-ion beam and nitrogen-radical beam source PVD system with in-situ AES constitution and HEED structure analysisApplication to the growth of Cu-N film.
The construction and the operation mode of an ultrahigh vacuum PVD system with integrated electron spectroscopic surface analysis is described. It consists of two metal-ion beam sources and a nitrogen radical beam source. High-energy electron diffraction (HEED) with grazing incidence of the electron beam is applied in-situ to determine the crystallographic data, as texture and structure of the growing layer. Chemical composition and bonding states of the components of the layer are determined also in-situ using an Auger electron spectrometer (AES). In-situ is taken to mean that analysis takes place during deposition of the layer. This work shows that the information depth of HEED with grazing incidence of the beam (theta< 1 degrees ) is of the same order of magnitude as the information depthof AES i.e. a few atom layers. This enables constitution and structure of the near-surface region of the growing layer to be directly determined as a function of the PVD parameters. In the initial experiments Cu/Al bilayers, homogeneous Cu(3)N and heterogeneous Cu/Cu(3)N layers were deposited. The influence of the Cu-ion energy and of the radical portion in the nitrogen reactive gas on the formation of the homogeneous Cu(3)N layer was investigated.


Role of locus coeruleus in attention and behavioral flexibility.
Previous findings have implicated the noradrenergic locus coeruleus (LC) system in functions along the dimension of arousal or attention. It has remained uncertain what role this system has in attention, or what mechanisms may be involved. We review our recent work examining activity of LC neurons in monkeys performing a visual discrimination task that requires focused attention. Results indicate that LC cells exhibit phasic or tonic modes of activity, that closely correspond to good or poor performance on this task, respectively. A computational model was used to simulate these results. This model predicts that alterations in electrotonic coupling among LC cells may produce the different modes of activity and corresponding differences in performance. This model also indicates that the phasic mode of LC activity may promote focused or selective attention, whereas the tonic mode may produce a state of high behavioral flexibility or scanning attentiveness. The implications of these results for clinical disorders such as attention-deficit hyperactivity disorder, stress disorders, and emotional and affective disorders are discussed.


Frequency tuning allows flow direction control in microfluidic networks with passive features.
Frequency tuning has emerged as an attractive alternative to conventional pumping techniques in microfluidics. Oscillating (AC) flow driven through a passive valve can be rectified to create steady (DC) flow, and tuning the excitation frequency to the characteristic (resonance) frequency of the underlying microfluidic network allows control of flow magnitude using simple hardware, such as an on-chip piezo buzzer. In this paper, we report that frequency tuning can also be used to control the direction (forward or backward) of the rectified DC flow in a single device. Initially, we observed that certain devices provided DC flow in the "forward" direction expected from previous work with a similar valve geometry, and the maximum DC flow occurred at the same frequency as a prominent peak in the AC flow magnitude, as expected. However, devices of a slightly different geometry provided the DC flow in the opposite direction and at a frequency well below the peak AC flow. Using an equivalent electrical circuit model, we found that the "forward" DC flow occurred at the series resonance frequency (with large AC flow peak), while the "backward" DC flow occurred at a less obvious parallel resonance (a valley in AC flow magnitude). We also observed that the DC flow occurred only when there was a measurable differential in the AC flow magnitude across the valve, and the DC flow direction was from the channel with large AC flow magnitude to that with small AC flow magnitude. Using these observations and the AC flow predictions from the equivalent circuit model, we designed a device with an AC flowrate frequency profile that was expected to allow the DC flow in opposite directions at two distinct frequencies. The fabricated device showed the expected flow reversal at the expected frequencies. This approach expands the flow control toolkit to include both magnitude and direction control in frequency-tuned microfluidic pumps. The work also raises interesting questions about the origin of flow reversal behavior that may be addressed by the further study of the circuit model behavior or dynamic modeling of the fluid-solid mechanics of the valve under the AC flow.


Robust visual tracking using an adaptive coupled-layer visual model.
This paper addresses the problem of tracking objects which undergo rapid and significant appearance changes. We propose a novel coupled-layer visual model that combines the target's global and local appearance by interlacing two layers. The local layer in this model is a set of local patches that geometrically constrain the changes in the target's appearance. This layer probabilistically adapts to the target's geometric deformation, while its structure is updated by removing and adding the local patches. The addition of these patches is constrained by the global layer that probabilistically models the target's global visual properties, such as color, shape, and apparent local motion. The global visual properties are updated during tracking using the stable patches from the local layer. By this coupled constraint paradigm between the adaptation of the global and the local layer, we achieve a more robust tracking through significant appearance changes. We experimentally compare our tracker to 11 state-of-the-art trackers. The experimental results on challenging sequences confirm that our tracker outperforms the related trackers in many cases by having a smaller failure rate as well as better accuracy. Furthermore, the parameter analysis shows that our tracker is stable over a range of parameter values.


'Doing' health policy analysis: methodological and conceptual reflections and challenges.
The case for undertaking policy analysis has been made by a number of scholars and practitioners. However, there has been much less attention given to how to do policy analysis, what research designs, theories or methods best inform policy analysis. This paper begins by looking at the health policy environment, and some of the challenges to researching this highly complex phenomenon. It focuses on research in middle and low income countries, drawing on some of the frameworks and theories, methodologies and designs that can be used in health policy analysis, giving examples from recent studies. The implications of case studies and of temporality in research design are explored. Attention is drawn to the roles of the policy researcher and the importance of reflexivity and researcher positionality in the research process. The final section explores ways of advancing the field of health policy analysis with recommendations on theory, methodology and researcher reflexivity.


Diffusion-ordered NMR spectroscopy in the structural characterization of functionalized carbon nanotubes.
The emerging applications of functionalized carbon nanotubes (CNTs) in various research domains necessitate the use of many different analytical techniques to confirm their structural modifications in a fast and reliable manner. Thus far, NMR spectroscopy has not been among the main tools for characterization of organically modified carbon nanostructures. (1)H analysis is limited because the signals in these derivatives are typically weak and broad, resulting in uncertainties of a few parts per million, and because of the strong interference of residual solvent signals. To overcome these limitations, we investigated the applicability of proton NMR spectroscopy based on gradient-edited diffusion pulse sequences (1D diffusion-ordered spectroscopy, DOSY) in the characterization of CNT derivatives. In general, diffusion NMR experiments allow the separation of NMR signals of different species present in a mixture, according to their own diffusion coefficients, merging spectroscopy information with size analysis. In the present study, a selected set of CNT derivatives was synthesized and analyzed using 1D DOSY experiments by applying strong magnetic field gradients (up to 42.6 G cm(-1)). Colorimetric tests (i.e., Kaiser test) and TGA analysis support the NMR findings, which are related to isolated and/or bundled short SWNTs, on the basis of TEM and AFM characterization. The overall results show that the diffusion-based NMR spectroscopy is a fast and promising approach for the characterization of covalently modified CNT derivatives.


