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We studied ontogenetic variation in skull morphology in tiger snakes sampled from mainland South Australia (Coffin Bay), mainland Western Australia (Herdsman Lake), Franklin Island, and Hopkins Island. The snakes from the two islands were selected because of their unusually large absolute body and head size, likely attained as a result of dietary constraints and strong selective pressure during thousands of years of isolation on islands. We performed geometric morphometric analysis of the skulls from these snakes to identify and precisely quantify morphological differences. Island snakes are born larger (trunk length) than mainland snakes, and consequently also tend to have larger absolute head size at birth. The heads of island snakes also show a faster relative growth rate (positive allometry) compared to those of mainland snakes, likely to cope with the large prey items found on these islands. However, the snakes from the two islands differ from each other in terms of morphological change associated with ontogeny, especially with regard to a palatal bone (ectopterygoid), which, compared to mainland snakes, is relatively longer in the snakes from Hopkins Island but shorter in the snakes from Franklin Island. Some morphological traits potentially associated with promoting a larger gape were also observed in one of the mainland populations (Herdsman Lake), consistent with standing variability for selection. Our results reveal that discernible changes in morphology and allometry in skull bones have evolved in island populations of tiger snakes in less than 10 000 years, and suggest that the large heads of island tiger snakes might develop via slightly different paths through morphospace on different islands. [ABSTRACT FROM AUTHOR]

Background: Integrating molecular-targeted agents into combination chemotherapy is transformative for enhancing treatment outcomes in cancer. However, realizing the full potential of this approach requires a clear comprehension of the genetic dependencies underlying drug synergy. While the interactions between conventional chemotherapeutics are well-explored, the interplay of molecular-targeted agents with conventional chemotherapeutics remains a frontier in cancer treatment. Hence, we leveraged a powerful functional genomics approach to decode genomic dependencies that drive synergy in molecular-targeted agent/chemotherapeutic combinations in gastric adenocarcinoma, addressing a critical need in gastric cancer therapy. Methods: We screened pharmacological interactions between fifteen molecular-targeted agent/conventional chemotherapeutic pairs in gastric adenocarcinoma cells, and examined the genome-scale genetic dependencies of synergy integrating genome-wide CRISPR screening with the shRNA-based signature assay. We validated the synergy in cell death using fluorescence-based and lysis-dependent inference of cell death kinetics assay, and validated the genetic dependencies by single-gene knockout experiments. Results: Our combination screen identified SN-38/erlotinib as the drug pair with the strongest synergism. Functional genomics assays unveiled a genetic dependency signature of SN-38/erlotinib identical to SN-38. Remarkably, the enhanced cell death with improved kinetics induced by SN-38/erlotinib was attributed to erlotinib's off-target effect, inhibiting ABCG2, rather than its on-target effect on EGFR. Conclusion: In the era of precision medicine, where emphasis on primary drug targets prevails, our research challenges this paradigm by showcasing a robust synergy underpinned by an off-target dependency. Further dissection of the intricate genetic dependencies that underlie synergy can pave the way to developing more effective combination strategies in gastric cancer therapy. [ABSTRACT FROM AUTHOR]

We develop a Bayesian method for aggregating partial ranking data using the Thurstone model. Our implementation is a JAGS graphical model that allows each individual to rank any subset of items, and provides an inference about the latent true ranking of the items and the relative expertise of each individual. We demonstrate the method by analyzing data from new experiments that collected partial ranking data. In one experiment, participants were assigned subsets of items to rank; in the other experiment, participants could choose how many and which items they ranked. We show that our method works effectively for both sorts of partial ranking in applications to US city populations and the chronology of US presidents. We discuss the potential of the method for studying the wisdom of the crowd and other research problems that require aggregating incomplete or partial rankings. [ABSTRACT FROM AUTHOR]

The living coelacanth Latimeria (Sarcopterygii: Actinistia) is an iconic, so-called 'living fossil' within one of the most apparently morphologically conservative vertebrate groups. We describe a new, 3-D preserved coelacanth from the Late Devonian Gogo Formation in Western Australia. We assemble a comprehensive analysis of the group to assess the phylogeny, evolutionary rates, and morphological disparity of all coelacanths. We reveal a major shift in morphological disparity between Devonian and post-Devonian coelacanths. The newly described fossil fish fills a critical transitional stage in coelacanth disparity and evolution. Since the mid-Cretaceous, discrete character changes (representing major morphological innovations) have essentially ceased, while meristic and continuous characters have continued to evolve within coelacanths. Considering a range of putative environmental drivers, tectonic activity best explains variation in the rates of coelacanth evolution. Coelacanths are known for their conservative morphology. Here, the authors describe a 380 million year-old coelacanth fossil from the Gogo Formation (Western Australia) with morphology representative of a key transition where coelacanth morphology disparity shifts. [ABSTRACT FROM AUTHOR]

We study how people solve the optimal stopping problem of buying an airline ticket. Over a set of problems, people were given 12 opportunities to buy a ticket ranging from 12 months before travel to 1 day before. The distributions from which prices were sampled changed over time, following patterns observed in industry analysis of flight ticket pricing. We characterize the optimal decision process in terms of a set of thresholds that set the maximum purchase price for each time point. In a behavioral analysis, we find that the average price people pay is above the optimal, that there is little evidence people learn over the sequence of problems, but that there are likely significant individual differences in the way people make decisions. In a model-based analysis, we propose a set of nine possible decision strategies, based on how purchasing probabilities change according to time and the price of the ticket. Using Bayesian latent-mixture methods, we infer the strategies used by the participants, finding that some use purely time-based strategies, while others also attend to the price of the tickets. We conclude by noting the limitations in the strategies as accounts of people's decision making, highlighting the need to consider sequential effects and other context effects on purchasing behavior. [ABSTRACT FROM AUTHOR]

Background: Health care systems are increasingly screening for unmet social needs. The association between patient-reported social needs and health care utilization is not well understood. Objective: To investigate the association between patient-reported social needs, measured by the Protocol for Responding to and Assessing Patients' Assets, Risks, and Experiences (PRAPARE), and inpatient and emergency department (ED) utilization. Design: This cohort study analyzed merged 2017–2019 electronic health record (EHR) data across multiple health systems. Participants: Adult patients from a federally qualified health center (FQHC) in central North Carolina who completed PRAPARE as part of a primary care visit with behavioral health services. Main Measures: The count of up to 12 unmet social needs, aggregated as 0, 1, 2, or 3 +. Outcomes include the probability of an ED visit and hospitalization 12 months after PRAPARE assessment, modeled by logistic regressions controlling for age, sex, race, ethnicity, comorbidity burden, being uninsured, and prior utilization in the past 12 months. Key Results: The study population consisted of 1924 adults (38.7% male, 50.1% Black, 36.3% Hispanic, 55.9% unemployed, 68.2% of patients reported 1 + needs). Those with more needs were younger, more likely to be unemployed, and experienced greater comorbidity burden. 35.3% of patients had ED visit(s) and 36.3% had hospitalization(s) 1 year after PRAPARE assessment. In adjusted analysis, having 3 + needs was associated with a percentage point increase in the predicted probability of hospitalization (average marginal effect 0.06, SE 0.03, p < 0.05) compared with having 0 needs. Similarly, having 2 needs (0.07, SE 0.03, p < 0.05) or 3 + needs (0.06, SE 0.03, p < 0.05) was associated with increased probability of ED visits compared to 0 needs. Conclusions: Patient-reported social needs were common and associated with health care utilization patterns. Future research should identify interventions to address unmet social needs to improve health and avoid potentially preventable escalating medical intervention. [ABSTRACT FROM AUTHOR]

