The oncogenic fusion protein TAZ::CAMTA1 promotes genomic instability and senescence through hypertranscription.

TAZ::CAMTA1 is a fusion protein found in over 90% of Epithelioid Hemangioendothelioma (EHE), a rare vascular sarcoma with an unpredictable disease course. To date, how TAZ::CAMTA1 initiates tumour formation remains unexplained. To study the oncogenic mechanism leading to EHE initiation, we developed a model system whereby TAZ::CAMTA1 expression is induced by doxycycline in primary endothelial cells. Using this model, we establish that upon TAZ::CAMTA1 expression endothelial cells rapidly enter a hypertranscription state, triggering considerable DNA damage. As a result, TC-expressing cells become trapped in S phase. Additionally, TAZ::CAMTA1-expressing endothelial cells have impaired homologous recombination, as shown by reduced BRCA1 and RAD51 foci formation. Consequently, the DNA damage remains unrepaired and TAZ::CAMTA1-expressing cells enter senescence. Knockout of Cdkn2a, the most common secondary mutation found in EHE, allows senescence bypass and uncontrolled growth. Together, this provides a mechanistic explanation for the clinical course of EHE and offers novel insight into therapeutic options.

Risk of Bleeding Associated With Outpatient Use of Rivaroxaban in VTE Management at a National Referral Hospital in Western Kenya.

There is limited data on the bleeding safety profile of direct oral anticoagulants, such as rivaroxaban, in low- and middle-income country settings like Kenya. In this prospective observational study, patients newly started on rivaroxaban or switching to rivaroxaban from warfarin for the management of venous thromboembolism (VTE) within the national referral hospital in western Kenya were assessed to determine the frequency of bleeding during treatment. Bleeding events were assessed at the 1- and 3-month visits, as well as at the end of follow-up. The International Society of Thrombosis and Hemostasis (ISTH) and the Bleeding Academic Research Consortium (BARC) criteria were used to categorize the bleeding events, and descriptive statistics were used to summarize categorical variables. Univariate and multivariate logistic regression model was used to calculate unadjusted and adjusted associations between patient characteristics and bleeding. The frequency of any type of bleeding was 14.4% (95% CI: 9.3%-20.8%) for an incidence rate of 30.9 bleeding events (95% CI: 20.1-45.6) per 100 patient-years of follow-up. The frequency of major bleeding was 1.9% while that of clinically relevant non-major bleeding was 13.8%. In the multivariate logistic regression model, being a beneficiary of the national insurance plan was associated with a lower risk of bleeding, while being unemployed was associated with a higher bleeding risk. The use of rivaroxaban in the management of VTE was associated with a higher frequency of bleeding. These findings warrant confirmation in larger and more targeted investigations in a similar population.

Current Model Systems for Investigating Epithelioid Haemangioendothelioma.

Epithelioid haemangioendothelioma (EHE) is a rare sarcoma of the vascular endothelium with an unpredictable disease course. EHE tumours can remain indolent for long period of time but may suddenly evolve into an aggressive disease with widespread metastases and a poor prognosis. Two mutually exclusive chromosomal translocations define EHE tumours, each involving one of the transcription co-factors TAZ and YAP. The TAZ-CAMTA1 fusion protein results from a t(1;3) translocation and is present in 90% of EHE tumours. The remaining 10% of EHE cases harbour a t(X;11) translocation, resulting in the YAP1-TFE3 (YT) fusion protein. Until recently, the lack of representative EHE models made it challenging to study the mechanisms by which these fusion proteins promote tumorigenesis. Here, we describe and compare the recently developed experimental approaches that are currently available for studying this cancer. After summarising the key findings obtained with each experimental approach, we discuss the advantages and limitations of these different model systems. Our survey of the current literature shows how each experimental approach can be utilised in different ways to improve our understanding of EHE initiation and progression. Ultimately, this should lead to better treatment options for patients.

Causes and timing of 30-day rehospitalization from skilled nursing facilities after a hospital admission for pneumonia or sepsis.

