After neoadjuvant chemoradiotherapy for oesophageal cancer, roughly half of the patients with squamous cell carcinoma and a quarter of those with adenocarcinoma have a pathological complete response ...of the primary tumour before surgery. Thus, the necessity of standard oesophagectomy after neoadjuvant chemoradiotherapy should be reconsidered for patients who respond sufficiently to neoadjuvant treatment. In this study, we aimed to establish the accuracy of detection of residual disease after neoadjuvant chemoradiotherapy with different diagnostic approaches, and the optimal combination of diagnostic techniques for clinical response evaluations.
The preSANO trial was a prospective, multicentre, diagnostic cohort study at six centres in the Netherlands. Eligible patients were aged 18 years or older, had histologically proven, resectable, squamous cell carcinoma or adenocarcinoma of the oesophagus or oesophagogastric junction, and were eligible for potential curative therapy with neoadjuvant chemoradiotherapy (five weekly cycles of carboplatin area under the curve 2 mg/mL per min plus paclitaxel 50 mg/m2 of body-surface area combined with 41·4 Gy radiotherapy in 23 fractions) followed by oesophagectomy. 4–6 weeks after completion of neoadjuvant chemoradiotherapy, patients had oesophagogastroduodenoscopy with biopsies and endoscopic ultrasonography with measurement of maximum tumour thickness. Patients with histologically proven locoregional residual disease or no-pass during endoscopy and without distant metastases underwent immediate surgical resection. In the remaining patients a second clinical response evaluation was done (PET–CT, oesophagogastroduodenoscopy with biopsies, endoscopic ultrasonography with measurement of maximum tumour thickness, and fine-needle aspiration of suspicious lymph nodes), followed by surgery 12–14 weeks after completion of neoadjuvant chemoradiotherapy. The primary endpoint was the correlation between clinical response during clinical response evaluations and the final pathological response in resection specimens, as shown by the proportion of tumour regression grade (TRG) 3 or 4 (>10% residual carcinoma in the resection specimen) residual tumours that was missed during clinical response evaluations. This study was registered with the Netherlands Trial Register (NTR4834), and has been completed.
Between July 22, 2013, and Dec 28, 2016, 219 patients were included, 207 of whom were included in the analyses. Eight of 26 TRG3 or TRG4 tumours (31% 95% CI 17–50) were missed by endoscopy with regular biopsies and fine-needle aspiration. Four of 41 TRG3 or TRG4 tumours (10% 95% CI 4–23) were missed with bite-on-bite biopsies and fine-needle aspiration. Endoscopic ultrasonography with maximum tumour thickness measurement missed TRG3 or TRG4 residual tumours in 11 of 39 patients (28% 95% CI 17–44). PET–CT missed six of 41 TRG3 or TRG4 tumours (15% 95% CI 7–28). PET–CT detected interval distant histologically proven metastases in 18 (9%) of 190 patients (one squamous cell carcinoma, 17 adenocarcinomas).
After neoadjuvant chemoradiotherapy for oesophageal cancer, clinical response evaluation with endoscopic ultrasonography, bite-on-bite biopsies, and fine-needle aspiration of suspicious lymph nodes was adequate for detection of locoregional residual disease, with PET–CT for detection of interval metastases. Active surveillance with this combination of diagnostic modalities is now being assessed in a phase 3 randomised controlled trial (SANO trial; Netherlands Trial Register NTR6803).
Dutch Cancer Society.
Widespread in the subtropics and tropics of the Southern Hemisphere, savannas are highly heterogeneous and seasonal natural vegetation types, which makes change detection (natural vs. anthropogenic) ...a challenging task. The Brazilian Cerrado represents the largest savanna in South America, and the most threatened biome in Brazil owing to agricultural expansion. To assess the native Cerrado vegetation (NV) areas most susceptible to natural and anthropogenic change over time, we classified 33 years (1985–2017) of Landsat imagery available in the Google Earth Engine (GEE) platform. The classification strategy used combined empirical and statistical decision trees to generate reference maps for machine learning classification and a novel annual dataset of the predominant Cerrado NV types (forest, savanna, and grassland). We obtained annual NV maps with an average overall accuracy ranging from 87% (at level 1 NV classification) to 71% over the time series, distinguishing the three main NV types. This time series was then used to generate probability maps for each NV class. The native vegetation in the Cerrado biome declined at an average rate of 0.5% per year (748,687 ha yr−1), mostly affecting forests and savannas. From 1985 to 2017, 24.7 million hectares of NV were lost, and now only 55% of the NV original distribution remains. Of the remnant NV in 2017 (112.6 million hectares), 65% has been stable over the years, while 12% changed among NV types, and 23% was converted to other land uses but is now in some level of secondary NV. Our results were fundamental in indicating areas with higher rates of change in a long time series in the Brazilian Cerrado and to highlight the challenges of mapping distinct NV types in a highly seasonal and heterogeneous savanna biome.
