We aimed to identify a five-fraction schedule of adjuvant radiotherapy (radiation therapy) delivered in 1 week that is non-inferior in terms of local cancer control and is as safe as an international ...standard 15-fraction regimen after primary surgery for early breast cancer. Here, we present 5-year results of the FAST-Forward trial.
FAST-Forward is a multicentre, phase 3, randomised, non-inferiority trial done at 97 hospitals (47 radiotherapy centres and 50 referring hospitals) in the UK. Patients aged at least 18 years with invasive carcinoma of the breast (pT1–3, pN0–1, M0) after breast conservation surgery or mastectomy were eligible. We randomly allocated patients to either 40 Gy in 15 fractions (over 3 weeks), 27 Gy in five fractions (over 1 week), or 26 Gy in five fractions (over 1 week) to the whole breast or chest wall. Allocation was not masked because of the nature of the intervention. The primary endpoint was ipsilateral breast tumour relapse; assuming a 2% 5-year incidence for 40 Gy, non-inferiority was predefined as ≤1·6% excess for five-fraction schedules (critical hazard ratio HR of 1·81). Normal tissue effects were assessed by clinicians, patients, and from photographs. This trial is registered at isrctn.com, ISRCTN19906132.
Between Nov 24, 2011, and June 19, 2014, we recruited and obtained consent from 4096 patients from 97 UK centres, of whom 1361 were assigned to the 40 Gy schedule, 1367 to the 27 Gy schedule, and 1368 to the 26 Gy schedule. At a median follow-up of 71·5 months (IQR 71·3 to 71·7), the primary endpoint event occurred in 79 patients (31 in the 40 Gy group, 27 in the 27 Gy group, and 21 in the 26 Gy group); HRs versus 40 Gy in 15 fractions were 0·86 (95% CI 0·51 to 1·44) for 27 Gy in five fractions and 0·67 (0·38 to 1·16) for 26 Gy in five fractions. 5-year incidence of ipsilateral breast tumour relapse after 40 Gy was 2·1% (1·4 to 3·1); estimated absolute differences versus 40 Gy in 15 fractions were −0·3% (−1·0 to 0·9) for 27 Gy in five fractions (probability of incorrectly accepting an inferior five-fraction schedule: p=0·0022 vs 40 Gy in 15 fractions) and −0·7% (−1·3 to 0·3) for 26 Gy in five fractions (p=0·00019 vs 40 Gy in 15 fractions). At 5 years, any moderate or marked clinician-assessed normal tissue effects in the breast or chest wall was reported for 98 of 986 (9·9%) 40 Gy patients, 155 (15·4%) of 1005 27 Gy patients, and 121 of 1020 (11·9%) 26 Gy patients. Across all clinician assessments from 1–5 years, odds ratios versus 40 Gy in 15 fractions were 1·55 (95% CI 1·32 to 1·83, p<0·0001) for 27 Gy in five fractions and 1·12 (0·94 to 1·34, p=0·20) for 26 Gy in five fractions. Patient and photographic assessments showed higher normal tissue effect risk for 27 Gy versus 40 Gy but not for 26 Gy versus 40 Gy.
26 Gy in five fractions over 1 week is non-inferior to the standard of 40 Gy in 15 fractions over 3 weeks for local tumour control, and is as safe in terms of normal tissue effects up to 5 years for patients prescribed adjuvant local radiotherapy after primary surgery for early-stage breast cancer.
National Institute for Health Research Health Technology Assessment Programme.
Living materials, which are composites of living cells residing in a polymeric matrix, are designed to utilize the innate functionalities of the cells to address a broad range of applications such as ...fermentation and biosensing. Herein, we demonstrate the additive manufacturing of catalytically active living materials (AMCALM) for continuous fermentation. A multi-stimuli-responsive yeast-laden hydrogel ink, based on F127-dimethacrylate, was developed and printed using a direct-write 3D printer. The reversible stimuli-responsive behaviors of the polymer hydrogel inks to temperature and pressure are critical, as they enabled the facile incorporation of yeast cells and subsequent fabrication of 3D lattice constructs. Subsequent photo-cross-linking of the printed polymer hydrogel afforded a robust elastic material. These yeast-laden living materials were metabolically active in the fermentation of glucose into ethanol for 2 weeks in a continuous batch process without significant reduction in efficiency (∼90% yield of ethanol). This cell immobilization platform may potentially be applicable toward other genetically modified yeast strains to produce other high-value chemicals in a continuous biofermentation process.
