Daytime, evening, and overnight: the 24-h radiology cycle and impact on interpretative accuracy.

PURPOSE: To assess the influence of time of day when a study is interpreted on discrepancy rates for common and advanced studies performed in the acute community setting. METHODS: This retrospective study used the databank of a U.S. teleradiology company to retrieve studies between 2012 and 2016 with a preliminary report followed by a final report by the on-site client hospital. Neuroradiology, abdominal radiology, and musculoskeletal radiology studies were included. Teleradiologists were fellowship trained in one of these subspecialty areas. Daytime, evening, and overnight times were defined. Associations between major and minor discrepancies, time of day, and whether the study was common or advanced were tested with significance set at p = .05. RESULTS: A total of 5,883,980 studies were analyzed. There were 8444 major discrepancies (0.14%) and 17,208 minor discrepancies (0.29%). For common studies, daytime (0.13%) and evening (0.13%) had lower major discrepancy rates compared to overnight (0.14%) (daytime to overnight, RR = 0.57, 95%CI: 0.45, 0.72, p < 0.01 and evening to overnight, RR = 0.57, 95%CI: 0.49,0.67, p < 0.01). Minor discrepancy rates for common studies were decreased for evening (0.29%) compared to overnight (0.30%) (RR = 0.89, 95%CI: 0.80,0.99, p = 0.029). For advanced studies, daytime (.15%) had lower major discrepancy rates compared to evening (0.20%) and overnight (.23%) (daytime to evening, RR = 0.77, 95%CI: 0.61, 0.97, p = 0.028 and daytime to overnight, RR = 0.66, 95%CI: 0.50, 0.87, p ≤ 0.01). CONCLUSION: Significantly higher major discrepancy rates for studies interpreted overnight suggest the need for radiologists to exercise greater caution when interpreting studies overnight and may require practice management strategies to help optimize overnight work conditions. The lower major discrepancy rates on advanced studies interpreted during the daytime suggest the need for reserving advanced studies for interpretation during the day when possible.

Radiologist age and diagnostic errors.

PURPOSE: Previous investigations into the causes of error by radiologists have addressed work schedule, volume, shift length, and sub-specialization. Studies regarding possible associations between radiologist errors and radiologist age and timing of residency training are lacking in the literature, to our knowledge. The aim of our study was to determine if radiologist age and residency graduation date is associated with diagnostic errors. METHODS: Our retrospective analysis included 1.9 million preliminary interpretations (out of a total of 5.2 million preliminary and final interpretations) of imaging examinations by 361 radiologists in a US-based national teleradiology practice between 1/1/2019 and 1/1/2020. Quality assurance data regarding the number of radiologist errors was generated through client facility feedback to the teleradiology practice. With input from both the client radiologist and the teleradiologist, the final determination of the presence, absence, and severity of a teleradiologist error was determined by the quality assurance committee of radiologists within the teleradiology company using standardized criteria. Excluded were 3.2 million final examination interpretations and 93,963 (1.8%) of total examinations from facilities reporting less than one discrepancy in examination interpretation in 2019. Logistic regression with covariates radiologist age and residency graduation date was performed for calculation of relative risk of overall error rates and by major imaging modality. Major errors were separated from minor errors as those with a greater likelihood of affecting patient care. Logistic regression with covariates radiologist age, residency graduation date, and log total examinations interpreted was used to calculate odds of making a major error to that of making a minor error. RESULTS: Mean age of the 361 radiologists was 51.1 years, with a mean residency graduation date of 2001. Mean error rate for all examinations was 0.5%. Radiologist age at any residency graduation date was positively associated with major errors (p < 0.05), with a relative risk 1.021 for each 1-year increase in age and relative risk 1.235 for each decade as well as for minor errors (p < 0.05, relative risk 1.007 for each year, relative risk 1.082 for each decade). By major imaging modality, radiologist age at any residency graduation date was positively associated with computed tomography (CT) and X-ray (XR) major and minor error, magnetic resonance imaging (MRI) major error, and ultrasound (US) minor error (p < 0.05). Radiologist age was positively associated with odds of making a major vs. minor error (p < 0.05). CONCLUSIONS: The mean error rate for all radiologists was low. We observed that increasing age at any residency graduation date was associated with increasing relative risk of major and minor errors as well as increasing odds of a major vs. minor error among providers. Further study is needed to corroborate these results, determine clinical relevance, and highlight strategies to address these findings.

