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Abstract Background The incidence of non-communicable diseases (NCDs) is increasing in rural India. The National Family Health Survey-5 (NFHS-5) provides estimates of the burden of NCDs and their risk factors in women aged 15–49 and men aged 15–54 years. The aim of this study is to estimate the prevalence of hypertension and body-mass index (BMI) in adults aged 35–70 years in rural India and to compare these estimates, where age ranges overlap, to routinely available data. Methods The Non-Communicable Disease in Rural India (NCDRI) Study was a cross-sectional household survey of 1005 women and 1025 men aged 35–70 conducted in Bihar in July 2019. Information was collected on personal characteristics, self-reported medical history and physical measurements (blood pressure, height and weight). Prevalence estimates for hypertension (systolic blood pressure ≥ 140 mmHg or diastolic blood pressure ≥ 90 mmHg, or diagnosed and treated for hypertension), and for underweight (body-mass index

Abstract Background Cardiovascular disease accounts for about one-third of all premature deaths (ie, age =120 mmHg), diabetes, and BMI (>=22.5 kg/m2): 20 mmHg higher usual SBP about doubled cardiovascular mortality (RR 2.02, 95%CI 1.88–2.18]), as did diabetes (2.15, 1.95–2.37), and 10 kg/m2 higher usual BMI (1.92, 1.64–2.25). RR were similar in men and in women. The association with BMI and cardiovascular mortality was almost completely attenuated following adjustment for the mediating effect of SBP. Elevated SBP (>=120 mmHg), diabetes and raised BMI (>=22.5 kg/m2) accounted for 27%, 14%, and 16% of cardiovascular deaths, respectively. Conclusions This large prospective study provides direct evidence for the effects of these major risk factors on cardiovascular mortality in Cuba. Despite comparatively low levels of these risk factors by international standards, the strength of their association with cardiovascular death means they nevertheless exert a substantial impact on premature mortality in Cuba.

Background Whether factor V Leiden is associated with lower bleeding risk in patients with acute coronary syndromes using (dual) antiplatelet therapy has yet to be investigated. Methods and Results We pooled data from 3 randomized clinical trials, conducted in patients with acute coronary syndromes, with adjudicated bleeding outcomes. Cox regression models were used to obtain overall and cause‐specific hazard ratios (HRs) to account for competing risk of atherothrombotic outcomes (ie, composite of ischemic stroke, myocardial infarction, and cardiovascular death) in each study. Estimates from the individual studies were pooled using fixed effect meta‐analysis. The 3 studies combined included 17 623 patients of whom 969 (5.5%) were either heterozygous or homozygous (n=23) carriers of factor V Leiden. During 1 year of follow‐up, a total of 1289 (7.3%) patients developed major (n=559) or minor bleeding. Factor V Leiden was associated with a lower risk of combined major and minor bleeding (adjusted cause‐specific HR, 0.75; 95% CI, 0.56–1.00; P=0.046; I2=0%) but a comparable risk of major bleeding (adjusted cause‐specific HR, 0.93; 95% CI, 0.62–1.39; P=0.73; I2=0%). Adjusted pooled cause‐specific HRs for the association of factor V Leiden with atherothrombotic events alone and in combination with bleeding events were 0.75 (95% CI, 0.55–1.02; P=0.06; I2=0%) and 0.75 (95% CI, 0.61–0.92; P=0.007; I2=0%), respectively. Conclusions Given that the lower risk of bleeding conferred by factor V Leiden was not counterbalanced by a higher risk of atherothrombotic events, these findings warrant future assessment for personalized medicine such as selecting patients for extended or intensive antiplatelet therapy.

South Asians (SAs), originating from the Indian subcontinent (India, Pakistan, Sri Lanka, Bangladesh, Nepal, and Bhutan), represent one quarter of the global population and are the largest visible minority in Canada. SAs experience the highest rates of coronary artery disease in Canada. Although conventional cardiovascular risk factors remain predictive in SA, the excess risk is not fully explained by these risk factors alone. Abdominal obesity, metabolic syndrome, and insulin resistance likely contribute a greater risk in SAs than in other populations. The South Asian Heart Alliance has been recently formed to investigate and recommend the best strategies for the prevention of cardiometabolic disease in SAs in Canada. This topic review represents a comprehensive overview of the magnitude of cardiovascular disease in SAs in Canada, with a review of conventional and novel risk markers in the SA population. Both primary and secondary prevention strategies are suggested and when possible, adapted specifically for the SA population. The need for SAs and their healthcare professionals to be more aware of the problem and potential solutions, along with the need for population-specific research, is highlighted. Résumé: Les Asiatiques du sud originaires du sous-continent indien (Inde, Pakistan, Sri Lanka, Bangladesh, Népal et Bhoutan) représentent le quart de la population mondiale et constituent la plus importante minorité visible au Canada. C’est aussi au sein de cette population qu’on observe les taux de coronaropathie les plus élevés au Canada. Bien que les facteurs de risque cardiovasculaire classiques conservent leur valeur prédictive chez les Asiatiques du sud, ils n’expliquent pas à eux seuls le risque excédentaire observé. L’obésité abdominale, le syndrome métabolique et l’insulinorésistance constituent vraisemblablement des facteurs de risque plus importants chez les Asiatiques du sud que dans les autres populations. La South Asian Heart Alliance a récemment été mise sur pied afin d’explorer les stratégies exemplaires pour la prévention des maladies cardiométaboliques chez les Asiatiques du sud au Canada et de formuler des recommandations à cet égard. Cette revue thématique présente un aperçu de l’importance des maladies cardiovasculaires au sein de la population des Asiatiques du sud du Canada, ainsi qu’un résumé des marqueurs de risque classiques et nouveaux dans cette population. Les auteurs proposent des stratégies de prévention primaire et secondaire adaptées, dans la mesure du possible, à la population des Asiatiques du sud. Ils font également ressortir l’importance de sensibiliser davantage les Asiatiques du sud et les professionnels de la santé aux risques et aux solutions possibles, ainsi que la nécessité de mener des recherches axées sur cette population particulière.

[This corrects the article DOI: 10.1371/journal.pmed.1003536.].