Head-related transfer functions (HRTFs) capture the direction-dependant way that sound interacts with the head and torso. In virtual audio systems, which aim to emulate these effects, ...non-individualized, generic HRTFs are typically used leading to an inaccurate perception of virtual sound location. Training has the potential to exploit the brain's ability to adapt to these unfamiliar cues. In this study, three virtual sound localization training paradigms were evaluated; one provided simple visual positional confirmation of sound source location, a second introduced game design elements ("gamification") and a final version additionally utilized head-tracking to provide listeners with experience of relative sound source motion ("active listening"). The results demonstrate a significant effect of training after a small number of short (12-minute) training sessions, which is retained across multiple days. Gamification alone had no significant effect on the efficacy of the training, but active listening resulted in a significantly greater improvements in localization accuracy. In general, improvements in virtual sound localization following training generalized to a second set of non-individualized HRTFs, although some HRTF-specific changes were observed in polar angle judgement for the active listening group. The implications of this on the putative mechanisms of the adaptation process are discussed.
Bioinformatics, a discipline that combines aspects of biology, statistics, mathematics, and computer science, is becoming increasingly important for biological research. However, bioinformatics ...instruction is not yet generally integrated into undergraduate life sciences curricula. To understand why we studied how bioinformatics is being included in biology education in the US by conducting a nationwide survey of faculty at two- and four-year institutions. The survey asked several open-ended questions that probed barriers to integration, the answers to which were analyzed using a mixed-methods approach. The barrier most frequently reported by the 1,260 respondents was lack of faculty expertise/training, but other deterrents-lack of student interest, overly-full curricula, and lack of student preparation-were also common. Interestingly, the barriers faculty face depended strongly on whether they are members of an underrepresented group and on the Carnegie Classification of their home institution. We were surprised to discover that the cohort of faculty who were awarded their terminal degree most recently reported the most preparation in bioinformatics but teach it at the lowest rate.
We develop roadmaps to transform the all-purpose energy infrastructures (electricity, transportation, heating/cooling, industry, agriculture/forestry/fishing) of 139 countries to ones powered by ...wind, water, and sunlight (WWS). The roadmaps envision 80% conversion by 2030 and 100% by 2050. WWS not only replaces business-as-usual (BAU) power, but also reduces it ∼42.5% because the work: energy ratio of WWS electricity exceeds that of combustion (23.0%), WWS requires no mining, transporting, or processing of fuels (12.6%), and WWS end-use efficiency is assumed to exceed that of BAU (6.9%). Converting may create ∼24.3 million more permanent, full-time jobs than jobs lost. It may avoid ∼4.6 million/year premature air-pollution deaths today and ∼3.5 million/year in 2050; ∼$22.8 trillion/year (12.7 ¢/kWh-BAU-all-energy) in 2050 air-pollution costs; and ∼$28.5 trillion/year (15.8 ¢/kWh-BAU-all-energy) in 2050 climate costs. Transitioning should also stabilize energy prices because fuel costs are zero, reduce power disruption and increase access to energy by decentralizing power, and avoid 1.5°C global warming.
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•Roadmaps for 139 countries to use 100% wind-water-solar in all energy sectors•Roadmaps avoid 1.5°C global warming and millions of annual air-pollution deaths•Roadmaps reduce social cost of energy and create 24.3 million net long-term jobs•Roadmaps reduce power disruption and increase worldwide access to energy
For the world to reverse global warming, eliminate millions of annual air-pollution deaths, and provide secure energy, every country must have an energy roadmap based on widely available, reliable, zero-emission energy technologies. This study presents such roadmaps for 139 countries of the world. These roadmaps are far more aggressive than what the Paris agreement calls for, but are still technically and economically feasible. The solution is to electrify all energy sectors (transportation, heating/cooling, industry, agriculture/forestry/fishing) and provide all electricity with 100% wind, water, and solar (WWS) power. If fully implemented by 2050, the roadmaps will enable the world to avoid 1.5°C global warming and millions of annual air-pollution deaths, create 24.3 million net new long-term, full-time jobs, reduce energy costs to society, reduce energy end-use by 42.5%, reduce power disruption, and increase worldwide access to energy.