Selection of human single domain antibodies (sdAb) against thymidine kinase 1 and their incorporation into sdAb-Fc antibody constructs for potential use in cancer therapy.

Thymidine Kinase 1 (TK1) is primarily known as a cancer biomarker with good prognostic capabilities for both hematological and solid malignancies. However, recent studies targeting TK1 at protein and mRNA levels have shown that TK1 may be useful as a therapeutic target. In order to examine the use of TK1 as a therapeutic target, it is necessary to develop therapeutics specific for it. Single domain antibodies (sdAbs), represent an exciting approach for the development of immunotherapeutics due to their cost-effective production and higher tumor penetration than conventional antibodies. In this study, we isolated sdAb fragments specific to human TK1 from a human sdAb library. A total of 400 sdAbs were screened through 5 rounds of selection by monoclonal phage ELISA. The most sensitive sdAb fragments were selected as candidates for preclinical testing. The sdAb fragments showed specificity for human TK1 in phage ELISA, Western blot analysis and had an estimated limit of detection of 3.9 ng/ml for the antibody fragments 4-H-TK1_A1 and 4-H-TK1_D1. The antibody fragments were successfully expressed and used for detection of membrane associated TK1 (mTK1) through flow cytometry on cancer cells [lung (~95%), colon (~87%), breast (~53%)] and healthy human mononuclear cells (MNC). The most sensitive antibody fragments, 4-H-TK1_A1 and 4-H-TK1_D1 were fused to an engineered IgG1 Fc fragment. When added to cancer cells expressing mTK1 co-cultured with human MNCs, the anti-TK1-sdAb-IgG1_A1 and D1 were able to elicit a significant antibody-dependent cell-mediated cytotoxicity (ADCC) response against lung cancer cells compared to isotype controls (P<0.0267 and P<0.0265, respectively). To our knowledge this is the first time that the isolation and evaluation of human anti-TK1 single domain antibodies using phage display technology has been reported. The antibody fragments isolated here may represent a valuable resource for the detection and the targeting of TK1 on tumor cells.

Interpretations of Examinations Outside of Radiologists' Fellowship Training: Assessment of Discrepancy Rates Among 5.9 Million Examinations From a National Teleradiology Databank.

