Polarized Hyperspectral Microscopic Imaging for Zebrafish.

Zebrafish is a well-established animal model for developmental and disease studies. Its optical transparency at early developmental stages is ideal for tissue visualization. Interaction of light with zebrafish tissues provides information on their structure and properties. In this study, we developed a microscopic imaging system for improving the visualization of unstained zebrafish tissues on tissue slides, with two different setups: polarized light imaging and polarized hyperspectral imaging. Based on the polarized light imaging setup, we collected the RGB images of Stokes vector parameters (S0, S1, S2, and S3), and calculated the Stokes vector derived parameters: the degree of polarization (DOP), the degree of linear polarization (DOLP)). We also calculated Stokes vector data based on the polarized hyperspectral imaging setup. The preliminary results demonstrate that Stokes vector data in two imaging setups (polarized light imaging and polarized hyperspectral imaging) are capable of improving the visualization of different types of zebrafish tissues (brain, muscle, skin cells, blood vessels, and yolk). Using the images collected from larval zebrafish samples by polarized light imaging, we found that DOP and DOLP could show clearer structural information of the brain and of skin cells, muscle and blood vessels in the tail. Furthermore, DOP and DOLP parameters derived from images collected by polarized hyperspectral imaging could show clearer structural information of skin cells developing around yolk as well as the surrounding blood vessel network. In addition, polarized hyperspectral imaging could provide complementary spectral information to the spatial information on Stokes vector data of zebrafish tissues. The polarized light imaging & polarized hyperspectral imaging systems provide a better insight into the microstructures of zebrafish tissues.

Molecular mechanisms controlling the biogenesis of the TGF-ß signal Vg1.

The TGF-beta signals Vg1 (Dvr1/Gdf3) and Nodal form heterodimers to induce vertebrate mesendoderm. The Vg1 proprotein is a monomer retained in the endoplasmic reticulum (ER) and is processed and secreted upon heterodimerization with Nodal, but the mechanisms underlying Vg1 biogenesis are largely elusive. Here, we clarify the mechanisms underlying Vg1 retention, processing, secretion, and signaling and introduce a Synthetic Processing (SynPro) system that enables the programmed cleavage of ER-resident and extracellular proteins. First, we find that Vg1 can be processed by intra- or extracellular proteases. Second, Vg1 can be processed without Nodal but requires Nodal for secretion and signaling. Third, Vg1-Nodal signaling activity requires Vg1 processing, whereas Nodal can remain unprocessed. Fourth, Vg1 employs exposed cysteines, glycosylated asparagines, and BiP chaperone-binding motifs for monomer retention in the ER. These observations suggest two mechanisms for rapid mesendoderm induction: Chaperone-binding motifs help store Vg1 as an inactive but ready-to-heterodimerize monomer in the ER, and the flexibility of Vg1 processing location allows efficient generation of active heterodimers both intra- and extracellularly. These results establish SynPro as an in vivo processing system and define molecular mechanisms and motifs that facilitate the generation of active TGF-beta heterodimers.

f-block MOFs: A Pathway to Heterometallic Transuranics.

A novel series of heterometallic f-block-frameworks including the first examples of transuranic heterometallic 238 U/239 Pu-metal-organic frameworks (MOFs) and a novel monometallic 239 Pu-analog are reported. In combination with theoretical calculations, we probed the kinetics and thermodynamics of heterometallic actinide(An)-MOF formation and reported the first value of a U-to-Th transmetallation rate. We concluded that formation of uranyl species could be a driving force for solid-state metathesis. Density of states near the Fermi edge, enthalpy of formation, band gap, proton affinity, and thermal/chemical stability were probed as a function of metal ratios. Furthermore, we achieved 97 % of the theoretical maximum capacity for An-integration. These studies shed light on fundamental aspects of actinide chemistry and also foreshadow avenues for the development of emerging classes of An-containing materials, including radioisotope thermoelectric generators or metalloradiopharmaceuticals.

Prevalence of Toxocara canis infection in dogs and Toxocara egg environmental contamination in Baybay City, Leyte, Philippines.

