Clinical and Genomic Characterization of Interval Colorectal Cancer in 3 Prospective Cohorts.

BACKGROUND & AIMS: Interval colorectal cancers (CRCs), cancers diagnosed after a screening/surveillance examination in which no cancer is detected, and before the date of next recommended examination, reflect an unprecedented challenge in CRC detection and prevention. To better understand this poorly characterized CRC variant, we examined the clinical and mutational characteristics of interval CRCs in comparison with screen detected CRCs. METHODS: We included 1175 CRCs documented in the Prostate, Lung, Colorectal, and Ovarian (PLCO) cancer screening trial and 3661 CRCs in the Nurses' Health Study (NHS) and Health Professionals Follow-up Study (HPFS). Multivariable Cox models were performed to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of death risk. Whole exome sequencing was conducted in 147 PLCO cases and 796 NHS/HPFS cases. RESULTS: A total of 619 deaths (312 CRC-specific) and 2404 deaths (1904 CRC-specific) were confirmed during follow-up of PLCO and NHS/HPFS, respectively. Compared with screen detected CRCs, interval CRCs had a multivariate-adjusted HR (95% CI) of 1.47 (1.21-1.78) for CRC-specific mortality and 1.27 (1.09-1.47) for overall mortality (meta-analysis combining all 3 cohorts). However, we did not observe significant differences in mutational features between interval and screen detected CRCs (false discovery rate adjusted P > .05). CONCLUSION: Interval CRCs had a significantly increased risk of death compared with screen detected CRCs that were not explained by established clinical prognostic factors, including stage at diagnosis. The survival disadvantage of interval CRCs did not appear to be explained by differences in the genomic landscape of tumors characterized by whole exome sequencing.

The Effect of Hydrogenation on the Contest between Aromaticity and Antiaromaticity in Norcorrole.

Magnetic shielding studies demonstrate that successive hydrogenation of NiII norcorrole (NiNc), a stable molecule combining aromatic and antiaromatic features, first weakens and then eliminates the central antiaromatic region, even though the NiNc antiaromatic "core", a 14-membered conjugated cycle with 16 π electrons, is formally preserved throughout the H2 NiNc-H8 NiNc series. The differences between aromatic and non-aromatic isotropic shielding distributions and nucleus-independent chemical shift (NICS) values in these hydrogenated porphyrin analogues are highlighted by comparing the results for the members of the H2 NiNc-H8 NiNc series to those for the aromatic NiII porphyrin complex. The results strongly support the unexpected and counterintuitive conclusion that H8 NiNc will be nonaromatic, without even a trace of antiaromaticity. Based on these findings, H8 NiNc is predicted to be the most stable member of the H2 NiNc-H8 NiNc series.

"Getting better at getting better": How Sharing Mental Health Stories Can Shape Young People's Wellbeing.

Sharing lived-experience of mental ill-health is increasingly recognised as a promising youth mental health intervention. batyr is a preventative mental health organization that trains young people to share their story of mental ill-health safely through a speaker development program. This qualitative study aimed to understand how the role of batyr speakers shapes individual wellbeing, help-seeking behaviour, and stigma as well as how young people talk about mental health within their social circles. Data was collected using in-depth semi-structured interviews with 18 batyr speakers (age 18-35 years). Thematic analysis revealed five themes: Getting better at getting better, Growing towards self-acceptance, Breaking the wall by talking about mental health, Increasing connectedness and Reaching out for support. The participants reported overall improved wellbeing, as a result of increased confidence, greater self-awareness, and an increased ability to talk safely about their mental illness. Findings suggested that the program led to a reduction of self-stigma and stigma.

Identification of large cryptic plasmids in Clostridioides (Clostridium) difficile.

Clostridioides (Clostridium) difficile is a major bacterial pathogen of both humans and animals. Several species of pathogenic clostridia are known to harbour large plasmids with combinations of virulence, antibiotic resistance and metabolism determinants. Small cryptic plasmids have been previously identified in C. difficile, but there is a lack of recent work examining the prevalence and heterogeneity of plasmids in this diverse bacterial species. A survey of clinical and historical isolates of C. difficile showed that several strains carry large plasmids. Following whole-genome sequencing of these diverse strains, 42-47 kb plasmids with high nucleotide identity were found to be carried in 4.9% (n = 451) of isolates, with no firm connection to the strain backgrounds. These plasmids appear to have arisen as a result of recombination with a bacteriophage, but contain key plasmid features, such as a putative plasmid replication and partitioning locus. As no virulence factors or antibiotic resistance determinants were identified, further work is required to identify the selective advantage that must exist for the host isolates to maintain these large plasmids.

Data sharing in clinical trials: An experience with two large cancer screening trials.

Paul Pinsky of the US National Cancer Institute and colleagues describe the implementation and outcomes of web-based data sharing from the PLCO and NLST cancer screening trials.

