Patient-Provider Communication and Colorectal Cancer Screening Completion Using Multi-target Stool DNA Testing.

Colorectal cancer (CRC) screening continues to be underutilized in the USA despite the availability of multiple effective, guideline-recommended screening options. Provider recommendation has been consistently shown to improve screening completion. Understanding how patient-provider communication influences CRC screening can inform interventions to improve screening completion. We developed a behavioral theory-informed survey to identify patient-provider communication factors associated with multi-target stool DNA (mt-sDNA) screening completion. The survey was administered by RTI International between 03/2022 and 06/2022 to a sample of US adults ages 45-75 who received a valid order for mt-sDNA screening with a shipping date between 5/2021 and 9/2021. Respondents completed an electronic or paper survey. Multivariable logistic regression was used to identify patient-provider communication factors associated with mt-sDNA test completion. A total of 2973 participants completed the survey (response rate, 21.7%) and 81.6% of them (n = 2427) reported having had a conversation with provider about mt-sDNA testing before the test was ordered. Having a conversation with the provider about the test, including discussions about costs, the need for follow-up testing and test instructions were associated with higher odds of test completion and being "very likely" to use the test in the future. Lack of discussion about advantages and disadvantages of available CRC screening options and lack of patient involvement in CRC screening decision-making were associated with reduced odds of test completion and likelihood of future use. Healthcare providers play a key role in patient adherence to CRC screening and must be appropriately prepared and resourced to educate and to engage patients in shared decision-making about CRC screening.

On the wrong DNA track: Molecular mechanisms of repeat-mediated genome instability.

Expansions of simple tandem repeats are responsible for almost 50 human diseases, the majority of which are severe, degenerative, and not currently treatable or preventable. In this review, we first describe the molecular mechanisms of repeat-induced toxicity, which is the connecting link between repeat expansions and pathology. We then survey alternative DNA structures that are formed by expandable repeats and review the evidence that formation of these structures is at the core of repeat instability. Next, we describe the consequences of the presence of long structure-forming repeats at the molecular level: somatic and intergenerational instability, fragility, and repeat-induced mutagenesis. We discuss the reasons for gender bias in intergenerational repeat instability and the tissue specificity of somatic repeat instability. We also review the known pathways in which DNA replication, transcription, DNA repair, and chromatin state interact and thereby promote repeat instability. We then discuss possible reasons for the persistence of disease-causing DNA repeats in the genome. We describe evidence suggesting that these repeats are a payoff for the advantages of having abundant simple-sequence repeats for eukaryotic genome function and evolvability. Finally, we discuss two unresolved fundamental questions: (i) why does repeat behavior differ between model systems and human pedigrees, and (ii) can we use current knowledge on repeat instability mechanisms to cure repeat expansion diseases?

Cross-sectional adherence with the multi-target stool DNA test for colorectal cancer screening in a large, nationally insured cohort.

PURPOSE: Colorectal cancer (CRC) is the second most deadly cancer in the USA. Early detection can improve CRC outcomes, but recent national screening rates (62%) remain below the 80% goal set by the National Colorectal Cancer Roundtable. Multiple options are endorsed for average-risk CRC screening, including the multi-target stool DNA (mt-sDNA) test. We evaluated cross-sectional mt-sDNA test completion in a population of commercially and Medicare-insured patients. METHODS: Participants included individuals ages 50 years and older with commercial insurance or Medicare, with a valid mt-sDNA test shipped by Exact Sciences Laboratories LLC between January 1, 2018, and December 31, 2018 (n = 1,420,460). In 2020, we analyzed cross-sectional adherence, as the percent of successfully completed tests within 365 days of shipment date. RESULTS: Overall cross-sectional adherence was 66.8%. Adherence was 72.1% in participants with Traditional Medicare, 69.1% in participants with Medicare Advantage, and 61.9% in participants with commercial insurance. Adherence increased with age: 60.8% for ages 50-64, 71.3% for ages 65-75, and 74.7% for ages 76 + years. Participants with mt-sDNA tests ordered by gastroenterologists had a higher adherence rate (78.3%) than those with orders by primary care clinicians (67.2%). Geographically, adherence rates were highest among highly rural patients (70.8%) and ordering providers in the Pacific region (71.4%). CONCLUSIONS: Data from this large, national sample of insured patients demonstrate high cross-sectional adherence with the mt-sDNA test, supporting its role as an accepted, noninvasive option for average-risk CRC screening. Attributes of mt-sDNA screening, including home-based convenience and accompanying navigation support, likely contributed to high completion rates.

