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Many philosophers and Effective Altruist researchers have argued that the overall welfare of wild fish is negative. Since there are more fish than any other kind of wild vertebrate on earth (even when taken together), the view that suffering is predominate among wild fish is a key part of their larger suggestion that the overall welfare of wild vertebrates is negative, a view I'll call 'wildlife pessimism.' Correspondingly, undermining the wildlife pessimist's view might largely be accomplished simply by taking a closer look at their arguments concerning fish. Focusing on fish alone will allow for a greater depth of empirical analysis than has hitherto been possible in the wildlife welfare debate, which usually features attempts to discuss all wild animals at once. As I will show, wildlife optimism is at least as likely as wildlife pessimism. That is, it seems just as plausible that wild fish have a welfare level that is neutral or positive overall. [ABSTRACT FROM AUTHOR]

Introduction: Knee osteoarthritis is a prevalent condition frequently necessitating knee replacement surgery, with demand projected to rise substantially. Partial knee arthroplasty (PKA) offers advantages over total knee arthroplasty (TKA), yet its utilisation remains low despite guidance recommending consideration alongside TKA in shared decision making. Radiographic decision aids exist but are underutilised due to clinician time constraints. Materials and methods: This research develops a novel radiographic artificial intelligence (AI) tool using a dataset of knee radiographs and a panel of expert orthopaedic surgeons' assessments. Six AI models were trained to identify PKA candidacy. Results: 1241 labelled four-view radiograph series were included. Models achieved statistically significant accuracies above random assignment, with EfficientNet-ES demonstrating the highest performance (AUC 95%, F1 score 83% and accuracy 80%). Conclusions: The AI decision tool shows promise in identifying PKA candidates, potentially addressing underutilisation of this procedure. Its integration into clinical practice could enhance shared decision making and improve patient outcomes. Further validation and implementation studies are warranted to assess real-world utility and impact. [ABSTRACT FROM AUTHOR]

We present major progress towards the determination of the last missing piece for the pressure of a Yang-Mills plasma at high temperatures at order g6 in the strong coupling constant. This order is of key importance due to its role in resolving the long-standing infrared problem of finite-temperature field theory within a dimensionally reduced effective field theory setup. By systematically applying linear transformations of integration variables, or momentum shifts, we resolve equivalences between different representations of Feynman sum-integrals on the integrand level, transforming those into a canonical form. At the order g6, this results in reducing a sum of O (100000) distinct sum-integrals which are produced from all four-loop vacuum diagrams down to merely 21. Furthermore, we succeed to map 11 of those onto known lower-loop structures. This leaves only 10 genuine 4-loop sum-integrals to be evaluated, thereby bringing the finalization of three decades of theoretical efforts within reach. [ABSTRACT FROM AUTHOR]

Assessing physical frailty (PF) is vital for early risk detection, tailored interventions, preventive care, and efficient healthcare planning. However, traditional PF assessments are often impractical, requiring clinic visits and significant resources. We introduce a video-based frailty meter (vFM) that utilizes machine learning (ML) to assess PF indicators from a 20 s exercise, facilitating remote and efficient healthcare planning. This study validates the vFM against a sensor-based frailty meter (sFM) through elbow flexion and extension exercises recorded via webcam and video conferencing app. We developed the vFM using Google's MediaPipe ML model to track elbow motion during a 20 s elbow flexion and extension exercise, recorded via a standard webcam. To validate vFM, 65 participants aged 20–85 performed the exercise under single-task and dual-task conditions, the latter including counting backward from a random two-digit number. We analyzed elbow angular velocity to extract frailty indicators—slowness, weakness, rigidity, exhaustion, and unsteadiness—and compared these with sFM results using intraclass correlation coefficient analysis and Bland–Altman plots. The vFM results demonstrated high precision (0.00–7.14%) and low bias (0.00–0.09%), showing excellent agreement with sFM outcomes (ICC(2,1): 0.973–0.999), unaffected by clothing color or environmental factors. The vFM offers a quick, accurate method for remote PF assessment, surpassing previous video-based frailty assessments in accuracy and environmental robustness, particularly in estimating elbow motion as a surrogate for the 'rigidity' phenotype. This innovation simplifies PF assessments for telehealth applications, promising advancements in preventive care and healthcare planning without the need for sensors or specialized infrastructure. [ABSTRACT FROM AUTHOR]

A medium-to-high level of physical activity (PA) may have at least a short-term positive effect on psychopathology in children and adolescents. Hence, the objective of this study was to investigate the long-term effects of PA in non-adult age groups on their general mental health problems and/or ADHD symptoms, using trajectories of concurrent development over a period of 10 years. This study employed data from the German Health Interview and Examination Survey for Children and Adolescents (KiGGS) collected at three time points (baseline, Wave 1, Wave 2, over 10 years) from 17,640 children and adolescents. Using parent-reported data from the Strengths and Difficulties Questionnaire (SDQ), different developmental trajectories of general mental health problems (SDQ-total) and ADHD symptoms (SDQ-H/I) were identified with latent class mixed models (LCMM) statistics. This was also applied to parent- and self-reported data of three levels of PA. The latter was assessed according to WHO recommendations. The joint probability of class membership for SDQ-total as well as ADHD symptoms with PA was calculated to generate the concurrent developmental trajectories between variables. Results showed a 4-class trajectory model for both SDQ-total and ADHD symptoms among boys and girls. The majority of children and adolescents showed "low general difficulties" and "low ADHD symptoms" over the period of 10 years. Three distinct trajectories in boys and four distinct trajectories in girls were found for PA. Most of the participants showed an "increasing–decreasing activity" trajectory. No statistically significant correlations were found between the different SDQ-total or ADHD symptom trajectories and the trajectories of PA in the two genders. Taken together, our findings did not indicate any significant relationship between waxing and waning PA course over 10 years and various classes of mental health problems for children and adolescents. In contrast to our cross-sectional findings, no steady long-term medium/high-level of PA was present, which could (at least partly) explain the non-significant findings. [ABSTRACT FROM AUTHOR]