Toxocara canis is a parasitic gastrointestinal nematode of dogs causing toxocariasis in humans, a neglected tropical disease. This study examined the burden of T. canis infection in dogs and egg contamination in school playgrounds and public parks in Baybay City, Leyte, Philippines. Fecalysis and egg detection in soils were performed to determine the parasite prevalence in dogs and the environment. In addition, pet owner's survey and GIS mapping were employed to identify the risk factors of infection and map the parasite distribution. Fecalysis revealed a T. canis prevalence of 64.44% (95% CI: 48.78-78.13) at the barangay level and 17.96% (95% CI: 14.12-21.80) at the animal level. Rural areas showed a much higher T. canis prevalence than urban. Factors associated with high T. canis infection included dog's age, specifically puppy (2-8 mo) relative to young (> 8-24 mo) [Adjusted Odds Ratio (AOR): 2.282; 95% CI: 1.137-4.579; p = 0.020] and adult (> 24 mo) (AOR: 3.542; 95% CI: 1.714-7.319; p = 0.001), access to dirty water (AOR: 2.749; 95% CI: 1.575-4.798; p < 0.001), and non-deworming (AOR: 2.961; 95%: CI 1.009-8.684; p = 0.048). Furthermore, we observed high Toxocara egg contamination in school playgrounds and public parks, with a prevalence of 51.11% (95% CI: 35.77-66.3) at the barangay level and 15.45% (95% CI: 10.67-20.23) in soil samples. This epidemiological study is the first in the central Philippines to report a high burden of T. canis infection in dogs and the environment, thus providing crucial data that will help understand the epidemiology of toxocariasis. Supplementary Information: The online version contains supplementary material available at 10.1007/s12639-022-01525-y.

Pleistocene-Holocene vicariance, not Anthropocene landscape change, explains the genetic structure of American black bear (Ursus americanus) populations in the American Southwest and northern Mexico.

The phylogeography of the American black bear (Ursus americanus) is characterized by isolation into glacial refugia, followed by population expansion and genetic admixture. Anthropogenic activities, including overharvest, habitat loss, and transportation infrastructure, have also influenced their landscape genetic structure. We describe the genetic structure of the American black bear in the American Southwest and northern Mexico and investigate how prehistoric and contemporary forces shaped genetic structure and influenced gene flow. Using a suite of microsatellites and a sample of 550 bears, we identified 14 subpopulations organized hierarchically following the distribution of ecoregions and mountain ranges containing black bear habitat. The pattern of subdivision we observed is more likely a product of postglacial habitat fragmentation during the Pleistocene and Holocene, rather than a consequence of contemporary anthropogenic barriers to movement during the Anthropocene. We used linear mixed-effects models to quantify the relationship between landscape resistance and genetic distance among individuals, which indicated that both isolation by resistance and geographic distance govern gene flow. Gene flow was highest among subpopulations occupying large tracts of contiguous habitat, was reduced among subpopulations in the Madrean Sky Island Archipelago, where montane habitat exists within a lowland matrix of arid lands, and was essentially nonexistent between two isolated subpopulations. We found significant asymmetric gene flow supporting the hypothesis that bears expanded northward from a Pleistocene refugium located in the American Southwest and northern Mexico and that major highways were not yet affecting gene flow. The potential vulnerability of the species to climate change, transportation infrastructure, and the US-Mexico border wall highlights conservation challenges and opportunities for binational collaboration.

Role of hydrogen bonding in bulk aqueous phase decomposition, complexation, and covalent hydration of pyruvic acid.

Pyruvic acid (PA) is a model for amphiphilic oxygenated organic compounds, and together with its hydrogen-bonded (H-bonded) water complexes, their presence can alter atmospheric aerosol formation. However, the fundamental understanding of PA reaction mechanisms in different environments is still being debated. Here, the role of H-bonding on PA's degradation, complexation, and covalent hydration in bulk aqueous phase is investigated theoretically. Using CCSD(T)-F12/aug-cc-pVDZ-F12 on B2PLYP-D3BJ structures with solvation model based on density, we revealed the stabilization by intramolecular H-bonding of an intermediate, PA hydrogen-transferred tautomer, altered the PA degradation mechanisms compared to gas phase. We also found that the intramolecular H-bonding in the most stable gas phase conformer (Tc) is weakened due to bulk solvation, leading to slower acetaldehyde production rate. Natural bond orbital analysis characterized the primary intermolecular H-bond in PA-water complexes as electron donation of an Owater lone pair (p) to the σ* orbital of the OH group of PA. Stronger H-bonding is correlated to p to σ* interaction, wider OH-O angles, and larger differences in the H-bond lengths between phases. The less charge difference between phases on H-bonded atoms also indicates aggressive competition of H-bonding with solvation. Water's cooperative behavior was observed by lowering the water-complexed 2,2-dihydroxypropanoic acid (DHPA-H2O) barrier from PA-water complexes compared to DHPA in both phases, stabilizing the transition state and product with intermolecular H-bonding. PA is vital in atmospheric keto-acid chemistry; thus, changes in PA reaction mechanisms in different environments due to H-bond behavior will affect aerosol formation.