BACKGROUND: Pneumonia and sepsis are among the most common causes of hospitalization in the United States and often result in discharges to a skilled nursing facility (SNF) for rehabilitation. We described the timing and most common causes of 30-day unplanned hospital readmission following an index hospitalization for pneumonia or sepsis. METHODS AND FINDINGS: This national retrospective cohort study included adults ≥65 years who were hospitalized for pneumonia or sepsis and were discharged to a SNF between July 1, 2012 and July 4, 2015. We quantified the ten most common 30-day unplanned readmission diagnoses and estimated the daily risk of first unplanned rehospitalization for four causes of readmission (circulatory, infectious, respiratory, and genitourinary). The index hospitalization was pneumonia for 92,153 SNF stays and sepsis for 452,254 SNF stays. Of these SNF stays, 20.9% and 25.9%, respectively, resulted in a 30-day unplanned readmission. Overall, septicemia was the single most common readmission diagnosis for residents with an index hospitalization for pneumonia (16.7% of 30-day readmissions) and sepsis (22.4% of 30-day readmissions). The mean time to unplanned readmission was approximately 14 days overall. Respiratory causes displayed the highest daily risk of rehospitalization following index hospitalizations for pneumonia, while circulatory and infectious causes had the highest daily risk of rehospitalization following index hospitalizations for sepsis. The day of highest risk for readmission occurred within two weeks of the index hospitalization discharge, but the readmission risk persisted across the 30-day follow-up. CONCLUSION: Among older adults discharged to SNFs following a hospitalization for pneumonia or sepsis, hospital readmissions for infectious, circulatory, respiratory, and genitourinary causes occurred frequently throughout the 30-day post-discharge period. Our data suggests further study is needed, perhaps on the value of closer monitoring in SNFs post-hospital discharge and improved communication between hospitals and SNFs, to reduce the risk of potentially preventable hospital readmissions.

Structure of Chimpanzee Gut Microbiomes across Tropical Africa.

Understanding variation in host-associated microbial communities is important given the relevance of microbiomes to host physiology and health. Using 560 fecal samples collected from wild chimpanzees (Pan troglodytes) across their range, we assessed how geography, genetics, climate, vegetation, and diet relate to gut microbial community structure (prokaryotes, eukaryotic parasites) at multiple spatial scales. We observed a high degree of regional specificity in the microbiome composition, which was associated with host genetics, available plant foods, and potentially with cultural differences in tool use, which affect diet. Genetic differences drove community composition at large scales, while vegetation and potentially tool use drove within-region differences, likely due to their influence on diet. Unlike industrialized human populations in the United States, where regional differences in the gut microbiome are undetectable, chimpanzee gut microbiomes are far more variable across space, suggesting that technological developments have decoupled humans from their local environments, obscuring regional differences that could have been important during human evolution. IMPORTANCE Gut microbial communities are drivers of primate physiology and health, but the factors that influence the gut microbiome in wild primate populations remain largely undetermined. We report data from a continent-wide survey of wild chimpanzee gut microbiota and highlight the effects of genetics, vegetation, and potentially even tool use at different spatial scales on the chimpanzee gut microbiome, including bacteria, archaea, and eukaryotic parasites. Microbial community dissimilarity was strongly correlated with chimpanzee population genetic dissimilarity, and vegetation composition and consumption of algae, honey, nuts, and termites were potentially associated with additional divergence in microbial communities between sampling sites. Our results suggest that host genetics, geography, and climate play a far stronger role in structuring the gut microbiome in chimpanzees than in humans.

Recent genetic connectivity and clinal variation in chimpanzees.

Much like humans, chimpanzees occupy diverse habitats and exhibit extensive behavioural variability. However, chimpanzees are recognized as a discontinuous species, with four subspecies separated by historical geographic barriers. Nevertheless, their range-wide degree of genetic connectivity remains poorly resolved, mainly due to sampling limitations. By analyzing a geographically comprehensive sample set amplified at microsatellite markers that inform recent population history, we found that isolation by distance explains most of the range-wide genetic structure of chimpanzees. Furthermore, we did not identify spatial discontinuities corresponding with the recognized subspecies, suggesting that some of the subspecies-delineating geographic barriers were recently permeable to gene flow. Substantial range-wide genetic connectivity is consistent with the hypothesis that behavioural flexibility is a salient driver of chimpanzee responses to changing environmental conditions. Finally, our observation of strong local differentiation associated with recent anthropogenic pressures portends future loss of critical genetic diversity if habitat fragmentation and population isolation continue unabated.

Environmental variability supports chimpanzee behavioural diversity.

Large brains and behavioural innovation are positively correlated, species-specific traits, associated with the behavioural flexibility animals need for adapting to seasonal and unpredictable habitats. Similar ecological challenges would have been important drivers throughout human evolution. However, studies examining the influence of environmental variability on within-species behavioural diversity are lacking despite the critical assumption that population diversification precedes genetic divergence and speciation. Here, using a dataset of 144 wild chimpanzee (Pan troglodytes) communities, we show that chimpanzees exhibit greater behavioural diversity in environments with more variability - in both recent and historical timescales. Notably, distance from Pleistocene forest refugia is associated with the presence of a larger number of behavioural traits, including both tool and non-tool use behaviours. Since more than half of the behaviours investigated are also likely to be cultural, we suggest that environmental variability was a critical evolutionary force promoting the behavioural, as well as cultural diversification of great apes.

