Introducing the Bacterial and Viral Bioinformatics Resource Center (BV-BRC): a resource combining PATRIC, IRD and ViPR.

The National Institute of Allergy and Infectious Diseases (NIAID) established the Bioinformatics Resource Center (BRC) program to assist researchers with analyzing the growing body of genome sequence and other omics-related data. In this report, we describe the merger of the PAThosystems Resource Integration Center (PATRIC), the Influenza Research Database (IRD) and the Virus Pathogen Database and Analysis Resource (ViPR) BRCs to form the Bacterial and Viral Bioinformatics Resource Center (BV-BRC) https://www.bv-brc.org/. The combined BV-BRC leverages the functionality of the bacterial and viral resources to provide a unified data model, enhanced web-based visualization and analysis tools, bioinformatics services, and a powerful suite of command line tools that benefit the bacterial and viral research communities.

Single vs. multiple fraction non-inferiority trial of stereotactic ablative radiotherapy for the comprehensive treatment of oligo-metastases/progression: SIMPLIFY-SABR-COMET.

BACKGROUND: Radiotherapy delivery regimens can vary between a single fraction (SF) and multiple fractions (MF) given daily for up to several weeks depending on the location of the cancer or metastases. With limited evidence comparing fractionation regimens for oligometastases, there is support to explore toxicity levels to nearby organs at risk as a primary outcome while using SF and MF stereotactic ablative radiotherapy (SABR) as well as explore differences in patient-reported quality of life and experience. METHODS: This study will randomize 598 patients in a 1:1 ratio between the standard arm (MF SABR) and the experimental arm (SF SABR). This trial is designed as two randomized controlled trials within one patient population for resource efficiency. The primary objective of the first randomization is to determine if SF SABR is non-inferior to MF SABR, with respect to healthcare provider (HCP)-reported grade 3-5 adverse events (AEs) that are related to SABR. Primary endpoint is toxicity while secondary endpoints include lesional control rate (LCR), and progression-free survival (PFS). The second randomization (BC Cancer sites only) will allocate participants to either complete quality of life (QoL) questionnaires only; or QoL questionnaires and a symptom-specific survey with symptom-guided HCP intervention. The primary objective of the second randomization is to determine if radiation-related symptom questionnaire-guided HCP intervention results in improved reported QoL as measured by the EuroQoL-5-dimensions-5levels (EQ-5D-5L) instrument. The primary endpoint is patient-reported QoL and secondary endpoints include: persistence/resolution of symptom reporting, QoL, intervention cost effectiveness, resource utilization, and overall survival. DISCUSSION: This study will compare SF and MF SABR in the treatment of oligometastases and oligoprogression to determine if there is non-inferior toxicity for SF SABR in selected participants with 1-5 oligometastatic lesions. This study will also compare patient-reported QoL between participants who receive radiation-related symptom-guided HCP intervention and those who complete questionnaires alone. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT05784428. Date of Registration: 23 March 2023.

Comparative analysis of electrodermal activity metrics and their association with child behavior in autism spectrum disorder.

Researchers are increasingly utilizing physiological data like electrodermal activity (EDA) to understand how stress "gets under the skin." Results of EDA studies in autistic children are mixed, with some suggesting autistic hyperarousal, others finding hypoarousal, and yet others detecting no difference compared to non-autistics. Some of this variability likely stems from the different techniques used to assess EDA. Therefore, the purpose of this study is to investigate and compare commonly used metrics of EDA (frequency of peaks, average amplitude of peaks, and standard deviation of skin conductance level) using two data processing programs (NeuroKit2 and Ledalab) and their link to observed child behavior. EDA data were collected using Empatica E4 wristbands from 60 autistic children and adolescents (5-18 years old) during a 7-min play interaction with their primary caregiver. The play interaction was coded for a range of child behaviors including mood, social responsiveness, dysregulation, and cooperation. Results indicate a strong correlation between NeuroKit2 and Ledalab and a weak correlation between metrics within each program. Furthermore, the frequency of peaks was associated with more positive child social behaviors, and the magnitude of peaks was associated with less adaptive child behaviors. Recommendations for replication and the need for generalizability of this research are given.

