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Drawing on 662 studies from 102 countries, we present a systematic review of published empirical studies about site-level biodiversity conservation initiated between 1970 and 2019. Within this sample, we find that knowledge production about the Global South is largely produced by researchers in the Global North, implying a neocolonial power dynamic. We also find evidence of bias in reported ecological outcomes linked to lack of independence in scientific studies, serving to uphold narratives about who should lead conservation. We explore relationships in the sample studies between conservation initiative types, the extent of Indigenous Peoples' and local communities' influence in governance, and reported social and ecological outcomes. Findings reveal positive ecological and social outcomes are strongly associated with higher levels of influence of Indigenous Peoples and local communities and their institutions, implying equity in conservation practice should be advanced not only for moral reasons, but because it can enhance conservation effectiveness. [ABSTRACT FROM AUTHOR]

Modern consensus panel guidelines recommend restriction from most organized sports for patients with moderate or severe aortic stenosis (AS). However, there is little published data on how frequently physicians deviate from guidelines, how well patients adhere to exercise restrictions, or the effect of restriction on patient-reported quality of life. In this study, we surveyed 93 subjects with AS and their cardiologists regarding participation in organized sports, physical activity, weightlifting, and exercise restriction. Subjects completed the pediatric quality of life inventory (PedsQL) and the pediatric cardiac quality of life inventory (PCQLI). We found that subjects with severe AS (n = 3) were commonly, but not universally, restricted from organized sports (n = 2, 66%). Subjects with moderate AS (n = 40) were rarely restricted from organized sports (n = 6, 17%). No physician-specific characteristics were associated with increased likelihood of recommending exercise restriction. Subjects were more likely to be restricted if they were older (16 years vs. 13 years, p 0.02) and had moderate versus mild AS (p 0.013). PCQLI scores for teens and young adults with AS (age 13–25) were lower than a comparison group of patients with mild congenital heart disease. For all age groups, the PedsQL social functioning score was lower for subjects with exercise restriction (p 0.052). In summary, cardiologists apply consensus guidelines leniently when restricting patients with moderate/severe AS from organized sports and weightlifting. Patients with AS routinely adhere to exercise restriction recommendations. Children and young adults with AS and exercise restriction have lower QOL scores in the social functioning domain. [ABSTRACT FROM AUTHOR]

Depression is a risk factor for suicide attempt, but its ability to differentiate individuals at heightened risk as a total score falls short. Prospective investigations of individual depressive symptoms in relation to adolescent suicide attempt are limited and seldom control for established risk factors such as attempt history and other depressive symptoms. Participants (n = 854) were suicidal adolescents enrolled in intensive outpatient treatment targeting suicidality. Depressive symptoms (composite measures of mood, sleep, appetite/weight, and psychomotor disturbance, as well as single-item measures of disturbed concentration, negative self-appraisal, suicidal ideation (SI), anhedonia, and low energy) were measured at entry. Suicide attempts between treatment entry and six months after discharge were recorded (n = 156; 'future attempters'). Bivariate comparisons found significant differences between future attempters and non-attempters on all depressive symptoms besides appetite/weight and psychomotor disturbances. Logistic regression showed that only sleep disturbance and SI contributed to future attempt while controlling for age, sex, attempt history, and other depressive symptoms. A subsequent model revealed that middle and late insomnia largely accounted for sleep's relationship with future attempt. Age, attempt history, and SI were significant predictors in both models. Difficulty with maintaining sleep, early morning awakenings, and severe SI might signal an additional warning for proximate suicide attempt, particularly in youth with attempt history. These results support the measurement of deconstructed depressive symptoms as a practical addition to risk assessment for clinicians managing suicidal adolescents. Such specific risk indicators might signal the need for more intensive care and closer post-discharge monitoring. [ABSTRACT FROM AUTHOR]

Treeline is a global ecological phenomenon in which tree populations decline, often abruptly, above a specific elevation or latitude. Temperature is thought to be a key determinant of treeline because it affects the rates at which trees establish, grow, produce seeds, and die. As climate change causes temperature increases, treelines have been observed to move in response—but there is considerable variability. In this study, we present a general mathematical model that provides possible explanations for both the general patterns observed in treelines and some of the variation. Avoiding system-specific details, our model assumes simply that all life processes are temperature-dependent. We incorporate the possibility of positive or negative feedback, in which the presence of trees either increases or decreases the temperature at their location. Our results indicate that this feedback and the relationship between temperature thresholds for growth, seed production, and seedling establishment are the key determinants of tree line form and movement. The model also shows that under many conditions bistability is predicted: treeline can equilibrate at two different elevations under the same conditions, depending on the system's history. General, flexible models like ours are essential for generating a unifying theory of treeline form and dynamics across multiple ecosystems. [ABSTRACT FROM AUTHOR]

Immunoglobin light chain (AL) amyloidosis is a rare disease in which a plasma cell dyscrasia leads to deposition of insoluble amyloid fibrils in multiple organs. To facilitate development of new therapies for this heterogenous disease, a public–private partnership was formed between the nonprofit Amyloidosis Research Consortium and the US Food and Drug Administration Center for Drug Evaluation and Research. In 2020, the Amyloidosis Forum launched an initiative to identify clinical trial endpoints and analytic strategies across affected organ systems and life impacts via specialized working groups. This review summarizes the proceedings of the Statistical Group and proposes a pathway for development and validation of multi-domain endpoints (MDEs) for potential use in AL amyloidosis clinical trials. Specifically, drawing on candidate domain-specific endpoints recommended by each organ-specific working group, different approaches to constructing MDEs were considered. Future studies were identified to assess the validity, meaningfulness and performance of MDEs through use of natural history and clinical trial data. Ultimately, for drug development, the context of use in a regulatory evaluation, the specific patient population, and the investigational therapeutic mechanism should drive selection of appropriate endpoints. MDEs for AL amyloidosis, once developed and validated, will provide important options for advancing patient-focused drug development in this multi-system disease. [ABSTRACT FROM AUTHOR]