Multiparameter flow cytometric detection and quantification of senescent cells in vitro.
It has been over half a century since cellular senescence was first noted and characterized, and yet no consensus senescent marker has been reliably established. This challenge is compounded by the complexity and heterogenic phenotypes of senescent cells. This necessitates the use of multiple biomarkers to confidently characterise senescent cells. Despite cytochemical staining of senescence associated-beta-galactosidase being a single marker approach, as well as being time and labour-intensive, it remains the most popular detection method. We have developed an alternative flow cytometry-based method that simultaneously quantifies multiple senescence markers at a single-cell resolution. In this study, we applied this assay to the quantification of both replicative and induced senescent primary cells. Using this assay, we were able to quantify the activity level of SA β-galactosidase, the expression level of p16INK4a and γH2AX in these cell populations. Our results show this flow cytometric approach to be sensitive, robust, and consistent in discriminating senescent cells in different cell senescence models. A strong positive correlation between these commonly- used senescence markers was demonstrated. The method described in this paper can easily be scaled up to accommodate high-throughput screening of senescent cells in applications such as therapeutic cell preparation, and in therapy-induced senescence following cancer treatment.


The immunoglobulin-superfamily molecule basigin is a binding protein for oligomannosidic carbohydrates: an anti-idiotypic approach.
Recognition molecules that carry carbohydrate structures regulate cell interactions during development and play important roles in synaptic plasticity and regeneration in the adult. Glycans appear to be involved in these interactions. We have searched for binding proteins for oligomannosidic structures using the L3 antibody directed against high mannose-type glycans in an anti-idiotypic approach. A selected monoclonal anti-idiotype antibody was used for affinity chromatography and identified basigin as a binding protein from mouse brain detergent lysates. Basigin was found to bind to high mannose-carrying cell recognition molecules, such as myelin-associated glycoprotein, L1, the beta2-subunit of Na+/K+-ATPase and an oligomannosidic neoglycolipid. Furthermore, basigin was involved in outgrowth of astrocytic processes in vitro. A striking homology between the first immunoglobulin (Ig)-like domain of basigin and the fourth Ig-like domain of NCAM, previously shown to bind to oligomannosidic glycans, and the lectin domain of the mannose receptor confirms that basigin is an oligomannose binding lectin. To our knowledge this is the first report that anti-idiotypic antibodies can be used to identify binding partners for carbohydrates.


Proteomics-based identification of protein gene product 9.5 as a tumor antigen that induces a humoral immune response in lung cancer.
We used a proteomic approach to identify proteins that commonly induce an antibody response in lung cancer. Sera from 64 newly diagnosed patients with lung cancer, 99 patients with other types of cancer, and 71 noncancer controls were analyzed for antibody-based reactivity against lung adenocarcinoma proteins resolved by two-dimensional PAGE. Unlike controls, autoantibodies against a protein identified by mass spectrometry as protein gene product 9.5 (PGP 9.5) were detected in sera from 9 of 64 patients with lung cancer. Circulating PGP 9.5 antigen was detected in sera from two additional patients with lung cancer, without detectable PGP 9.5 autoantibodies. PGP 9.5 is a neurospecific polypeptide previously proposed as a marker for non-small cell lung cancer, based on its expression in tumor tissue. Using A549 lung adenocarcinoma cell line, we have demonstrated that PGP 9.5 was present at the cell surface, as well as secreted. Thus, the findings of PGP 9.5 antigen and/or antibodies in serum of patients with lung cancer suggest that PGP 9.5 may have utility in lung cancer screening and diagnosis.


TPL-2-ERK1/2 signaling promotes host resistance against intracellular bacterial infection by negative regulation of type I IFN production.
Tuberculosis, caused by Mycobacterium tuberculosis, remains a leading cause of mortality and morbidity worldwide, causing ≈ 1.4 million deaths per year. Key immune components for host protection during tuberculosis include the cytokines IL-12, IL-1, and TNF-α, as well as IFN-γ and CD4(+) Th1 cells. However, immune factors determining whether individuals control infection or progress to active tuberculosis are incompletely understood. Excess amounts of type I IFN have been linked to exacerbated disease during tuberculosis in mouse models and to active disease in patients, suggesting tight regulation of this family of cytokines is critical to host resistance. In addition, the immunosuppressive cytokine IL-10 is known to inhibit the immune response to M. tuberculosis in murine models through the negative regulation of key proinflammatory cytokines and the subsequent Th1 response. We show in this study, using a combination of transcriptomic analysis, genetics, and pharmacological inhibitors, that the TPL-2-ERK1/2 signaling pathway is important in mediating host resistance to tuberculosis through negative regulation of type I IFN production. The TPL-2-ERK1/2 signaling pathway regulated production by macrophages of several cytokines important in the immune response to M. tuberculosis as well as regulating induction of a large number of additional genes, many in a type I IFN-dependent manner. In the absence of TPL-2 in vivo, excess type I IFN promoted IL-10 production and exacerbated disease. These findings describe an important regulatory mechanism for controlling tuberculosis and reveal mechanisms by which type I IFN may promote susceptibility to this important disease.


