Nutrition education in medical school: a time of opportunity.
Undergraduate medical education has undergone significant changes in development of new curricula, new pedagogies, and new forms of assessment since the Nutrition Academic Award was launched more than a decade ago. With an emphasis on a competency-based curriculum, integrated learning, longitudinal clinical experiences, and implementation of new technology, nutrition educators have an opportunity to introduce nutrition and diet behavior-related learning experiences across the continuum of medical education. Innovative learning opportunities include bridging personal health and nutrition to community, public, and global health concerns; integrating nutrition into lifestyle medicine training; and using nutrition as a model for teaching the continuum of care and promoting interprofessional team-based care. Faculty development and identification of leaders to serve as champions for nutrition education continue to be a challenge.


Physical activity and knee structural change: a longitudinal study using MRI.
Exercise therapy is effective in improving symptoms of knee osteoarthritis, but its effect on structural change remains unclear. To describe the associations between physical activity and structural changes of the knee joint as assessed by magnetic resonance imaging (MRI) in adult male and female subjects. A convenience sample of 325 subjects (mean age 45 yr, range 26-61) was measured at baseline and approximately 2 yr later. Measures of physical activity included questionnaire items, physical work capacity (PWC(170)), and lower-limb muscle strength. Knee cartilage volume, tibial plateau area, and cartilage defect score (0-4) were determined using T1-weighted fat saturation MRI. Lower-limb muscle strength at baseline was positively associated with both percent-per-year changes in total cartilage volume (r = 0.13) and lateral and total tibial plateau area (r = 0.15 and 0.17) but not other sites. Change in muscle strength was negatively associated with annual changes in lateral and total tibial plateau area (r = -0.13 and -0.17). In females only, PWC170 at baseline was negatively associated with percent-per-year changes in lateral and total cartilage volume (r = -0.16 and -0.17) and positively for lateral and total tibial plateau area (r = 0.18 and 0.16). Conversely, change in PWC(170) was positively associated with changes in cartilage volume at all sites (r = 0.24-0.26). For all associations, P < 0.05. Overall, these associations were modest in magnitude, but they suggest that knee cartilage volume and tibial plateau area are dynamic structures that can respond to physical stimuli. Greater muscle strength and endurance fitness, especially in women, may be protective against cartilage loss, but it also may result in a maladaptive enlargement of subchondral bone in both sexes, suggesting that physical activity may have both good and bad effects on the knee.


Antipsychotic medication in schizophrenia: a review.
Antipsychotic medications are mainstays in the treatment of schizophrenia and a range of other psychotic disorders. Recent meta-analyses of antipsychotic efficacy and tolerability have been included in this review, along with key papers on antipsychotic use in schizophrenia and other psychotic illnesses. The heterogeneity in terms of individuals' response to antipsychotic treatment and the current inability to predict response leads to a trial-and-error strategy with treatment choice. Clozapine is the only effective medication for treatment-resistant schizophrenia. There are a significant number of side effects associated with antipsychotic use. With a reduction in the frequency of extrapyramidal side effects with the use of second-generation antipsychotics, there has been a significant shift in the side effect burden, with an increase in the risk of cardiometabolic dysfunction. There exist small and robust efficacy differences between medications (other than clozapine), and response and tolerability to each antipsychotic drug vary, with there being no first-line antipsychotic drug that is suitable for all patients. A focus on the different symptom domains of schizophrenia may lead to endophenotypic markers being identified, e.g. for negative symptoms and cognitive deficits (as well as for positive symptoms) that can promote the development of novel therapeutics, which will rationally target cellular and molecular targets, rather than just the dopamine 2 receptor. Future developments will target additional processes, including glutamatergic, cholinergic and cannabinoid receptor targets and will utilize personalized medicine techniques, such as pharmacogenetic variants and biomarkers allowing for a tailored and safer use of antipsychotics.


The check-up: in-person, computerized, and telephone adaptations of motivational enhancement treatment to elicit voluntary participation by the contemplator.
Countless barriers come between people who are struggling with substance abuse and those charged with providing substance abuse treatment. The check-up, a form of motivational enhancement therapy, is a harm reduction intervention that offers a manner of supporting individuals by lowering specific barriers to reaching those who are untreated. The check-up was originally developed to reach problem drinkers who were neither seeking treatment nor self-initiating change. The intervention, marketed as an opportunity to take stock of one's experiences, involves an assessment and personalized feedback delivered with a counseling style termed motivational interviewing. Check-ups can be offered in care settings to individuals who, as a result of screening, manifest risk factors for specific disorders such as alcoholism. They can also be free-standing and publicized widely to the general public. This paper will discuss illustrations of in-person, computerized, in-school, and telephone applications of the free-standing type of check-up with reference to alcohol consumers, adult and adolescent marijuana smokers, and gay/bisexual males at risk for sexual transmission of HIV. The paper's major focus is to highlight how unique features of each application have the potential of reducing barriers to reaching specific at-risk populations. Also considered are key policy issues such as how check-up services can be funded, which venues are appropriate for the delivery of check-up interventions, pertinent competency criteria in evaluating staff who deliver this intervention, how marketing can be designed to reach contemplators in untreated at-risk populations, and how a check-up's success ought to be defined.


Current issues confounding the rapid toxicological assessment of oil spills.
Oil spills of varying magnitude occur every year, each presenting a unique challenge to the local ecosystem. The complex, changeable nature of oil makes standardised risk assessment difficult. Our review of the state of science regarding oil's unique complexity; biological impact of oil spills and use of rapid assessment tools, including commercial toxicity kits and bioassays, allows us to explore the current issues preventing effective, rapid risk assessment of oils. We found that despite the advantages to monitoring programmes of using well validated standardised tests, which investigate impacts across trophic levels at environmentally relevant concentrations, only a small percentage of the available tests are specialised for use within the marine environment, or validated for the assessment of crude oil toxicity. We discuss the use of rapid tests at low trophic levels in addition to relevant sublethal toxicity assays to allow the characterisation of oil, dispersant and oil and dispersant mixture toxicity. We identify novel, passive dosing techniques as a practical and reproducible means of improving the accuracy and maintenance of nominal concentrations. Future work should explore the possibility of linking this tiered testing system with ecosystem models to allow the prediction and risk assessment of the entire ecosystem.


Effect of puerarin on the expression of extracellular matrix in rats with streptozotocin-induced diabetic nephropathy.
Inhibition of the formation of advanced glycation end-products delays the development of diabetic nephropathy. Puerarin decreases the formation of these products. We studied the effect of puerarin in a rat model of diabetic nephropathy. Three groups of rats were studied: a control group, a diabetic group in whom diabetic nephropathy was induced by intraperitoneal injection of streptozotocin, and a puerarin group in which diabetic rats were treated with puerarin. During and after treatment, measurements were made on the rats' general status, blood glucose level, blood urea nitrogen, serum creatinine, creatinine clearance rate and urinary albumin excretion over 24 hours. The expression of collagen I and heparan sulphate proteoglycan in the extracellular matrix of the glomerulus was assessed by immunohistochemistry. Rats in the puerarin group had a better general condition than those with diabetes. They also had lower blood urea nitrogen, serum creatinine and urinary albumin excretion rate over 24 hours compared with those in the diabetic group. The creatinine clearance and expression of heparan sulphate proteoglycan in the kidney also increased significantly in the puerarin group compared with that in the diabetic group. Puerarin seems to have certain protective effects on diabetic nephropathy induced by streptozotocin. This is caused possibly by regulating the expression of glomerular extracellular matrix.


Serologic Response to Borrelia Antigens Varies with Clinical Phenotype in Children and Young Adults with Lyme Disease.
Lyme disease is commonly diagnosed by serologic response to Borrelia burgdorferi and related species, but the relationship between serologic targets and clinical features is unknown. We developed a multiantigen Luminex-based panel and evaluated IgG responses in 527 children 1 to 21 years of age assessed for Lyme disease across 4 Pedi Lyme Net emergency departments, including 127 Lyme cases defined by either an erythema migrans (EM) lesion or positive C6 enzyme immunoassay followed by immunoblotting and 400 patients considered clinical mimics. Of 42 antigens tested, 26 elicited specific reactivity in Lyme patients without marked age-dependent variation. Children with single EM lesions typically lacked Borrelia-specific IgG. By principal-component analysis, children with early disseminated and late Lyme disease clustered separately from clinical mimics and also from each other. Neurological disease and arthritis exhibited distinct serologic responses, with OspC variants overrepresented in neurological disease and p100, BmpA, p58, and p45 overrepresented in arthritis. Machine learning identified a 3-antigen panel (VlsE_Bb, p41_Bb, and OspC_Bafz) that distinguished Lyme disease from clinical mimics with a sensitivity of 86.6% (95% confidence interval [CI], 80.3 to 92.1) and a specificity of 95.5% (95% CI, 93.4 to 97.4). Sensitivity was much lower in early Lyme disease (38.5%; 95% CI, 15.4 to 69.2). Interestingly, 17 children classified as Lyme mimics had a positive 3-antigen panel, suggesting that more comprehensive serologic analysis could help refine Lyme diagnosis. In conclusion, multiplex antigen panels provide a novel approach to understanding the immune response in Lyme disease, potentially helping to facilitate accurate diagnosis and to understand differences between clinical stages.


Randomized, placebo controlled phase I trial of safety, pharmacokinetics, pharmacodynamics and acceptability of tenofovir and tenofovir plus levonorgestrel vaginal rings in women.
To prevent the global health burdens of human immunodeficiency virus [HIV] and unintended/mistimed pregnancies, we developed an intravaginal ring [IVR] that delivers tenofovir [TFV] at ~10mg/day alone or with levonorgestrel [LNG] at ~20μg/day for 90 days. We present safety, pharmacokinetics, pharmacodynamics, acceptability and drug release data in healthy women. CONRAD A13-128 was a randomized, placebo controlled phase I study. We screened 86 women; 51 were randomized to TFV, TFV/LNG or placebo IVR [2:2:1] and 50 completed all visits, using the IVR for approximately 15 days. We assessed safety by adverse events, colposcopy, vaginal microbiota, epithelial integrity, mucosal histology and immune cell numbers and phenotype, cervicovaginal [CV] cytokines and antimicrobial proteins and changes in systemic laboratory measurements, and LNG and TFV pharmacokinetics in multiple compartments. TFV pharmacodynamic activity was measured by evaluating CV fluid [CVF] and tissue for antiviral activity using in vitro models. LNG pharmacodynamic assessments were timed based on peak urinary luteinizing hormone levels. All IVRs were safe with no significant colposcopic, mucosal, immune and microbiota changes and were acceptable. Among TFV containing IVR users, median and mean CV aspirate TFV concentrations remained above 100,000 ng/mL 4 hours post IVR insertion and mean TFV-diphosphate [DP] concentrations in vaginal tissue remained above 1,000 fmol/mg even 3 days post IVR removal. CVF of women using TFV-containing IVRs completely inhibited [94-100%] HIV infection in vitro. TFV/LNG IVR users had mean serum LNG concentrations exceeding 300 pg/mL within 1 hour, remaining high throughout IVR use. All LNG IVR users had a cervical mucus Insler score <10 and the majority [95%] were anovulatory or had abnormal cervical mucus sperm penetration. Estimated in vivo TFV and LNG release rates were within expected ranges. All IVRs were safe with the active ones delivering sustained high concentrations of TFV locally. LNG caused changes in cervical mucus, sperm penetration, and ovulation compatible with contraceptive efficacy. The TFV and TFV/LNG rings are ready for expanded 90 day clinical testing. Trial registration ClinicalTrials.gov #NCT02235662.