We consider the distribution of the Galois groups Gal (K un / K) of maximal unramified extensions as K ranges over Γ -extensions of ℚ or F q (t) . We prove two properties of Gal (K un / K) coming from number theory, which we use as motivation to build a probability distribution on profinite groups with these properties. In Part I, we build such a distribution as a limit of distributions on n -generated profinite groups. In Part II, we prove as q → ∞ , agreement of Gal (K un / K) as K varies over totally real Γ -extensions of F q (t) with our distribution from Part I, in the moments that are relatively prime to q (q − 1) | Γ | . In particular, we prove for every finite group Γ , in the q → ∞ limit, the prime-to- q (q − 1) | Γ | -moments of the distribution of class groups of totally real Γ -extensions of F q (t) agree with the prediction of the Cohen–Lenstra–Martinet heuristics. [ABSTRACT FROM AUTHOR]

The original article can be found online at https://doi.org/10.1007/s00222-024-01257-1The publication of this article unfortunately contained mistakes. The style of the references was not correct. The corrected reference list is given below.The original article has been corrected.Publisher's NoteSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.By Yuan Liu; Melanie Matchett Wood and David Zureick-BrownReported by Author; Author; Author [Extracted from the article]

To compare the efficacy and safety of the proposed aflibercept biosimilar SCD411 and reference aflibercept in patients with neovascular age-related macular degeneration, this randomized, double-masked, parallel-group, multicenter study was conducted in 14 countries from 13 August 2020 to 8 September 2022. Patients with neovascular age-related macular degeneration. With subfoveal, juxtafoveal, or extrafoveal choroidal neovascularization were aged 50 years or older. Intravitreal injection of SCD411 or aflibercept (2.0 mg) were administered every 4 weeks for the first three injections and every 8 weeks until week 48. The primary efficacy endpoint was the change in best-corrected visual acuity from baseline to week 8 with an adjusted equivalence margin of ± 3.0 letters. Patients were randomly assigned to receive either SCD411 (n = 288) or reference aflibercept (n = 288). A total of 566 participants (98.3%) completed week 8 of the study. The least-squares mean difference of change in best-corrected visual acuity from baseline to week 8 (SCD411—aflibercept) was − 0.4 letters (90% confidence interval = − 1.6 to 0.9). The incidence of ocular (69 of 287 [24.0%] vs. 71 of 286 [24.8%]) and serious ocular (5 of 287 [1.7%] vs. 3 of 286 [1.0%]) treatment-emergent adverse effects were similar between the SCD411 and aflibercept groups. Immunogenicity analysis revealed a low incidence of neutralizing antibody formation in both groups. In conclusion, SCD411 has equivalent efficacy compared with reference aflibercept in patients with neovascular age-related macular degeneration and has a comparable safety profile. The results support the potential use of SCD411 for the treatment of neovascular age-related macular degeneration. [ABSTRACT FROM AUTHOR]

Using the formalism of Newton hyperplane arrangements, we resolve the open questions regarding angle rank left over from work of the first two authors with Roe and Vincent. As a consequence we end up generalizing theorems of Lenstra–Zarhin and Tankeev proving several new cases of the Tate conjecture for abelian varieties over finite fields. We also obtain an effective version of a recent theorem of Zarhin bounding the heights of coefficients in multiplicative relations among Frobenius eigenvalues. [ABSTRACT FROM AUTHOR]

There is a long history in environmental sciences to investigate and understand the fate of chemicals in the environment. For pesticides, this has led to systematic assessments of compounds by both academic and regulatory bodies, particularly for soil and water. As we show here, in recent years, there is an increasing interest in the potential presence of pesticide residues in air and related exposure risks. Based on a literature review for the years 2002–2022, we find a growing number of air monitoring studies with an average of 6.7 studies/year since 2020, with passive sampling methods contributing significantly to this rise. Most studies are concentrated in Europe and North America, with France leading in the number of monitoring studies. However, due to a lack of harmonization, and thus, the use of diverse methods and approaches, it remains challenging to derive potential exposure risks, to assess data quality of studies, and to compare datasets. In this perspective, we focus on current and emerging trends of different air monitoring approaches and highlight how they influence the interpretation of data. To improve the comparability and utility of data, and to ensure that air monitorings meet certain quality requirements, we propose a path forward, including: (1) Standardization and harmonization of methods: Adopting well-characterized and widely applied methods from air quality research as a basis for standardizing pesticide monitoring, with a clear distinction between relevant exposure and total air concentrations. (2) Tiered approach for monitoring programs: A dynamic concept where initial passive sampling identifies potential exposure risks, followed by active sampling for quantitative data, and, if necessary, extensive monitoring programs. This approach balances the need for detailed data with resource constraints. (3) Data interpretation and transparency: Public availability of data and clear reporting of methods, analysis, and uncertainties are crucial for the credibility and utility of monitoring studies. Overall, we see that harmonization of standards is critical for assessing exposure risks from pesticides in air and for informing regulatory decisions and mitigation strategies. Collaboration with the air quality and atmospheric research community is strongly recommended to leverage existing expertise in sampling, analysis, and data interpretation. [ABSTRACT FROM AUTHOR]

CDH1 (E-cadherin) bi-allelic inactivation is the hallmark alteration of breast invasive lobular carcinoma (ILC), resulting in its discohesive phenotype. A subset of ILCs, however, lack CDH1 genetic/epigenetic inactivation, and their genetic underpinning is unknown. Through clinical targeted sequencing data reanalysis of 364 primary ILCs, we identified 25 ILCs lacking CDH1 bi-allelic genetic alterations. CDH1 promoter methylation was frequent (63%) in these cases. Targeted sequencing reanalysis revealed 3 ILCs harboring AXIN2 deleterious fusions (n = 2) or loss-of-function mutation (n = 1). Whole-genome sequencing of 3 cases lacking bi-allelic CDH1 genetic/epigenetic inactivation confirmed the AXIN2 mutation and no other cell-cell adhesion genetic alterations but revealed a new CTNND1 (p120) deleterious fusion. AXIN2 knock-out in MCF7 cells resulted in lobular-like features, including increased cellular migration and resistance to anoikis. Taken together, ILCs lacking CDH1 genetic/epigenetic alterations are driven by inactivating alterations in other cell adhesion genes (CTNND1 or AXIN2), endorsing a convergent phenotype in ILC. [ABSTRACT FROM AUTHOR]