Background: Suboptimal nitrogen availability is a primary constraint for crop production in low-input agroecosystems, while nitrogen fertilization is a primary contributor to the energy, economic, and environmental costs of crop production in high-input agroecosystems. In this article we consider avenues to develop crops with improved nitrogen capture and reduced requirement for nitrogen fertilizer. Scope: Intraspecific variation for an array of root phenotypes has been associated with improved nitrogen capture in cereal crops, including architectural phenotypes that colocalize root foraging with nitrogen availability in the soil; anatomical phenotypes that reduce the metabolic costs of soil exploration, improve penetration of hard soil, and exploit the rhizosphere; subcellular phenotypes that reduce the nitrogen requirement of plant tissue; molecular phenotypes exhibiting optimized nitrate uptake kinetics; and rhizosphere phenotypes that optimize associations with the rhizosphere microbiome. For each of these topics we provide examples of root phenotypes which merit attention as potential selection targets for crop improvement. Several cross-cutting issues are addressed including the importance of soil hydrology and impedance, phenotypic plasticity, integrated phenotypes, in silico modeling, and breeding strategies using high throughput phenotyping for co-optimization of multiple phenes. Conclusions: Substantial phenotypic variation exists in crop germplasm for an array of root phenotypes that improve nitrogen capture. Although this topic merits greater research attention than it currently receives, we have adequate understanding and tools to develop crops with improved nitrogen capture. Root phenotypes are underutilized yet attractive breeding targets for the development of the nitrogen efficient crops urgently needed in global agriculture. [ABSTRACT FROM AUTHOR]

Objectives: To quantify brain microstructural changes in recently diagnosed relapsing-remitting multiple sclerosis (RRMS) using longitudinal T1 measures, and determine their associations with clinical disability. Methods: Seventy-nine people with recently diagnosed (< 6 months) RRMS were recruited from a single-centre cohort sub-study, and underwent baseline and 1-year brain MRI, including variable flip angle T1 mapping. Median T1 was measured in white matter lesions (WML), normal-appearing white matter (NAWM), cortical/deep grey matter (GM), thalami, basal ganglia and medial temporal regions. Prolonged T1 (≥ 2.00 s) and supramedian T1 (relative to cohort WML values) WML voxel counts were also measured. Longitudinal change was assessed with paired t-tests and compared with Bland-Altman limits of agreement from healthy control test-retest data. Regression analyses determined relationships with Expanded Disability Status Scale (EDSS) score and dichotomised EDSS outcomes (worsening or stable/improving). Results: Sixty-two people with RRMS (mean age 37.2 ± 10.9 [standard deviation], 48 female) and 11 healthy controls (age 44 ± 11, 7 female) contributed data. Prolonged and supramedian T1 WML components increased longitudinally (176 and 463 voxels, respectively; p <.001), and were associated with EDSS score at baseline (p <.05) and follow-up (supramedian: p <.01; prolonged: p <.05). No cohort-wide median T1 changes were found; however, increasing T1 in WML, NAWM, cortical/deep GM, basal ganglia and thalami was positively associated with EDSS worsening (p <.05). Conclusion: T1 is sensitive to brain microstructure changes in early RRMS. Prolonged WML T1 components and subtle changes in NAWM and GM structures are associated with disability. Clinical relevance statement: MRI T1 brain mapping quantifies disability-associated white matter lesion heterogeneity and subtle microstructural damage in normal-appearing brain parenchyma in recently diagnosed RRMS, and shows promise for early objective disease characterisation and stratification. Key Points: • Quantitative T1 mapping detects brain microstructural damage and lesion heterogeneity in recently diagnosed relapsing-remitting multiple sclerosis. • T1 increases in lesions and normal-appearing parenchyma, indicating microstructural damage, are associated with worsening disability. • Brain T1 measures are objective markers of disability-relevant pathology in early multiple sclerosis. [ABSTRACT FROM AUTHOR]

This non-experimental quantitative study investigated medical school faculty members' behavioral intention to use and actual usage behavior of technology in inquiry-based learning activities in medical schools in the United States by applying the unified theory of acceptance and use of technology (UTAUT). In medical education, situational problems for students to solve typically incorporate instructive clinical cases to guide problem-solving and prepare them for their professional lives as clinicians. Technology-infused inquiry-based learning pedagogy can require significant paradigm shifts for both students and instructors. It can impact the level of responsibility students take upon themselves for their own learning, and use of a pedagogy instructors may find unfamiliar, to deliver content. Major findings demonstrated performance expectancy, effort expectancy, and social influence had a significant relationship with behavioral intention to use technology for teaching medical education inquiry-based activities. Gender and voluntariness of use were both found to have significant effects on the relationship between performance expectancy and behavioral intention to use technology. The results of this study can aid stakeholders in providing support mechanisms for faculty to adopt technology for teaching and learning. This is possibly the first of its kind on the application of this theoretical model to address medical educators' behavioral intention to use and actual usage behavior of educational technologies for the delivery of inquiry-based learning activities. [ABSTRACT FROM AUTHOR]

Genome-wide association studies (GWAS) in long-lived human populations have led to identification of variants associated with Alzheimer's disease and cardiovascular disease, the latter being the most common cause of mortality in people worldwide. In contrast, naturally occurring cancer represents the leading cause of death in pet dogs, and specific breeds like the Golden Retriever (GR) carry up to a 65% cancer-related death rate. We hypothesized that GWAS of long-lived GRs might lead to the identification of genetic variants capable of modifying longevity within this cancer-predisposed breed. A GWAS was performed comparing GR dogs ≥ 14 years to dogs dying prior to age 12 which revealed a significant association to ERBB4, the only member of the epidermal growth factor receptor family capable of serving as both a tumor suppressor gene and an oncogene. No coding variants were identified, however, distinct haplotypes in the 5′UTR were associated with reduced lifespan in two separate populations of GR dogs. When all GR dogs were analyzed together (n = 304), the presence of haplotype 3 was associated with shorter survival (11.8 years vs. 12.8 years, p = 0.024). GRs homozygous for haplotype 3 had the shortest survival, and GRs homozygous for haplotype 1 had the longest survival (11.6 years vs. 13.5 years, p = 0.0008). Sub-analyses revealed that the difference in lifespan for GRs carrying at least 1 copy of haplotype 3 was specific to female dogs (p = 0.009), whereas survival remained significantly different in both male and female GRs homozygous for haplotype 1 or haplotype 3 (p = 0.026 and p = 0.009, respectively). Taken together, these findings implicate a potential role for ERBB4 in GR longevity and provide evidence that within-breed canine lifespan studies could serve as a mechanism to identify favorable or disease-modifying variants important to the axis of aging and cancer. [ABSTRACT FROM AUTHOR]