Background: The associations of cause-specific mortality with alcohol consumption have been studied mainly in higher-income countries. We relate alcohol consumption to mortality in Cuba. Methods: In 1996-2002, 146 556 adults were recruited into a prospective study from the general population in five areas of Cuba. Participants were interviewed, measured and followed up by electronic linkage to national death registries until January 1, 2017. After excluding all with missing data or chronic disease at recruitment, Cox regression (adjusted for age, sex, province, education, and smoking) was used to relate mortality rate ratios (RRs) at ages 35–79 years to alcohol consumption. RRs were corrected for long-term variability in alcohol consumption using repeat measures among 20 593 participants resurveyed in 2006-08. Findings: After exclusions, there were 120 623 participants aged 35-79 years (mean age 52 [SD 12]; 67 694 [56%] women). At recruitment, 22 670 (43%) men and 9490 (14%) women were current alcohol drinkers, with 15 433 (29%) men and 3054 (5%) women drinking at least weekly; most alcohol consumption was from rum. All-cause mortality was positively and continuously associated with weekly alcohol consumption: each additional 35cl bottle of rum per week (110g of pure alcohol) was associated with ∼10% higher risk of all-cause mortality (RR 1.08 [95%CI 1.05-1.11]). The major causes of excess mortality in weekly drinkers were cancer, vascular disease, and external causes. Non-drinkers had ∼10% higher risk (RR 1.11 [1.09-1.14]) of all-cause mortality than those in the lowest category of weekly alcohol consumption (

BackgroundVitamin D deficiency has been associated with type 1 diabetes in observational studies, but evidence from randomized controlled trials (RCTs) is lacking. The aim of this study was to test whether genetically decreased vitamin D levels are causally associated with type 1 diabetes using Mendelian randomization (MR).Methods and findingsFor our two-sample MR study, we selected as instruments single nucleotide polymorphisms (SNPs) that are strongly associated with 25-hydroxyvitamin D (25OHD) levels in a large vitamin D genome-wide association study (GWAS) on 443,734 Europeans and obtained their corresponding effect estimates on type 1 diabetes risk from a large meta-analysis of 12 type 1 diabetes GWAS studies (Ntot = 24,063, 9,358 cases, and 15,705 controls). In addition to the main analysis using inverse variance weighted MR, we applied 3 additional methods to control for pleiotropy (MR-Egger, weighted median, and mode-based estimate) and compared the respective MR estimates. We also undertook sensitivity analyses excluding SNPs with potential pleiotropic effects. We identified 69 lead independent common SNPs to be genome-wide significant for 25OHD, explaining 3.1% of the variance in 25OHD levels. MR analyses suggested that a 1 standard deviation (SD) decrease in standardized natural log-transformed 25OHD (corresponding to a 29-nmol/l change in 25OHD levels in vitamin D-insufficient individuals) was not associated with an increase in type 1 diabetes risk (inverse-variance weighted (IVW) MR odds ratio (OR) = 1.09, 95% CI: 0.86 to 1.40, p = 0.48). We obtained similar results using the 3 pleiotropy robust MR methods and in sensitivity analyses excluding SNPs associated with serum lipid levels, body composition, blood traits, and type 2 diabetes. Our findings indicate that decreased vitamin D levels did not have a substantial impact on risk of type 1 diabetes in the populations studied. Study limitations include an inability to exclude the existence of smaller associations and a lack of evidence from non-European populations.ConclusionsOur findings suggest that 25OHD levels are unlikely to have a large effect on risk of type 1 diabetes, but larger MR studies or RCTs are needed to investigate small effects.

Observational studies have reported an association between obesity, as measured by elevated body mass index (BMI), in early adulthood and risk of multiple sclerosis (MS). However, bias potentially introduced by confounding and reverse causation may have influenced these findings. Therefore, we elected to perform Mendelian randomization (MR) analyses to evaluate whether genetically increased BMI is associated with an increased risk of MS.Employing a two-sample MR approach, we used summary statistics from the Genetic Investigation of Anthropometric Traits (GIANT) consortium and the International MS Genetics Consortium (IMSGC), the largest genome-wide association studies for BMI and MS, respectively (GIANT: n = 322,105; IMSGC: n = 14,498 cases and 24,091 controls). Seventy single nucleotide polymorphisms (SNPs) were genome-wide significant (p < 5 x 10-8) for BMI in GIANT (n = 322,105) and were investigated for their association with MS risk in the IMSGC. The effect of each SNP on MS was weighted by its effect on BMI, and estimates were pooled to provide a summary measure for the effect of increased BMI upon risk of MS. Our results suggest that increased BMI influences MS susceptibility, where a 1 standard deviation increase in genetically determined BMI (kg/m2) increased odds of MS by 41% (odds ratio [OR]: 1.41, 95% CI 1.20-1.66, p = 2.7 x 10-5, I2 = 0%, 95% CI 0-29). Sensitivity analyses, including MR-Egger regression, and the weighted median approach provided no evidence of pleiotropic effects. The main study limitations are that, while these sensitivity analyses reduce the possibility that pleiotropy influenced our results, residual pleiotropy is difficult to exclude entirely.Genetically elevated BMI is associated with risk of MS, providing evidence for a causal role for obesity in MS etiology. While obesity has been associated with many late-life outcomes, these findings suggest an important consequence of childhood and/or early adulthood obesity.

BackgroundObservational studies have demonstrated an association between decreased vitamin D level and risk of multiple sclerosis (MS); however, it remains unclear whether this relationship is causal. We undertook a Mendelian randomization (MR) study to evaluate whether genetically lowered vitamin D level influences the risk of MS.Methods and findingsWe identified single nucleotide polymorphisms (SNPs) associated with 25-hydroxyvitamin D (25OHD) level from SUNLIGHT, the largest (n = 33,996) genome-wide association study to date for vitamin D. Four SNPs were genome-wide significant for 25OHD level (p-values ranging from 6 × 10-10 to 2 × 10-109), and all four SNPs lay in, or near, genes strongly implicated in separate mechanisms influencing 25OHD. We then ascertained their effect on 25OHD level in 2,347 participants from a population-based cohort, the Canadian Multicentre Osteoporosis Study, and tested the extent to which the 25OHD-decreasing alleles explained variation in 25OHD level. We found that the count of 25OHD-decreasing alleles across these four SNPs was strongly associated with lower 25OHD level (n = 2,347, F-test statistic = 49.7, p = 2.4 × 10-12). Next, we conducted an MR study to describe the effect of genetically lowered 25OHD on the odds of MS in the International Multiple Sclerosis Genetics Consortium study, the largest genetic association study to date for MS (including up to 14,498 cases and 24,091 healthy controls). Alleles were weighted by their relative effect on 25OHD level, and sensitivity analyses were performed to test MR assumptions. MR analyses found that each genetically determined one-standard-deviation decrease in log-transformed 25OHD level conferred a 2.0-fold increase in the odds of MS (95% CI: 1.7-2.5; p = 7.7 × 10-12; I2 = 63%, 95% CI: 0%-88%). This result persisted in sensitivity analyses excluding SNPs possibly influenced by population stratification or pleiotropy (odds ratio [OR] = 1.7, 95% CI: 1.3-2.2; p = 2.3 × 10-5; I2 = 47%, 95% CI: 0%-85%) and including only SNPs involved in 25OHD synthesis or metabolism (ORsynthesis = 2.1, 95% CI: 1.6-2.6, p = 1 × 10-9; ORmetabolism = 1.9, 95% CI: 1.3-2.7, p = 0.002). While these sensitivity analyses decreased the possibility that pleiotropy may have biased the results, residual pleiotropy is difficult to exclude entirely.ConclusionsA genetically lowered 25OHD level is strongly associated with increased susceptibility to MS. Whether vitamin D sufficiency can delay, or prevent, MS onset merits further investigation in long-term randomized controlled trials.