Structural Studies on Porphyrin-PNA Conjugates in Parallel PNA:PNA Duplexes: Effect of Stacking Interactions on Helicity.

Parallel PNA:PNA duplexes were synthesized and conjugated with meso-tris(pyridyl)phenylporphyrin carboxylic acid at the N-terminus. The introduction of one porphyrin unit was shown to affect slightly the stability of the PNA:PNA parallel duplex, whereas the presence of two porphyrin units at the same end resulted in a dramatic increase of the melting temperature, accompanied by hysteresis between melting and cooling curves. The circular dichroism (CD) profile of the Soret band and fluorescence quenching strongly support the occurrence of a face-to-face interaction between the two porphyrin units. Introduction of a L-lysine residue at the C-terminal of one strand of the parallel duplex induced a left-handed helical structure in the PNA:PNA duplex if the latter contains only one or no porphyrin moiety. The left-handed helicity was revealed by nucleobase CD profile at 240-280 nm and by the induced-CD observed in the presence of the DiSC2 (5) cyanine dye at ~500-550 nm. Surprisingly, the presence of two porphyrin units led to the disappearance of the nucleobase CD signal and the absence of CD exciton coupling within the Soret band region. In addition, a dramatic decrease of induced CD of DiSC2 (5) was observed. These results are in agreement with a model where the porphyrin-porphyrin interactions cause partial loss of chirality of the PNA:PNA parallel duplex, forcing it to adopt a ladder-like conformation.

Provider communication contributes to colorectal cancer screening intention through improving screening outcome expectancies and perceived behavioral control.

Colorectal cancer (CRC) screening continues to be underutilized in the US despite the availability of multiple effective, guideline-recommended screening options. Provider recommendation has been consistently shown to improve screening completion. Yet, available literature provides little information as to how specific information providers communicate influence patient decision-making about CRC screening. We tested the pathways through which information communicated by providers about the "Why" and "How" of CRC screening using the mt-sDNA test contributes to intention to complete the test. Data came from a behavioral theory-informed survey that we developed to identify psychosocial factors associated with mt-sDNA screening. RTI International administered the survey between 03/2022-06/2022 to a sample of US adults ages 45-75 who received a valid order for mt-sDNA screening with a shipping date between 5/2021-9/2021. Participants completed an electronic or paper survey. We tested the proposed relationships using structural equation modeling and tested indirect effects using Monte Carlo method. A total of 2,973 participants completed the survey (response rate: 21.7%) and 81.6% (n = 2,427) reported have had a conversation with their health care provider about mt-sDNA screening before the test was ordered. We found that "Why" information from providers was positively associated with perceived effectiveness of mt-sDNA screening, while "How" information was positively associated with perceived ease of use. "Why" information contributed to screening intention through perceived effectiveness while "How" information contributed to screening intention through perceived ease of use. These findings emphasize the critical role of provider communication in shaping patient decision-making regarding CRC screening. CRC screening interventions could consider implementing provider-patient communication strategies focusing on improving patient understanding of the rationale for CRC screening and the effectiveness of available screening options as well as addressing barriers and enhancing patients' self-efficacy in completing their preferred screening option.

Colorectal cancer screening uptake and adherence by modality at a large tertiary care center in the United States: a retrospective analysis.

