Ex situ conservation tools, such as captive breeding for reintroduction, are considered a last resort to recover threatened or endangered species, but they may also help reduce anthropogenic threats ...where it is difficult or impossible to address them directly. Headstarting, or captive rearing of eggs or neonate animals for subsequent release into the wild, is controversial because it treats only a symptom of a larger conservation problem; however, it may provide a mechanism to address multiple threats, particularly near population centers. We conducted a population viability analysis of Australia's most widespread freshwater turtle, Chelodina longicollis, to determine the effect of adult roadkill (death by collision with motor vehicles), which is increasing, and reduced recruitment through nest predation from introduced European red foxes (Vulpes vulpesj. We also modeled management scenarios to test the effectiveness of headstarting, fox management, and measures to reduce mortality on roads. Only scenarios with headstarting from source populations eliminated all risks of extinction and allowed population growth. Small increases in adult mortality (2%) had the greatest effect on population growth and extinction risk. Where threats simultaneously affected other life-history stages (e.g., recruitment), eliminating harvest pressures on adult females alone did not eliminate the risk of population extinction. In our models, one source population could supply enough hatchlings annually to supplement 25 other similar-sized populations such that extinction was avoided. Based on our results, we believe headstarting should be a primary tool for managing freshwater turtles for which threats affect multiple life-history stages. We advocate the creation of source populations for managing freshwater turtles that are greatly threatened at multiple life-history stages, such as depredation of eggs by invasive species and adult mortality via roadkill. Las herramientas de conservación ex situ, como la crianza en cautiverio para la reintroducción, son consideradas como el último recurso para recuperar a las especies amenazadas o en peligro, pero también pueden ayudar a reducir las amenazas antropogénicas en donde es difícil o imposible tratarlas directamente. El inicio con ventaja, o la crianza en cautiverio de huevos o animales neonatos para su liberación subsecuente a lá vida libre, es controversial porque solamente trata un síntoma de un problema mayor de la conservación; sin embargo, puede proporcionar un mecanismo para lidiar con múltiples amenazas, particularmente cerca de los centros poblacionales. Realizamos un análisis de viabilidad poblacional con la tortuga de agua dulce con mayor distribución en Australia, Chelodiina longicollis, para determinar el efecto de los atropellamientos de adultos (muerte por colisión con automóviles)，los cuales son cada vez más frecuentes，y redujimos el reclutamiento por medio de la depredación de nidos realizada por los zorros rojos Europeos introducidos (Yulpes vulpes). También modelamos escenarios de manejo para evaluar la efectividad del inicio con ventaja, el manejo de los zorros y las medidas para reducir la mortalidad en los caminos. Sólo los escenarios con inicio con ventaja a partir de poblaciones fuente eliminaron todos los riesgos de extinción y permitieron el crecimiento de la población. Los pequeños incrementos en la mortalidad adulta (2%) tuvieron el mayor efecto sobre el crecimiento poblacionaly el riesgo de extinción. En donde las amenazas afectaron simultáneamente a otras etapas de la ontogenia (p. ej.: el reclutamiento)，sólo controlar las presiones de cosecha sobre las hembras no eliminó el riesgo de extinción de la población. En nuestros modelos, una población fuente pudo proporcionar suficientes crías para abastecer a otras 25 poblaciones de tamaño similar de tal forma que se evitó la extinción. Con base en nuestros resultados, creemos que el inicio con ventaja debería ser una herramienta primaria para el manejo de tortugas de agua dulce para las cuales las amenazas afectan a múltiples etapas de la ontogenia. Proponemos la creación de poblaciones fuente para el manejo de tortugas de agua dulce que están enormemente amenazadas durante varias etapas de su historia de vida, como la depredación de los huevos por especies invasoras o la mortalidad adulta por atropellamientos.
•The conformational itinerary describes the changes in sugar shape during catalysis.•Stereoelectronic requirements for glycoside hydrolysis are discussed.•Major and emerging approaches to define ...conformational itineraries are reviewed.•New assignments of glycosidase conformational itineraries are summarized.
Glycoside hydrolases (GHs) are classified into >100 sequence-based families. These enzymes process a wide variety of complex carbohydrates with varying stereochemistry at the anomeric and other ring positions. The shapes that these sugars adopt upon binding to their cognate GHs, and the conformational changes that occur along the catalysis reaction coordinate is termed the conformational itinerary. Efforts to define the conformational itineraries of GHs have focussed upon the critical points of the reaction: substrate-bound (Michaelis), transition state, intermediate (if relevant) and product-bound. Recent approaches to defining conformational itineraries that marry X-ray crystallography of enzymes bound to ligands that mimic the critical points, along with advanced computational methods and kinetic isotope effects are discussed.
