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This study introduces the prostate cancer linear energy transfer sensitivity index (PCLSI) as a novel method to predict relative biological effectiveness (RBE) in prostate cancer using linear energy transfer (LET) in proton therapy based on screening for DNA repair mutations.
Materials and Methods:
Five prostate cancer cell lines with DNA repair mutations known to cause sensitivity to LET and DNA repair inhibitors were examined using published data. Relative Du145 LET sensitivity data were leveraged to deduce the LET equivalent of olaparib doses. The PCLSI model was built using three of the prostate cancer cell lines (LNCaP, 22Rv1 and Du145) with DNA mutation frequency from patient cohorts. The PCLSI model was compared against two established RBE models, McNamara and McMahon, for LET-optimized prostate cancer treatment plans.
Results:
The PCLSI model relies on the presence of eight DNA repair mutations: AR, ATM, BRCA1, BRCA2, CDH1, ETV1, PTEN and TP53, which are most likely to predict increased LET sensitivity and RBE in proton therapy. In the LET-optimized plan, the PCLSI model indicates that prostate cancer cells with these DNA repair mutations are more sensitive to increased LET than the McNamara and McMahon RBE models, with expected RBE increases ranging from 11%–33% at 2keV/µm.
Conclusions:
The PCLSI model predicts increasing RBE as a function of LET in the presence of certain genetic mutations. The integration of LET-optimized proton therapy and genetic mutation profiling could be a significant step toward the use of individualized medicine to improve outcomes using RBE escalation without the potential toxicity of physical dose escalation.
Tversky's contrast model of proximity was initially formulated to account for the observed violations of the metric axioms often found in empirical proximity data. This set-theoretic approach models the similarity/dissimilarity between any two stimuli as a linear (or ratio) combination of measures of the common and distinctive features of the two stimuli. This paper proposes a new spatial multidimensional scaling (MDS) procedure called TSCALE based on Tversky's linear contrast model for the analysis of generally asymmetric three-way, two-mode proximity data. We first review the basic structure of Tversky's conceptual contrast model. A brief discussion of alternative MDS procedures to accommodate asymmetric proximity data is also provided. The technical details of the TSCALE procedure are given, as well as the program options that allow for the estimation of a number of different model specifications. The nonlinear estimation framework is discussed, as are the results of a modest Monte Carlo analysis. Two consumer psychology applications are provided: one involving perceptions of fast-food restaurants and the other regarding perceptions of various competitive brands of cola softdrinks. Finally, other applications and directions for future research are mentioned.
The gut microbiome is impacted by certain types of dietary fibre. However, the type, duration and dose needed to elicit gut microbial changes and whether these changes also influence microbial metabolites remain unclear. This study investigated the effects of supplementing healthy participants with two types of non-digestible carbohydrates (resistant starch (RS) and polydextrose (PD)) on the stool microbiota and microbial metabolite concentrations in plasma, stool and urine, as secondary outcomes in the Dietary Intervention Stem Cells and Colorectal Cancer (DISC) Study. The DISC study was a double-blind, randomised controlled trial that supplemented healthy participants with RS and/or PD or placebo for 50 d in a 2 × 2 factorial design. DNA was extracted from stool samples collected pre- and post-intervention, and V4 16S rRNA gene sequencing was used to profile the gut microbiota. Metabolite concentrations were measured in stool, plasma and urine by high-performance liquid chromatography. A total of fifty-eight participants with paired samples available were included. After 50 d, no effects of RS or PD were detected on composition of the gut microbiota diversity (alpha- and beta-diversity), on genus relative abundance or on metabolite concentrations. However, Drichlet’s multinomial mixture clustering-based approach suggests that some participants changed microbial enterotype post-intervention. The gut microbiota and fecal, plasma and urinary microbial metabolites were stable in response to a 50-d fibre intervention in middle-aged adults. Larger and longer studies, including those which explore the effects of specific fibre sub-types, may be required to determine the relationships between fibre intake, the gut microbiome and host health.