A genomic data resource for predicting antimicrobial resistance from laboratory-derived antimicrobial susceptibility phenotypes.

Antimicrobial resistance (AMR) is a major global health threat that affects millions of people each year. Funding agencies worldwide and the global research community have expended considerable capital and effort tracking the evolution and spread of AMR by isolating and sequencing bacterial strains and performing antimicrobial susceptibility testing (AST). For the last several years, we have been capturing these efforts by curating data from the literature and data resources and building a set of assembled bacterial genome sequences that are paired with laboratory-derived AST data. This collection currently contains AST data for over 67 000 genomes encompassing approximately 40 genera and over 100 species. In this paper, we describe the characteristics of this collection, highlighting areas where sampling is comparatively deep or shallow, and showing areas where attention is needed from the research community to improve sampling and tracking efforts. In addition to using the data to track the evolution and spread of AMR, it also serves as a useful starting point for building machine learning models for predicting AMR phenotypes. We demonstrate this by describing two machine learning models that are built from the entire dataset to show where the predictive power is comparatively high or low. This AMR metadata collection is freely available and maintained on the Bacterial and Viral Bioinformatics Center (BV-BRC) FTP site ftp://ftp.bvbrc.org/RELEASE_NOTES/PATRIC_genomes_AMR.txt.

Signals of Significantly Increased Vaccine Breakthrough, Decreased Hospitalization Rates, and Less Severe Disease in Patients with Coronavirus Disease 2019 Caused by the Omicron Variant of Severe Acute Respiratory Syndrome Coronavirus 2 in Houston, Texas.

Genetic variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continue to dramatically alter the landscape of the coronavirus disease 2019 (COVID-19) pandemic. The recently described variant of concern designated Omicron (B.1.1.529) has rapidly spread worldwide and is now responsible for the majority of COVID-19 cases in many countries. Because Omicron was recognized recently, many knowledge gaps exist about its epidemiology, clinical severity, and disease course. A genome sequencing study of SARS-CoV-2 in the Houston Methodist health care system identified 4468 symptomatic patients with infections caused by Omicron from late November 2021 through January 5, 2022. Omicron rapidly increased in only 3 weeks to cause 90% of all new COVID-19 cases, and at the end of the study period caused 98% of new cases. Compared with patients infected with either Alpha or Delta variants in our health care system, Omicron patients were significantly younger, had significantly increased vaccine breakthrough rates, and were significantly less likely to be hospitalized. Omicron patients required less intense respiratory support and had a shorter length of hospital stay, consistent with on average decreased disease severity. Two patients with Omicron stealth sublineage BA.2 also were identified. The data document the unusually rapid spread and increased occurrence of COVID-19 caused by the Omicron variant in metropolitan Houston, Texas, and address the lack of information about disease character among US patients.

Delta Variants of SARS-CoV-2 Cause Significantly Increased Vaccine Breakthrough COVID-19 Cases in Houston, Texas.

Genetic variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have repeatedly altered the course of the coronavirus disease 2019 (COVID-19) pandemic. Delta variants are now the focus of intense international attention because they are causing widespread COVID-19 globally and are associated with vaccine breakthrough cases. We sequenced 16,965 SARS-CoV-2 genomes from samples acquired March 15, 2021, through September 20, 2021, in the Houston Methodist hospital system. This sample represents 91% of all Methodist system COVID-19 patients during the study period. Delta variants increased rapidly from late April onward to cause 99.9% of all COVID-19 cases and spread throughout the Houston metroplex. Compared with all other variants combined, Delta caused a significantly higher rate of vaccine breakthrough cases (23.7% for Delta compared with 6.6% for all other variants combined). Importantly, significantly fewer fully vaccinated individuals required hospitalization. Vaccine breakthrough cases caused by Delta had a low median PCR cycle threshold value (a proxy for high virus load). This value was similar to the median cycle threshold value for unvaccinated patients with COVID-19 caused by Delta variants, suggesting that fully vaccinated individuals can transmit SARS-CoV-2 to others. Patients infected with Alpha and Delta variants had several significant differences. The integrated analysis indicates that vaccines used in the United States are highly effective in decreasing severe COVID-19, hospitalizations, and deaths.