Conservation requires rapid action to be effective, which is often difficult because of funding limitations, political constraints, and limited data. Turtles are among the world's most endangered ...vertebrate taxa, with almost half of 356 species threatened with extinction. In Australia's Murray River, nest predation by invasive foxes (Vulpes vulpes) was predicted to drive turtle declines in the 1980s. We assessed populations of the broad-shelled turtle (Chelodina expansa), eastern long-necked turtle (C. longicollis), and Murray River turtle (Emydura macquarii) in the Murray River and some of its associated waterways. Our results suggest that the predicted decline is occurring. All three species are rare in the lower Murray River region, and were undetected in many locations in South Australia. Moreover, E. macquarii had considerable population aging almost everywhere, possibly due to comprehensive nest destruction by foxes. Chelodina longicollis also had population aging at some sites. Sustained low recruitment has potential to lead to collapses as turtles age, which is particularly worrying because it was predicted over 30 years ago and may have already occurred in South Australia. Our results show that turtle declines were not mitigated since that prediction. If the crash continues, a vertebrate guild responsible for considerable nutrient cycling in the aquatic ecosystem will disappear. Our results highlight a worst-case outcome when species declines are predicted, but insufficiently mitigated.
In 2014, the Society of Gynecologic Oncology's Clinical Practice Committee published a clinical update reviewing the treatment of women with endometrial cancer. At that time, there had been ...significant advances in the diagnosis, work-up, surgical management, and available treatment options allowing for more optimal care of affected women. Despite these advances, the incidence of endometrial cancer as well as the deaths attributable to the disease have continued to rise; from 1987 to 2014 there has been a 75% increase in cases and almost 300% increase in endometrial cancer deaths. Fortunately, since then, there has been progress in the treatment of patients with endometrial cancer with increased utilization of molecular pathology, greater understanding of genetic predisposition, enhanced methods for lymph node assessment, a broader understanding of the efficacy of radiation and chemotherapy, and a more efficient approach to survivorship and surveillance. The purpose of this document is to present a comprehensive review of this progress.
The authors reviewed the available evidence, contributed to the development of this manuscript, provided critical review of the guidelines, and finalized the manuscript recommendations. The review was also presented to and approved by the Society of Gynecologic Oncology (SGO) Clinical Practice Committee, SGO Publications Committee, and the SGO board members prior to submission for publication.
The recommendations for this manuscript were developed by a panel of gynecologic oncologists who were members of the SGO Clinical Practice and Education Committees. Panelists reviewed and considered evidence from current uterine cancer literature. The terminology used in these guidelines was adopted from the ASCCP management guidelines 1 using a two-part rating system to grade the strength of recommendation and quality of evidence (Table 1). The rating for each recommendation is given in parentheses.
•Advances in molecular pathology complement clinical management of endometrial cancer.•Increased estrogen exposure and genetic predisposition remain important risk factors•Judicious evaluation of abnormal bleeding and cancer referrals to gynecologic oncologists optimize management•Most patients benefit from minimally invasive surgery and tailored lymph node evaluation.•Risk stratification based on recent trials should influence adjuvant therapy decisions.
Standard treatment for locally advanced cervical cancer is chemoradiotherapy, but many patients relapse and die of metastatic disease. We aimed to determine the effects on survival of adjuvant ...chemotherapy after chemoradiotherapy.
