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Abstract Background Assessment for risks associated with acute stable COVID-19 is important to optimize clinical trial enrollment and target patients for scarce therapeutics. To assess whether healthcare system engagement location is an independent predictor of outcomes we performed a secondary analysis of the ACTIV-4B Outpatient Thrombosis Prevention trial. Methods A secondary analysis of the ACTIV-4B trial that was conducted at 52 US sites between September 2020 and August 2021. Participants were enrolled through acute unscheduled episodic care (AUEC) enrollment location (emergency department, or urgent care clinic visit) compared to minimal contact (MC) enrollment (electronic contact from test center lists of positive patients).We report the primary composite outcome of cardiopulmonary hospitalizations, symptomatic venous thromboembolism, myocardial infarction, stroke, transient ischemic attack, systemic arterial thromboembolism, or death among stable outpatients stratified by enrollment setting, AUEC versus MC. A propensity score for AUEC enrollment was created, and Cox proportional hazards regression with inverse probability weighting (IPW) was used to compare the primary outcome by enrollment location. Results Among the 657 ACTIV-4B patients randomized, 533 (81.1%) with known enrollment setting data were included in this analysis, 227 from AUEC settings and 306 from MC settings. In a multivariate logistic regression model, time from COVID test, age, Black race, Hispanic ethnicity, and body mass index were associated with AUEC enrollment. Irrespective of trial treatment allocation, patients enrolled at an AUEC setting were 10-times more likely to suffer from the adjudicated primary outcome, 7.9% vs. 0.7%; p

The porosity of porous materials is a critical quality attribute of many products ranging from catalysis and separation technologies to porous paper and pharmaceutical tablets. The open porosity in particular, which reflects the pore space accessible from the surface, is crucial for applications where a fluid needs to access the pores in order to fulfil the functionality of the product. This study presents a methodology that uses terahertz time-domain spectroscopy (THz-TDS) coupled with an index-matching medium to measure the open porosity and analyze scattering losses of powder compacts. The open porosity can be evaluated without the knowledge of the refractive index of the fully dense material. This method is demonstrated for pellets compressed of pharmaceutical-grade lactose powder. Powder was compressed at four different pressures and measured by THz-TDS before and after they were soaked in an index-matching medium, i.e., paraffin. Determining the change in refractive index of the dry and soaked samples enabled the calculation of the open porosity. The results reveal that the open porosity is consistently lower than the total porosity and it decreases with increasing compression pressure. The scattering losses reduce significantly for the soaked samples and the scattering centers (particle and/or pore sizes) are of the order of or somewhat smaller than the terahertz wavelength. This new method facilitates the development of a better understanding of the links between material properties (particles size), pellet properties (open porosity) and performance-related properties, e.g., disintegration and dissolution performance of pharmaceutical tablets.

Abstract Osteosarcoma is the most common primary bone malignancy in children and young adults, and it has few treatment options. As a result, there has been little improvement in survival outcomes in the past few decades. The need for models to test novel therapies is especially great in this disease since it is both rare and does not respond to most therapies. To address this, an NCI-funded consortium has characterized and utilized a panel of patient-derived xenograft models of osteosarcoma for drug testing. The exomes, transcriptomes, and copy number landscapes of these models have been presented previously. This study now adds whole genome sequencing and reverse-phase protein array profiling data, which can be correlated with drug testing results. In addition, four additional osteosarcoma models are described for use in the research community.

Abstract Background Radical radiotherapy for muscle-invasive bladder cancer (MIBC) is challenging due to large variations in bladder shape, size and volume during treatment, with drinking protocols often employed to mitigate geometric uncertainties. Utilising adaptive radiotherapy together with CBCT imaging to select a treatment plan that best fits the bladder target and reduce normal tissue irradiation is an attractive option to compensate for anatomical changes. The aim of this retrospective study was to compare a bladder empty (BE) protocol to a bladder filling (BF) protocol with regards to variations in target volumes, plan of the day (PoD) selection and plan dosimetry throughout treatment. Methods Forty patients were included in the study; twenty were treated with a BE protocol and twenty with a BF protocol to a total prescribed dose of 55 Gy in 20 fractions. Small, medium and large bladder plans were generated using three different CTV to PTV margins. Bladder (CTV) volumes were delineated on planning CTs and online pre-treatment CBCTs. Differences in CTV volumes throughout treatment, plan selection, PTV volumes and resulting dose metrics were compared for both protocols. Results Mean bladder volume differed significantly on both the planning CTs and online pre-treatment CBCTs between the protocols (p

Abstract Pulmonary veno‐occlusive disease (PVOD) is a rare form of pulmonary vascular disease that is difficult to distinguish clinically from pulmonary arterial hypertension (PAH). Multiple genes have been implicated in disease pathogenesis in PAH and PVOD and the diseases are thought to be genetically distinct. In this report we present a case of first‐degree relatives with pathological evidence of PVOD and PAH. The index patient was diagnosed with PAH at age 42, was treated with escalating pulmonary vasodilator therapy, but eventually succumbed to her disease. On autopsy, her pathology was consistent with PAH. Her son was diagnosed with PAH at age 16, did well on pulmonary vasodilator therapy for over 10 years, but ultimately developed refractory right ventricular failure and received a heart and lung transplantation. Pathology of his explanted lung was consistent with PVOD, and genetic testing was negative for recognized variants that cause PAH or PVOD.