Semaphorin-3A (SEMA3A) functions as a chemorepulsive signal during development and can affect T cells by altering their filamentous actin (F-actin) cytoskeleton. The exact extent of these effects on tumour-specific T cells are not completely understood. Here we demonstrate that Neuropilin-1 (NRP1) and Plexin-A1 and Plexin-A4 are upregulated on stimulated CD8+ T cells, allowing tumour-derived SEMA3A to inhibit T cell migration and assembly of the immunological synapse. Deletion of NRP1 in both CD4+ and CD8+ T cells enhance CD8+ T-cell infiltration into tumours and restricted tumour growth in animal models. Conversely, over-expression of SEMA3A inhibit CD8+ T-cell infiltration. We further show that SEMA3A affects CD8+ T cell F-actin, leading to inhibition of immune synapse formation and motility. Examining a clear cell renal cell carcinoma patient cohort, we find that SEMA3A expression is associated with reduced survival, and that T-cells appear trapped in SEMA3A rich regions. Our study establishes SEMA3A as an inhibitor of effector CD8+ T cell tumour infiltration, suggesting that blocking NRP1 could improve T cell function in tumours. Interactions between Semaphorin-3A (SEMA3A) and Neuropilin-1 (NRP1) and Plexin-A1 and Plexin-A4 have been shown to affect T cell development. Here the authors investigate how these interactions affect CD8+ T cells in tumour immunity, showing that NRP-1, Plexin-A1 and Plexin-A4 are upregulated on T cells allowing tumour derived SEMA3A to inhibit CD8+ T cell migration and function. [ABSTRACT FROM AUTHOR]

Introduction: There is a lack of data on the use of thermography for elbow joint inflammation assessment among patients with rheumatoid arthritis (RA). Hence, we aimed to compare thermography with ultrasonography (a more established imaging modality for joint inflammation assessment) in the assessment of inflammation in the elbows of patients with RA. Methods: Standardised minimum (Tmin), maximum (Tmax) and average (Tavg) temperatures at each elbow (medial, lateral, posterior and anterior aspects) were summed to obtain the thermographic parameters MIN, MAX and AVG, respectively. Ultrasound parameters of elbow joint inflammation included total greyscale (TGS) and total power Doppler (TPD) scores. Pearson's correlation coefficient was utilized for correlation analysis between parameters. The relationship between parameters was characterized using simple linear regression. Results: Sixty elbows were evaluated from 30 patients with RA in this cross-sectional study. Thermographic parameters (MIN, MAX and AVG) showed significant correlation (P < 0.05) with (1) TPD scores at both elbows (correlation coefficient ranging 0.40 to 0.55) and (2) TGS scores at the right elbow (correlation coefficient ranging 0.39 to 0.42). A statistically significant relationship (P values ranging from 0.002 to 0.033) between parameters was demonstrable as follows: (1) MIN, MAX and AVG versus TPD scores (bilateral elbows) and (2) MIN, MAX and AVG versus TGS scores (right elbow). Conclusion: Thermographic temperatures have been demonstrated to correlate with ultrasound-detected joint inflammation at the elbow in patients with RA. The association is more consistently observed with ultrasound PD joint inflammation than its GS counterpart. [ABSTRACT FROM AUTHOR]

Modern photon counting detectors allow the calculation of virtual monoenergetic or material decomposed X-ray images but are not yet used for dental panoramic radiography systems. To assess the diagnostic potential and image quality of photon counting detectors in dental panoramic radiography, ethics approval from the local ethics committee was obtained for this retrospective study. Conventional CT scans of the head and neck region were segmented into bone and soft tissue. The resulting datasets were used to calculate panoramic equivalent thickness bone and soft tissue images by forward projection, using a geometry like that of conventional panoramic radiographic systems. The panoramic equivalent thickness images were utilized to generate synthetic conventional panoramic radiographs and panoramic virtual monoenergetic radiographs at various energies. The conventional, two virtual monoenergetic images at 40 keV and 60 keV, and material-separated bone and soft tissue panoramic equivalent thickness X-ray images simulated from 17 head CTs were evaluated in a reader study involving three experienced radiologists regarding their diagnostic value and image quality. Compared to conventional panoramic radiographs, the material-separated bone panoramic equivalent thickness image exhibits a higher image quality and diagnostic value in assessing the bone structure p <. 001 and details such as teeth or root canals p <. 001 . Panoramic virtual monoenergetic radiographs do not show a significant advantage over conventional panoramic radiographs. The conducted reader study shows the potential of spectral X-ray imaging for dental panoramic imaging to improve the diagnostic value and image quality. [ABSTRACT FROM AUTHOR]

Interleukin-10 (IL-10) is a key anti-inflammatory cytokine that can limit immune cell activation and cytokine production in innate immune cell types1. Loss of IL-10 signalling results in life-threatening inflammatory bowel disease in humans and mice—however, the exact mechanism by which IL-10 signalling subdues inflammation remains unclear2–5. Here we find that increased saturated very long chain (VLC) ceramides are critical for the heightened inflammatory gene expression that is a hallmark of IL-10 deficiency. Accordingly, genetic deletion of ceramide synthase 2 (encoded by Cers2), the enzyme responsible for VLC ceramide production, limited the exacerbated inflammatory gene expression programme associated with IL-10 deficiency both in vitro and in vivo. The accumulation of saturated VLC ceramides was regulated by a decrease in metabolic flux through the de novo mono-unsaturated fatty acid synthesis pathway. Restoring mono-unsaturated fatty acid availability to cells deficient in IL-10 signalling limited saturated VLC ceramide production and the associated inflammation. Mechanistically, we find that persistent inflammation mediated by VLC ceramides is largely dependent on sustained activity of REL, an immuno-modulatory transcription factor. Together, these data indicate that an IL-10-driven fatty acid desaturation programme rewires VLC ceramide accumulation and aberrant activation of REL. These studies support the idea that fatty acid homeostasis in innate immune cells serves as a key regulatory node to control pathologic inflammation and suggests that ‘metabolic correction’ of VLC homeostasis could be an important strategy to normalize dysregulated inflammation caused by the absence of IL-10.IL-10 exerts its anti-inflammatory activity in macrophages by increasing the expression of enzymes that promote fatty acid desaturation and downstream regulation of the transcription factor REL. [ABSTRACT FROM AUTHOR]