To evaluate the efficacy of dichloroacetate (DCA) in the treatment of mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS).
High levels of ventricular lactate, the ...brain spectroscopic signature of MELAS, correlate with more severe neurologic impairment. The authors hypothesized that chronic cerebral lactic acidosis exacerbates neuronal injury in MELAS and therefore, investigated DCA, a potent lactate-lowering agent, as potential treatment for MELAS.
The authors conducted a double-blind, placebo-controlled, randomized, 3-year cross-over trial of DCA (25 mg/kg/day) in 30 patients (aged 10 to 60 years) with MELAS and the A3243G mutation. Primary outcome measure was a Global Assessment of Treatment Efficacy (GATE) score based on a health-related event inventory, and on neurologic, neuropsychological, and daily living functioning. Biologic outcome measures included venous, CSF, and 1H MRSI-estimated brain lactate. Blood tests and nerve conduction studies were performed to monitor safety.
During the initial 24-month treatment period, 15 of 15 patients randomized to DCA were taken off study medication, compared to 4 of 15 patients randomized to placebo. Study medication was discontinued in 17 of 19 patients because of onset or worsening of peripheral neuropathy. The clinical trial was terminated early because of peripheral nerve toxicity. The mean GATE score was not significantly different between treatment arms.
DCA at 25 mg/kg/day is associated with peripheral nerve toxicity resulting in a high rate of medication discontinuation and early study termination. Under these experimental conditions, the authors were unable to detect any beneficial effect. The findings show that DCA-associated neuropathy overshadows the assessment of any potential benefit in MELAS.
The Brazilian Cerrado is the second largest biome in Latin America, extending over more than 200 million ha and hosts some of the most intensive agricultural activities for grain and beef production ...in the world. Because of the biodiversity richness and high levels of endemism, Cerrado is considered one of world's hotspot for biodiversity conservation. The objectives of this study are three-fold: to present a comprehensive division of Cerrado into different ecoregions that reflect the environmental heterogeneity within the biome; to analyze the ecoregions in terms of biophysical characteristics, protected areas, environmental liability in riparian permanent protection areas along watercourses, and priorities for biodiversity conservation; and to rank the ecoregions in terms of endangerment for biodiversity conservation and restoration. A previous study that delineated 22 ecoregions using geomorphology, vegetation, soil, geology, and plant diversity maps was revised using topography, vegetation, precipitation, and soil maps. Our new ecoregion map consists of 19 units that are unique in terms of landscape characteristics and has been adjusted to the current official boundary map of Cerrado. Some of the ecoregions consist of only one geomorphological compartment, whereas others are heterogeneous, consisting of up to eight compartments. Ferralsols comprise the dominant soil type in 14 of the ecoregions. The percentage of protected areas within ecoregions ranges from 1.7% to 51.5%. The most endangered ecoregion, where land use change critically threatens habitat integrity, is the Depressão Cárstica do São Francisco (states of Bahia, Minas Gerais, and Piauí), where environmental liability along riparian permanent protection areas amounts to 85.6% of the total area. Our proposed ecoregion map provides a spatial framework for regional and local assessments to improve decision-making processes to reconcile conservation and restoration planning, sustainable agriculture, and provision of ecosystem services. Besides de adjustment of the previous Cerrado's ecoregion map to the official biome boundary (relevant for the implementation of public policies of conservation as those regulated by the Brazilian Forest Code), the new analyses of the ecoregion map represent a substantial improvement in comparison to the ones conducted by the previous study in 2003. In addition, current web resources allow us to make all the information used or derived from this study available to other users. This opens the possibility of additional improvements of our findings by the scientific community or to be used effectively by decision makers.