Cost-effectiveness of Interventions to Manage Diabetes: Has the Evidence Changed Since 2008?
To synthesize updated evidence on the cost-effectiveness (CE) of interventions to manage diabetes, its complications, and comorbidities. We conducted a systematic literature review of studies from high-income countries evaluating the CE of diabetes management interventions recommended by the American Diabetes Association (ADA) and published in English between June 2008 and July 2017. We also incorporated studies from a previous CE review from the period 1985-2008. We classified the interventions based on their strength of evidence (strong, supportive, or uncertain) and levels of CE: cost-saving (more health benefit at a lower cost), very cost-effective (≤$25,000 per life year gained [LYG] or quality-adjusted life year [QALY]), cost-effective ($25,001-$50,000 per LYG or QALY), marginally cost-effective ($50,001-$100,000 per LYG or QALY), or not cost-effective (>$100,000 per LYG or QALY). Costs were measured in 2017 U.S. dollars. Seventy-three new studies met our inclusion criteria. These were combined with 49 studies from the previous review to yield 122 studies over the period 1985-2017. A large majority of the ADA-recommended interventions remain cost-effective. Specifically, we found strong evidence that the following ADA-recommended interventions are cost-saving or very cost-effective: In the cost-saving category are 1) ACE inhibitor (ACEI)/angiotensin receptor blocker (ARB) therapy for intensive hypertension management compared with standard hypertension management, 2) ACEI/ARB therapy to prevent chronic kidney disease and/or end-stage renal disease in people with albuminuria compared with no ACEI/ARB therapy, 3) comprehensive foot care and patient education to prevent and treat foot ulcers among those at moderate/high risk of developing foot ulcers, 4) telemedicine for diabetic retinopathy screening compared with office screening, and 5) bariatric surgery compared with no surgery for individuals with type 2 diabetes (T2D) and obesity (BMI ≥30 kg/m2). In the very cost-effective category are 1) intensive glycemic management (targeting A1C <7%) compared with conventional glycemic management (targeting an A1C level of 8-10%) for individuals with newly diagnosed T2D, 2) multicomponent interventions (involving behavior change/education and pharmacological therapy targeting hyperglycemia, hypertension, dyslipidemia, microalbuminuria, nephropathy/retinopathy, secondary prevention of cardiovascular disease with aspirin) compared with usual care, 3) statin therapy compared with no statin therapy for individuals with T2D and history of cardiovascular disease, 4) diabetes self-management education and support compared with usual care, 5) T2D screening every 3 years starting at age 45 years compared with no screening, 6) integrated, patient-centered care compared with usual care, 7) smoking cessation compared with no smoking cessation, 8) daily aspirin use as primary prevention for cardiovascular complications compared with usual care, 9) self-monitoring of blood glucose three times per day compared with once per day among those using insulin, 10) intensive glycemic management compared with conventional insulin therapy for T2D among adults aged ≥50 years, and 11) collaborative care for depression compared with usual care. Complementing professional treatment recommendations, our systematic review provides an updated understanding of the potential value of interventions to manage diabetes and its complications and can assist clinicians and payers in prioritizing interventions and health care resources.


A review of mind-body therapies in the treatment of cardiovascular disease. Part 1: Implications for the elderly.
A review of research on complementary and alternative treatments, specifically mind-body techniques, was conducted at Stanford University. The goals of the review were to establish a comprehensive literature review and to provide a rationale for future research concerning successful aging. Computerized searches were conducted using MEDLINE, PsychInfo, Stanford Library, Dissertation Abstracts, Lexus-Nexus, the Internet, and interviews conducted with practitioners. All studies since 1990 that examined mind-body treatments of cardiovascular disorders in the elderly were included. Mind-body practices evaluated were social support, cognitive-behavioral treatment, meditation, the placebo effect, hope, faith, imagery, spiritual healing, music therapy, hypnosis, yoga, t'ai chi, qigong and aikido. Studies conducted after 1990 were a priority, but when more recent literature was scarce, other studies using randomized, controlled trials were included. Mind-body techniques were found to be efficacious primarily as complementary and sometimes as stand-alone alternative treatments for cardiovascular disease-related conditions. Studies provided evidence for treatment efficacy, but the need for further controlled research was evident. Reviewers found only a handful of randomized, controlled research studies conducted in the United States. As a result, there is a lack of replicated studies with which to determine appropriate treatment dosage and the mechanisms by which many of the practices work. Compelling anecdotal evidence, the presence of some controlled research, overall cost effectiveness, and the lack of side effects resulting from mind-body treatments make further investigation a high priority.


Epilepsy care during the COVID-19 pandemic.
The coronavirus disease 2019 (COVID-19) pandemic has affected the care of all patients around the world. The International League Against Epilepsy (ILAE) COVID-19 and Telemedicine Task Forces examined, through surveys to people with epilepsy (PWE), caregivers, and health care professionals, how the pandemic has affected the well-being, care, and services for PWE. The ILAE included a link on their website whereby PWE and/or their caregivers could fill out a survey (in 11 languages) about the impact of the COVID-19 pandemic, including access to health services and impact on mental health, including the 6-item Kessler Psychological Distress Scale. An anonymous link was also provided whereby health care providers could report cases of new-onset seizures or an exacerbation of seizures in the context of COVID-19. Finally, a separate questionnaire aimed at exploring the utilization of telehealth by health care professionals since the pandemic began was available on the ILAE website and also disseminated to its members. Seventeen case reports were received; data were limited and therefore no firm conclusions could be drawn. Of 590 respondents to the well-being survey (422 PWE, 166 caregivers), 22.8% PWE and 27.5% caregivers reported an increase in seizure frequency, with difficulty in accessing medication and health care professionals reported as barriers to care. Of all respondents, 57.1% PWE and 21.5% caregivers had severe psychological distress (k score >13), which was significantly higher among PWE than caregivers (p<0.01). An increase in telemedicine use during the COVID-19 pandemic was reported by health care professionals, with 40% of consultations conducted by this method. Although 74.9% of health care providers thought that this impacted positively, barriers to care were also identified. As we move forward, there is a need to ensure ongoing support and care for PWE to prevent a parallel pandemic of unmet health care needs.


