Dissecting the genetic relationship between cardiovascular risk factors and Alzheimer's disease.
Cardiovascular (CV)- and lifestyle-associated risk factors (RFs) are increasingly recognized as important for Alzheimer's disease (AD) pathogenesis. Beyond the ε4 allele of apolipoprotein E (APOE), comparatively little is known about whether CV-associated genes also increase risk for AD. Using large genome-wide association studies and validated tools to quantify genetic overlap, we systematically identified single nucleotide polymorphisms (SNPs) jointly associated with AD and one or more CV-associated RFs, namely body mass index (BMI), type 2 diabetes (T2D), coronary artery disease (CAD), waist hip ratio (WHR), total cholesterol (TC), triglycerides (TG), low-density (LDL) and high-density lipoprotein (HDL). In fold enrichment plots, we observed robust genetic enrichment in AD as a function of plasma lipids (TG, TC, LDL, and HDL); we found minimal AD genetic enrichment conditional on BMI, T2D, CAD, and WHR. Beyond APOE, at conjunction FDR < 0.05 we identified 90 SNPs on 19 different chromosomes that were jointly associated with AD and CV-associated outcomes. In meta-analyses across three independent cohorts, we found four novel loci within MBLAC1 (chromosome 7, meta-p = 1.44 × 10-9), MINK1 (chromosome 17, meta-p = 1.98 × 10-7) and two chromosome 11 SNPs within the MTCH2/SPI1 region (closest gene = DDB2, meta-p = 7.01 × 10-7 and closest gene = MYBPC3, meta-p = 5.62 × 10-8). In a large 'AD-by-proxy' cohort from the UK Biobank, we replicated three of the four novel AD/CV pleiotropic SNPs, namely variants within MINK1, MBLAC1, and DDB2. Expression of MBLAC1, SPI1, MINK1 and DDB2 was differentially altered within postmortem AD brains. Beyond APOE, we show that the polygenic component of AD is enriched for lipid-associated RFs. We pinpoint a subset of cardiovascular-associated genes that strongly increase the risk for AD. Our collective findings support a disease model in which cardiovascular biology is integral to the development of clinical AD in a subset of individuals.


Prevalence of non-insulin-dependent diabetes mellitus and impaired glucose tolerance in two Algonquin communities in Quebec.
To assess and compare the prevalence of non-insulin-dependent diabetes mellitus (NIDDM) and impaired glucose tolerance (IGT) in two native Indian communities. Population-based study. Two Algonquin communities in Quebec: River Desert and Lac Simon. All native Indian residents aged at least 15 years were eligible; 621 (59%) of them volunteered to enroll in the study. The participation rate was 49% in River Desert and 76% in Lac Simon. Fasting blood glucose level and serum glucose level 2 hours after 75-g oral glucose tolerance test, as described by the World Health Organization, in all subjects except those with confirmed diabetes. Other measures included body mass index (BMI), fat distribution and blood pressure. The age-sex standardized prevalence rate of NIDDM was 19% in Lac Simon (95% confidence interval [CI] 16% to 21%); this was more than twice the rate of 9% in River Desert (95% CI 7% to 11%). The IGT rates were comparable in the two communities (River Desert 5%, Lac Simon 6%). NIDDM and IGT were uncommon under the age of 35 years. Only in Lac Simon was the NIDDM prevalence rate significantly higher among the women than among the men (23% v. 14%); almost half of the women aged 35 years or more had diabetes. In Lac Simon the rate of marked obesity (BMI greater than 30) was significantly higher among the women than among the men (37% v. 19%; p < 0.001); this sex-related difference was not found in River Desert (rates 31% and 23% respectively). Previously undiagnosed NIDDM accounted for 25% of all the cases. NIDDM and IGT were significantly associated with high BMI, sum of skinfold thicknesses and waist:hip circumference ratio (p < 0.001). The subscapular:triceps skinfold ratio, however, did not display such an association, nor did the age-adjusted systolic blood pressure. The prevalence of NIDDM is high in Algonquin communities and may vary markedly between communities. Although widespread, particularly in women, obesity cannot entirely explain the much higher rate of NIDDM in Lac Simon. Family and lifestyle risk factors, in particular diet and activity patterns, are being analysed in the two communities.


Real and fictive outcomes are processed differently but converge on a common adaptive mechanism.
The ability to learn not only from experienced but also from merely fictive outcomes without direct rewarding or punishing consequences should improve learning and resulting value-guided choice. Using an instrumental learning task in combination with multiple single-trial regression of predictions derived from a computational reinforcement-learning model on human EEG, we found an early temporospatial double dissociation in the processing of fictive and real feedback. Thereafter, real and fictive feedback processing converged at a common final path, reflected in parietal EEG activity that was predictive of future choices. In the choice phase, similar parietal EEG activity related to certainty of the impending response was predictive for the decision on the next trial as well. These parietal EEG effects may reflect a common adaptive cortical mechanism of updating or strengthening of stimulus values by integrating outcomes, learning rate, and certainty, which is active during both decision making and evaluation. Neuronal processing of real (rewarding, punishing) and fictive action outcomes (which would have happened had one acted differently) differs for 400 ms and then converges on a common adaptive mechanism driving future decision making and learning.


Risk as feelings.
Virtually all current theories of choice under risk or uncertainty are cognitive and consequentialist. They assume that people assess the desirability and likelihood of possible outcomes of choice alternatives and integrate this information through some type of expectation-based calculus to arrive at a decision. The authors propose an alternative theoretical perspective, the risk-as-feelings hypothesis, that highlights the role of affect experienced at the moment of decision making. Drawing on research from clinical, physiological, and other subfields of psychology, they show that emotional reactions to risky situations often diverge from cognitive assessments of those risks. When such divergence occurs, emotional reactions often drive behavior. The risk-as-feelings hypothesis is shown to explain a wide range of phenomena that have resisted interpretation in cognitive-consequentialist terms.


What does cooking mean to you?: Perceptions of cooking and factors related to cooking behavior.
Despite the importance of cooking in American life and evidence suggesting that meals cooked at home are healthier, little is known about perceptions of what it means to cook in the United States. The objective of this study was to describe perceptions of cooking and factors important to how cooking is perceived and practiced among American adults. Seven focus groups (N = 53; 39 female; 35 Black, 16 White, 2 Asian) were conducted from November 2014 to January 2015 in Baltimore City, Maryland. Participants were recruited from two neighborhoods; one with higher median income and access to healthy food and the other with lower income and low access to healthy food. Focus groups were audio recorded, transcribed verbatim and analyzed using a grounded theory approach. Participants' perceptions of cooking varied considerably, regardless of neighborhood income or food access, and spanned a continuum from all scratch cooking to anything made at home. Perceptions of cooking incorporated considerations of whether or how food was heated and the degree of time, effort and love involved if convenience foods were used. Key barriers to cooking included affordability, lack of time, and lack of enjoyment. Key facilitators of frequent cooking included extensive organization and time management to enable participants to incorporate cooking into their daily lives. Cooking is a complex concept and not uniformly understood. Efforts to encourage healthy cooking at home should consider the broad spectrum of activities Americans recognize as cooking as well as the barriers and facilitators to preparing food at home. Public health messages to encourage more frequent cooking should account for the heterogeneity in perspectives about cooking. More research should explore differences in perceptions about cooking in other diverse populations.


Comparing indocyanine green videoangiography to the gold standard of intraoperative digital subtraction angiography used in aneurysm surgery.
The purpose of aneurysm surgery is complete aneurysm obliteration while sparing associated arteries. Indocyanine green (ICG) videoangiography is a new technique that allows for real-time evaluation of blood flow in the aneurysm and vessels. The authors performed a retrospective study to compare the accuracy of ICG videoangiography with intraoperative angiography (IA), and determine if ICG videoangiography can be used without follow-up IA. From June 2007 through September 2009, 155 patients underwent craniotomies for clipping of aneurysms. Operative summaries, angiograms, and operative and ICG videoangiography videos were reviewed. The number, size, and location of aneurysms, the ICG videoangiography and IA findings, and the need for clip adjustment after ICG videoangiography and IA were recorded. Discordance between ICG videoangiography and IA was defined as ICG videoangiography demonstrating aneurysm obliteration and normal vessel flow, but post-IA showing either an aneurysmal remnant and/or vessel occlusion requiring clip adjustment. Thirty-two percent of patients (49 of 155) underwent both ICG videoangiography and IA. The post-ICG videoangiography clip adjustment rate was 4.1% (2 of 49). The overall rate of ICG videoangiography-IA agreement was 75.5% (37 of 49) and the ICG videoangiography-IA discordance rate requiring post-IA clip adjustment was 14.3% (7 of 49). Adjustments were due to 3 aneurysmal remnants and 4 vessel occlusions. These adjustments were attributed to obscuration of the residual aneurysm or the affected vessel from the field of view and the presence of dye in the affected vessel via collateral flow. Although not statistically significant, there was a trend for ICG videoangiography-IA discordance requiring clip adjustment to occur in cases involving the anterior communicating artery complex, with an odds ratio of 3.3 for ICG videoangiography-IA discordance in these cases. These results suggest that care should be taken when considering ICG videoangiography as the sole means for intraoperative evaluation of aneurysm clip application. The authors further conclude that IA should remain the gold standard for evaluation during aneurysm surgery. However, a combination of ICG videoangiography and IA may ultimately prove to be the most effective strategy for maximizing the safety and efficacy of aneurysm surgery.