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•The Brazilian tropical savanna (Cerrado) is divided into 19 ecoregions.•The ecoregions are delineated according to their biophysical attributes.•The ecoregions are ranked according to endangerment of conservation and restoration.•The ecoregion map is relevant for several decision-making processes.
Species of the genus
Bothrops induce the vast majority of snakebite envenomings in Latin America. A preclinical study was performed in the context of a regional network of public laboratories ...involved in the production, quality control and development of antivenoms in Latin America. The ability of seven polyspecific antivenoms, produced in Argentina, Brazil, Peru, Bolivia, Colombia and Costa Rica, to neutralize lethal, hemorrhagic, coagulant, defibrinogenating and myotoxic activities of the venoms of
Bothrops neuwiedi (
diporus) (Argentina),
Bothrops jararaca (Brazil),
B. neuwiedi (
mattogrossensis) (Bolivia),
Bothrops atrox (Peru and Colombia) and
Bothrops asper (Costa Rica) was assessed using standard laboratory tests. Despite differences in the venom mixtures used in the immunization of animals for the production of these antivenoms, a pattern of extensive cross-neutralization was observed between these antivenoms and all the venoms tested, with quantitative differences in the values of effective doses. This study reveals the capacity of these antivenoms to neutralize, in preclinical tests, homologous and heterologous
Bothrops venoms in Central and South America, and also highlight quantitative differences in the values of Median Effective Doses (ED50s) between the various antivenoms.
To evaluate the role of chronic cerebral lactic acidosis in mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS).
The authors studied 91 individuals from 34 families ...with MELAS and the A3243G point mutation and 15 individuals from two families with myoclonus epilepsy and ragged red fibers (MERRF) and the A8344G mutation. Subjects were divided into four groups. Paternal relatives were studied as controls (Group 1). The maternally related subjects were divided clinically into three groups: asymptomatic (no clinical evidence of neurologic disease) (Group 2), oligosymptomatic (neurologic symptoms but without the full clinical picture of MELAS or MERRF) (Group 3), and symptomatic (fulfilling MELAS or MERRF criteria) (Group 4). The authors performed a standardized neurologic examination, neuropsychological testing, MRS, and leukocyte DNA analysis in all subjects.
The symptomatic and oligosymptomatic MELAS subjects had significantly higher ventricular lactate than the other groups. There was a significant correlation between degree of neuropsychological and neurologic impairment and cerebral lactic acidosis as estimated by ventricular MRS lactate levels.
High levels of ventricular lactate, the brain spectroscopic signature of MELAS, are associated with more severe neurologic impairment.
The dissemination of carbapenem-resistant and third generation cephalosporin-resistant pathogens is a critical issue that is no longer restricted to hospital settings. The rapid spread of critical ...priority pathogens in Brazil is notably worrying, considering its continental dimension, the diversity of international trade, livestock production, and human travel. We conducted a nationwide genomic investigation under a One Health perspective that included Escherichia coli strains isolated from humans and nonhuman sources, over 45 years (1974-2019). One hundred sixty-seven genomes were analyzed extracting clinically relevant information (i.e., resistome, virulome, mobilome, sequence types STs, and phylogenomic). The endemic status of extended-spectrum β-lactamase (ESBL)-positive strains carrying a wide diversity of
variants, and the growing number of colistin-resistant isolates carrying
-type genes was associated with the successful expansion of international ST10, ST38, ST115, ST131, ST354, ST410, ST648, ST517, and ST711 clones; phylogenetically related and shared between human and nonhuman hosts, and polluted aquatic environments. Otherwise, carbapenem-resistant ST48, ST90, ST155, ST167, ST224, ST349, ST457, ST648, ST707, ST744, ST774, and ST2509 clones from human host harbored
and
genes. A broad resistome to other clinically relevant antibiotics, hazardous heavy metals, disinfectants, and pesticides was further predicted. Wide virulome associated with invasion/adherence, exotoxin and siderophore production was related to phylogroup B2. The convergence of wide resistome and virulome has contributed to the persistence and rapid spread of international high-risk clones of critical priority E. coli at the human-animal-environmental interface, which must be considered a One Health challenge for a post-pandemic scenario.