Disease management and epidemiological investigations of porcine reproductive and respiratory syndrome virus-type 2 (PRRSV-2) often rely on grouping together highly related sequences. In the USA, the last five years have seen a major shift within the swine industry when classifying PRRSV-2, beginning to move away from RFLP (restriction fragment length polymorphisms)-typing and adopting the use of phylogenetic lineage-based classification. However, lineages and sub-lineages are large and genetically diverse, making them insufficient for identifying new and emerging variants. Thus, within the lineage system, a dynamic fine-scale classification scheme is needed to provide better resolution on the relatedness of PRRSV-2 viruses to inform disease management and monitoring efforts and facilitate research and communication surrounding circulating PRRSV viruses. Here, we compare fine-scale systems for classifying PRRSV-2 variants (i.e., genetic clusters of closely related ORF5 sequences at finer scales than sub-lineage) using a database of 28,730 sequences from 2010 to 2021, representing >55% of the U.S. pig population. In total, we compared 140 approaches that differed in their tree-building method, criteria, and thresholds for defining variants within phylogenetic trees. Three approaches resulted in variant classifications that were reproducible and robust even when the input data or input phylogenies were changed. For these approaches, the average genetic distance among sequences belonging to the same variant was 2.1–2.5%, and the genetic divergence between variants was 2.5–2.7%. Machine learning classification algorithms were trained to assign new sequences to an existing variant with >95% accuracy, which shows that newly generated sequences can be assigned to a variant without repeating the phylogenetic and clustering analyses. Finally, we identified 73 sequence-clusters (dated

Abstract Stained glass windows are a precious heritage to pass on to future generations. However, medieval stained glass windows are particularly altered due to their chemical composition and the effects of climatic (mainly water and temperature), environmental (pollution) and biological factors. In this review, we present the alteration patterns observed on ancient Si-K-Ca stained glass windows. To better understand their formation mechanisms and determine the alteration rates, different exposure campaigns to the current atmosphere in a position sheltered from rain or not and laboratory experiments in aqueous medium or in gaseous phase have been conducted. Either model glass or ancient stained glass windows were studied. Isotopic tracers (D, 18O, 29Si) have been used as they constitute a powerful tool to elucidate the involved processes and to measure their kinetics. Thanks to all of these data, an alteration scenario of medieval stained glass alteration is proposed. Besides, the extrapolation of kinetic data based on several hypotheses over seven centuries gives very consistent results compared to the ancient stained glass samples.

Since 2020, the world has faced two unprecedented shocks: lockdowns (regulation) and the invasion of Ukraine (war). Although we realise the health and economic effects of these shocks, more research is needed on the effect on happiness and whether the type of shock plays a role. Therefore, in this paper, we determine whether these macro-level shocks affected happiness, how these effects differ, and how long it takes for happiness to adapt to previous levels. The latter will allow us to test whether adaptation theory holds at the macro level. We use a unique dataset of ten countries spanning the Northern and Southern hemispheres derived from tweets extracted in real-time per country. Applying Natural Language Processing, we obtain these tweets' underlying sentiment scores, after which we calculate a happiness score (Gross National Happiness) and derive daily time series data. Our Twitter dataset is combined with Oxford's COVID-19 Government Response Tracker data. Considering the results of the Difference-in-Differences and event studies jointly, we are confident that the shocks led to lower happiness levels, both with the lockdown and the invasion shock. We find that the effect size is significant and that the lockdown shock had a bigger effect than the invasion. Considering both types of shocks, the adaptation to previous happiness levels occurred within two to three weeks. Following our findings of similar behaviour in happiness to both types of shocks, the question of whether other types of shocks will have similar effects is posited. Regardless of the length of the adaptation period, understanding the effects of macro-level shocks on happiness is essential for policymakers, as happiness has a spillover effect on other variables such as production, safety and trust.

Abstract This work aims to investigate the role played by a model Mn-oxidizing bacterial strain and its exudates on the alteration of Mn-bearing potash-lime silicate glasses representative of medieval stained glass windows. Two model glasses, with or without manganese, were prepared and used for abiotic and Pseudomonas putida inoculated dissolution experiments. Results show that the presence of P. putida slows down the dissolution kinetics while changing the dissolution stoichiometry. In biotic experiments, the acidification of the solution at the beginning of the experiment favors the release of K. After a few days, a drop in Mn and P in solution is observed, retained by bacterial cells. Reciprocally, the amount of glass influences bacterial behavior. The more glass, the faster the bacterial population increases in size and produces siderophore. In the presence of the Mn-bearing glass, siderophore production is followed by the formation of brown phases, identified as Mn oxides.

Heat stress-induced or stress-accelerated leaf senescence is related to the accumulation of ethylene and loss of chlorophyll in cool-season grass species. The objective of this study was to determine whether foliar-spraying the ethylene inhibitor, aminoethoxyvinylglycine (AVG), may suppress heat-induced leaf senescence through effects on chlorophyll synthesis and degrading enzymes in creeping bentgrass (Agrostis stolonifera). Plants were maintained in environmentally controlled growth chambers under non-stress (22/17 °C day/night) or heat stress (35/30 °C day/night) temperature conditions for 25 days, and turf quality, electrolyte leakage, and chlorophyll content were measured to assess the extent of leaf senescence. Activities of chlorophyll-synthesizing and chlorophyll-degrading enzymes were quantified to determine whether AVG may regulate chlorophyll metabolism. Plants were foliar-sprayed with 25 µm AVG before and during heat stress at 7-day intervals. From 21 through 25 days of heat stress, AVG-treated plants had significantly higher turf quality and chlorophyll content, whereas electrolyte leakage was significantly lower in comparison with untreated controls. The activity of a chlorophyll-synthesizing enzyme, porphobilinogen deaminase, was significantly increased in AVG-treated plants at 21 days of heat stress. The activity of chlorophyll-degrading enzymes was significantly lower in plants treated with AVG from 14 through 25 days of heat stress for peroxidase, from 21 through 25 days of heat stress for pheophytinase, and at 25 days of heat stress for chlorophyllase. AVG may have suppressed heat-induced leaf senescence by regulating chlorophyll metabolic activities in cool-season grass species.