Abstract Background The management of acute pulmonary embolism (PE) has become increasingly complex with the expansion of advanced therapeutic options, resulting in the development and widespread adoption of multidisciplinary Pulmonary Embolism Response Teams (PERTs). Much of the literature evaluating the impact of PERTs has been limited by pre- postimplementation study design, leading to confounding by changes in global practice patterns over time, and has yielded mixed results. To address this ambiguity, we conducted a retrospective cohort study to evaluate the impact of the distinct exposures of PERT availability and direct PERT consultation. Methods At a single tertiary center, we conducted propensity-matched analyses of hospitalized patients with intermediate or high-risk PE. To assess the impact of PERT availability, we evaluated the changes in 30-day mortality, hospital length of stay (HLOS), time to therapeutic anticoagulation (TAC), in-hospital bleeding complications, and use of advanced therapies between the two years preceding and following PERT implementation. To evaluate the impact of direct PERT consultation, we conducted the same analyses in the post-PERT era, comparing patients who did and did not receive PERT consultation. Results Six hundred eighty four patients were included, of which 315 were pre-PERT patients. Of the 367 postPERT patients, 201 received PERT consultation. For patients who received PERT consultation, we observed a significant reduction in 30-day mortality (5% vs 20%, OR 0.38, p = 0.0024), HLOS. (-5.4 days, p

El distanciamiento social en conjunto con otras medidas para evitar o disminuir la transmisión de la COVID-19, han tenido consecuencias en la salud mental de los estudiantes. Objetivo: Evaluar la salud mental de estudiantes de medicina en Nariño (Colombia), durante la pandemia por COVID-19. Metodología: Estudio cuantitativo, observacional, descriptivo, de corte transversal. Se aplicó una encuesta virtual autodiligenciada a estudiantes mayores de 18 años, de cuarto semestre y de semilleros de la Facultad de Medicina de la Universidad Cooperativa de Colombia Campus Pasto, quienes participaron voluntariamente del estudio; se excluyó a quienes tuvieron problemas de conexión a Internet. Resultados: 54 estudiantes respondieron la encuesta, en su mayoría de 19 años (33,3%), solteros (96,3%), de estratos 2 al 4 (87,0%), de cuarto semestre (96,0%) y de sexo femenino (59,0%). Hubo mayor prevalencia de ansiedad (31,3%) que de estrés (16,7%) y depresión (16,7%). Para la ansiedad el mayor nivel fue moderado (52,9%), al igual que para la depresión (55,6%), mientras que para la ansiedad fue muy severo (20,0%). El 100% presentó desesperanza en diferentes niveles y 33,3% mostraron ideación suicida. Conclusión: Es necesario implementar medidas que ayuden a mejorar y prevenir afectaciones de la salud mental de los estudiantes, así como realizar estudios analíticos que permitan indagar en la asociación de COVID-19 y su impacto en la salud mental.

Abstract Identification of long‐term calcium channel blocker (CCB) responders with acute vasodilator challenge is critical in the evaluation of patients with pulmonary arterial hypertension. Currently there is no standardized approach for use of supplemental oxygen during acute vasodilator challenge. In this retrospective analysis of patients identified as acute vasoresponders, treated with CCBs, all patients had hemodynamic measurements in three steps: (1) at baseline; (2) with 100% fractional inspired oxygen; and (3) with 100% fractional inspired oxygen plus inhaled nitric oxide (iNO). Those meeting the definition of acute vasoresponsiveness only after first normalizing for the effects of oxygen in step 2 were labeled “iNO Responders.” Those who met the definition of acute vasoresponsiveness from a combination of the effects of 100% FiO2 and iNO were labeled “oxygen responders.” Survival, hospitalization for decompensated right heart failure, duration of CCB monotherapy, and functional data were collected. iNO responders, when compared to oxygen responders, had superior survival (100% vs. 50.1% 5‐year survival, respectively), fewer hospitalizations for acute decompensated right heart failure (0% vs. 30.4% at 1 year, respectively), longer duration of CCB monotherapy (80% vs. 52% at 1 year, respectively), and superior 6‐min walk distance. Current guidelines for acute vasodilator testing do not standardize oxygen coadministration with iNO. This study demonstrates that adjusting for the effects of supplemental oxygen before assessing for acute vasoresponsiveness identifies a cohort with superior functional status, tolerance of CCB monotherapy, and survival while on long‐term CCB therapy.