Dynamics and functional diversity of the smallest phytoplankton on the Northeast US Shelf.

Picophytoplankton are the most abundant primary producers in the ocean. Knowledge of their community dynamics is key to understanding their role in marine food webs and global biogeochemical cycles. To this end, we analyzed a 16-y time series of observations of a phytoplankton community at a nearshore site on the Northeast US Shelf. We used a size-structured population model to estimate in situ division rates for the picoeukaryote assemblage and compared the dynamics with those of the picocyanobacteria Synechococcus at the same location. We found that the picoeukaryotes divide at roughly twice the rate of the more abundant Synechococcus and are subject to greater loss rates (likely from viral lysis and zooplankton grazing). We describe the dynamics of these groups across short and long timescales and conclude that, despite their taxonomic differences, their populations respond similarly to changes in the biotic and abiotic environment. Both groups appear to be temperature limited in the spring and light limited in the fall and to experience greater mortality during the day than at night. Compared with Synechococcus, the picoeukaryotes are subject to greater top-down control and contribute more to the region's primary productivity than their standing stocks suggest.

Trajectory of Growth of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Variants in Houston, Texas, January through May 2021, Based on 12,476 Genome Sequences.

Certain genetic variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are of substantial concern because they may be more transmissible or detrimentally alter the pandemic course and disease features in individual patients. SARS-CoV-2 genome sequences from 12,476 patients in the Houston Methodist health care system diagnosed from January 1 through May 31, 2021 are reported here. Prevalence of the B.1.1.7 (Alpha) variant increased rapidly and caused 63% to 90% of new cases in the latter half of May. Eleven B.1.1.7 genomes had an E484K replacement in spike protein, a change also identified in other SARS-CoV-2 lineages. Compared with non-B.1.1.7-infected patients, individuals with B.1.1.7 had a significantly lower cycle threshold (a proxy for higher virus load) and significantly higher hospitalization rate. Other variants [eg, B.1.429 and B.1.427 (Epsilon), P.1 (Gamma), P.2 (Zeta), and R.1] also increased rapidly, although the magnitude was less than that in B.1.1.7. Twenty-two patients infected with B.1.617.1 (Kappa) or B.1.617.2 (Delta) variants had a high rate of hospitalization. Breakthrough cases (n = 207) in fully vaccinated patients were caused by a heterogeneous array of virus genotypes, including many not currently designated variants of interest or concern. In the aggregate, this study delineates the trajectory of SARS-CoV-2 variants circulating in a major metropolitan area, documents B.1.1.7 as the major cause of new cases in Houston, TX, and heralds the arrival of B.1.617 variants in the metroplex.

Sequence Analysis of 20,453 Severe Acute Respiratory Syndrome Coronavirus 2 Genomes from the Houston Metropolitan Area Identifies the Emergence and Widespread Distribution of Multiple Isolates of All Major Variants of Concern.

Since the beginning of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, there has been international concern about the emergence of virus variants with mutations that increase transmissibility, enhance escape from the human immune response, or otherwise alter biologically important phenotypes. In late 2020, several variants of concern emerged globally, including the UK variant (B.1.1.7), the South Africa variant (B.1.351), Brazil variants (P.1 and P.2), and two related California variants of interest (B.1.429 and B.1.427). These variants are believed to have enhanced transmissibility. For the South Africa and Brazil variants, there is evidence that mutations in spike protein permit it to escape from some vaccines and therapeutic monoclonal antibodies. On the basis of our extensive genome sequencing program involving 20,453 coronavirus disease 2019 patient samples collected from March 2020 to February 2021, we report identification of all six of these SARS-CoV-2 variants among Houston Methodist Hospital (Houston, TX) patients residing in the greater metropolitan area. Although these variants are currently at relatively low frequency (aggregate of 1.1%) in the population, they are geographically widespread. Houston is the first city in the United States in which active circulation of all six current variants of concern has been documented by genome sequencing. As vaccine deployment accelerates, increased genomic surveillance of SARS-CoV-2 is essential to understanding the presence, frequency, and medical impact of consequential variants and their patterns and trajectory of dissemination.