Paraneoplastic cerebellar degeneration associated with antineuronal antibodies: analysis of 50 patients.
Paraneoplastic cerebellar degeneration (PCD) is a heterogeneous group of disorders characterized by subacute cerebellar ataxia, specific tumour types and (often) associated antineuronal antibodies. Nine specific antineuronal antibodies are associated with PCD. We examined the relative frequency of the antineuronal antibodies associated with PCD and compared the neurological symptoms and signs, associated tumours, disability and survival between groups of PCD with different antibodies. Also, we attempted to identify patient-, tumour- and treatment-related characteristics associated with functional outcome and survival. In a 12-year period, we examined >5000 samples for the presence of antineuronal antibodies. A total of 137 patients were identified with a paraneoplastic neurological syndrome and high titre (> or =400) antineuronal antibodies. Fifty (36%) of these patients had antibody-associated PCD, including 19 anti-Yo, 16 anti-Hu, seven anti-Tr, six anti-Ri and two anti-mGluR1. Because of the low number, the anti-mGluR1 patients were excluded from the statistical analysis. While 100% of patients with anti-Yo, anti-Tr and anti-mGluR1 antibodies suffered PCD, 86% of anti-Ri and only 18% of anti-Hu patients had PCD. All patients presented with subacute cerebellar ataxia progressive over weeks to months and stabilized within 6 months. The majority of patients in all antibody groups had both truncal and appendicular ataxia. The frequency of nystagmus and dysarthria was lower in anti-Ri patients (33 and 0%). Later in the course of the disease, involvement of non-cerebellar structures occurred most frequently in anti-Hu patients (94%). In 42 patients (84%), a tumour was detected. The most commonly associated tumours were gynaecological and breast cancer (anti-Yo and anti-Ri), lung cancer (anti-Hu) and Hodgkin's lymphoma (anti-Tr and anti-mGluR1). In one anti-Hu patient, a suspect lung lesion on CT scan disappeared while the PCD evolved. Seven patients improved by at least 1 point on the Rankin scale, while 16 remained stable and 27 deteriorated. All seven patients that improved received antitumour treatment for their underlying cancer, resulting in complete remission. The functional outcome was best in the anti-Ri patients, with three out of six improving neurologically and five were able to walk at the time of last follow-up or death. Only four out of 19 anti-Yo and four out of 16 anti-Hu patients remained ambulatory. Also, survival from time of diagnosis was significantly worse in the anti-Yo (median 13 months) and anti-Hu (median 7 months) patients compared with anti-Tr (median >113 months) and anti-Ri (median >69 months). Patients receiving antitumour treatment (with or without immunosuppressive therapy) lived significantly longer [hazard ratio (HR) 0.3; 95% confidence interval (CI) 0.1-0.6; P = 0.004]. Patients > or =60 years old lived somewhat shorter from time of diagnosis, although statistically not significant (HR 2.9; CI 1.0-8.5; P = 0.06).


A switch from parallel to antiparallel strand orientation in a coiled-coil X-ray structure via two core hydrophobic mutations.
The coiled-coil is one of the most ubiquitous and well studied protein structural motifs. Significant effort has been devoted to dissecting subtle variations of the typical heptad repeat sequence pattern that can designate larger topological features such as relative α-helical orientation and oligomer size. Here we report the X-ray structure of a model coiled-coil peptide, HA2-Del-L2seM, which forms an unanticipated core antiparallel dimer with potential sites for discrete higher-order multimerization (trimer or tetramer). In the X-ray structure, a third, partially-ordered α-helix is weakly associated with the antiparallel dimer and analytical ultracentrifugation experiments indicate the peptide forms a well-defined tetramer in solution. The HA2-Del-L2seM sequence is closely related to a parent model peptide, HA2-Del, which we previously reported adopts a parallel trimer; HA2-Del-L2seM differs by only hydrophobic leucine to selenomethione mutations and thus this subtle difference is sufficient to switch both relative α-helical topology and number of α-helices participating in the coiled-coil. Comparison of the X-ray structures of HA2-Del-L2seM (reported here) with the HA2-Del parent (reported previously) reveals novel interactions involving the selenomethionine residues that promote antiparallel coiled-coil configuration and preclude parallel trimer formation. These novel atomic insights are instructive for understanding subtle features that can affect coiled-coil topology and provide additional information for design of antiparallel coiled-coils.


Hydroxyapatites: Key Structural Questions and Answers from Dynamic Nuclear Polarization.
We demonstrate that NMR/DNP (Dynamic Nuclear Polarization) allows an unprecedented description of carbonate substituted hydroxyapatite (CHAp). Key structural questions related to order/disorder and clustering of carbonates are tackled using distance sensitive DNP experiments using 13C-13C recoupling. Such experiments are easily implemented due to unprecedented DNP gain (orders of magnitude). DNP is efficiently mediated by quasi one-dimensional spin diffusion through the hydroxyl columns present in the CHAp structure (thought of as "highways" for spin diffusion). For spherical nanoparticles and ϕ < 100 nm, it is numerically shown that spin diffusion allows their study as a whole. Most importantly, we demonstrate also that the DNP study at 100 K leads to data which are comparable to data obtained at room temperature (in terms of spin dynamics and line shape resolution). Finally, all 2D DNP experiments can be interpreted in terms of domains exhibiting well identified types of substitution: local order and carbonate clustering are clearly favored.


Tools and factors predictive of the severity of COVID-19.
The outbreak of the novel coronavirus infection caused worldwide confusion. The problem with this infection is that it causes severe illness in some patients, resulting in a high rate of death if appropriate treatment is not given. If patients with severe illness that requires treatment are appropriately identified, treatment can be focused on these patients. However, in the early days of the COVID-19 outbreak, the inability to predict and diagnose the disease led to hospitals being overwhelmed. Therefore, various methods for the diagnosis of severe disease were developed early on, and various methods are still being investigated to predict high-risk patients. The currently available prediction methods are divided into those that predict the onset of severe disease and those used to determine the severity of the disease. Specifically, the main methods include genetic factors, serum humoral factors, laboratory tests, and diagnostic imaging. Since each of these factors has different features, using them in combination is likely to be advantageous.


Comparison of Different Algorithms for Calculating Velocity and Stride Length in Running Using Inertial Measurement Units.
Running has a positive impact on human health and is an accessible sport for most people. There is high demand for tracking running performance and progress for amateurs and professionals alike. The parameters velocity and distance are thereby of main interest. In this work, we evaluate the accuracy of four algorithms, which calculate the stride velocity and stride length during running using data of an inertial measurement unit (IMU) placed in the midsole of a running shoe. The four algorithms are based on stride time, foot acceleration, foot trajectory estimation, and deep learning, respectively. They are compared using two studies: a laboratory-based study comprising 2377 strides from 27 subjects with 3D motion tracking as a reference and a field study comprising 12 subjects performing a 3.2-km run in a real-world setup. The results show that the foot trajectory estimation algorithm performs best, achieving a mean error of 0.032 ± 0.274 m/s for the velocity estimation and 0.022 ± 0.157 m for the stride length. An interesting alternative for systems with a low energy budget is the acceleration-based approach. Our results support the implementation decision for running velocity and distance tracking using IMUs embedded in the sole of a running shoe.


The Utility of 68Ga-PSMA PET/CT in Poorly Differentiated Metastatic Prostate Cancer.
We aimed to emphasize how useful PSMA PET/CT findings can be while trying to restage prostate cancer after radical prostatectomy in the presence of low prostate-specific antigen values. A 64-year-old man with pT3b N1 M0 Gleason 7 adenocarcinoma of the prostate presented 5 years postoperatively with a palpable axillary mass, whereas his prostate-specific antigen was 0.08 ng/mL. Conventional imaging studies and histopathologic findings of the axillary mass biopsy revealed inconclusive results. Ga-PSMA PET/CT demonstrated PSMA-positive metastatic lesions, the largest one being located in the right axilla. This finding confirmed metastatic poorly differentiated prostate cancer, and androgen deprivation therapy was initiated.


The hepatoprotective effect of Phyllanthus emblica L. fruit on high fat diet-induced non-alcoholic fatty liver disease (NAFLD) in SD rats.
Non-alcoholic fatty liver disease (NAFLD), the most common chronic liver disease, is closely associated with metabolic syndrome and refers to the accumulation of hepatic steatosis not due to excess alcohol consumption. Phyllanthus emblica L. is a rich source of gallic acid and many known medicinally phytochemicals such as tannins, lignans, flavonoids, alkaloids, vitamin C, mucic acid, and ellagic acid. Our previous study has revealed that P. emblica exhibits inhibitory effects on hepatic steatosis and liver fibrosis in vitro, as well as gallic acid improves high fat diet (HFD)-induced dyslipidaemia, hepatosteatosis, and oxidative stress in vivo. Therefore, the aim of this study was to investigate the hepatoprotective effect of the water extract of P. emblica L. fruit (WEPE) on NAFLD in an animal model. The results showed that WEPE could significantly decrease body weight, peritoneal fat and epididymal fat, enhance the antioxidant enzyme activities, and improve steatosis through elevating adiponectin in adipocytes and PPAR-α in the liver as well as lowering SREBP-1c in the liver of rats fed with a high fat diet (HFD). This might be an explanation for the hepatic fat deposition-lowering effect of WEPE. These results demonstrate that WEPE could be beneficial for the amelioration of HFD-induced steatosis.


Augmentation of citalopram with aspirin for treating major depressive disorder, a double blind randomized placebo controlled clinical trial.
There are contradictory reports about the association of cytokines levels and major depressive disorder and the possible therapeutic role of aspirin for treating major depressive disorder (MDD). A clinical sample of adult out-patients with MDD was recruited. At recruitment, they were interviewed face to face according to DSM-IV diagnostic criteria. In addition, Hamilton depression rating scale was completed by a psychiatrist. The patients were invited to receive aspirin or placebo. All the 10 patients received 160mg/day aspirin plus citlaopram 20 mg/day. Eight out of ten patients showed severe anxiety and akathesia from early days of this trial. Except for two patients, we discontinued the medication during 14 days of this trial. Three patients were hospitalized due to anxiety and akathesia. Two patients reported suicidal behavior after the onset of this trial. This trial of aspirin adjuvant therapy for treating MDD suggests that this combination is not safe and there are some serious and intolerable adverse effects. This finding is in contrast to the suggestions assuming that aspirin may be effective for treating MDD. Aspirin may negatively impact on both pro- and anti-inflammatory cytokines balance in depression. Aspirin may antagonize the antidepressant effect of citalopram.


Participation following traumatic spinal cord injury: an evidence-based review for research.
To report an evidence-based review of participation instruments that have been used in spinal cord injury (SCI) clinical practice and research. Rehabilitation literature was searched for instruments used by at least 2 independent SCI researchers since 2000. Each instrument was reviewed by 2 committee members. One person reviewed the scale and documented the level of use and psychometric properties. The second committee member verified the values and made suggestions for changes. Three instruments met the review criteria: Craig Handicap Assessment and Reporting Technique (CHART), Assessment of Life Habits (LIFE-H), and the Impact on Participation and Autonomy (IPA). Each instrument incorporates different perspectives in the measurement of participation. The LIFE-H uses a qualitative approach, whereas the CHART adopts a quantitative approach; both are based on societal norms of participation. In contrast, the IPA integrates individual choice and control in defining participation. CHART is the most widely used instrument, although its development predates the development of the ICF. The IPA is a relatively new instrument, and its psychometric properties have only recently published. Continuing research is needed to develop conceptually and psychometric valid measures of participation for use with people with SCI. Priorities include understanding the relationship between objective and subjective indicators of participation, describing the dimensions of participation, and identifying appropriate measurement models and psychometric approaches to evaluate the nonhierarchical character of participation. Researchers and clinicians should be aware of the strengths and limitations of existing measures to make informed decisions about appropriate instruments.