Spontaneous fracture (sfx): a mouse genetic model of defective peripubertal bone formation.
A new mouse model of stage-specific bone growth failure and fracture has been recovered as an autosomal recessive mutation, designated spontaneous fracture (sfx). The sfx/sfx mice are phenotypically normal until shortly after weaning, when reduced mobility and impaired somatic growth are first noted. By 6 weeks of age, body, spleen, and thymus weights, as well as hematocrits and serum calcium, inorganic phosphate, total alkaline phosphatase, insulin-like growth factor-I, and osteocalcin levels are decreased. The sfx/sfx mice also show reduced femoral cortical density and diaphyseal circumference, as well as a paucity of mature osteoblasts on bone surfaces. Histological analyses of the femur and tibia in the mutants show subtle reduction of chondrocyte numbers in epiphyseal-plate columns, reduction of matrix, and near absence of osteoid below the differentiated chondrocytes. Trabeculae in proximal tibiae, iliacs, and vertebral bodies are sparse and thin. Cortical bone thickness of mutants is markedly thinned in all sites examined. By 7-8 weeks, radiographic films routinely show spontaneous impact fractures of the distal femur accompanied by callus formation, whereas complete fractures are less commonly observed. Volumetric bone mineral density (BMD) of mutant femurs is similar to +/? littermates in the center of the femoral diaphysis, but BMD declines as either end of the femoral diaphysis is approached. We have mapped the gene responsible for this phenotype to central Chromosome 14. Reduced bone mass, impaired bone formation, abnormalities of bone architecture, and a disposition to spontaneous fracture identify sfx/sfx mice as a useful model for understanding the mechanisms responsible for peripubertal bone formation.


Excess deaths associated with covid-19 pandemic in 2020: age and sex disaggregated time series analysis in 29 high income countries.
To estimate the direct and indirect effects of the covid-19 pandemic on mortality in 2020 in 29 high income countries with reliable and complete age and sex disaggregated mortality data. Time series study of high income countries. Austria, Belgium, Czech Republic, Denmark, England and Wales, Estonia, Finland, France, Germany, Greece, Hungary, Israel, Italy, Latvia, Lithuania, the Netherlands, New Zealand, Northern Ireland, Norway, Poland, Portugal, Scotland, Slovakia, Slovenia, South Korea, Spain, Sweden, Switzerland, and United States. Mortality data from the Short-term Mortality Fluctuations data series of the Human Mortality Database for 2016-20, harmonised and disaggregated by age and sex. Covid-19 pandemic and associated policy measures. Weekly excess deaths (observed deaths versus expected deaths predicted by model) in 2020, by sex and age (0-14, 15-64, 65-74, 75-84, and ≥85 years), estimated using an over-dispersed Poisson regression model that accounts for temporal trends and seasonal variability in mortality. An estimated 979 000 (95% confidence interval 954 000 to 1 001 000) excess deaths occurred in 2020 in the 29 high income countries analysed. All countries had excess deaths in 2020, except New Zealand, Norway, and Denmark. The five countries with the highest absolute number of excess deaths were the US (458 000, 454 000 to 461 000), Italy (89 100, 87 500 to 90 700), England and Wales (85 400, 83 900 to 86 800), Spain (84 100, 82 800 to 85 300), and Poland (60 100, 58 800 to 61 300). New Zealand had lower overall mortality than expected (-2500, -2900 to -2100). In many countries, the estimated number of excess deaths substantially exceeded the number of reported deaths from covid-19. The highest excess death rates (per 100 000) in men were in Lithuania (285, 259 to 311), Poland (191, 184 to 197), Spain (179, 174 to 184), Hungary (174, 161 to 188), and Italy (168, 163 to 173); the highest rates in women were in Lithuania (210, 185 to 234), Spain (180, 175 to 185), Hungary (169, 156 to 182), Slovenia (158, 132 to 184), and Belgium (151, 141 to 162). Little evidence was found of subsequent compensatory reductions following excess mortality. Approximately one million excess deaths occurred in 2020 in these 29 high income countries. Age standardised excess death rates were higher in men than women in almost all countries. Excess deaths substantially exceeded reported deaths from covid-19 in many countries, indicating that determining the full impact of the pandemic on mortality requires assessment of excess deaths. Many countries had lower deaths than expected in children <15 years. Sex inequality in mortality widened further in most countries in 2020.


International consensus recommendations on the diagnostic work-up for malformations of cortical development.
Malformations of cortical development (MCDs) are neurodevelopmental disorders that result from abnormal development of the cerebral cortex in utero. MCDs place a substantial burden on affected individuals, their families and societies worldwide, as these individuals can experience lifelong drug-resistant epilepsy, cerebral palsy, feeding difficulties, intellectual disability and other neurological and behavioural anomalies. The diagnostic pathway for MCDs is complex owing to wide variations in presentation and aetiology, thereby hampering timely and adequate management. In this article, the international MCD network Neuro-MIG provides consensus recommendations to aid both expert and non-expert clinicians in the diagnostic work-up of MCDs with the aim of improving patient management worldwide. We reviewed the literature on clinical presentation, aetiology and diagnostic approaches for the main MCD subtypes and collected data on current practices and recommendations from clinicians and diagnostic laboratories within Neuro-MIG. We reached consensus by 42 professionals from 20 countries, using expert discussions and a Delphi consensus process. We present a diagnostic workflow that can be applied to any individual with MCD and a comprehensive list of MCD-related genes with their associated phenotypes. The workflow is designed to maximize the diagnostic yield and increase the number of patients receiving personalized care and counselling on prognosis and recurrence risk.


Multiple Cu-ATPase genes are differentially expressed and transcriptionally regulated by Cu exposure in sea bream, Sparus aurata.
Copper (Cu) is an essential metal, although in excess is highly toxic due to its redox properties and, therefore intracellular Cu homeostasis is a highly regulated process. Cu-ATPases are pivotal regulatory, proteins of intracellular and bodily Cu homeostasis. Two Cu-ATPases, ATP7A and ATP7B with distinct, functions are found in mammals and herein we report the structure and expression under Cu stress of, homologues of ATP7A and ATP7B in gilthead sea bream (Sparus aurata), the first such report for any, fish. The deduced protein sequences of S. aurata ATP7A (saATP7A) and ATP7B (saATP7B), displayed 63% and 75% identity respectively to their human homologues. All characteristic structural, features of Cu-ATPases were conserved between fish and mammals, although the number of Cu-binding, domains was less in fish ATP7B than in mammalian ATP7B. The tissue expression of sea bream, Cu-ATPases was similar to that observed in mammals, saATP7A being ubiquitously expressed, although low in liver, whilst saATP7B was mainly expressed in the intestine and liver. By analysis of the sequenced genomes of other species we have confirmed the presence of ATP7A and ATP7B genes in fish and propose that the presence of two Cu-ATPase genes in vertebrates represents a retention and neo-functionalization of a duplicated ancestral gene coincident with the development of a closed circulatory system and discrete hepato-biliary system. Expression of Cu-ATPase mRNA was changed after exposure to excess Cu in a manner dependent on exposure route and tissue type. Excess dietary Cu (130mgkg(-1) Cu dry diet) reduced saATP7A mRNA levels in intestine, gill, kidney and liver, and increased hepatic saATP7B mRNA consistent with increased biliary excretion. Whilst after waterborne Cu exposure (0.3mgL(-1) Cu), expression of ATP7A mRNA was increased in intestine and liver and toxic responses were observed in gill and liver. Our results indicate that Cu-ATPases in both fish and mammals have similar functions in maintenance of Cu homeostasis and are consistent with previous physiological evidence from various fish species for the involvement of multiple Cu-ATPases in Cu transport. Furthermore, our evidence suggests that fish can detoxify excess dietary Cu relatively efficiently but are unable to cope with excess dissolved Cu in the water, demonstrating that the exposure route is critical to toxicity.


Production of cold-adapted amylase by marine bacterium Wangia sp. C52: optimization, modeling, and partial characterization.
The aim of this work was to optimize the fermentation parameters in the shake-flask culture of marine bacterium Wangia sp. C52 to increase cold-adapted amylase production using two statistical experimental methods including Plackett-Burman design, which was applied to find the key ingredients for the best medium composition, and response surface methodology, which was used to determine the optimal concentrations of these components. The results showed starch, tryptone, and initial pH had significant effects on the cold-adapted amylase production. A central composite design was then employed to further optimize these three factors. The experimental results indicated that the optimized composition of medium was 6.38 g L(-1) starch, 33.84 g L(-1) tryptone, 3.00 g L(-1) yeast extract, 30 g L(-1) NaCl, 0.60 g L(-1) MgSO(4) and 0.56 g L(-1) CaCl(2). The optimized cultivation conditions for amylase production were pH 7.18, a temperature of 20°C, and a shaking speed of 180 rpm. Under the proposed optimized conditions, the amylase experimental yield (676.63 U mL(-1)) closely matched the yield (685.60 U mL(-1)) predicted by the statistical model. The optimization of the medium contributed to tenfold higher amylase production than that of the control in shake-flask experiments.