The pharmacokinetics of dobutamine in pediatric intensive care unit patients.
Dobutamine is used for hemodynamic support in critically ill patients; however, due to the relative insensitivity of most available assays, there is little detailed information about its pharmacokinetics. We studied the pharmacokinetics of dobutamine in 27 children and infants using a high-sensitivity HPLC technique. The patients' ages ranged from 0.13 to 16.6 years; 17 received dobutamine for treatment of shock while 10 received it for treatment of post-cardiac surgery. Blood samples were collected before (N = 27) and after (N = 10, 9 time points each) the cessation of dobutamine infusion. The duration of dobutamine infusion before sampling was 1.87 +/- 0.29 days (range: 0.2-5.5; median: 1). The steady-state plasma concentration of dobutamine (infusion rate corrected to 5.0 micrograms/kg/min) was 105 +/- 19 ng/ml (range: 3.79-400; median: 76). The clearance rate was 151.1 +/- 47.5 ml/kg/min (range: 12.5-1319; median: 66). Most post-infusion time-concentration data were best fit to a biexponential function suggestive of a two-compartment model. The t1/2 alpha was 1.65 +/- 0.20 min (range: 0.64-3.01; median: 1.52) while the t1/2 beta was 25.8 +/- 11.5 min (range: 4.6-68.6; median: 16.9). Neither age, weight, sex, disease state, duration of infusion, nor blood measures of renal or hepatic dysfunction were found to be covariates of the above parameters. It was found, however, that the concomitant administration of dopamine altered dobutamine's pharmacokinetics, indicating the possible presence of a competitive component in dobutamine's disposition.


Service organisation for the secondary prevention of ischaemic heart disease in primary care.
Ischaemic heart disease (IHD) is a major cause of mortality and morbidity and its prevalence is set to increase. Secondary prevention aims to prevent subsequent acute events in people with established IHD. While the benefits of individual medical and lifestyle interventions is established, the effectiveness of interventions which seek to improve the way secondary preventive care is delivered in primary care or community settings is less so. To assess the effectiveness of service organisation interventions, identifying which types and elements of service change are associated with most improvement in clinician and patient adherence to secondary prevention recommendations relating to risk factor levels and monitoring (blood pressure, cholesterol and lifestyle factors such as diet, exercise, smoking and obesity) and appropriate prophylactic medication. We searched the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library 2007, Issue 4), MEDLINE (1966 to Feb 2008), EMBASE (1980 to Feb 2008), and CINAHL (1981 to Feb 2008). Bibliographies were checked. No language restrictions were applied. Randomised or quasi-randomised controlled trials of service organisation interventions in primary care or community settings in populations with established IHD. Analyses were conducted according to Cochrane recommendations and Odds Ratios (with 95% confidence intervals) reported for dichotomous outcomes, mean differences (with 95% CIs) for continuous outcomes. Eleven studies involving 12,074 people with IHD were included. Increased proportions of patients with total cholesterol levels within recommended levels at 12 months, OR 1.90 (1.04 to 3.48), were associated with interventions that included regular planned appointments, patient education and structured monitoring of medication and risk factors, but significant heterogeneity was apparent. Results relating to blood pressure within target levels bordered on statistical significance. There were no significant effects of interventions on mean blood pressure or cholesterol levels, prescribing, smoking status or body mass index. Few data were available on the effect on diet. There was some suggestion of a "ceiling effect" whereby interventions have a diminishing beneficial effect once certain levels of risk factor management are reached. There is weak evidence that regular planned recall of patients for appointments, structured monitoring of risk factors and prescribing, and education for patients can be effective in increasing the proportions of patients within target levels for cholesterol control and blood pressure. Further research in this area would benefit from greater standardisation of the outcomes measured.


Effects of taurine on stress-evoked hemodynamic and plasma catecholamine changes in spontaneously hypertensive rats.
Cardiovascular hemodynamics (microspheres) and plasma norepinephrine and epinephrine levels at rest and during short-term shaker stress were investigated in conscious spontaneously hypertensive rats and Wistar-Kyoto rats, with or without oral taurine (1.5%) treatment for 8 weeks. Taurine effects were evaluated by comparing data on the taurine-treated and untreated rats. Taurine affected neither the resting hemodynamics nor the resting plasma catecholamine levels in spontaneously hypertensive and Wistar-Kyoto rats. Taurine slightly but significantly reduced the left ventricular/body weight ratio in the spontaneously hypertensive rats (p less than 0.05) and caused an insignificant 10 mm Hg decrease in the resting mean arterial pressure. Spontaneously hypertensive and Wistar-Kyoto rats responded in a qualitatively similar manner to stress, as evidenced by resistance-dominated increases in mean arterial pressure and increases in heart rate, with a blood flow redistribution from splanchnic, cutaneous, and testicular to skeletal muscle and cerebral circulations and by increases in plasma norepinephrine and epinephrine levels. These changes were more marked in the spontaneously hypertensive rats. Taurine significantly reduced the stress values of mean arterial pressure (untreated, 189 +/- 4 (SE) mm Hg; treated, 166 +/- 4 mm Hg in the spontaneously hypertensive rats; p less than 0.05), while it significantly reduced stress values of heart rate in spontaneously hypertensive and Wistar-Kyoto rats (p less than 0.05). Taurine also blunted the stress values of splanchnic, testicular, and cutaneous vascular resistance in the spontaneously hypertensive rats. There were no or only slight regional effects in the Wistar-Kyoto rats. Taurine substantially decreased plasma levels of norepinephrine (untreated, 615 +/- 76 pg/ml; treated, 383 +/- 49 pg/ml) and epinephrine (untreated, 892 +/- 187 pg/ml; treated, 232 +/- 59 pg/ml) during stress in the spontaneously hypertensive rats. These results indicate that chronic taurine treatment attenuates short-term shaker stress-induced hemodynamic and plasma catecholamine changes in spontaneously hypertensive rats.


One Hand Clapping: detection of condition-specific transcription factor interactions from genome-wide gene activity data.
We present One Hand Clapping (OHC), a method for the detection of condition-specific interactions between transcription factors (TFs) from genome-wide gene activity measurements. OHC is based on a mapping between transcription factors and their target genes. Given a single case-control experiment, it uses a linear regression model to assess whether the common targets of two arbitrary TFs behave differently than expected from the genes targeted by only one of the TFs. When applied to osmotic stress data in S. cerevisiae, OHC produces consistent results across three types of expression measurements: gene expression microarray data, RNA Polymerase II ChIP-chip binding data and messenger RNA synthesis rates. Among the eight novel, condition-specific TF pairs, we validate the interaction between Gcn4p and Arr1p experimentally. We apply OHC to a large gene activity dataset in S. cerevisiae and provide a compendium of condition-specific TF interactions.