A method is given to reduce the problem of finding a nontrivial factorization of a positive integer α , greater than one, to the problem of finding a solution to a system of Boolean equations, that is, a system of equations such that each equation is of the form f = g where f and g are Boolean functions, meaning { 0 , 1 } -valued functions in zero or more Boolean ( { 0 , 1 } -valued) variables. Our system is obtained by applying a sequence of reductions to an initial system of equations of the form { f i (x → , y →) = α i ∣ i ∈ { 0 , ⋯ , 2 n } } where for each i f i (x → , y →) = f i (x 0 , ⋯ , x n , y 0 , ⋯ , y n) gives the coefficient of 2 i in the binary expansion of (x 0 + 2 x 1 + ⋯ + 2 n x n) (y 0 + 2 y 1 + ⋯ + 2 n y n) , α i gives the coefficient of 2 i in the binary expansion of α , and x i and y i are { 0 , 1 } -valued variables. That is, the initial system represents a binary multiplier whose output bits have been set equal to the bits of α . It is shown that each Boolean function in our reduced system, that is, each Boolean function (g - h) mod 2 = 0 ⟺ g = h 1 ⟺ g ≠ h such that g = h is an equation in the reduced system, can be represented by a type of graph called an ordered binary decision diagram (OBDD) with an upper bound on its number of vertices of O log 2 (α / log 2 (α)) ) 3 . Previous work has shown that the initial system has at least one Boolean function with an OBDD representation with number of vertices exponential in log 2 (α) . [ABSTRACT FROM AUTHOR]

Involving and engaging people with intellectual disabilities on issues relating to their mental wellbeing is essential if relevant tools and solutions are to be developed. This research explores how inclusive and participatory co-design techniques and principles can be used to engage people with intellectual disabilities in designing innovations in mental wellbeing tangible technologies. In particular, individuals with intellectual disabilities participated in a co-design process via a series of workshops and focus groups to design tangible interfaces for mental wellbeing as their wellbeing challenges are often diagnostically overshadowed. The workshops helped participants explore new technologies, including sensors and feedback mechanisms that can help monitor and potentially improve mental wellbeing. The adopted co-design approach resulted in a range of effective and suitable interfaces being developed for varying ages. [ABSTRACT FROM AUTHOR]

This study aims to investigate the presence of SARS-CoV-2 in public spaces and assess the utility of inexpensive air purifiers equipped with high-efficiency particulate air (HEPA) filters for viral detection. Samples were collected from six community-based organizations in underserved minority neighborhoods in Northwest Miami, Florida, from February to May 2022. Reverse transcription–quantitative polymerase chain reaction (RT-qPCR) was used to detect SARS-CoV-2 in air purifier filters and surface swabs. Among 32 filters tested, three yielded positive results, while no positive surface swabs were found. Notably, positive samples were obtained exclusively from child daycare centers. These findings highlight the potential for airborne transmission of SARS-CoV-2 in indoor air, particularly in child daycare centers. Moreover, the study demonstrates the effectiveness of readily available HEPA filters in detecting the virus. Improving indoor ventilation and implementing air filtration systems are crucial in reducing COVID-19 transmission where people gather. Air filtration systems incorporating HEPA filters offer a valuable approach to virus detection and reducing transmission risks. Future research should explore the applicability of this technology for early identification and mitigation of viral outbreaks. [ABSTRACT FROM AUTHOR]

Plastic debris is thought to be widespread in freshwater ecosystems globally1. However, a lack of comprehensive and comparable data makes rigorous assessment of its distribution challenging2,3. Here we present a standardized cross-national survey that assesses the abundance and type of plastic debris (>250 μm) in freshwater ecosystems. We sample surface waters of 38 lakes and reservoirs, distributed across gradients of geographical position and limnological attributes, with the aim to identify factors associated with an increased observation of plastics. We find plastic debris in all studied lakes and reservoirs, suggesting that these ecosystems play a key role in the plastic-pollution cycle. Our results indicate that two types of lakes are particularly vulnerable to plastic contamination: lakes and reservoirs in densely populated and urbanized areas and large lakes and reservoirs with elevated deposition areas, long water-retention times and high levels of anthropogenic influence. Plastic concentrations vary widely among lakes; in the most polluted, concentrations reach or even exceed those reported in the subtropical oceanic gyres, marine areas collecting large amounts of debris4. Our findings highlight the importance of including lakes and reservoirs when addressing plastic pollution, in the context of pollution management and for the continued provision of lake ecosystem services.Analysis of plastic debris found in surface waters shows that lakes and reservoirs in densely populated and urbanized regions, as well as those with elevated deposition areas, are particularly vulnerable to plastic contamination. [ABSTRACT FROM AUTHOR]