Mitochondrial Ca2+ overload can mediate mitochondria-dependent cell death, a major contributor to several human diseases. Indeed, Duchenne muscular dystrophy (MD) is driven by dysfunctional Ca2+ influx across the sarcolemma that causes mitochondrial Ca2+ overload, organelle rupture, and muscle necrosis. The mitochondrial Ca2+ uniporter (MCU) complex is the primary characterized mechanism for acute mitochondrial Ca2+ uptake. One strategy for preventing mitochondrial Ca2+ overload is deletion of the Mcu gene, the pore forming subunit of the MCU-complex. Conversely, enhanced MCU-complex Ca2+ uptake is achieved by deleting the inhibitory Mcub gene. Here we show that myofiber-specific Mcu deletion was not protective in a mouse model of Duchenne MD. Specifically, Mcu gene deletion did not reduce muscle histopathology, did not improve muscle function, and did not prevent mitochondrial Ca2+ overload. Moreover, myofiber specific Mcub gene deletion did not augment Duchenne MD muscle pathology. Interestingly, we observed MCU-independent Ca2+ uptake in dystrophic mitochondria that was sufficient to drive mitochondrial permeability transition pore (MPTP) activation and skeletal muscle necrosis, and this same type of activity was observed in heart, liver, and brain mitochondria. These results demonstrate that mitochondria possess an uncharacterized MCU-independent Ca2+ uptake mechanism that is sufficient to drive MPTP-dependent necrosis in MD in vivo. [ABSTRACT FROM AUTHOR]

Rosacea, a chronic skin condition affecting millions of people in the USA, leads to significant social and professional stigmatization. Effective management strategies are crucial to alleviate symptoms and improve patients' quality of life. Encapsulated benzoyl peroxide 5% (E-BPO 5%) is a newly FDA-approved topical treatment for rosacea that shows promise in enhancing therapeutic response and minimizing skin irritation. This review aims to assess the role of recently FDA approved E-BPO 5% in the current treatment landscape for rosacea management, as it is not yet included in clinical guidelines that predominantly rely on older approved therapies. The review focuses on randomized controlled trials conducted in English-speaking adults. It evaluates the efficacy, safety, and tolerability of various US Food and Drug Administration (FDA)-approved agents used for rosacea treatment, including E-BPO cream, metronidazole gel, azelaic acid gel and foam, ivermectin cream, minocycline foam, oral doxycycline, brimonidine gel, and oxymetazoline HCl cream. Existing therapies have been effective in reducing papulopustular lesions and erythema associated with rosacea for many years. E-BPO 5% offers a promising addition to the treatment options due to its microencapsulation technology, which prolongs drug delivery time and aims to improve therapeutic response while minimizing skin irritation. Further research is necessary to determine the exact role of E-BPO 5% in the therapeutic landscape for rosacea. However, based on available evidence, E-BPO 5% shows potential as a valuable treatment option for managing inflammatory lesions of rosacea, and it may offer benefits to patients including: rapid onset of action, demonstrated efficacy by Week 2, excellent tolerability, and sustained long-term results for up to 52 weeks of treatment. [ABSTRACT FROM AUTHOR]

We derive analytic results for scalar massless bosonic vacuum sum-integrals at two loops. Building upon a recent factorization proof of massive two-loop vacuum integrals, we are able to solve the corresponding Matsubara sums and map the result onto one-loop structures, thereby proving factorization also in the sum-integral setting. Analytic results are provided for generic integer-valued propagator- and numerator-powers of the class of sum-integrals under consideration, allowing to eliminate them from any perturbative expansion, dramatically simplifying the evaluation of some observables encountered e.g. in hot QCD. [ABSTRACT FROM AUTHOR]

We explored the behavioral flexibility of Commissaris’s long-tongued bats through a spatial serial reversal foraging task. Bats kept in captivity for short periods were trained to obtain nectar rewards from two artificial flowers. At any given time, only one of the flowers provided rewards and these reward contingencies reversed in successive blocks of 50 flower visits. All bats detected and responded to reversals by making most of their visits to the currently active flower. As the bats experienced repeated reversals, their preference re-adjusted faster. Although the flower state reversals were theoretically predictable, we did not detect anticipatory behavior, that is, frequency of visits to the alternative flower did not increase within each block as the programmed reversal approached. The net balance of these changes was a progressive improvement in performance in terms of the total proportion of visits allocated to the active flower. The results are compatible with, but do not depend on, the bats displaying an ability to ‘learn to learn’ and show that the dynamics of allocation of effort between food sources can change flexibly according to circumstances. [ABSTRACT FROM AUTHOR]

Tolvaptan is the first disease-modifying drug proven to slow eGFR decline in high-risk patients with ADPKD. However, barriers from the patient perspective to its use in real-life settings have not been systemically examined in a large cohort. This was a single-center, retrospective study of 523 existing or new patients with ADPKD followed at the Center for Innovative Management of PKD in Toronto, Ontario, between January 1, 2016 to December 31, 2018. All patients underwent clinical assessment including total kidney volume measurements and Mayo Clinic Imaging Class (MCIC). Those who were deemed to be at high risk were offered tolvaptan with their preference (yes or no) and reasons for their choices recorded. Overall, 315/523 (60%) patients had MCIC 1C-1E; however, only 96 (30%) of them were treated with tolvaptan at their last follow-up. Among these high-risk patients, those not treated versus treated with tolvaptan were more likely to have a higher eGFR (82 ± 26 vs. 61 ± 27 ml/min/1.73 m2), CKD stages 1–2 (79% vs. 41%), and MCIC 1C (63% vs. 31%). The most common reasons provided for not taking tolvaptan were lifestyle preference related to the aquaretic effect (51%), older age ≥ 60 (12%), and pregnancy/family planning (6%). In this real-world experience, at least 60% of patients with ADPKD considered to be at high risk for progression to ESKD by imaging were not treated with tolvaptan; most of them had early stages of CKD with well-preserved eGFR and as such, were prime targets for tolvaptan therapy to slow disease progression. Given that the most common reason for tolvaptan refusal was the concern for intolerability of the aquaretic side-effect, strategies to mitigate this may help to reduce this barrier to tolvaptan therapy. [ABSTRACT FROM AUTHOR]