Evaluating scenarios toward zero plastic pollution.

Plastic pollution is a pervasive and growing problem. To estimate the effectiveness of interventions to reduce plastic pollution, we modeled stocks and flows of municipal solid waste and four sources of microplastics through the global plastic system for five scenarios between 2016 and 2040. Implementing all feasible interventions reduced plastic pollution by 40% from 2016 rates and 78% relative to "business as usual" in 2040. Even with immediate and concerted action, 710 million metric tons of plastic waste cumulatively entered aquatic and terrestrial ecosystems. To avoid a massive build-up of plastic in the environment, coordinated global action is urgently needed to reduce plastic consumption; increase rates of reuse, waste collection, and recycling; expand safe disposal systems; and accelerate innovation in the plastic value chain.

Author Correction: Chimpanzee ethnography reveals unexpected cultural diversity.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Chimpanzee ethnography reveals unexpected cultural diversity.

Human ethnographic knowledge covers hundreds of societies, whereas chimpanzee ethnography encompasses at most 15 communities. Using termite fishing as a window into the richness of chimpanzee cultural diversity, we address a potential sampling bias with 39 additional communities across Africa. Previously, termite fishing was known from eight locations with two distinguishable techniques observed in only two communities. Here, we add nine termite-fishing communities not studied before, revealing 38 different technical elements, as well as community-specific combinations of three to seven elements. Thirty of those were not ecologically constrained, permitting the investigation of chimpanzee termite-fishing culture. The number and combination of elements shared among individuals were more similar within communities than between them, thus supporting community-majority conformity via social imitation. The variation in community-specific combinations of elements parallels cultural diversity in human greeting norms or chopstick etiquette. We suggest that termite fishing in wild chimpanzees shows some elements of cumulative cultural diversity.

Conversational Language in 3-Year-Old Children Born Very Preterm and at Term.

Purpose Language difficulties are prevalent among children born preterm. Existing studies have largely used standardized language tests, providing limited scope for detailed descriptive examination of preterm language. This study aimed to examine differences in conversational language between children born < 30 weeks and at term as well as correlations between language sample analysis (LSA) and a standardized language tool. Method Two hundred four 3-year-olds (103 born < 30 weeks, 101 born at term) recruited at birth provided a 10-min language sample and completed the Preschool Language Scales-Fifth Edition (I. Zimmerman, Steiner, & Pond, 2011). LSA was conducted using the Systematic Analysis of Language Transcripts and Index of Productive Syntax. Group differences were analyzed using linear regression, and Pearson correlation coefficient (coef) was used to determine correlations between measures. Results Children born < 30 weeks scored lower than term-born peers on multiple metrics when controlled for confounding factors (sex, high social risk, multilingualism, and diagnosed neurodevelopmental disorders), including mean length of utterance in morphemes (coef = -0.28, 95% confidence interval [CI] [-0.56, 0.01]) and words (coef = -0.29, 95% CI [-0.53, -0.05]), number of different word roots (coef = -10.04, 95% CI [-17.93, -2.14]), and Index of Productive Syntax sentence structures (coef = -1.81, 95% CI [-3.10, -0.52]). Other variables (e.g., number of utterances, number of nouns and adjectives) were not significantly different between groups. LSA and the Preschool Language Scales-Fifth Edition were at most moderately correlated (≤ .45). Conclusions Three-year-old children born preterm demonstrated poorer conversational language than children born at term, with some specific areas of deficit emerging. Furthermore, formal assessment and LSA appear to provide relatively distinct and yet complementary data to guide diagnostic and intervention decisions. Supplemental Material https://doi.org/10.23641/asha.11368073.

Sensitivity of Magnetic Anisotropy in the Solid State for Lanthanide Complexes with Small Crystal Field Splitting.

Knowledge of the crystal structure of a monometallic inorganic molecule is often sufficient to calculate its electronic structure and interpret its magnetic properties. Here we show that for a series of nine-coordinate lanthanide complexes based on the 1,4,7-tris[(6-carboxypyridin-2-yl)methyl]-1,4,7-triazacyclononane ligand, the electronic structure is hypersensitive to geometric structure and to the presence of noncoordinated lattice solvent, which renders the magnetic and spectroscopic properties very difficult to interpret. We explore possible explanations for the peculiar electron paramagnetic resonance (EPR) spectra and conclude that a number of entangled factors are at play across the samples. Hence, great care should be taken in the interpretation of EPR spectra for systems with small magnetic anisotropy, even when the molecular structure is known.