Transcriptomic reprogramming of the oceanic diatom Skeletonema dohrnii under warming ocean and acidification.
Under ocean warming and acidification, diatoms use a unique acclimation and adaptation strategy by saving energy and utilizing it for other cellular processes. However, the molecular mechanisms that underlie this reprogramming of energy utilization are currently unknown. Here, we investigate the metabolic reprogramming of the ecologically important diatom Skeletonema dohrnii grown under two different temperature (21°C and 25°C) and pCO2 (400 and 1000 ppm) levels, utilizing global transcriptomic analysis. We find that evolutionary changes in the baseline gene expression, which we termed transcriptional up- and downregulation, is the primary mechanism used by diatoms to acclimate to the combined conditions of ocean warming and acidification. This transcriptional regulation shows that under higher temperature and pCO2 conditions, photosynthesis, electron transport and carboxylation were modified with increasing abundances of genes encoding ATP, NADPH and carbon gaining for the carbon-dioxide-concentrating mechanisms (CCMs). Our results also indicate that changes in the transcriptional regulation of CCMs led to a decrease in the metabolic cost to save energy by promoting amino acid synthesis and nitrogen assimilation for the active protein processing machinery to adapt to warming and ocean acidification. This study generated unique metabolic insights into diatoms and suggests that future climate change conditions will cause evolutionary changes in oceanic diatoms that will facilitate their acclimation strategy.


Morphological and structural plasticity of grassland species in response to a gradient in saline-sodic soils.
The abundance and distribution of species can be ascribed to both environmental heterogeneity and stress tolerance, with the latter measure sometimes associated with phenotypic plasticity. Although phenotypic plasticity varies predictably in response to common forms of stress, we lack a mechanistic understanding of the response of species to high saline-sodic soils. We compared the phenotypic plasticity of three pairs of high and low saline-sodic tolerant congeners from the families Poaceae (Leymus chinensis versus L. secalinus), Fabaceae (Lespedeza davurica versus L. bicolor) and Asteraceae (Artemisia mongolica versus A. sieversiana) in a controlled pot experiment in the Songnen grassland, China. The low tolerant species, L. secalinus and A. sieversiana exhibited higher plasticity in response to soil salinity and sodicity than their paired congeners. Highly tolerant species, L. chinensis and A. mongolica, had higher values for several important morphological traits, such as shoot length and total biomass under the high saline-sodic soil treatment than their paired congeners. In contrast, congeners from the family Fabaceae, L. davurica and L. bicolor, did not exhibit significantly different plasticity in response to soil salinity and sodicity. All species held a constant reproductive effort in response to saline-sodic soil stress. The different responses between low and high tolerant species offer an explanation for the distribution patterns of these species in the Songnen grassland. Highly tolerant species showed less morphological plasticity over a range of saline-sodic conditions than their paired congeners, which may manifest as an inability to compete with co-occurring species in locations where saline-sodic soils are absent.


Improved in situ beta-galactosidase staining for histological analysis of transgenic mice.
The present study describes a novel method for the histochemical demonstration of beta-galactosidase activity on tissue sections. We have replaced 5-bromo-4-chloro-3-indolyl-beta-D-galactoside (X-Gal) with 5-bromo-indolyl-beta-o-galactopyranoside (Bluo-Gal) as a chromogenic substrate for the bacterial beta-galactosidase (lacZ). After beta-galactosidic cleavage, Bluo-Gal precipitates in form of fine birefringent crystals, whereas X-gal gives rise to an amorphous precipitate. Upon microscopic examination under polarized light, the crystals emit a strong signal consisting of yellow reflected light. This property of Bluo-Gal results in greatly enhanced sensitivity of the staining method for beta-galactosidase and allows for optimal morphological resolution. To exemplify the applications of this technique, the expression is demonstrated in transgenic mice of beta-galactosidase driven by a fragment of the human tissue-type plasminogen activator promoter.


Treatment of head injuries in the American Civil War.
At the time of the American Civil War (1861-1865), a great deal was known about closed head injury and gunshot wounds to the head. Compression was differentiated from concussion, but localization of lesions was not precise. Ether and especially chloroform were used to provide anesthesia. Failure to understand how to prevent infection discouraged physicians from aggressive surgery. Manuals written to educate inexperienced doctors at the onset of the war provide an overview of the advice given by senior surgeons. The Union experiences in the treatment of head injury in the Civil War were discussed in the three surgical volumes of The Medical and Surgical History of the War of the Rebellion. Wounds were divided into incised and puncture wounds, blunt injuries, and gunshot wounds, which were analyzed separately. Because the patients were not stratified by severity of injury and because there was no neuroimaging, it is difficult to understand the clinical problems and the effectiveness of surgery. Almost immediately after the war, increased knowledge about cerebral localization and the development of antisepsis (and then asepsis) permitted the development of modern neurosurgery.


Effect of platinum deposits on TiO2 on the anoxic photocatalytic degradation pathways of alkylamines in water: dealkylation and N-alkyation.
Most photocatalytic degradation (PCD) reactions of aquatic pollutants require the presence of dissolved oxygen and hence do not occur in anoxic suspensions. We investigated the PCD reactions of alkylamines in anoxic water using TiO2 deposited with Pt nanoparticles. Unlike typical PCD reactions, the absence of dissolved oxygen increases the PCD rates of alkylamines on Pt/TiO2 and generates products that are different from those formed on pure TiO2. In particular, N-alkylated amines (e.g., (CH3)3N produced from (CH3)2NH) as well as dealkylated amines are generated in a deaerated Pt/TiO2 suspension. This anoxic N-alkylation pathway is enabled only in the presence of Pt deposits on TiO2 and is applicable only to neutral alkylamines and not to alkylammonium cations. The Pt surface appears to interactwith the lone-pair electron on the N atom and catalyze the anoxic degradation of alkylamines mainly through a radical mechanism. Methyl radicals generated on Pt participate in the N-methylation reaction. The presence of intermediate methyl radicals on the Pt surface was verified by the detection of CH4 and CH3CH3 gases evolved during the PCD of (CH3)3N in an anoxic Pt/TiO2 suspension, whereas no such products were observed in a pure TiO2 suspension. The anoxic PCD of N-methylethylamine on Pt/TiO2 also produces both N-ethylated and N-methylated amines as byproducts, which indicates that both methyl and ethyl radicals are generated during the anoxic degradation process. From a practical point of view, the present finding that undesirable alkylated amines can be produced on Pt/TiO2 in anoxic conditions indicates that caution is necessary when applying Pt/TiO2 photocatalyst to the treatment of water that contains amines.