OBJECTIVE: Real-world data is crucial to inform existing opportunistic colorectal cancer (CRC) prevention programs. This study aimed to assess CRC screening adherence and utilization of various screening modalities within a Primary Care network over a three-year period (2017-2019). METHODS: A retrospective review of individuals aged 50-75 years at average CRC risk, with at least one clinic visit in the previous 24 months. The primary outcome, CRC screening adherence (overall and by modality) was examined among the entire eligible population and newly adherent individuals each calendar year. The final sample included 107,366 patients and 218,878 records. RESULTS: Overall CRC screening adherence increased from 71% in 2017 to 78% in 2019. For "up-to-date" individuals, colonoscopy was the predominant modality (accounting for approximately 74%, versus 4% of adherence for non-invasive options). However, modality utilization trends changed over time in these individuals: mt-sDNA increased 10.2-fold, followed by FIT (1.6-fold) and colonoscopy (1.1-fold). Among newly adherent individuals, the proportion screened by colonoscopy and FOBT decreased over time (89% to 80% and 2.4% to 1.2%, respectively), while uptake of FIT and mt-sDNA increased (7.7% to 11.5% and 0.9% to 6.8%, respectively). Notably, FIT and mt-sDNA increases were most evident in age and race-ethnicity groups with the lowest screening rates. CONCLUSIONS: In an opportunistic CRC screening program, adherence increased but remained below the national 80% goal. While colonoscopy remained the most utilized modality, new colonoscopy uptake declined, compared with rising mt-sDNA and FIT utilization. Among minority populations, new uptake increased most with mt-sDNA and FIT.

Clinical performance of an automated stool DNA assay for detection of colorectal neoplasia.

BACKGROUND & AIMS: Colorectal cancer (CRC) and advanced precancers can be detected noninvasively by analyses of exfoliated DNA markers and hemoglobin in stool. Practical and cost-effective application of a stool DNA-based (sDNA) test for general CRC screening requires high levels of accuracy and high-capacity throughput. We optimized an automated sDNA assay and evaluated its clinical performance. METHODS: In a blinded, multicenter, case-control study, we collected stools from 459 asymptomatic patients before screening or surveillance colonoscopies and from 544 referred patients. Cases included CRC (n = 93), advanced adenoma (AA) (n = 84), or sessile serrated adenoma ≥1 cm (SSA) (n = 30); controls included nonadvanced polyps (n = 155) or no colonic lesions (n = 641). Samples were analyzed by using an automated multi-target sDNA assay to measure ß-actin (a marker of total human DNA), mutant KRAS, aberrantly methylated BMP3 and NDRG4, and fecal hemoglobin. Data were analyzed by a logistic algorithm to categorize patients as positive or negative for advanced colorectal neoplasia (CRC, advanced adenoma, and/or SSA ≥1 cm). RESULTS: At 90% specificity, sDNA analysis identified individuals with CRC with 98% sensitivity. Its sensitivity for stage I cancer was 95%, for stage II cancer it was 100%, for stage III cancer it was 96%, for stage IV cancer it was 100%, and for stages I-III cancers it was 97% (nonsignificant P value). Its sensitivity for advanced precancers (AA and SSA) ≥1 cm was 57%, for >2 cm it was 73%, and for >3 cm it was 83%. The assay detected AA with high-grade dysplasia with 83% sensitivity. CONCLUSIONS: We developed an automated, multi-target sDNA assay that detects CRC and premalignant lesions with levels of accuracy previously demonstrated with a manual process. This automated high-throughput system could be a widely accessible noninvasive approach to general CRC screening.

Comparison of phenotypic and molecular tests to identify lactic acid bacteria.

Twenty-nine lactic acid bacteria (LAB) isolates were submitted for identification using Biolog, API50CHL, 16S rDNA sequencing, and species-specific PCR reactions. The identification results were compared, and it was concluded that a polyphasic approach is necessary for proper LAB identification, being the molecular analyzes the most reliable.

What do 'false-positive' stool tests really mean? Data from the New Hampshire colonoscopy registry.