The OUTBACK trial was a multicentre, open-label, randomised, phase 3 trial done in 157 hospitals in Australia, China, Canada, New Zealand, Saudi Arabia, Singapore, and the USA. Eligible participants were aged 18 year or older with histologically confirmed squamous cell carcinoma, adenosquamous cell carcinoma, or adenocarcinoma of the cervix (FIGO 2008 stage IB1 disease with nodal involvement, or stage IB2, II, IIIB, or IVA disease), Eastern Cooperative Oncology Group performance status 0–2, and adequate bone marrow and organ function. Participants were randomly assigned centrally (1:1) using a minimisation approach and stratified by pelvic or common iliac nodal involvement, requirement for extended-field radiotherapy, FIGO 2008 stage, age, and site to receive standard cisplatin-based chemoradiotherapy (40 mg/m2 cisplatin intravenously once-a-week for 5 weeks, during radiotherapy with 45·0–50·4 Gy external beam radiotherapy delivered in fractions of 1·8 Gy to the whole pelvis plus brachytherapy; chemoradiotherapy only group) or standard cisplatin-based chemoradiotherapy followed by adjuvant chemotherapy with four cycles of carboplatin (area under the receiver operator curve 5) and paclitaxel (155 mg/m2) given intravenously on day 1 of a 21 day cycle (adjuvant chemotherapy group). The primary endpoint was overall survival at 5 years, analysed in the intention-to-treat population (ie, all eligible patients who were randomly assigned). Safety was assessed in all patients in the chemoradiotherapy only group who started chemoradiotherapy and all patients in the adjuvant chemotherapy group who received at least one dose of adjuvant chemotherapy. The OUTBACK trial is registered with ClinicalTrials.gov, NCT01414608, and the Australia New Zealand Clinical Trial Registry, ACTRN12610000732088.
Between April 15, 2011, and June 26, 2017, 926 patients were enrolled and randomly assigned to the chemoradiotherapy only group (n=461) or the adjuvant chemotherapy group (n=465), of whom 919 were eligible (456 in the chemoradiotherapy only group and 463 in the adjuvant chemotherapy group; median age 46 years IQR 37 to 55; 663 72% were White, 121 13% were Black or African American, 53 6% were Asian, 24 3% were Aboriginal or Pacific islander, and 57 6% were other races) and included in the analysis. As of data cutoff (April 12, 2021), median follow-up was 60 months (IQR 45 to 65). 5-year overall survival was 72% (95% CI 67 to 76) in the adjuvant chemotherapy group (105 deaths) and 71% (66 to 75) in the chemoradiotherapy only group (116 deaths; difference 1% 95% CI –6 to 7; hazard ratio 0·90 95% CI 0·70 to 1·17; p=0·81). In the safety population, the most common clinically significant grade 3–4 adverse events were decreased neutrophils (71 20% in the adjuvant chemotherapy group vs 34 8% in the chemoradiotherapy only group), and anaemia (66 18% vs 34 8%). Serious adverse events occurred in 107 (30%) in the adjuvant chemotherapy group versus 98 (22%) in the chemoradiotherapy only group, most commonly due to infectious complications. There were no treatment-related deaths.
Adjuvant carboplatin and paclitaxel chemotherapy given after standard cisplatin-based chemoradiotherapy for unselected locally advanced cervical cancer increased short-term toxicity and did not improve overall survival; therefore, it should not be given in this setting.
National Health and Medical Research Council and National Cancer Institute.
In 2014, the Society of Gynecologic Oncology's Clinical Practice Committee published a clinical update reviewing the treatment of women with endometrial cancer. At that time, there had been ...significant advances in the diagnosis, work-up, surgical management, and available treatment options allowing for more optimal care of affected women.
This manuscript, Part II in a two-part series, includes specific recommendations on treatment of recurrent disease, post treatment surveillance and survivorship, considerations for younger women, and special situations. Part I covered histopathology and molecular pathology, risk factors, presentation and diagnostic approach, surgical approach and adjuvant therapy.
•Context of recurrence drives treatment options to include combination approaches.•Surveillance and survivorship should be tailored for endometrial cancer patients.•Fertility and ovarian preservation can be considered for select patients.•Primary radiation is reasonable for patients who are not surgical candidates.
To review our institutional outcomes of patients treated with radiation therapy (RT) for Graves' orbitopathy (GO), assess the role of orbital reirradiation, and identify prognostic factors of ...complete response (CR).
This is a retrospective review of 211 patients who presented with a diagnosis of GO and received RT between January 2000-2010. RT dose was 20 Gy in 10 fractions. Patient median age was 51 years (range, 15-84 years), median follow-up was 11 months (range, 1-88 months). Patient symptoms included any combination of proptosis (90.9%), extraocular muscle dysfunction (78.9%), soft tissue signs (68.4%), and diplopia (58.4%). Corticosteroids were used as first-line therapy in 20.6% of patients. Among those who achieved either CR or partial response (PR), prognostic factors were evaluated.