In the context of ever-growing demand for food and associated concerns regarding the environmental impacts of high-input agricultural systems, there is growing interest in mixed farm enterprises to deliver greater sustainability compared with mono-enterprise production systems. However, assessments of such systems are complex and require high-resolution data to determine the true value and interconnectivity across enterprises. Given the scarcity of information on mixed crop–livestock systems and the difficulties of its analysis, we perform life cycle assessment using temporally high-resolution data (2019–2022) from a long-term experiment in South America to evaluate the 'cradle-to-farmgate exit' greenhouse gas emissions intensities of four rotational crop–livestock systems. Systems evaluated were continuous cropping: 2 years of continuous cropping; short rotation: 2-year continuous cropping plus 2-year pasture; long rotation: 2-year continuous cropping followed by 4-year pasture; and forage rotation: continuous pasture. Emissions intensities for beef throughput were reported as kilograms of carbon dioxide equivalents (CO2-eq) per kilogram of liveweight gain (LWG) using the Intergovernmental Panel for Climate Change's Sixth Assessment Report (AR6 2021) CO2 characterisation factors. Point estimate results were found to be 11.3, 11.8, 11.8 and 16.4 kg CO2-eq/kg/LWG for continuous cropping, short rotation, long rotation and forage rotation, respectively. Emission averages arising from crops, which were separated from animal-based emissions using economic allocation, were 1.23, 0.53 and 0.52 kg CO2-eq/kg for soybean, wheat and oat, respectively. The inclusion of soil organic carbon stock changes had notable effects on reducing each system's emissions: by 22.4%, 19.2%, 25.3% and 42.1% under continuous cropping, short rotation, long rotation and forage rotation, respectively, when soil organic carbon was included. Given there are few life cycle assessment studies available on such mixed-enterprise 'semi-circular' systems, particularly with novel primary data, this study adds critical knowledge to agri-food-related sustainability literature by addressing environmental issues in complex production systems compared to extant and broad coverage of mono-enterprise systems. [ABSTRACT FROM AUTHOR]

This study addresses the effect of using animal excreta on the nutritional content of forages, focusing on macro- and micro-element concentrations (nitrogen; N, phosphorus; P, sulphur; S, copper; Cu, zinc; Zn, manganese; Mn, selenium; Se) from animal feed to excreta, soil, and plants. Data were collected from pot and field trials using separate applications of sheep or cattle urine and faeces. Key findings indicate that soil organic carbon (SOC) and the type of excreta significantly influences nutrient uptake by forages, with varied responses among the seven elements defined above. Although urine contributes fewer micronutrients compared to faeces (as applied at a natural volume/mass basis, respectively), it notably improves forage yield and micronutrient accumulation, thus potentially delivering positive consequences at the farm level regarding economic performance and soil fertility when swards upon clayey soil types receive said urine in temperate agro-climatic regions (i.e., South West England in the current context). In contrast, faeces application in isolation hinders Se and Mn uptake, once again potentially delivering unintended consequences such as micronutrient deficiencies in areas of high faeces deposition. As it is unlikely that (b)ovine grazing fields will receive either urine or faeces in isolation, we also explored combined applications of both excreta types which demonstrates synergistic effects on N, Cu, and Zn uptake, with either synergistic or dilution effects being observed for P and S, depending largely on SOC levels. Additionally, interactions between excreta types can result in dilution or antagonistic effects on Mn and Se uptake. Notably, high SOC combined with faeces reduces Mn and Se in forages, raising concerns for grazed ruminant systems under certain biotic situations, e.g., due to insufficient soil Se levels typically observed in UK pastures for livestock growth. These findings underscore the importance of considering SOC and excreta nutritional composition when designing forage management to optimize nutrient uptake. It should be noted that these findings have potential ramifications for broader studies of sustainable agriculture through system-scale analyses, as the granularity of results reported herein elucidate gaps in knowledge which could affect, both positively and negatively, the interpretation of model-based environmental impact assessments of cattle and sheep production (e.g., in the case of increased yields [beneficial] or the requirement of additional synthetic supplementation [detrimental]). [ABSTRACT FROM AUTHOR]

Understanding patient non-adherence to prescribed antibiotics can inform clinical practices, patient counseling, and antibiotic efficacy study design in dermatology. The primary objective was to determine the rate of and reasons for antibiotic non-adherence in the dermatologic surgery setting. The secondary objective was to test the applicability of previously studied survey questions for antibiotic non-adherence screening in the dermatologic surgery setting. Five academic outpatient dermatologic surgery centers across the United States conducted one multicenter prospective cohort study. Dermatologic surgery patients ≥ 18 years of age who were prescribed an antibiotic were included as part of this study. 15.2% (42/276) of patients did not adhere to their antibiotic regimen after dermatologic surgery. Most common reasons for incomplete antibiotic courses included forgotten antibiotics (42.9%,18/42) and side effects (28.6%, 12/42). Previously evaluated questions to identify and predict non-adherence had modest performance in the dermatologic surgery setting (Area under the curve of 0.669 [95% CI (0.583–0.754)]). Antibiotic non-adherence after skin surgery is prevalent and commonly due to reasons that physicians can address with patients. [ABSTRACT FROM AUTHOR]

Carbon dots (CDs) with a size range of 0.2 to 2 nm were prepared using a hydrothermal treatment of sucrose and oleic acid. The as-synthesized CDs were used to reduce H2PdCl4 to metallic Pd nanoparticles with dPd = 9.3 ± 3.7 nm, as confirmed by PXRD and HRTEM data. Pd particles were made to be larger than the CDs, to observe any inverse support effects, however, TEM data revealed that the CDs were transformed to carbon sheets in the reduction reaction at 100 °C. The synthesized Pd-CDs catalysts (0.81 wt. % loading) and CDs were both tested for the liquid phase hydrogenation of cinnamaldehyde. The influence of mass, temperature, and hydrogen flow rate on the activity and selectivity of the CDs and Pd-CDs catalyst on the hydrogenation of cinnamaldehyde was investigated. The CDs gave a cinnamaldehyde conversion (40%, 4 h) with selectivity towards the reduction of the C = O bond (cinnamyl alcohol) while the Pd-carbon catalyst was only selective to the reduction of the C = C bond (conversion 78%) indicating the dominance of Pd in the reaction. Post analysis of the deactivated catalysts indicated formation of carbon sheets and sintering of the Pd nanoparticles. It is thus shown that the presence of Pd induces the CDs to carbon sheet formation and thus indicates the limited use of CDs as a support for the olefin hydrogenation reaction with the CDs produced carbon support. This finding has implications for other studies using CDs as supports. [ABSTRACT FROM AUTHOR]