A novel carbon-fibre adjustable reusable accessory (CARA) for supine breast positioning to reduce toxicity in breast adjuvant radiotherapy: a study protocol for a multicentre phase III randomized controlled trial.

BACKGROUND: A novel device for supine positioning in breast radiotherapy for patients with large or pendulous breasts has been developed and tested in phase II studies. This trial is designed to assess the efficacy of the device to reduce skin toxicity and unwanted normal tissue dose in comparison to the current clinical standard for supine breast support during breast radiotherapy. METHODS: Patients at high risk for moist desquamation, having infra-mammary fold or lateral ptosis, will be randomized into two arms. Patients in the control arm will receive breast radiotherapy with supine positioning using current standard of care. Patients in the experimental arm will be positioned supine with the novel device. The primary endpoint is the incidence of moist desquamation in the infra-mammary fold. We hypothesize a 20% reduction (from 50 to 30%) in the rate of moist desquamation in the study arm versus the control arm. For 80% power, two-tailed α = 0.05 and 10% loss to follow up, 110 patients will be assigned to each arm. The proportion of patients experiencing moist desquamation in the two arms will be compared using logistic regression adjusting for brassiere cup size, skin fold size, body mass index, smoking status, and dose fractionation schedule. An unadjusted comparison will also be made using the chi-square test, or Fisher's exact test, if appropriate. Secondary endpoints include dose-volume statistics for the lung and heart, skin dose and clinical parameters including setup time, reproducibility, and staff experience with setup procedures. Patient-reported pain, skin condition interference with sleep and daily activities, and comfort during treatment are also secondary endpoints. DISCUSSION: Based on results from earlier phase II studies, it is expected that the device-enabled elimination of infra-mammary fold should reduce toxicity and improve quality of life for this patient population. Earlier studies showed reduction in dose to organs at risk including lung and heart, indicating potential for other long-term benefits for patients using the device. This study is limited to acute skin toxicity, patient-reported outcomes, and clinical factors to inform integration of the device into standard breast radiotherapy procedures. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT04257396 . Registered February 6 2020.

Patient-reported outcomes and complications during head and neck cancer radiotherapy before versus during the COVID-19 pandemic.

PURPOSE: This study compares patient-reported outcomes and treatment-related complications during radiotherapy before (August 2019-January 2020) versus during (March-Sept 2020) the COVID-19 pandemic. MATERIALS AND METHODS: The MD Anderson Symptom Inventory-head and neck module was used to assess curative intent in H&N cancer patients' symptoms during radiotherapy. RESULTS: There were 158 patients in the pre-pandemic cohort and 137 patients in the pandemic cohort. There was no significant difference in enteral feeding requirements between the cohorts (21% versus 30%, p = 0.07). Weight loss was higher during the pandemic (mean - 5.6% versus 6.8%, p = 0.03). On multivariate analysis, treatment during the pandemic was associated with higher symptom scores for coughing/choking while eating (2.7 versus 2.1, p = 0.013). CONCLUSIONS: Complication rates during H&N radiotherapy during the COVID-19 pandemic were similar at our institution relative to the pre-pandemic era, although weight loss was greater and patients reported more severe choking/coughing while eating.

Population-based comparison of cancer survival outcomes in patients with and without psychiatric disorders.

BACKGROUND: Individuals with psychiatric disorders (PD) have a high prevalence of tobacco use. Patients with PD also potentially receive substandard care in comparison to the general population. Previous research has shown that individuals with PD have a decreased risk of receiving a tobacco related (TR) cancer diagnosis. To further assess this trend, this study assesses the survival of patients with a TR cancer with or without a PD. MATERIALS AND METHODS: Our study utilized multiple databases, with methods described elsewhere,6 to identify people in British Columbia that have been diagnosed with psychiatric disorders and appendicitis (our control group). From these groups, we selected individuals who also had a TR cancer. We subsequently extracted information pertaining to these patients from these databases. RESULTS: Thirty-nine thousand eight hundred forty-one patients with cancer were included in our study. Analyses of these patients were controlled for by age, gender, cancer type and diagnosis year. This analysis displayed shorter survival time among patients who were diagnosed with depression (HR = 1.16; p = 0.01; 95% CI: 1.04-1.29), schizophrenia (HR = 1.62; p < 0.01; 95% CI: 1.43-1.84), or bipolar disorder (HR = 1.35; p < 0.01; 95% CI: 1.12-1.64) compared to the cancer patients without a PD, all of which were statistically significant. People that were diagnosed with anxiety disorders did not have a survival time that was significantly different from our control population (HR = 1.07; p = 0.22; 95% CI: 0.96-1.19). CONCLUSIONS: Individuals with PD, except for those with anxiety, were found to have a shorter survival time following diagnosis with a TR cancer as compared to our control group. We hypothesize several factors, which may account for this statistically significant difference: (1) delayed diagnosis, (2) poor access to care, (3) poor assessment or follow-up, or (4) physician beliefs of poor treatment adherence.