Targeting of low-dose CT screening according to the risk of lung-cancer death.

BACKGROUND: In the National Lung Screening Trial (NLST), screening with low-dose computed tomography (CT) resulted in a 20% reduction in lung-cancer mortality among participants between the ages of 55 and 74 years with a minimum of 30 pack-years of smoking and no more than 15 years since quitting. It is not known whether the benefits and potential harms of such screening vary according to lung-cancer risk. METHODS: We assessed the variation in efficacy, the number of false positive results, and the number of lung-cancer deaths prevented among 26,604 participants in the NLST who underwent low-dose CT screening, as compared with the 26,554 participants who underwent chest radiography, according to the quintile of 5-year risk of lung-cancer death (ranging from 0.15 to 0.55% in the lowest-risk group [quintile 1] to more than 2.00% in the highest-risk group [quintile 5]). RESULTS: The number of lung-cancer deaths per 10,000 person-years that were prevented in the CT-screening group, as compared with the radiography group, increased according to risk quintile (0.2 in quintile 1, 3.5 in quintile 2, 5.1 in quintile 3, 11.0 in quintile 4, and 12.0 in quintile 5; P=0.01 for trend). Across risk quintiles, there were significant decreasing trends in the number of participants with false positive results per screening-prevented lung-cancer death (1648 in quintile 1, 181 in quintile 2, 147 in quintile 3, 64 in quintile 4, and 65 in quintile 5). The 60% of participants at highest risk for lung-cancer death (quintiles 3 through 5) accounted for 88% of the screening-prevented lung-cancer deaths and for 64% of participants with false positive results. The 20% of participants at lowest risk (quintile 1) accounted for only 1% of prevented lung-cancer deaths. CONCLUSIONS: Screening with low-dose CT prevented the greatest number of deaths from lung cancer among participants who were at highest risk and prevented very few deaths among those at lowest risk. These findings provide empirical support for risk-based targeting of smokers for such screening. (Funded by the National Cancer Institute.).

Selection criteria for lung-cancer screening.

BACKGROUND: The National Lung Screening Trial (NLST) used risk factors for lung cancer (e.g., ≥30 pack-years of smoking and <15 years since quitting) as selection criteria for lung-cancer screening. Use of an accurate model that incorporates additional risk factors to select persons for screening may identify more persons who have lung cancer or in whom lung cancer will develop. METHODS: We modified the 2011 lung-cancer risk-prediction model from our Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial to ensure applicability to NLST data; risk was the probability of a diagnosis of lung cancer during the 6-year study period. We developed and validated the model (PLCO(M2012)) with data from the 80,375 persons in the PLCO control and intervention groups who had ever smoked. Discrimination (area under the receiver-operating-characteristic curve [AUC]) and calibration were assessed. In the validation data set, 14,144 of 37,332 persons (37.9%) met NLST criteria. For comparison, 14,144 highest-risk persons were considered positive (eligible for screening) according to PLCO(M2012) criteria. We compared the accuracy of PLCO(M2012) criteria with NLST criteria to detect lung cancer. Cox models were used to evaluate whether the reduction in mortality among 53,202 persons undergoing low-dose computed tomographic screening in the NLST differed according to risk. RESULTS: The AUC was 0.803 in the development data set and 0.797 in the validation data set. As compared with NLST criteria, PLCO(M2012) criteria had improved sensitivity (83.0% vs. 71.1%, P<0.001) and positive predictive value (4.0% vs. 3.4%, P=0.01), without loss of specificity (62.9% and. 62.7%, respectively; P=0.54); 41.3% fewer lung cancers were missed. The NLST screening effect did not vary according to PLCO(M2012) risk (P=0.61 for interaction). CONCLUSIONS: The use of the PLCO(M2012) model was more sensitive than the NLST criteria for lung-cancer detection.

Non-compliance with the initial screening exam visit in the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial.

OBJECTIVE: Identify predictors of non-compliance with first round screening exams in the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. METHOD: The PLCO was conducted from 1993 to 2011 at 10 US institutions. A total of 154,897 healthy men and women ages 55-74 years were randomized. Intervention arm participants were invited to receive gender-appropriate screening exams for prostate, lung, colorectal and ovarian cancer. Using intervention-arm data (73,036 participants), non-compliance percentages for 13 covariates were calculated, as were unadjusted and adjusted odds ratios (ORs), and 95% confidence intervals. Covariates included demographic factors as well as factors specific to PLCO (e.g., method of consent, distance from screening center). RESULTS: The rate of non-compliance was 11% overall but varied by screening center. Significant associations were observed for most covariates but indicated modest increases or decreases in odds. An exception was the use of a two-step consent process (consented intervention arm participants for exams after randomization) relative to a one-step process (consented all participants prior to randomization) (OR: 2.2, 95% CI: 2.0-2.5). Non-compliance percentages increased with further distance from screening centers, but ORs were not significantly different from 1. CONCLUSIONS: Many factors modestly influenced compliance. Consent process was the strongest predictor of compliance.