Long-term results after the Fontan operation for tricuspid atresia.
Between 1968 and 1977, 32 patients who underwent the Fontan operation for tricuspid atresia at Bordeaux, France, or Leiden, The Netherlands, survived at least 1 year after surgery. These patients were evaluated clinically 7 to 16 years (mean 8.9 years) after surgery by review of clinical records, questionnaire, or direct examination. There were five deaths: one during arrhythmia, the second sudden and unexplained, and three others after reoperation. Four of the five patients had evidence of obstruction of the atriopulmonary or atrioventricular conduit. There were eight reoperations. Two were for residual atrial septal defects, one for an atrial septal defect and an intrapulmonary arteriovenous fistula, and one for a residual ventricular septal defect. The other four were reoperated for severe conduit or homograft obstruction. One of these four also had a residual shunt, severe mitral regurgitation, and reduced left ventricular function. One patient was found to have left ventricular dysfunction 3 months after surgery, which persisted. Another patient had left ventricular dysfunction unmasked after successful mitral annuloplasty for severe mitral regurgitation. No other patients had clinical evidence of left ventricular dysfunction. Recurrent supraventricular tachycardia occurred in four patients and was eventually fatal in one patient with associated conduit obstruction. Of the 27 survivors, 13 are in NYHA class I, 13 are in class II, and one is in class III. We conclude that clinical results of the Fontan operation remain good in most patients 7 to 16 years after surgery.(ABSTRACT TRUNCATED AT 250 WORDS)


Target virus log10 reduction values determined for two reclaimed wastewater irrigation scenarios in Japan based on tolerable annual disease burden.
Multiple-barriers are widely employed for managing microbial risks in water reuse, in which different types of wastewater treatment units (biological treatment, disinfection, etc.) and health protection measures (use of personal protective gear, vegetable washing, etc.) are combined to achieve a performance target value of log10 reduction (LR) of viruses. The LR virus target value needs to be calculated based on the data obtained from monitoring the viruses of concern and the water reuse scheme in the context of the countries/regions where water reuse is implemented. In this study, we calculated the virus LR target values under two exposure scenarios for reclaimed wastewater irrigation in Japan, using the concentrations of indigenous viruses in untreated wastewater and a defined tolerable annual disease burden (10-4 or 10-6 disability-adjusted life years per person per year (DALYpppy)). Three genogroups of norovirus (norovirus genogroup I (NoV GI), geogroup II (NoV GII), and genogroup IV (NoV GIV)) in untreated wastewater were quantified as model viruses using reverse transcription-microfluidic quantitative PCR, and only NoV GII was present in quantifiable concentration. The probabilistic distribution of NoV GII concentration in untreated wastewater was then estimated from its concentration dataset, and used to calculate the LR target values of NoV GII for wastewater treatment. When an accidental ingestion of reclaimed wastewater by Japanese farmers was assumed, the NoV GII LR target values corresponding to the tolerable annual disease burden of 10-6 DALYpppy were 3.2, 4.4, and 5.7 at 95, 99, and 99.9%tile, respectively. These percentile values, defined as "reliability," represent the cumulative probability of NoV GII concentration distribution in untreated wastewater below the corresponding tolerable annual disease burden after wastewater reclamation. An approximate 1-log10 difference of LR target values was observed between 10-4 and 10-6 DALYpppy. The LR target values were influenced mostly by the change in the logarithmic standard deviation (SD) values of NoV GII concentration in untreated wastewater and the reliability values, which highlights the importance of accurately determining the probabilistic distribution of reference virus concentrations in source water for water reuse.


Long-term cardiovascular outcomes in patients with atrial fibrillation and atherothrombosis in the REACH Registry.
Patients with atrial fibrillation (AF) are at increased risk of thromboembolic events. The long-term prognostic implications of AF in patients with atherothrombosis are unknown. We compared 4-year CV outcomes in patients with and without a history of AF recorded at their baseline visit in the REACH Registry, an international, prospective cohort of patients with established atherosclerotic arterial disease (CAD, CVD, PAD) or at least 3 risk factors (RFO). AF status and 4 year follow-up data were available on 44,518 patients. The prevalence of AF at baseline was 10.3% (n=4582). Overall, patients with AF had approximately a 2-fold increase in the composite of CV death, MI, or stroke compared with patients without AF after adjustment for age, gender, prior ischemic event, vascular disease, congestive heart failure, diabetes, smoking, body mass index, region, aspirin and statin use (18.9% vs. 9.4%, p<0.0001). This increased risk was observed both in patients with established atherothrombosis (CAD: 15.5% vs. 8.0%, p=0.0001; CVD: 23.6% vs. 13.6%, p<0.0001; PAD: 24.3% vs. 13.5%, p=0.089) and those with multiple risk factors (RFO: 12.1% vs. 5.9%, p=0.017). Only 52% of patients with a history of AF at baseline were receiving anticoagulation at 4 years. Patients with a history of both AF and atherothrombosis have particularly high long-term CV risk. Despite this increased risk, almost half of all patients with AF do not receive guideline recommended anticoagulation, highlighting an important public health priority.


DC-SIGN is the major Mycobacterium tuberculosis receptor on human dendritic cells.
Early interactions between lung dendritic cells (LDCs) and Mycobacterium tuberculosis, the etiological agent of tuberculosis, are thought to be critical for mounting a protective anti-mycobacterial immune response and for determining the outcome of infection. However, these interactions are poorly understood, at least at the molecular level. Here we show that M. tuberculosis enters human monocyte-derived DCs after binding to the recently identified lectin DC-specific intercellular adhesion molecule-3 grabbing nonintegrin (DC-SIGN). By contrast, complement receptor (CR)3 and mannose receptor (MR), which are the main M. tuberculosis receptors on macrophages (Mphis), appeared to play a minor role, if any, in mycobacterial binding to DCs. The mycobacteria-specific lipoglycan lipoarabinomannan (LAM) was identified as a key ligand of DC-SIGN. Freshly isolated human LDCs were found to express DC-SIGN, and M. tuberculosis-derived material was detected in CD14(-)HLA-DR(+)DC-SIGN(+) cells in lymph nodes (LNs) from patients with tuberculosis. Thus, as for human immunodeficiency virus (HIV), which is captured by the same receptor, DC-SIGN-mediated entry of M. tuberculosis in DCs in vivo is likely to influence bacterial persistence and host immunity.


No short-term effects of high-frequency electromagnetic fields on the mammalian pineal gland.
There is ample experimental evidence that changes of earth-strength static magnetic fields, pulsed magnetic fields, or alternating electric fields (60 Hz) depress the nocturnally enhanced melatonin synthesis of the pineal gland of certain mammals. No data on the effects of high-frequency electromagnetic fields on melatonin synthesis is available. In the present study, exposure to 900 MHz electromagnetic fields [0.1 to 0.6 mW/cm2, approximately 0.06 to 0.36 W/kg specific absorption rate (SAR) in rats and 0.04 W/kg in Djungarian hamsters; both continuous and/or pulsed at 217 Hz, for 15 min to 6 h] at day or night had no notable short-term effect on pineal melatonin synthesis in male and female Sprague-Dawley rats and Djungarian hamsters. Pineal synaptic ribbon profile numbers (studied in rats only) were likewise not affected. The 900 MHz electromagnetic fields, unpulsed or pulsed at 217 Hz, as applied in the present study, have no short-term effect on the mammalian pineal gland.


The utility of procollagen type 1 N-terminal propeptide for the bone status assessment in postmenopausal women.
The utility of procollagen type 1 N-terminal propeptide (P1NP) in the management of metabolic bone diseases remains a subject of debate since the reference ranges are not rigorously established and fail to account for many of the preanalytical variables. We aimed to establish reference intervals for P1NP level in healthy and osteoporotic postmenopausal females stratified by age, body mass index and menopausal duration. We also aimed to assess the relationship between P1NP and BMD. This cross-sectional study enrolled 183 postmenopausal females who were divided in osteoporosis group (N=93) and control group (N=90) with preserved bone mass based on BMD assessed by DXA. In the osteoporosis group median P1NP was significantly higher (51.7 ng / mL; 95%CI 43.2-53.7) compared to control group (38.9 ng/mL; 95%CI 34.2-43.9)(p<0.01). After controlling for age, BMI and years since menopause, there was significant inverse association between BMD and P1NP at the femoral neck (r=-0.18), total hip (r=-0.207) and lumbar spine (r=-0.236). There was no significant difference in P1NP concentration across quartiles of age in postmenopausal females. P1NP was significantly lower in obese postmenopausal females with preserved bone mass compared to normal weight and overweight females in control and in osteoporosis group. In conclusion, we showed that P1NP is inversely associated with BMD even after controlling for age, BMI and years since menopause. Although, P1NP is significantly higher in postmenopausal females with osteoporosis compared to postmenopausal females with preserved bone mass its low specificity does not warrant its utility is diagnosing osteoporosis.


Rab11b regulates the trafficking and recycling of the epithelial sodium channel (ENaC).
Expression of the epithelial sodium channel (ENaC) at the apical membrane of cortical collecting duct (CCD) principal cells is modulated by regulated trafficking mediated by vesicle insertion and retrieval. Small GTPases are known to facilitate vesicle trafficking, recycling, and membrane fusion events; however, little is known about the specific Rab family members that modify ENaC surface density. Using a mouse CCD cell line that endogenously expresses ENaC (mpkCCD), the channel was localized to both Rab11a- and Rab11b-positive endosomes by immunoisolation and confocal fluorescent microscopy. Expression of a dominant negative (DN) form of Rab11a or Rab11b significantly reduced the basal and cAMP-stimulated ENaC-dependent sodium (Na(+)) transport. The greatest reduction in Na(+) transport was observed with the expression of DN-Rab11b. Furthermore, small interfering RNA-mediated knockdown of each Rab11 isoform demonstrated the requirement for Rab11b in ENaC surface expression. These data indicate that Rab11b, and to a lesser extent Rab11a, is involved in establishing the constitutive and cAMP-stimulated Na(+) transport in mpkCCD cells.


Sex chromosomes, synapsis, and cohesins: a complex affair.
During first meiotic prophase, homologous chromosomes are held together by the synaptonemal complex, a tripartite proteinaceous structure that extends along the entire length of meiotic bivalents. While this feature is applicable for autosomes, sex chromosomes often escape from this rule. Many species present sex chromosomes that differ between them in their morphology, length, and gene content. Moreover, in some species, sex chromosomes appear in a single dose in one of the sexes. In all of these cases, the behavior of sex chromosomes during meiosis is conspicuously affected, and this includes the assembly and dynamics of the synaptonemal complex. We review in this study the structure of the synaptonemal complex in the sex chromosomes of three groups of organisms, namely: mammals, orthopterans, and hemipterans, which present different patterns of sex chromosome structure and behavior. Of special interest is the analysis of the organization of the axial/lateral elements of the synaptonemal complex in relation to other axial structures organized along meiotic chromosomes, mainly the cohesin axis. The differences found in the behavior of both axial structures reveal that while the organization of a cohesin axis along sex chromosomes is a conserved feature in most organisms and it shows very little morphological variations, the axial/lateral elements of the synaptonemal complex present a wide range of structural modifications on these chromosomes.