A G1 glycoprotein epitope of La Crosse virus: a determinant of infection of Aedes triseriatus.
Arthropod-borne viruses (arboviruses) have specific vector-vertebrate host cycles in nature. The molecular basis of restriction of virus replication to a very limited number of vector species is unknown, but the present study suggests that viral attachment proteins are important determinants of vector-virus interactions. The principal vector of La Crosse (LAC) virus is the mosquito Aedes triseriatus, and LAC virus efficiently infects the mosquito when ingested. However, a variant (V22) of LAC virus, which was selected by growing the virus in the presence of a monoclonal antibody, was markedly restricted in its ability to infect Ae. triseriatus when it was ingested. Only 15% of the mosquitoes that ingested V22 became infected and 5% of these developed disseminated infections. In contrast, 89% of the mosquitoes that ingested LAC became infected and 74% developed disseminated infections. When V22 was passed three times in mosquitoes by feeding, a revertant virus, V22M3, was obtained that infected 85% of Ae. triseriatus ingesting this virus. In addition, V22M3 regained the antigenic phenotype and fusion capability of the parent LAC virus. These results suggest that the specificity of LAC virus-vector interactions is markedly influenced by the efficiency of the fusion function of the G1 envelope glycoprotein operating at the midgut level in the arthropod vector.


A common pro-opiomelanocortin-binding element mediates leukemia inhibitory factor and corticotropin-releasing hormone transcriptional synergy.
Using murine AtT20 pituitary cells transfected with a rat pro-opiomelanocortin (POMC) promoter (-706/+64) linked to the luciferase reporter, we showed leukemia inhibitory factor (LIF) to strongly potentiate corticotropin-releasing hormone (CRH) induction of POMC gene expression. We therefore tested mechanisms for molecular interactions between LIF and CRH. Although LIF and CRH synergized to induce an 8-fold induction of POMC transcription, CRH alone (but not LIF) induced cAMP response element-binding protein phosphorylation (5-fold) or an increase of c-fos mRNA levels (>100-fold), suggesting that these pathways are not implicated in LIF transcriptional synergistic effects. Using a DNase I footprint assay, POMC promoter regions protected by AtT20 cell nuclear extracts were identified (-121/-109, and -143/-134, and -173/-160). The protected -173/-160 element fused to a heterologous promoter conferred LIF-CRH synergy (6.5-fold induction of POMC) and formed a specific complex with AtT20 cell nuclear extracts. This complex was supershifted by an anti-phosphoserine antibody, and a serine/threonine kinase inhibitor also altered both this complex and LIF-CRH transcriptional synergy on the POMC promoter-luciferase reporter construct, indicating that these events depend on post-translational serine phosphorylations. LIF-CRH synergy on POMC transcription is therefore mediated at least in part by -173/-160 sequences conferring confluent transcriptional activity of both peptides.


Factors influencing the return of inactive blood donors in a Cameroonian blood bank.
Identify factors that influence the return of donors to increase their loyalty while improving blood safety is crucial in our context. Between October 2017 and April 2018, we conducted a descriptive cross-sectional study at the Blood Bank of the Yaoundé University Teaching Hospital. The study included all former donors who had not donated blood voluntarily for over a year. Quantitative variables were described using means and standard deviations. Fisher's exact test and Chi2 test were used for association measures between qualitative variables. Statistical test results were considered significant for a P<0.05 value. We interviewed a total of 101 inactive donors. The study population was 74.3% male, donors average 30±7 years. Female gender and good staff hospitality were the factors most associated with the intention to return. The barriers to donor return were mainly lack of information on blood needs (35.60%) and time constraint for blood donation (26.73%). Pro-social motivations such as altruism (30.70%) were the main possible sources of motivation cited. To reduce blood deficiency and mortality due to lack of blood products, non-financial material compensation, good outreach and communication strategy can increase inactive donors' loyalty and consequently in improving blood safety in our context.


Validation and Generalizability of Preoperative PROMIS Scores to Predict Postoperative Success in Foot and Ankle Patients.
A recent publication reported preoperative Patient-Reported Outcomes Measurement Instrumentation System (PROMIS) scores to be highly predictive in identifying patients who would and would not benefit from foot and ankle surgery. Their applicability to other patient populations is unknown. The aim of this study was to assess the validation and generalizability of previously published preoperative PROMIS physical function (PF) and pain interference (PI) threshold t scores as predictors of postoperative clinically meaningful improvement in foot and ankle patients from a geographically unique patient population. Prospective PROMIS PF and PI scores of consecutive patient visits to a tertiary foot and ankle clinic were obtained between January 2014 and November 2016. Patients undergoing elective foot and ankle surgery were identified and PROMIS values obtained at initial and follow-up visits (average, 7.9 months). Analysis of variance was used to assess differences in PROMIS scores before and after surgery. The distributive method was used to estimate a minimal clinically important difference (MCID). Receiver operating characteristic curve analysis was used to determine thresholds for achieving and failing to achieve MCID. To assess the validity and generalizability of these threshold values, they were compared with previously published threshold values for accuracy using likelihood ratios and pre- and posttest probabilities, and the percentages of patients identified as achieving and failing to achieve MCID were evaluated using χ2 analysis. There were significant improvements in PF ( P < .001) and PI ( P < .001) after surgery. The area under the curve for PF (0.77) was significant ( P < .01), and the thresholds for achieving MCID and not achieving MCID were similar to those in the prior study. A significant proportion of patients (88.9%) identified as not likely to achieve MCID failed to achieve MCID ( P = .03). A significant proportion of patients (84.2%) identified as likely to achieve MCID did achieve MCID ( P < .01). The area under the curve for PROMIS PI was not significant. PROMIS PF threshold scores from published data were successful in classifying patients from a different patient and geographic population who would improve with surgery. If functional improvement is the goal, these thresholds could be used to help identify patients who will benefit from surgery and, most important, those who will not, adding value to foot and ankle health care. Level II, Prospective Comparative Study.