The PATRIC Bioinformatics Resource Center: expanding data and analysis capabilities.

The PathoSystems Resource Integration Center (PATRIC) is the bacterial Bioinformatics Resource Center funded by the National Institute of Allergy and Infectious Diseases (https://www.patricbrc.org). PATRIC supports bioinformatic analyses of all bacteria with a special emphasis on pathogens, offering a rich comparative analysis environment that provides users with access to over 250 000 uniformly annotated and publicly available genomes with curated metadata. PATRIC offers web-based visualization and comparative analysis tools, a private workspace in which users can analyze their own data in the context of the public collections, services that streamline complex bioinformatic workflows and command-line tools for bulk data analysis. Over the past several years, as genomic and other omics-related experiments have become more cost-effective and widespread, we have observed considerable growth in the usage of and demand for easy-to-use, publicly available bioinformatic tools and services. Here we report the recent updates to the PATRIC resource, including new web-based comparative analysis tools, eight new services and the release of a command-line interface to access, query and analyze data.

PATRIC as a unique resource for studying antimicrobial resistance.

The Pathosystems Resource Integration Center (PATRIC, www.patricbrc.org) is designed to provide researchers with the tools and services that they need to perform genomic and other 'omic' data analyses. In response to mounting concern over antimicrobial resistance (AMR), the PATRIC team has been developing new tools that help researchers understand AMR and its genetic determinants. To support comparative analyses, we have added AMR phenotype data to over 15 000 genomes in the PATRIC database, often assembling genomes from reads in public archives and collecting their associated AMR panel data from the literature to augment the collection. We have also been using this collection of AMR metadata to build machine learning-based classifiers that can predict the AMR phenotypes and the genomic regions associated with resistance for genomes being submitted to the annotation service. Likewise, we have undertaken a large AMR protein annotation effort by manually curating data from the literature and public repositories. This collection of 7370 AMR reference proteins, which contains many protein annotations (functional roles) that are unique to PATRIC and RAST, has been manually curated so that it projects stably across genomes. The collection currently projects to 1 610 744 proteins in the PATRIC database. Finally, the PATRIC Web site has been expanded to enable AMR-based custom page views so that researchers can easily explore AMR data and design experiments based on whole genomes or individual genes.

Predicting antimicrobial resistance using conserved genes.

A growing number of studies are using machine learning models to accurately predict antimicrobial resistance (AMR) phenotypes from bacterial sequence data. Although these studies are showing promise, the models are typically trained using features derived from comprehensive sets of AMR genes or whole genome sequences and may not be suitable for use when genomes are incomplete. In this study, we explore the possibility of predicting AMR phenotypes using incomplete genome sequence data. Models were built from small sets of randomly-selected core genes after removing the AMR genes. For Klebsiella pneumoniae, Mycobacterium tuberculosis, Salmonella enterica, and Staphylococcus aureus, we report that it is possible to classify susceptible and resistant phenotypes with average F1 scores ranging from 0.80-0.89 with as few as 100 conserved non-AMR genes, with very major error rates ranging from 0.11-0.23 and major error rates ranging from 0.10-0.20. Models built from core genes have predictive power in cases where the primary AMR mechanisms result from SNPs or horizontal gene transfer. By randomly sampling non-overlapping sets of core genes, we show that F1 scores and error rates are stable and have little variance between replicates. Although these small core gene models have lower accuracies and higher error rates than models built from the corresponding assembled genomes, the results suggest that sufficient variation exists in the core non-AMR genes of a species for predicting AMR phenotypes.