We utilized the population-based New Hampshire Colonoscopy Registry to calculate false discovery rates (FDR) and positive predictive values (PPVs) using three 'positive' colonoscopy definitions. Understanding the frequency of meaningful 'true positive' mt-sDNA and Fecal Immunochemical Test (FIT) results can optimize the use of these colorectal cancer (CRC) screening tests. We calculated FDR (positive stool test followed by negative colonoscopy divided by all positive stool tests) and PPV for mt-sDNA and FIT cohorts using the following definitions: 1) DeeP-C Study (CRC, adenomas/serrated polyps ≥ 1 cm, villous/High Grade Dysplasia); 2) < 10 year US Multi-Society Task Force (USMSTF) follow-up: DeeP-C findings & ≥1 sessile serrated polyps (SSPs) < 1 cm (with/without dysplasia) or ≥ 1 tubular adenomas < 1 cm. 3) Clinically Significant: DeeP-C + USMSTF + clinically significant serrated polyps: traditional serrated adenomas, SSPs, hyperplastic polyps (HPs) > 1 cm, and 5-9 mm proximal HPs. The sample included 549 mt-sDNA + and 410 FIT + and patients (mean age 66.4, 43.0% male). Using the most limited definition of positive colonoscopy, DeeP-C, FDR was 71.9% for mt-sDNA + and 81.7% for FIT +. Using the USMSTF definition, FDR decreased substantially: mt-sDNA+:33.2% and FIT+:47.6%. Adding all CSSPs resulted in the lowest FDR: mt-sDNA+:32.2% and FIT+:47.1%. Decreasing FDRs corresponded to increasing PPVs: mt-sDNA+:28.1% and FIT+:18.3% (DeeP-C definition) and mt-sDNA+:67.8% and FIT+:52.9% (DeeP-C + USMSTF + CSSP) (Table 1). FDRs decreased substantially when the definition of positive exams included all significant precancerous findings. These data present a comprehensive understanding of false positive outcomes at colonoscopies following positive stool tests, which to our knowledge is the first such analysis.

Diagnostic accuracy of the multi-target stool DNA test in detecting colorectal cancer: A hospital-based study.

BACKGROUND: The multi-target stool DNA test (MT-sDNA) has potential utility in the detection of colorectal cancer (CRC), but validation of its clinical accuracy has been limited in China. AIM: To evaluate the diagnostic performance of MT-sDNA and investigate the combined diagnostic value of alpha-fetoprotein (AFP), carcinoembryonic antigen (CEA), and carbohydrate antigen 199 (CA199) with MT-sDNA in CRC and adenomas. METHODS: We evaluated the performance of the MT-sDNA kit based on a hospital clinical trial. In this case-control study, 135 participants from the Affiliated Hospital of Medical School of Ningbo University, including 51 CRC patients, 23 patients with adenomas, and 61 healthy controls were enrolled. We used a risk scoring system to determine the positivity of tests with histological diagnosis or colonoscopy as the reference standard. RESULTS: The main indices of sensitivity, specificity and accuracy were evaluated. The sensitivity and specificity for CRC detection were 90.2% and 83.3%, respectively, with an accuracy of 89.8%. For adenoma, the sensitivity and specificity were 56.5% and 68.9%, respectively, with an accuracy of 73.1%. The sensitivity and specificity of MT-sDNA combined with CEA in the diagnosis of adenoma were 78.3% and 60.7%, respectively. CONCLUSION: The MT-sDNA test showed better performance in the detection of CRC, which was superior to AFP, CEA, and CA199 separately, but not for predicting adenomas. The combination of MT-sDNA with CEA further improved the sensitivity for adenoma diagnosis.

Exploring the Quantitative Assessment of Spatial Risk in Response to Major Epidemic Disasters in Megacities: A Case Study of Qingdao.

With the global spread of various human-to-human epidemics, public health issues have become a focus of attention. Therefore, it is of great importance to improve the quantitative risk assessment of the construction of resilient cities in terms of epidemic disasters. Starting with the dimensions of social activities and material space, this paper took Qingdao, China, with a population of 5 million, as an example, and took its seven municipal districts as the research scope. In this paper, five risk factors, including the Population density index, Night light index, Closeness index of roads, Betweenness index of roads and Functional mixed nuclear density index were selected for weighted superposition analysis. We conducted a quantitative assessment of the spatial risk of epidemic disaster so as to obtain the classification and spatial structure of the epidemic disaster risk intensity. The results show that: ① The roads with a large traffic flow are most likely to lead to the risk of urban spatial agglomeration, and the areas with a large population density and large mixture of infrastructure functions are also important factors causing the risk of epidemic agglomeration. ② The analysis results regarding the population, commerce, public services, transportation, residence, industry, green space and other functional places can reflect the high-risk areas for epidemic diseases with different natures of transmission. ③ The risk intensity of epidemic disasters is divided into five risk grade areas. Among them, the spatial structure of epidemic disasters, composed of the first-level risk areas, is characterized by "one main area, four secondary areas, one belt and multiple points" and has the characteristics of spatial diffusion. ④ Catering, shopping, life services, hospitals, schools and transportation functional places are more likely to cause crowd gathering. The management of these places should be focused on prevention and control. At the same time, medical facilities should be established at fixed points in all high-risk areas to ensure the full coverage of services. In general, the quantitative assessment of the spatial risk of major epidemic disasters improves the disaster risk assessment system in the construction of resilient cities. It also focuses on risk assessment for public health events. It is helpful to accurately locate the agglomeration risk areas and epidemic transmission paths that are prone to outbreak or cause epidemic transmission in cities so as to assist the relevant practitioners in containing the epidemic from the initial stage of transmission in a timely manner and prevent the further spread of the epidemic.