Virtual reality exposure therapy (VRET) is a novel intervention technique that allows individuals to experience anxiety-evoking stimuli in a safe environment, recognise specific triggers and gradually increase their exposure to perceived threats. Public-speaking anxiety (PSA) is a prevalent form of social anxiety, characterised by stressful arousal and anxiety generated when presenting to an audience. In self-guided VRET, participants can gradually increase their tolerance to exposure and reduce anxiety-induced arousal and PSA over time. However, creating such a VR environment and determining physiological indices of anxiety-induced arousal or distress is an open challenge. Environment modelling, character creation and animation, psychological state determination and the use of machine learning (ML) models for anxiety or stress detection are equally important, and multi-disciplinary expertise is required. In this work, we have explored a series of ML models with publicly available data sets (using electroencephalogram and heart rate variability) to predict arousal states. If we can detect anxiety-induced arousal, we can trigger calming activities to allow individuals to cope with and overcome distress. Here, we discuss the means of effective selection of ML models and parameters in arousal detection. We propose a pipeline to overcome the model selection problem with different parameter settings in the context of virtual reality exposure therapy. This pipeline can be extended to other domains of interest where arousal detection is crucial. Finally, we have implemented a biofeedback framework for VRET where we successfully provided feedback as a form of heart rate and brain laterality index from our acquired multimodal data for psychological intervention to overcome anxiety. [ABSTRACT FROM AUTHOR]

The recent years have witnessed an increasing number of manufacturers in developed markets pursuing service-led innovation to secure their sustainable growth and competitive positions. This study compares the manufacturing firm performance outcomes of two types of innovation activities in the value chain (i.e., service innovation and product innovativeness) contingent on institutional environment but in an aspirant market – China. To do so we conducted two studies: A secondary data study (Study 1) used a longitudinal panel dataset of 1,167 manufacturing firms and a robustness study (Study 2) used primary survey data from 171 manufacturing firms. Both studies offer consistent empirical results that in the dysfunctional competition environment, and in contrast to product innovativeness, service innovation is less effective for manufacturing performance but works more effectively for performance in the complicated institutional environment when government support and dysfunctional competition co-exist. The research contributes to the fields of aspirant markets and innovation by developing our understanding of the firm's strategic responses pertaining to innovation in the context of a complicated institutional environment, the latter informed by structuration theory. The paper offers a fine-grained view to manufacturing innovation and provides the practical implications for managers and clear guidance to firms and governments in the aspirant markets in regards to innovation practice, strategy, and policy. [ABSTRACT FROM AUTHOR]

Visual programming tools allow users to create interactive media projects such as games and animations using visual representations of programming concepts. Although these tools have been shown to have huge potential for teaching children, research has shown that they may not be accessible for children with cognitive impairments, including those with autism spectrum condition. Therefore, this study proposes a set of recommendations for the design of accessible visual programming tools for children with autism spectrum condition. Semi-structured interviews with experts ( n = 7 ) were conducted and thematically analysed to identify initial recommendations. A second set of semi-structured interviews with a subset of the initial experts ( n = 3 ) were then conducted to validate and produce a final set of recommendations. [ABSTRACT FROM AUTHOR]

We examine the reductions in electricity procurement costs that can be secured when gain-sharing regulation is employed to induce a regulated load serving entity (LSE) to undertake forward contracting despite associated political risk. We identify arguably plausible conditions under which a modest degree of gain sharing can induce an LSE to undertake forward contracting that substantially reduces the LSE's procurement costs, to the benefit of retail consumers. [ABSTRACT FROM AUTHOR]

Central arterial pressure rises to much higher levels during heavy isometric exercise compared to other forms of exercise. For this reason, patients with bicuspid aortic valves (BAV) are often restricted from heavy isometric exercise. Although this approach may be theoretically appealing, no data exist regarding the efficacy of this activity restriction.Patients between 12 and 21 years old with isolated BAV were enrolled if they had a previous echocardiogram at least 2 years prior to the current clinic visit. Patients were excluded if they had additional congenital heart disease, a diagnosed syndrome, or had undergone a procedure involving the aortic valve or ascending aorta. Patients completed a questionnaire regarding frequency and intensity of isometric exercise during the 3-month period prior to the visit. We compared aortic dimensions (Z-score), aortic stenosis, and aortic insufficiency between an echocardiogram performed as part of the current visit and one obtained 2–5 years previously using paired t tests and multivariable regression controlling for age, gender, degree of aortic stenosis, and the presence of isometric exercise. In this sample of 50 adolescents with isolated bicuspid aortic valve, 30 (60%) subjects did not participate in any isometric exercise. Over an average of 2.9 years (SD 0.9 years), we did not find a significant difference between changes in the Z-score diameters of the aortic root (0.9 vs 0.9, p = 0.913) and ascending aorta Z-score (2.9 vs 2.9, p = 0.757), between subjects engaging and not engaging in isometric exercise. Further, we did not find that changes in valve function (i.e., aortic stenosis and aortic insufficiency) differed between the two groups.In this sample of adolescents with isolated bicuspid aortic valve, there was no medium-term increase in aortic dilation or worsening valve function in those who engaged in isometric exercise versus those who refrained from isometric exercise. [ABSTRACT FROM AUTHOR]

Communication between parents and providers of children with cardiac disease is essential to parental decision-making. This study explored how parents of hospitalized children with advanced heart disease perceived communication with their child's providers. We performed a prospective survey study of parents and physicians of children with advanced heart disease age 30 days to 19 years admitted to the hospital for > 7 days over a 1-year period at a single institution (n = 160 parent-provider pairs). Descriptive statistics were primarily used and Fisher exact tests and kappa statistics were used to assess agreement. All parents rated communication with their child's care team as excellent, very good, or good, but 56% of parents reported having received conflicting information. Parental perception of "too many" people giving them information was associated with overall poorer communication and less preparedness for decision-making. One-third (32%) of parents felt unprepared for decision-making, despite 88% feeling supported. Parents and physicians showed poor agreement with respect to overall adequacy of communication, receipt of conflicting information, and evaluation of the most effective way for parents to receive information. Interventions involving physician communication training and proactive assessment of parent communication preferences may be beneficial. [ABSTRACT FROM AUTHOR]

The chronic coronary syndromes (CCS) include patients with a classic history of angina pectoris in the presence of either risk factors for or known atherosclerotic coronary artery disease. Randomized, controlled trials conducted in the optimal medical therapy (OMT) era have convincingly demonstrated that adherence to the outdated paradigm focused on treatment of obstructive coronary disease with initial revascularization fails to reduce death or myocardial infarction and inconsistently reduces angina symptoms. Rather, OMT reduces events and improves symptoms and should be considered first-line treatment for patients with CCS. [ABSTRACT FROM AUTHOR]