A One Health approach for antimicrobial resistance must integrate whole-genome sequencing surveillance data of critical priority pathogens from human, animal and environmental sources to track hot spots and routes of transmission and developing effective prevention and control strategies. As part of the Grand Challenges Explorations: New Approaches to Characterize the Global Burden of Antimicrobial Resistance Program, we present genomic data of WHO critical priority carbapenemase-resistant, ESBL-producing, and/or colistin-resistant Escherichia coli strains isolated from humans and nonhuman sources in Brazil, a country with continental proportions and high levels of antimicrobial resistance. The present study provided evidence of epidemiological and clinical interest, highlighting that the convergence of wide virulome and resistome has contributed to the persistence and rapid spread of international high-risk clones of E. coli at the human-animal-environmental interface, which must be considered a One Health threat that requires coordinated actions to reduce its incidence in humans and nonhuman hosts.
Abstract
Core-collapse supernovae are among the most magnificent events in the observable universe. They produce many of the chemical elements necessary for life to exist and their remnants—neutron ...stars and black holes—are interesting astrophysical objects in their own right. However, despite millennia of observations and almost a century of astrophysical study, the explosion mechanism of core-collapse supernovae is not yet well understood. Hyper-Kamiokande is a next-generation neutrino detector that will be able to observe the neutrino flux from the next galactic core-collapse supernova in unprecedented detail. We focus on the first 500 ms of the neutrino burst, corresponding to the accretion phase, and use a newly-developed, high-precision supernova event generator to simulate Hyper-Kamiokande's response to five different supernova models. We show that Hyper-Kamiokande will be able to distinguish between these models with high accuracy for a supernova at a distance of up to 100 kpc. Once the next galactic supernova happens, this ability will be a powerful tool for guiding simulations toward a precise reproduction of the explosion mechanism observed in nature.
ABSTRACT
We present a new Australian Square Kilometre Array Pathfinder (ASKAP) sample of 14 radio supernova remnants (SNR) candidates in the Large Magellanic Cloud (LMC). This new sample is a ...significant increase to the known number of older, larger, and low surface brightness LMC SNRs. We employ a multifrequency search for each object and found possible traces of optical and occasionally X-ray emission in several of these 14 SNR candidates. One of these 14 SNR candidates (MCSNR J0522 – 6543) has multifrequency properties that strongly indicate a bona fide SNR. We also investigate a sample of 20 previously suggested LMC SNR candidates and confirm the SNR nature of MCSNR J0506 – 6815. We detect lower surface brightness SNR candidates which were likely formed by a combination of shock waves and strong stellar winds from massive progenitors (and possibly surrounding OB stars). Some of our new SNR candidates are also found in lower density environments in which SNe type Ia explode inside a previously excavated interstellar medium.
To assess the cost-effectiveness of high-resolution anoscopy (HRA), anal cytology, and anal human papillomavirus (HPV) detection in screening for histologic high-grade anal intraepithelial neoplasia ...(AIN 2/3) in HIV-positive MSM.
Participants were 401 HIV-positive MSM who were screened for anal cancer in a tertiary care HIV clinic.
A decision analytical model was used to determine the cost-effectiveness of three anal cancer screening strategies: the direct use of HRA; HRA only if anal cytology was abnormal; and HRA only if oncogenic HPV was present. The model included the use of different thresholds for abnormal cytology and also combined cytology and HPV testing. The outcome was the number of AIN 2/3 cases detected. Costs were estimated from institutional data and sensitivity/specificity of cytology and HPV tests were obtained from the screening study.
The costs ($ US) per procedure for HRA, cytology, and HPV testing were $193, $90, and $95, respectively. The direct use of HRA was the most cost-effective strategy. It detected 98 individuals with AIN 2/3 and had a cost-effectiveness of $809 per AIN 2/3 case detected. Using probabilistic sensitivity analysis, three other strategies had similar costs per case detected and might be as cost-effective as HRA.
In HIV-infected MSM, the direct use of HRA is the most cost-effective strategy for detecting AIN 2/3. The higher cost per use for HRA was offset by the high sensitivity and low specificity of HPV and cytology testing.
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