Clinical evaluation of a multitarget fecal immunochemical test-sDNA test for colorectal cancer screening in a high-risk population: a prospective, multicenter clinical study.

Colorectal cancer (CRC) is a major malignancy threatening the health of people in China and screening could be effective for preventing the occurrence and reducing the mortality of CRC. We conducted a multicenter, prospective clinical study which recruited 4,245 high-risk CRC individuals defined as having positive risk-adapted scores or fecal immunochemical test (FIT) results, to evaluate the clinical performance of the multitarget fecal immunochemical and stool DNA (FIT-sDNA) test for CRC screening. Each participant was asked to provide a stool sample prior to bowel preparation, and FIT-sDNA test and FIT were performed independently of colonoscopy. We found that 186 (4.4%) were confirmed to have CRC, and 375 (8.8%) had advanced precancerous neoplasia among the high CRC risk individuals. The sensitivity of detecting CRC for FIT-sDNA test was 91.9% (95% CI, 86.8-95.3), compared with 62.4% (95% CI, 54.9-69.3) for FIT (P < 0.001). The sensitivity for detecting advanced precancerous neoplasia was 63.5% (95% CI, 58.3-68.3) for FIT-sDNA test, compared with 30.9% (95% CI, 26.3-35.6) for FIT (P < 0.001). Multitarget FIT-sDNA test detected more colorectal advanced neoplasia than FIT. Overall, these findings indicated that in areas with limited colonoscopy resources, FIT-sDNA test could be a promising further risk triaging modality to select patients for colonoscopy in CRC screening.

Healthcare costs, resource utilization, and productivity loss associated with colorectal cancer screening.

OBJECTIVES: To evaluate healthcare costs, resource utilization, associated costs, and lost productivity for colorectal cancer (CRC) screening in an average-risk population. METHODS: This retrospective cohort study identified average-risk individuals (50-75 years) with claims in the Optum Research Database for CRC screening test between 1 January 2014 to 31 December 2018. Index date was defined as the first date of a claim for colonoscopy, fecal immunochemical test (FIT), guaiac-based fecal occult blood test (FOBT) or multi-target stool DNA test (mt-sDNA). Screening costs were evaluated with descriptive statistics and multivariable analyses, adjusting for patient characteristics and index screening costs. RESULTS: In total, 903,831 individuals were identified by test groups: mt-sDNA (n = 29,614), FIT (n = 254,002), guaiac-based FOBT (n = 112,757) and colonoscopy (n = 507,458). Adjusted costs for index screening were, colonoscopy ($3,029), mt-sDNA ($752), FIT ($45), and (FOBT ($153). Adjusted costs across the six months following the index screening were $146 for colonoscopy, $329 for mt-sDNA, $306 for FIT, and $412 for FOBT. Colonoscopy had the highest costs for lost productivity. CONCLUSIONS: Screening colonoscopy had the highest productivity loss and healthcare costs up-front, suggesting potential cost benefits for noninvasive screening modalities. The more frequent screening interval required for FIT and FOBT resulted in a higher yearly cost than colonoscopy or mt-sDNA.