A rapid resazurin bioassay for assessing the toxicity of fungicides.
Fungicides are widely used in agriculture, and released in large amounts to the environment. Methods used for antifungal susceptibility testing are cumbersome and time-consuming. As a result, very little attention has been paid to including fungal tests in the routine screening of pesticides and there are no reports in the literature of fungicide focussed effects directed analysis (EDA). In addition very little is known on the toxicity of fungicides to environmentally significant fungi. Here we report a rapid microplate-based resorufin fluorescence inhibition bioassay and compare it with a 24h microplate-based yeast growth inhibition bioassay using eight fungicides. The growth inhibition bioassay was sensitive, giving IC50 and IC90 values comparable to previously reported IC50 or MICs of these fungicides for Saccharomyces cerevisiae and other fungi. The resorufin fluorescence inhibition bioassay was both faster and more sensitive than the growth inhibition bioassay. Inhibitory concentrations obtained just after 30min of incubation with amphotericin B (AMB) and captan were at least a hundred fold lower than IC50s in the literature for fungi. The fluorescence bioassay showed only a small response to pyrazophos and thiabendazole but these only inhibited growth at high concentrations so this may reflect low sensitivity of S. cerevisiae to these particular fungicides. This bioassay can detect toxic effects of a range of fungicides from different chemical classes with different modes of action. It will be valuable for screening chemical libraries for fungicides and as a biomarker for detecting the effects of fungicides to non-target fungi.


Chlorpheniramine, selective serotonin-reuptake inhibitors (SSRIs) and over-the-counter (OTC) treatment.
Some old antihistamines were selective serotonin-reuptake inhibitors (SSRIs) and the SSRI effect was discovered by Nobel Laureate Professor Arvid Carlsson as early as 1969. Chlorpheniramine was the most active of the tested drugs, and it compares favourably with amitriptyline and imipramine with respect to actions on both serotonergic and noradrenergic neurons. Chlorpheniramine can be called a SSRI, since the blocking of 5HT is stronger than the effect on noradrenaline neurons; however it might also be called a selective serotonin and noradrenaline reuptake inhibitor (SSNRI) and be compared with new drugs, such as venlafaxine. Carlsson suggested the potential value of clinical studies of the antidepressant properties of this and related antihistamine drugs. But, in the event, no such trials were ever performed at the time. However, later clinical observations of the benefits of dex-chlorpheniramine treatment in panic disorder have been published. Clinical experience suggests that patients using chlorpheniramine, and having also a concomitant depression or panic disorder, may experience a return of symptoms when their old drug is changed to a new antihistamine lacking SSRI effects. Yet this phenomenon is not known to many doctors, and even less known to the large number of patients buying chlorpheniramine under various trade names over-the-counter (OTC) at a low price for self-treatment of hay fewer or as a cold remedy. Chlorpheniramine was introduced in USA under the name Chlor-Trimeton as long ago as July 1950, and is still on the market. Therefore, this SSRI is now over 50 years old. If chlorpheniramine had been tested in depression in the nineteen seventies, it is probable that a safe, inexpensive SSRI drug could have been used some 15 years earlier than fluoxetine - which became available in 1987. Chlorpheniramine might have been the first safe, non-cardiotoxic and well-tolerated antidepressant. Billions of dollars in the development and marketing costs would have been saved, and the suffering of millions of patients alleviated.


Recombinant CD40 ligand therapy has significant antitumor effects on CD40-positive ovarian tumor xenografts grown in SCID mice and demonstrates an augmented effect with cisplatin.
CD40 is a member of the tumor necrosis factor receptor family and was first identified with a monoclonal antibody raised against bladder carcinoma. Recombinant human CD40L has been shown previously to have a direct antitumor effect on an ovarian cancer cell line and ovarian carcinoma cells isolated from ascites fluid. We show here that rhuCD40L inhibits the growth of several ovarian adenocarcinomas derived from surgical specimens and grown as xenografts in severe combined immunodeficient mice. Two 14-day treatment cycles were more effective than one. This effect is apparently not mediated by natural killer cells, because blocking natural killer cell activity by antiasialo GM-1 did not diminish this effect. In addition to suppression of tumor growth, treatment with rhuCD40L resulted in an increased expression of FasL, an increase in apoptosis, and histological changes including increased fibrosis and areas of tumor destruction. Using this model, we examined the efficacy of rhuCD40L in combination with chemotherapeutic agents. The antitumor effect of rhuCD40L in combination with 4 mg/kg cisplatin (CDDP) was increased over the effect of CDDP alone. Furthermore, rhuCD40L increased the efficacy of a suboptimal dose of CDDP (2mg/kg) such that it matched that of high-dose CDDP alone. These data suggest a role for rhuCD40L therapy in combination with platinum based regimens for primary treatment of epithelial ovarian tumors.


High-throughput amplicon sequencing of the full-length 16S rRNA gene with single-nucleotide resolution.
Targeted PCR amplification and high-throughput sequencing (amplicon sequencing) of 16S rRNA gene fragments is widely used to profile microbial communities. New long-read sequencing technologies can sequence the entire 16S rRNA gene, but higher error rates have limited their attractiveness when accuracy is important. Here we present a high-throughput amplicon sequencing methodology based on PacBio circular consensus sequencing and the DADA2 sample inference method that measures the full-length 16S rRNA gene with single-nucleotide resolution and a near-zero error rate. In two artificial communities of known composition, our method recovered the full complement of full-length 16S sequence variants from expected community members without residual errors. The measured abundances of intra-genomic sequence variants were in the integral ratios expected from the genuine allelic variants within a genome. The full-length 16S gene sequences recovered by our approach allowed Escherichia coli strains to be correctly classified to the O157:H7 and K12 sub-species clades. In human fecal samples, our method showed strong technical replication and was able to recover the full complement of 16S rRNA alleles in several E. coli strains. There are likely many applications beyond microbial profiling for which high-throughput amplicon sequencing of complete genes with single-nucleotide resolution will be of use.


Potential Synergies between Nature-Based Tourism and Sustainable Use of Marine Resources: Insights from Dive Tourism in Territorial User Rights for Fisheries in Chile.
Novel solutions to conserve biodiversity whilst allowing for resource harvesting are urgently needed. In marine systems, Territorial User Rights for Fisheries (TURFs) are promoted to enable sustainable use of resources. We investigate the potential for synergies between nature-based tourism and TURFs on Chile's central coast. Of 135 recreational divers surveyed, 77% indicated that the fish species they preferred sighting were declining and 80% indicated that they would dive more often in TURFs, which have higher abundance of favoured species. Regression analysis shows that respondents that perceive that TURFs fulfil a conservation function are more willing to pay to dive in a TURF. However, respondents who understand the bureaucratic functioning of a TURF are less willing to pay, and there is diversity in how divers feel payments should be made. A participatory approach is required to navigate these complexities to achieve synergies between nature-based tourism and resource harvesting in TURFs.