Abstract Thermal-stress events on coral reefs lead to coral bleaching, mortality, and changes in species composition. The coral reefs of Yap, in the Federated States of Micronesia, however, remained largely unaffected by major thermal-stress events until 2020, when temperatures were elevated for three months. Twenty-nine study sites were examined around Yap to determine geographical and taxonomic patterns of coral abundance, bleaching susceptibility, and environmental predictors of bleaching susceptibility. Island-wide, 21% (± 14%) of the coral cover was bleached in 2020. Although inner reefs had a greater proportion of thermally-tolerant Porites corals, the prevalence of bleaching was consistently lower on inner reefs (10%) than on outer reefs (31%) for all coral taxa. Corals on both inner and outer reefs along the southwestern coast exhibited the lowest prevalence of coral bleaching and had consistently elevated chlorophyll-a concentrations. More broadly, we revealed a negative relationship between bleaching prevalence and (moderate) chlorophyll-a concentrations that may have facilitated resistance to thermal stress by reducing irradiance and providing a heterotrophic energy source to benefit some corals exposed to autotrophic stress. Southwestern reefs also supported a high but declining fish biomass, making these bleaching-resistant and productive reefs a potential climate-change refuge and a prime target for conservation.

In embryonal rhabdomyosarcoma (ERMS) and generally in sarcomas, the role of wild-type and loss- or gain-of-function TP53 mutations remains largely undefined. Eliminating mutant or restoring wild-type p53 is challenging; nevertheless, understanding p53 variant effects on tumorigenesis remains central to realizing better treatment outcomes. In ERMS, >70% of patients retain wild-type TP53, yet mutations when present are associated with worse prognosis. Employing a kRASG12D-driven ERMS tumor model and tp53 null (tp53-/-) zebrafish, we define wild-type and patient-specific TP53 mutant effects on tumorigenesis. We demonstrate that tp53 is a major suppressor of tumorigenesis, where tp53 loss expands tumor initiation from 97% of animals. Characterizing three patient-specific alleles reveals that TP53C176F partially retains wild-type p53 apoptotic activity that can be exploited, whereas TP53P153Δ and TP53Y220C encode two structurally related proteins with gain-of-function effects that predispose to head musculature ERMS. TP53P153Δ unexpectedly also predisposes to hedgehog-expressing medulloblastomas in the kRASG12D-driven ERMS-model.

Abstract To better understand the impact of the COVID‐19 pandemic on the care of patients with pulmonary hypertension, we conducted a retrospective cohort study evaluating health insurance status, healthcare access, disease severity, and patient reported outcomes in this population. Using the Pulmonary Hypertension Association Registry (PHAR), we defined and extracted a longitudinal cohort of pulmonary arterial hypertension (PAH) patients from the PHAR's inception in 2015 until March 2022. We used generalized estimating equations to model the impact of the COVID‐19 pandemic on patient outcomes, adjusting for demographic confounders. We assessed whether insurance status modified these effects via covariate interactions. PAH patients were more likely to be on publicly‐sponsored insurance during the COVID‐19 pandemic compared with prior, and did not experience statistically significant delays in access to medications, increased emergency room visits or nights in the hospital, or worsening of mental health metrics. Patients on publicly‐sponsored insurance had higher healthcare utilization and worse objective measures of disease severity compared with privately insured individuals irrespective of the COVID‐19 pandemic. The relatively small impact of the COVID‐19 pandemic on pulmonary hypertension‐related outcomes was unexpected but may be due to pre‐established access to high quality care at pulmonary hypertension comprehensive care centers. Irrespective of the COVID‐19 pandemic, patients who were on publicly‐sponsored insurance seemed to do worse, consistent with prior studies highlighting outcomes in this population. We speculate that previously established care relationships may lessen the impact of an acute event, such as a pandemic, on patients with chronic illness.

Introduction: It has been proposed that an increased susceptivity to oxidative stress caused by the absence of the protein dystrophin from the inner surface of the sarcolemma is a trigger of skeletal muscle necrosis in the destructive dystrophin deficient muscular dystrophies. Here we use the mdx mouse model of human Duchenne Muscular Dystrophy to test the hypothesis that adding the antioxidant NAC at 2% to drinking water for six weeks will treat the inflammatory phase of the dystrophic process and reduce pathological muscle fiber branching and splitting resulting in a reduction of mass in mdx fast-twitch EDL muscles.Methods: Animal weight and water intake was recorded during the six weeks when 2% NAC was added to the drinking water. Post NAC treatment animals were euthanised and the EDL muscles dissected out and placed in an organ bath where the muscle was attached to a force transducer to measure contractile properties and susceptibility to force loss from eccentric contractions. After the contractile measurements had been made the EDL muscle was blotted and weighed. In order to assess the degree of pathological fiber branching mdx EDL muscles were treated with collagenase to release single fibers. For counting and morphological analysis single EDL mdx skeletal muscle fibers were viewed under high magnification on an inverted microscope.Results: During the six-week treatment phase NAC reduced body weight gain in three- to nine-week-old mdx and littermate control mice without effecting fluid intake. NAC treatment also significantly reduced the mdx EDL muscle mass and abnormal fiber branching and splitting.Discussion: We propose chronic NAC treatment reduces the inflammatory response and degenerative cycles in the mdx dystrophic EDL muscles resulting in a reduction in the number of complexed branched fibers reported to be responsible for the dystrophic EDL muscle hypertrophy.