Acid-base titrations and attenuated total reflectance-infrared (ATR-IR) spectroscopy of solutions containing Zn(NO3)2 and the herbicide 3-amino-1,2,4-triazole suggested that soluble complexes ZnL2+ and Zn(OH)L+ form, where L represents aminotriazole. Sorption experiments and modeling in systems containing K-saturated Wyoming (SWy-K) montmorillonite suggest that at low concentrations the aminotriazole sorbs primarily in cationic form via an ion-exchange mechanism. Sorption isotherms for aminotriazole are ‘s’-shaped, indicating a co-operative sorption mechanism as the concentration of the molecule increases. At higher concentrations, ATR-IR spectroscopy indicated the presence of cationic and neutral triazole molecules on the surface, while X-ray diffraction data suggest interaction with interlayer regions of the clay. When the concentration of the herbicide was high, initial sorption of aminotriazole cations modified the clay to make the partitioning of neutral molecules to the surface more favorable. Experiments conducted in the presence of Zn(II) indicated that below pH 7, Zn(II) and aminotriazole compete for sorption sites, while above pH 7 the presence of Zn(II) enhances the uptake of aminotriazole. The enhancement was attributed to the formation of an inner-sphere ternary surface complex at hydroxyl sites (SOH) on crystal edges, having the form [(SOZn(OH)L)]0.
Simple extended constant capacitance surface complexation models have been developed to represent the adsorption of polyaromatic dyes (9-aminoacridine, 3,6-diaminoacridine, azure A and safranin O) to kaolinite, and the competitive adsorption of the dyes with Cd. The formulation of the models was based on data from recent publications, including quantitative adsorption measurements over a range of conditions (varying pH and concentration), acid-base titrations and attenuated total reflectance-Fourier transform infrared spectroscopic data. In the models the dye molecules adsorb as aggregates of three or four, forming outer-sphere complexes with sites on the silica face of kaolinite. Both electrostatic and hydrophobic interactions are implicated in the adsorption processes. Despite their simplicity, the models fit a wide range of experimental data, thereby supporting the underlying hypothesis that the flat, hydrophobic, but slightly charged silica faces of kaolinite facilitate the aggregation and adsorption of the flat, aromatic, cationic dye molecules.
To examine the impact of SARS-CoV-2 infection on CLABSI rate and characterize the patients who developed a CLABSI. We also examined the impact of a CLABSI-reduction quality-improvement project in patients with and without COVID-19.
Design:
Retrospective cohort analysis.
Setting:
Academic 889-bed tertiary-care teaching hospital in urban Los Angeles.
Patients or participants:
Inpatients 18 years and older with CLABSI as defined by the National Healthcare Safety Network (NHSN).
Intervention(s):
CLABSI rate and patient characteristics were analyzed for 2 cohorts during the pandemic era (March 2020–August 2021): COVID-19 CLABSI patients and non–COVID-19 CLABSI patients, based on diagnosis of COVID-19 during admission. Secondary analyses were non–COVID-19 CLABSI rate versus a historical control period (2019), ICU CLABSI rate in COVID-19 versus non–COVID-19 patients, and CLABSI rates before and after a quality- improvement initiative.
Results:
The rate of COVID-19 CLABSI was significantly higher than non–COVID-19 CLABSI. We did not detect a difference between the non–COVID-19 CLABSI rate and the historical control. COVID-19 CLABSIs occurred predominantly in the ICU, and the ICU COVID-19 CLABSI rate was significantly higher than the ICU non–COVID-19 CLABSI rate. A hospital-wide quality-improvement initiative reduced the rate of non–COVID-19 CLABSI but not COVID-19 CLABSI.
Conclusions:
Patients hospitalized for COVID-19 have a significantly higher CLABSI rate, particularly in the ICU setting. Reasons for this increase are likely multifactorial, including both patient-specific and process-related issues. Focused quality-improvement efforts were effective in reducing CLABSI rates in non–COVID-19 patients but were less effective in COVID-19 patients.
We disentangle the effects of biodiesel incentives and shale oil expansion on the long-run equilibrium price relationships among biodiesel feedstocks and crude oil in the United States (US) and European Union (EU). We find that the 2005 Energy Policy Act in the US substantially increased the responsiveness of soy oil, canola oil, and corn oil prices to crude oil price movements. However, in recent years, expansion in the global supply of crude oil from shale oil extraction has offset the effects of US biodiesel incentives and blending mandates. In the EU, the Indirect Land Use Change Directive of 2015 substantially reduced the responsiveness of biodiesel feedstock prices to crude oil price movements.