New algorithms are developed to adapt the convergence tolerances for the constraint and adjoint equations for practical engineering optimization problems solved using the discrete adjoint approach. The algorithms are designed to achieve design order convergence of the optimization algorithm at reduced computational cost. We have found based on analysis and supported by numerical experimentation that adapting both the constraint and adjoint equation tolerances based on the norm of the gradient is sufficient to achieve design order convergence. We have also found that adapting the constraint equation tolerance is necessary, though we were not able to show analytically that adapting the adjoint equation tolerance is necessary. Based on the numerical experimentation, it appears that design order convergence can be achieved without adapting the adjoint equation in some cases but not others. The gain in computational efficiency using the new algorithms over using fixed tolerances is demonstrated through three numerical test problems. [ABSTRACT FROM AUTHOR]

The average number of hours we spend at work varies dramatically by country. Previous research focuses on tax policy, social security, and labor market regulation to explain the differences. This paper builds on previous work by focusing on politics. Specifically, it examines the relationship between democracy and the average number of hours worked per person employed. Using data on the supply of labor from the Penn World Tables 9.1, I find there is an important difference between democracies and dictatorships: as GDP/capita increases, individuals in democracies spend fewer hours at work than their counterparts in dictatorships. The results are robust to various specifications of the model that account for selection bias and data that are missing not at random (MNAR). These findings imply that the elections, civil rights, and the political liberties associated with democracy influence the amount of time people spend at work. [ABSTRACT FROM AUTHOR]

Purpose: The present study was to determine whether OP2113 could limit myocardial infarction size and the no-reflow phenomenon in a rat myocardial ischemia/reperfusion model. Methods: Rat heart–isolated mitochondria (RHM) were used to investigate mitochondrial respiration and mitochondrial reactive oxygen species (mtROS) generation both in normal conditions and in ischemia/reperfusion-mimicking conditions (using high concentrations of succinate). Human skeletal muscle myoblasts (HSMM) in culture were used to investigate the cellular intermittent deprivation in energy substrates and oxygen as reported in ischemia/reperfusion conditions. In vivo, rats were anesthetized and subjected to 30 min of left coronary artery occlusion followed by 3 h of reperfusion. Rats were randomized to receive OP2113 as an intravenous infusion starting either 5 min prior to coronary artery occlusion (preventive), or 5 min prior to reperfusion (curative), or to receive vehicle starting 5 min prior to coronary artery occlusion. Infusions continued until the end of the study (3 h of reperfusion). Results: RHM treated with OP2113 showed a concentration-dependent reduction of succinate-induced mtROS generation. In HSMM cells, OP2113 treatment (5–10 μM) during 48H prevented the reduction in the steady-state level of ATP measured just after reperfusion injuries and decreased the mitochondrial affinity to oxygen. In vivo, myocardial infarct size, expressed as the percentage of the ischemic risk zone, was significantly lower in the OP2113-treated preventive group (44.5 ± 2.9%) versus that in the vehicle group (57.0 ± 3.6%; p < 0.05), with a non-significant trend toward a smaller infarct size in the curative group (50.8 ± 3.9%). The area of no reflow as a percentage of the risk zone was significantly smaller in both the OP2113-treated preventive (28.8 ± 2.4%; p = 0.026 vs vehicle) and curative groups (30.1 ± 2.3%; p = 0.04 vs vehicle) compared with the vehicle group (38.9 ± 3.1%). OP2113 was not associated with any hemodynamic changes. Conclusions: These results suggest that OP2113 is a promising mitochondrial ROS–modulating agent to reduce no-reflow as well as to reduce myocardial infarct size, especially if it is on board early in the course of the infarction. It appears to have benefit on no-reflow even when administered relatively late in the course of ischemia. [ABSTRACT FROM AUTHOR]

With the development of advanced technologies in cell-based phenotypic screening, phenotypic drug discovery (PDD) strategies have re-emerged as promising approaches in the identification and development of novel and safe drugs. However, phenotypic screening does not rely on knowledge of specific drug targets and needs to be combined with chemical biology approaches to identify therapeutic targets and mechanisms of actions induced by drugs and associated with an observable phenotype. In this study, we developed a system pharmacology network integrating drug-target-pathway-disease relationships as well as morphological profile from an existing high content imaging-based high-throughput phenotypic profiling assay known as "Cell Painting". Furthermore, from this network, a chemogenomic library of 5000 small molecules that represent a large and diverse panel of drug targets involved in diverse biological effects and diseases has been developed. Such a platform and a chemogenomic library could assist in the target identification and mechanism deconvolution of some phenotypic assays. The usefulness of the platform is illustrated through examples. [ABSTRACT FROM AUTHOR]

We previously reported that growth promoter-induced skeletal muscle hypertrophy co-ordinately upregulated expression of genes associated with an integrated stress response (ISR), as well as potential ISR regulators. We therefore used Adeno-Associated Virus (AAV)-mediated overexpression of these genes, individually or in combination, in mouse skeletal muscle to test whether they induced muscle hypertrophy. AAV of each target gene was injected into mouse Tibialis anterior (TA) and effects on skeletal muscle growth determined 28 days later. Individually, AAV constructs for Arginase-2 (Arg2) and Activating transcription factor-5 (Atf5) reduced hindlimb muscle weights and upregulated expression of genes associated with an ISR. AAV-Atf5 also decreased Myosin heavy chain (MyHC)-IIB mRNA, but increased MyHC-IIA and isocitrate dehydrogenase-2 (Idh2) mRNA, suggesting ATF5 is a novel transcriptional regulator of Idh2. AAV-Atf5 reduced the size of both TA oxidative and glycolytic fibres, without affecting fibre-type proportions, whereas Atf5 combined with Cebpg (CCAAT enhancer binding protein-gamma) only reduced the size of glycolytic fibres and tended to increase the proportion of oxidative fibres. It is likely that persistent Atf5 overexpression maintains activation of the ISR, thereby reducing protein synthesis and/or increasing protein degradation and possibly apoptosis, resulting in inhibition of muscle growth, with overexpression of Arg2 having a similar effect. [ABSTRACT FROM AUTHOR]