Factors affecting quality of life in patients with systemic lupus erythematosus: important considerations and potential interventions.
Patients with systemic lupus erythematosus (SLE) have a better survival than decades ago; nevertheless, they still experience a low health-related (HR) quality of life (QoL). Areas covered: After defining QoL and HRQoL, we review the need to assess it, its elements, how to measure it, its predictors, and its impact and potential interventions to improve it. Expert commentary: Physicians assessments of disease activity and damage do not capture the patients' perspective of their health, and these differences could lead to nonadherence to therapy. Based on that, a comprehensive evaluation of SLE should include the assessment of HRQoL or the sum of the physical, psychological, and social perception of wellbeing, influenced by the patient's illness. The most consistent predictors of low HRQoL are older age, poverty, lower educational level, behavioral issues, some clinical manifestations, and comorbidities. HRQoL impacts negatively on dealing with stress, intimal relationship, home and job-related activities, and treatment adherence. At the present, there are no successful specific therapeutic strategies aimed at improving it.


Nitrous oxide production in nearshore marine sediments.
Coastal marine sediments are shown to be a net source of nitrous oxide. The rates of nitrous oxide flux from sediments in Narragansett Bay, Rhode Island, ranged from 20 to more than 900 nanomoles per square meter per hour. Sediments from a eutrophic area had higher rates of net nitrous oxide production than sediments from relatively unpolluted sites. The benthic, nitrous oxide source exceeds the nitrous oxide source to the bay from sewage treatment plant effluent.


The analysis of variance in anaesthetic research: statistics, biography and history.
Multiple t-tests (or their non-parametric equivalents) are often used erroneously to compare the means of three or more groups in anaesthetic research. Methods for correcting the p value regarded as significant can be applied to take account of multiple testing, but these are somewhat arbitrary and do not avoid several unwieldy calculations. The appropriate method for most such comparisons is the 'analysis of variance' that not only economises on the number of statistical procedures, but also indicates if underlying factors or sub-groups have contributed to any significant results. This article outlines the history, rationale and method of this analysis.


Non-native grass invasion suppresses forest succession.
Multiple factors can affect the process of forest succession including seed dispersal patterns, seedling survival, and environmental heterogeneity. A relatively understudied factor affecting the process of succession is invasions by non-native plants. Invasions can increase competition, alter abiotic conditions, and provide refuge for consumers. Functional traits of trees such as seed size and life history stage may mediate the effects of invasions on succession. We tested the effects of the forest invader Microstegium vimineum on planted and naturally regenerating trees in a multi-year field experiment. We established plots containing nine species of small- and large-seeded tree species planted as seeds or saplings, and experimentally added Microstegium to half of all plots. Over 3 years, Microstegium invasion had an overall negative effect on small-seeded species driven primarily by the effect on sweetgum, the most abundant small-seeded species, but did not affect large-seeded species such as hickory and oak species, which have more stored seed resources. Natural regeneration was over 400% greater in control than invaded plots for box elder, red maple, and spicebush, and box elder seedlings were 58% smaller in invaded plots. In contrast to the effects on tree seedlings, invasion did not affect tree sapling survival or growth. Microstegium may be directly reducing tree regeneration through competition. Invaded plots had greater overall herbaceous biomass in 2006 and 2008 and reduced light availability late in the growing season. Indirect effects may also be important. Invaded plots had 120% more thatch biomass, a physical barrier to seedling establishment, and significantly greater vole damage to tree saplings during 2006 and 2007. Our results show that two tree functional traits, seed size and life history stage, determined the effects of Microstegium on tree regeneration. Suppression of tree regeneration by Microstegium invasions may slow the rate of forest succession and alter tree species composition.


Treatment of peritoneal surface malignancies with hyperthermic intraperitoneal chemotherapy-current perspectives.
Peritoneal carcinomatosis (ptc) represents advanced malignant disease and has generally been associated with a grim prognosis. Peritoneal surface malignancy is often the major source of morbidity and mortality; it is of major concern in cancer management. Although ptc is categorized as metastatic disease, it represents a special disease pattern considered to be a locoregional disease limited to the abdominal cavity. The combination of cytoreductive surgery (crs) and intraoperative hyperthermic intraperitoneal chemotherapy (hipec) has successfully been used as locoregional treatment for selected patients with ptc from gastric, colorectal, and ovarian cancer; with mesothelioma; and with pseudomyxoma peritonei. In the prophylactic setting, hipec can also be used to prevent ptc in high-risk patients, and the first results of the "second-look" approach are promising. Patient selection-in which the risks of perioperative morbidity and mortality, which are analogous to those for any other major gastrointestinal surgery, are assessed-is of utmost importance. Those risks have to be weighed against the anticipated survival benefit, which depends mainly on tumour biology, extent of disease, and probability of achieving complete crs. The present review discusses the principles of crs and hipec, the most significant recent clinical data, and current perspectives concerning the application of this treatment modality in various malignancies. Ongoing trials and future directions are noted. It appears that the combination of crs and hipec is an indispensable tool in the oncologist's armamentarium.


Predicting furan content in a fried dough system using image analysis.
The aim of this paper is to test different models for predicting furan content in a dough system, based on partial least squares regression using colour images. Starch dough systems were fried at five temperatures between 150 and 190 °C and for 5, 7, 9, 11 and 13 min. The furan content was quantified using gas chromatography/mass spectrometry, while the corresponding images were simultaneously obtained and processed in order to extract 2914 features. Good furan content predictions were obtained using computer vision image chromatic features using correlation coefficient of prediction (Rp = 0.86). However, the best prediction correlation was obtained using the image textural features (Rp = 0.93), when the number of features was reduced to 10 by algorithms applications. These results suggest that furan content in fried dough systems can be predicted using features of computer vision images.


Putting to a bigger hole: golf performance relates to perceived size.
When people are engaged in a skilled behavior, such as occurs in sports, their perceptions relate optical information to their performance. In the present research, we demonstrate the effects of performance on size perception in golfers. We found that golfers who played better judged the hole to be bigger than did golfers who did not play as well. In follow-up laboratory experiments, participants putted on a golf mat from a location near or far from the hole and then judged the size of the hole. Participants who putted from the near location perceived the hole to be bigger than did participants who putted from the far location. Our results demonstrate that perception is influenced by the perceiver's current ability to act effectively in the environment.


Convergence in light capture efficiencies among tropical forest understory plants with contrasting crown architectures: a case of morphological compensation.
Leaf and crown characteristics were examined for 24 tree and herbaceous species of contrasting architectures from the understory of a lowland rainforest. Light-capture efficiency was estimated for the crowns of the different species with a three-dimensional geometric modeling program. Causal relationships among traits affecting light absorption at two hierarchical levels (leaf and whole crown) were quantified using path analysis. Light-capture and foliage display efficiency were found to be very similar among the 24 species studied, with most converging on a narrow range of light absorption efficiencies (ratio of absorbed vs. available light of 0.60-0.75). Exceptionally low values were found for the climber vines and, to a lesser extent, for the Bromeliad Aechmea magdalenae. Differences in photosynthetic photon flux density (PFD) absorbed per unit leaf area by individual plants were mostly determined by site to site variation in PFD and not by the differences in crown architecture among individuals or species. Leaf angle, and to a lesser extent also supporting biomass, specific leaf area, and internode length, had a significant effect on foliage display efficiency. Potential constraints on light capture such as the phyllotactic pattern were generally offset by other compensatory adjustments of crown structure such as internode length, arching stems, and plagiotropy. The variety of shoot morphologies capable of efficiently capturing light in tropical forest understories is greater than initially thought, extending over species with very different phyllotactic patterns, crown architectures, leaf sizes, and morphologies.


Exercise-associated collapse: an evidence-based review and primer for clinicians.
Exercise-associated collapse (EAC) commonly occurs after the completion of endurance running events. EAC is a collapse in conscious athletes who are unable to stand or walk unaided as a result of light headedness, faintness and dizziness or syncope causing a collapse that occurs after completion of an exertional event. Although EAC is perhaps the most common aetiology confronted by the medical provider attending to collapsed athletes in a finish-line tent, providers must first maintain vigilance for other potential life-threatening aetiologies that cause collapse, such as cardiac arrest, exertional heat stroke or exercise-associated hyponatraemia. Previously, it has been believed that dehydration and hyperthermia were primary causes of EAC. On review of the evidence, EAC is now believed to be principally the result of transient postural hypotension caused by lower extremity pooling of blood once the athlete stops running and the resultant impairment of cardiac baroreflexes. Once life-threatening aetiologies are ruled out, treatment of EAC is symptomatic and involves oral hydration and a Trendelenburg position - total body cooling, intravenous hydration or advanced therapies is generally not needed.


Assembled monolayers of hydrophilic particles on water surfaces.
A facile and quick approach to prepare self-assembled monolayers of water-dispersible particles on the water surface is presented. Particle suspensions in alcohols were dropped on a water reservoir to form long-range ordered monolayers of various particles, including spherical solid particles, soft hydrogel particles, metal nanoparticles, quantum dots, nanowires, single-wall carbon nanotubes (SWCNTs), nanoplates, and nanosheets. A systematic study was conducted on the variables affecting the monolayer assembly: the solubility parameter of spreading solvents, particle concentration, zeta potential of the particles in the suspension, surface tension of the water phase, hardness of the particles, and addition of a salt in the suspension. This method requires no hydrophobic surface treatment of the particles, which is useful to exploit these monolayer films without changing the native properties of the particles. The study highlights a quick 2D colloidal assembly without cracks in the wafer scale as well as transparent conductive thin films made of SWCNTs and graphenes.