Abstract Intelligent manipulation of handheld tools marks a major discontinuity between humans and our closest ancestors. Here we identified neural representations about how tools are typically manipulated within left anterior temporal cortex, by shifting a searchlight classifier through whole-brain real action fMRI data when participants grasped 3D-printed tools in ways considered typical for use (i.e., by their handle). These neural representations were automatically evocated as task performance did not require semantic processing. In fact, findings from a behavioural motion-capture experiment confirmed that actions with tools (relative to non-tool) incurred additional processing costs, as would be suspected if semantic areas are being automatically engaged. These results substantiate theories of semantic cognition that claim the anterior temporal cortex combines sensorimotor and semantic content for advanced behaviours like tool manipulation.

Abstract Many disciplines are facing a “reproducibility crisis”, which has precipitated much discussion about how to improve research integrity, reproducibility, and transparency. A unified effort across all sectors, levels, and stages of the research ecosystem is needed to coordinate goals and reforms that focus on open and transparent research practices. Promoting a more positive incentive culture for all ecosystem members is also paramount. In this commentary, we—the Local Network Leads of the UK Reproducibility Network—outline our response to the UK House of Commons Science and Technology Committee’s inquiry on research integrity and reproducibility. We argue that coordinated change is needed to create (1) a positive research culture, (2) a unified stance on improving research quality, (3) common foundations for open and transparent research practice, and (4) the routinisation of this practice. For each of these areas, we outline the roles that individuals, institutions, funders, publishers, and Government can play in shaping the research ecosystem. Working together, these constituent members must also partner with sectoral and coordinating organisations to produce effective and long-lasting reforms that are fit-for-purpose and future-proof. These efforts will strengthen research quality and create research capable of generating far-reaching applications with a sustained impact on society.

We use daily happiness scores (Gross National Happiness (GNH)) to illustrate how happiness changed throughout 2020 in ten countries across Europe and the Southern hemisphere. More frequently and regularly available than survey data, the GNH reveals how happiness sharply declined at the onset of the pandemic and lockdown, quickly recovered, and then trended downward throughout much of the year in Europe. GNH is derived by applying sentiment and emotion analysis-based on Natural Language Processing using machine learning algorithms-to Twitter posts (tweets). Using a similar approach, we generate another 11 variables: eight emotions and three new context-specific variables, in particular: trust in national institutions, sadness in relation to loneliness, and fear concerning the economy. Given the novelty of the dataset, we use multiple methods to assess validity. We also assess the correlates of GNH. The results indicate that GNH is negatively correlated with new COVID-19 cases, containment policies, and disgust and positively correlated with staying at home, surprise, and generalised trust. Altogether the analyses indicate tools based on Big Data, such as the GNH, offer relevant data that often fill information gaps and can valuably supplement traditional tools. In this case, the GNH results suggest that both the severity of the pandemic and containment policies negatively correlated with happiness.

Heat stress symptoms in cool-season plants are characterized by loss of chlorophyll (Chl) and membrane stability, as well as oxidative damage. The objectives of this study were to determine whether foliar application of β-sitosterol, a naturally occurring plant metabolite, may promote heat tolerance by suppressing heat-induced leaf senescence as indicated by the maintenance of healthy turf quality (TQ), and Chl and membrane stability; and to determine its roles in regulating antioxidant metabolism in creeping bentgrass (Agrostis stolonifera). ‘Penncross’ plants were exposed to heat stress (35/30 °C day/night) optimal temperature conditions (nonstressed control, 22/17 °C day/night) for a duration of 28 days in environment-controlled growth chambers. Plants were foliar-treated with β-sitosterol (400 µM) or water only (untreated control) before heat stress, and at 7-day intervals through 28 days of heat stress. Plants treated with β-sitosterol had significantly greater TQ and Chl content, and significantly less electrolyte leakage (EL) than untreated controls at 21 and 28 days of heat stress. Application of β-sitosterol reduced malondialdehyde (MDA) content significantly at 21 and 28 days of heat stress, and promoted the activities of superoxide dismutase (SOD), peroxidase (POD), catalase (CAT), and ascorbate peroxidase (APX) from 14 through 28 days of heat stress. β-Sitosterol effectively improved heat tolerance through suppression of leaf senescence in creeping bentgrass exposed to heat stress in association with the alleviation of membrane lipid peroxidation and activation of the enzymatic antioxidant system.

Effects of amino acids and nitrogen on plant regrowth or recovery from drought stress remain largely unknown. The objectives of this study were to examine how gamma-aminobutyric acid (GABA) or proline, alone and in combination, or inorganic nitrogen [ammonium nitrate (NN)] may differentially affect turf performance during drought stress and rewatering, and to determine which specific endogenous amino acids regulated by GABA, proline, or NN priming were associated with plant tolerance to drought stress and postdrought recuperation in cool-season grass species. Creeping bentgrass (Agrostis stolonifera cv. Penncross) planted in porous ceramic fritted clay medium were exposed to well-watered conditions or drought stress by withholding irrigation for 21 days in growth chambers. Plants were treated with water (untreated control), GABA, or proline alone and in combination, or NN through foliar spray before drought stress and every 7 days during the 21-day stress period. For postdrought recovery, at 21 days of drought treatment, plants were rewatered for 14 days to return soil water content to prestress levels. Plants treated with GABA or proline alone or in combination maintained higher turf quality (TQ), dark green color index (DGCI), and stolon length by 21 days of drought stress, whereas proline-treated plants also maintained higher leaf relative water content (RWC) during drought as well as longer stolon length during rewatering. Plants treated with NN maintained higher TQ and leaf RWC during drought and had improved percent canopy cover, DGCI, and stolon length during postdrought rewatering. Accumulation of endogenous amino acids under drought stress, including proline and alanine, for proline-treated creeping bentgrass may have contributed to the enhancement of drought tolerance and postdrought regrowth. Nitrogen-enhanced accumulation of GABA, proline, and glutamic acid may have played a role in active amino acid assimilation and subsequent postdrought regrowth. Results from this study indicate that GABA or proline were mainly effective in promoting the tolerance of creeping bentgrass to drought stress while inorganic NN was effective in promoting rapid postdrought recovery and regrowth potential through the activation of amino acid metabolism. Endogenous amino acids, including GABA, proline, alanine, and glutamic acid, may be used as biomarkers to select for drought-tolerant plants and biostimulant components for improvement of drought stress tolerance and poststress recovery in cool-season turfgrass species.