Barbara McClintock recognized transposable elements originally by the movement of a site of chromosomal breakage, a genetic element called Dissociation (Ds) that was induced to break or transpose by another element she called Activator. The chromosome breaking version, when analyzed on the molecular level was one transposon inside another. It is now known that transposition involving transposon termini in non-standard orientation with reference to each other results in chromosomal breakage. Here we used engineered transposon ends together with a phenotypic marker to cause targeted chromosomal breaks. The results indicate that engineered direct orientation of the naturally inverted repeats of Dissociation can cause chromosomal breakage at the transgenic sites of insertion. [ABSTRACT FROM AUTHOR]

To investigate the effectiveness of paced breathing guided by biofeedback on clinical and functional outcomes of patients with chronic obstructive pulmonary disease (COPD). An uncontrolled pilot study comprising a training with paced breathing guided by biofeedback (three sessions of 35 min per week) was conducted over four weeks (12 sessions). Assessments included respiratory muscle strength (using a manovacuometer), anxiety (Beck Anxiety Inventory), depression (Beck Depression Inventory), dyspnea (Baseline Dyspnea Index), functionality (Timed Up and Go Test), health status (COPD Assessment Test) and health-related quality of life (Saint George's Respiratory Questionnaire). The sample consisted of nine patients with a mean age of 68.2 ± 7.8 years. After intervention, patients significantly improved in health status and health-related quality of life, assessed using the COPD Assessment Test (p < 0.001) and Saint George's Respiratory Questionnaire (p < 0.001); anxiety (p < 0.001); and depression (p = 0.001). Patients also significantly improved in dyspnea (p = 0.008), TUG (p = 0.015), CC Score (p = 0.031), and maximum inspiratory (p = 0.004) and expiratory pressures (p < 0.001). An intervention with paced breathing guided by biofeedback promoted positive results on dyspnea, anxiety, depression, health status and perceived health-related quality of life in patients with COPD. Moreover, gains in respiratory muscle strength and functional performance were observed, affecting the performance of daily activities. [ABSTRACT FROM AUTHOR]

Scholars have spent decades arguing that policy entrepreneurs, change agents who work individually and in groups to influence the policy process, can be crucial in introducing policy innovation and spurring policy change. How to identify policy entrepreneurs empirically has received less attention. This oversight is consequential because scholars trying to understand when policy entrepreneurs emerge, and why, and what makes them more or less successful, need to be able to identify these change agents reliably and accurately. This paper explores the ways policy entrepreneurs are currently identified and highlights issues with current approaches. We introduce a new technique for eliciting and distinguishing policy entrepreneurs, coupling automated and manual analysis of local news media and a survey of policy entrepreneur candidates. We apply this technique to the empirical case of unconventional oil and gas drilling in Pennsylvania and derive some tentative results concerning factors which increase entrepreneurial efficacy. [ABSTRACT FROM AUTHOR]

Microencapsulation has received extensive attention because of its various applications. Since its inception in the 1940s, this technology has been used across several areas, including the chemical, food, and pharmaceutical industries. Over-the-counter skin products often contain ingredients that readily and unevenly degrade upon contact with the skin. Enclosing these substances within a silica shell can enhance their stability and better regulate their delivery onto and into the skin. Silica microencapsulation uses silica as the matrix material into which ingredients can be embedded to form microcapsules. The FDA recognizes amorphous silica as a safe inorganic excipient and recently approved two new topical therapies for the treatment of rosacea and acne. The first approved formulation uses a novel silica-based controlled vehicle delivery technology to improve the stability of two active ingredients that are normally not able to be used in the same formulation due to potential instability and drug degradation. The formulation contains 3.0% benzoyl peroxide (BPO) and 0.1% tretinoin topical cream to treat acne vulgaris in adults and pediatric patients. The second formulation contains silica microencapsulated 5.0% BPO topical cream to treat inflammatory rosacea lesions in adults. Both formulations use the same amorphous silica sol–gel microencapsulation technology to improve formulation stability and skin compatibility parameters. [ABSTRACT FROM AUTHOR]

Objectives: This study aims to describe physicians' perspectives on the use of computed tomography (CT) in patients with sepsis. Methods: In January 2022, physicians of a large European university medical center were surveyed using a web-based questionnaire asking about their views on the role of CT in sepsis. A total of 371 questionnaires met the inclusion criteria and were analyzed using work experience, workplace, and medical specialty of physicians as variables. Chi-square tests were performed. Results: Physicians considered the ability to detect an unknown focus as the greatest benefit of CT scans in sepsis (70.9%, n = 263/371). Two clinical criteria — "signs of decreased vigilance" (89.2%, n = 331/371) and "increased catecholamine demand" (84.7%, n = 314/371) — were considered highly relevant for a CT request. Elevated procalcitonin (82.7%, n = 307/371) and lactate levels (83.6%, n = 310/371) were consistently found to be critical laboratory values to request a CT. As long as there is evidence of infection in one organ region, most physicians (42.6%, n = 158/371) would order a CT scan based on clinical assessment. Combined examination of the chest, abdomen, and pelvis was favored (34.8%, n = 129/371) in cases without clinical clues of an infection source. A time window of ≥ 1–6 h was preferred for both CT examinations (53.9%, n = 200/371) and CT-guided interventions (59.3%, n = 220/371) in patients with sepsis. Conclusion: Despite much consensus, there are significant differences in attitudes towards the use of CT in septic patients among physicians from different workplaces and medical specialties. Knowledge of these perspectives may improve patient management and interprofessional communication. Key Points: Despite interdisciplinary consensus on the use of CT in sepsis, statistically significant differences in the responses are apparent among physicians from different workplaces and medical specialties. The detection of a previously unknown source of infection and the ability to plan interventions and/or surgery based on CT findings are considered key advantages of CT in septic patients. Timing of CT reflects the requirements of specific disciplines. [ABSTRACT FROM AUTHOR]