MHC-dependent survival in a wild population: evidence for hidden genetic benefits gained through extra-pair fertilizations.
Females should prefer to be fertilized by males that increase the genetic quality of their offspring. In vertebrates, genes of the major histocompatibility complex (MHC) play a key role in the acquired immune response and have been shown to affect mating preferences. They are therefore important candidates for the link between mate choice and indirect genetic benefits. Higher MHC diversity may be advantageous because this allows a wider range of pathogens to be detected and combated. Furthermore, individuals harbouring rare MHC alleles might better resist pathogen variants that have evolved to evade common MHC alleles. In the Seychelles warbler, females paired with low MHC-diversity males elevate the MHC diversity of their offspring to levels comparable to the population mean by gaining extra-pair fertilizations. Here, we investigate whether increased MHC diversity results in higher life expectancy and whether there are any additional benefits of extra-pair fertilizations. Our 10-year study found a positive association between MHC diversity and juvenile survival, but no additional survival advantage of extra-pair fertilizations. In addition, offspring with a specific allele (Ase-ua4) had a fivefold longer life expectancy than offspring without this allele. Consequently, the interacting effects of sexual selection and pathogen-mediated viability selection appear to be important for maintaining MHC variation in the Seychelles warbler. Our study supports the prediction that MHC-dependent extra-pair fertilizations result in genetic benefits for offspring in natural populations. However, such genetic benefits might be hidden and not necessarily apparent in the widely used fitness comparison of extra- and within-pair offspring.


Naringenin Protects against Acute Pancreatitis in Two Experimental Models in Mice by NLRP3 and Nrf2/HO-1 Pathways.
Naringenin (Nar) is a type of flavonoid and has been shown to have anti-inflammatory and antioxidative properties. However, the effects of Nar on acute pancreatitis (AP) have not been well studied. In this study, we aimed to investigate the function of Nar in a mouse model of AP. Mild acute pancreatitis (MAP) was induced by caerulein (Cae), and severe acute pancreatitis (SAP) was induced by L-arginine in mice. Nar was administered intraperitoneally at doses of 25, 50, or 100 mg/kg following MAP induction and at a dose of 100 mg/kg following SAP induction. The serum levels of cytokines, lipase, and amylase were determined, and pancreatic and pulmonary tissues were harvested. The serum levels of amylase, lipase, and cytokines were significantly decreased in both MAP and SAP models after Nar treatment. The malondialdehyde (MDA) levels of the pancreatic tissue was significantly reduced in both MAP and SAP after Nar treatment. In contrast, glutathione peroxidase (GPx), glutathione reductase (GR), glutathione S-transferase (GST), total sulfhydryl (T-SH), and non-proteinsulthydryl (NP-SH) were markedly increased in both MAP and SAP after Nar treatment. The injury in pancreatic and pulmonary tissues was markedly improved as evidenced by the inhibited expression of myeloperoxidase, nod-like receptor protein 3, and interleukin 1 beta as well as the enhanced expression of nuclear factor erythroid 2-related factor 2/heme oxygenase-1 in pancreatic tissues. Nar exerted protective effects on Cae-induced MAP and L-arginine-induced SAP in mice, suggesting that Nar may be a potential therapeutic intervention for AP.


Thirty-five-year follow-up analysis of clinical and pathologic outcomes of thymoma surgery.
The impact of myasthenia gravis on patients with thymoma is still controversial when perioperative and long-term outcomes are analyzed. With the unique opportunity of a 35-year follow-up in a single institution, thymomatous myasthenia gravis cohort, we investigated the influence of early and long-term clinical predictors. We reviewed a surgical series of 317 (1972 to 2007) patients with thymoma: clinical and pathologic features were analyzed as prognostic factors matched against the short- and long-term survival and recurrence rates. Male to female ratio was 153:164; median age, 49 years. Myasthenia gravis coexisted in 276 patients (87.1%). Thymomas were classified according to the Masaoka (42.0% stage I, 32.2% stage II, 21.5% stage III, and 4.4% stage IV) and the World Health Organization (3.5% type A, 9.5% type AB, 19.2% type B1, 57.7% type B2, 8.2% type B3, and 1.9% thymic carcinoma) staging systems. The resection was complete in 295 patients (93.1%). Operative mortality and morbidity were respectively 1.6% and 7.6%. No differences were recorded in postoperative outcome stratifying for myasthenia gravis or comorbidities. Mean follow-up was 144.7 +/- 104.4 months. The overall 5-, 10-, 20-, and 30-year survival rates were 89.9%, 84.1%, 73%, and 58.6%, respectively. The completeness of resection (p < 0.001), the Masaoka staging (p = 0.010), and the World Health Organization classification (p < 0.001) all significantly influenced the long-term survival (univariate analysis). Only completeness of resection was significantly correlated with a better prognosis (p < 0.001) in multivariate analysis. Masaoka staging (p < 0.001) and World Health Organization classification (p < 0.001) significantly correlated with the disease-free survival in the univariate and multivariate analyses as significant prognostic factors (Masaoka, p < 0.001; World Health Organization, p = 0.011). Myasthenia gravis patients showed a better prognosis in terms of long-term survival (p = 0.046) and disease-free survival (p = 0.012) in the univariate analysis. We confirm the evidence that the clinical staging and the histologic classification influence long-term survival. The presence of myasthenia gravis was not significantly related to operative outcome, but prolongs both long-term survival and disease-free survival.


Accelerated immune senescence and reduced response to vaccination in ovariectomized female rhesus macaques.
Aging is associated with a general dysregulation in immune function, commonly referred to as "immune senescence". Several studies have shown that female sex steroids can modulate the immune response. However, the impact of menopause-associated loss of estrogen and progestins on immune senescence remains poorly understood. To help answer this question, we examined the effect of ovariectomy on T-cell homeostasis and function in adult and aged female rhesus macaques. Our data show that in adult female rhesus macaques, ovariectomy increased the frequency of naïve CD4 T cells. In contrast, ovariectomized (ovx) aged female rhesus macaques had increased frequency of terminally differentiated CD4 effector memory T cells and inflammatory cytokine-secreting memory T cells. Moreover, ovariectomy reduced the immune response (T-cell cytokine and IgG production) following vaccination with modified vaccinia ankara in both adult and aged female rhesus macaques compared to ovary-intact age-matched controls. Interestingly, hormone therapy (estradiol alone or in conjunction with progesterone) partially improved the T-cell response to vaccination in aged ovariectomized female rhesus macaques. These data suggest that the loss of ovarian steroids, notably estradiol and progesterone, may contribute to reduced immune function in post-menopausal women and that hormone therapy may improve immune response to vaccination in this growing segment of the population.


Reduction of Baltic Sea nutrient inputs and allocation of abatement costs within the Baltic Sea catchment.
The Baltic Sea Action Plan (BSAP) requires tools to simulate effects and costs of various nutrient abatement strategies. Hierarchically connected databases and models of the entire catchment have been created to allow decision makers to view scenarios via the decision support system NEST. Increased intensity in agriculture in transient countries would result in increased nutrient loads to the Baltic Sea, particularly from Poland, the Baltic States, and Russia. Nutrient retentions are high, which means that the nutrient reduction goals of 135 000 tons N and 15 000 tons P, as formulated in the BSAP from 2007, correspond to a reduction in nutrient loadings to watersheds by 675 000 tons N and 158 000 tons P. A cost-minimization model was used to allocate nutrient reductions to measures and countries where the costs for reducing loads are low. The minimum annual cost to meet BSAP basin targets is estimated to 4.7 billion Euro.


Redox-regulation of protein import into chloroplasts and mitochondria: similarities and differences.
Redox signals play important roles in many developmental and metabolic processes, in particular in chloroplasts and mitochondria. Furthermore, redox reactions are crucial for protein folding via the formation of inter- or intramolecular disulfide bridges. Recently, redox signals were described to be additionally involved in regulation of protein import: in mitochondria, a disulfide relay system mediates retention of cystein-rich proteins in the intermembrane space by oxidizing them. Two essential proteins, the redox-activated receptor Mia40 and the sulfhydryl oxidase Erv1 participate in this pathway. In chloroplasts, it becomes apparent that protein import is affected by redox signals on both the outer and inner envelope: at the level of the Toc complex (translocon at the outer envelope of chloroplasts), the formation/reduction of disulfide bridges between the Toc components has a strong influence on import yield. Moreover, the stromal metabolic redox state seems to be sensed by the Tic complex (translocon at the inner envelope of chloroplasts) that is able to adjust translocation efficiency of a subgroup of redox-related preproteins accordingly. This review summarizes the current knowledge of these redox-regulatory pathways and focuses on similarities and differences between chloroplasts and mitochondria.


Unboxing AI - Radiological Insights Into a Deep Neural Network for Lung Nodule Characterization.
To explain predictions of a deep residual convolutional network for characterization of lung nodule by analyzing heat maps. A 20-layer deep residual CNN was trained on 1245 Chest CTs from National Lung Screening Trial (NLST) trial to predict the malignancy risk of a nodule. We used occlusion to systematically block regions of a nodule and map drops in malignancy risk score to generate clinical attribution heatmaps on 103 nodules from Lung Image Database Consortium image collection and Image Database Resource Initiative (LIDC-IDRI) dataset, which were analyzed by a thoracic radiologist. The features were described as heat inside nodule -bright areas inside nodule, peripheral heat continuous/interrupted bright areas along nodule contours, heat in adjacent plane -brightness in scan planes juxtaposed with the nodule, satellite heat - a smaller bright spot in proximity to nodule in the same scan plane, heat map larger than nodule bright areas corresponding to the shape of the nodule seen outside the nodule margins and heat in calcification. These six features were assigned binary values. This feature vector was fedinto a standard J48 decision tree with 10-fold cross-validation, which gave an 85 % weighted classification accuracy with a 77.8% True Positive (TP) rate, 8% False Positive (FP) rate for benign cases and 91.8% TP and 22.2% FP rates for malignant cases. Heat Inside nodule was more frequently observed in nodules classified as malignant whereas peripheral heat, heat in adjacent plane, and satellite heat were more commonly seen in nodules classified as benign. We discuss the potential ability of a radiologist to visually parse the deep learning algorithm generated "heat map" to identify features aiding classification.


European recommendations for the management of healthcare workers occupationally exposed to hepatitis B virus and hepatitis C virus.
Exposure prevention is the primary strategy to reduce the risk of occupational bloodborne pathogen infections in healthcare workers (HCW). HCWs should be made aware of the medicolegal and clinical relevance of reporting an exposure, and have ready access to expert consultants to receive appropriate counselling, treatment and follow-up. Vaccination against hepatitis B virus (HBV), and demonstration of immunisation before employment are strongly recommended. HCWs with postvaccinal anti-HBs levels, 1-2 months after vaccine completion, >or=10 mIU/mL are considered as responders. Responders are protected against HBV infection: booster doses of vaccine or periodic antibody concentration testing are not recommended. Alternative strategies to overcome non-response should be adopted. Isolated anti-HBc positive HCWs should be tested for anti-HBc IgM and HBV-DNA: if negative, anti-HBs response to vaccination can distinguish between infection (anti-HBs >or=50 mUI/ml 30 days after 1st vaccination: anamnestic response) and false positive results(anti-HBs >or=10 mUI/ml 30 days after 3rd vaccination: primary response); true positive subjects have resistance to re-infection. and do not need vaccination The management of an occupational exposure to HBV differs according to the susceptibility of the exposed HCW and the serostatus of the source. When indicated, post-exposure prophylaxis with HBV vaccine, hepatitis B immunoglobulin or both must be started as soon as possible (within 1-7 days). In the absence of prophylaxis against hepatitis C virus (HCV) infection, follow-up management of HCV exposures depends on whether antiviral treatment during the acute phase is chosen. Test the HCW for HCV-Ab at baseline and after 6 months; up to 12 for HIV-HCV co-infected sources. If treatment is recommended, perform ALT (amino alanine transferase) activity at baseline and monthly for 4 months after exposure, and qualitative HCV-RNA when an increase is detected.