The role of self-efficacy and catastrophizing in explaining improvements in disability, pain and fatigue among patients with chronic widespread pain treated with physiotherapy: an exploratory analysis.

OBJECTIVES: Most research exploring the relationship between cognitive factors (catastrophizing and self-efficacy beliefs) and levels of pain, disability and fatigue in patients with chronic widespread pain has been performed in multidisciplinary environments. It is less clear whether these associations are valid in other clinical environments. This study therefore aimed to establish whether changes in cognitive factors were related to changes in pain, disability and fatigue among patients treated in a physiotherapy-led symptom management programme. DESIGN: A longitudinal pre-post treatment study. Regression analyses were performed with change in pain, disability, physical and mental fatigue as the dependent measures. Demographics, change in pain and fatigue (when not dependent variables) and cognitive factors were entered as independent variables. ß values were calculated for the final model. SETTING: Two out-patient physiotherapy departments in Manchester, UK. PARTICIPANTS: Fifty patients with persistent widespread pain. INTERVENTION: A physiotherapist-led symptom management programme. MAIN OUTCOME MEASURES: Disability (Fibromyalgia Impact Questionnaire), Pain (Numeric Pain Rating Scale and Fatigue (Chalder Fatigue Scale) RESULTS: Significant changes in disability, fatigue and cognitive factors were observed after treatment. Changes in self-efficacy beliefs (ß=-0.38, P<0.05) and catastrophizing (ß=0.41, P<0.05) were significantly related to reductions in disability. There was no significant relationship between change in the cognitive variables and change in pain or fatigue. CONCLUSIONS: Self-efficacy beliefs and catastrophizing were important determinants of change in disability, but not pain or fatigue among patients with chronic widespread pain attending physiotherapy. Cognitively-informed physiotherapy appeared to be effective in reducing disability and fatigue and modifying cognitive factors. Such interventions may offer an effective treatment option for patients with chronic widespread pain and future randomised controlled trials are required to fully assess this.

Assessment of microhardness and color stability of micro-hybrid and nano-filled composite resins.

BACKGROUND AND AIMS: Composite resins are among the most popular restorative dental materials because of the strength and esthetic properties. The goal of this study was to assess the effect of commonly consumed beverages on microhardness and color stability of microhybrid (MH) and nanofilled NF) composite resins. MATERIAL AND METHODS: 240 samples were prepared from the composite material [MH = 120 (material I) and NF = 120 (material II)] and allocated into eight groups of 30 samples. In each group, half of the samples were tested for microhardness and another-half for color stability. After baseline measurements, the samples were immersed in test media, that is, distilled water and beverages (tea, cola, and coffee) for 15 days. Microhardness and color stability measurements were carried out after 15 days to assess the effect of beverages. The color stability and microhardness values were compared and evaluated by analysis of variance (ANOVA) using Tukey's alteration test. RESULTS: It was reported that the microhardness decreased for both the materials after immersion in all the beverages. Percentage change in microhardness was considerably higher in material II in comparison to the material I in cola drink. Color change was significantly higher in material II compared to material I in water and coffee. Cola drink caused the maximum change in microhardness among all the beverages and coffee caused the maximum color change among all the beverages. CONCLUSION: Both composite materials (I and II) showed a reduction in microhardness and change in color after immersion in a different type of test media.

PROMISE: Working with the CF community to understand emerging clinical and research needs for those treated with highly effective CFTR modulator therapy.