In response to physical damage, organisms must balance recovery with adaptive responses to other environmental stressors. Understanding how damage and repair influence adaptive responses to high environmental temperatures is of particular interest in light of global climate change. We investigate the impact of damage and subsequent repair on heat-avoidance behaviors in Cydia saltitans larvae using host seeds (Sebastiania pavoniana) as protective structures (together colloquially known as "Mexican jumping beans"). These larvae perform temperature-dependent "jumping" or "rolling" behaviors to escape extreme heat, which are crucial for larval survival in their native arid and hot subtropical dry forests. Due to possible costs of repair and limited energetic resources, we hypothesized that experiencing damage and investing in subsequent repair to a host seed would reduce larval displacement distance from extreme heat when compared to individuals that experienced damage without repairing the host seed, or the undamaged control group. Results suggest that larvae in control conditions exhibited greater displacement from heat compared to those in either damage treatment group. Contrary to predictions, damage and subsequent repair impaired heat avoidance behavior to same extent as damage without investing in repair. This reduced displacement distance in both damage treatment groups may be linked to energy allocation or an adaptive antipredator response. These findings contribute to our understanding of how environmental stressors interact to shape behavioral responses in insects with "extended architecture." As global temperatures rise, insights into the flexibility of adaptive behaviors are increasingly crucial. [ABSTRACT FROM AUTHOR]

Purpose: To determine a potential threshold optic nerve diameter (OND) that could reliably differentiate healthy nerves from those affected by optic atrophy (OA) and to determine correlations of OND in OA with retinal nerve fiber layer (RNFL) thickness, visual acuity (VA), and visual field mean deviation (VFMD). Methods: This was a retrospective case control study. Magnetic resonance (MR) images were reviewed from individuals with OA aged 18 years or older with vision loss for more than 6 months and an OA diagnosis established by a neuro-ophthalmologist. Individuals without OA who underwent MR imaging of the orbit for other purposes were also collected. OND was measured on coronal T2-weighted images in the midorbital section, 1cm posterior to the optic disc. Measurements of mean RNFL thickness, VA and VFMD were also collected. Results: In this study 47 OA subjects (63% women, 78 eyes) and 75 normal subjects (42.7% women, 127 eyes) were assessed. Healthy ONDs (mean 2.73 ± 0.24 mm) were significantly greater than OA nerve diameters (mean 1.94 ± 0.32 mm; P < 0.001). A threshold OND of ≤2.3 mm had a sensitivity of 0.92 and a specificity of 0.93 in predicting OA. Mean RNFL (r = 0.05, p = 0.68), VA (r = 0.17, p = 0.14), and VFMD (r = 0.18, p = 0.16) were not significantly associated with OND. Conclusion: ONDs are significantly reduced in patients with OA compared with healthy nerves. A threshold OND of ≤2.3 mm is highly sensitive and specific for a diagnosis of OA. OND was not significantly correlated with RNFL thickness, VA, or VFMD. [ABSTRACT FROM AUTHOR]

Goats fulfil a central role in food and nutritional security across Africa with over half of households owning or rearing goats in rural areas. However, goat performance is poor and mortality high. This study assessed the nutritional quality of commonly used feeds and proposes feed-baskets to enhance goat nutrition and health. Feeds were collected from 11 areas within the Central District of Botswana, and macronutrient analyses were conducted, including crude protein, fibre fractions, ash, and metabolizable energy (ME). Forage nutrition was compared across seasons and soil types. Additionally, seasonal supplementation trials were conducted to evaluate consumption rates of various supplements, including crop residues, pellets, Lablab purpureus, and Dichrostachys cinerea. Each supplement was provided ad libitum for a 24-h period, and consumption rates determined. Findings revealed significant differences in nutrition among various feed sources, across seasons, and in relation to soil types (p < 0.001). Consumption rates of supplements were higher during the dry season, possibly due to reduced forage availability. Supplement consumption rates varied across supplement type, with crop residues accounting for approximately 1% of dry matter intake, compared to up to 45% for pellets, 13% for L. purpureus, and 15% for D. cinerea. While wet season feed baskets exhibited higher ME values compared to dry-season feed-baskets, the relative impact of supplementation was more pronounced during the dry season. These results highlight the potential for optimizing goat diets through improved grazing and browsing management, especially during the reduced nutritional availability in the dry season in Botswana. Such diet optimisation may improve goat health and productivity, which may positively impact the food and financial security of smallholders by providing both increased yields and increased resilience. Importantly, rural communities can experience some of the lowest food security levels in the region. The interventions explored in this study utilise natural capital, often freely available, which can be deployed through existing husbandry systems, potentially making them accessible and practical to smallholders. [ABSTRACT FROM AUTHOR]

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The PTEN gene negatively regulates the oncogenic PI3K-AKT pathway by encoding a lipid and protein phosphatase that dephosphorylates lipid phosphatidylinositol-3,4,5-triphosphate (PIP3) resulting in the inhibition of PI3K and downstream inhibition of AKT. Overexpression of PTEN in mice leads to a longer lifespan compared to control littermates, although the mechanism is unknown. Here, we provide evidence that young adult PTENOE mice exhibit many characteristics shared by other slow-aging mouse models, including those with mutations that affect GH/IGF1 pathways, calorie-restricted mice, and mice treated with anti-aging drugs. PTENOE white adipose tissue (WAT) has increased UCP1, a protein linked to increased thermogenesis. WAT of PTENOE mice also shows a change in polarization of fat-associated macrophages, with elevated levels of arginase 1 (Arg1, characteristic of M2 macrophages) and decreased production of inducible nitric oxide synthase (iNOS, characteristic of M1 macrophages). Muscle and hippocampus showed increased expression of the myokine FNDC5, and higher levels of its cleavage product irisin in plasma, which has been linked to increased conversion of WAT to more thermogenic beige/brown adipose tissue. PTENOE mice also have an increase, in plasma and liver, of GPLD1, which is known to improve cognition in mice. Hippocampus of the PTENOE mice has elevation of both BDNF and DCX, indices of brain resilience and neurogenesis. These changes in fat, macrophages, liver, muscle, hippocampus, and plasma may be considered "aging rate indicators" in that they seem to be consistently changed across many of the long-lived mouse models and may help to extend lifespan by delaying many forms of late-life illness. Our new findings show that PTENOE mice can be added to the group of long-lived mice that share this multi-tissue suite of biochemical characteristics. [ABSTRACT FROM AUTHOR]

The relevance of KRAS mutation alleles to clinical outcome remains inconclusive in pancreatic adenocarcinoma (PDAC). We conducted a retrospective study of 803 patients with PDAC (42% with metastatic disease) at MD Anderson Cancer Center. Overall survival (OS) analysis demonstrated that KRAS mutation status and subtypes were prognostic (p < 0.001). Relative to patients with KRAS wildtype tumors (median OS 38 months), patients with KRASG12R had a similar OS (median 34 months), while patients with KRASQ61 and KRASG12D mutated tumors had shorter OS (median 20 months [HR: 1.9, 95% CI 1.2–3.0, p = 0.006] and 22 months [HR: 1.7, 95% CI 1.3–2.3, p < 0.001], respectively). There was enrichment of KRASG12D mutation in metastatic tumors (34% vs 24%, OR: 1.7, 95% CI 1.2–2.4, p = 0.001) and enrichment of KRASG12R in well and moderately differentiated tumors (14% vs 9%, OR: 1.7, 95% CI 1.05–2.99, p = 0.04). Similar findings were observed in the external validation cohort (PanCAN's Know Your Tumor® dataset, n = 408). [ABSTRACT FROM AUTHOR]