The incidence of pulmonary tumor embolism in patients with solid tumors is estimated to be between 3% and 26% yet is rarely diagnosed. In this case, a 74-year-old male with sarcomatoid variant of urothelial carcinoma and recently diagnosed left renal vein thrombus treated with low-molecular-weight-heparin, presented to the emergency department with acute syncope and dyspnea. He was found to have CT imaging of segmental and subsegmental arterial filling defects, a right atrial filling defect concerning for thrombus in transit and was diagnosed with pulmonary tumor embolism syndrome. The patient was treated with aspiration thrombectomy, with pathology demonstrating sarcomatoid urothelial carcinoma cells. He was initiated on a combination of gemcitabine plus carboplatin to decrease the tumor burden. While pulmonary tumor embolism syndrome is associated with a poor prognosis, prompt diagnosis and initiation of cancer-specific therapies can significantly improve survival.

Abstract Background Modern sequencing technologies should make the assembly of the relatively small mitochondrial genomes an easy undertaking. However, few tools exist that address mitochondrial assembly directly. Results As part of the Vertebrate Genomes Project (VGP) we develop mitoVGP, a fully automated pipeline for similarity-based identification of mitochondrial reads and de novo assembly of mitochondrial genomes that incorporates both long (> 10 kbp, PacBio or Nanopore) and short (100–300 bp, Illumina) reads. Our pipeline leads to successful complete mitogenome assemblies of 100 vertebrate species of the VGP. We observe that tissue type and library size selection have considerable impact on mitogenome sequencing and assembly. Comparing our assemblies to purportedly complete reference mitogenomes based on short-read sequencing, we identify errors, missing sequences, and incomplete genes in those references, particularly in repetitive regions. Our assemblies also identify novel gene region duplications. The presence of repeats and duplications in over half of the species herein assembled indicates that their occurrence is a principle of mitochondrial structure rather than an exception, shedding new light on mitochondrial genome evolution and organization. Conclusions Our results indicate that even in the “simple” case of vertebrate mitogenomes the completeness of many currently available reference sequences can be further improved, and caution should be exercised before claiming the complete assembly of a mitogenome, particularly from short reads alone.

Rhabdomyosarcomas are tumours blocked in myogenic differentiation, which despite the expression of master muscle regulatory factors, including MYOD, are unable to differentiate. Here, the authors show that SNAI2 is upregulated by MYOD through super enhancers, binds to MYOD target enhancers, and arrests differentiation.

Abstract Background Aging is a comorbidity of breast cancer suggesting that aging-associated transcriptome changes may promote breast cancer progression. However, the mechanism underlying the age effect on breast cancer remains poorly understood. Method We analyzed transcriptomics of the matched normal breast tissues from the 82 breast cancer patients in The Cancer Genome Atlas (TCGA) dataset with linear regression for genes with age-associated expression that are not associated with menopause. We also analyzed differentially expressed genes between the paired tumor and non-tumor breast tissues in TCGA for the identification of age and breast cancer (ABC)-associated genes. A few of these genes were selected for further investigation of their malignancy-regulating activities with in vitro and in vivo assays. Results We identified 148 upregulated and 189 downregulated genes during aging. Overlapping of tumor-associated genes between normal and tumor tissues with age-dependent genes resulted in 14 upregulated and 24 downregulated genes that were both age and breast cancer associated. These genes are predictive in relapse-free survival, indicative of their potential tumor promoting or suppressive functions, respectively. Knockdown of two upregulated genes (DYNLT3 and P4HA3) or overexpression of the downregulated ALX4 significantly reduced breast cancer cell proliferation, migration, and clonogenicity. Moreover, knockdown of P4HA3 reduced growth and metastasis whereas overexpression of ALX4 inhibited the growth of xenografted breast cancer cells in mice. Conclusion Our study suggests that transcriptome alterations during aging may contribute to breast tumorigenesis. DYNLT3, P4HA3, and ALX4 play significant roles in breast cancer progression.

We describe nearly complete skeletons of basal Anseriformes from the Latest Paleocene to the early Eocene of North America and Europe. Collectively, these birds appear to be representative of anseriforms near the divergence of Anhimae and Anseres, but their exact positions relative to these clades remains uncertain. A new family, Anachronornithidae nov. fam., is erected on the basis of one of these, Anachronornis anhimops nov. gen., nov. gen. et sp., to which the others cannot be confidently assigned. The new fossils augment a growing collection of early Pan-Anseriformes, which in their diversity do not paint an unambiguous picture of phylogeny or character state evolution on the path to or within crown-Anseriformes. Anachronornis nov. gen. is similar in some aspects of both cranial and postcranial anatomy to other well-represented early Paleogene Anseriformes and members of Anseres, such as Presbyornis Wetmore, 1926. However, it exhibits a more landfowl-like bill, like that of Anhimae and unlike the spatulate bill of Anseres. Additional specimens of similar basal Anseriformes of uncertain affinities from the early Eocene of North America and Europe further complicate interpretation of character state polarity due to the mosaicism of primitive and derived characters they exhibit.