Highly effective CFTR modulator drug therapy is increasingly available to those with cystic fibrosis. Multiple observational research studies are now being conducted to better understand the impacts of this important therapeutic milestone on long-term outcomes, patient care needs, and future research priorities. PROMISE is a large, multi-disciplinary academic study focused on the broad impacts of starting elexacaftor/tezacaftor/ivacaftor in the US population age 6 years and older. The many areas of investigation and rationale for each are discussed by organ systems, along with recognition of remaining important questions that will not be addressed by this study alone. Knowledge gained through this and multiple complementary studies around the world will help to understand important health outcomes, clinical care priorities, and research needs for a large majority of people treated with these or similarly effective medications targeting the primary cellular impairment in cystic fibrosis.

Long-term azithromycin use is not associated with QT prolongation in children with cystic fibrosis.

Chronic Azithromycin (AZM) is a common treatment for lung infection. Among adults at risk of cardiac events, AZM use has been associated with cardiovascular harm. We assessed cardiovascular safety of AZM among children with CF, as a secondary analysis of a placebo-controlled, clinical trial, in which study drug was taken thrice-weekly for a planned 18 months. Safety assessments using electrocardiogram (ECG) occurred at study enrollment, and then after 3 weeks and 18 months of participation. Among 221 study participants with a median of 18 months follow-up, increased corrected QT interval (QTc) of ≥30 msec was rare, at 3.4 occurrences per 100 person-years; and incidence of QTc prolongation was no higher in the AZM arm than the placebo arm (1.8 versus 5.4 per 100 person-years). No persons experienced QTc intervals above 500 msec. Long-term chronic AZM use was not associated with increased QT prolongation.

Cystic fibrosis - Ten promising therapeutic approaches in the current era of care.

INTRODUCTION: Cystic fibrosis (CF) is a genetic disease affecting multiple organ systems. Research and innovations in novel therapeutic agents and health care delivery have resulted in dramatic improvements in quality of life and survival for people with CF. Despite this, significant disease burden persists for many and this is compounded by disparities in treatment access and care which globally necessitates further work to improve outcomes. Because of the advent of numerous therapies which include gene-targeted modulators in parallel with specialized care delivery models, innovative efforts continue. AREAS COVERED: In this review, we discuss the available data on investigational agents in clinical development and currently available treatments for CF. We also evaluate approaches to care delivery, consider treatment gaps, and propose future directions for advancement. EXPERT OPINION: Since the discovery of the CF gene, CFTR modulators have provided a hallmark of success, even though it was thought not previously possible. This has led to reinvigorated efforts and innovations in treatment approaches and care delivery. Numerous challenges remain because of genetic and phenotypic heterogeneity, access issues, and therapeutic costs, but the collaborative approach between stakeholders for continued innovation fuels optimism. Abbreviations: CF cystic fibrosis; CFF Cystic Fibrosis Foundation (USA); CFTR cystic fibrosis transmembrane regulator; CRISPR clustered regularly interspaced short palindromic repeats; COX cyclo oxygenase; FDA US Food and Drug Administration; FEV1% forced expiratory volume in one second % predicted; F508del deletion of phenylalanine (F) in the 508th position (most common mutation); G551D substitution of the amino acid glycine by aspartate at position 551 in the nucleotide binding domain-1 of the CFTR gene; LMIC low- and middle-income country; LTB4 leukotriene B4; MDT multi-disciplinary care team; NO nitric oxide; NSAIDs non-steroidal anti-inflammatory drugs; SLPI secretory leukocyte protease inhibitor.

Cognitive factors are associated with disability and pain, but not fatigue among physiotherapy attendees with persistent pain and fatigue.

OBJECTIVES: Most research exploring the relationship between cognitive factors and pain, disability and fatigue in patients with persistent pain/fatigue has been performed in multi disciplinary environments. It is unclear whether these associations are consistent in other contexts. This study therefore aimed to establish the relationships between these factors in patients with persistent pain/fatigue referred for physiotherapy treatment. DESIGN: Cross-sectional observational study assessing the association between cognitive factors (self-efficacy and catastrophizing) and levels of pain, disability, mental fatigue and physical fatigue in patients with persistent pain/fatigue disorders. Data were analysed using regression analyses. SETTING: Two out-patient physiotherapy departments, Manchester, UK. PARTICIPANTS: 166 patients with persistent pain and fatigue disorders chronic widespread pain, fibromyalgia and chronic fatigue syndrome/myalgic encephalopathy). MAIN OUTCOME MEASURES: Disability was assessed using the Fibromyalgia Impact Questionnaire, whilst mental and physical fatigue were assessed with the sub-scales of the Chalder Fatigue Scale. Pain intensity was measured with a Numeric Pain Rating Scale, self-efficacy with the Chronic Pain Self-efficacy Questionnaire and catastrophizing with the Pain Catastrophizing Scale. RESULTS: Cognitive factors were significantly associated with pain (self-efficacy beliefs ß=-0.30, P<0.05; catastrophizing ß=0.24, P<0.05) and disability (self-efficacy beliefs ß=-0.62, P<0.05), but not fatigue. CONCLUSIONS: Similar associations were observed in patients referred to physiotherapy as to those observed in patients treated in multi disciplinary clinical environments. Self-efficacy beliefs appear to be particularly strong determinants of disability, but exert a lesser influence over pain or fatigue. Targeting self-efficacy may be an effective method to reduce disability in patients with persistent pain and fatigue disorders.