Hemophagocytic lymphohistiocytosis (HLH) is a rare disease with high mortality. Liver involvement is common (based on elevated liver function tests) with most patients demonstrating acute hepatitis. Liver biopsies are frequently obtained in the setting of suspected HLH for the purpose of identification of erythrophagocytosis, and if present, this finding is thought to suggest or support the diagnosis of HLH. However, there are problems with this approach; in particular, we do not know whether this finding is reproducible or whether it is specific to HLH. Therefore, we conducted a multi-institutional study in which experienced liver pathologists reviewed images taken from liver biopsies from patients with normal liver, acute hepatitis, possible HLH, and clinical HLH to determine if there was agreement about the presence or absence of erythrophagocytosis, and to ascertain whether the finding corresponds to a clinical diagnosis of HLH. Twelve liver pathologists reviewed 141 images in isolation (i.e., no clinical information or diagnosis provided). These came from 32 patients (five normal, 17 acute hepatitis, six HLH, four possible HLH). The pathologists classified each image as negative, equivocal, or positive for erythrophagocytosis. Kappa was.08 (no agreement) for case-level and 0.1 for image-level (1.4% agreement, based on two images which were universally considered negative). There was no difference in the proportion of pathologists who diagnosed erythrophagocytosis among those with different diagnoses at case or image-level (p = 0.82 and p = 0.82, respectively). Thus, erythrophagocytosis is an entirely unreliable histologic parameter in liver, as it is irreproducible and not demonstrably associated with a clinical disease (namely, HLH). Unless and until more reliable guidelines can be established, pathologists should refrain from commenting on the presence or absence of erythrophagocytosis in liver biopsy. [ABSTRACT FROM AUTHOR]

Recent studies have found correlations between the shape of snake teeth/fangs and diet. These studies were done at a very broad phylogenetic scale, making it desirable to test if correlations are still detectable at a narrower evolutionary scale, specifically within the family Elapidae. To this end, we studied fang shape in a dense selection of elapids representing most genera worldwide (74%). We used three-dimensional geometric morphometrics to analyse fang diversity and evaluate possible correlations between fang shape, fang size, and diet. We detected weak phylogenetic signal for both shape and absolute fang size, and found that evolutionary allometry contributes a small proportion of the among-species variation. The distribution of elapid fangs in morphospace was found to be surprisingly conservative, with only a few outliers. The only three dietary categories that were found to have a significant effect on fang shape are mammals, lizards, and reptile eggs, with mammals having a significant effect also on absolute but not relative fang size. Our results show that there are disparate patterns in fang-diet relationships at different evolutionary scales. Across all venomous snakes, previous work found that fangs are strongly influenced by diet, but within elapids our study shows these same associations are weaker and often non-significant. This could result from limitations in these types of studies, or could reflect the fact that elapids are a relatively young clade, where recent extensive divergences in diet have yet to be mirrored in fang shape, suggesting a lag between changes in ecology and dental morphology. [ABSTRACT FROM AUTHOR]

Background: Investigating patients with unprovoked venous thromboembolism (uVTE) for occult malignancy can prove a diagnostic dilemma and imaging is often used extensively in this patient group. Aims: The primary objective of this study was to determine the incidence of malignancy on CT and other imaging over a 10-year period. A secondary objective was to evaluate the role of laboratory and other non-imaging tests performed. Methods: A retrospective key word search of our hospital's imaging system was performed to identify patients with unprovoked DVT/PE over the last 10 years. All imaging, histology, endoscopy, laboratory tests, and clinical follow-up over 2 years were analysed. Patients with provoked VTE were excluded. Results: 150 patients had uVTE. 9 patients were diagnosed with occult malignancy by different investigations on index hospital admission (3 patients) or subsequently on clinical follow-up (6 patients). Mean age of patients was 62 years. 116 patients had CT body imaging. The incidence of malignancy diagnosed by initial CT imaging was 1.7% with a sensitivity of 22%, specificity 87%, and PPV 12.5%. Overall incidence of malignancy identified by imaging alone during the index hospital admission was 2%. Total incidence of malignancy including index admission and follow-up was 6%. Median time to cancer diagnosis was 12 months. Conclusion: CT imaging had a low yield for diagnosing malignancy. Extensive imaging strategies increase cost and radiation exposure without improving mortality. Clinical follow-up, history taking, and physical examination guiding appropriate investigations remain the best tool for unmasking occult malignancy in patients with uVTE. [ABSTRACT FROM AUTHOR]

The Rydberg blockade is a key ingredient for entangling atoms in arrays. However, it requires atoms to be spaced well within the blockade radius, which limits the range of local quantum gates. Here we break this constraint using Floquet frequency modulation, with which we demonstrate Rydberg-blockade entanglement beyond the traditional blockade radius and show how the enlarged entanglement range improves qubit connectivity in a neutral atom array. Further, we find that the coherence of entangled states can be extended under Floquet frequency modulation. Finally, we realize Rydberg anti-blockade states for two sodium Rydberg atoms within the blockade radius. Such Rydberg anti-blockade states for atoms at close range enables the robust preparation of strongly-interacting, long-lived Rydberg states, yet their steady-state population cannot be achieved with only the conventional static drive. Our work transforms between the paradigmatic regimes of Rydberg blockade versus anti-blockade and paves the way for realizing more connected, coherent, and tunable neutral atom quantum processors with a single approach. Ultracold atoms in arrays represent a useful platform to study quantum processes. Here the authors use Floquet frequency modulation to entangle neutral atoms beyond the usual Rydberg blockade range, protect entangled-state coherence, and realize Rydberg anti-blockade states for two atoms at close range. [ABSTRACT FROM AUTHOR]

Average and maximal lifespan can be increased in mice, in one or both sexes, by four drugs: rapamycin, acarbose, 17a-estradiol, and canagliflozin. We show here that these four drugs, as well as a calorie-restricted diet, can induce a common set of changes in fat, macrophages, plasma, muscle, and brain when evaluated in young adults at 12 months of age. These shared traits include an increase in uncoupling protein UCP1 in brown fat and in subcutaneous and intra-abdominal white fat, a decline in proinflammatory M1 macrophages and corresponding increase in anti-inflammatory M2 macrophages, an increase in muscle fibronectin type III domain containing 5 (FNDC5) and its cleavage product irisin, and higher levels of doublecortin (DCX) and brain-derived neurotrophic factor (BDNF) in brain. Each of these proteins is thought to play a role in one or more age-related diseases, including metabolic, inflammatory, and neurodegenerative diseases. We have previously shown that the same suite of changes is seen in each of four varieties of slow-aging single-gene mutant mice. We propose that these changes may be a part of a shared common pathway that is seen in slow-aging mice whether the delayed aging is due to a mutation, a low-calorie diet, or a drug. [ABSTRACT FROM AUTHOR]