Colorectal cancer (CRC) is a prominent healthcare concern the United States, which accounted for 149,500 new cases and 52,980 deaths in 2021. Screening is effective for diagnosing the condition at earlier more treatable stages, and reducing deaths. However, screening is largely underutilized in part due to perceived cost barriers. This observational study used insurance claims data to calculate healthcare costs, resource use, and lost productivity for CRC screening in an average-risk population aged 50­75 years. A total of 903,831 individuals were identified by test groups: multi-target stool DNA test (mt-sDNA test; 29,614 individuals), fecal immunochemical test (FIT; 254,002 individuals), guaiac-based fecal occult blood test (FOBT; 112,757 individuals) and colonoscopy (507,458 individuals). Adjusted costs for initial screening were $3,029 for colonoscopy, $752 for mt-sDNA, $45 for FIT, and $153 for FOBT. Adjusted colonoscopy-related costs combined across the six months following the initial screening were $146 for the colonoscopy cohort, $329 for mt-sDNA, $306 for FIT, and $412 for FOBT. Colonoscopy had the highest costs for lost productivity. Overall, screening colonoscopy was accompanied by the highest productivity loss and up-front costs, suggesting potential cost benefits for noninvasive screening modalities ­ mt-sDNA, FIT, and FOBT; however, the more frequent screening interval required by FIT and FOBT resulted in a higher estimated average yearly screening cost.

Attitudes and Experiential Factors Associated with Completion of mt-sDNA Test Kit for Colorectal Cancer Screening.

Colorectal cancer (CRC) is the third leading cause of cancer-related deaths in the United States. Despite the availability of multiple screening options, CRC screening is underutilized. We conducted a survey of patients (n = 2973) who were prescribed the multi-target stool DNA (mt-sDNA) screening test (commercialized as Cologuard® and manufactured by Exact Sciences Corporation) to understand attitudes and experiences that influence test completion and likelihood of future test completion. Using exploratory factor analyses, we developed three scales: Perceived Effectiveness, Perceived Ease of Use, and Perceived Comfort.

Inappropriate Multi-Target Stool DNA Use for Colorectal Cancer Screening: Risks, Compliance, and Outcomes.

Background Inappropriate or "off-label" use of multi-target stool DNA (mt-sDNA) tests refers to their use in patients for whom colonoscopy or no testing at all is warranted. Examples include a positive family history of colorectal cancer, a history of inflammatory bowel disease, or medical issues necessitating diagnostic colonoscopy, among others. Current understanding of off-label mt-sDNA use for colorectal cancer screening, its associated risks, and outcomes is lacking. We examined off-label mt-sDNA prescription and compliance with testing in an outpatient setting in southeast Michigan. Aims The primary aims of the study were determining the extent of off-label mt-sDNA testing and compliance, and results of all testing, as well as demographic factors associated with off-label prescriptions. The secondary aims were to examine explanations for incomplete testing and factors contributing to successful completion. Methods Using a retrospective design, we identified mt-sDNA orders from outpatient internal medicine clinics between January 1, 2018, to July 31, 2019, to evaluate the proportion of off-label mt-sDNA, results of testing, and follow-up colonoscopies up to one year after order placement. Patients were categorized as "off-label" if any inappropriate criteria were met. Statistical analysis was performed for primary and secondary outcomes. Results From 679 mt-sDNA orders within the study period, 81 (12.1%) had at least one off-label criterion for testing. In total, 404/679 (59.5%) patients completed testing. Lack of follow-up comprised the majority of incompletions (216/275; 78.6%). Only 52 (70.3%) out of 74 positive results were followed by diagnostic colonoscopy. Retired employment status (OR = 1.87; 95%CI, 1.17-2.98; P = 0.008) and age of 76 years or older (OR = 2.28; 95%CI, 0.99-5.21; P = 0.044) were significantly associated with increased risk of off-label mt-sDNA prescription. Increasing age range was associated with higher test completion (χ2 (5) = 12.085, p = 0.034). Multinomial logistic regression revealed an increasing age range (OR = 1.29; 95% CI, 1.09-1.54; P = 0.004), predictive of a positive mt-sDNA result for both groups. There was no significant difference between off-label or on-label groups in the mean number of resected polyps or pathology scores on follow-up colonoscopy. Conclusions Off-label mt-sDNA use remains a concern in the outpatient setting. Compliance for test completion and follow-up colonoscopy for positive results require further improvement. Our findings shed new light on the factors associated with off-label testing while reiterating its burden. We also describe common reasons for incomplete tests in an attempt to augment future colorectal cancer (CRC) screening initiatives.