Background WHO Group 1 pulmonary arterial hypertension is a progressive and potentially fatal disease. Individuals living at higher altitude are exposed to lower barometric pressure and hypobaric hypoxemia. This may result in pulmonary vasoconstriction and contribute to disease progression. We sought to examine the relationship between living at moderately high altitude and pulmonary arterial hypertension characteristics. Methods Forty-two US centers participating in the Pulmonary Hypertension Association Registry enrolled patients who met the definition of WHO Group 1 pulmonary arterial hypertension. We utilized baseline data and patient questionnaire responses. Patients were divided into two groups: moderately high altitude residence (home ≥4000 ft) and low altitude residence (home

Church history is dead, long live historical theology! This restatement of the monarchical law of le mort saisit le vif is at once a statement of irreparable discontinuity and assumed continuity. The old monarch is no more, yet a new and different monarch ascends to fill the same vacant throne. This is the paradox of church history becoming historical theology. Reviewing the work of W.A Dreyer and J. Pillay on the re-imagining of church history as historical theology, this article explores the tension between the demise of church history as a subject in South Africa and the emerging understanding and application of historical theology, arguing that more can be made of trans-disciplinary dialogues.

Environmental security is generally held to be a contemporary or even futuristic concern. However, as with many facets of security thought, this overlooks how the unparalleled technological, economic and social changes of the 19th Century forged much of the international political landscape we now inhabit. The tendency for ecological political enquiry to focus on the rise of ecocentric policy serves to obscure how many aspects of national and human security relating to environmental change were apparent in the 19th century. Human insecurity in the face of pollution and resource depletion was a part of the emergence of ecological science in response to the industrialisation of Europe and North America. In addition, this was the era when European imperialism reached its apex and European nationalisms fully emerged; both of which contributed to the national securitization of the environment around much of the world in contrasting ways as the desire to both conquer and preserve nature became more evident. Environmental questions of national, human and ecological security are not peculiar to the present age and were very much apparent in 19th Century global politics.

The radiation and chemotherapy used for treating medulloblastoma patients cause debilitating side effects. Here, the authors show that miR-584 acts as a therapeutic adjuvant as it sensitizes medulloblastoma to radiation and chemotherapy by targeting HDAC1 or eIF4E3 to enhance spindle defects and DNA damage.

ABSTRACT IMPACT: By assessing function of mutant (patient-specific) tp53 in zebrafish embryonal rhabdomyosarcoma will inform clinicians of the severity of mutant tp53 alleles. OBJECTIVES/GOALS: This study aims to define loss- and gain-of-function TP53 mutations by comparing effects in tp53-null and wild-type tumors. In addition, it aims to generate a rapid in vivo analysis platform to assign function to patient specific TP53 mutations in the clinic METHODS/STUDY POPULATION: To define tp53 function in ERMS pathogenesis, we previously generated a new tp53-null mutant (tp53-/-) in zebrafish by deleting the entire tp53 genomic locus using TALEN mutagenesis. tp53-/- zebrafish spontaneously develop a spectrum of tumors including sarcomas, leukemia and germ cell tumors (Ignatius…Baxi et. al., eLife) reminiscent of tumors observed in Trp53-null mice. Using the tp53-/- mutants to generate kRASG12D-induced ERMS, we discovered that tp53 is a potent repressor of metastases but rather surprisingly had no effect on self-renewal (Ignatius…Baxi et. al., eLife). Here, using tp53-/- zebrafish, we assessed effects of wild-type and mutant (patient specific) tp53 on tumor initiation, proliferation and apoptosis. RESULTS/ANTICIPATED RESULTS: ERMS tumor initiation in the tp53-/- background is observed in > 97% of animals whereas only

Objective: Acute kidney injury (AKI) is a significant cause of morbidity and mortality among hospitalised patients. The objectives in this study were (i) to investigate the incidence of AKI using the National Health Services (NHS) AKI e-alert algorithm as a means of identifying AKI; and (ii) in a randomly selected sub-group of children with AKI identified using the algorithm, to evaluate the recognition and management of AKI.Patients and Methods: Retrospective cross-sectional study with initial electronic retrieval of creatinine measurements at six hospitals in England over a six-month period. Results were evaluated using the NHS AKI e-alert algorithm with recognition and management of AKI stages 1, 2 and 3 reviewed in a sub-set of randomly selected patient case notes. Patients aged 29 to 17 years were included. AKI stage 1 was defined as a rise of 1.5 – ≤2x baseline creatinine level; AKI stage 2 a rise of ≤ 2.0 and < 3.0; AKI stage 3 a rise of ≥ 3.0. Urine output was not considered for AKI staging.Results: 57,278 creatinine measurements were analysed. 5,325 (10.8%) AKI alerts were noted in 1,112 patients with AKI 1 (62%), AKI 2 (16%) and AKI 3 (22%). There were 222 (20%)

Ewing sarcoma is a small round blue cell malignancy arising from bone or soft tissue and most commonly affects adolescents and young adults. Metastatic and relapsed Ewing sarcoma have poor outcomes and recurrences remain common. Owing to the poor outcomes associated with advanced disease and the need for a clear research strategy, the Children’s Oncology Group Bone Tumor Committee formed the New Agents for Ewing Sarcoma Task Force to bring together experts in the field to evaluate and prioritize new agents for incorporation into clinical trials. This group’s mission was to evaluate scientific and clinical challenges in moving new agents forward and to recommend agents and trial designs to the Bone Tumor Committee. The task force generated a framework for vetting prospective agents that included critical evaluation of each drug by using both clinical and non-clinical parameters. Representative appraisal of agents of highest priority, including eribulin, dinutuximab, cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors, anti-angiogenic tyrosine kinase inhibitors, and poly-ADP-ribose polymerase (PARP) inhibitors, is described. The task force continues to analyze new compounds by using the paradigm established.