The thermal conversion of oil sludge has been presented as a promising alternative for treating this residue in the petroleum industry. The chemical and energetic characterization of residues is essential in determining the most suitable thermochemical conversion process for their treatment and the appropriate operational parameters for the process. In this sense, this study focuses on a non-isothermal thermo-kinetic analysis of oil sludge to determine the influence of temperature and heating rate on the composition of the evolved gases produced during pyrolysis. Using the thermogravimetric analysis coupled with a Fourier-Transform Infrared Spectroscopy (FTIR), the kinetic and thermodynamic analysis of oil sludge were carried out by applying the Kissinger, Friedman, Ozawa-Flynn-Wall, and the Coats-Redfern methods, leading to the determination of oil sludge activation energy (Ea) consonant with its pyrolysis. In a dry nitrogen atmosphere, four different heating rates were used (5, 10, 20, and 50 K min−1). The active region occurs between 373 and 873 K. The overall pyrolysis process was considered a two-step process with two conversion stages. The first one ranges from 5 to 55% conversion, with the Ea ranging from 44.10 to 45.83 kJmol−1 and the pre-exponential factor (A) ranging from 1.95 × 105 to 1.05 × 10−3 min−1. The second stage presents an Ea range from 107.38 to 134.04 kJ mol−1 and a ranging from 7.93 × 1013 to 2.91 × 10–3 min−1. The FTIR results and thermogravimetric data indicate the generation of mainly H2O, CO2, and aliphatic hydrocarbons such as –CH3, –CH2, and CH4. At 10 and 20 K min−1, the results present higher quantities of hydrocarbons and lower amounts of H2O. The results show that by increasing the process temperature and heating rate, pyrolysis can be an efficient method for treatment and simultaneous energy recovery, bio-char, and bio-oil from oil sludge. [ABSTRACT FROM AUTHOR]

Endosomal maturation is critical for robust and timely cargo transport to specific cellular compartments. The most prominent model of early endosomal maturation involves a phosphoinositide-driven gain or loss of specific proteins on individual endosomes, emphasising an autonomous and stochastic description. However, limitations in fast, volumetric imaging long hindered direct whole cell-level measurements of absolute numbers of maturation events. Here, we use lattice light-sheet imaging and bespoke automated analysis to track individual very early (APPL1-positive) and early (EEA1-positive) endosomes over the entire population, demonstrating that direct inter-endosomal contact drives maturation between these populations. Using fluorescence lifetime, we show that this endosomal interaction is underpinned by asymmetric binding of EEA1 to very early and early endosomes through its N- and C-termini, respectively. In combination with agent-based simulation which supports a 'trigger-and-convert' model, our findings indicate that APPL1- to EEA1-positive maturation is driven not by autonomous events but by heterotypic EEA1-mediated interactions, providing a mechanism for temporal and population-level control of maturation. Newly formed endosomes mature into early endosomes by shedding one protein and acquiring another. Here, the authors describe a trigger-and-convert mechanism driven by endosomal collisions and fusions that govern timeliness in ensemble maturations. [ABSTRACT FROM AUTHOR]

Background: Many surgeons in low- and middle-income countries have described performing surgery using gasless (lift) laparoscopy due to inaccessibility of carbon dioxide and reliable electricity, but the safety and feasibility of the technique has not been well documented. We describe preclinical testing of the in vivo safety and utility of KeyLoop, a laparoscopic retractor system to enable gasless laparoscopy. Methods: Experienced laparoscopic surgeons completed a series of four laparoscopic tasks in a porcine model: laparoscopic exposure, small bowel resection, intracorporeal suturing with knot tying, and cholecystectomy. For each participating surgeon, the four tasks were completed in a practice animal using KeyLoop. Surgeons then completed these tasks using standard-of-care (SOC) gas laparoscopy and KeyLoop in block randomized order to minimize learning curve effect. Vital signs, task completion time, blood loss and surgical complications were compared between SOC and KeyLoop using paired nonparametric tests. Surgeons completed a survey on use of KeyLoop compared to gas laparoscopy. Abdominal wall tissue was evaluated for injury by a blinded pathologist. Results: Five surgeons performed 60 tasks in 15 pigs. There were no significant differences in times to complete the tasks between KeyLoop and SOC. For all tasks, there was a learning curve with task completion times related to learning the porcine model. There were no significant differences in blood loss, vital signs or surgical complications between KeyLoop and SOC. Eleven surgeons from the United States and Singapore felt that KeyLoop could be used to safely perform several common surgical procedures. No abdominal wall tissue injury was observed for either KeyLoop or SOC. Conclusions: Procedure times, blood loss, abdominal wall tissue injury and surgical complications were similar between KeyLoop and SOC gas laparoscopy for basic surgical procedures. This data supports KeyLoop as a useful tool to increase access to laparoscopy in low- and middle-income countries. [ABSTRACT FROM AUTHOR]

Volumetric muscle loss (VML) results in permanent functional deficits and remains a substantial regenerative medicine challenge. A coordinated immune response is crucial for timely myofiber regeneration, however the immune response following VML has yet to be fully characterized. Here, we leveraged dimensionality reduction and pseudo-time analysis techniques to elucidate the cellular players underlying a functional or pathological outcome as a result of subcritical injury or critical VML in the murine quadriceps, respectively. We found that critical VML resulted in a sustained presence of M2-like and CD206hiLy6Chi 'hybrid' macrophages whereas subcritical defects resolved these populations. Notably, the retained M2-like macrophages from critical VML injuries presented with aberrant cytokine production which may contribute to fibrogenesis, as indicated by their co-localization with fibroadipogenic progenitors (FAPs) in areas of collagen deposition within the defect. Furthermore, several T cell subpopulations were significantly elevated in critical VML compared to subcritical injuries. These results demonstrate a dysregulated immune response in critical VML that is unable to fully resolve the chronic inflammatory state and transition to a pro-regenerative microenvironment within the first week after injury. These data provide important insights into potential therapeutic strategies which could reduce the immune cell burden and pro-fibrotic signaling characteristic of VML. The immune cell dynamics that influence the pathological phenotype of a critical volumetric muscle loss (VML) injury that cannot regenerate versus a subcritical injury capable of regeneration are characterized using quadriceps VML mouse models. [ABSTRACT FROM AUTHOR]