The giant accipitrid Dynatoaetus gaffae gen. et sp. nov. is described from existing and newly collected material. Initial fossil remains were collected from Mairs Cave (Flinders Ranges, South Australia) in 1956 and 1969, and comprised a sternum, distal humerus and two ungual phalanges. A further 28 bones from this individual—including the neurocranium, vertebrae, furculum, and additional wing and leg bones, most of which were incomplete—were discovered at the site in 2021. This allowed identification of additional fossils from the same species in collections from Cooper Creek (Lake Eyre Basin, SA), Victoria Fossil Cave (Naracoorte, SA) and Wellington Caves (Wellington, NSW). Dynatoaetus has variable similarity across elements to those of living species in the Perninae, Gypaetinae, Circaetinae and Aegypiinae. Parsimony and Bayesian phylogenetic analyses of combined morphological and DNA data resolved it as the immediate sister-group to the Aegypiinae within the Circaetinae + Aegypiinae clade. The robust and eagle-like morphology of the lower hindlimbs suggest that the species was a predator, rather than a scavenger, and thus functionally similar to large circaetines such as the Philippine Eagle Pithecophaga jefferyi. Furthermore, this new species is the largest known bird of prey from Australia, much larger than the modern Wedge-Tailed Eagle Aquila audax. It is outsized in Australasia only by female Hieraaetus moorei (the extinct Haast's Eagle from New Zealand). It is inferred to have been Australia's top terrestrial avian predator during the Pleistocene, ranging from arid inland Australia to the more temperate coast, and likely became extinct around the time of the megafaunal mass extinction which peaked around 50 Ka. Its extinction in the late Pleistocene, along with the recently described scavenging vulture Cryptogyps lacertosus, marked a distinct decline in the diversity and function of Australia's raptor guild. [ABSTRACT FROM AUTHOR]

Background and aims: The intake of selenium, an essential element for animals and humans, in ruminants is largely determined by selenium concentration in ingested forages, which take up selenium mainly from soil. Ruminant excreta is a common source of organic fertilizer, which provides both nutrients and organic matter. This study aims to unentangle the unclear effect of applying different types of ruminant excreta in soils of different organic matter contents on selenium uptake by forage. Methods: Perennial ryegrass (Lolium perenne) was grown in soils of different organic matter contents. Urine and/or feces collected from sheep fed with organic or inorganic mineral supplements, including selenium, were applied to the soils. The selenium in the collected samples were analyzed using ICP-MS. The associated biogeochemical reactions were scrutinized by wet chemistry. Results: The application of urine and/or feces resulted in either the same or lower selenium concentrations in perennial ryegrass. The excreta type did not affect total selenium accumulation in grass grown in low organic matter soil, whereas in high organic matter soil, feces resulted in significantly lower total selenium accumulation than urine, which was attributed to a possible interaction of selenium sorption in soil and microbial reduction of Se. Conclusion: This one-time excreta application did not increase, but further decrease in some treatments, selenium concentration and accumulation in the perennial ryegrass. Consequently, to increase ruminant selenium intake, supplementing selenium directly to animals is more recommended than applying animal manure to soil, which might drive selenium reduction and decrease selenium uptake by grass. [ABSTRACT FROM AUTHOR]

Social support is vital in promoting the health, well-being, and performance of students and clinicians in health professions. Health settings' demanding and competitive nature imposes unique challenges on students and clinicians with disabilities. This paper aims to explore the trajectories and experiences of social support interactions amongst students and clinicians with disabilities in health professions. In a qualitative longitudinal study, 124 in-depth semi-structured interviews were conducted with 27 health students and 29 health clinicians with disabilities. Data analysis was informed by grounded theory as an adapted analytic approach involving constant comparisons. A few main characteristics of social support and trajectories in which social support is negotiated emerged from the data: (1) The need to be accepted and not questioned when asking for support, (2) Support interactions that do not heighten otherness, (3) Failure to acknowledge the challenges, (4) Interactions that support the process of disclosure (5) Interactions that allow mobilization of social support without strain or an extra effort. These findings have important implications for designing more supportive health professions, educational programs, and workplaces for people living with disabilities. [ABSTRACT FROM AUTHOR]

α-Synuclein is a major component of Lewy bodies (LB) and Lewy neurites (LN) appearing in the postmortem brain of Parkinson's disease (PD) and other α-synucleinopathies. While most studies of α-synucleinopathies have focused on neuronal and synaptic alterations as well as dysfunctions of the astrocytic homeostatic roles, whether the bidirectional astrocyte–neuronal communication is affected in these diseases remains unknown. We have investigated whether the astrocyte Ca2+ excitability and the glutamatergic gliotransmission underlying astrocyte–neuronal signaling are altered in several transgenic mouse models related to α-synucleinopathies, i.e., mice expressing high and low levels of the human A53T mutant α-synuclein (G2-3 and H5 mice, respectively) globally or selectively in neurons (iSyn mice), mice expressing human wildtype α-synuclein (I2-2 mice), and mice expressing A30P mutant α-synuclein (O2 mice). Combining astrocytic Ca2+ imaging and neuronal electrophysiological recordings in hippocampal slices of these mice, we have found that compared to non-transgenic mice, astrocytes in G2-3 mice at different ages (1–6 months) displayed a Ca2+ hyperexcitability that was independent of neurotransmitter receptor activation, suggesting that the expression of α-synuclein mutant A53T altered the intrinsic properties of astrocytes. Similar dysregulation of the astrocyte Ca2+ signal was present in H5 mice, but not in I2-2 and O2 mice, indicating α-synuclein mutant-specific effects. Moreover, astrocyte Ca2+ hyperexcitability was absent in mice expressing the α-synuclein mutant A53T selectively in neurons, indicating that the effects on astrocytes were cell-autonomous. Consistent with these effects, glutamatergic gliotransmission was enhanced in G2-3 and H5 mice, but was unaffected in I2-2, O2 and iSyn mice. These results indicate a cell-autonomous effect of pathogenic A53T expression in astrocytes that may contribute to the altered neuronal and synaptic function observed in α-synucleinopathies. [ABSTRACT FROM AUTHOR]

Plant-bee networks are rarely, if ever, studied quantitatively at continental scales, yet these have the potential to inform how biota and ecosystems are assembled beyond narrower regional biomes. The short-tongued bee family Colletidae comprises the major component of bee diversity in Australia, with three key subfamilies: the Neopasiphaeinae, Hylaeinae, and Euryglossinae. We use museum data (> 27,000 records) to record binary interactions between these bees (from each of these subfamilies, resolved to subgenera) and plants (resolved to genera). The resulting networks were analysed using bipartite graphs and associated indices of network structure. The three bee subfamilies showed markedly different network structures with their floral hosts. Euryglossinae had strong interactions with Myrtaceae and an otherwise relatively narrow host breadth, Neopasiphaeinae had little signal of host specialisation above genera and a very broad host breadth, and Hylaeinae appeared intermediate in network structure. Furthermore, Euryglossinae is more speciose within Australia (404 species, or ~ 25% of described Australian bee fauna) than Hylaeinae and Neopasiphaeinae, but these differences do not correspond to the stem ages of the three subfamilies, suggesting that time-since-origin does not explain bee species diversity or floral host breadth. Patterns of host breadth persist after rarefaction analyses that correct for differing numbers of observation records. We suggest that visitation networks could be influenced by evolutionary constraints to expansion of floral host breadth, but it is also possible that many bee-plant interactions are shaped by bees exploiting floral traits that are driven by non-bee fauna operating at large biogeographical scales. [ABSTRACT FROM AUTHOR]