Background: Interstage mortality (IM) remains high for patients with single-ventricle congenital heart disease (SVCHD) in the period between Stage 1 Palliation (S1P) and Glenn operation. We sought to characterize IM. Methods: This was a descriptive analysis of 2184 patients with SVCHD discharged home after S1P from 60 National Pediatric Cardiology Quality Improvement Collaborative sites between 2008 and 2015. Patients underwent S1P with right ventricle-pulmonary artery conduit (RVPAC), modified Blalock–Taussig–Thomas shunt (BTT), or Hybrid; transplants were excluded. Results: IM occurred in 153 (7%) patients (median gestational age 38 weeks, 54% male, 77% white), at 88 (IQR 60,136) days of life, and 39 (IQR 17,84) days after hospital discharge; 13 (8.6%) occurred ≤ 30 days after S1P. The mortality rate for RVPAC was lower (5.2%; 59/1138) than BTT (9.1%; 65/712) and Hybrid (20.1%; 27/134). More than half of deaths occurred at home (20%) or in the emergency department (33%). The remainder occurred while inpatient at center of S1P (cardiac intensive care unit 36%, inpatient ward 5%) or at a different center (5%). Fussiness and breathing problems were most often cited as harbingers of death; distance to surgical center was the biggest barrier cited to seeking care. Cause of death was unknown in 44% of cases overall; in the subset of patients who underwent post-mortem autopsy, the cause of death remained unknown in 30% of patients, with the most common diagnosis being low cardiac output. Conclusions: Most IM occurred in the outpatient setting, with non-specific preceding symptoms and unknown cause of death. These data indicate the need for research to identify occult causes of death, including arrhythmia. [ABSTRACT FROM AUTHOR]

Microbial community profiling using high-throughput sequencing relies in part on the preservation of the DNA and the effectiveness of the DNA extraction method. This study aimed at understanding to what extent these parameters affect the profiling. We obtained samples treated with and without a preservation solution. Also, we compared DNA extraction kits from Qiagen and Zymo-Research. The types of samples were defined strains, both as single species and mixtures, as well as undefined indigenous microbial communities from soil. We show that the use of a preservation solution resulted in substantial changes in the 16S rRNA gene profiles either due to an overrepresentation of Gram-positive bacteria or to an underrepresentation of Gram-negative bacteria. In addition, 16S rRNA gene profiles were substantially different depending on the type of kit that was used for extraction. The kit from Zymo extracted DNA from different types of bacteria in roughly equal amounts. In contrast, the kit from Qiagen preferentially extracted DNA from Gram-negative bacteria while DNA from Gram-positive bacteria was extracted less effectively. These differences in kit performance strongly influenced the interpretation of our microbial ecology studies. [ABSTRACT FROM AUTHOR]

Elevated exposure to ambient manganese (Mn) is associated with adverse health outcomes. In Marietta, Ohio, the primary source of ambient Mn exposure is from the longest operating ferromanganese refinery in North America. In this study, the US EPA air dispersion model, AERMOD, was used to estimate ambient air Mn levels near the refinery for the years 2008–2013. Modeled air Mn concentrations for 2009–2010 were compared to concentrations obtained from a stationary air sampler. Census block population data were used to estimate population sizes exposed to an annual average air Mn > 50 ng/m3, the US EPA guideline for chronic exposure, for each year. Associations between modeled air Mn, measured soil Mn, and measured indoor dust Mn in the modeled area were also examined. Median modeled air Mn concentrations ranged from 6.3 to 43 ng/m3 across the years. From 12,000–56,000 individuals, including over 2000 children aged 0–14 years, were exposed to respirable annual average ambient air Mn levels exceeding 50 ng/m3 in five of the six years. For 2009–2010, the median modeled air Mn concentration at the stationary site was 20 ng/m3, compared to 18 ng/m3 measured with the stationary air sampler. All model performance measures for monthly modeled concentrations compared to measured concentrations were within acceptable limits. The study shows that AERMOD modeling of ambient air Mn is a viable method for estimating exposure from refinery emissions and that the Marietta area population was at times exposed to Mn levels that exceeded US EPA guidelines. [ABSTRACT FROM AUTHOR]

Previous studies have investigated the character and distribution of intense precipitation events across the United States. Increasing trends in intense, daily precipitation events at heavy (90–< 95th percentile), very heavy (95–< 99th percentile), and extreme (≥ 99th percentile) thresholds have all been reported. However, no previous studies have investigated the potential application of stochastic weather generators in determining future, site-specific distributions of such intense precipitation occurrences. In this study, two scenarios of future changes in intense precipitation for Weatherford, Oklahoma were examined through the use of a specific weather generator, SYNTOR, and by examination of heavy, very heavy, and extreme precipitation categories. All precipitation events across the three categories were increased multiple times by eight different percentages ranging from 5% to 75%, while precipitation events within the three categories were simultaneously increased by 14%, 20%, and 30%, respectively. Projected changes in the occurrence and categorical thresholds of intense precipitation events, as well as total monthly and annual precipitation and wet-dry transition probabilities, were assessed. The findings of this study show that projected increases in intense precipitation ranging from 5% to 40% are plausible and within the margin of error, based on the application of the two intensification scenarios to the synthetically generated weather data. Overall, the precipitation intensification scenarios markedly impacted estimates of intense precipitation, as well as average annual and monthly precipitation totals, but did not markedly impact the temporal distribution of precipitation annually or across seasons, nor the transition probabilities of projected precipitation between wet and dry days. Precipitation intensification scenarios can ultimately benefit in simulating erosion, runoff, and crop productivity responses to future precipitation distributions in agricultural watersheds of the Southern Great Plains as well as other locations. [ABSTRACT FROM AUTHOR]