Abstract Background There is limited information on the distribution of virulence-associated genes (VAGs) in U.S. Streptococcus suis isolates, resulting in little understanding of the pathogenic potential of these isolates. This lack also reduces our understanding of the epidemiology associated with S. suis in the United States and thus affects the efficiency of control and prevention strategies. In this study we applied whole genome sequencing (WGS)-based approaches for the characterization of S. suis and identification of VAGs. Results Of 208 S. suis isolates classified as pathogenic, possibly opportunistic, and commensal pathotypes, the genotype based on the classical VAGs (epf, mrp, and sly encoding the extracellular protein factor, muramidase-release protein, and suilysin, respectively) was identified in 9% (epf+/mrp+/sly+) of the pathogenic pathotype. Using the chi-square test and LASSO regression model, the VAGs ofs (encoding the serum opacity factor) and srtF (encoding sortase F) were selected out of 71 published VAGs as having a significant association with pathotype, and both genes were found in 95% of the pathogenic pathotype. The ofs+/srtF+ genotype was also present in 74% of ‘pathogenic’ isolates from a separate validation set of isolates. Pan-genome clustering resulted in the differentiation of a group of isolates from five swine production companies into clusters corresponding to clonal complex (CC) and virulence-associated (VA) genotypes. The same CC-VA genotype patterns were identified in multiple production companies, suggesting a lack of association between production company, CC, or VA genotype. Conclusions The proposed ofs and srtF genes were stronger predictors for differentiating pathogenic and commensal S. suis isolates compared to the classical VAGs in two sets of U.S. isolates. Pan-genome analysis in combination with metadata (serotype, ST/CC, VA genotype) was illustrated to be a valuable subtyping tool to describe the genetic diversity of S. suis.

Heat-induced leaf senescence has been associated with stress-induced oxidative damage. The major objective of this study was to determine whether exogenous application of β-carotene may improve heat tolerance in creeping bentgrass (Agrostis stolonifera cv. Penncross) by suppressing leaf senescence and activating antioxidant metabolism. Plants were subjected to heat stress at 35/30 °C (day/night) or at the optimal temperature of 22/18 °C (day/night), and were treated with either β-carotene (1 mm) or water (untreated control) by foliar spraying every 7 days for 28 days in controlled-environment growth chambers. β-Carotene application suppressed heat-induced leaf senescence, as demonstrated by an increase in turf quality (TQ) and leaf chlorophyll content as well as a reduction in electrolyte leakage (EL). β-Carotene-treated plants had a significantly lower malondialdehyde (MDA) content and significantly greater activity of antioxidant enzymes, including superoxide dismutase (SOD), peroxidase (POD), and catalase (CAT) from 14 through 28 days of heat stress, and ascorbate peroxidase (APX) activity from 21 through 28 days of heat stress. These findings suggest that β-carotene may promote heat tolerance by enhancing antioxidant activity to suppress leaf senescence.

COVID-19 severely impacted world health and, as a consequence of the measures implemented to stop the spread of the virus, also irreversibly damaged the world economy. Research shows that receiving the COVID-19 vaccine is the most successful measure to combat the virus and could also address its indirect consequences. However, vaccine hesitancy is growing worldwide and the WHO names this hesitancy as one of the top ten threats to global health. This study investigates the trend in positive attitudes towards vaccines across ten countries since a positive attitude is important. Furthermore, we investigate those variables related to having a positive attitude, as these factors could potentially increase the uptake of vaccines. We derive our text corpus from vaccine-related tweets, harvested in real-time from Twitter. Using Natural Language Processing (NLP), we derive the sentiment and emotions contained in the tweets to construct daily time-series data. We analyse a panel dataset spanning both the Northern and Southern hemispheres from 1 February 2021 to 31 July 2021. To determine the relationship between several variables and the positive sentiment (attitude) towards vaccines, we run various models, including POLS, Panel Fixed Effects and Instrumental Variables estimations. Our results show that more information about vaccines’ safety and the expected side effects are needed to increase positive attitudes towards vaccines. Additionally, government procurement and the vaccine rollout should improve. Accessibility to the vaccine should be a priority, and a collective effort should be made to increase positive messaging about the vaccine, especially on social media. The results of this study contribute to the understanding of the emotional challenges associated with vaccine uptake and inform policymakers, health workers, and stakeholders who communicate to the public during infectious disease outbreaks. Additionally, the global fight against COVID-19 might be lost if the attitude towards vaccines is not improved.

Abstract Background Cholangiocarcinoma is a rapidly fatal cancer entity with a median survival of less than one year. In contrast to many other malignancies, no substantial therapeutic breakthrough has been made in the past few decades, thereby limiting the treatment to cytotoxic chemotherapy with little beneficial effect for most patients. Targeted therapy tailored to the individual has shown substantial success in the recent past as a promising avenue for cancer therapy. Methods In this study, we determined the frequency of amplification of the HER2 gene in a comprehensive and well-characterized European cholangiocarcinoma cohort encompassing 436 patients including intrahepatic (n = 155), proximal (n = 155) and distal (n = 126) cholangiocarcinoma by strict application of a combined immunohistochemical and in situ hybridization algorithm following the current guidelines for HER2 assessment in gastric cancer. Results We identified a proportion of 1.4% (n = 6) patients that demonstrated HER2 gene amplification, with the highest rate among the distal cholangiocarcinoma patients (2.4%). None of the patients with equivocal (2+) immunohistochemical staining results exhibited gene amplification molecularly. In four of the five patients with HER2 positivity, gene amplification was already present in concomitantly tested high-grade biliary intraepithelial neoplasia (80%). HER2 gene amplification was not significantly associated with other clinical parameters, including survival. Conclusions This study identifies HER2 gene amplification as a rare event in cholangiocarcinoma of the Western population, occurring already in high-grade BilIN in a subset of patients. Furthermore, we provide a robust testing algorithm that may be used prior to therapy administration in future clinical trials evaluating the role of HER2 as a predictive marker in cholangiocarcinoma.