Cumulative delivery rates in different age groups after artificial insemination with donor sperm.
Although the age-effect on in vitro fertilization outcomes has been well documented, data on donor insemination are scarce hampering accurate patient counseling. This cohort study therefore aims at analyzing cumulative delivery rates after donor insemination for various indications. A large retrospective analysis was performed on 6630 insemination cycles in 1654 women. Delivery rates were calculated by life-table analysis after a maximum of 12 cycles in five subgroups of age when starting inseminations. Multivariable modeling was used to explore the effects according to age, indication (male infertility, lesbian couple or single-parent request) and ovarian stimulation protocol (none, clomiphene citrate or gonadotrophins). Overall, 928 deliveries were observed, i.e. a delivery rate of 14% per cycle and an expected cumulative delivery of 77% after 12 cycles. Subgroup analysis showed an expected cumulative delivery after 12 cycles of 87% for the group aged 20-29, 77% for ages 30-34, 76% for ages 35-37, 66% for ages 38-39 and 52% for ages 40-45. Drop-out analysis in the latter subgroup showed that only one patient discontinued treatment because of medical reasons. In contrast to age, neither indication nor ovarian stimulation protocol had any significant effect on the delivery rate. Our study corroborates the impact of age on donor insemination outcome. Nevertheless, even in some older age subgroups, acceptable expected cumulative delivery rates were observed. Despite this, the main reason for discontinuing treatment, however, was the anticipated low success rate. Women, up until 42 years of age, could be encouraged to continue treatment.


C-C Motif Ligand 20 (CCL20) and C-C Motif Chemokine Receptor 6 (CCR6) in Human Peripheral Blood Mononuclear Cells: Dysregulated in Ulcerative Colitis and a Potential Role for CCL20 in IL-1β Release.
The chemokine C-C motif ligand 20 (CCL20) is increased in the colonic mucosa during active inflammatory bowel disease (IBD) and can be found both in the epithelium and immune cells in the lamina propria. The present study investigated CCL20 and C-C motif Chemokine Receptor 6 (CCR6) in peripheral blood mononuclear cells (PBMCs) (n = 40) from IBD patients and healthy controls, to identify inductors of CCL20 release encountered in a local proinflammatory environment. CCL20 release from PBMCs was increased when activating TLR2/1 or NOD2, suggesting that CCL20 is part of a first line response to danger-associated molecular patterns also in immune cells. Overall, ulcerative colitis (UC) had a significantly stronger CCL20 release than Crohn's disease (CD) (+242%, p < 0.01), indicating that the CCL20-CCR6 axis may be more involved in UC. The CCL20 receptor CCR6 is essential for the chemotactic function of CCL20. UC with active inflammation had significantly decreased CCR6 expression and a reduction in CCR6⁺ cells in circulation, indicating chemoattraction of CCR6⁺ cells from circulation towards peripheral tissues. We further examined CCL20 induced release of cytokines from PBMCs. Stimulation with CCL20 combined with TNF increased IL-1β release from PBMCs. By attracting additional immune cells, as well as inducing proinflammatory IL-1β release from immune cells, CCL20 may protract the inflammatory response in ulcerative colitis.


Errors in corticospinal axon guidance in mice lacking the neural cell adhesion molecule L1.
Neural cell adhesion molecules of the immunoglobulin superfamily (IgCAMs) have been implicated in both the fasciculation and guidance of axons, but direct genetic evidence of a role for neural IgCAMs in axon guidance in vertebrates is lacking. The L1 subfamily of vertebrate neural IgCAMs function as both homophilic and heterophilic receptors for a variety of cell-surface and extracellular ligands and may signal through intracellular kinases or by recruitment of the fibroblast growth factor receptor. L1 itself has been implicated in many neural processes and is expressed widely in the embryonic and adult nervous systems. In humans, mutations in the L1 gene are linked with a spectrum of brain disorders, including loss of the corticospinal tract, but the mechanistic basis for these disorders is unknown. We show that mice that do not express L1 have defects in the guidance of axons of the corticospinal tract, a major motor control pathway projecting from the cortex to the spinal cord. Although the pathway to the caudal medulla appears normal, a substantial proportion of axons fail to cross the midline to the opposite dorsal column as normal. In adults, this results in a reduced decussation and in large numbers of axons projecting ipsilaterally. There is also a varying, but reduced, number of corticospinal axons in the dorsal columns of the spinal cord. These do not project beyond cervical levels. We show that these are defects in axon guidance, because they arise during the early stages of the development of the decussation. The presence of a ligand for L1, CD24, specifically at the point of decussation suggests a mechanism in which L1 functions to guide corticospinal axons across the midline. L1 function is necessary for the guidance of corticospinal axons across the pyramidal decussation in mice. Some of the defects in the corticospinal tract of humans with mutations in L1 could be due to errors in axon guidance at the pyramidal decussation.


Incorporating a Fresh Mixed Annual Ryegrass and Berseem Clover Forage Into the Winter Diet of Dairy Cows Resulted in Reduced Milk Yield, but Reduced Nitrogen Excretion and Reduced Methane Yield.
The winter diet of dairy cows in Mediterranean climate regions is usually a total mixed ration with a base of conserved summer crops such as corn silage and alfalfa hay. However, there is increased labor and financial cost related to this kind of feeding, which could be reduced if fresh forages were used in place of some of the conserved forage in the cow diet. The objective of our study was to evaluate the effect of including fresh mixed annual ryegrass and berseem clover into the diet of dairy cows on milk, nitrogen utilization, and methane emission. Twenty-four lactating dairy cows were split into two groups and offered either a diet similar to that usually offered to the cows (CON) or one where a mixture of fresh annual ryegrass and berseem clover was used to partially substitute the corn silage and alfalfa hay in the diet (MIX). Milk yield was recorded automatically, and methane emissions were estimated using the SF6 tracer technique. The MIX diet had lower crude protein concentration (148 vs. 170 g/kg DM) but higher DM digestibility (81.6 vs. 78.6%) than the CON diet. Compared to the cows offered the CON diet, milk yield was reduced when cows were fed the MIX diet (36.4 vs. 31.9 kg/d), but methane emissions (381 vs. 332 g/d) and nitrogen excretion were also reduced (238 vs. 180 g/d). Nitrogen use efficiency was unaffected (30.8%). In addition, milk from cows fed the MIX diet had a fatty acid profile considered to be more beneficial to human health than that of the milk from cows fed the CON diet. Increasing the protein concentration in the MIX diet, either by direct supplementation or increasing the proportion of legume in the mixed herbage, could overcome the reduction on milk and positively affect methane emission and N use efficiency.


A novel regulatory event-based gene set analysis method for exploring global functional changes in heterogeneous genomic data sets.
Analyzing gene expression data by assessing the significance of pre-defined gene sets, rather than individual genes, has become a main approach in microarray data analysis and this has promisingly derive new biological interpretations of microarray data. However, the detection power of conventional gene list or gene set-based approaches is limited on highly heterogeneous samples, such as tumors. We developed a novel method, the regulatory event-based Gene Set Analysis (eGSA), which considers not only the consistently changed genes but also every gene regulation (event) of each sample to overcome the detection limit. In comparison with conventional methods, eGSA can detect functional changes in heterogeneous samples more precisely and robustly. Furthermore, by utilizing eGSA, we successfully revealed novel functional characteristics and potential mechanisms of very early hepatocellular carcinoma (HCC). Our study creates a novel scheme to directly target the major cellular functional changes in heterogeneous samples. All potential regulatory routines of a functional change can be further analyzed by the regulatory event frequency. We also provide a case study on early HCCs and reveal a novel insight at the initial stage of hepatocarcinogenesis. eGSA therefore accelerates and refines the interpretation of heterogeneous genomic data sets in the absence of gene-phenotype correlations.


The effects of trypsin on ATP-sensitive potassium channel properties and sulfonylurea receptors in the CRI-G1 insulin-secreting cell line.
The effects of the proteolytic enzyme trypsin upon ATP-sensitive potassium (KATP) channel activity were examined in the CRI-G1 insulin-secreting cell line. Trypsin activated channels only when applied to the intracellular surface of the cell membrane. The activation could be prevented by the concomitant application of trypsin inhibitor or by heat inactivation of the enzyme. The trypsin-induced change in channel activity was accompanied by a reduction in the rate of channel rundown. However, trypsin did not affect the mean single channel conductance (55.2 pS), the ionic selectivity, or rectification of the KATP channel. Concentration response curves for various KATP channel inhibitors were constructed in the presence and absence of intracellular trypsin. The EC50 for tolbutamide was shifted from 30.0 +/- 4.5 microM, with 100 micrograms/ml heat-inactivated trypsin present to 9.7 +/- 1.0 mM with active trypsin in the intracellular solution. Treatment of the cells' external surface with 1 mg/ml trypsin did not alter the potency of tolbutamide. Intracellular trypsin also produced a significant fall in the potency of glibenclamide, meglitinide, and phentolamine but did not alter the effectiveness of thiopentone. Radioligand binding studies demonstrated a total loss of 3H-labeled glibenclamide binding when the intracellular surface of the cells was exposed to trypsin. In contrast, 3H-labeled glibenclamide binding was not affected when the enzyme was applied to the external surface. Trypsin treatment, therefore, alters a number of characteristics of KATP channel pharmacology, and we suggest that this is due to action at possibly more than one site but includes the functional cleavage of the sulfonylurea receptor from the KATP channel.