A history of abortion is associated with cervical dysfunction during pregnancy, but there remains uncertainty about whether risk can be stratified by the abortion type, the abortion procedure, or number of previous abortions. The objective of this study was to verify the relationship between cervical dysfunction measures in pregnancies with and without a history of termination. Embase and Medline databases were searched from 01 January 1960 to 01 March 2022 resulting in a full-text review of 28 studies. The Newcastle–Ottawa Scale (NOS) was used to assess the quality and risk of bias for non-randomized studies. The meta-analysis consisted of 6 studies that met all inclusion and exclusion criteria and included a combined total of 2,513,044 pregnancies. Cervical dysfunction was defined as either cervical insufficiency/incompetence in 4 of the studies and as short cervix in the others. Results from a random-effects model using reported adjusted odds ratios (aOR) estimated an increase in the odds of 2.71 (95% CI 1.76, 4.16) for cervical dysfunction in the current pregnancy related to a history of induced or spontaneous abortion. Subgroup analyses with only induced abortions (surgical/medical) estimated an aOR of 2.54 (95% CI 1.41, 4.57), while studies limited to surgical abortions had an aOR of 4.08 (95% CI 2.84, 5.86). The risk of cervical dysfunction in the current pregnancy was also found to be dependent on the number of previous abortions. In this meta-analysis, a prior history of abortion, and specifically induced abortions, was associated with cervical dysfunction. The protocol was registered in PROSPERO (CRD42020209723). [ABSTRACT FROM AUTHOR]

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Thiol dioxygenases are a subset of non-heme mononuclear iron oxygenases that catalyze the O2-dependent oxidation of thiol-bearing substrates to yield sulfinic acid products. Cysteine dioxygenase (CDO) and 3-mercaptopropionic acid (3MPA) dioxygenase (MDO) are the most extensively characterized members of this enzyme family. As with many non-heme mononuclear iron oxidase/oxygenases, CDO and MDO exhibit an obligate-ordered addition of organic substrate before dioxygen. As this substrate-gated O2-reactivity extends to the oxygen-surrogate, nitric oxide (NO), EPR spectroscopy has long been used to interrogate the [substrate:NO:enzyme] ternary complex. In principle, these studies can be extrapolated to provide information about transient iron-oxo intermediates produced during catalytic turnover with dioxygen. In this work, we demonstrate that cyanide mimics the native thiol-substrate in ordered-addition experiments with MDO cloned from Azotobacter vinelandii (AvMDO). Following treatment of the catalytically active Fe(II)-AvMDO with excess cyanide, addition of NO yields a low-spin (S = 1/2) (CN/NO)-Fe-complex. Continuous wave and pulsed X-band EPR characterization of this complex produced in wild-type and H157N variant AvMDO reveal multiple nuclear hyperfine features diagnostic of interactions within the first- and outer-coordination sphere of the enzymatic Fe-site. Spectroscopically validated computational models indicate simultaneous coordination of two cyanide ligands replaces the bidentate (thiol and carboxylate) coordination of 3MPA allowing for NO-binding at the catalytically relevant O2-binding site. This promiscuous substrate-gated reactivity of AvMDO with NO provides an instructive counterpoint to the high substrate-specificity exhibited by mammalian CDO for l-cysteine. [ABSTRACT FROM AUTHOR]

Introduction: Cartilage defects in the knee can be caused by injury, various types of arthritis, or degeneration. As a long-term consequence of cartilage defects, osteoarthritis can develop over time, often leading to the need for a total knee replacement (TKR). The treatment alternatives of chondral defects include, among others, microfracture, and matrix-associated autologous chondrocyte implantation (M-ACI). The purpose of this study was to determine cost-effectiveness of M-ACI in Germany with available mid- and long-term outcome data, with special focus on the avoidance of TKR. Materials and methods: We developed a discrete-event simulation (DES) that follows up individuals with cartilage defects of the knee over their lifetimes. The DES was conducted with a status-quo scenario in which M-ACI is available and a comparison scenario with no M-ACI available. The model included 10,000 patients with articular cartilage defects. We assumed Weibull distributions for short- and long-term effects for implant failures. Model outcomes were costs, number of TKRs, and quality-adjusted life years (QALYs). All analyses were performed from the perspective of the German statutory health insurance. Results: The majority of patients was under 45 years old, with defect sizes between 2 and 7 cm2 (mean: 4.5 cm2); average modeled lifetime was 48 years. In the scenario without M-ACI, 26.4% of patients required a TKR over their lifetime. In the M-ACI scenario, this was the case in only 5.5% of cases. Thus, in the modeled cohort of 10,000 patients, 2700 TKRs, including revisions, could be avoided. Patients treated with M-ACI experienced improved quality of life (22.53 vs. 21.21 QALYs) at higher treatment-related costs (18,589 vs. 14,134 € /patient) compared to those treated without M-ACI, yielding an incremental cost‐effectiveness ratio (ICER) of 3376 € /QALY. Conclusion: M-ACI is projected to be a highly cost‐effective treatment for chondral defects of the knee in the German healthcare setting. [ABSTRACT FROM AUTHOR]