Deletion of pregnancy-associated plasma protein-A (PAPP-A), a protease that cleaves some but not all IGF1 binding proteins, postpones late-life diseases and extends lifespan in mice, but the mechanism of this effect is unknown. Here we show that PAPP-A knockout (PKO) mice display a set of changes, in multiple tissues, that are characteristic of other varieties of slow-aging mice with alterations in GH production or GH responsiveness, including Ames dwarf, Snell dwarf, and GHRKO mice. PKO mice have elevated UCP1 in brown and white adipose tissues (WAT), and a change in fat-associated macrophage subsets that leads to diminished production of inflammatory cytokines. PKO mice also show increased levels of muscle FNDC5 and its cleavage product, the myokine irisin, thought to cause changes in fat cell differentiation. PKO mice have elevated production of hepatic GPLD1 and plasma GPLD1, consistent with their elevation of hippocampal BDNF and DCX, used as indices of neurogenesis. In contrast, disruption of PAPP-A limited to muscle ("muPKO" mice) produces an unexpectedly complex set of changes, in most cases opposite in direction from those seen in PKO mice. These include declines in WAT UCP1, increases in inflammatory macrophages and cytokines in WAT, and a decline in muscle FNDC5 and plasma irisin. muPKO mice do, however, resemble global PKO mice in their elevation of hippocampal BDNF and DCX. The data for the PKO mice support the idea that these changes in fat, macrophages, liver, muscle, plasma, and brain are consistent and biologically significant features of the slow-aging phenotype in mice. The results on the muPKO mice provide a foundation for further investigation of the complex, local, and global circuits by which PAPP-A modulates signals ordinarily controlled by GH and/or IGF1. [ABSTRACT FROM AUTHOR]

Repeated island colonisation by Australian tiger snakes (Notechis scutatus) has become a model system demonstrating how prey size on islands influences a snake's body and jaw size. Tiger snakes on islands with large prey have relatively longer jaws compared to their mainland counterparts, due to diet-induced phenotypic plasticity followed by assimilation of favourable traits. We present the first examination of the effects of diet on all skull elements that are involved in feeding, by analysing shape and size differences using CT imaging and a combination of linear measurements and three dimensional geometric morphometrics. We compared two populations of tiger snakes, one from Carnac Island, where the snakes were first introduced approximately 100 years ago, and another from Herdsman Lake on the mainland (a putative source population). Each population was divided into two groups, one was fed small prey and the other large prey. While snakes from the island exhibited relatively longer trophic bones at birth, they also had slightly slower growth rates for these elements regardless of diet. The island forms showed diet-induced plasticity within specific trophic elements, the mandible and palatopterygoid, which grew longer when the snakes were fed larger prey. Importantly, skull plasticity was expressed only after prolonged dietary stress, and was not clearly observable until the snakes approached adulthood. We hypothesize that this plastic response resulting in increased gape may be adaptive, allowing ingestion of large prey items available to adult tiger snakes on Carnac Island. In contrast, no plastic response was observed in the mainland population. [ABSTRACT FROM AUTHOR]

Over the past two decades of successive clinical trials in metastatic colorectal cancer (CRC), the median overall survival of both control and experimental arms has steadily improved. However, the incremental change in survival for metastatic CRC patients not treated on trial has not yet been quantified. We performed a retrospective review of 1420 patients with de novo metastatic CRC who received their primary treatment at the University of Texas M.D. Anderson Cancer Center (UTMDACC) from 2004 through 2019. Median OS was roughly stable for patients diagnosed between 2004 and 2012 (22.6 months) but since has steadily improved for those diagnosed in 2013 to 2015 (28.8 months), and 2016 to 2019 (32.4 months). Likewise, 5-year survival rate has increased from 15.7% for patients diagnosed from 2004 to 2006 to 26% for those diagnosed from 2013 to 2015. Notably, survival improved for patients with BRAFV600E mutant as well as microsatellite unstable (MSI-H) tumors. Multivariate regression analysis identified surgical resection of liver metastasis (HR = 0.26, 95% CI, 0.19–0.37), use of immunotherapy (HR = 0.44, 95% CI, 0.29–0.67) and use of third line chemotherapy (regorafenib or trifluridine/tipiracil, HR = 0.74, 95% CI, 0.58–0.95), but not year of diagnosis (HR = 0.99, 95% CI, 0.98–1), as associated with better survival, suggesting that increased use of these therapies are the drivers of the observed improvement in survival. [ABSTRACT FROM AUTHOR]

Rats are abundant in the urban ecosystem, posing concerns for public health, infrastructural damage, and negative impacts for other urban wildlife. Sewers are considered to be one of the main reservoirs for urban rat populations, and rats may migrate between sewers and other surface areas in search of food and harbouring sites. Yet the ecology of rats in sewers has received little attention. To address this knowledge gap, this review identifies a number of sewer ecosystem characteristics that have been associated with rat activity. We demonstrate that sewers with narrower pipes, lower flow rates, and construction materials, such as brick and clay, are associated with more rat activity. Further, this review suggests that poorly maintained sewers may contain more crevices and cracks for rats to burrow, leading to greater levels of infestation. Finally, we find that sewers located in residential areas, or closer to food establishment, are more prone to rat presence. Together, these findings uncovered several significant implications for management of rats in sewers, as well as highlight the need for these characteristics to be considered in the urban planning process. Future work is needed to explore how rats in sewers and their management impact above ground populations of rats and other urban wildlife. [ABSTRACT FROM AUTHOR]

To better understand the potential relationship between COVID-19 disease and hologenome microbial community dynamics and functional profiles, we conducted a multivariate taxonomic and functional microbiome comparison of publicly available human bronchoalveolar lavage fluid (BALF) metatranscriptome samples amongst COVID-19 (n = 32), community acquired pneumonia (CAP) (n = 25), and uninfected samples (n = 29). We then performed a stratified analysis based on mortality amongst the COVID-19 cohort with known outcomes of deceased (n = 10) versus survived (n = 15). Our overarching hypothesis was that there are detectable and functionally significant relationships between BALF microbial metatranscriptomes and the severity of COVID-19 disease onset and progression. We observed 34 functionally discriminant gene ontology (GO) terms in COVID-19 disease compared to the CAP and uninfected cohorts, and 21 GO terms functionally discriminant to COVID-19 mortality (q < 0.05). GO terms enriched in the COVID-19 disease cohort included hydrolase activity, and significant GO terms under the parental terms of biological regulation, viral process, and interspecies interaction between organisms. Notable GO terms associated with COVID-19 mortality included nucleobase-containing compound biosynthetic process, organonitrogen compound catabolic process, pyrimidine-containing compound biosynthetic process, and DNA recombination, RNA binding, magnesium and zinc ion binding, oxidoreductase activity, and endopeptidase activity. A Dirichlet multinomial mixtures clustering analysis resulted in a best model fit using three distinct clusters that were significantly associated with COVID-19 disease and mortality. We additionally observed discriminant taxonomic differences associated with COVID-19 disease and mortality in the genus Sphingomonas, belonging to the Sphingomonadacae family, Variovorax, belonging to the Comamonadaceae family, and in the class Bacteroidia, belonging to the order Bacteroidales. To our knowledge, this is the first study to evaluate significant differences in taxonomic and functional signatures between BALF metatranscriptomes from COVID-19, CAP, and uninfected cohorts, as well as associating these taxa and microbial gene functions with COVID-19 mortality. Collectively, while this data does not speak to causality nor directionality of the association, it does demonstrate a significant relationship between the human microbiome and COVID-19. The results from this study have rendered testable hypotheses that warrant further investigation to better understand the causality and directionality of host–microbiome–pathogen interactions. [ABSTRACT FROM AUTHOR]