BACKGROUND. In community settings, radiologists commonly function as multispecialty radiologists, interpreting examinations outside of their area of fellowship training. OBJECTIVE. The purpose of this article was to compare discrepancy rates for preliminary interpretations of acute community-setting examinations that are concordant versus discordant with interpreting radiologists' area of fellowship training. METHODS. This retrospective study used the databank of a U.S. teleradiology company that provides preliminary interpretations for client community hospitals. The analysis included 5,883,980 acute examinations performed from 2012 to 2016 that were preliminarily interpreted by 269 teleradiologists with a fellowship of neuroradiology, abdominal radiology, or musculoskeletal radiology. When providing final interpretations, client on-site radiologists voluntarily submitted quality assurance (QA) requests if preliminary and final interpretations were discrepant; the teleradiology company's QA committee categorized discrepancies as major (n = 8444) or minor (n = 17,208). Associations among examination type (common vs advanced), relationship between examination subspecialty and the teleradiologist's fellowship (concordant vs discordant), and major and minor discrepancies were assessed using three-way conditional analyses with generalized estimating equations. RESULTS. For examinations with a concordant subspecialty, the major discrepancy rate was lower for common than for advanced examinations (0.13% vs 0.26%; relative risk [RR], 0.50, 95% CI, 0.42-0.60; p < .001). For examinations with a discordant subspecialty, the major discrepancy rate was lower for common than advanced examinations (0.14% vs 0.18%; RR, 0.81; 95% CI, 0.72-0.90; p < .001). For common examinations, the major discrepancy rate was not different between examinations with concordant versus discordant subspecialty (0.13% vs 0.14%; RR, 0.90; 95% CI, 0.81-1.01; p = .07). For advanced examinations, the major discrepancy rate was higher for examinations with concordant versus discordant subspecialty (0.26% vs 0.18%; RR, 1.45; 95% CI, 1.18-1.79; p < .001). The minor discrepancy rate was higher among advanced examinations for those with concordant versus discordant subspecialty (0.34% vs 0.29%; RR, 1.17; 95% CI, 1.00-1.36; p = .04), but not different for other comparisons (p > .05). CONCLUSION. Major and minor discrepancy rates were not higher for acute community-setting examinations outside of interpreting radiologists' fellowship training. Discrepancy rates increased for advanced examinations. CLINICAL IMPACT. The findings support multispecialty radiologist practice in acute community settings. Efforts to match examination and interpreting radiologist sub-specialty may not reduce diagnostic discrepancies.

Radiologist errors by modality, anatomic region, and pathology for 1.6 million exams: what we have learned.

PURPOSE: To evaluate the feasibility of adding pathology to recent radiologist error characterization schemes of modality and anatomic region and the potential of this data to more specifically inform peer review and peer learning. METHODS: Quality assurance data originating from 349 radiologists in a national teleradiology practice were collected for 2019. Interpretive errors were simply categorized as major or minor. Reporting or communication errors were classified as administrative errors. Interpretive errors were then divided by modality, anatomic region and placed into one of 64 pathologic categories. RESULTS: Out of 1,628,464 studies, the discrepancy rate was 0.5% (8181/1,634,201). The 8181 total errors consisted of 2992 major errors (0.18%) and 5189 minor errors (0.32%). Precisely, 3.1% (257/8181) of total errors were administrative. Of major interpretive errors, 75.5% occurred on CT, with CT abdomen and pelvis accounting for 40.4%. The most common pathologic discrepancy for all exams was in the category of mass, nodule, or adenopathy (1583/8181), the majority of which were minor (1315/1583). The most common pathologic discrepancy for the 2937 major interpretive errors was fracture or dislocation (27%; 793/2937), followed by bleed (10.7%; 315/2937). CONCLUSION: The addition of error-related pathology to peer review is both feasible and practical and provides a more detailed guide to targeted individual and practice-wide peer learning quality improvement efforts. Future research is needed to determine if there are measurable improvements in detection or interpretation of specific pathologies following error feedback and educational interventions.

Radiologist Opinions of a Quality Assurance Program: The Interaction Between Error, Emotion, and Preventative Action.

RATIONALE AND OBJECTIVES: To investigate inter-relationships between radiologist opinions of a quality assurance (QA) program, QA Committee communications, negative emotions, self-identified risk factors, and preventive actions taken following major errors. MATERIALS AND METHODS: A 48 question electronic survey was distributed to all 431 radiologists within the same teleradiology organization between June 15 and July 3, 2018. Two reminders were sent during the survey time period. Descriptive statistics were generated, and comparisons were made with Fisher exact test. Significance level was set at p < 0.05. RESULTS: Response rate was 67.5% (291/431), and 72.5% of respondents completed all survey questions. A total of 64.3% of respondents were male, and the highest proportion of radiologists (28.9%, 187/291) had been in practice >20 years. Preventative actions following an error were positively correlated to a higher opinion of the QA process, self-identification of personal risk factors for error, and greater negative emotions following an error (all p < 0.05). A higher opinion of communications with the QA committee was associated with a positive opinion of the QA process (p < 0.001). An inverse relationship existed between negative emotion and opinion of QA committee communications (p < 0.05) and negative emotion and opinion of the QA process (p < 0.05). Radiologist gender and full time versus part time status had a significant effect on perception of the QA process (p < 0.05). CONCLUSION: Radiologist opinions of their institutional QA process was related to the number of negative emotions experienced and preventative actions taken following major errors. Nurturing trust and incorporating more positive feedback in the QA process may improve interactions with QA Committees and mitigate future errors.