Evolutionary relationships among pathogenic and nonpathogenic Escherichia coli strains inferred from multilocus enzyme electrophoresis and mdh sequence studies.
Within the species Escherichia coli, there are commensal strains and a variety of pathogenic strains, including enteropathogenic E. coli (EPEC), enterohemorrhagic E. coli (EHEC), enterotoxigenic E. coli (ETEC), enteroinvasive E. coli (EIEC), and urinary tract infection (UTI) strains. The pathogenic strains are identified by serotype and by possession of specific virulence determinants (toxins and adhesions, etc.) encoded by either monocistronic genes, plasmids, or pathogenicity islands. Although there are studies on the relationships between selected pathogenic strains, the relatedness among the majority of the pathogenic forms to each other, to commensal E. coli, and to the genus Shigella (which has often been suggested to be part of E. coli) has not been determined. We used multilocus enzyme electrophoresis (MLEE) at 10 enzyme loci and the sequence of the mdh housekeeping gene to study the genetic relationships of pathogenic E. coli strains (including Shigella clones), namely, 5 EPEC strains (serotypes O111 and O55), 3 EHEC strains (serotype O157), 6 ETEC strains (serotypes O78, O159, and O148), 5 EIEC strains (serotypes O124, O28, and O112), and 13 Shigella strains representing clones Flexneri, Dysenteriae, Boydii, and Sonnei, to commensal E. coli strains. Both the MLEE and mdh sequence trees reveal that EPEC, EHEC, ETEC, EIEC, and UTI strains are distributed among the ECOR set groups, with no overall clustering of EPEC, ETEC, EIEC, or UTI strains. The genus Shigella is shown to comprise a group of closely related pathogenic E. coli strains. Six pathogenic strains, i.e., M502 (EIEC; O112ac:NM), M503 (EPEC; O111:H12), M526 (ETEC; O159:H4), M522 (EPEC; O111ac:H12), M524 (ETEC; O78:H11), and M506 (ETEC; O78:H11), were found to have mdh sequences identical to those of five ECOR group A strains (ECOR5, ECOR10, ECOR14, ECOR6, and K-12). All 11 strains are closely related by MLEE. The results indicate that pathogenic strains of E. coli do not have a single evolutionary origin within E. coli but have arisen many times. The results also suggest the possibility that any E. coli strain acquiring the appropriate virulence factors may give rise to a pathogenic form.


Nucleus accumbens core lesions retard instrumental learning and performance with delayed reinforcement in the rat.
Delays between actions and their outcomes severely hinder reinforcement learning systems, but little is known of the neural mechanism by which animals overcome this problem and bridge such delays. The nucleus accumbens core (AcbC), part of the ventral striatum, is required for normal preference for a large, delayed reward over a small, immediate reward (self-controlled choice) in rats, but the reason for this is unclear. We investigated the role of the AcbC in learning a free-operant instrumental response using delayed reinforcement, performance of a previously-learned response for delayed reinforcement, and assessment of the relative magnitudes of two different rewards. Groups of rats with excitotoxic or sham lesions of the AcbC acquired an instrumental response with different delays (0, 10, or 20 s) between the lever-press response and reinforcer delivery. A second (inactive) lever was also present, but responding on it was never reinforced. As expected, the delays retarded learning in normal rats. AcbC lesions did not hinder learning in the absence of delays, but AcbC-lesioned rats were impaired in learning when there was a delay, relative to sham-operated controls. All groups eventually acquired the response and discriminated the active lever from the inactive lever to some degree. Rats were subsequently trained to discriminate reinforcers of different magnitudes. AcbC-lesioned rats were more sensitive to differences in reinforcer magnitude than sham-operated controls, suggesting that the deficit in self-controlled choice previously observed in such rats was a consequence of reduced preference for delayed rewards relative to immediate rewards, not of reduced preference for large rewards relative to small rewards. AcbC lesions also impaired the performance of a previously-learned instrumental response in a delay-dependent fashion. These results demonstrate that the AcbC contributes to instrumental learning and performance by bridging delays between subjects' actions and the ensuing outcomes that reinforce behaviour.


Identification and expression analysis of two developmentally regulated myosin heavy chain gene transcripts in carp (Cyprinus carpio).
Whilst developmentally regulated genes for the myosin heavy chain (MyoHC) have been characterised in mammalian, avian and amphibian species, no developmental MyoHC gene has previously been characterised in a species of fish. In this study, we identify two developmentally regulated MyoHC gene transcripts (named Eggs22 and Eggs24) in carp (Cyprinus carpio) and characterise their expression patterns during embryonic and larval development. The transcripts showed an identical temporal pattern of expression commencing 22 h post-fertilisation (18 degrees C incubation temperature), coincident with the switch from exclusive expression of genes for beta-actin to expression of genes for both beta- and alpha-actin, and continuing for 2 weeks post-hatching. No expression of these myosin transcripts was detected in juvenile or adult carp. Wholemount in situ hybridisation showed that both transcripts are expressed initially in the rostral region of the developing trunk and progress caudally. Both are expressed in the developing pectoral fin and protractor hyoideus muscles. However, the muscles of the lower jaw express only the Eggs22 transcript. No expression of either transcript was detected in cardiac or smooth muscle. A distinct chevron pattern of expression was observed in the myotomal muscle. This was shown to be caused by localisation of the mRNAs to the myoseptal regions of the fibres, the sites of new sarcomere addition during muscle growth, suggesting transport of MyoHC mRNA transcripts. The 3' untranslated region of the Eggs24 transcript contains a 10 base pair motif (AAAATGTGAA) which is shown to be also present in the 3' untranslated regions of MyoHC genes from a wide range of species. Possible reasons for the need for developmental isoforms of myosin heavy chain isoforms are discussed.


Where communities intermingle, diversity grows - The evolution of topics in ecosystem service research.
We analyze how the content of ecosystem service research has evolved since the early 1990s. Conducting a computational bibliometric content analysis we process a corpus of 14,118 peer-reviewed scientific article abstracts on ecosystem services (ES) from Web of Science records. To provide a comprehensive content analysis of ES research literature, we employ a latent Dirichlet allocation algorithm. For three different time periods (1990-2000, 2001-2010, 2011-2016), we derive nine main ES topics arising from content analysis and elaborate on how they are related over time. The results show that natural science-based ES research analyzes oceanic, freshwater, agricultural, forest, and soil ecosystems. Pollination and land cover emerge as traceable standalone topics around 2001. Social science ES literature demonstrates a reflexive and critical lens on the role of ES research and includes critiques of market-oriented perspectives. The area where social and natural science converge most is about land use systems such as agriculture. Overall, we provide evidence of the strong natural science foundation, the highly interdisciplinary nature of ES research, and a shift in social ES research towards integrated assessments and governance approaches. Furthermore, we discuss potential reasons for observable topic developments.


Internal Consistency and Structural Validity of the Norwegian Translation of the Ten-Item Personality Inventory.
Background: The Ten-Item Personality Inventory (TIPI) is a validated brief instrument measuring the five-factor model (FFM) personality dimensions, developed for instances where more comprehensive FFM instruments are impractical to use. The TIPI has been translated into several languages, but psychometric properties of the Norwegian version (N-TIPI) have not been systematically explored. Objectives: This study aimed to explore the psychometric properties of the N-TIPI, in terms of internal consistency and structural validity. Methods: In a cross-sectional study, responses on the N-TIPI were collected from 5,009 Norwegian master graduates. Descriptive statistics for the subscales and correlations between subscales were calculated. Internal consistency was assessed with inter-item correlations, Cronbach's α and Spearman-Brown coefficients. Structural validity was explored with principal component analysis, parallel analysis, and visual scree plot inspection. Results for the N-TIPI were compared with those previously reported for the original TIPI as well as the German, French, Spanish, and Portuguese versions. Results: Compared with the original and non-English versions of TIPI, results for N-TIPI showed comparable subscale rank order of means, standard deviations, and pattern of correlations between subscales, as well as inter-item correlations and Cronbach's α. The 10 N-TIPI items were adequately reduced to five components, theoretically corresponding with the FFM personality domains. Conclusion: The N-TIPI demonstrated acceptable internal consistency and satisfactory structural validity. Although further research is warranted, the instrument stands out as feasible when it is essential to minimize participants' response burden in studies that aim to explore personality as one among several concepts or utilize personality traits as covariates.


Haptic palpation for medical simulation in virtual environments.
Palpation is a physical examination technique where objects, e.g., organs or body parts, are touched with fingers to determine their size, shape, consistency and location. Many medical procedures utilize palpation as a supplementary interaction technique and it can be therefore considered as an essential basic method. However, palpation is mostly neglected in medical training simulators, with the exception of very specialized simulators that solely focus on palpation, e.g., for manual cancer detection. In this article we propose a novel approach to enable haptic palpation interaction for virtual reality-based medical simulators. The main contribution is an extensive user study conducted with a large group of medical experts. To provide a plausible simulation framework for this user study, we contribute a novel and detailed interaction algorithm for palpation with tissue dragging, which utilizes a multi-object force algorithm to support multiple layers of anatomy and a pulse force algorithm for simulation of an arterial pulse. Furthermore, we propose a modification for an off–the–shelf haptic device by adding a lightweight palpation pad to support a more realistic finger grip configuration for palpation tasks. The user study itself has been conducted on a medical training simulator prototype with a specific procedure from regional anesthesia, which strongly depends on palpation. The prototype utilizes a co-rotational finite-element approach for soft tissue simulation and provides bimanual interaction by combining the aforementioned techniques with needle insertion for the other hand. The results of the user study suggest reasonable face validity of the simulator prototype and in particular validate medical plausibility of the proposed palpation interaction algorithm.