Rats are abundant and ubiquitous in urban environments. There has been increasing attention to the need for evidence-based, integrated rat management and surveillance approaches because rats can compromise public health and impose economic costs. Yet there are few studies that characterize rat distributions in sewers and there are no studies that incorporate the complexity of sewer networks that encompass multiple sewer lines, all comprised of their own unique characteristics. To address this knowledge gap, this study identifies sewer characteristics that are associated with rat presence in the city of Seattle's urban sewer system. We obtained sewer baiting data from 1752 geotagged manholes to monitor rat presence and constructed generalized additive models to account for spatial autocorrelation. Sewer rats were unevenly distributed across sampled manholes with clusters of higher rat presence at upper elevations, within sanitary pipes, narrower pipes, pipes at a shallower depth, and older pipes. These findings are important because identifying features of urban sewers that promote rat presence may allow municipalities to target areas for rat control activities and sewer maintenance. These findings suggest the need to evaluate additional characteristics of the surface environment and identify the factors driving rat movement within sewers, across the surface, and between the surface and the sewers. [ABSTRACT FROM AUTHOR]

Introduction: Modern targeted cancer therapies are carefully crafted small molecules. These exquisite technologies exhibit an astonishing diversity of observed failure modes (drug resistance mechanisms) in the clinic. This diversity is surprising because back of the envelope calculations and classic modeling results in evolutionary dynamics suggest that the diversity in the modes of clinical drug resistance should be considerably smaller than what is observed. These same calculations suggest that the outgrowth of strong pre-existing genetic resistance mutations within a tumor should be ubiquitous. Yet, clinically relevant drug resistance occurs in the absence of obvious resistance conferring genetic alterations. Quantitatively, understanding the underlying biological mechanisms of failure mode diversity may improve the next generation of targeted anticancer therapies. It also provides insights into how intratumoral heterogeneity might shape interpatient diversity during clinical relapse. Materials and Methods: We employed spatial agent-based models to explore regimes where spatial constraints enable wild type cells (that encounter beneficial microenvironments) to compete against genetically resistant subclones in the presence of therapy. In order to parameterize a model of microenvironmental resistance, BT20 cells were cultured in the presence and absence of fibroblasts from 16 different tissues. The degree of resistance conferred by cancer associated fibroblasts in the tumor microenvironment was quantified by treating mono- and co-cultures with letrozole and then measuring the death rates. Results and Discussion: Our simulations indicate that, even when a mutation is more drug resistant, its outgrowth can be delayed by abundant, low magnitude microenvironmental resistance across large regions of a tumor that lack genetic resistance. These observations hold for different modes of microenvironmental resistance, including juxtacrine signaling, soluble secreted factors, and remodeled ECM. This result helps to explain the remarkable diversity of resistance mechanisms observed in solid tumors, which subverts the presumption that the failure mode that causes the quantitatively fastest growth in the presence of drug should occur most often in the clinic. Conclusion: Our model results demonstrate that spatial effects can interact with low magnitude of resistance microenvironmental effects to successfully compete against genetic resistance that is orders of magnitude larger. Clinical outcomes of solid tumors are intrinsically connected to their spatial structure, and the tractability of spatial agent-based models like the ones presented here enable us to understand this relationship more completely. [ABSTRACT FROM AUTHOR]

This document is a letter published in the journal CardioVascular & Interventional Radiology. The author agrees with a recent article arguing for interventional radiology (IR) to pursue independent specialty status. The author highlights the lack of structured training and access to IR training in many European countries, as well as the shortage of interventional radiologists. A joint study by the European Society of Radiology and the Cardiovascular and Interventional Radiological Society of Europe found poor bed availability for IR care and a shortage of IRs in Europe. The author believes that independent specialty status is necessary to address these issues and improve patient care. [Extracted from the article]

Tamoxifen is a selective estrogen receptor (ER) modulator that is used to treat ER-positive breast cancer, but that at high doses kills both ER-positive and ER-negative breast cancer cells. We recapitulate this off-target effect in Caenorhabditis elegans, which does not have an ER ortholog. We find that different bacteria dramatically modulate tamoxifen toxicity in C. elegans, with a three-order of magnitude difference between animals fed Escherichia coli, Comamonas aquatica, and Bacillus subtilis. Remarkably, host fatty acid (FA) biosynthesis mitigates tamoxifen toxicity, and different bacteria provide the animal with different FAs, resulting in distinct FA profiles. Surprisingly these bacteria modulate tamoxifen toxicity by different death mechanisms, some of which are modulated by FA supplementation and others by antioxidants. Together, this work reveals a complex interplay between microbiota, FA metabolism and tamoxifen toxicity that may provide a blueprint for similar studies in more complex mammals. Here, Diot et al. use the nematode Caenorhabditis elegans as a model to identify off-target toxicity mechanisms for tamoxifen, and find that these include fatty acid metabolism and cell death, which can be modulated by different bacterial species. [ABSTRACT FROM AUTHOR]

Mindfulness-based programs (MBPs) are increasingly utilized to improve mental health. Interest in the putative effects of MBPs on cognitive function is also growing. This is the first meta-analysis of objective cognitive outcomes across multiple domains from randomized MBP studies of adults. Seven databases were systematically searched to January 2020. Fifty-six unique studies (n = 2,931) were included, of which 45 (n = 2,238) were synthesized using robust variance estimation meta-analysis. Meta-regression and subgroup analyses evaluated moderators. Pooling data across cognitive domains, the summary effect size for all studies favored MBPs over comparators and was small in magnitude (g = 0.15; [0.05, 0.24]). Across subgroup analyses of individual cognitive domains/subdomains, MBPs outperformed comparators for executive function (g = 0.15; [0.02, 0.27]) and working memory outcomes (g = 0.23; [0.11, 0.36]) only. Subgroup analyses identified significant effects for studies of non-clinical samples, as well as for adults aged over 60. Across all studies, MBPs outperformed inactive, but not active comparators. Limitations include the primarily unclear within-study risk of bias (only a minority of studies were considered low risk), and that statistical constraints rendered some p-values unreliable. Together, results partially corroborate the hypothesized link between mindfulness practices and cognitive performance. This review was registered with PROSPERO [CRD42018100904]. [ABSTRACT FROM AUTHOR]

Purpose: This study evaluated the clinical safety and efficacy of tanfanercept (HBM9036) ophthalmic solution as a novel treatment for dry eye disease (DED) in a controlled adverse environment (CAE) study conducted in China. Methods: In a single-center, double-masked, randomized, placebo-controlled study, 100 patients received 0.25% tanfanercept, or placebo, twice daily for eight weeks. A mobile international CAE® DE Model was used for patient selection with a standardized challenge endpoint. Primary efficacy endpoint was fluorescein inferior corneal staining score (ICSS) pre- to post-CAE challenge from baseline. Secondary endpoints included Schirmer's Tear Test, Tear-Film Break-Up Time, Ocular Discomfort Score, Ora Calibra® Ocular Discomfort and 4-Symptom Questionnaire, total corneal staining score (TCSS), and drop comfort. Signs and symptoms were assessed both pre- and post-CAE to evaluate the efficacy of tanfanercept on both environmental and CAE endpoints. Results: The tanfanercept treatment group showed improvement in ICSS pre- to post-CAE change from baseline scores when compared to placebo (− 0.61 ± 0.11 and − 0.54 ± 0.11, respectively; mean difference = 0.07, p = 0.65). TCSS pre–post-CAE change from baseline scores was also in favor of active when compared to placebo (− 1.03 ± 0.21 and − 0.67 ± 0.21, respectively; mean difference = 0.37, p = 0.23). Schirmer's score improvement was demonstrated in favor of active (1.87 ± 0.62 mm) as compared to placebo (1.28 ± 0.62 mm; mean difference = 0.59 mm, p = 0.50). Change from baseline in mean Tear-Film Break-up Time favored active treatment over placebo (mean difference = 1.21 s, p = 0.45). Notably, the tanfanercept showed more obvious benefits for each DED sign in a subgroup of subjects ≥ 35 years of age. Tanfanercept was well tolerated with no serious adverse events occurring during the study. Conclusion: Tanfanercept demonstrated improvements in favor of active as compared to placebo in the signs of DED, being safe and well tolerated. These data support further evaluation of tanfanercept for the treatment of DED in China. Trial registration: This study was retrospectively registered at ClinicalTrials.gov (NCT04092907) on September 17, 2019. [ABSTRACT FROM AUTHOR]