Effect of intravenous contrast for CT abdomen and pelvis on detection of urgent and non-urgent pathology: can repeat CT within 72 hours be avoided?

PURPOSE: To determine if administering IV contrast for CT abdomen and pelvis improves detection of urgent and clinically important non-urgent pathology in patients with urgent clinical symptoms compared to patients not receiving IV contrast, and in turn to determine whether repeat CT exams on the same patient within 72 h were of low diagnostic benefit if the first CT was performed with IV contrast. METHODS: We evaluated 400 consecutive patients who had CT abdomen and pelvis (CT AP) examinations repeated within 72 h. For each patient, demographic data, reason for examination, examination time stamps, and examination technique were documented. CT AP radiology reports were reviewed and both urgent and non-urgent pathology was extracted. RESULTS: Of 400 patients, 63% had their initial CT AP without contrast. Administration of IV contrast for the first CT AP was associated with increased detection of urgent findings compared with non-contrast CT (p = 0.004) and a contrast-enhanced CT AP following an initial non-contrast CT AP examination better characterized both urgent (p = 0.002) and non-urgent findings (p < 0.001). Adherence to ACR appropriateness criteria for IV contrast administration was associated with increased detection of urgent pathology on the first CT (p = 0.02), and the second CT was more likely to be performed with IV contrast if recommended by the radiologist reading the first CT (p = 0.0006). CONCLUSION: In the absence of contraindications, encouraging urgent care physicians to preferentially order IV contrast-enhanced CT AP examinations in adherence with ACR appropriateness criteria may increase detection of urgent pathology and avoid short-term repeat CT AP.

Proteomic Analysis of Resistance of Gram-Negative Bacteria to Chlorhexidine and Impacts on Susceptibility to Colistin, Antimicrobial Peptides, and Ceragenins.

Use of chlorhexidine in clinical settings has led to concerns that repeated exposure of bacteria to sub-lethal doses of chlorhexidine might result in chlorhexidine resistance and cross resistance with other cationic antimicrobials including colistin, endogenous antimicrobial peptides (AMPs) and their mimics, ceragenins. We have previously shown that colistin-resistant Gram-negative bacteria remain susceptible to AMPs and ceragenins. Here, we investigated the potential for cross resistance between chlorhexidine, colistin, AMPs and ceragenins by serial exposure of standard strains of Gram-negative bacteria to chlorhexidine to generate resistant populations of organisms. Furthermore, we performed a proteomics study on the chlorhexidine-resistant strains and compared them to the wild-type strains to find the pathways by which bacteria develop resistance to chlorhexidine. Serial exposure of Gram-negative bacteria to chlorhexidine resulted in four- to eight-fold increases in minimum inhibitory concentrations (MICs). Chlorhexidine-resistant organisms showed decreased susceptibility to colistin (8- to 32-fold increases in MICs) despite not being exposed to colistin. In contrast, chlorhexidine-resistant organisms had the same MICs as the original strains when tested with representative AMPs (LL-37 and magainin I) and ceragenins (CSA-44 and CSA-131). These results imply that there may be a connection between the emergence of highly colistin-resistant Gram-negative pathogens and the prevalence of chlorhexidine usage. Yet, use of chlorhexidine may not impact innate immune defenses (e.g., AMPs) and their mimics (e.g., ceragenins). Here, we also show that chlorhexidine resistance is associated with upregulation of proteins involved in the assembly of LPS for outer membrane biogenesis and virulence factors in Pseudomonas aeruginosa. Additionally, resistance to chlorhexidine resulted in elevated expression levels of proteins associated with chaperones, efflux pumps, flagella and cell metabolism. This study provides a comprehensive overview of the evolutionary proteomic changes in P. aeruginosa following exposure to chlorhexidine and colistin. These results have important clinical implications considering the continuous application of chlorhexidine in hospitals that could influence the emergence of colistin-resistant strains.