Pulmonary Outcomes Associated with Long-Term Azithromycin Therapy in Cystic Fibrosis.

Rationale: Chronic azithromycin is commonly used in cystic fibrosis based on short controlled clinical trials showing reductions in pulmonary exacerbations and improved FEV1. Long-term effects are unknown.Objectives: Examine pulmonary outcomes among chronic azithromycin users compared with matched controls over years of use and consider combined azithromycin use in cohorts using chronic inhaled tobramycin or aztreonam.Methods: This retrospective cohort study used the U.S. cystic fibrosis Foundation Patient Registry. Incident chronic azithromycin users were compared with matched controls by FEV1% predicted rate of decline and rates of intravenous antibiotic use to treat pulmonary exacerbations. Propensity score methods were utilized to address confounding by indication. Predefined sensitivity analyses based on lung function, Pseudomonas aeruginosa (PA) status, and follow-up time intervals were conducted.Measurements and Main Results: Across 3 years, FEV1% predicted per-year decline was nearly 40% less in those with PA using azithromycin compared with matched controls (slopes, -1.53 versus -2.41% predicted per yr; difference: 0.88; 95% confidence interval [CI], 0.30-1.47). This rate of decline did not differ based on azithromycin use in those without PA. Among all cohorts, use of intravenous antibiotics was no different between azithromycin users and controls. Users of inhaled tobramycin and azithromycin had FEV1% predicted per-year decline of -0.16 versus nonusers (95% CI, -0.44 to 0.13), whereas users of inhaled aztreonam lysine and azithromycin experienced a mean 0.49% predicted per year slower decline than matched controls (95% CI, -0.11 to 1.10).Conclusions: Results from this study provide additional rationale for chronic azithromycin use in PA-positive patients to reduce lung function decline.

Incidence of Knee Injuries on Artificial Turf Versus Natural Grass in National Collegiate Athletic Association American Football: 2004-2005 Through 2013-2014 Seasons.

BACKGROUND: The use of artificial turf in American football continues to grow in popularity, and the effect of these playing surfaces on athletic injuries remains controversial. Knee injuries account for a significant portion of injuries in the National Collegiate Athletic Association (NCAA) football league; however, the effect of artificial surfaces on knee injuries remains ill-defined. HYPOTHESIS: There is no difference in the rate or mechanism of knee ligament and meniscal injuries during NCAA football events on natural grass and artificial turf playing surfaces. STUDY DESIGN: Descriptive epidemiology study. METHODS: The NCAA Injury Surveillance System Men's Football Injury and Exposure Data Sets for the 2004-2005 through 2013-2014 seasons were analyzed to determine the incidence of anterior cruciate ligament (ACL), posterior cruciate ligament (PCL), medial collateral ligament (MCL), medial meniscus, and lateral meniscal tear injuries. Injury rates were calculated per 10,000 athlete exposures, and rate ratios (RRs) were used to compare injury rates during practices and competitions on natural grass and artificial turf in NCAA football as a whole and by competition level (Divisions I, Divisions II and III). Mechanisms of injury were calculated for each injury on natural grass and artificial turf surfaces. RESULTS: A total of 3,009,205 athlete exposures and 2460 knee injuries were reported from 2004 to 2014: 1389 MCL, 522 ACL, 269 lateral meniscal, 164 medial meniscal, and 116 PCL. Athletes experienced all knee injuries at a significantly higher rate when participating in competitions as compared with practices. Athletes participating in competitions on artificial turf experienced PCL injuries at 2.94 times the rate as those playing on grass (RR = 2.94; 95% CI, 1.61-5.68). When stratified by competition level, Division I athletes participating in competitions on artificial turf experienced PCL injuries at 2.99 times the rate as those playing on grass (RR = 2.99; 95% CI, 1.39-6.99), and athletes in lower NCAA divisions (II and III) experienced ACL injuries at 1.63 times the rate (RR = 1.63; 95% CI, 1.10-2.45) and PCL injuries at 3.13 times the rate (RR = 3.13; 95% CI, 1.14-10.69) on artificial turf as compared with grass. There was no statistically significant difference in the rate of MCL, medial meniscal, or lateral meniscal injuries on artificial turf versus grass when stratified by event type or level of NCAA competition. No difference was found in the mechanisms of knee injuries on natural grass and artificial turf. CONCLUSION: Artificial turf is an important risk factor for specific knee ligament injuries in NCAA football. Injury rates for PCL tears were significantly increased during competitions played on artificial turf as compared with natural grass. Lower NCAA divisions (II and III) also showed higher rates of ACL injuries during competitions on artificial turf versus natural grass.