In vitro and in vivo gene therapy vector evolution via multispecies interbreeding and retargeting of adeno-associated viruses.
Adeno-associated virus (AAV) serotypes differ broadly in transduction efficacies and tissue tropisms and thus hold enormous potential as vectors for human gene therapy. In reality, however, their use in patients is restricted by prevalent anti-AAV immunity or by their inadequate performance in specific targets, exemplified by the AAV type 2 (AAV-2) prototype in the liver. Here, we attempted to merge desirable qualities of multiple natural AAV isolates by an adapted DNA family shuffling technology to create a complex library of hybrid capsids from eight different wild-type viruses. Selection on primary or transformed human hepatocytes yielded pools of hybrids from five of the starting serotypes: 2, 4, 5, 8, and 9. More stringent selection with pooled human antisera (intravenous immunoglobulin [IVIG]) then led to the selection of a single type 2/type 8/type 9 chimera, AAV-DJ, distinguished from its closest natural relative (AAV-2) by 60 capsid amino acids. Recombinant AAV-DJ vectors outperformed eight standard AAV serotypes in culture and greatly surpassed AAV-2 in livers of naïve and IVIG-immunized mice. A heparin binding domain in AAV-DJ was found to limit biodistribution to the liver (and a few other tissues) and to affect vector dose response and antibody neutralization. Moreover, we report the first successful in vivo biopanning of AAV capsids by using a new AAV-DJ-derived viral peptide display library. Two peptides enriched after serial passaging in mouse lungs mediated the retargeting of AAV-DJ vectors to distinct alveolar cells. Our study validates DNA family shuffling and viral peptide display as two powerful and compatible approaches to the molecular evolution of novel AAV vectors for human gene therapy applications.


Cystic tumor of the atrioventricular node of the heart appears to be the heart equivalent of the solid cell nests (ultimobranchial rests) of the thyroid.
We studied a series of 10 solid cell nests (SCNs) of the thyroid and a case of cystic tumor of the atrioventricular node (CTAVN) of the heart and reviewed the literature. The CTAVN and SCNs appeared as cystic and/or solid (squamoid) structures mainly composed of polygonal or oval cells (main cells) admixed with occasional clear cells (neuroendocrine and C cells). Main cells were immunoreactive for simple and stratified epithelial-type cytokeratins, epithelial membrane antigen, carcinoembryonic antigen, carbohydrate antigen 19.9, p63, bcl-2, and galectin-3. Neuroendocrine (and C) cells were positive for simple-type cytokeratins, carcinoembryonic antigen, calcitonin, chromogranin, synaptophysin, and thyroid transcription factor-1. Our data support the hypothesis that the CTAVN of the heart and the SCNs of the thyroid are identical structures that represent the same lesional process. The assumption that CTAVN is a ultimobranchial heterotopia fits with the known role of cardiac neural crest cells in cardiovascular development.


Shared Decision-Making in Growth Hormone Therapy-Implications for Patient Care.
Several studies have shown that adherence to growth hormone therapy (GHT) is not optimal. There are several reasons why patients may not fully adhere to their treatment regimen and this may have implications on treatment success, patient outcomes and healthcare spending and resourcing. A change in healthcare practices, from a physician paternalistic to a more patient autonomous approach to healthcare, has encouraged a greater onus on a shared decision-making (SDM) process whereby patients are actively encouraged to participate in their own healthcare decisions. There is growing evidence to suggest that SDM may facilitate patient adherence to GHT. Improved adherence to therapy in this way may consequently positively impact treatment outcomes for patients. Whilst SDM is widely regarded as a healthcare imperative, there is little guidance on how it should be best implemented. Despite this, there are many opportunities for the implementation of SDM during the treatment journey of a patient with a GH-related disorder. Barriers to the successful practice of SDM within the clinic may include poor patient education surrounding their condition and treatment options, limited healthcare professional time, lack of support from clinics to use SDM, and healthcare resourcing restrictions. Here we discuss the opportunities for the implementation of SDM and the barriers that challenge its effective use within the clinic. We also review some of the potential solutions to overcome these challenges that may prove key to effective patient participation in treatment decisions. Encouraging a sense of empowerment for patients will ultimately enhance treatment adherence and improve clinical outcomes in GHT.


Internet based vestibular rehabilitation with and without physiotherapy support for adults aged 50 and older with a chronic vestibular syndrome in general practice: three armed randomised controlled trial.
To investigate the clinical effectiveness and safety of stand alone and blended internet based vestibular rehabilitation (VR) in the management of chronic vestibular syndromes in general practice. Pragmatic, three armed, parallel group, individually randomised controlled trial. 59 general practices in the Netherlands. 322 adults aged 50 and older with a chronic vestibular syndrome. Stand alone VR comprising a six week, internet based intervention with weekly online sessions and daily exercises (10-20 minutes a day). In the blended VR group, the same internet based intervention was supplemented by face-to-face physiotherapy support (home visits in weeks 1 and 3). Participants in the usual care group received standard care from a general practitioner, without any restrictions. The primary outcome was vestibular symptoms after six months as measured by the vertigo symptom scale-short form (VSS-SF range 0-60, clinically relevant difference ≥3 points). Secondary outcomes were dizziness related impairment, anxiety, depressive symptoms, subjective improvement of vestibular symptoms after three and six months, and adverse events. In the intention-to-treat analysis, participants in the stand alone and blended VR groups had lower VSS-SF scores at six months than participants in the usual care group (adjusted mean difference -4.1 points, 95% confidence interval -5.8 to -2.5; and -3.5 points, -5.1 to -1.9, respectively). Similar differences in VSS-SF scores were seen at three months follow-up. Participants in the stand alone and blended VR groups also experienced less dizziness related impairment, less anxiety, and more subjective improvement of vestibular symptoms at three and six months. No serious adverse events related to online VR occurred during the trial. Stand alone and blended internet based VR are clinically effective and safe interventions to treat adults aged 50 and older with a chronic vestibular syndrome. Online VR is an easily accessible form of treatment, with the potential to improve care for an undertreated group of patients in general practice. Netherlands Trial Register NTR5712.


Parameters of a dynamic mechanistic model of cattle growth retain enough biological interpretation for genotype-to-phenotype mapping.
This study aimed to investigate the predictability of a phenotype when using a dynamic model of cattle growth. Genotypic and phenotypic information on Nellore (Bos indicus) cattle were used in a genome-wide association analysis designed to contrast the biological interpretation of core parameters [conversion efficiency of metabolizable energy to net energy for gain (kg) and adjusted final shrunk body weight (AFSBW)] to their associated genomic regions and nearby quantitative trait loci (QTLs). Single nucleotide polymorphisms (SNPs) were used to develop prediction equations for kg and AFSBW, which enter the model for simulative prediction purposes. QTLs and genes, one related to mature body weight and another to growth efficiency, are consistent with the model equations. Significantly associated SNPs were used to compute parameters, which yielded reasonable model outcomes when compared with regular parameter computations. Our results provide evidence of the biological validity of using such parameters as component traits of higher phenotypes and the possibility of using genomic data for genotype-to-parameter mapping.


Cloning and functional characterization of a superfamily of microbial inwardly rectifying potassium channels.
Our understanding of the mammalian inwardly rectifying family of K+ channels (Kir family) has recently been advanced by X-ray crystal structures of two homologous prokaryotic orthologs (KirBac1.1 and KirBac3.1). However, the functional properties of these KirBac channels are still poorly understood. To address this problem, we cloned and characterized genes encoding KirBac orthologs from a wide variety of different prokaryotes and a simple unicellular eukaryote. The functional properties of these KirBacs were then examined by growth complementation in a K+ uptake-deficient strain of Escherichia coli (TK2420). Whereas some KirBac genes exhibited robust growth complementation, others either did not complement or showed temperature-dependent complementation including KirBac1.1 and KirBac3.1. In some cases, KirBac expression was also toxic to the growth of E. coli. The KirBac family exhibited a range of sensitivity to the K+ channel blockers Ba2+ and Cs+ as well as differences in their ability to grow on very low-K+ media, thus demonstrating major differences in their permeation properties. These results reveal the existence of a functionally diverse superfamily of microbial KirBac genes and present an excellent resource for the structural and functional analysis of this class of K+ channels. Furthermore, the complementation assay used in this study provides a simple and robust method for the functional characterization of a range of prokaryotic K+ channels that are difficult to study by traditional methods.


Analysis of the sagittal balance of the spine and pelvis using shape and orientation parameters.
The purpose of this study is to introduce a method to analyze and characterize the global sagittal balance of the human trunk using indexes derived from the shape and orientation of the pelvis and cervical, thoracic, and lumbar spine. Standing lateral x-rays of a cohort of 160 asymptomatic young adult volunteers were obtained. On each radiograph, a simplified model of the spine and pelvis was created using a dedicated computer software, and the following shape and orientation variables were calculated at each anatomic level: pelvic incidence, pelvic tilt, sacral slope, cervical curvature and tilt, thoracic curvature and tilt, and lumbar curvature and tilt. Significant linear correlations were found between each single adjacent shape parameter as well as between each single adjacent orientation parameter at all anatomic levels. Significant correlations were also found between some shape and orientation parameters at the same anatomic level as well as between adjacent anatomic areas. In general, the linear correlations were stronger between shape and orientation variables at the pelvic, lumbar, and cervical areas and weaker at the thoracic level and between the thoracic and lumbar areas. These results confirm that the pelvis and spine in the sagittal plane can be considered as a linear chain linking the head to the pelvis where the shape and orientation of each anatomic segment are closely related and influence the adjacent segment to maintain a stable posture with a minimum of energy expenditure. Changes in shape or orientation at one level will have a direct influence on the adjacent segment. Knowledge of these normal relationships is of prime importance for the comprehension of sagittal balance in normal and pathologic conditions of the spine and pelvis.


Human pDCs Are Superior to cDC2s in Attracting Cytolytic Lymphocytes in Melanoma Patients Receiving DC Vaccination.
Plasmacytoid dendritic cells (pDCs) and type 2 conventional dendritic cells (cDC2s) are currently under evaluation for use in cancer vaccines. Although both DC subsets can activate adaptive and innate lymphocytes, their capacity to recruit such cells is rarely considered. Here, we show that pDCs and cDC2s display a striking difference in chemokine secretion, which correlates with the recruitment of distinct types of immune effector cells. Activated pDCs express high levels of CXCR3 ligands and attract more CD8+ T cells, CD56+ T cells, and γδ T cells in vitro, compared to cDC2s. Skin from melanoma patients shows an influx of immune effector cells following intradermal vaccination with pDCs or cDC2s, with pDCs inducing the strongest influx of lymphocytes known to possess cytolytic activity. These findings suggest that combining both DC subsets could unite the preferred chemoattractive properties of pDCs with the superior T cell priming properties of cDC2s to ultimately enhance vaccine efficacy.