Signature pathway expression of xylose utilization in the genetically engineered industrial yeast Saccharomyces cerevisiae.

Haploid laboratory strains of Saccharomyces cerevisiae are commonly used for genetic engineering to enable their xylose utilization but little is known about the industrial yeast which is often recognized as diploid and as well as haploid and tetraploid. Here we report three unique signature pathway expression patterns and gene interactions in the centre metabolic pathways that signify xylose utilization of genetically engineered industrial yeast S. cerevisiae NRRL Y-50463, a diploid yeast. Quantitative expression analysis revealed outstanding high levels of constitutive expression of YXI, a synthesized yeast codon-optimized xylose isomerase gene integrated into chromosome XV of strain Y-50463. Comparative expression analysis indicated that the YXI was necessary to initiate the xylose metabolic pathway along with a set of heterologous xylose transporter and utilization facilitating genes including XUT4, XUT6, XKS1 and XYL2. The highly activated transketolase and transaldolase genes TKL1, TKL2, TAL1 and NQM1 as well as their complex interactions in the non-oxidative pentose phosphate pathway branch were critical for the serial of sugar transformation to drive the metabolic flow into glycolysis for increased ethanol production. The significantly increased expression of the entire PRS gene family facilitates functions of the life cycle and biosynthesis superpathway for the yeast. The outstanding higher levels of constitutive expression of YXI and the first insight into the signature pathway expression and the gene interactions in the closely related centre metabolic pathways from the industrial yeast aid continued efforts for development of the next-generation biocatalyst. Our results further suggest the industrial yeast is a desirable delivery vehicle for new strain development for efficient lignocellulose-to-advanced biofuels production.

Ceragenins are active against drug-resistant Candida auris clinical isolates in planktonic and biofilm forms.

Background: Candida auris has emerged as a serious threat to human health. Of particular concern are the resistance profiles of many clinical isolates, with some being resistant to multiple classes of antifungals. Objectives: Measure susceptibilities of C. auris isolates, in planktonic and biofilm forms, to ceragenins (CSAs). Determine the effectiveness of selected ceragenins in gel and cream formulations in eradicating fungal infections in tissue explants. Materials and methods: A collection of 100 C. auris isolates available at CDC was screened for susceptibility to a lead ceragenin. A smaller collection was used to characterize antifungal activities of other ceragenins against organisms in planktonic and biofilm forms. Effects of ceragenins on fungal cells and biofilms were observed via microscopy. An ex vivo model of mucosal fungal infection was used to evaluate formulated forms of lead ceragenins. Results: Lead ceragenins displayed activities comparable to those of known antifungal agents against C. auris isolates with MICs of 0.5-8 mg/L and minimum fungicidal concentrations (MFCs) of 2-64 mg/L. No cross-resistance with other antifungals was observed. Fungal cell morphology was altered in response to ceragenin treatment. Ceragenins exhibited activity against sessile organisms in biofilms. Gel and cream formulations including 2% CSA-44 or CSA-131 resulted in reductions of over 4 logs against established fungal infections in ex vivo mucosal tissues. Conclusions: Ceragenins demonstrated activity against C. auris, suggesting that these compounds warrant further study to determine whether they can be used for topical applications to skin and mucosal tissues for treatment of infections with C. auris and other fungi.

Tolerant industrial yeast Saccharomyces cerevisiae posses a more robust cell wall integrity signaling pathway against 2-furaldehyde and 5-(hydroxymethyl)-2-furaldehyde.