Oral Azithromycin Use and the Recovery of Lung Function from Pulmonary Exacerbations Treated with Intravenous Tobramycin or Colistimethate in Adults with Cystic Fibrosis.

Rationale: The potential of azithromycin to alter the antimicrobial and clinical benefits of inhaled tobramycin in patients with cystic fibrosis (CF) has been previously reported. The potential interaction between azithromycin and intravenous antibiotics in the treatment of pulmonary exacerbations is unknown. Objectives: To determine if chronic azithromycin use as a concomitant therapy is associated with change in lung function after receiving intravenous antibiotic regimens including tobramycin or colistimethate. Methods: This was a retrospective cohort study evaluating the association of azithromycin with intravenous tobramycin or colistimethate in adult patients with CF treated for a pulmonary exacerbation. The primary outcome was relative lung function recovery (forced expiratory volume in 1 s [FEV1]) after exacerbation treatment. Generalized estimating equations were applied to account for repeated events with independent correlation structures and robust standard errors, incorporating several confounders. Results: A total of 220 exacerbation events occurred in 121 patients in the tobramycin group (47% using azithromycin), and 207 exacerbation events occurred in 86 patients in the colistimethate group (59% using azithromycin). Azithromycin use was associated with less FEV1% recovery in patients treated with tobramycin (-3% relative FEV1% recovery [95% confidence interval (CI), -7 to 0.2] and -2.64% absolute FEV1% change [95% CI, -4.52 to -0.76]). Azithromycin use was associated with greater recovery of FEV1% when treated with colistimethate (+3% relative FEV1% recovery [95% CI, -0.1 to 7] and 2.00% absolute improvement in FEV1% [95% CI, 0.13 to 3.87]). The odds of 90% or 100% recovery to baseline FEV1% were lower with azithromycin use in the tobramycin cohort and higher with azithromycin use in the colistimethate cohort but were not statistically significant. Conclusions: Azithromycin use was associated with a more favorable response in adult patients with CF treated with intravenous colistimethate but a less favorable response in those treated with intravenous tobramycin.

Manipulating the mechanics of extracellular matrix to study effects on the nucleus and its structure.

Tissues such as brain, muscle, and bone differ greatly not only in their biological functions but also in their mechanical properties. Brain is far softer than muscle while bone is the stiffest tissue. Stiffness of extracellular microenvironments affects fundamental cell biological processes such as polarization and DNA replication, which affect nuclear size, shape, and levels of nuclear proteins such as the lamins that modulate gene expression. Reductionist approaches have helped dissect the effects of matrix mechanics away from confounding biochemical signals. Here, we summarize materials and methods for synthesizing and characterizing soft and stiff synthetic hydrogels widely used for mechanobiological studies. Such gels are also easily made to mimic the mechanical heterogeneity of fibrotic tissues. We further describe a nano-thin collagen fiber system, which enables control of anisotropy in addition to stiffness. With the different systems, we illustrate the effects of matrix mechanics on nuclear size, shape, and proteins including the lamins.

Erratum: Author Correction: Breast-cancer-specific mortality in patients treated based on the 21-gene assay: a SEER population-based study.

[This corrects the article DOI: 10.1038/npjbcancer.2016.17.].