We develop energy roadmaps to significantly slow global warming and nearly eliminate air-pollution mortality in 139 countries. These plans call for electrifying all energy sectors (transportation, heating/cooling, industry, agriculture/forestry/fishing) and providing the electricity with 100% wind, water, and solar (WWS) power. Fully implementing the roadmaps by 2050 avoids 1.5°C global warming and millions of deaths from air pollution annually; creates 24.3 million net new long-term, full-time jobs; reduces energy costs to society; reduces power requirements 42.5%; reduces power disruption; and increases worldwide access to energy.
Although bioinformatics is becoming increasingly central to research in the life sciences, bioinformatics skills and knowledge are not well integrated into undergraduate biology education. This ...curricular gap prevents biology students from harnessing the full potential of their education, limiting their career opportunities and slowing research innovation. To advance the integration of bioinformatics into life sciences education, a framework of core bioinformatics competencies is needed. To that end, we here report the results of a survey of biology faculty in the United States about teaching bioinformatics to undergraduate life scientists. Responses were received from 1,260 faculty representing institutions in all fifty states with a combined capacity to educate hundreds of thousands of students every year. Results indicate strong, widespread agreement that bioinformatics knowledge and skills are critical for undergraduate life scientists as well as considerable agreement about which skills are necessary. Perceptions of the importance of some skills varied with the respondent's degree of training, time since degree earned, and/or the Carnegie Classification of the respondent's institution. To assess which skills are currently being taught, we analyzed syllabi of courses with bioinformatics content submitted by survey respondents. Finally, we used the survey results, the analysis of the syllabi, and our collective research and teaching expertise to develop a set of bioinformatics core competencies for undergraduate biology students. These core competencies are intended to serve as a guide for institutions as they work to integrate bioinformatics into their life sciences curricula.
Threat-related emotional function is supported by a neural circuit that includes the prefrontal cortex (PFC), hippocampus, and amygdala. The function of this neural circuit is altered by negative ...life experiences, which can potentially affect threat-related emotional processes. Notably, Black-American individuals disproportionately endure negative life experiences compared to White-American individuals. However, the relationships among negative life experiences, race, and the neural substrates that support threat-related emotional function remains unclear. Therefore, the current study investigated whether the brain function that supports threat-related emotional processes varies with racial differences in negative life experiences. In the present study, adolescent violence exposure, family income, and neighborhood disadvantage were measured prospectively (i.e., at 11–19 years of age) for Black-American and White-American volunteers. Participants then, as young adults (i.e., 18–23 years of age), completed a Pavlovian fear conditioning task during functional magnetic resonance imaging (fMRI). Cued and non-cued threats were presented during the conditioning task and behavioral (threat expectancy) and psychophysiological responses (skin conductance response; SCR) were recorded simultaneously with fMRI. Racial differences were observed in neural (fMRI activity), behavioral (threat expectancy), and psychophysiological (SCR) responses to threat. These threat-elicited responses also varied with negative life experiences (violence exposure, family income, and neighborhood disadvantage). Notably, racial differences in brain activity to threat were smaller after accounting for negative life experiences. The present findings suggest that racial differences in the neural and behavioral response to threat are due, in part, to exposure to negative life experiences and may provide new insight into the mechanisms underlying racial disparities in mental health.
•Studied racial differences in emotional function linked to developmental environment.•Childhood exposure to negative life events (e.g., violence, poverty) varied by race.•Threat-elicited brain and emotional responses varied by race.•Racial disparities in negative life events accounted for differences in brain function.