Assessing the applicability of theory to major adaptive radiations in deep time represents an extremely difficult problem in evolutionary biology. Neoaves, which includes 95% of living birds, is believed to have undergone a period of rapid diversification roughly coincident with the Cretaceous–Paleogene (K-Pg) boundary. We investigate whether basal neoavian lineages experienced an ecological release in response to ecological opportunity, as evidenced by density compensation. We estimated effective population sizes (Ne) of basal neoavian lineages by combining coalescent branch lengths (CBLs) and the numbers of generations between successive divergences. We used a modified version of Accurate Species TRee Algorithm (ASTRAL) to estimate CBLs directly from insertion–deletion (indel) data, as well as from gene trees using DNA sequence and/or indel data. We found that some divergences near the K-Pg boundary involved unexpectedly high gene tree discordance relative to the estimated number of generations between speciation events. The simplest explanation for this result is an increase in Ne, despite the caveats discussed herein. It appears that at least some early neoavian lineages, similar to the ancestor of the clade comprising doves, mesites, and sandgrouse, experienced ecological release near the time of the K-Pg mass extinction.

Acute eosinophilic pneumonia (AEP) is a rare but important and potentially fatal complication of daptomycin therapy. Here, we present the case of an 85-year-old man with a history of resected esophageal cancer and osteomyelitis treated with daptomycin on two separate occasions who presented for workup of recurrent pneumonia. X-ray and computed tomography of the chest showed right upper lobe and left lower lobe infiltrates. Bronchoscopy with bronchoalveolar lavage showed a WBC of 200/µL with 75% eosinophils. No infectious etiology was found despite multiple cultures for pathogens. His presenting symptoms improved over the course of hospitalization despite cessation of all antibiotics. Given the clinical picture and bronchoscopy results, his presentation was attributed to daptomycin-related eosinophilic pneumonia. Since the approval of daptomycin in 2003, approximately 20 case reports have been published demonstrating AEP associated with daptomycin use. We suggest that daptomycin-associated AEP is an under recognized complication and that the incidence will increase with greater use of the drug. Physicians should be especially cognizant of elderly male patients being treated with prolonged courses.

Throughout the 1990s and the first decade of the new millennium, some second language acquisition (SLA) researchers have begun to conduct research from a perspective on learner development that foregrounds the effects of situational or environmental variables on the learning process. These researchers, according to Swain and Deters (2007), privilege a “participation” metaphor over the more traditional focus on “acquisition.” Important researchers in this tradition (e.g., Lantolf, 1994; Pierce, 1995; Duff & Uchida, 1997; Norton & Toohey, 2001) have drawn upon poststructuralist social theory, as well as Vygotsky’s (1978) earlier notions of learning situated in a zone of proximal development, to emphasize the influence of the learner’s environment in shaping learning behaviors, and consequently language learning outcomes.

The consistent supply of fresh fish to commercial markets may mask growing fishing footprints and localized depletions, as fishing expands to deeper/further reefs, smaller fish, and more resilient species. To test this hypothesis, species-based records and fisher interviews were gathered over one year within a large, demand-driven coral-reef fishery in Chuuk, Micronesia. We first assessed catch statistics with respect to high windspeeds and moon phases that are known to constrain both catch and effort. While lower daily catch success was predicted by higher windspeeds and greater lunar illumination, total daily landings fluctuated less than fishing success across environmental gradients. Instead, daily landings were mainly driven by the number of flights from Chuuk to Guam (i.e., international demand). Given that demand masked local drivers of overall catch volume, we further evaluated species-based indicators of fisheries exploitation. Most target species (75%) had either a positively skewed size distribution or proportional contributions that were dependent upon favorable conditions (i.e. season and moon phases). Skewed size distributions indicated truncated growth associated with fishing mortality, and in turn, suggested that size-based management policies may be most effective for these species. In contrast, environmentally-constrained catch success indicated species that may be more susceptible to growing fishing footprints and may respond better to gear/quota/area policies compared to size policies. Species-based responses offered a simplified means to combine species into fisheries management units. Finally, a comparison of commercial and subsistence landings showed higher vulnerability to fishing among species preferentially targeted by commercial fisheries, offering new insights into how commercial harvesting can disproportionately impact resources, despite having lower annual catch volumes.

“Genomic Analyses of Avian Evolution” is a “state of the art” showcase of the varied and rapidly evolving fields of inquiry enabled and driven by powerful new methods of genome sequencing and assembly as they are applied to some of the world’s most familiar and charismatic organisms—birds. The contributions to this Special Issue are as eclectic as avian genomics itself, but loosely interrelated by common underpinnings of phylogenetic inference, de novo genome assembly of non-model species, and genome organization and content.