Healthcare personnel (HCP) with unprotected exposures to aerosol-generating procedures (AGPs) on patients with coronavirus disease 2019 (COVID-19) are at risk of infection with severe acute respiratory coronavirus virus 2 (SARS-CoV-2). A retrospective review at an academic medical center demonstrated an infection rate of <1% among HCP involved in AGPs without a respirator and/or eye protection.
During the initial surge of the COVID-19 pandemic in the spring and summer of 2020, paediatric heart centres were forced to rapidly alter the way patient care was provided to minimise interruption to patient care as well as exposure to the virus. In this survey-based descriptive study, we characterise changes that occurred within paediatric cardiology practices across the United States and described provider experience and attitudes towards these changes during the pandemic. Common changes that were implemented included decreased numbers of procedures, limiting visitors and shifting towards telemedicine encounters. The information obtained from this survey may be useful in guiding and standardising responses to future public health crises.
To determine the utility of the Sofia SARS rapid antigen fluorescent immunoassay (FIA) to guide hospital-bed placement of patients being admitted through the emergency department (ED).
Design:
Cross-sectional analysis of a clinical quality improvement study.
Setting:
This study was conducted in 2 community hospitals in Maryland from September 21, 2020, to December 3, 2020. In total, 2,887 patients simultaneously received the Sofia SARS rapid antigen FIA and SARS-CoV-2 RT-PCR assays on admission through the ED.
Methods:
Rapid antigen results and symptom assessment guided initial patient placement while confirmatory RT-PCR was pending. The sensitivity, specificity, positive predictive values, and negative predictive values of the rapid antigen assay were calculated relative to RT-PCR, overall and separately for symptomatic and asymptomatic patients. Assay sensitivity was compared to RT-PCR cycle threshold (Ct) values. Assay turnaround times were compared. Clinical characteristics of RT-PCR–positive patients and potential exposures from false-negative antigen assays were evaluated.
Results:
For all patients, overall agreement was 97.9%; sensitivity was 76.6% (95% confidence interval [CI], 71%–82%), and specificity was 99.7% (95% CI, 99%–100%). We detected no differences in performance between asymptomatic and symptomatic individuals. As RT-PCR Ct increased, the sensitivity of the antigen assay decreased. The mean turnaround time for the antigen assay was 1.2 hours (95% CI, 1.0–1.3) and for RT-PCR it was 20.1 hours (95% CI, 18.9–40.3) (P < .001). No transmission from antigen-negative/RT-PCR–positive patients was identified.
Conclusions:
Although not a replacement for RT-PCR for detection of all SARS-CoV-2 infections, the Sofia SARS antigen FIA has clinical utility for potential initial timely patient placement.
Trainees and investigators from underrepresented minority (URM) backgrounds face unique challenges to establishing successful careers in clinical and translational research. Structured training for mentors is an important mechanism to increase the diversity of the research workforce. This article presents data from an evaluation of the University of California, San Francisco (UCSF) Center for AIDS Research (CFAR) Mentoring the Mentors program aimed at improving mentors’ competency in working with diverse mentees in HIV research.
Methods:
Mentors from around the USA who had in one of seven separate 2-day training workshops conducted from 2013 to 2020 were invited to participate in an online evaluation survey of their experiences with the training and their subsequent mentoring activities.
Results:
There was a high response rate (80%) among the 226 mentors invited to complete the survey. The 180 respondents were diverse in demographics, professional disciplines, and geographic distribution. Quantitative and qualitative data indicate a lasting positive impact of the training, with sustained improvements documented on a validated measure of self-appraised mentoring competency. Respondents also endorsed high interest in future, follow-up training with continued focus on topics related to mentoring in the context of diversity.
Conclusion:
The evaluation of the UCSF CFAR Mentoring the Mentors program showed lasting impact in improving mentoring practices, coupled with high interest in continued in-depth training in areas focused on diversity, equity, and inclusion.