A magnetically focused molecular beam of ortho-water.
Like dihydrogen, water exists as two spin isomers, ortho and para, with the nuclear magnetic moments of the hydrogen atoms either parallel or antiparallel. The ratio of the two spin isomers and their physical properties play an important role in a wide variety of research fields, ranging from astrophysics to nuclear magnetic resonance (NMR). Unlike ortho and para H(2), however, the two water isomers remain challenging to separate, and as a consequence, very little is currently known about their different physical properties. Here, we report the formation of a magnetically focused molecular beam of ortho-water. The beam we formed also had a particular spin projection. Thus, in the presence of holding magnetic fields, the water molecules are hyperpolarized, laying the foundation for ultrasensitive NMR experiments in the future.


Genome-wide association study identifies six new loci influencing pulse pressure and mean arterial pressure.
Numerous genetic loci have been associated with systolic blood pressure (SBP) and diastolic blood pressure (DBP) in Europeans. We now report genome-wide association studies of pulse pressure (PP) and mean arterial pressure (MAP). In discovery (N = 74,064) and follow-up studies (N = 48,607), we identified at genome-wide significance (P = 2.7 × 10(-8) to P = 2.3 × 10(-13)) four new PP loci (at 4q12 near CHIC2, 7q22.3 near PIK3CG, 8q24.12 in NOV and 11q24.3 near ADAMTS8), two new MAP loci (3p21.31 in MAP4 and 10q25.3 near ADRB1) and one locus associated with both of these traits (2q24.3 near FIGN) that has also recently been associated with SBP in east Asians. For three of the new PP loci, the estimated effect for SBP was opposite of that for DBP, in contrast to the majority of common SBP- and DBP-associated variants, which show concordant effects on both traits. These findings suggest new genetic pathways underlying blood pressure variation, some of which may differentially influence SBP and DBP.


Infection-induced host translational blockage inhibits immune responses and epithelial renewal in the Drosophila gut.
Typically, immune responses control the pathogen, while repair and stress pathways limit damage caused by pathogenesis. The relative contribution of damage to the outcome of pathogenesis and the mechanistic links between the immune and repair pathways are poorly understood. Here, we analyze how the entomopathogenic bacterium Pseudomonas entomophila induces irreversible damage to the Drosophila gut. We find that P. entomophila ingestion induces a global translational blockage that impairs both immune and repair programs in the fly gut. P. entomophila-induced translational inhibition is dependent on bacterial pore forming toxins and reactive oxygen species produced by the host in response to infection. Translational arrest is mediated through activation of the GCN2 kinase and inhibition of the TOR pathway as a consequence of host damage. Together, our study draws a model of pathogenesis in which bacterial inhibition of translation by excessive activation of stress responsive pathways inhibits both immune and regenerative epithelial responses.


Effect of rater training on reliability of Melbourne Assessment of Unilateral Upper Limb Function scores.
The aim of this study was to explore the effect of rater training on interrater reliability, internal consistency, standard error of measurement, and rater familiarity for the Melbourne Assessment of Unilateral Upper Limb Function. Twenty-four participants (raters) were randomly assigned to either 'trained' (n=12) or 'untrained' (n=12) interventions; they then scored the same nine video recordings of children completing the instrument. The age range of the children was 5 years 5 months to 12 years; there were six males, three females, all with spastic cerebral palsy (five with quadriparesis and four with hemiparesis); Gross Motor Function Classification System levels were I (n=3), II (n=3), III (n=1), and IV (n=2). All participants were novice occupational therapists and had no previous experience of using the instrument. A significant difference in perceived test familiarity was found after scoring but not before: trained raters scored higher. A significant difference in total scores for all cases was found and in eight of 16 individual item total raw scores. Again, trained raters scored higher. Interrater reliability was high in both groups, except item 6 (untrained). Internal consistency was high in both groups, except items 6 and 9 (untrained). We conclude that training for novice users increases familiarity and results in raters' perceiving higher levels of performance in some items. The Melbourne Assessment has high reliability even for novice users.


Use of a questionnaire in general practice to increase the recognition of patients with excessive alcohol consumption.
A self administered questionnaire, the health survey questionnaire, was designed to detect excessive alcohol consumption and mailed to patients who were registered with two general practices. Replies were received from 2572(75%) of 3452 patients. Excessive consumption was taken as 42 units of alcohol per week or more for men and 21 units per week or more for women: 1 unit = approximately 10 g ethanol and is equivalent to a half pint of beer, one glass of wine, or one standard measure of spirits. One hundred and twenty men (11%) and 68 women (5%) were identified by their responses to the questionnaire as excessive drinkers. According to their responses, roughly half of these expressed some concern about their drinking. In the practice where a disease register was kept 18 patients had been recorded as heavy drinkers before the study, and an additional 74 were detected by the questionnaire. Within 12 months after the questionnaire survey three groups of respondents were reviewed: (a) the excessive drinkers, (b) those who indicated concern about drinking but did not exceed the limits for excessive consumption, and (c) a random sample of those who were in neither of these two categories. Patients in these three groups were interviewed in a standard fashion to determine their alcohol consumption. Breath alcohol measurement was also carried out and a blood sample taken for the estimation of mean cell volume, gamma glutamyltranspeptidase activity, and serum aspartate transaminase activity. There were highly significant correlations between estimates of consumption obtained by the questionnaire and those obtained at interview except among the women who were excessive consumers, whose responses to the questionnaire indicated levels of consumption that were much higher than those to which they admitted at interview. Stated weekly consumption at interview that was above the limits set for the study was used as the standard measure for comparing the questionnaire with the other indicators of excessive drinking. The questionnaire had a considerably greater estimated sensitivity in detecting male excessive consumers than any of the blood tests. Among the women it apparently performed less well, although the numbers stating excessive consumption at interview were small. Breath alcohol measurement was positive in only a few of the excessive drinkers. The use of this simple and inexpensive instrument is likely to prove widely acceptable to patients in general practice and should result in a considerable increase in the recognition by general practitioners of patients with excessive alcohol consumption.