A national study on the inter-observer variability in the delineation of organs at risk in the brain.
The Danish Neuro Oncology Group (DNOG) has established national consensus guidelines for the delineation of organs at risk (OAR) structures based on published literature. This study was conducted to finalise these guidelines and evaluate the inter-observer variability of the delineated OAR structures by expert observers. The DNOG delineation guidelines were formed by participants from all Danish centres that treat brain tumours with radiotherapy. In a two-day workshop, guidelines were discussed and finalised based on a pilot study. Following this, the ten participants contoured the following OARs on T1-weighted gadolinium enhanced MRI from 13 patients with brain tumours: optic tracts, optic nerves, chiasm, spinal cord, brainstem, pituitary gland and hippocampus. The metrics used for comparison were the Dice similarity coefficient (Dice), mean surface distance (MSD) and others. A total of 968 contours were delineated across the 13 patients. On average eight (range six to nine) individual contour sets were made per patient. Good agreement was found across all structures with a median MSD below 1 mm for most structures, with the chiasm performing the best with a median MSD of 0.45 mm. The Dice was as expected highly volume dependent, the brainstem (the largest structure) had the highest Dice value with a median of 0.89 whereas smaller volumes such as the chiasm had a Dice of 0.71. Except for the caudal definition of the spinal cord, the variances observed in the contours of OARs in the brain were generally low and consistent. Surface mapping revealed sub-regions of higher variance for some organs. The data set is being prepared as a validation data set for auto-segmentation algorithms for use within the Danish Comprehensive Cancer Centre - Radiotherapy and potential collaborators.


Multifunctional polymeric micelles with folate-mediated cancer cell targeting and pH-triggered drug releasing properties for active intracellular drug delivery.
A new type of multifunctional polymeric micelle drug carrier for active intracellular drug delivery was prepared and characterized in this study. The micelle is a nano-supramolecular assembly with a spherical core-shell structure, and its surface and core were modified with piloting molecules for cancer cells and pH-sensitive drug binding linkers for controlled drug release, respectively. In order to prepare such micelles, self-assembling amphiphilic block copolymers, folate-poly(ethylene glycol)-poly(aspartate hydrazone adriamycin) [Fol-PEG-P(Asp-Hyd-ADR)], were specially designed and synthesized by installing a molecular promoter to enhance intracellular transport, folate (Fol), at the end of the shell-forming PEG chain and conjugating the anticancer drug, adriamycin (ADR), to the side chain of the core-forming PAsp segment through an acid-sensitive hydrazone bond. Because folate-binding proteins (FBP) are selectively overexpressed on the cancer cell membranes, the folate-bound micelles (FMA) can be guided to the cancer cells in the body, and after the micelles enter the cells, hydrazone bonds are cleaved by the intracellular acidic environment (pH 5-6) so that the drug release profile of the micelles is controlled pH-dependently. In this regard, FBP-binding selectivity of the prepared FMA was evaluated by surface plasmon resonance (SPR) measurements. The tetrazolium dye method (MTT assay) using human pharyngeal cancer cells (KB cell) revealed that FMA significantly improved cell growth inhibitory activity in spite of a short exposure time due to the selective and strong interaction between folate molecules and their receptors. Subsequent flow cytometric analysis showed that cellular uptake of FMA significantly increased. Consequently, these findings would provide one of the most effective approaches for cancer treatment using intracellular environment-targeting supramolecular drug carriers.


Isoenzymes of adenosine deaminase in pleural effusions: a diagnostic tool?
Tygerberg Hospital, an academic teaching hospital, Republic of South Africa. To identify the adenosine deaminase (ADA) isoenzymes as a diagnostic tool for tuberculosis in pleural effusions with increased ADA activity. Patients (n = 157) with exudative effusions and ADA activities >20 U/l, due to causes which satisfied predetermined diagnostic criteria, participated in the study. They consisted of 87 tuberculous effusions, 27 infective effusions (12 empyematous and 15 non-empyematous), 37 malignant effusions and six other exudative effusions (systemic lupus erythematosus, pancreatitis and lung embolus). In each case the ADA isoenzymes in the pleural fluid were identified using polyacrylamide gel electrophoresis. In addition, microbiology and cytology (including differential cell counts) were also carried out. Although ADA1c and ADA2 were the predominant isoenzymes observed in tuberculous effusions, while ADA1c and ADA1m were predominant in infective non-empyematous effusions, no additional diagnostic value was obtained. In the case of neoplastic effusions and other exudates, determination of ADA isoenzyme patterns also did not assist in diagnosing these conditions. Determination of patterns of ADA isoenzymes does not enhance the overall diagnostic value of ADA activity in pleural effusions.


Elevated Energy Production in Chronic Fatigue Syndrome Patients.
Chronic Fatigue Syndrome (CFS) is a debilitating disease characterized by physical and mental exhaustion. The underlying pathogenesis is unknown, but impairments in certain mitochondrial functions have been found in some CFS patients. To thoroughly reveal mitochondrial deficiencies in CFS patients, here we examine the key aspects of mitochondrial function in blood cells from a paired CFS patient-control series. Surprisingly, we discover that in patients the ATP levels are higher and mitochondrial cristae are more condensed compared to their paired controls, while the mitochondrial crista length, mitochondrial size, shape, density, membrane potential, and enzymatic activities of the complexes in the electron transport chain remain intact. We further show that the increased ATP largely comes from non-mitochondrial sources. Our results indicate that the fatigue symptom in this cohort of patients is unlikely caused by lack of ATP and severe mitochondrial malfunction. On the contrary, it might be linked to a pathological mechanism by which more ATP is produced by non-mitochondrial sources.


Nitric oxide, nitrite, and Fnr regulation of hmp (flavohemoglobin) gene expression in Escherichia coli K-12.
Escherichia coli possesses a soluble flavohemoglobin, with an unknown function, encoded by the hmp gene. A monolysogen containing an hmp-lacZ operon fusion was constructed to determine how the hmp promoter is regulated in response to heme ligands (O2, NO) or the presence of anaerobically utilized electron acceptors (nitrate, nitrite). Expression of the phi (hmp-lacZ)1 fusion was similar during aerobic growth in minimal medium containing glucose, glycerol, maltose, or sorbitol as a carbon source. Mutations in cya (encoding adenylate cyclase) or changes in medium pH between 5 and 9 were without effect on aerobic expression. Levels of aerobic and anaerobic expression in glucose-containing minimal media were similar; both were unaffected by an arcA mutation. Anaerobic, but not aerobic, expression of phi (hmp-lacZ)1 was stimulated three- to four-fold by an fnr mutation; an apparent Fnr-binding site is present in the hmp promoter. Iron depletion of rich broth medium by the chelator 2'2'-dipyridyl (0.1 mM) enhanced hmp expression 40-fold under anaerobic conditions, tentatively attributed to effects on Fnr. At a higher chelator concentration (0.4 mM), hmp expression was also stimulated aerobically. Anaerobic expression was stimulated 6-fold by the presence of nitrate and 25-fold by the presence of nitrite. Induction by nitrate or nitrite was unaffected by narL and/or narP mutations, demonstrating regulation of hmp by these ions via mechanisms alternative to those implicated in the regulation of other respiratory genes. Nitric oxide (10 to 20 microM) stimulated aerobic phi (hmp-lacZ)1 activity by up to 19-fold; soxS and soxR mutations only slightly reduced the NO effect. We conclude that hmp expression is negatively regulated by Fnr under anaerobic conditions and that additional regulatory mechanisms are involved in the responses to oxygen, nitrogen compounds, and iron availability. Hmp is implicated in reactions with small nitrogen compounds.


Retinol dehydrogenase 10 is a feedback regulator of retinoic acid signalling during axis formation and patterning of the central nervous system.
Retinoic acid (RA) is an important morphogen that regulates many biological processes, including the development of the central nervous system (CNS). Its synthesis from vitamin A (retinol) occurs in two steps, with the second reaction--catalyzed by retinal dehydrogenases (RALDHs)--long considered to be crucial for tissue-specific RA production in the embryo. We have recently identified the Xenopus homologue of retinol dehydrogenase 10 (XRDH10) that mediates the first step in RA synthesis from retinol to retinal. XRDH10 is specifically expressed in the dorsal blastopore lip and in other domains of the early embryo that partially overlap with XRALDH2 expression. We show that endogenous RA suppresses XRDH10 gene expression, suggesting negative-feedback regulation. In mRNA-injected Xenopus embryos, XRDH10 mimicked RA responses, influenced the gene expression of organizer markers, and synergized with XRALDH2 in posteriorizing the developing brain. Knockdown of XRDH10 and XRALDH2 by specific antisense morpholino oligonucleotides had the opposite effects on organizer gene expression, and caused a ventralized phenotype and anteriorization of the brain. These data indicate that the conversion of retinol into retinal is a developmentally controlled step involved in specification of the dorsoventral and anteroposterior body axes, as well as in pattern formation of the CNS. We suggest that the combinatorial gene expression and concerted action of XRDH10 and XRALDH2 constitute a ;biosynthetic enzyme code' for the establishment of a morphogen gradient in the embryo.


Investigating associations between caffeinated beverage consumption and later alcohol consumption among early adolescents.
Previous research has demonstrated that caffeinated beverage consumption predicts alcohol consumption among early adolescents. This study aimed to investigate this association in two ways: (1) by examining if this association remained significant once other established risk factors for alcohol were adjusted for statistically; and (2) by considering three possible moderators of this association: gender, sensation-seeking, and parental monitoring. Data from the Camden Youth Development Study, a longitudinal, community-based study of middle-school students, were used. Youth were initially assessed in 6th and 7th grade and followed-up 16 months later. Self-reports of frequency of energy drink, coffee, and alcohol consumption, as well as sensation-seeking, perceived peer and best friend alcohol use, alcohol expectancies, and parental monitoring, were used. Results indicated that both energy drink and coffee consumption predicted later alcohol consumption, even after adjusting for other risk factors for alcohol consumption. Parental monitoring was a significant moderator of this link, such that youth who consumed energy drinks and reported low parental monitoring were particularly at risk for later alcohol consumption. These findings indicate that the link between earlier caffeine consumption and later alcohol consumption is not simply due to the co-occurrence of caffeine consumption with other risk factors for alcohol use. In addition, risk associated with early energy drink consumption appears to be particularly pronounced for youth in families characterized by low parental monitoring.