Altered composition of gut bacteria and changes to the production of their bioactive metabolites, the short-chain fatty acids (SCFAs), have been implicated in the development of multiple sclerosis (MS). However, the immunomodulatory actions of SCFAs and intermediaries in their ability to influence MS pathogenesis are uncertain. In this study, levels of serum SCFAs were correlated with immune cell abundance and phenotype as well as with other relevant serum factors in blood samples taken at first presentation of Clinically Isolated Syndrome (CIS; an early form of MS) or MS and compared to healthy controls. There was a small but significant reduction in propionate levels in the serum of patients with CIS or MS compared with healthy controls. The frequencies of circulating T follicular regulatory cells and T follicular helper cells were significantly positively correlated with serum levels of propionate. Levels of butyrate associated positively with frequencies of IL-10-producing B-cells and negatively with frequencies of class-switched memory B-cells. TNF production by polyclonally-activated B-cells correlated negatively with acetate levels. Levels of serum SCFAs associated with changes in circulating immune cells and biomarkers implicated in the development of MS. [ABSTRACT FROM AUTHOR]

The causes and consequences of spatial heterogeneity in population dynamics are of both theoretical and practical interest. Previously, we described (Kummel et al., Oikos 122:896–906, 2013) a field system in which predation by ladybugs drives the development of strong spatial heterogeneity among aphid populations living on nearby plants. In this paper, we investigate the detailed mechanisms responsible for this phenomenon. We develop a detailed mathematical model of the system, parameterized by an extensive experimental work showing that ladybugs tend to remain on plants with high aphid numbers and are attracted to plants on which ladybugs are actively feeding. The model reproduces important aspects of the field system and allows us to explore how various behavioral features contribute to these dynamics. The results indicate that spatial heterogeneity results from the random aspect of ladybug foraging that causes some large aphid populations to be under-exploited. For parameter values that are unrealistic for our system, the model displays other types of complex dynamics, including predator swarming and chaos. Our study illustrates how a realistic, carefully parameterized model can connect individual behavior to larger scale spatiotemporal dynamics. [ABSTRACT FROM AUTHOR]

Using data from Texas's wholesale electricity market, we investigate the relationship between nodal prices and investment location decisions of utility-scale generation. We find some evidence that new investment arises in areas with recently elevated nodal prices. However, we find no evidence that new generation resources receive a nodal price premium post-entry as projected by the expectation of higher nodal prices. Further, a logit regression analysis suggests that the probability of natural-gas-fired generation investments tends to increase with expected nodal prices in peak hours. However, the estimated relationship is statistically and economically weak and sensitive to model specification. These findings suggest other factors are more important drivers than nodal prices of location decisions for utility-scale generation investments in Texas. [ABSTRACT FROM AUTHOR]

This paper examines the effects of population growth and decline on county-level income inequality in the rural United States from 1980 to 2016. Findings from previous research have shown that population growth is positively associated with income inequality. However, these studies are largely motivated by theories of urbanization and growth in metropolitan areas and do not explicitly test for differences between the impacts of population growth and decline. Examining the effects of both forms of population change on income inequality is particularly important in rural areas of the United States, the majority of which are experiencing population decline. We analyze county-level data (N = 11,320 county-decades) from the U.S. Decennial Census and American Community Survey, applying fixed effects regression models to estimate the respective effects of population growth and decline on income inequality within rural counties. We find that both forms of population change have significant effects on income inequality relative to stable growth. Population decline is associated with increases in income inequality, while population growth is marginally associated with decreases in inequality. These relationships are consistent across a variety of model specifications, including models that account for counties' employment, sociodemographic, and ethno-racial composition. We also find that the relationship between income inequality and population change varies by counties' geographic region, baseline level of inequality, and baseline population size, suggesting that the links between population change and income inequality are not uniform across rural America. [ABSTRACT FROM AUTHOR]

Crop varieties should fulfill multiple requirements, including agronomic performance and product quality. Variety evaluations depend on data generated from field trials and sensory analyses, performed with different levels of participation from farmers and consumers. Such multi-faceted variety evaluation is expensive and time-consuming; hence, any use of these data should be optimized. Data synthesis can help to take advantage of existing and new data, combining data from different sources and combining it with expert knowledge to produce new information and understanding that supports decision-making. Data synthesis for crop variety evaluation can partly build on extant experiences and methods, but it also requires methodological innovation. We review the elements required to achieve data synthesis for crop variety evaluation, including (1) data types required for crop variety evaluation, (2) main challenges in data management and integration, (3) main global initiatives aiming to solve those challenges, (4) current statistical approaches to combine data for crop variety evaluation and (5) existing data synthesis methods used in evaluation of varieties to combine different datasets from multiple data sources. We conclude that currently available methods have the potential to overcome existing barriers to data synthesis and could set in motion a virtuous cycle that will encourage researchers to share data and collaborate on data-driven research. [ABSTRACT FROM AUTHOR]

Mitochondrial dysfunction contributes to cardiac pathologies. Barriers to new therapies include an incomplete understanding of underlying molecular culprits and a lack of effective mitochondria-targeted medicines. Here, we test the hypothesis that the cardiolipin-binding peptide elamipretide, a clinical-stage compound under investigation for diseases of mitochondrial dysfunction, mitigates impairments in mitochondrial structure-function observed after rat cardiac ischemia-reperfusion. Respirometry with permeabilized ventricular fibers indicates that ischemia-reperfusion induced decrements in the activity of complexes I, II, and IV are alleviated with elamipretide. Serial block face scanning electron microscopy used to create 3D reconstructions of cristae ultrastructure reveals that disease-induced fragmentation of cristae networks are improved with elamipretide. Mass spectrometry shows elamipretide did not protect against the reduction of cardiolipin concentration after ischemia-reperfusion. Finally, elamipretide improves biophysical properties of biomimetic membranes by aggregating cardiolipin. The data suggest mitochondrial structure-function are interdependent and demonstrate elamipretide targets mitochondrial membranes to sustain cristae networks and improve bioenergetic function. Allen and Pennington et al. show that the cardiolipin-binding peptide elamipretide mitigates disease-induced fragmentation of cristae networks following cardiac ischemia reperfusion in rats. This study suggests that elamipretide targets mitochondrial membranes to sustain cristae networks, improving their bioenergetic function. [ABSTRACT FROM AUTHOR]