Paro cardiorrespiratorio extrahospitalario. Realidad de un hospital terciario chileno / Out of hospital cardiac arrest events at an urban Hospital in Chile

Background: The incidence of out of hospital cardiac arrest (OHCA) is approximately 20 to 140 per 100.000 inhabitants. International registries, based on Utstein criteria have allowed standardized reporting of OHCA profiles and outcomes in different countries. We proposed to create a local OHCA registry. Aim: To assess the quality of the information about OHCA currently recorded in medical records according to Utstein guidelines. Material and Methods: A retrospective analysis of medical records of patients arriving in the emergency room of a public hospital with OHCA during a 3-year period. Data regarding the patient characteristics, event and outcomes were analyzed. Results: During the revision period, 317 patients arrived with an OHCA. None of the medical records had complete data on items that are considered a minimum requirement by Utstein guidelines. Mean age of patients was 63 years old, 60% were men, the most common arrest rhythm was asystole (43%) and 8% of patients were discharged alive. Conclusions: Data recorded in medical records is insufficient to inform the profile of OHCA. A prospective registry is currently being implemented based on the information provided by this study. This registry should optimize reporting and data analysis.

Induced europium CPL for the selective signalling of phosphorylated amino-acids and O-phosphorylated hexapeptides.

Two bright, europium(iii) complexes based on an achiral heptadentate triazacyclononane ligand bearing two strongly absorbing chromophores have been evaluated for the selective emission and CPL signalling of various chiral O-phosphono-anions. Binding of O-phosphono-Ser and Thr gives rise to a strong induced CPL signature and a favoured Δ complex configuration is adopted. A similarly large induced CPL signal arises when [Eu·](2+) binds to lysophosphatidic acid (LPA), where the strong binding (log K 5.25 (295 K)) in methanol allowed its detection over the range 5 to 40 µM. Strong and chemoselective binding to the phosphorylated amino-acid residues was also observed with a set of four structurally related hexapeptides: in one case, the sign of the gem value in the ΔJ = 1 transition allowed differentiation between the binding to O-P-Ser and O-P-Tyr residues.

Chiral probe development for circularly polarised luminescence: comparative study of structural factors determining the degree of induced CPL with four heptacoordinate europium(III) complexes.

A series of bright, europium(iii) complexes has been prepared based on an achiral heptadentate triazacyclononane ligand bearing two strongly absorbing, coordinated aralkynyl pyridyl moieties. The binding of chiral carboxylates, including α-hydroxy acids such as lactate and mandelate, has been monitored by emission spectroscopy and is signalled by the switching on of strong circularly polarised emission. In each case, an R-chiral carboxylate gave rise to emission typical of a Δ complex, most clearly shown in the form of the ΔJ = 4 transition manifold around 700 nm. Variations in the sign and magnitude of the CPL allow the enantiomeric purity and absolute configuration of the acid to be assessed in a sample. Analysis of the relative energies of the parent aqua complexes and their stereoisomeric adducts has been aided by lifetime measurements and density functional theory calculations.

Critical analysis of the limitations of Bleaney's theory of magnetic anisotropy in paramagnetic lanthanide coordination complexes.

The origins of the breakdown of Bleaney's theory of magnetic anisotropy are described, based on an analysis of eleven different complexes of the second half of the 4f elements that form isostructural series. An examination of the chemical shift and relaxation rate behaviour of resonances located at least four bonds away from the paramagnetic centre was undertaken, and correlated to theoretical predictions. The key limitations relate to comparability of ligand field splitting with spin-orbit coupling, variation in the position of the principal magnetic axis between Ln complexes and the importance of multipolar terms in describing lanthanide ligand field interactions.

EuroTracker® dyes: design, synthesis, structure and photophysical properties of very bright europium complexes and their use in bioassays and cellular optical imaging.

The development of the brightest luminescent europium(iii) complexes is traced, including analysis of the C3-symmetric core complex based on a functionalized triazacyclononane and identification of the most suitable strongly absorbing chromophore. Strategies for the synthesis of the complexes, including enantiopure analogues, are outlined and opportunities for applications in time-resolved microscopy and spectral imaging emphasised. Practicable examples are introduced, including selective organelle staining for cellular optical imaging at 65 nm resolution and the development of new bioassays using time-resolved FRET methods.