Patient-reported outcome measures in patients undergoing radiotherapy for head and neck cancer.

OBJECTIVES: Head and neck (H&N) cancer patients experience significant acute side effects from treatment. This study evaluates prospectively collected patient-reported outcomes (PROs) in H&N patients undergoing radiotherapy (RT) to assess feasibility of electronically collecting PROs and to objectively document symptom acuity and trajectory during RT. MATERIALS AND METHODS: H&N patients undergoing radical RT at our multicentre institution completed a 12-item partial survey of the Vanderbilt Head & Neck Symptom Survey 2.0 prior to RT and weekly on RT. Between October 2016 and October 2018, 318 of 333 patients completed a baseline survey and at least one weekly survey. RESULTS: The average number of weekly questionnaires completed was 5 (range 1-8). The mean maximum symptom scores were highest for dysgeusia (5.8/10), pain (5.4/10), mucositis (4.8/10), weight loss due to swallowing (4.5/10) and mucus causing choking/gagging (4.3/10). On multivariate analysis, female gender, sinonasal, nasopharynx and oropharynx primaries were associated with a greater risk of moderate-severe pain (p < 0.05). Sinonasal, nasopharynx, oral cavity, oropharynx and thyroid primaries were associated with a greater risk of moderate-severe mucositis during radiation (p < 0.0001). Salivary gland, sinonasal, nasopharynx and oropharynx primaries and higher radiation dose were associated with a greater risk of moderate-severe dysgeusia (all p < 0.05). CONCLUSIONS: Electronic PRO collection during H&N cancer RT is feasible. H&N cancer patients experience significant symptoms during RT, and the most severe symptoms reported were dysgeusia, pain and mucositis. Oropharynx cancer patients reported the highest symptom scores during RT.

Stereotactic ablative radiotherapy versus standard of care palliative treatment in patients with oligometastatic cancers (SABR-COMET): a randomised, phase 2, open-label trial.

BACKGROUND: The oligometastatic paradigm suggests that some patients with a limited number of metastases might be cured if all lesions are eradicated. Evidence from randomised controlled trials to support this paradigm is scarce. We aimed to assess the effect of stereotactic ablative radiotherapy (SABR) on survival, oncological outcomes, toxicity, and quality of life in patients with a controlled primary tumour and one to five oligometastatic lesions. METHODS: This randomised, open-label phase 2 study was done at 10 hospitals in Canada, the Netherlands, Scotland, and Australia. Patients aged 18 or older with a controlled primary tumour and one to five metastatic lesions, Eastern Cooperative Oncology Group score of 0-1, and a life expectancy of at least 6 months were eligible. After stratifying by the number of metastases (1-3 vs 4-5), we randomly assigned patients (1:2) to receive either palliative standard of care treatments alone (control group), or standard of care plus SABR to all metastatic lesions (SABR group), using a computer-generated randomisation list with permuted blocks of nine. Neither patients nor physicians were masked to treatment allocation. The primary endpoint was overall survival. We used a randomised phase 2 screening design with a two-sided α of 0·20 (wherein p<0·20 designates a positive trial). All analyses were intention to treat. This study is registered with ClinicalTrials.gov, number NCT01446744. FINDINGS: 99 patients were randomised between Feb 10, 2012, and Aug 30, 2016. Of 99 patients, 33 (33%) were assigned to the control group and 66 (67%) to the SABR group. Two (3%) patients in the SABR group did not receive allocated treatment and withdrew from the trial; two (6%) patients in the control group also withdrew from the trial. Median follow-up was 25 months (IQR 19-54) in the control group versus 26 months (23-37) in the SABR group. Median overall survival was 28 months (95% CI 19-33) in the control group versus 41 months (26-not reached) in the SABR group (hazard ratio 0·57, 95% CI 0·30-1·10; p=0·090). Adverse events of grade 2 or worse occurred in three (9%) of 33 controls and 19 (29%) of 66 patients in the SABR group (p=0·026), an absolute increase of 20% (95% CI 5-34). Treatment-related deaths occurred in three (4·5%) of 66 patients after SABR, compared with none in the control group. INTERPRETATION: SABR was associated with an improvement in overall survival, meeting the primary endpoint of this trial, but three (4·5%) of 66 patients in the SABR group had treatment-related death. Phase 3 trials are needed to conclusively show an overall survival benefit, and to determine the maximum number of metastatic lesions wherein SABR provides a benefit. FUNDING: Ontario Institute for Cancer Research and London Regional Cancer Program Catalyst Grant.