Noninvasive fecal testing for colorectal cancer.

INTRODUCTION: Colorectal cancer (CRC) is the third most common malignancy worldwide, with the second highest mortality rate among all malignancies. In this review, we describe the current utility of stool diagnostic biomarkers for CRC. METHODS: We reviewed stool-related tests and biomarker candidates for the diagnosis of CRC. The guaiac-based fecal occult blood test (gFOBT), fecal immunochemical test (FIT), and multitarget stool DNA test (MT-sDNA) have been used as clinical CRC screening tools. Although microRNAs, protein biomarkers, and microbiota have not yet been used in clinical CRC screening, there is growing evidence that they have the potential to function as CRC screening tools. RESULTS: According to the literature, the sensitivity of MT-sDNA for detecting CRC was 87.0-100%, 32.7-82.0% for advanced adenomas, and the specificity was 86.1-95.2%. The sensitivity of individual biomarkers of fecal microRNAs for detecting CRC was 34.2-88.2%, 73.0% for advanced adenomas, and the specificity was 68-100%. The sensitivity of fecal protein markers for detecting CRC was 63.6-93.0%, 47.7-69.4% for advanced adenomas, and the specificity was 38.3-97.5%. The sensitivity of fecal microbiota for detecting CRC was 54.0-100.0%, 32.0-48.3% for advanced adenomas, and the specificity was 61.3-90.0%. CONCLUSION: MT-sDNA is the most sensitive CRC screening test, and its sensitivity is the highest for advanced adenomas; however, its detection cost is high. MT-sDNA was more sensitive to CRC and advanced precancerous lesions than FIT, but compared to three years of MT-sDNA, annual FIT as the first non-invasive screening test for CRC seemed to be more effective.

Cross-sectional adherence with the multi-target stool DNA test for colorectal cancer screening in a medicaid population.

Colorectal cancer (CRC) is the third leading cause of cancer death in the US. Early detection improves CRC outcomes and multiple options are endorsed for CRC screening; however, adherence remains challenging. Among Medicaid enrollees, the fecal immunochemical test (FIT) is often used for average-risk CRC screening, with suboptimal adherence rates reported (12.3-23.2 %). The navigation-supported (personalized outreach by phone, mail, email and text), at home collection, multi-target stool DNA (mt-sDNA) test represents a relatively recent and broadly accessible option for average-risk CRC screening in Medicaid enrollees. We assessed cross-sectional mt-sDNA adherence in a national sample of Medicaid patients. Data from Exact Sciences Laboratories LLC (ESL; Madison, WI) were retrospectively analyzed. Participants included individuals 45 + years covered by Fee-For-Service (FFS)- or Managed-Medicaid. Primary analysis focused on the 50-74 age cohort and included those with valid mt-sDNA orders between January 1-December 31, 2018. Data from 25,794 individuals who received valid orders for mt-sDNA were included in analysis (61.2 % women; mean age at order 57.5 years). Overall adherence - completion of an ordered test - was 51.3 %. Adherence was 54.6 % in Managed-Medicaid and 38.9 % in FFS-Medicaid. Adherence by age was: 51.5 % for 50-64 years and 47.7 % for 65-74 years. Mt-sDNA tests ordered by gastroenterologists had higher adherence (60.5 %) compared with primary care clinicians (51.3 %). These data from a large, national sample of Medicaid-insured patients substantiate mt-sDNA testing as a viable patient-supported, home-based option to improve average-risk CRC screening participation in Medicaid enrollees.

Understanding protein diffusion on force-induced stretched DNA conformation.