The early radiation of Neoaves has been hypothesized to be an intractable “hard polytomy”. We explore the fundamental properties of insertion/deletion alleles (indels), an under-utilized form of genomic data with the potential to help solve this. We scored >5 million indels from >7000 pan-genomic intronic and ultraconserved element (UCE) loci in 48 representatives of all neoavian orders. We found that intronic and UCE indels exhibited less homoplasy than nucleotide (nt) data. Gene trees estimated using indel data were less resolved than those estimated using nt data. Nevertheless, Accurate Species TRee Algorithm (ASTRAL) species trees estimated using indels were generally similar to nt-based ASTRAL trees, albeit with lower support. However, the power of indel gene trees became clear when we combined them with nt gene trees, including a striking result for UCEs. The individual UCE indel and nt ASTRAL trees were incongruent with each other and with the intron ASTRAL trees; however, the combined indel+nt ASTRAL tree was much more congruent with the intronic trees. Finally, combining indel and nt data for both introns and UCEs provided sufficient power to reduce the scope of the polytomy that was previously proposed for several supraordinal lineages of Neoaves.

Quaternary alkaloids are the major alkaloids isolated from Tinospora species. A previous study pointed to the necessary presence of quaternary nitrogens for strong acetylcholinesterase (AChE) inhibitory activity in such alkaloids. Repeated column chromatography of the vine of Tinospora crispa extract led to the isolation of one new protoberberine alkaloid, 4,13-dihydroxy-2,8,9-trimethoxydibenzo[a,g]quinolizinium (1), along with six known alkaloids—dihydrodiscretamine (2), columbamine (3), magnoflorine (4), N-formylannonaine (5), N-formylnornuciferine (6), and N-trans-feruloyltyramine (7). The seven compounds were isolated and structurally elucidated by spectroscopic analysis. Two known alkaloids, namely, dihydrodiscretamine and columbamine are reported for the first time for this plant. The compounds were tested for AChE inhibitory activity using Ellman’s method. In the AChE inhibition assay, only columbamine (3) showed strong activity with IC50 48.1 µM. The structure–activity relationships derived from these results suggest that the quaternary nitrogen in the skeleton has some effect, but that a high degree of methoxylation is more important for acetylcholinesterase inhibition.

STAT3 is a transcription factor involved in cytokine and receptor kinase signal transduction that is aberrantly activated in a variety of sarcomas, promoting metastasis and chemotherapy resistance. The purpose of this work was to develop and test a novel putative STAT3 inhibitor, LY5.An in silico fragment-based drug design strategy was used to create LY5, a small molecule inhibitor that blocks the STAT3 SH2 domain phosphotyrosine binding site, inhibiting homodimerization. LY5 was evaluated in vitro demonstrating good biologic activity against rhabdomyosarcoma, osteosarcoma and Ewing's sarcoma cell lines at high nanomolar/low micromolar concentrations, as well as specific inhibition of STAT3 phosphorylation without effects on other STAT3 family members. LY5 exhibited excellent oral bioavailability in both mice and healthy dogs, and drug absorption was enhanced in the fasted state with tolerable dosing in mice at 40 mg/kg BID. However, RNAi-mediated knockdown of STAT3 did not phenocopy the biologic effects of LY5 in sarcoma cell lines. Moreover, concentrations needed to inhibit ex vivo metastasis growth using the PuMA assay were significantly higher than those needed to inhibit STAT3 phosphorylation in vitro. Lastly, LY5 treatment did not inhibit the growth of sarcoma xenografts or prevent pulmonary metastasis in mice.LY5 is a novel small molecule inhibitor that effectively inhibits STAT3 phosphorylation and cell proliferation at nanomolar concentrations. LY5 demonstrates good oral bioavailability in mice and dogs. However LY5 did not decrease tumor growth in xenograft mouse models and STAT3 knockdown did not induce concordant biologic effects. These data suggest that the anti-cancer effects of LY5 identified in vitro were not mediated through STAT3 inhibition.

The article gives an overview of the most important linguistic publications on the Burgenland Croatian dialects so far and concludes that our picture of these dialects is still far from complete. Two examples are given of unsolved questions that illustrate why a more complete picture than we have at the moment is necessary. The author wishes to point out that good quality linguistic fieldwork in this region deserves higher priority than it is given now, especially since the dialects are dying out so fast.

Artiklen er en invitation til overvejelser over begrebet ’kompetence’ som pædagogisk begreb med afsæt i fem forskellige kompetencebegreber: Et uddannelsespolitisk, et didaktisk, et læringsteoretisk, et kompleksitetshåndterende og et politisk dannende kompetencebegreb. De fem kompetencebegreber er ingenlunde dækkende for alt, hvad der kan siges om kompetencer i skole og uddannelse. Men hver på sin måde bidrager de til den aktuelle pædagogiske og skole- og uddannelsespolitiske diskurs. Artiklen introducerer og behandler de fem kompetencebegreber i nævnte rækkefølge og i en samlet bestræbelse på at kvalificere ’kompetence’ som pædagogisk begreb.