Maize (Zea mays L.) is the most important food crop in the world, with significant acreage and production across the globe. However, it is affected by low temperatures throughout its growth process, especially during germination. Therefore, it is important to identify more QTLs or genes associated with germination under low-temperature conditions. For the QTL analysis of traits related to low-temperature germination, we used a high-res genetic map of 213 lines of the intermated B73 × Mo17 (IBM) Syn10 doubled haploid (DH) population, which had 6618 bin markers. We detected 28 QTLs of eight phenotypic characteristics associated with low-temperature germination, while they explained the phenotypic contribution rate of 5.4 ~ 13.34%. Additionally, 14 overlapping QTLs produced six QTL clusters on every chromosome, except for 8 and 10. RNA-Seq found six genes related to low-temperature tolerance in these QTLs, while qRT-PCR analysis demonstrated that the expression trends of the Zm00001d045568 gene in the LT_BvsLT_M group and the CK_BvsCK_M group were highly significantly different at all four-time points (P < 0.01), and encoded the RING zinc finger protein. It was located on qRTL9-2 and qRSVI9-1 and is related to the total length and simple vitality index. These results provided potential candidate genes for further gene cloning and improving the low-temperature tolerance of maize. [ABSTRACT FROM AUTHOR]

Sotatercept is an activin receptor type IIA-Fc (ActRIIA-Fc) fusion protein that improves cardiopulmonary function in patients with pulmonary arterial hypertension (PAH) by selectively trapping activins and growth differentiation factors. However, the cellular and molecular mechanisms of ActRIIA-Fc action are incompletely understood. Here, we determined through genome-wide expression profiling that inflammatory and immune responses are prominently upregulated in the lungs of a Sugen-hypoxia rat model of severe angio-obliterative PAH, concordant with profiles observed in PAH patients. Therapeutic treatment with ActRIIA-Fc—but not with a vasodilator—strikingly reversed proinflammatory and proliferative gene expression profiles and normalized macrophage infiltration in diseased rodent lungs. Furthermore, ActRIIA-Fc normalized pulmonary macrophage infiltration and corrected cardiopulmonary structure and function in Bmpr2 haploinsufficient mice subjected to hypoxia, a model of heritable PAH. Three high-affinity ligands of ActRIIA-Fc each induced macrophage activation in vitro, and their combined immunoneutralization in PAH rats produced cardiopulmonary benefits comparable to those elicited by ActRIIA-Fc. Our results in complementary experimental and genetic models of PAH reveal therapeutic anti-inflammatory activities of ActRIIA-Fc that, together with its known anti-proliferative effects on vascular cell types, could underlie clinical activity of sotatercept as either monotherapy or add-on to current PAH therapies. [ABSTRACT FROM AUTHOR]

The Balloon Analogue Risk Task (BART) is widely-used to measure risk propensity in theoretical, clinical, and applied research. In the task, people choose either to pump a balloon to increase its value at the risk of the balloon bursting and losing all value, or to bank the current value of the balloon. Risk propensity is most commonly measured as the average number of pumps on trials for which the balloon does not burst. Burst trials are excluded because they necessarily underestimate the number of pumps people intended to make. However, their exclusion discards relevant information about people's risk propensity. A better measure of risk propensity uses the statistical method of censoring to incorporate all of the trials. We develop a new Bayesian method, based on censoring, for measuring both risk propensity and behavioral consistency in the BART. Through applications to previous data we demonstrate how the method can be extended to consider the correlation of risk propensity with external measures, and to compare differences in risk propensity between groups. We provide implementations of all of these methods in R, MATLAB, and the GUI-based statistical software JASP. [ABSTRACT FROM AUTHOR]

Background: To evaluate Inferior vena cava (IVC) filter retrieval practices over a 9-year period at an academic hospital with a prospectively maintained IVC filter registry. Method: An IVC filter registry was maintained prospectively within our institution. We reviewed cases between August 2011 and June 2020, following filter status, retrieval plans, and eventual retrieval date. The validity of the database was cross referenced with a Picture Archiving and Communication System and patient records. Results: Three hundred forty-three patients had IVC filters inserted. Three filter types were used, Celect (Cook Medical) in 189, Gunther Tulip (GT) (Cook Medical) in 65, ALN (ALN) in 89. 196 (57%) filters were retrieved, 108 (31.5%) were made permanent, 36 (10.5%) died before retrieval, and 3 (1%) were yet to be retrieved. Retrieval rates were 92.5% overall (86% for GT, 93% for Celect and 94.5% for ALN). The mean dwell time for successful retrieval was 59 days with the majority of insertions (85%) removed in under 100 days. Failed initial retrieval occurred in 23 patients, 10 (43%) were retrieved at second attempt, 13/23 filters remained in-situ and were deemed permanent. Conclusion: The removal of IVC filters, when indication for insertion has past, is no longer the sole responsibility of the referring physician but also the responsibility of the Interventionalist. Our retrieval rates of 92.5% of eligible IVC filters highlights the value of maintaining a prospective IVC filter registry. [ABSTRACT FROM AUTHOR]

Previous primary studies have explored the association between blood pressure (BP) and mortality in ambulatory heart failure (HF) patients reporting varying and contrasting associations. The aim is to determine the pooled BP prognostic value and explore potential reasons for between-study inconsistency. We searched Medline, Cochrane, EMBASE and CINAHL from January 2005 to October 2018 for studies with ≥ 50 events (mortality and/or hospitalization) and included BP in a multivariable model in ambulatory HF patients. We pooled hazard ratios (random effects model) for systolic BP (SBP) or diastolic BP (DBP) effect on mortality and/or hospitalization risk. We used a priori defined sub-group analyses to explore heterogeneity and GRADE approach to assess the certainty of the evidence. Seventy-one eligible articles (239,467 screened) at low to moderate risk of bias included 235,752 participants. Higher SBP was associated with reduced all-cause mortality (HR 0.93, 95%CI 0.91–0.95, I2 = 87.13%, moderate certainty), all-cause hospitalization events (HR 0.91, 95%CI 0.88–0.93, I2 = 44.4%, high certainty) and their composite endpoint (HR 0.93 per 10 mmHg, 95%CI 0.91–0.94, I2 = 86.3%, high certainty). DBP did not demonstrate a statistically significant effect for all outcomes. The association strength was significantly weaker in studies following patients with either LVEF > 40%, higher average SBP (> 130 mmHg), increasing age and diabetes. All other a priori subgroup hypotheses did not explain between study differences. Higher ambulatory SBP is associated with reduced risk of all-cause mortality and hospitalization. Patients with lower BP and reduced LVEF are in a high-risk group of developing adverse events with moderate certainty of evidence. [ABSTRACT FROM AUTHOR]