Relationship between financial impact and coverage of drugs in Australia.
The aim of this study was to estimate the relationship between the financial impact of a new drug and the recommendation for reimbursement by the Australian Pharmaceutical Benefits Advisory Committee (PBAC). Data in the PBAC summary database were abstracted for decisions made between July 2005 and November 2009. Financial impact-the upper bound of the values presented in the PBAC summary database-was categorized as ≤A$0, >A$0 up to A$10 million, A$10 million up to A$30 million, and >A$30 million per year. Descriptive, logistic, survival, and recursive partitioning decision analyses were used to estimate the relationship between the financial impact of a new drug indication and the recommendation for reimbursement. Multivariable analyses controlled for other clinical and economic variables, including cost per quality-adjusted life-year gained. Financial impact was a significant predictor of the recommendation for reimbursement. In the logistic analysis, the odds ratios of reimbursement for drug submissions with financial impacts ≥A$10 million to ≥A$30 million or >A$0 to <A$10 million compared with ≤A$0 were 0.12 (95 percent confidence interval [CI]: 0.03-0.51) and 0.16 (95 percent CI: 0.04-0.60), respectively. In the recursive partition decision analysis, the first split of the data was for submissions with a positive financial impact compared with those with a zero or negative financial impact. In Australia, financial impact on the drug budget is an important determinant of whether a new drug is recommended for reimbursement when cost-effectiveness estimates and other clinical and economic variables are controlled.


Modulation and Regulation of Canonical Transient Receptor Potential 3 (TRPC3) Channels.
Canonical transient receptor potential 3 (TRPC3) channel is a non-selective cation permeable channel that plays an essential role in calcium signalling. TRPC3 is highly expressed in the brain and also found in endocrine tissues and smooth muscle cells. The channel is activated directly by binding of diacylglycerol downstream of G-protein coupled receptor activation. In addition, TRPC3 is regulated by endogenous factors including Ca2+ ions, other endogenous lipids, and interacting proteins. The molecular and structural mechanisms underlying activation and regulation of TRPC3 are incompletely understood. Recently, several high-resolution cryogenic electron microscopy structures of TRPC3 and the closely related channel TRPC6 have been resolved in different functional states and in the presence of modulators, coupled with mutagenesis studies and electrophysiological characterisation. Here, we review the recent literature which has advanced our understanding of the complex mechanisms underlying modulation of TRPC3 by both endogenous and exogenous factors. TRPC3 plays an important role in Ca2+ homeostasis and entry into cells throughout the body, and both pathological variants and downstream dysregulation of TRPC3 channels have been associated with a number of diseases. As such, TRPC3 may be a valuable therapeutic target, and understanding its regulatory mechanisms will aid future development of pharmacological modulators of the channel.


Core symptoms of autism improved after vitamin D supplementation.
Autism spectrum disorder (ASD) is a common neurodevelopmental disorder caused by a complex interaction between genetic and environmental risk factors. Among the environmental factors, vitamin D3 (cholecaliferol) seems to play a significant role in the etiology of ASD because this vitamin is important for brain development. Lower concentrations of vitamin D3 may lead to increased brain size, altered brain shape, and enlarged ventricles, which have been observed in patients with ASD. Vitamin D3 is converted into 25-hydroxyvitamin D3 in the liver. Higher serum concentrations of this steroid may reduce the risk of autism. Importantly, children with ASD are at an increased risk of vitamin D deficiency, possibly due to environmental factors. It has also been suggested that vitamin D3 deficiency may cause ASD symptoms. Here, we report on a 32-month-old boy with ASD and vitamin D3 deficiency. His core symptoms of autism improved significantly after vitamin D3 supplementation. This case suggests that vitamin D3 may play an important role in the etiology of ASD, stressing the importance of clinical assessment of vitamin D3 deficiency and the need for vitamin D3 supplementation in case of deficiency.


Discovery Path: a retention strategy for mid-career nurses.
As health care administrators, policymakers, nursing organizations, and nurses begin to deal with the reality of a looming (and to an increasing extent, existing) serious shortage of nurses both in Canada and globally, recruitment and retention issues are again in the news. Much attention has been directed towards two responses: (a) attracting young people into the profession and helping them integrate into and identify with nursing as a lifelong career, and (b) developing sustainable retention strategies to ensure that nurses remain in nursing. One population that requires particular attention is the mid-career group of nurses. Those nurses, in their late 30s and 40s with 15 and more years of experience, have the professional memory that employers count on, the expertise that patients and clients require, and the experience and wisdom that young nurses depend on for coaching, mentoring, and support. Retention strategies targeted to these mid-career nurses require a diverse set of activities that are focused on those nurses' specific stage of personal and professional development and that recognize their unique needs. The purpose of this article is to describe a program that targets mid-career nurses, predominantly women who, having spent much of their careers and lives caring for others-children, parents, patients-are beginning to question their own futures. The goals of the program and the experiences of one group of nurses in the program, as well as the results of a two-year follow up with them, will be discussed. Recommendations for future retention strategies will also be offered.


Dietary walnut as food factor to rescue from NSAID-induced gastrointestinal mucosal damages.
Nuclear factor erythroid-derived 2-like 2 (Nrf-2) is transcription factor implicated in the antioxidant response element-mediated induction of endogenous antioxidant enzyme such as heme oxygenase-1 (HO-1), glutamate-cysteine ligase, and NAD(P)H quinone dehydrogenase 1, among which HO-1 is an enzyme catalyzing the degradation of heme.producing biliverdin, ferrous iron, and carbon monoxide. In the stomach, as much as regulating gastric acid secretions, well-coordinated establishment of defense system stands for maintaining gastric integrity. In previous study, author et al. for the first time discovered HO-1 induction was critical in affording faithful gastric defense against various irritants including Helicobacter pylori infection, stress, alcohol, non-steroidal anti-inflammatory drugs (NSAIDs), aspirin, and toxic bile acids. In this review article, we can add the novel evidence that dietary walnut intake can be reliable way to rescue from NSAIDs-induced gastrointestinal damages via the induction of HO-1 transcribed with Nrf-2 through specific inactivation of Keap-1. From molecular exploration to translational animal model of indomethacin-induced gastrointestinal damages, significant induction of HO-1 contributed to rescuing from damages. In addition to HO-1 induction action relevant to walnut, we added the description the general actions of walnut extracts or dietary intake of walnut regarding cytoprotection and why we have focused on to NSAID damages.


Increasing the X-ray diffraction power of protein crystals by dehydration: the case of bovine serum albumin and a survey of literature data.
Serum albumin is one of the most widely studied proteins. It is the most abundant protein in plasma with a typical concentration of 5 g/100 mL and the principal transporter of fatty acids in plasma. While the crystal structures of human serum albumin (HSA) free and in complex with fatty acids, hemin, and local anesthetics have been characterized, no crystallographic models are available on bovine serum albumin (BSA), presumably because of the poor diffraction power of existing hexagonal BSA crystals. Here, the crystallization and diffraction data of a new BSA crystal form, obtained by the hanging drop method using MPEG 5K as precipitating agent, are presented. The crystals belong to space group C2, with unit-cell parameters a = 216.45 Å, b = 44.72 Å, c = 140.18 Å, β = 114.5°. Dehydration was found to increase the diffraction limit of BSA crystals from ~8 Å to 3.2 Å, probably by improving the packing of protein molecules in the crystal lattice. These results, together with a survey of more than 60 successful cases of protein crystal dehydration, confirm that it can be a useful procedure to be used in initial screening as a method of improving the diffraction limits of existing crystals.


Recent progress in translational research on neurovascular and neurodegenerative disorders.
The already established and widely used intravenous application of recombinant tissue plasminogen activator as a re-opening strategy for acute vessel occlusion in ischemic stroke was recently added by mechanical thrombectomy, representing a fundamental progress in evidence-based medicine to improve the patient's outcome. This has been paralleled by a swift increase in our understanding of pathomechanisms underlying many neurovascular diseases and most prevalent forms of dementia. Taken together, these current advances offer the potential to overcome almost two decades of marginally successful translational research on stroke and dementia, thereby spurring the entire field of translational neuroscience. Moreover, they may also pave the way for the renaissance of classical neuroprotective paradigms.This review reports and summarizes some of the most interesting and promising recent achievements in neurovascular and dementia research. It highlights sessions from the 9th International Symposium on Neuroprotection and Neurorepair that have been discussed from April 19th to 22nd in Leipzig, Germany. To acknowledge the emerging culture of interdisciplinary collaboration and research, special emphasis is given on translational stories ranging from fundamental research on neurode- and -regeneration to late stage translational or early stage clinical investigations.


Functional Loss of the Inner Retina in Childhood Optic Gliomas Detected by Photopic Negative Response.
To determine whether the Ganzfeld ERG photopic negative response (PhNR), an assay of inner retinal activity, is altered in childhood optic glioma (OPG). Seventeen pediatric patients with a diagnosis of OPG, established on neuro-ophthalmologic and brain/orbit magnetic resonance imaging (MRI) criteria, were enrolled. The examination protocol included determination of visual acuity (VA), fundus examination, retinal nerve fiber layer (RNFL) measurement with spectral-domain optical coherence tomography (SD-OCT) and photopic ERG. Fifteen normal children served as control group. Ten of the 17 OPG patients were retested 1 to 3 months after the first examination. Photopic ERGs were recorded after 10 minutes of light adaptation in response to a Ganzfeld flash presented on a steady light-adapting background. Amplitude and peak-time of b-wave and PhNR were measured. Compared with normal values, PhNR amplitude was significantly reduced (P < 0.0001) in the OPG group. Peak-time of PhNR as well as b-wave amplitude and peak-time were similar in both patients and controls. Losses of PhNR were found in patients with involvement of either anterior or retro-chiasmatic optic pathways. Linear regression analysis showed significant positive correlation between RNFL thickness and PhNR amplitude (r2 = 0.34, P = 0.008). Mean percentage test-retest difference for PhNR amplitude and peak-time was 12% and 6%, respectively. These findings indicate that flash ERG PhNR can detect a loss of inner retinal function in childhood OPGs supporting the use of this technique, as an adjunct to standard psychophysical and electrophysiological tests, to monitor visual function in OPG.