The recently extinct New Zealand adzebills (Aptornithidae, Aptornis spp.) were an enigmatic group of large flightless birds that have long eluded precise taxonomic assignment as they do not closely resemble any extant birds. Adzebills were nearly wingless, weighed approximately 16⁻19 kg, and possessed massive adze-like reinforced bills whose function remains unknown. Using hybridisation enrichment and high-throughput sequencing of DNA extracted from subfossil bone and eggshell, near-complete mitochondrial genomes were successfully assembled from the two Quaternary adzebill species: the North Island Adzebill (Aptornis otidiformis) and South Island Adzebill (A. defossor). Molecular phylogenetic analyses confirm that adzebills are members of the Ralloidea (rails and allies) and are sister-taxon to the Sarothruridae, which our results suggest comprises the Madagascan wood rails (Mentocrex, two likely sp.) in addition to the tiny (Sarothrura, 9 spp.). Node age estimates indicate that the split between adzebills and Sarothruridae occurred ~39.6 Ma, suggesting that the ancestors of the adzebills arrived in New Zealand by long-distance dispersal rather than continental vicariance. This newly identified biogeographic link between physically distant New Zealand and Afro-Madagascar, echoed by the relationship between the New Zealand kiwi (Apterygiformes) and Madagascan elephant-birds (Aepyornithiformes), suggests that the adzebill’s near relatives were formerly more widespread. In addition, our estimate for the divergence time between the two Quaternary adzebill species (0.2⁻2.3 Ma) coincides with the emergence of a land-bridge between the North and South islands of New Zealand (ca. 1.5⁻2 Ma). This relatively recent divergence suggests that North Island adzebills are the result of a relatively recent dispersal from the South Island, from which the earliest (Miocene) adzebill fossil has been described.

Van Eemeren and Houtlosser observe that Walton’s (and Walton and Krabbe’s) notion of ‘dialogue type’ involves a mixture of an empirical notion on a par with a speech event or activity type and a normative notion such as the model of a critical discussion. Then they discuss Walton’s contextual analysis of fallacies as illegitimate dialectical shifts of dialogue types and offer an alternative in which both the empirical and the normative dimension are given their due.

Understanding how and why coral reefs have changed over the last twenty to thirty years is crucial for sustaining coral-reef resilience. We used a historical baseline from Kosrae, a typical small island in Micronesia, to examine changes in fish and coral assemblages since 1986. We found that natural gradients in the spatial distribution of fish and coral assemblages have become amplified, as island geography is now a stronger determinant of species abundance patterns, and habitat forming Acropora corals and large-bodied fishes that were once common on the leeward side of the island have become scarce. A proxy for fishing access best predicted the relative change in fish assemblage condition over time, and in turn, declining fish condition was the only factor correlated with declining coral condition, suggesting overfishing may have reduced ecosystem resilience. Additionally, a proxy for watershed pollution predicted modern coral assemblage condition, suggesting pollution is also reducing resilience in densely populated areas. Altogether, it appears that unsustainable fishing reduced ecosystem resilience, as fish composition has shifted to smaller species in lower trophic levels, driven by losses of large predators and herbivores. While prior literature and anecdotal reports indicate that major disturbance events have been rare in Kosrae, small localized disturbances coupled with reduced resilience may have slowly degraded reef condition through time. Improving coral-reef resilience in the face of climate change will therefore require improved understanding and management of growing artisanal fishing pressure and watershed pollution.

This article details novel research methodology developed through a researcher-practitioner partnership and employed in a three-phase research effort that explored relationships between the co-operative model and sustainable development. Firstly, a basic understanding of the characteristics of the co-operative model was established using the co-operative principles as a framework, and their complementarity to sustainable development was examined by comparing them with sustainability theory, principles and best practices (defined through seminal journal articles on the topic). Secondly, relationships between sustainability theory and the ideas and operations of currently functioning co-operatives were investigated, namely, whether co-operatives had integrated sustainability into their organizations. Thirdly, an integrated analysis that examined the relationship between co-operatives, the co-operative principles and sustainability concepts was conducted, and output from this work was used to build a visualization (referred to as the ‘Co-operative Star’), specifically designed to communicate a synthesis of research findings to diverse audiences. This study specifically focused on co-operatives and sustainability; however, the analytical techniques developed and employed have applications for other research involving comparisons between concepts and large bodies of literature, and it is particularly useful for comparing theoretical works (such as academic literature) with texts that discuss operations and practices (such as website and reports).

In the mutualistic relationship between the squid Euprymna tasmanica and the bioluminescent bacterium Vibrio fischeri, several host factors, including immune-related proteins, are known to interact and respond specifically and exclusively to the presence of the symbiont. In squid and octopus, the white body is considered to be an immune organ mainly due to the fact that blood cells, or hemocytes, are known to be present in high numbers and in different developmental stages. Hence, the white body has been described as the site of hematopoiesis in cephalopods. However, to our knowledge, there are no studies showing any molecular evidence of such functions. In this study, we performed a transcriptomic analysis of white body tissue of the Southern dumpling squid, E. tasmanica. Our primary goal was to gain insights into the functions of this tissue and to test for the presence of gene transcripts associated with hematopoietic and immune processes. Several hematopoiesis genes including CPSF1, GATA 2, TFIID, and FGFR2 were found to be expressed in the white body. In addition, transcripts associated with immune-related signal transduction pathways, such as the toll-like receptor/NF-κβ, and MAPK pathways were also found, as well as other immune genes previously identified in E. tasmanica's sister species, E. scolopes. This study is the first to analyze an immune organ within cephalopods, and to provide gene expression data supporting the white body as a hematopoietic tissue.