Cell wall integrity signaling pathway in Saccharomyces cerevisiae is a conserved function for detecting and responding to cell stress conditions but less understood for industrial yeast. We examined gene expression dynamics for a tolerant industrial yeast strain NRRL Y-50049 in response to challenges of furfural and HMF through comparative quantitative gene expression analysis using pathway-based qRT-PCR array assays. All tested genes from Y-50049, except for MLP2, demonstrated more resistant and significantly increased gene expression than that from a laboratory strain BY4741. While all five sensor encoding genes WSC1, WSC2, WSC3, MID2 and MTL1 from both strains were activated in response to the furfural-HMF treatment, WSC3 from Y-50049 demonstrated the most increased expression over time compared with any other sensor genes. These results suggested the industrial yeast poses more robust cell wall integrity pathway, and gene WSC3 could have the special capability for signal transmission against furfural and HMF. Among five single nucleotide variations discovered in WSC3 from Y-50049, three were found to be non-synonymous mutations resulting in amino acid alterations of Ser158 → Tyr158, Val186 → Ile186, and Glu430 → Asp430. Our results suggest the industrial yeast as a more desirable delivery vehicle for the next-generation biocatalyst development.

Effect of Shift, Schedule, and Volume on Interpretive Accuracy: A Retrospective Analysis of 2.9 Million Radiologic Examinations.

Purpose To determine whether there is an association between radiologist shift length, schedule, or examination volume and interpretive accuracy. Materials and Methods This study was institutional review board approved and HIPAA compliant. A retrospective analysis of all major discrepancies from a 2015 quality assurance database of a teleradiology practice was performed. Board-certified radiologists provided initial preliminary interpretations. Discrepancies were identified during a secondary review by a practicing radiologist or through an internal quality assurance process and were vetted through a consensus radiology quality assurance committee. Unique anonymous radiologist identifiers were used to link the discrepancies to radiologists' shifts and schedules. Data were analyzed by using analysis of variance, t test, or χ2 test. Results A total of 4294 major discrepancies resulted from 2 922 377 examinations (0.15%). There was a significant difference for shift length (P < .0001) and volume (P < .0001) for shifts with versus those without discrepancies. On average, errors occurred a mean (± standard deviation) of 8.97 hours ± 2.28 into the shift (median, 10 hours; interquartile range, 2.0 hours). Significantly more errors occurred late in shifts than early (P < .0001), peaking between 10 and 12 hours. The number of major discrepancies in a single shift ranged from one to four, with a significant difference in the number of discrepancies as a function of study volume (volume for all shifts, 67.60 ± 60.24; volume for shifts with major discrepancies, 118.96 ± 66.89; P < .001). Despite a trend for more discrepancies after more consecutive days worked, the difference was not significant (P = .0893). Conclusion Longer shifts and higher diagnostic examination volumes are associated with increased major interpretive discrepancies. These are more likely to occur later in a shift, peaking after the 10th hour of work. © RSNA, 2017.

Susceptibility of Colistin-Resistant, Gram-Negative Bacteria to Antimicrobial Peptides and Ceragenins.

The susceptibility of colistin-resistant clinical isolates of Klebsiella pneumoniae to ceragenins and antimicrobial peptides (AMPs) suggests that there is little to no cross-resistance between colistin and ceragenins/AMPs and that lipid A modifications are found in bacteria with modest changes in susceptibility to ceragenins and with high levels of resistance to colistin. These results suggest that there are differences in the resistance mechanisms to colistin and ceragenins/AMPs.

Two New Native ß-Glucosidases from Clavispora NRRL Y-50464 Confer Its Dual Function as Cellobiose Fermenting Ethanologenic Yeast.