Background: Amid the rapid global spread of the coronavirus disease 2019 (COVID-19), many governments enforced country-wide lockdowns, likely with severe well-being consequences. The actions by governments triggered a debate on whether the costs of a lockdown, economically and in well-being, surpass the benefits perceived from a lower infection rate. Aim: To use the Gross National Happiness index (GNH), derived from Big Data, to investigate the determinants of happiness before and during the first few months of a lockdown in a country as an extreme case, South Africa (a country with low levels of well-being and stringent lockdown regulations). Next, to estimate (1) the probability of being happy during a pandemic year, before and after the implemented lockdown, relative to the mean happiness levels of the previous year, and (2) to utilise simulations to estimate the probability of being happy if there were no lockdown. Setting: This study considers the effect of government-mandated lockdown on happiness in South Africa. Methods: We use Big Data in the forms of Twitter and Google Trends to derive variables and ordinary least squares and ordered probit estimation methods. Results: What contributes to happiness under lockdown, except for COVID-19 cases, are the factors linked to the implemented regulations themselves. If we compare scenarios pre- and post-lockdown, we report a happiness cost of 9%. The simulations indicate that assuming there were no lockdown in 2020, the relative well-being gain is 3%. Conclusion: If policymakers want to increase happiness levels and the probability of achieving the same happiness levels as in 2019, they should consider factors related to the regulations that can increase happiness levels.

Happiness levels often fluctuate from one day to the next, and an exogenous shock such as a pandemic can likely disrupt pre-existing happiness dynamics. This paper fits a Marko Switching Dynamic Regression Model (MSDR) to better understand the dynamic patterns of happiness levels before and during a pandemic. The estimated parameters from the MSDR model include each state's mean and duration, volatility and transition probabilities. Once these parameters have been estimated, we use the one-step method to predict the unobserved states' evolution over time. This gives us unique insights into the evolution of happiness. Furthermore, as maximising happiness is a policy priority, we determine the factors that can contribute to the probability of increasing happiness levels. We empirically test these models using New Zealand's daily happiness data for May 2019 -November 2020. The results show that New Zealand seems to have two regimes, an unhappy and happy regime. In 2019 the happy regime dominated; thus, the probability of being unhappy in the next time period (day) occurred less frequently, whereas the opposite is true for 2020. The higher frequency of time periods with a probability of being unhappy in 2020 mostly correspond to pandemic events. Lastly, we find the factors positively and significantly related to the probability of being happy after lockdown to be jobseeker support payments and international travel. On the other hand, lack of mobility is significantly and negatively related to the probability of being happy.

Amidst the rapid global spread of Covid-19, many governments enforced country-wide lockdowns, with likely severe well-being consequences. In this regard, South Africa is an extreme case suffering from low levels of well-being, but at the same time enforcing very strict lockdown regulations. In this study, we analyse the causal effect of a lockdown and consequently, the determinants of happiness during the aforementioned. A difference-in-difference approach is used to make causal inferences on the lockdown effect on happiness, and an OLS estimation investigates the determinants of happiness after lockdown. The results show that the lockdown had a significant and negative impact on happiness. In analysing the determinants of happiness after lockdown, we found that stay-at-home orders have positively impacted happiness during this period. On the other hand, other lockdown regulations such as a ban on alcohol sales, a fear of becoming unemployed and a greater reliance on social media have negative effects, culminating in a net loss in happiness. Interestingly, Covid-19, proxied by new deaths per day, had an inverted U-shape relationship with happiness. Seemingly people were, at the onset of Covid-19 positive and optimistic about the low fatality rates and the high recovery rates. However, as the pandemic progressed, they became more concerned, and this relationship changed and became negative, with peoples' happiness decreasing as the number of new deaths increased.

Introduction Recent evidence has implicated the precuneus of the medial parietal lobe as one of the first brain areas to show pathological changes in Alzheimer’s disease (AD). Damage to the precuneus through focal brain injury is associated with impaired visually guided reaching, particularly for objects in peripheral vision. This raises the hypothesis that peripheral misreaching may be detectable in patients with prodromal AD. The aim of this study is to assess the frequency and severity of peripheral misreaching in patients with mild cognitive impairment (MCI) and AD.Methods and analysis Patients presenting with amnestic MCI, mild-to-moderate AD and healthy older-adult controls will be tested (target N=24 per group). Peripheral misreaching will be assessed using two set-ups: a tablet-based task of lateral reaching and motion-tracked radial reaching (in depth). There are two versions of each task, one where participants can look directly at targets (free reaching), another wheren they must maintain central fixation (peripheral reaching). All tasks will be conducted first on their dominant, and then their non-dominant side. For each combination of task and side, a Peripheral Misreaching Index (PMI) will be calculated as the increase in absolute reaching error between free and peripheral reaching. Each patient will be classified as showing peripheral misreaching if their PMI is significantly abnormal, by comparison to control performance, on either side of space. We will then test whether the frequency of peripheral misreaching exceeds the chance level in each patient group and compare the overall severity of misreaching between groups.Ethics and dissemination Ethical approval was provided by the National Health Service (NHS) East of England, Cambridge Central Research Ethics Committee (REC 19/EE/0170). The results of this study will be published in a peer-reviewed journal and presented at academic conferences.

Auditory distance perception and its neuronal mechanisms are poorly understood, mainly because 1) it is difficult to separate distance processing from intensity processing, 2) multiple intensity-independent distance cues are often available, and 3) the cues are combined in a context-dependent way. A recent fMRI study identified human auditory cortical area representing intensity-independent distance for sources presented along the interaural axis (Kopco et al. PNAS, 109, 11019-11024). For these sources, two intensity-independent cues are available, interaural level difference (ILD) and direct-to-reverberant energy ratio (DRR). Thus, the observed activations may have been contributed by not only distance-related, but also direction-encoding neuron populations sensitive to ILD. Here, the paradigm from the previous study was used to examine DRR-based distance representation for sounds originating in front of the listener, where ILD is not available. In a virtual environment, we performed behavioral and fMRI experiments, combined with computational analyses to identify the neural representation of distance based on DRR. The stimuli varied in distance (15–100 ​cm) while their received intensity was varied randomly and independently of distance. Behavioral performance showed that intensity-independent distance discrimination is accurate for frontal stimuli, even though it is worse than for lateral stimuli. fMRI activations for sounds varying in frontal distance, as compared to varying only in intensity, increased bilaterally in the posterior banks of Heschl’s gyri, the planum temporale, and posterior superior temporal gyrus regions. Taken together, these results suggest that posterior human auditory cortex areas contain neuron populations that are sensitive to distance independent of intensity and of binaural cues relevant for directional hearing.

Aspartate is the most critical amino acid in the aspartate metabolic pathway, which is associated with multiple metabolic pathways, such as protein synthesis, nucleotide metabolism, TCA cycle, glycolysis, and hormone biosynthesis. Aspartate also plays an important role in plant resistance to abiotic stress, such as cold stress, drought stress, salt stress or heavy metal stress. This study found that the chlorophyll content and antioxidant active enzyme content (SOD, CAT, POD and APX) of perennial ryegrass treated with 2 mM aspartate were significantly higher than those treated with water under heat stress. The electrolyte leakage rate, MDA content and peroxide levels (O2− and H2O2) of perennial ryegrass treated with aspartate were significantly lower than those of perennial ryegrass treated with water, indicating that exogenous aspartate increases the content of chlorophyll, maintain the integrity of cell membrane system, and enhances SOD-CAT antioxidant pathway to eliminate the oxidative damage caused by ROS in perennial ryegrass under heat stress. Furthermore, exogenous aspartate could enhance the TCA cycle, the metabolism of the amino acids related to the TCA cycle, and pyrimidine metabolism to enhance the heat tolerance of perennial ryegrass.