Radial Acceleration Relation in Rotationally Supported Galaxies.
We report a correlation between the radial acceleration traced by rotation curves and that predicted by the observed distribution of baryons. The same relation is followed by 2693 points in 153 galaxies with very different morphologies, masses, sizes, and gas fractions. The correlation persists even when dark matter dominates. Consequently, the dark matter contribution is fully specified by that of the baryons. The observed scatter is small and largely dominated by observational uncertainties. This radial acceleration relation is tantamount to a natural law for rotating galaxies.


miR-146a is critical for endotoxin-induced tolerance: IMPLICATION IN INNATE IMMUNITY.
The human toll-like receptor 4 (TLR4) pathway is activated in response to lipopolysaccharide (LPS), and subsequent signal transductions lead to the production of cytokines such as tumor necrosis factor-alpha (TNF-alpha) by innate immune cells. Defects in innate immune response may contribute to the overproduction of TNF-alpha leading to systemic inflammation and diseases. Thus, the innate immune response needs to be tightly regulated by elaborate mechanisms to control its onset and termination. LPS tolerance is a state of hyporesponsiveness to subsequent LPS challenge and is achieved by monocytic cells after prolonged exposure to LPS. In this report, kinetics of endotoxin-responsive microRNAs expression analysis revealed a unique pattern of gradual increase for miR-146a starting 4 h after LPS stimulation in THP-1 cells and continued up to 35-fold over 24 h. Conversely, TNF-alpha increased up to 4 h and then decreased gradually implicating a negative correlation with miR-146a progression. The characteristic up-regulation of miR-146a toward subsequent LPS challenge in THP-1 cells was studied. Strikingly, microRNA expression analysis during the tolerized state of THP-1 cells showed only miR-146a overexpression suggesting its important role in LPS tolerance. In addition, LPS tolerance was dependent on a LPS-priming dose and associated miR-146a up-regulation. LPS-tolerized cells were observed to regain responsiveness in TNF-alpha production 22 h after LPS removal correlating with a decrease in miR-146a level. Transfection of miR-146a into THP-1 cells mimicked LPS priming, whereas transfection of miR-146a inhibitor largely abolished LPS tolerance. Thus our studies demonstrated that miR-146a is critical for the in vitro monocytic cell-based endotoxin tolerance.


Clinical Trial in a Dish: Using Patient-Derived Induced Pluripotent Stem Cells to Identify Risks of Drug-Induced Cardiotoxicity.
Drug-induced cardiotoxicity is a significant clinical issue, with many drugs in the market being labeled with warnings on cardiovascular adverse effects. Treatments are often prematurely halted when cardiotoxicity is observed, which limits their therapeutic potential. Moreover, cardiotoxicity is a major reason for abandonment during drug development, reducing available treatment options for diseases and creating a significant financial burden and disincentive for drug developers. Thus, it is important to minimize the cardiotoxic effects of medications that are in use or in development. To this end, identifying patients at a higher risk of developing cardiovascular adverse effects for the drug of interest may be an effective strategy. The discovery of human induced pluripotent stem cells has enabled researchers to generate relevant cell types that retain a patient's own genome and examine patient-specific disease mechanisms, paving the way for precision medicine. Combined with the rapid development of pharmacogenomic analysis, the ability of induced pluripotent stem cell-derivatives to recapitulate patient-specific drug responses provides a powerful platform to identify subsets of patients who are particularly vulnerable to drug-induced cardiotoxicity. In this review, we will discuss the current use of patient-specific induced pluripotent stem cells in identifying populations who are at risk to drug-induced cardiotoxicity and their potential applications in future precision medicine practice. Graphic Abstract: A graphic abstract is available for this article.


Evaluation of ultrasound assisted potassium permanganate pre-treatment of spent coffee waste.
In the present study, novel pre-treatment for spent coffee waste (SCW) has been proposed which utilises the superior oxidising capacity of alkaline KMnO4 assisted by ultra-sonication. The pre-treatment was conducted for different exposure times (10, 20, 30 and 40min) using different concentrations of KMnO4 (1, 2, 3, 4, 5%w/v) at room temperature with solid/liquid ratio of 1:10. Pretreating SCW with 4% KMnO4 and exposing it to ultrasound for 20min resulted in 98% cellulose recovery and a maximum lignin removal of 46%. 1.7 fold increase in reducing sugar yield was obtained after enzymatic hydrolysis of KMnO4 pretreated SCW as compared to raw. SEM, XRD and FTIR analysis of the pretreated SCW revealed the various effects of pretreatment. Thermal behaviour of the pretreated substrate against the native biomass was also studied using DSC. Ultrasound-assisted potassium permanganate oxidation was found to be an effective pretreatment for SCW, and can be a used as a potential feedstock pretreatment strategy for bioethanol production.


An examination of socioeconomic equity in health experiences in six Latin American and Caribbean countries.
Most Latin American and Caribbean (LAC) countries are working toward the provision of universal health coverage, and ensuring equity is a priority for those nations. The goal of this study was to examine the extent to which adults' socioeconomic status was related to health care experience in six LAC countries. This cross-sectional study examined the relationship between educational attainment and seven health experience outcomes in three areas: assessment of the health system, access to care, and experience with general practitioner. For this work, we used data from an Inter-American Development Bank survey of adults in Brazil, Colombia, El Salvador, Jamaica, Mexico, and Panama that was conducted in 2012-2014. Brazil and Jamaica, the two countries with unified public coverage, stood out for having substantially greater inequality, according to the results of bivariate analyses, with more-educated respondents reporting better health care experiences for five of the seven outcomes. For Jamaica, educational differences largely remained in multivariate analyses: college graduates were less likely (odds ratio (OR) = 0.37) than those with primary education to report their health system needs major reform and were more likely (OR = 2.57) to have a regular doctor. In Brazil, educational differences were mostly eliminated in multivariate models, though people with private insurance consistently reported better outcomes than those with public coverage. Colombia, in contrast, exhibited the least inequality despite having the highest income inequality of the six countries. Future research is needed to understand the policies and strategies that have resulted in Colombia achieving high levels of equity in patient health care experience, and Jamaica and Brazil demonstrating high levels of inequality.


Development of a urinary riboflavin adherence marker for a wheat bran fiber community intervention trial.
Development of a reliable marker of adherence to high-fiber diets is essential for accurately assessing dietary fiber intake in community interventions and clinical trials. The objective of this study was to evaluate the feasibility of using a riboflavin tracer incorporated into wheat bran cereal to determine fiber intake and compare results to the more traditional methodology of measuring stool weight. The inpatient phase of the study established that the excretion of urinary riboflavin was highly correlated with the dose of the riboflavin-spiked wheat bran cereal (r = 0.95, P < 0.005) and could be used as a biomarker to validate fiber supplement intake. The outpatient clinical intervention included a group of seven African-American men and women, who were asked to incorporate 1/2 cup of wheat bran cereal (11.6 g of dietary fiber) into their daily diet for a 6-week period. The cereal was spiked with a 28-mg dose of riboflavin. Baseline measurements of urinary riboflavin and stool weight were compared to postintervention levels. Comparison of pre- and postintervention measures of riboflavin excretion showed a significant increase (0.8 +/- 0.1 versus 6.0 +/- 0.6 mg/day, P < 0.02), which confirmed a high level of adherence to the dietary intervention. Although wet stool weights at baseline were significantly lower than postintervention (106 +/- 20 versus 146 +/- 23 g/day; P < 0.03), differences in dry stool weights did not reach significant levels (28 +/- 4 versus 33 +/- 5 g/day, P < 0.30). Furthermore, pre- and poststool measurements overlapped and could not provide definitive data on participant adherence. These results indicate that the riboflavin tracer was a more sensitive biomarker of wheat bran fiber supplementation than stool weight and provided an accurate method for validating adherence to the dietary intervention. A riboflavin marker provides a valid technique for adherence assessment in large-scale community trials, in which collection of 3-day fecal samples is not a manageable option.


Embryonic expression profile of chicken CHD7, the ortholog of the causative gene for CHARGE syndrome.
CHARGE syndrome represents a constellation of malformations: C, coloboma of the iris or retina; H, heart defects; A, atresia of the choanae; R, retardation of growth and/or development; G, genital anomalies; and E, ear abnormalities. Recently, the Chromodomain helicase DNA-binding protein-7 (CHD7) at chromosome 8q12.1 was identified as a causative gene for CHARGE syndrome. Because CHD7 was identified as a causative gene using a positional cloning approach, the role of CHD7 in early embryogenesis needs to be further investigated. Fertilized chick eggs were incubated to Hamburger and Hamilton stages 4-20 and were studied using whole mount in situ hybridization. Chicken EST clones corresponding to the chicken CHD7 (cChd7) sequence were identified using the chicken EST sequence database. From the EST clones, a digoxigenin-labeled RNA probe was synthesized and hybridized in situ to the embryonic specimens. The expression of cChd7 was pan-neuronal at stages 8-20. It was expressed throughout the rostral neural ectoderm and along the rostrocaudal axis but was absent from the more lateral, non-neuronal ectoderm. Adjacent to the neural tube, cChd7 transcripts were detected at the optic and otic placodes. At stage 20, cChd7 expression was observed in the branchial arches and olfactory placodes in addition to brain and optic and otic placodes. cChd7 was expressed in the neural epithelium, the otic placodes, the optic placodes, the branchial arches, and the olfactory placodes, which are the primordial tissues that give rise to organs affected in human CHARGE syndrome patients.


Protective actions of sex steroid hormones in Alzheimer's disease.
Risk for Alzheimer's disease (AD) is associated with age-related loss of sex steroid hormones in both women and men. In post-menopausal women, the precipitous depletion of estrogens and progestogens is hypothesized to increase susceptibility to AD pathogenesis, a concept largely supported by epidemiological evidence but refuted by some clinical findings. Experimental evidence suggests that estrogens have numerous neuroprotective actions relevant to prevention of AD, in particular promotion of neuron viability and reduction of beta-amyloid accumulation, a critical factor in the initiation and progression of AD. Recent findings suggest neural responsiveness to estrogen can diminish with age, reducing neuroprotective actions of estrogen and, consequently, potentially limiting the utility of hormone therapies in aged women. In addition, estrogen neuroprotective actions are also modulated by progestogens. Specifically, continuous progestogen exposure is associated with inhibition of estrogen actions whereas cyclic delivery of progestogens may enhance neural benefits of estrogen. In recent years, emerging literature has begun to elucidate a parallel relationship of sex steroid hormones and AD risk in men. Normal age-related testosterone loss in men is associated with increased risk to several diseases including AD. Like estrogen, testosterone has been established as an endogenous neuroprotective factor that not only increases neuronal resilience against AD-related insults, but also reduces beta-amyloid accumulation. Androgen neuroprotective effects are mediated both directly by activation of androgen pathways and indirectly by aromatization to estradiol and initiation of protective estrogen signaling mechanisms. The successful use of hormone therapies in aging men and women to delay, prevent, and or treat AD will require additional research to optimize key parameters of hormone therapy and may benefit from the continuing development of selective estrogen and androgen receptor modulators.