Widespread dietary exposure of the population of Britain to bovine spongiform encephalopathy (BSE) prions in the 1980s and 1990s led to the emergence of variant Creutzfeldt-Jakob Disease (vCJD) in humans. Two previous appendectomy sample surveys (Appendix-1 and -2) estimated the prevalence of abnormal prion protein (PrP) in the British population exposed to BSE to be 237 per million and 493 per million, respectively. The Appendix-3 survey was recommended to measure the prevalence of abnormal PrP in population groups thought to have been unexposed to BSE. Immunohistochemistry for abnormal PrP was performed on 29,516 samples from appendices removed between 1962 and 1979 from persons born between 1891 through 1965, and from those born after 1996 that had been operated on from 2000 through 2014. Seven appendices were positive for abnormal PrP, of which two were from the pre-BSE-exposure era and five from the post BSE-exposure period. None of the seven positive samples were from appendices removed before 1977, or in patients born after 2000 and none came from individuals diagnosed with vCJD. There was no statistical difference in the prevalence of abnormal PrP across birth and exposure cohorts. Two interpretations are possible. Either there is a low background prevalence of abnormal PrP in human lymphoid tissues that may not progress to vCJD. Alternatively, all positive specimens are attributable to BSE exposure, a finding that would necessitate human exposure having begun in the late 1970s and continuing through the late 1990s. [ABSTRACT FROM AUTHOR]

Kentucky has lost over 80% of its wetlands, and because state-wide monitoring was historically minimal, this number is likely underestimated. The Kentucky Wetland Rapid Assessment Method (KY-WRAM) was developed to assess wetland condition. Our objective was to determine if the KY-WRAM reflects condition by comparing it to intensive assessment of amphibian communities, while simultaneously addressing which environmental variables explain the distribution and abundance of amphibian species in riverine wetlands. Wetlands (n = 44) were randomly selected and stratified by score for comparison of amphibian communities across a disturbance gradient. Factors including KY-WRAM score, nutrients, dissolved oxygen, landscape disturbance, predatory fish, and atrazine were included as model parameters to potentially explain species richness and abundance. KY-WRAM score explained the majority of variation in richness (R2 = 0.62), which was significantly greater at medium and high category sites compared to low. KY-WRAM was also an important predictor of abundance for seven amphibian species. Results indicate KY-WRAM is a good predictor of wetland condition and strongly relates to amphibian communities. Other variables that contributed to explaining abundance were landscape disturbance, wetland size, predatory fish, and river basin. Our study contributes to overall validation of the KY-WRAM. Future validation studies should focus on other basins, wetland types, and taxa. [ABSTRACT FROM AUTHOR]

We present new high-resolution absorption data for the important sesquioxide laser material Yb:Lu2O3 for the spectral range of 880–1020 nm, at various temperatures between 8 and 300 K, and for the zero-phonon region from 960 to 990 nm, at temperatures from 8 to 300 K. We have experimentally observed the C3i (0,1)–(1,3) transition for the first time, located at 880.7 nm at 8 K. Based on high confidence fitting functions to the experimental data, we provide the first complete compilation of all observed electronic and electronic–vibrational transitions. Detailed fitting and plots of the C2 and C3i zero-line data show an evolution of the linewidth from being predominantly electronic below about 100 K to being dominated by thermal processes above 100 K. We have also found evidence for a "soft" phase transition between 80 and 100 K that changes the local coordination environment. [ABSTRACT FROM AUTHOR]

Post-graduate training for physicians involves a high level of stress. High stress during training has the potential to cause burnout, a well-studied phenomenon in medical trainees. Burnout has previously been shown to increase the risk of mental health problems and medical error in trainees. Little research has been done on the impact of stress on new fellows in general and pediatric cardiology fellows in particular; understanding common sources of stress offers the opportunity to design targeted interventions to support trainee wellness. New trainees in Boston Children's Hospital's Pediatric Cardiology Fellowship program were asked to answer to the following question at the beginning of their training: "What are you afraid of in the coming year?" A qualitative content analysis was done on their anonymous responses. Responses were coded and analyzed for common themes. The overall analysis found that 83% of fellows reported fear of "fellowship/career responsibilities." The second most common theme was "failure/disappointment" (78%) followed by "personal life" (74%), "emotional exhaustion" (61%); least common was "new hospital environment" (37%). The most common individual fear was "increased clinical responsibility" reported by 65% of the new fellows, while 62% reported fears of "imposter syndrome," and 58% about "burnout." We found that fellows commonly report fears about both clinical and personal responsibilities, similar to stressors found in studies on residency. It is important for pediatric cardiology fellowships to develop early and specific interventions designed to assist fellows in managing both their new clinical responsibilities and their other stressors. [ABSTRACT FROM AUTHOR]

Because electrostatic flux does not depend on the location of the charges it links, it is independent of the quantum mechanical charge distribution in a molecule. By identifying a chemical bond with the electrostatic flux linking an atom's core to its valence charge, one can generate a purely classical model of chemical bonding. The resulting bond flux model shows that the chemical bond is a classical, not a quantum, concept. It makes no distinction between covalent and ionic bonds, but provides quantitative insights into chemical structure and properties that complement those of quantum theory. [ABSTRACT FROM AUTHOR]