Optimal use of a panel of methylation markers with GSTP1 hypermethylation in the diagnosis of prostate adenocarcinoma.
In this study, we tested the ability of a panel of hypermethylation markers to improve the sensitivity of histologic prostate cancer detection in sextant needle biopsies. We obtained fresh-frozen sextant biopsies from 72 excised prostates and directly compared blinded histologic review and quantitative real-time methylation-specific PCR for hypermethylation of four genes, Tazarotene-induced gene 1 (TIG1), adenomatous polyposis coli (APC), retinoic acid receptor beta2 (RARbeta2), and glutathione S-transferase pi (GSTP1) to detect the presence of prostate cancer. Results were compared with the final surgical pathological review of the resected prostates as the gold standard. Histologic review alone detected carcinoma with a sensitivity of 64% (39 of 61 cases) and 100% specificity. Quantitative real-time methylation-specific PCR for TIG1, APC, RARbeta2, and GSTP1 detected carcinoma with a sensitivity of 70%, 79%, 89%, and 75%, respectively, with 100% specificity for all of the genes. Using this panel of methylation markers in combination with histology resulted in the detection of 59 of 61 (97%) cases of prostate with 100% specificity, a 33% improvement over histology alone. The use of a panel of methylation markers as an adjunct to histologic review may substantially augment prostate cancer diagnosis from needle biopsies.


First Report of Impatiens Downy Mildew Caused by Plasmopara obducens in Ohio.
Single and double flowered impatiens (Impatiens walleriana Hook.f.) plants with symptoms of downy mildew were found in commercial greenhouses in Delaware, Wayne, and Holmes counties, Ohio, in April 2012. Plants were stunted and defoliated. Symptoms on remaining leaves included general chlorosis without discrete spots and downward curling of leaves. A downy white growth was observed on the lower surface of infected leaves. The disease was widespread in affected greenhouses and incidence in cvs. Shimmer Coral, Accent Mix, and Super Elfin was nearly 90%. The downy growth consisted of coenocytic mycelia, monopodial sporangiophores, and ovoid, hyaline sporangia typical of Plasmopara obducens (J. Schröt.) J. Schröt in Cohn (1,2,4). Sporangia were borne on branchlets measuring 5 to 15 μm long (average 10 μm) at right angles to the main axis of the sporangiophore. Sporangia were 9.4 to 17.5 × 12.8 to 16.3 μm. No oospores were observed. Total DNA was extracted directly from plant tissue with the Wizard SV Genomic DNA Purification System (Promega, Madison, WI) following the manufacturer's instructions. Large ribosomal subunit DNA was amplified by PCR using primers NL-1 and NL-4 (3). Amplicons of 690 bp and 834 bp were produced from each diseased sample, while only the 690-bp amplicon was produced from healthy tissue. DNA from each amplicon of sample IDM041712 was purified using the Wizard SV Gel and PCR Clean-Up System (Promega), sequenced, and the sequence of the diagnostic 834-bp amplicon was deposited in GenBank (JX142134). The sequence of the 834-bp amplicon was 99% similar to those of P. obducens isolates from Serbia (HQ246451) (1), the UK (AY587558), and Austria (EF196869). The sequence of the 690-bp amplicon (JX142135) was 99% similar to that of I. walleriana (HQ223336). Twelve young impatiens 'Shimmer Coral' plants were inoculated with sporangia washed from infected leaves (1 × 104 sporangia/ml). Plants were incubated at room temperature for 24 h in a moist chamber and then maintained in a greenhouse (21 to 23°C) until symptoms appeared. Control plants were sprayed with sterile water and maintained in the same environment. After 12 to 14 days, typical symptoms of downy mildew developed on the inoculated plants and microscopic examination revealed the same pathogen morphology as the original isolate. All non-inoculated control plants remained disease free. To our knowledge, this is the first report of downy mildew on impatiens in Ohio. This disease caused considerable economic losses in Ohio in 2012 and is likely to be a recurring problem requiring intensive preventative management. References: (1) A. Bulajic et al. Plant Dis. 95:491, 2011. (2) O. Constantinescu. Mycologia 83:473, 1991. (3) W. Maier et al. Can. J. Bot. 81:12, 2003. (4) S. N. Wegulo et al. Plant Dis. 88:909, 2004.


Comparative clinical outcomes between direct oral anticoagulants and warfarin among elderly patients with non-valvular atrial fibrillation in the CMS medicare population.
Atrial fibrillation (AF) prevalence increases with age; > 80% of US adults with AF are aged ≥ 65 years. Compare the risk of stroke/systemic embolism (SE), major bleeding (MB), net clinical outcome (NCO), and major adverse cardiac events (MACE) among elderly non-valvular AF (NVAF) Medicare patients prescribed direct oral anticoagulants (DOACs) VS warfarin. NVAF patients aged ≥ 65 years who initiated DOACs (apixaban, dabigatran, and rivaroxaban) or warfarin were selected from 01JAN2013-31DEC2015 in CMS Medicare data. Propensity score matching was used to balance DOAC and warfarin cohorts. Cox proportional hazards models estimated the risk of stroke/SE, MB, NCO, and MACE. 37,525 apixaban-warfarin, 18,131 dabigatran-warfarin, and 55,359 rivaroxaban-warfarin pairs were included. Compared to warfarin, apixaban (HR: 0.69; 95% CI 0.59-0.81) and rivaroxaban (HR: 0.82; 95% CI 0.73-0.91) had lower risk of stroke/SE, and dabigatran (HR: 0.88; 95% CI 0.72-1.07) had similar risk of stroke/SE. Apixaban (MB: HR: 0.61; 95% CI 0.57-0.67; NCO: HR: 0.64; 95% CI 0.60-0.69) and dabigatran (MB: HR: 0.79; 95% CI 0.71-0.89; NCO: HR: 0.84; 95% CI 0.76-0.93) had lower risk of MB and NCO, and rivaroxaban had higher risk of MB (HR: 1.08; 95% CI 1.02-1.14) and similar risk of NCO (HR: 1.04; 95% CI 0.99-1.09). Compared to warfarin, apixaban had a lower risk for stroke/SE, MB, and NCO; dabigatran had a lower risk of MB and NCO; and rivaroxaban had a lower risk of stroke/SE but higher risk of MB. All DOACs had lower risk of MACE compared to warfarin.


Coinfection with human herpesvirus 8 is associated with persistent inflammation and immune activation in virologically suppressed HIV-infected patients.
Infection with co-pathogens is one of the postulated factors contributing to persistent inflammation and non-AIDS events in virologically-suppressed HIV-infected patients. We aimed to investigate the relationship of human herpesvirus-8 (HHV-8), a vasculotropic virus implicated in the pathogenesis of Kaposi's sarcoma, with inflammation and subclinical atherosclerosis in HIV-infected patients. Prospective study including virologically suppressed HIV-infected patients. Several blood biomarkers (highly-sensitive C-reactive protein [hsCRP], tumour necrosis factor-α, interleukin-6, monocyte chemoattractant protein-1, vascular cell adhesion molecule-1, intercellular cell adhesion molecule-1, malondialdehyde, plasminogen activator inhibitor [PAI-1], D-dimer, sCD14, sCD163, CD4/CD38/HLA-DR, and CD8/CD38/HLA-DR), serological tests for HHV-8 and the majority of herpesviruses, carotid intima-media thickness, and endothelial function through flow-mediated dilatation of the brachial artery were measured. A total of 136 patients were included, 34.6% of them infected with HHV-8. HHV-8-infected patients were more frequently co-infected with herpes simplex virus type 2 (HSV-2) (P<0.001), and less frequently with hepatitis C virus (HCV) (P = 0.045), and tended to be older (P = 0.086). HHV-8-infected patients had higher levels of hsCRP (median [interquartile range], 3.63 [1.32-7.54] vs. 2.08 [0.89-4.11] mg/L, P = 0.009), CD4/CD38/HLA-DR (7.67% [4.10-11.86]% vs. 3.86% [2.51-7.42]%, P = 0.035) and CD8/CD38/HLA-DR (8.02% [4.98-14.09]% vs. 5.02% [3.66-6.96]%, P = 0.018). After adjustment for the traditional cardiovascular risk factors, HCV and HSV-2 infection, the associations remained significant: adjusted difference between HHV-8 positive and negative patients (95% confidence interval) for hsCRP, 74.19% (16.65-160.13)%; for CD4/CD38/HLA-DR, 89.65% (14.34-214.87)%; and for CD8/CD38/HLA-DR, 58.41% (12.30-123.22)%. Flow-mediated dilatation and total carotid intima-media thickness were not different according to HHV-8 serostatus. In virologically suppressed HIV-infected patients, coinfection with HHV-8 is associated with increased inflammation and immune activation. This might contribute to increase the risk of non-AIDS events, including accelerated atherosclerotic disease.


Informed consent, community engagement, and study participation at a research site in Kigali, Rwanda.
People enroll in medical research for many reasons ranging from decisions regarding their own or family members' health situation to broader considerations including access to health and financial resources. In socially vulnerable communities the choice to participate is often based on a risk-benefit assessment that goes beyond the medical aspects of the research, and considers the benefits received. In this qualitative study, we examined the motivations of Rwandan women to participate in a non-commercial collaborative research study examining the safety, acceptability, and adherence of a contraceptive vaginal ring in Rwanda juxtaposed with the perceptions of the research within the community. 351 women attended the screening visit, four were excluded because they were not able to complete the assessment of understanding. The remaining participants' ages ranged from 17 to 38 and 80% had primary level of education or below. 120 were enrolled. Findings highlighted motivations for joining the study that were relayed both formally by the clinic (e.g. testing and treatment) and informally by the community including the positive aspects of the ring. There were also some negative rumors circulating regarding the research site, likely from excluded participants who faced potential stigma based on that exclusion. It was understood by most participants that they were enrolled in a research study and participants actively sought out enrollment in the research for a variety of reasons. The experiences demonstrate that although inequalities in access to health care may create conflicting situations around the study, it is possible to form partnerships between a research center and participants/their partners, for research about reproductive health.


Dietary cholecalciferol and calcium levels in a Western-style defined rodent diet alter energy metabolism and inflammatory responses in mice.
Male and female C57Bl6 mice were fed a control AIN76A diet, a new Western-style diet (NWD1) reflecting dietary patterns linked to elevated colon cancer incidence (higher fat, lower cholecalciferol, calcium, methyl donors, fiber), or NWD1 with elevated cholecalciferol and calcium (NWD2) from weaning. After 24 wk, serum 25-hydroxyvitamin D [25(OH)D] decreased by >80% in the NWD1 group compared with controls, but with no alteration in serum calcium or bone mineral density. The decreased serum 25(OH)D was prevented in the NWD2 group. After 32 wk, the NWD1 group compared with controls reduced overall energy expenditure by 15% without altering food consumption or physical activity and induced glucose intolerance, phenotypes associated with metabolic syndrome. These responses were unexpectedly exacerbated in the NWD2 group, further shifting mice toward greater fatty acid storage rather than oxidation compared with both control and NWD1 groups, but there was no change in physical activity, causing significant weight gain due to increased fat mass. The NWD1 group also exhibited inflammatory responses compared with controls, including macrophage-associated crown-like structures in epididymal adipose tissue and increased serum concentrations of the proinflammatory cytokine IL-1β, and of its targets, MCP-1 and Rantes, which were prevented or greatly mitigated in the NWD2 group. However, there was also elevated lipid storage in the liver and steatosis not seen in the control and NWD1 groups. Thus, elevating cholecalciferol and calcium in a Western-style diet can reduce inflammation associated with risk for colon tumor development, but interaction of nutrients in this diet can compromise liver function when fed long term.