Using age- and height-adjusted total kidney volume, the Mayo Clinic Imaging Classification provides a validated approach to assess the risk of chronic kidney disease (CKD) progression in autosomal dominant polycystic kidney disease (ADPKD), but requires excluding patients with atypical imaging patterns, whose clinical characteristics have been poorly defined. We report an analysis of the prevalence, clinical and genetic characteristics of patients with atypical polycystic kidney disease by imaging. Patients from the extended Toronto Genetic Epidemiology Study of Polycystic Kidney Disease recruited between 2016 and 2018 completed a standardized clinical questionnaire, kidney function assessment, genetic testing, and kidney imaging by magnetic resonance or computed tomography. We compared the prevalence, clinical features, genetics, and renal prognosis of atypical versus typical polycystic kidney disease by imaging. Forty-six of the 523 (8.8%) patients displayed atypical polycystic kidney disease by imaging; they were older (55 vs. 43 years; P < 0.001), and less likely to have a family history of ADPKD (26.1% vs. 74.6%; P < 0.001), a detectable PKD1 or PKD2 mutation (9.2% vs. 80.4%; P < 0.001), or progression to CKD stage 3 or stage 5 (P < 0.001). Patients with atypical polycystic kidney disease by imaging represent a distinct prognostic group with a low likelihood of progression to CKD. [ABSTRACT FROM AUTHOR]

Little guidance is available to assist wetland managers in developing climate adaptation plans. To facilitate development of recommendations for adaptation strategies, it is essential to first determine if or how wetland managers are addressing these challenges. We used an online survey to solicit feedback from wetland managers and biologists in the Southern Great Plains of North America to gain information on perceptions of wetland managers regarding climate change; assess how the effects of climate change are being addressed through management; and identify barriers to implementing climate change adaptation. The majority of wetland managers (63%) agreed they are currently experiencing effects of climate change in wetlands, and most respondents (76%) reported that changes in the timing of water availability throughout the year was the most likely impact. Managers reported using a diversity of approaches in managing for changing precipitation, with management of native and invasive plant species being the two most common practices. Lack of funding and personnel were the most commonly identified factors limiting manager's response to changing precipitation patterns. In addition, >50% of managers indicated uncertainty about the effects of climate change on wetlands as a barrier to management, which may relate to limited access to peer-reviewed science. While most of the management practices reported were short-term measures and may not reflect long-term adaptation for climate change, the fact that many managers are considering climate change in their management suggests that there is considerable opportunities to continue developing capacity for climate change adaptation in the region. [ABSTRACT FROM AUTHOR]

Introduction: Thyroidectomy is one of the most commonly performed surgical procedures worldwide. Although the mortality rate is currently approaching 0%, the incidence of complications in such a frequent surgery is not insignificant. The most frequent are postoperative hypoparathyroidism, recurrent injury, and asphyxial hematoma. The size of the thyroid gland has traditionally been considered one of the most important risk factors, but there is currently no study that analyzes it independently. The objective of this study is to analyze whether the size of the thyroid gland is an isolated risk factor for the development of postoperative complications. Patients and method: A prospective review of all patients who underwent total thyroidectomy at a third-level hospital between January 2019 and December 2021 was conducted. The thyroid volume was calculated preoperatively using ultrasound and, together with the weight of the definitive piece, was correlated with the development of postoperative complications. Results: One hundred twenty-one patients were included. When analyzing the incidence of complications based on the quartiles of weight and glandular volume, there were no significant differences in the incidence of transient or permanent hypoparathyroidism in any of the groups. No differences were found in terms of recurrent paralysis. No fewer parathyroid glands were visualized intraoperatively in patients with larger thyroid glands, nor did the number of them accidentally removed during surgery increase. In fact, a certain protective trend was observed with regard to the number of glands visualized and glandular size or in the relationship between thyroid volume and accidental gland removal, with no significant differences. Conclusion: The size of the thyroid gland has not been shown to be a risk factor for the development of postoperative complications, contrary to what has traditionally been considered. [ABSTRACT FROM AUTHOR]

Synthetic prions, generated de novo from minimal, non-infectious components, cause bona fide prion disease in animals. Transmission of synthetic prions to hosts expressing syngeneic PrPC results in extended, variable incubation periods and incomplete attack rates. In contrast, murine synthetic prions (MSP) generated via PMCA with minimal cofactors readily infected mice and hamsters and rapidly adapted to both species. To investigate if hamster synthetic prions (HSP) generated under the same conditions as the MSP are also highly infectious, we inoculated hamsters with HSP generated with either hamster wild type or mutant (ΔG54, ΔG54/M139I, M139I/I205M) recombinant PrP. None of the inoculated hamsters developed clinical signs of prion disease, however, brain homogenate from HSPWT- and HSPΔG54-infected hamsters contained PrPSc, indicating subclinical infection. Serial passage in hamsters resulted in clinical disease at second passage accompanied by changes in incubation period and PrPSc conformational stability between second and third passage. These data suggest the HSP, in contrast to the MSP, are not comprised of PrPSc, and instead generate authentic PrPSc via deformed templating. Differences in infectivity between the MSP and HSP suggest that, under similar generation conditions, the amino acid sequence of PrP influences generation of authentic PrPSc. [ABSTRACT FROM AUTHOR]

The harmful alga Heterosigma akashiwo possesses a hybrid nitrate reductase (NR) enzyme, NR2-2/2HbN, which has the potential to convert NO to nitrate for assimilation into biomass. In previous research, NR transcription in H. akashiwo was induced by nitrate while NR activity was inhibited by ammonium. Here, the capacity of H. akashiwo to use NO in the presence of nitrate and/or ammonium was investigated to understand the regulation of NO assimilation. Continuous cultures of H. akashiwo were acclimated to growth on nitrate, ammonium, or a mixture of both. Aliquots from these cultures were spiked with 15N-labeled NO. The expression of genes involved in nitrogen assimilation was evaluated, as well as nitrate reductase activity and assimilation of 15N-labeled nitrogen into algal biomass. Results showed that NO induced expression and activity of NR, and upregulated expression of GOGAT regardless of the presence of other inorganic nitrogen sources, while GS expression decreased over time. Furthermore, 15NO uptake and assimilation was significantly higher in cultures acclimated for growth on ammonium compared to cultures acclimated for growth on nitrate alone. Assimilation of NO may provide H. akashiwo with a competitive advantage in N-poor environments or areas with elevated NO. [ABSTRACT FROM AUTHOR]