There is strong evidence that foods containing dietary fibre protect against colorectal cancer, resulting at least in part from its anti-proliferative properties. This study aimed to investigate the effects of supplementation with two non-digestible carbohydrates, resistant starch (RS) and polydextrose (PD), on crypt cell proliferative state (CCPS) in the macroscopically normal rectal mucosa of healthy individuals. We also investigated relationships between expression of regulators of apoptosis and of the cell cycle on markers of CCPS. Seventy-five healthy participants were supplemented with RS and/or PD or placebo for 50 d in a 2 × 2 factorial design in a randomised, double-blind, placebo-controlled trial (the Dietary Intervention, Stem cells and Colorectal Cancer (DISC) Study). CCPS was assessed, and the expression of regulators of the cell cycle and of apoptosis was measured by quantitative PCR in rectal mucosal biopsies. SCFA concentrations were quantified in faecal samples collected pre- and post-intervention. Supplementation with RS increased the total number of mitotic cells within the crypt by 60 % (P = 0·001) compared with placebo. This effect was limited to older participants (aged ≥50 years). No other differences were observed for the treatments with PD or RS as compared with their respective controls. PD did not influence any of the measured variables. RS, however, increased cell proliferation in the crypts of the macroscopically-normal rectum of older adults. Our findings suggest that the effects of RS on CCPS are not only dose, type of RS and health status-specific but are also influenced by age.
Bowel cancer risk is strongly influenced by lifestyle factors including diet and physical activity. Several studies have investigated the effects of adherence to the World Cancer Research Fund (WCRF)/American Institute for Cancer Research (AICR) cancer prevention recommendations on outcomes such as all-cause and cancer-specific mortality, but the relationships with molecular mechanisms that underlie the effects on bowel cancer risk are unknown. This study aimed to investigate the relationships between adherence to the WCRF/AICR cancer prevention recommendations and wingless/integrated (WNT)-pathway-related markers of bowel cancer risk, including the expression of WNT pathway genes and regulatory microRNA (miRNA), secreted frizzled-related protein 1 (SFRP1) methylation and colonic crypt proliferative state in colorectal mucosal biopsies. Dietary and lifestyle data from seventy-five healthy participants recruited as part of the DISC Study were used. A scoring system was devised including seven of the cancer prevention recommendations and smoking status. The effects of total adherence score and scores for individual recommendations on the measured outcomes were assessed using Spearman’s rank correlation analysis and unpaired t tests, respectively. Total adherence score correlated negatively with expression of Myc proto-oncogene (c-MYC) (P=0·039) and WNT11 (P=0·025), and high adherers had significantly reduced expression of cyclin D1 (CCND1) (P=0·042), WNT11 (P=0·012) and c-MYC (P=0·048). Expression of axis inhibition protein 2 (AXIN2), glycogen synthase kinase (GSK3β), catenin β1 (CTNNB1) and WNT11 and of the oncogenic miRNA miR-17 and colonic crypt kinetics correlated significantly with scores for individual recommendations, including body fatness, red meat intake, plant food intake and smoking status. The findings from this study provide evidence for positive effects of adherence to the WCRF/AICR cancer prevention recommendations on WNT-pathway-related markers of bowel cancer risk.
OBJECTIVES/SPECIFIC AIMS: Obesity is a rapidly growing epidemic and long-term interventions aimed to reduce body weight are largely unsuccessful due to an increased drive to eat and a reduced metabolic rate established during weight loss. Previously, our lab demonstrated that exercise has beneficial effects on weight loss maintenance by increasing total energy expenditure above and beyond the cost of an exercise bout and reducing the drive to eat when allowed to eat ad libitum (relapse). We hypothesized that exercise’s ability to counter these obesogenic-impetuses are mediated via improvements in skeletal muscle oxidative capacity, and tested this using a mouse model with augmented oxidative capacity in skeletal muscle. METHODS/STUDY POPULATION: We recapitulated the exercise-induced improvements in oxidative capacity using FVB mice that overexpress lipoprotein lipase in skeletal muscle (mLPL). mLPL and wild type (WT) mice were put through a weight-loss-weight-regain paradigm consisting of a high fat diet challenge for 13 weeks, with a subsequent 1-week calorie-restricted medium fat diet to induce a ~15% weight loss. This newly established weight was maintained for 2 weeks and followed with a 24-hour relapse. Metabolic phenotype was characterized by indirect calorimetry during each phase. At the conclusion of the relapse day, mice were sacrificed and tissues were harvested for molecular analysis. RESULTS/ANTICIPATED RESULTS: During weight loss maintenance, mLPL mice had a higher metabolic rate (p=0.0256) that was predominantly evident in the dark cycle (p=0.0015). Furthermore, this increased metabolic rate was not due to differences in activity (p=0.2877) or resting metabolic rate (p=0.4881). During relapse, mLPL mice ingested less calories and were protected from rapid weight regain (p=0.0235), despite WT mice exhibiting higher metabolic rates during the light cycle (p=0.0421). DISCUSSION/SIGNIFICANCE OF IMPACT: These results highlight the importance of muscular oxidative capacity in preventing a depression in total energy expenditure during weight loss maintenance, and in curbing overfeeding and weight regain during a relapse. Moreover, our data suggest that the thermic effect of food is responsible for the differences in metabolic rate, because no differences were found in activity or resting metabolic rate. Additional studies are warranted to determine the molecular mechanisms driving the ability of oxidative capacity to assist with weight loss maintenance.