Stem cells: their role in breast cancer development and resistance to treatment.
About 20% of the total cells from primary breast tumors could generate palpable tumors in non-obese diabetic severe combined immunodeficient (NOD/SCID) immunocompromised mice. All the tumorigenic cells originate from a normal mammary stem cell. Human mammary stem cells are sensitive to oncogenic mutations and in mouse models they share similarities with breast cancer stem cells (BrCSCs). Tumorigenicity, invasion, progression and metastasization are further BrCSCs properties likely depending on their CD44+/CD24- phenotype. Local invasion and tumor metastasization seem to be facilitated by the epithelial to mesenchymal transition (EMT) program. This program may be reactivated from stable genetic alterations or through exposure of cancer cells to factors present in the surrounding micro-environment, or by an up-regulation of EMT-inducing transcription factors. One main explanation for resistance to treatment by cancer cells is that a rare subpopulation of cells in residual tumors with tumorigenic potential is intrinsically resistant to therapy. Consistent with this hypothesis, in human breast tumors, the subpopulation of tumor-initiating cancer cells with CD44(high)/CD24(low) cell surface-marker profile was found more resistant to cancer therapies (chemo, hormone and radiotherapy) than is the major population of more differentiated breast cancer cells. The reasons for CSC resistance to chemotherapy, hormone therapy and radiotherapy also have been examined and they opened new scenarios for cancer therapy.


Muscle-specific variations in use-dependent crossed-facilitation of corticospinal pathways mediated by transcranial direct current (DC) stimulation.
The tendency for contractions of muscles in the upper limb to give rise to increases in the excitability of corticospinal projections to the homologous muscles of the opposite limb is well known. Although the suppression of this tendency is integral to tasks of daily living, its exploitation may prove to be critical in the rehabilitation of acquired hemiplegias. Transcranial direct current (DC) stimulation induces changes in cortical excitability that outlast the period of application. We present evidence that changes in the reactivity of the corticospinal pathway induced by DC stimulation of the motor cortex interact systematically with those brought about by contraction of the muscles of the ipsilateral limb. During the application of flexion torques (up to 50% of maximum) applied at the left wrist, motor evoked potentials (MEPs) were evoked in the quiescent muscles of the right arm by magnetic stimulation of the left motor cortex (M1). The MEPs were obtained prior to and following 10 min of anodal, cathodal or sham DC stimulation of left M1. Cathodal stimulation counteracted increases in the crossed-facilitation of projections to the (right) wrist flexors that otherwise occurred as a result of repeated flexion contractions at the left wrist. In addition, cathodal stimulation markedly decreased the excitability of corticospinal projections to the wrist extensors of the right limb. Thus changes in corticospinal excitability induced by DC stimulation can be shaped (i.e. differentiated by muscle group) by focal contractions of muscles in the limb ipsilateral to the site of stimulation.


The effects of information framing on the practices of physicians.
The presentation format of clinical trial results, or the "frame," may influence perceptions about the worth of a treatment. The extent and consistency of that influence are unclear. We undertook a systematic review of the published literature on the effects of information framing on the practices of physicians. Relevant articles were retrieved using bibliographic and electronic searches. Information was extracted from each in relation to study design, frame type, parameter assessed, assessment scale, clinical setting, intervention, results, and factors modifying the frame effect. Twelve articles reported randomized trials investigating the effect of framing on doctors' opinions or intended practices. Methodological shortcomings were numerous. Seven papers investigated the effect of presenting clinical trial results in terms of relative risk reduction, or absolute risk reductions or the number needing to be treated; gain/loss (positive/negative) terms were used in four papers; verbal/numeric terms in one. In simple clinical scenarios, results expressed in relative risk reduction or gain terms were viewed most positively by doctors. Factors that reduced the impact of framing included the risk of causing harm, preexisting prejudices about treatments, the type of decision, the therapeutic yield, clinical experience, and costs. No study investigated the effect of framing on actual clinical practice. While a framing effect may exist, particularly when results are presented in terms of proportional or absolute measures of gain or loss, it appears highly susceptible to modification, and even neutralization, by other factors that influence doctors' decision making. Its effects on actual clinical practice are unknown.


Ictal laryngospasm monitored by video-EEG and polygraphy: a potential SUDEP mechanism.
A 56-year-old man with refractory bitemporal epilepsy was monitored in the Epilepsy Monitoring Unit (EMU). In a video-EEG captured seizure, brief oroalimentary automatisms were followed by increased inspiratory effort, accompanied by prominent, visible tracheal movements and audible inspiratory stridor. The patient's oxygen saturation rapidly declined to 62%; persistent severe hypoxemia ended with spontaneous effective respiration commencing at seizure end. Subsequent seizures necessitated intensive care unit admission for respiratory distress, and ventilator support. This case suggests that ictal laryngospasm, a rare seizure manifestation, may represent another potential mechanism of sudden unexpected death in epilepsy (SUDEP). [Published with video sequence on www.epilepticdisorders.com].


Effects of endothelin in portal hypertensive rats.
1. Effects of endothelin-1 on systemic arterial blood pressure, heart rate and portal venous pressure were compared in normal Sprague-Dawley rats and rats with portal hypertension induced by CCl4 and partial portal vein ligation. 2. Endothelin-1 produced biphasic effects on systemic blood pressure and portal venous pressure in all three groups of rats. However, the magnitude of the changes in blood pressure was less in portal hypertensive rats. 3. The ability of endothelin-1 to increase the portal venous pressure was also significantly diminished in portal hypertensive rats. On the other hand, the initial decrease in portal pressure was augmented in rats with partial portal vein ligation, and disappeared at higher dosage in CCl4-treated rats. 4. In accordance with the pressure recording in vivo, the dose-response vasoconstrictive activity of endothelin-1 was significantly attenuated in the intrahepatic vasculature. 5. The plasma immunoreactive endothelin concentration was significantly higher (5.55 +/- 0.81 fmol/ml) in Sprague-Dawley rats than in CCl4-treated rats (2.83 +/- 0.56 fmol/ml) and rats with partial portal vein ligation (2.68 +/- 0.53 fmol/ml). 6. It was concluded that a lower plasma level of endothelin and a reduced vascular responsiveness may contribute, at least in part, to the hyperdynamics of portal hypertension.


Dataset on flue gas composition during combustion in the fluidised bed reactor. Glycerol combustion.
The dataset presented in this article is the supplementary data for the research article by Żukowski and Berkowicz (doi:10.1016/j.combustflame.2019.05.024) [1], in which for the first time the inert and catalytic cenospheres were used as the fluidised bed material, giving the possibility to burn liquids inside the fluidised bed without the need for using specialised dosing systems. The instantaneous concentrations of the gaseous products during the combustion of glycerol samples were detected using Fourier Transform Infrared Spectroscopy (FTIR, Gasmet DX-4000). The accurate composition at the outlet of the reactor makes it possible to evaluate and verify new kinetic models of the glycerol combustion in the fluidised bed. It also will be helpful in creating new simplified models. The data presented here is essential for the evaluation of CFD combustion models which have to include accurate kinetic data.


Genetic analysis of emerging risk factors in coronary artery disease.
Type 2 diabetes (T2D), low-density lipoprotein-cholesterol (LDL-c), body mass index (BMI), blood pressure and smoking are established risk factors that play a causal role in coronary artery disease (CAD). Numerous common genetic variants associating with these and other risk factors have been identified, but their association with CAD has not been comprehensively examined in a single study. Our goal was to comprehensively evaluate the associations of established and emerging risk factors with CAD using genetic variants identified from Genome-wide Association Studies (GWAS). We tested the effect of 60 traditional and putative risk factors with CAD, using summary statistics obtained in GWAS. We approximated the regression of a response variable onto an additive multi-SNP genetic risk score in the Coronary Artery DIsease Genomewide Replication And Meta-analysis (CARDIoGRAM) consortium dataset weighted by the effect of the SNP on the risk factors. The strongest association with risk of CAD was for LDL-c SNPs (p = 3.96E-34). For non-established CAD risk factors, we found significant CAD associations for coronary artery calcification (CAC), Lp(a), LP-PLA2 activity, plaque, vWF and FVIII. In an attempt to identify independent associations between risk factors and CAD, only SNPs with an effect on the target trait were included. This identified CAD associations for Lp(a)(p = 1.77E-21), LDL-c (p = 4.16E-06), triglycerides (TG) (p = 1.94E-05), height (p = 2.06E-05), CAC (p = 3.13E-23) and carotid plaque (p = 2.08E-05). We identified SNPs associated with the emerging risk factors Lp(a), TG, plaque, height and CAC to be independently associated with risk of CAD. This provides further support for-ongoing clinical trials of Lp(a) and TG, and suggests that CAC and plaque could be used as surrogate markers for CAD in clinical trials.


Current approaches to secondary prevention after hip fracture in England and Wales - an analysis of trends between 2016 and 2020 using the National Hip Fracture Database (NHFD).
Hip fractures are strong risk factors for further fractures. However, using the National Hip Fracture Database, we observed that in England and Wales, 64% of patients admitted on oral bisphosphonates were discharged on the same and injectable drug use varies from 0-67% and 0.2%-83.6% were deemed "inappropriate" for bone protection. This variability requires further investigation. A key aim for the National Hip Fracture Database (NHFD) is to encourage secondary fracture prevention of the 75,000 patients who break their hip annually in the UK, through bone health assessment and appropriate provision of anti-osteoporosis medication (AOM). We set out to describe trends in anti-osteoporosis medication prescription and examine the types of oral and injectable AOMs being prescribed both before and after a hip fracture. We used data freely available from the NHFD www.nhfd.co.uk to analyse trends in oral and injectable AOM prescription across a quarter of a million patients presenting between 2016 and 2020, and more detailed information on the individual type of AOM prescribed for 63,705 patients from 171 hospitals in England and Wales who presented in 2020. Most patients (88.3%) are not taking any AOM when they present with a hip fracture. Half of all patients (50.8%) were prescribed AOM treatment by the time of discharge, but the proportion deemed 'inappropriate for AOM' varied hugely (0.2-83.6%) in different hospitals. Nearly two-thirds (64.2%) of those previously taking an oral bisphosphonate were simply discharged on the same type of medication. The total number of patients discharged on oral medication fell by over a quarter in these five years. The number discharged on injectables increased by nearly three-quarters to 14.2% over the same period, but remains hugely variable across the country, with rates ranging from 0-67% across different units. A recent hip fracture is a strong risk factor for future fractures. The huge variability in approaches, and in particular the use of injectables, in different trauma units across England and Wales requires further investigation.