Stabilization of disease without recurrence was clinically achieved overall in 202 patients (96.7%). At the completion of RT, 176 patients (84.2%) reported a symptomatic improvement of pretreatment symptoms. CR of GO symptoms was achieved using multiple treatment modalities, including RT by 93 patients (44.5%), of which 32 patients received RT only. Corticosteroids were discontinued in 97.8% of patients who received them as initial therapy. Surgical intervention following radiotherapy was required for 144 (68.9%) of all patients. Fourteen patients received orbital reirradiation for persistent or recurrent symptoms. Five of these achieved a CR, and the other nine achieved disease stabilization but retained persistent ocular symptoms. Long-term side effects of RT included dry eyes (12%). Of the prognostic factors we investigated, only gender predicted CR, which was less common in men (33.9%) than in women (49.7%) p = 0.0471.
Orbital radiation for GO is an established treatment modality for patients. Orbital reirradiation is beneficial for patients who do not respond to initial RT or experience symptom recurrence without an apparent risk of increased morbidity.
RBP4 is produced mainly by hepatocytes. In type 2 diabetes and obesity, circulating RBP4 is increased and may act systemically to cause insulin resistance and glucose intolerance. Observations that ...adipocyte RBP4 mRNA increases in parallel with circulating RBP4 in these conditions, whereas liver RBP4 mRNA does not, led to a widely held hypothesis that elevated circulating RBP4 is a direct result of increased production by adipocytes. To test this, we generated mice with hepatocyte-specific deletion of RBP4 (liver RBP4 knockout or LRKO mice). Adipose tissue RBP4 expression and secretion remained intact in LRKO mice and increased as expected in the setting of diet-induced insulin resistance. However, circulating RBP4 was undetectable in LRKO mice. We conclude that adipocyte RBP4 is not a significant source of circulating RBP4, even in the setting of insulin resistance. Adipocyte RBP4, therefore, may have a more important autocrine or paracrine function that is confined within the adipose tissue compartment.
Degradable polymers are integral components in many biomedical polymer applications. The ability of these materials to decompose in situ has become a critical component for tissue engineering, ...allowing scaffolds to guide cell and tissue growth while facilitating gradual regeneration of native tissue. The objective of this work is to understand the role of prepolymer molecular weight and functionality of photocurable poly(caprolactone) (PCL) in determining reaction kinetics, mechanical properties, polymer degradation, biocompatibility, and suitability for stereolithography. PCL, a degradable polymer used in a number of biomedical applications, was functionalized with acrylate groups to enable photopolymerization and three-dimensional printing via stereolithography. PCL prepolymers with different molecular weights and functionalities were studied to understand the role of molecular structure in reaction kinetics, mechanical properties, and degradation rates. The mechanical properties of photocured PCL were dependent on cross-link density and directly related to the molecular weight and functionality of the prepolymers. High-molecular weight, low-functionality PCLDA prepolymers exhibited a lower modulus and a higher strain at break, while low-molecular weight, high-functionality PCLTA prepolymers exhibited a lower strain at break and a higher modulus. Additionally, degradation profiles of cross-linked PCL followed a similar trend, with low cross-link density leading to degradation times up to 2.5 times shorter than those of more highly cross-linked polymers. Furthermore, photopolymerized PCL showed biocompatibility both in vitro and in vivo, causing no observed detrimental effects on seeded murine-induced pluripotent stem cells or when implanted into pig retinas. Finally, the ability to create three-dimensional PCL structures is shown by fabrication of simple structures using digital light projection stereolithography. Low-molecular weight, high-functionality PCLTA prepolymers printed objects with feature sizes near the hardware resolution limit of 50 μm. This work lays the foundation for future work in fabricating microscale PCL structures for a wide range of tissue regeneration applications.
Recent work has suggested that disorganised speech might be a powerful predictor of later psychotic illness in clinical high risk subjects. To that end, several automated measures to quantify ...disorganisation of transcribed speech have been proposed. However, it remains unclear which measures are most strongly associated with psychosis, how different measures are related to each other and what the best strategies are to collect speech data from participants. Here, we assessed whether twelve automated Natural Language Processing markers could differentiate transcribed speech excerpts from subjects at clinical high risk for psychosis, first episode psychosis patients and healthy control subjects (total N = 54). In-line with previous work, several measures showed significant differences between groups, including semantic coherence, speech graph connectivity and a measure of whether speech was on-topic, the latter of which outperformed the related measure of tangentiality. Most NLP measures examined were only weakly related to each other, suggesting they provide complementary information. Finally, we compared the ability of transcribed speech generated using different tasks to differentiate the groups. Speech generated from picture descriptions of the Thematic Apperception Test and a story re-telling task outperformed free speech, suggesting that choice of speech generation method may be an important consideration. Overall, quantitative speech markers represent a promising direction for future clinical applications.
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