Abstract Background The study highlights the shedding pattern of Senecavirus A (SVA) during an outbreak of vesicular disease in a sow farm from the South-central Minnesota, USA. In this study, 34 individual, mixed parity sows with clinical signs of vesicular lesions and 30 individual piglets from 15 individual litters from sows with vesicular lesions were conveniently selected for individual, longitudinal sampling. Serum, tonsil, rectal, and vesicular swabs were collected on day1 post outbreak, and then again at 1, 2, 3, 4, 6, and 9 weeks post outbreak. Samples were tested at the University of Minnesota Veterinary Diagnostic Laboratory for SVA via Real Time Polymerase Chain Reaction (RT-PCR) Results In sows, vesicular lesions had the highest concentration of SVA, but had the shortest duration of detection lasting only 2 weeks. Viremia was detected for 1 week post outbreak, and quickly declined thereafter. SVA was detected at approximately the same frequency for both tonsil and rectal swabs with the highest percentage of SVA positive samples detected in the first 6 weeks post outbreak. In suckling piglets, viremia quickly declined 1 week post outbreak and was prevalent in low levels during the first week after weaning (4 weeks post outbreak) and was also detected in piglets that were co-mingled from a SVA negative sow farm. Similar to sows, SVA detection on rectal and tonsil swabs in piglets lasted approximately 6 weeks post outbreak. Conclusion The study illustrates the variation of SVA shedding patterns in different sample types over a 9 week period in sows and piglets, and suggests the potential for viral spread between piglets at weaning.

Next generation sequencing (NGS) can be applied to identify and characterize the entire set of microbes within a sample. However, this platform does not provide a morphological context or specific association between the viral or bacterial sequences detected and the histological lesions. This limitation has generated uncertainty whether the sequences identified by NGS are actually contributing or not for the clinical outcome. Although in situ hybridization (ISH) and immunohistochemistry (IHC) can be used to detect pathogens in tissue samples, only ISH has the advantage of being rapidly developed in a context of an emerging disease, especially because it does not require development of specific primary antibodies against the target pathogen. Based on the sequence information provided by NGS, ISH is able to check the presence of a certain pathogen within histological lesions, by targeting its specific messenger RNA, helping to build the relationship between the pathogen and the clinical outcome. In this mini review we have compiled results of the application of NGS-ISH to the investigation of challenging diagnostic cases or emerging pathogens in pigs, that resulted in the detection of porcine circovirus type 3, porcine parvovirus type 2, Senecavirus A, and Mycoplasma hyorhinis.

Background: Since the early 1980s, many governments have investigated the possibility of utilising access to microloans as a pathway to grow economies out of unemployment and thereby improve people’s quality of life. Studies that have previously investigated the impact of microloans found a positive effect on quality of life. Unfortunately, these mainly measure quality of life using monetary (income) measures rather than assessing the entire multidimensionality of quality of life. Aim: This article investigates the relationship between objective multidimensional income-independent quality of life (IIQoL) and having access to micro- and informal loans (M&ILs). Specifically, we focus on South Africa’s most marginalised – ‘poor females’ and ‘poor females residing in rural areas’ – as their empowerment is a critical social objective aligned to that of international agencies. Setting: This study investigates the relationship between IIQoL and access to M&ILs in South Africa. Methods: We use a panel data set spanning four waves from 2008 to 2015 of the National Income Dynamics Survey. Principal component analysis is used to construct the IIQoL index and various panel and survey estimation techniques are applied in the regression analyses. Results: M&ILs are significant and negatively related to IIQoL for both ‘poor females’ and ‘poor females residing in rural areas’. This implies that those with loans failed to translate those monetary gains into higher levels of IIQoL over time. Conclusion: Access to M&ILs is not succeeding in raising the quality of life of South Africa’s most marginalised groups. Without intervention and education programmes imbedded within microloan initiatives, the marginalised will not experience an increase in their non-income quality of life.

Facial expressions of emotion are signals of high biological value. Whilst recognition of facial expressions has been much studied in central vision, the ability to perceive these signals in peripheral vision has only seen limited research to date, despite the potential adaptive advantages of such perception. In the present experiment, we investigate facial expression recognition and detection performance for each of the basic emotions (plus neutral) at up to 30 degrees of eccentricity. We demonstrate, as expected, a decrease in recognition and detection performance with increasing eccentricity, with happiness and surprised being the best recognized expressions in peripheral vision. In detection however, while happiness and surprised are still well detected, fear is also a well detected expression. We show that fear is a better detected than recognized expression. Our results demonstrate that task constraints shape the perception of expression in peripheral vision and provide novel evidence that detection and recognition rely on partially separate underlying mechanisms, with the latter more dependent on the higher spatial frequency content of the face stimulus.

Background: The authors of this article ‘Measuring the vulnerability of sub-national regions in South Africa’ (Naudé, McGillivray and Rossouw 2009b) present an exploration into economic vulnerability from a sub-national perspective. It is an important contribution because it recognises the heterogeneous nature of vulnerability across areas within a country, but its analysis is aspatial because it does not explicitly account for the relative location of or the potential for spillovers between areas. Aim: This article aims to provide a purely methodological contribution towards the debate surrounding the measurement of multidimensional vulnerability by: (1) augmenting Naudé et al. (2009b)’s model to take account of spatial contiguity, (2) comparing spatial and aspatial local vulnerability indices estimates to illustrate the presence and importance of spatial spillovers between contiguous areas and (3) extending their methodology on the Vulnerability Intervention Index to present results which highlight areas that are performing better and worse than expected. Methods: Principal components analysis, queen-contiguity weight matrix and local indication of spatial association (LISA) maps were utilised. Results: Application of the methodological extensions to South African Magisterial District data illustrates the presence and importance of spatial spillovers in shaping local vulnerability. Conclusions: Our results illustrate a clear urban–rural vulnerability divide and the need for appropriate policy. It is argued that account of spatial spillovers is an important issue if full and accurate vulnerability indices are to be identified.