DNA morphology is subjected to environmental conditions and is closely coupled with its function. For example, DNA experiences stretching forces during several biological processes, including transcription and genome transactions, that significantly alter its conformation from that of B-DNA. Indeed, a well-defined 1.5 times extended conformation of dsDNA, known as Σ-DNA, has been reported in DNA complexes with proteins such as Rad51 and RecA. A striking feature in Σ-DNA is that the nucleobases are partitioned into triplets of three locally stacked bases separated by an empty rise gap of ∼ 5 Å. The functional role of such a DNA base triplet was hypothesized to be coupled with the ease of recognition of DNA bases by DNA-binding proteins (DBPs) and the physical origin of three letters (codon/anti-codon) in the genetic code. However, the underlying mechanism of base-triplet formation and the ease of DNA base-pair recognition by DBPs remain elusive. To investigate, here, we study the diffusion of a protein on a force-induced stretched DNA using coarse-grained molecular dynamics simulations. Upon pulling at the 3' end of DNA by constant forces, DNA exhibits a conformational transition from B-DNA to a ladder-like S-DNA conformation via Σ-DNA intermediate. The resulting stretched DNA conformations exhibit non-uniform base-pair clusters such as doublets, triplets, and quadruplets, of which triplets are energetically more stable than others. We find that protein favors the triplet formation compared to its unbound form while interacting non-specifically along DNA, and the relative population of it governs the ruggedness of the protein-DNA binding energy landscape and enhances the efficiency of DNA base recognition. Furthermore, we analyze the translocation mechanism of a DBP under different force regimes and underscore the significance of triplet formation in regulating the facilitated diffusion of protein on DNA. Our study, thus, provides a plausible framework for understanding the structure-function relationship between triplet formation and base recognition by a DBP and helps to understand gene regulation in complex regulatory processes.

Genetic Profiling of Cell-Free DNA From Pleural Effusion in Advanced Lung Cancer as a Surrogate for Tumor Tissue and Revealed Additional Clinical Actionable Targets.

BACKGROUND: Pleural effusion (PE) has been one of the promising sources of liquid biopsy in advanced lung cancer patients. However, its clinical utility is not widely accepted due to the lack of full estimation of its potential versus routine clinical samples. METHOD: A total of 164 advanced lung cancer patients were enrolled with 164 matched tumor tissue and PE-cfDNA, 153 accompanied plasma and 63 1PE-sDNA. RESULT: PE-cfDNA displayed significantly higher median mutant allele frequency and an overall mutation concordance rate of 65% to tissue, which was higher than PE-sDNA (43%) and plasma-cfDNA (43%). The discrepancies between PE-cfDNA and tumor tissue were high in several genes, including SMARCA4, PIK3CA, ERBB2, KM T2A, ALK and NF1. For clinically actionable mutations, the concordance rate between PE-cfDNA and tumor tissue is 87%. Eleven patients were identified with actionable mutations in PE-cfDNA and four patients benefited from PE-cfDNA-guided targeted. Meanwhile, PE-cfDNA recapitulated mutations of diverse tissue origins and provided more mutational information under the circumstance that tumor tissue or tumor tissue of different origins were unavailable. The combination of tumor tissue and PE-cfDNA profiling increased positive detection rates of patients compared to tumor tissue alone. Our finding highlighted the importance of PE-cfDNA in the optimal selection of patients for targeted therapy. CONCLUSION: The PE-cfDNA-based liquid biopsy displays better performance in the characterization of gene alterations than PE-sDNA and plasma-cfDNA. PE-cfDNA together with tumor tissue profiling optimizes comprehensively genomic profiling of lung cancer patients, which might be important for selecting patients for better treatment management.

Life-years gained resulting from screening colonoscopy compared with follow-up colonoscopy after a positive stool-based colorectal screening test.

Screening colonoscopies for colorectal cancer (CRC) are typically covered without patient cost-sharing, whereas follow-up colonoscopies for positive stool-based screening tests often incur patient costs. The objective of this analysis was to estimate and compare the life-years gained (LYG) per average-risk screening colonoscopy and follow-up colonoscopy after a positive stool-based test to better inform CRC coverage policy and reimbursement decisions. CRC outcomes from screening and follow-up colonoscopies versus no screening were estimated using CRC-AIM in a simulated population of average-risk individuals screened between ages 45-75 years. The LYG/colonoscopy per 1000 individuals was 0.09 for screening colonoscopy and 0.29 for follow-up colonoscopy. 0.01 and 0.04 CRC cases and 0.01 and 0.02 CRC deaths were averted per screening and follow-up colonoscopies, respectively. Coverage policies should be revised to encourage individuals to complete recommended screening processes.