Primary chemoablation of low-grade upper tract urothelial carcinoma using UGN-101, a mitomycin-containing reverse thermal gel (OLYMPUS): an open-label, single-arm, phase 3 trial.
Most patients with low-grade upper tract urothelial cancer are treated by radical nephroureterectomy. We aimed to assess the safety and activity of a non-surgical treatment using instillation of UGN-101, a mitomycin-containing reverse thermal gel. In this open-label, single-arm, phase 3 trial, participants were recruited from 24 academic sites in the USA and Israel. Patients (aged ≥18 years) with primary or recurrent biopsy-proven, low-grade upper tract urothelial cancer (measuring 5-15 mm in maximum diameter) and an Eastern Cooperative Oncology Group performance status score of less than 3 (Karnofsky Performance Status score >40) were registered to receive six instillations of once-weekly UGN-101 (mitomycin 4 mg per mL; dosed according to volume of patient's renal pelvis and calyces, maximum 60 mg per instillation) via retrograde catheter to the renal pelvis and calyces. All patients had a planned primary disease evaluation 4-6 weeks after the completion of initial therapy, in which the primary outcome of complete response was assessed, defined as negative 3-month ureteroscopic evaluation, negative cytology, and negative for-cause biopsy. Activity (complete response, expected to occur in >15% of patients) and safety were assessed by the investigator in all patients who received at least one dose of UGN-101. Data presented are from the data cutoff on May 22, 2019. This study is registered with ClinicalTrials.gov, NCT02793128. Between April 6, 2017, and Nov 26, 2018, 71 (96%) of 74 enrolled patients received at least one dose of UGN-101. 42 (59%, 95% CI 47-71; p<0·0001) patients had a complete response at the primary disease evaluation visit. The median follow-up for patients with a complete response was 11·0 months (IQR 5·1-12·4). The most frequently reported all-cause adverse events were ureteric stenosis in 31 (44%) of 71 patients, urinary tract infection in 23 (32%), haematuria in 22 (31%), flank pain in 21 (30%), and nausea in 17 (24%). 19 (27%) of 71 patients had study drug-related or procedure-related serious adverse events. No deaths were regarded as related to treatment. Primary chemoablation of low-grade upper tract urothelial cancer with intracavitary UGN-101 results in clinically significant disease eradication and might offer a kidney-sparing treatment alternative for these patients. UroGen Pharma.


Melatonin in plants.
Once thought to be exclusively a molecule of the animal kingdom, melatonin has now been found to exist in plants as well. Among a number of actions, melatonin is a direct free radical scavenger and an indirect antioxidant. Melatonin directly detoxifies the hydroxyl radical (OH), hydrogen peroxide, nitric oxide, peroxynitrite anion, peroxynitrous acid, and hypochlorous acid. The products from each of these reactions have been identified in pure chemical systems and in at least one case in vivo; the interaction product of melatonin with the OH, ie., cyclic 3-hydroxymelatonin, is found in the urine of humans and rats. Some of the products that are produced when melatonin detoxifies reactive species are also highly efficient scavengers. As a result, a cascade of scavenging reactions may enhance the antioxidant capacity of melatonin. Additionally, melatonin increases the activity of several antioxidative enzymes, thereby improving its ability to protect macromolecules from oxidative stress. Melatonin is endogenously produced and is also consumed in edible plants. In animal experiments, feeding melatonin-containing foods raised blood levels of the indole. Because physiologic concentrations of melatonin in the blood are known to correlate with the total antioxidant capacity of the serum, consuming food-stuffs containing melatonin may be helpful in lowering oxidative stress.


Volitional pursed lips breathing in patients with stable chronic obstructive pulmonary disease improves exercise capacity.
Pursed lips breathing (PLB) is used by a proportion of patients with chronic obstructive pulmonary disease (COPD) to alleviate dyspnea. It is also commonly used in pulmonary rehabilitation. Data to support its use in patients who do not spontaneously adopt PLB are limited. We performed this study to assess the acute effects of PLB on exercise capacity in nonspontaneously PLB patients with stable COPD. We performed a randomized crossover study comparing 6-min walk test (6MWT) at baseline without PLB with 6WMT using volitional PLB. Spirometry, maximal inspiratory and expiratory mouth pressures, and diaphragmatic excursion during tidal and vital capacity breathing using B-mode ultrasonography were measured at baseline and after 10 min of PLB. A Visual Analog Scale (VAS) assessed subjective breathlessness at rest, after 6MWT and after 6MWT with PLB. p ≤ 0.01 was considered significant. Mean ± SD age of patients was 53.1 ± 7.4 years. Forced expiratory volume in 1 second was 1.1 ± 0.4 L/min (38.4 ± 13.2% predicted). Compared with spontaneous breathing, all but one patient with PLB showed a significant increment in 6MW distance (+34.9 ± 26.4 m; p = 0.002). There was a significant reduction in respiratory rate post 6MWT with PLB compared with spontaneous breathing (-4.4 ± 2.8 per minute; p = 0.003). There was no difference in VAS scores. There was a significant correlation between improvement in 6MWT distance and increase in diaphragmatic excursion during forced breathing. The improvement was greater in patients who had poorer baseline exercise performance. PLB has an acute benefit on exercise capacity. Sustained PLB or short bursts of PLB may improve exercise capacity in stable COPD.


Selecting Outcomes to Ensure Pragmatic Trials Are Relevant to People Living with Dementia.
Outcome measures for embedded pragmatic clinical trials (ePCTs) should reflect the lived experience of people living with dementia (PLWD) and their caregivers, yet patient- and caregiver-reported outcomes (PCROs) are rarely available in large clinical and administrative data sources. Although pragmatic methods may lead to use of existing administrative data rather than new data collected directly from PLWD, interventions are truly impactful only when they change outcomes prioritized by PLWD and their caregivers. The Patient- and Caregiver-Reported Outcomes Core (PCRO Core) of the IMbedded Pragmatic Alzheimer's Disease (AD) and AD-Related Dementias Clinical Trials (IMPACT) Collaboratory aims to promote optimal use of outcomes relevant to PLWD and their caregivers in pragmatic trials. The PCRO Core will address key scientific challenges limiting outcome measurement, such as gaps in existing measures, methodologic constraints, and burdensome data capture. PCRO Core investigators will create a searchable library of AD/AD-related dementias (ADRD) clinical outcome measures, including measures in existing data sources with potential for AD/ADRD ePCTs, and will support best practices in measure development, including pragmatic adaptation of PCROs. Working together with other Cores and Teams within the IMPACT Collaboratory, the PCRO Core will support investigators to select from existing outcome measures, and to innovate in methods for measurement and data capture. In the future, the work of the IMPACT Collaboratory may galvanize broader embedded use of outcomes that matter to PLWD and their care partners in large health systems. J Am Geriatr Soc 68:S55-S61, 2020.


Emergence of Maruca vitrata as a Major Pest of Food Legumes and Evolution of Management Practices in Asia and Africa.
Legume pod borer, Maruca vitrata, has emerged as a major pest on food legumes in Asia and Africa. It is an oligophagous pest, feeding on over 70 species in Fabaceae. We examine the species complex in Asia, Africa, Oceania, and the Americas, with an emphasis on molecular taxonomy. Studies on pheromone production and perception suggest the existence of pheromone polymorphism, especially in Asia and Africa. No Maruca-resistant varieties are available in the major food legumes including cowpea, pigeonpea, mungbean, and yard-long bean. Legume growers use chemical pesticides indiscriminately, leading to the development of pesticide resistance. However recent developments in habitat management, classical biocontrol with more efficient parasitoids, biopesticides, and judicious use of insecticides pave the way for sustainable management of M. vitrata, which can reduce the pesticide misuse. Active engagement of the private sector and policy makers can increase the adoption of integrated pest management approaches in food legumes.


Dynamics of Simultaneous and Imitative Bodily Coordination in Trust and Distrust.
Body synchronization between interacting people involves coordinative movements in time, space and form. The introduction of newer technologies for automated video analysis and motion tracking has considerably improved the accurate measurement of coordination, particularly in temporal and spatial terms. However, the form of interpersonal coordination has been less explored. In the present study we address this gap by exploring the effect of trust on temporal and morphological patterns of interpersonal coordination. We adapted an optical motion-capture system to record spontaneous body movements in pairs of individuals engaged in natural conversations. We conducted two experiments in which we manipulated trust through a breach of expectancy (Study 1: 10 trustful and 10 distrustful participants) and friendship (Study 2: 20 dyads of friends and 20 dyads of strangers). In Study 1, results show the participants' strong, early mirror-like coordination in response to the confederates' breach of trust. In Study 2, imitative coordination tended to be more pronounced in pairs of friends than in pairs of non-friends. Overall, our results show not only that listeners move in reaction to speakers, but also that speakers react to listeners with a chain of dynamic coordination patterns affected by the immediate disposition of, and long-term relationship with, their interlocutors.


Matricide: primal aggression in search of self-affirmation.
Three major theories of matricide are presented and critiqued using epidemiological data, case studies, and descriptive research. The strengths and weaknesses of psychoanalytic theory, family systems theory, and cognitive behaviorism in explaining matricide are described. The social-interaction theory of violence and, in particular, self-affirmation motive is presented as the most helpful perspective for understanding murder of the mother. This review covers those concepts within psychoanalysis, cognitive behaviorism, and family systems theory that have historically been used to understand matricide and is not a critique of modern psychoanalysis, cognitive behaviorism or family systems theory. Matricide occurs in less than 1% of all homicides. Offenders are heterogeneous in their characteristics with at least three different types. Most prominent characteristics across matricide types are severe mental illness, a domineering mother, a hostile-dependent relationship with the mother, a passive or withdrawn father, and over kill behavior. Self-affirmation motive suggests several interventions to prevent violence against the mother or its equivalents. The author makes several conclusions about the nature of human aggression and family dysfunction.