Trends in tuna carbon isotopes suggest global changes in pelagic phytoplankton communities.

Considerable uncertainty remains over how increasing atmospheric CO2 and anthropogenic climate changes are affecting open-ocean marine ecosystems from phytoplankton to top predators. Biological time series data are thus urgently needed for the world's oceans. Here, we use the carbon stable isotope composition of tuna to provide a first insight into the existence of global trends in complex ecosystem dynamics and changes in the oceanic carbon cycle. From 2000 to 2015, considerable declines in δ13 C values of 0.8‰-2.5‰ were observed across three tuna species sampled globally, with more substantial changes in the Pacific Ocean compared to the Atlantic and Indian Oceans. Tuna recorded not only the Suess effect, that is, fossil fuel-derived and isotopically light carbon being incorporated into marine ecosystems, but also recorded profound changes at the base of marine food webs. We suggest a global shift in phytoplankton community structure, for example, a reduction in 13 C-rich phytoplankton such as diatoms, and/or a change in phytoplankton physiology during this period, although this does not rule out other concomitant changes at higher levels in the food webs. Our study establishes tuna δ13 C values as a candidate essential ocean variable to assess complex ecosystem responses to climate change at regional to global scales and over decadal timescales. Finally, this time series will be invaluable in calibrating and validating global earth system models to project changes in marine biota.

Stereotactic ablative radiotherapy for the comprehensive treatment of 1-3 Oligometastatic tumors (SABR-COMET-3): study protocol for a randomized phase III trial.

BACKGROUND: A recent randomized phase II trial evaluated stereotactic ablative radiotherapy (SABR) in a group of patients with a small burden of oligometastatic disease (mostly with 1-3 metastatic lesions), and found that SABR was associated with a significant improvement in progression-free survival and a trend to an overall survival benefit, supporting progression to phase III randomized trials. METHODS: Two hundred and ninety-seven patients will be randomized in a 1:2 ratio between the control arm (consisting of standard of care [SOC] palliative-intent treatments), and the SABR arm (consisting of SOC treatment + SABR to all sites of known disease). Randomization will be stratified by two factors: histology (prostate, breast, or renal vs. all others), and disease-free interval (defined as time from diagnosis of primary tumor until first detection of the metastases being treated on this trial; divided as ≤2 vs. > 2 years). The primary endpoint is overall survival, and secondary endpoints include progression-free survival, cost effectiveness, time to development of new metastatic lesions, quality of life (QoL), and toxicity. Translational endpoints include assessment of circulating tumor cells, cell-free DNA, and tumor tissue as prognostic and predictive markers, including assessment of immunological predictors of response and long-term survival. DISCUSSION: This study will provide an assessment of the impact of SABR on survival, QoL, and cost effectiveness to determine if long-term survival can be achieved for selected patients with 1-3 oligometastatic lesions. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT03862911. Date of registration: March 5, 2019.

Seasons of Syn.

Synechococcus is a widespread and important marine primary producer. Time series provide critical information for identifying and understanding the factors that determine abundance patterns. Here, we present the results of analysis of a 16-yr hourly time series of Synechococcus at the Martha's Vineyard Coastal Observatory, obtained with an automated, in situ flow cytometer. We focus on understanding seasonal abundance patterns by examining relationships between cell division rate, loss rate, cellular properties (e.g., cell volume, phycoerythrin fluorescence), and environmental variables (e.g., temperature, light). We find that the drivers of cell division vary with season; cells are temperature-limited in winter and spring, but light-limited in the fall. Losses to the population also vary with season. Our results lead to testable hypotheses about Synechococcus ecophysiology and a working framework for understanding the seasonal controls of Synechococcus cell abundance in a temperate coastal system.