The associations between relationship adjustment and symptoms of depression and anxiety were evaluated in a sample of pregnant married or cohabiting women (N = 113) who were at risk for perinatal ...depression because of a prior history of major depression. Women completed self-report measures of relationship adjustment, depressive symptoms, and anxiety symptoms monthly during pregnancy and for the first six months following the birth of their child. Multilevel modeling was used to examine concurrent and time-lagged within-subjects effects for relationship adjustment and depressive and anxiety symptoms. Results revealed that (a) relationship adjustment was associated with both depressive symptoms and anxiety symptoms in concurrent analyses; (b) relationship adjustment was predictive of subsequent anxiety symptoms but not subsequent depressive symptoms in lagged analyses; and (c) depressive symptoms were predictive of subsequent relationship adjustment in lagged analyses with symptoms of depression and anxiety examined simultaneously. These results support the continued investigation into the cross-sectional and longitudinal associations between relationship functioning and depressive and anxiety symptoms in women during pregnancy and the postpartum period.
Abstract Current methods of fixing periprosthetic fractures after total knee arthroplasty (TKA) are variable, and include open reduction and internal fixation (ORIF) via plating, retrograde nailing, ...or revision using standard revision TKA components or a distal femoral arthroplasty (DFA). The purpose of this study is to compare patients who failed plating techniques requiring subsequent revision to DFA to patients who underwent primary DFA. Of the 13 patients (9.2%) who failed primary ORIF, causes included nonunion (53.8%), infection (30.8%), loosening (7.7%), and refracture (7.7%). There were significantly more surgical procedures for ORIF revision to DFA compared to primary DFA. Complications for patients who underwent primary reconstruction with DFAs included extensor mechanism disruption (8.3%), infection (5.6%), and dislocation (2.8%). Primary reconstruction via ORIF is beneficial for preserving bone stock, but primary DFA may be preferred in osteopenic patients, or those at high risk for nonunion.
Background:
The addition of genetic analysis to the evaluation of thyroid nodule fine-needle aspiration biopsy samples improves diagnostic accuracy of cytologically indeterminate thyroid nodules ...(ITNs) with Bethesda III or IV cytopathology. We previously reported the performance of a multiplatform molecular test, referred to in this study as MPTXv1, that includes a mutation panel (ThyGeNEXT
®
) plus an algorithmic microRNA (miRNA) risk classifier (ThyraMIR
®
). Complex interactions of growth-promoting and -suppressing miRNAs affect the phenotype. We previously demonstrated that accounting for these interactions with pairwise miRNA expression analysis improves the diagnosis of medullary thyroid carcinoma. In this study, we assess the impact of pairwise miRNA expression analysis on risk stratification of ITNs.
Methods:
Pairwise expression analysis of 11 miRNAs was performed on a training cohort of histopathology-proven benign nodules (
n
= 50) to define the mean and standard deviation of each pairwise analysis and create a Benign/Malignant Profiler (MPTXv2), deviations from which predicted the malignancy risk. Clinical validation of MPTXv2 was assessed using a cohort of 178 ITN (Bethesda III and IV) samples from a multicentered, blinded retrospective study, previously evaluated by MPTXv1.
Results:
Compared with MPTXv1, MPTXv2 significantly improved the test performance. The receiver operating characteristic (ROC) areas under the curve (AUC) increased from 0.85 to 0.97 (
p
< 0.001), and the diagnostic accuracy at the positive threshold increased significantly (
p
< 0.05) from 83% 95% confidence interval (CI) = 76–88 to 93% CI = 89–96. The significant improvement in the ROC AUC and the diagnostic accuracy was due to a strong statistical trend for improvement in specificity at the positive threshold. At the positive threshold, the specificity for MPTXv1 was 90% CI = 84–95 and improved to 98% CI = 94–99 for MPTXv2. Using the MPTXv2, the Moderate-Risk cohort decreased from 50 samples (28% of the cohort) to 24 samples (13% of the cohort). This 52% decrease is statistically significant (
p
< 0.001) and clinically meaningful.
Conclusion:
As compared with MPTXv1, pairwise miRNA expression analysis used in MPTXv2 significantly improved the diagnostic accuracy of ITN risk stratification and reduced the size of the Moderate-Risk group. Prospective trials are indicated to confirm these findings in a clinical practice setting.
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