Previous reports have suggested that bentazon [3-(1-methylethyl)-(1H)-2,1,3-benzothiadiazin-4(3H)-one 2,2-dioxide] tolerance among soybean genotypes is the result of differential translocation or metabolism. The basis for tolerance was reexamined using susceptible and tolerant genotypes. Tolerant genotypes (‘Hill’ and ‘Clark 63’) were found to tolerate 100- to 300-fold more bentazon than susceptible genotypes (‘L78–3263’, ‘Hurrelbrink’, and ‘PI 229.342’). Minor differences in absorption and translocation occurred among the genotypes but they did not correlate with tolerance. Tolerant genotypes metabolized 80 to 90% of absorbed bentazon within 24 h, while susceptible genotypes metabolized only 10 to 15%. Two major metabolites, the glycosyl conjugates of 6- and 8-hydroxybentazon, were formed in tolerant genotypes. Susceptible genotypes did not form the hydroxybentazon conjugates but instead produced relatively low levels of two unidentified metabolites. It is concluded that differential bentazon tolerance among soybean genotypes is linked to the ability to form both the 6- and 8-hydroxybentazon conjugates.
Field studies were conducted at three sites in 1993 and 1994 to evaluate weed control, crop response, and economic returns to 0.5× and 1× postemergence rates of chlorimuron, chlorimuron plus quizalofop, bentazon plus acifluorfen, fluazifop plus fenoxaprop, imazethapyr, and imazethapyr plus clethodim in no-till narrow-row soybean production. Common lambsquarters, ivyleaf morningglory, and common ragweed were controlled equally with 0.5× rates applied early postemergence and 1× rates applied mid-postemergence. Control of giant foxtail, large crabgrass, and common cocklebur was generally greater with 1× rates mid-postemergence than with 0.5× rates early postemergence. Soybean yields were equivalent with 0.5× and 1× rates. Soybean yields and net income were highest with 1× and 0.5× rates of chlorimuron plus quizalofop and imazethapyr plus clethodim, and metolachlor preemergence (PRE) followed by 0.5× bentazon plus acifluorfen.
The objectives of this research were to compare the weed control efficacy of liquid, granular, and microencapsulated formulations of preemergence herbicides in moldboard plow, chisel plow, ridge tillage, and no-tillage corn and soybean production systems, and to determine whether herbicide formulation can influence herbicide interception and retention on surface corn residue. Common lambsquarters populations were threefold higher in corn than in soybeans. A mixed population of giant foxtail and green foxtail was highest in the chisel plow and lowest in the ridge tillage system as were total weed numbers. Percent weed control was not influenced by tillage when considered across all herbicide treatments. Weed control was not influenced by herbicide formulation in the moldboard plow, chisel plow, or ridge tillage systems, but granular herbicide applications provided better weed control than liquid applications in the no-tillage system and across various rates of corn residue in an experiment with no tillage variables. Two- to threefold less granular-applied herbicide was intercepted by surface corn residue at the time of application compared to liquid-applied herbicide. Increasing amounts of postapplication rainfall decreased the difference among formulations with regard to both total soil reception of the herbicide and resultant weed control. There was no consistent advantage for the microencapsulated formulation over the other herbicide formulations. Surface corn residue controlled many weeds without the aid of a herbicide and actually contributed to overall weed control even where herbicides were applied. This suggests that the binding of preemergence herbicides on surface crop residue may not be the cause of weed control failures in reduced-tillage systems as is often assumed to be the case.