Osteoblasts lining the inner surface of bone support hematopoietic stem cell differentiation by virtue of proximity to the bone marrow. The osteoblasts also modify their own differentiation by producing various isoforms of fibronectin (FN). Despite evidence for immune regulation by osteoblasts, there is limited knowledge of how osteoblasts modulate cells of the immune system. Here, we show that extra domain A (EDA)-FN produced by osteoblasts increases arginase production in myeloid-derived cells, and we identify α5β1 as the mediating receptor. In different mouse models of cancer, osteoblasts or EDA-FN was found to up-regulate arginase-1 expression in myeloid-derived cells, resulting in increased cancer growth. This harmful effect can be reduced by interfering with the integrin α5β1 receptor or inhibiting arginase. Conversely, in tissue injury, the expression of arginase-1 is normally beneficial as it dampens the immune response to allow wound healing. We show that EDA-FN protects against excessive fibrotic tissue formation in a liver fibrosis model. Our results establish an immune regulatory function for EDA-FN originating from the osteoblasts and identify new avenues for enhancing the immune reaction against cancer.

Rotaviruses (RV) are important causes of diarrhea in animals, especially in domestic animals. Of the 9 RV species, rotavirus A, B, and C (RVA, RVB, and RVC, respectively) had been established as important causes of diarrhea in pigs. The Minnesota Veterinary Diagnostic Laboratory receives swine stool samples from North America to determine the etiologic agents of disease. Between November 2009 and October 2011, 7,508 samples from pigs with diarrhea were submitted to determine if enteric pathogens, including RV, were present in the samples. All samples were tested for RVA, RVB, and RVC by real time RT-PCR. The majority of the samples (82%) were positive for RVA, RVB, and/or RVC. To better understand the risk factors associated with RV infections in swine diagnostic samples, three-level mixed-effects logistic regression models (3L-MLMs) were used to estimate associations among RV species, age, and geographical variability within the major swine production regions in North America. The conditional odds ratios (cORs) for RVA and RVB detection were lower for 1-3 day old pigs when compared to any other age group. However, the cOR of RVC detection in 1-3 day old pigs was significantly higher (p < 0.001) than pigs in the 4-20 days old and >55 day old age groups. Furthermore, pigs in the 21-55 day old age group had statistically higher cORs of RV co-detection compared to 1-3 day old pigs (p < 0.001). The 3L-MLMs indicated that RV status was more similar within states than among states or within each region. Our results indicated that 3L-MLMs are a powerful and adaptable tool to handle and analyze large-hierarchical datasets. In addition, our results indicated that, overall, swine RV epidemiology is complex, and RV species are associated with different age groups and vary by regions in North America.

Oligogalacturonides (OGs) are known for their powerful ability to stimulate the plant immune system but little is known about their mode of action in pea (Pisum sativum). In the present study, we investigated the elicitor activity of two fractions of OGs, with polymerization degrees (DPs) of 2–25, in pea against Aphanomyces euteiches. One fraction was nonacetylated (OGs − Ac) whereas the second one was 30% acetylated (OGs + Ac). OGs were applied by injecting the upper two rachises of the plants at three- and/or four-weeks-old. Five-week-old roots were inoculated with 105 zoospores of A. euteiches. The root infection level was determined at 7, 10 and 14 days after inoculation using the quantitative real-time polymerase chain reaction (qPCR). Results showed significant root infection reductions namely 58, 45 and 48% in the plants treated with 80 µg OGs + Ac and 59, 56 and 65% with 200 µg of OGs − Ac. Gene expression results showed the upregulation of genes involved in the antifungal defensins, lignans and the phytoalexin pisatin pathways and a priming effect in the basal defense, SA and ROS gene markers as a response to OGs. The reduction of the efficient dose in OGs + Ac is suggesting that acetylation is necessary for some specific responses. Our work provides the first evidence for the potential of OGs in the defense induction in pea against Aphanomyces root rot.

When multiple persons speak simultaneously, it may be difficult for the listener to direct attention to correct sound objects among conflicting ones. This could occur, for example, in an emergency situation in which one hears conflicting instructions and the loudest, instead of the wisest, voice prevails. Here, we used cortically-constrained oscillatory MEG/EEG estimates to examine how different brain regions, including caudal anterior cingulate (cACC) and dorsolateral prefrontal cortices (DLPFC), work together to resolve these kinds of auditory conflicts. During an auditory flanker interference task, subjects were presented with sound patterns consisting of three different voices, from three different directions (45° left, straight ahead, 45° right), sounding out either the letters "A" or "O". They were asked to discriminate which sound was presented centrally and ignore the flanking distracters that were phonetically either congruent (50%) or incongruent (50%) with the target. Our cortical MEG/EEG oscillatory estimates demonstrated a direct relationship between performance and brain activity, showing that efficient conflict resolution, as measured with reduced conflict-induced RT lags, is predicted by theta/alpha phase coupling between cACC and right lateral frontal cortex regions intersecting the right frontal eye fields (FEF) and DLPFC, as well as by increased pre-stimulus gamma (60-110 Hz) power in the left inferior fontal cortex. Notably, cACC connectivity patterns that correlated with behavioral conflict-resolution measures were found during both the pre-stimulus and the pre-response periods. Our data provide evidence that, instead of being only transiently activated upon conflict detection, cACC is involved in sustained engagement of attentional resources required for effective sound object selection performance.

Cancer is associated with increased fracture risk, due either to metastasis or associated osteoporosis. After a fracture, blood clots form. Because proteins of the coagulation cascade and activated platelets promote cancer development, a fracture in patients with cancer often raises the question whether it is a pathologic fracture or whether the fracture itself might promote the formation of metastatic lesions. We therefore examined whether blood clot formation results in increased metastasis in a murine model of experimental breast cancer metastasis. For this purpose, a clot was surgically induced in the bone marrow of the left tibia of immundeficient mice. Either one minute prior to or five minutes after clot induction, human cancer cells were introduced in the circulation by intracardiac injection. The number of cancer cells that homed to the intervention site was determined by quantitative real-time PCR and flow cytometry. Metastasis formation and longitudinal growth were evaluated by bioluminescence imaging. The number of cancer cells that homed to the intervention site after 24 hours was similar to the number of cells in the opposite tibia that did not undergo clot induction. This effect was confirmed using two more cancer cell lines. Furthermore, no difference in the number of macroscopic lesions or their growth could be detected. In the control group 72% developed a lesion in the left tibia. In the experimental groups with clot formation 79% and 65% developed lesions in the left tibia (p = ns when comparing each experimental group with the controls). Survival was similar too. In summary, the growth factors accumulating in a clot/hematoma are neither enough to promote cancer cell homing nor support growth in an experimental model of breast cancer bone metastasis. This suggests that blood clot formation, as occurs in traumatic fractures, surgical interventions, and bruises, does not increase the risk of metastasis formation.