Yeast strain Clavispora NRRL Y-50464 is able to produce cellulosic ethanol from lignocellulosic materials without addition of external ß-glucosidase by simultaneous saccharification and fermentation. A ß-glucosidase BGL1 protein from this strain was recently reported supporting its cellobiose utilization capability. Here, we report two additional new ß-glucosidase genes encoding enzymes designated as BGL2 and BGL3 from strain NRRL Y-50464. Quantitative gene expression was analyzed and the gene function of BGL2 and BGL3 was confirmed by heterologous expression using cellobiose as a sole carbon source. Each gene was cloned and partially purified protein obtained separately for direct enzyme assay using varied substrates. Both proteins showed the highest specific activity at pH 5 and relatively strong affinity with a Km of 0.08 and 0.18 mM for BGL2 and BGL3, respectively. The optimum temperature was found to be 50°C for BGL2 and 55°C for BGL3. Both proteins were able to hydrolyze 1,4 oligosaccharides evaluated in this study. They also showed a strong resistance to glucose product inhibition with a Ki of 61.97 and 38.33 mM for BGL2 and BGL3, respectively. While BGL3 was sensitive showing a significantly reduced activity to 4% ethanol, BGL2 demonstrated tolerance to ethanol. Its activity was enhanced in the presence of ethanol but reduced at concentrations greater than 16%. The presence of the fermentation inhibitors furfural and HMF did not affect the enzyme activity. Our results suggest that a ß-glucosidase gene family exists in Clavispora NRRL Y-50464 with at least three members in this group that validate its cellobiose hydrolysis functions for lower-cost cellulosic ethanol production. Results of this study confirmed the cellobiose hydrolysis function of strain NRRL Y-50464, and further supported this dual functional yeast as a candidate for lower-cost cellulosic ethanol production and next-generation biocatalyst development in potential industrial applications.

Front-line, dose-escalated immunochemotherapy is associated with a significant progression-free survival advantage in patients with double-hit lymphomas: a systematic review and meta-analysis.

'Double-hit lymphomas' (DHL), defined by concurrent MYC and BCL2 (or, alternatively, BCL6) rearrangements, have a very poor outcome compared to standard-risk, diffuse large B-cell lymphomas (DLBCL). Consequently, dose-intensive (DI) therapies and/or consolidation with high-dose therapy and transplant have been explored in DHL, although benefit has been debated. This meta-analysis compared survival outcomes in DHL patients receiving dose-escalated regimens [DI: R-Hyper-CVAD (rituximab, cyclophosphamide, vincristine, doxorubicin, dexamethasone) or R-CODOX-M/IVAC (rituximab, cyclophosphamide, doxorubicin, vincristine, methotrexate/ifosfamide, etoposide, high dose cytarabine); or intermediate-dose: R-EPOCH (rituximab, etoposide, doxorubicin, cyclophosphamide, vincristine, prednisone)] versus standard-dose regimens (R-CHOP; rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) in the first-line setting. Data were synthesized to estimate hazard ratios of dose-escalated treatments versus R-CHOP using a Weibull proportional hazards model within a Bayesian meta-analysis framework. Eleven studies examining 394 patients were included. Patients were treated with either front-line R-CHOP (n = 180), R-EPOCH (n = 91), or R-Hyper-CVAD/rituximab, methotrexate, cytarabine (R-M/C), R-CODOX-M/R-IVAC (DI) (n = 123). Our meta-analysis revealed that median progression-free survival (n = 350) for the R-CHOP, R-EPOCH and DI groups was 12·1, 22·2, and 18·9 months, respectively. First-line treatment with R-EPOCH significantly reduced the risk of a progression compared with R-CHOP (relative risk reduction of 34%; P = 0·032); however, overall survival (n = 374) was not significantly different across treatment approaches. A subset of patients might benefit from intensive induction with/without transplant. Further investigation into the role of transplant and novel therapy combinations is necessary.

A community-based collaborative approach to improve breast cancer screening in underserved African American women.