The American Heart Association (AHA; Dallas, Texas USA) and European Resuscitation Council (Niel, Belgium) cardiac arrest (CA) guidelines recommend the intraosseous (IO) route when intravenous (IV) access cannot be obtained. Vasopressin has been used as an alternative to epinephrine to treat ventricular fibrillation (VF).
Hypothesis/Problem
Limited data exist on the pharmacokinetics and resuscitative effects of vasopressin administered by the humeral IO (HIO) route for treatment of VF. The purpose of this study was to evaluate the effects of HIO and IV vasopressin, on the occurrence, odds, and time of return of spontaneous circulation (ROSC) and pharmacokinetic measures in a swine model of VF.
Methods
Twenty-seven Yorkshire-cross swine (60 to 80 kg) were assigned randomly to three groups: HIO (n=9), IV (n=9), and a control group (n=9). Ventricular fibrillation was induced and untreated for two minutes. Chest compressions began at two minutes post-arrest and vasopressin (40 U) administered at four minutes post-arrest. Serial blood specimens were collected for four minutes, then the swine were resuscitated until ROSC or 29 post-arrest minutes elapsed.
Results
Fisher’s Exact test determined ROSC was significantly higher in the HIO 5/7 (71.5%) and IV 8/11 (72.7%) groups compared to the control 0/9 (0.0%; P=.001). Odds ratios of ROSC indicated no significant difference between the treatment groups (P=.68) but significant differences between the HIO and control, and the IV and control groups (P=.03 and .01, respectively). Analysis of Variance (ANOVA) indicated the mean time to ROSC for HIO and IV was 621.20 seconds (SD=204.21 seconds) and 554.50 seconds (SD=213.96 seconds), respectively, with no significant difference between the groups (U=11; P=.22). Multivariate Analysis of Variance (MANOVA) revealed the maximum plasma concentration (Cmax) and time to maximum concentration (Tmax) of vasopressin in the HIO and IV groups was 71753.9 pg/mL (SD=26744.58 pg/mL) and 61853.7 pg/mL (SD=22745.04 pg/mL); 111.42 seconds (SD=51.3 seconds) and 114.55 seconds (SD=55.02 seconds), respectively. Repeated measures ANOVA indicated no significant difference in plasma vasopressin concentrations between the treatment groups over four minutes (P=.48).
Conclusions
The HIO route delivered vasopressin effectively in a swine model of VF. Occurrence, time, and odds of ROSC, as well as pharmacokinetic measurements of HIO vasopressin, were comparable to IV.
BurgertJM, JohnsonAD, Garcia-BlancoJ, FultonLV, LoughrenMJ. The Resuscitative and Pharmacokinetic Effects of Humeral Intraosseous Vasopressin in a Swine Model of Ventricular Fibrillation. Prehosp Disaster Med. 2017;32(3):305–310.
Over 175 growers in each of six states (Illinois, Indiana, Iowa, Mississippi, Nebraska, and North Carolina) were surveyed by telephone to assess their perceptions of the benefits of utilizing the glyphosate-resistant (GR) crop trait in corn, cotton, and soybean. The survey was also used to determine the weed management challenges growers were facing after using this trait for a minimum of 4 yr. This survey allowed the development of baseline information on how weed management and crop production practices have changed since the introduction of the trait. It provided useful information on common weed management issues that should be addressed through applied research and extension efforts. The survey also allowed an assessment of the perceived levels of concern among growers about glyphosate resistance in weeds and whether they believed they had experienced glyphosate resistance on their farms. Across the six states surveyed, producers reported 38, 97, and 96% of their corn, cotton, and soybean hectarage planted in a GR cultivar. The most widely adopted GR cropping system was a GR soybean/non-GR crop rotation system; second most common was a GR soybean/GR corn crop rotation system. The non-GR crop component varied widely, with the most common crops being non-GR corn or rice. A large range in farm size for the respondents was observed, with North Carolina having the smallest farms in all three crops. A large majority of corn and soybean growers reported using some type of crop rotation system, whereas very few cotton growers rotated out of cotton. Overall, rotations were much more common in Midwestern states than in Southern states. This is important information as weed scientists assist growers in developing and using best management practices to minimize the development of glyphosate resistance.