Although African American women in the United States have a lower incidence of breast cancer compared with white women, those younger than 40 years actually have a higher incidence rate; additionally, African American women are more likely to die from breast cancer at every age compared with white women. Racial disparities in breast cancer mortality rates are especially significant in Maryland, which ranks fifth in the nation for breast cancer mortality, and in Baltimore City, which has the second highest annual death rate for African American women in Maryland. To address this disparity in care, Med-IQ, an accredited provider of CME, collaborated with Sisters Network Baltimore Metropolitan, Affiliate Chapter of Sisters Network® Inc., the only national African American breast cancer survivorship organization, to sponsor their community-based educational outreach initiative. The collaborative mission was to engage at-risk African American women, their families, local organizations, healthcare professionals, and clinics, with the goals of increasing awareness, addressing fears that affect timely care and diagnosis, and encouraging women to obtain regular mammograms. Intervention strategies included (1) a "Survivor Stories" video, (2) patient outreach consisting of neighborhood walks and an educational luncheon, and (3) a community outreach utilizing direct mailings to local businesses, community groups, and healthcare professionals. Trusted and well-known community resources were presented as mediums to promote the initiative, yielding achievement of broader and more effective outcomes. As a result of this patient-friendly initiative, two (2) of the women who sought screening were diagnosed with breast cancer and underwent treatment.

A new ß-glucosidase producing yeast for lower-cost cellulosic ethanol production from xylose-extracted corncob residues by simultaneous saccharification and fermentation.

This study reports a new yeast strain of Clavispora NRRL Y-50464 that is able to utilize cellobiose as sole source of carbon and produce sufficient native ß-glucosidase enzyme activity for cellulosic ethanol production using SSF. In addition, this yeast is tolerant to the major inhibitors derived from lignocellulosic biomass pre-treatment such as 2-furaldehyde (furfural) and 5-(hydroxymethyl)-2-furaldehyde (HMF), and converted furfural into furan methanol in less than 12h and HMF into furan-2,5-dimethanol within 24h in the presence of 15 mM each of furfural and HMF. Using xylose-extracted corncob residue as cellulosic feedstock, an ethanol production of 23 g/l was obtained using 25% solids loading at 37 °C by SSF without addition of exogenous ß-glucosidase. Development of this yeast aids renewable biofuels development efforts for economic consolidated SSF bio-processing.

Repression of xylose-specific enzymes by ethanol in Scheffersomyces (Pichia) stipitis and utility of repitching xylose-grown populations to eliminate diauxic lag.

During the fermentation of lignocellulosic hydrolyzates to ethanol by native pentose-fermenting yeasts such as Scheffersomyces (Pichia) stipitis NRRL Y-7124 (CBS 5773) and Pachysolen tannophilus NRRL Y-2460, the switch from glucose to xylose uptake results in a diauxic lag unless process strategies to prevent this are applied. When yeast were grown on glucose and resuspended in mixed sugars, the length of this lag was observed to be a function of the glucose concentration consumed (and consequently, the ethanol concentration accumulated) prior to the switch from glucose to xylose fermentation. At glucose concentrations of 95 g/L, the switch to xylose utilization was severely stalled such that efficient xylose fermentation could not occur. Further investigation focused on the impact of ethanol on cellular xylose transport and the induction and maintenance of xylose reductase and xylitol dehydrogenase activities when large cell populations of S. stipitis NRRL Y-7124 were pre-grown on glucose or xylose and then presented mixtures of glucose and xylose for fermentation. Ethanol concentrations around 50 g/L fully repressed enzyme induction although xylose transport into the cells was observed to be occurring. Increasing degrees of repression were documented between 15 and 45 g/L ethanol. Repitched cell populations grown on xylose resulted in faster fermentation rates, particularly on xylose but also on glucose, and eliminated diauxic lag and stalling during mixed sugar conversion by P. tannophilus or S. stipitis, despite ethanol accumulations in the 60 or 70 g/L range, respectively. The process strategy of priming cells on xylose was key to the successful utilization of high mixed sugar concentrations because specific enzymes for xylose utilization could be induced before ethanol concentration accumulated to an inhibitory level.