Implications for sequencing of biologic therapy and choice of second anti-TNF in patients with inflammatory bowel disease: results from the IMmunogenicity to Second Anti-TNF therapy (IMSAT) therapeutic drug monitoring study.

BACKGROUND: Anti-drug antibodies are associated with treatment failure to anti-TNF agents in patients with inflammatory bowel disease (IBD). AIM: To assess whether immunogenicity to a patient's first anti-TNF agent would be associated with immunogenicity to the second, irrespective of drug sequence METHODS: We conducted a UK-wide, multicentre, retrospective cohort study to report rates of immunogenicity and treatment failure of second anti-TNF therapies in 1058 patients with IBD who underwent therapeutic drug monitoring for both infliximab and adalimumab. The primary outcome was immunogenicity to the second anti-TNF agent, defined at any timepoint as an anti-TNF antibody concentration ≥9 AU/ml for infliximab and ≥6 AU/ml for adalimumab. RESULTS: In patients treated with infliximab and then adalimumab, those who developed antibodies to infliximab were more likely to develop antibodies to adalimumab, than patients who did not develop antibodies to infliximab (OR 1.99, 95%CI 1.27-3.20, p = 0.002). Similarly, in patients treated with adalimumab and then infliximab, immunogenicity to adalimumab was associated with subsequent immunogenicity to infliximab (OR 2.63, 95%CI 1.46-4.80, p < 0.001). For each 10-fold increase in anti-infliximab and anti-adalimumab antibody concentration, the odds of subsequently developing antibodies to adalimumab and infliximab increased by 1.73 (95% CI 1.38-2.17, p < 0.001) and 1.99 (95%CI 1.34-2.99, p < 0.001), respectively. Patients who developed immunogenicity with undetectable drug levels to infliximab were more likely to develop immunogenicity with undetectable drug levels to adalimumab (OR 2.37, 95% CI 1.39-4.19, p < 0.001). Commencing an immunomodulator at the time of switching to the second anti-TNF was associated with improved drug persistence in patients with immunogenic, but not pharmacodynamic failure. CONCLUSION: Irrespective of drug sequence, immunogenicity to the first anti-TNF agent was associated with immunogenicity to the second, which was mitigated by the introduction of an immunomodulator in patients with immunogenic, but not pharmacodynamic treatment failure.

Dedicated service improves the accuracy of Barrett's oesophagus surveillance: a prospective comparative cohort study.

OBJECTIVES: Standards for Barrett's oesophagus (BO) surveillance in the UK are outlined in the British Society of Gastroenterology (BSG) guidelines. This study aimed to assess the quality of current surveillance delivery compared with a dedicated service. DESIGN: All patients undergoing BO surveillance between January 2016 and July 2017 at a single National Health Service district general hospital were included. Patients had their endoscopy routed to a dedicated BO endoscopy list or a generic service list. Prospective data were analysed against the BSG guidelines and also compared with each patient's prior surveillance endoscopy. RESULTS: 361 patients were scheduled for surveillance of which 217 attended the dedicated list, 78 attended the non-dedicated list and 66 did not have their endoscopy. The dedicated list adhered more closely to the BSG guidelines when compared with the non-dedicated and prior endoscopy, respectively; Prague classification (100% vs 87.3% vs 82.5%, p<0.0001), hiatus hernia delineation (100% vs 64.8% vs 63.3%, p<0.0001), location and number of biopsies recorded (99.5% vs 5.6% vs 6.9%, p<0.0001), Seattle protocol adherence (72% vs 42% vs 50%, p<0.0001) and surveillance interval adherence (dedicated 100% vs prior endoscopy 75%, p<0.0001). Histology results from the dedicated and non-dedicated list cohorts revealed similar rates of intestinal metaplasia (79.8% vs 73.1%, p=0.12) and dysplasia/oesophageal adenocarcinoma (4.3% vs 2.6%, p=0.41). CONCLUSIONS: The post-BSG guideline era of BO surveillance remains suboptimal in this UK hospital setting. A dedicated service appears to improve the accuracy and consistency of surveillance care, although the clinical significance of this remains to be determined.

Data Processing and Analytic Support in the PLCO Cancer Screening Trial.

The Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial was a large, randomized controlled trial of cancer screening that also evolved over time into a unique epidemiologic cohort. Vast quantities of data have been collected since the beginning of the trial in 1993. Screening data was obtained through 2006. Questionnaire-based risk factor data (collected at baseline and at other points in the trial), vital status, cancer diagnoses and treatment, biospecimen data and additional ancillary efforts continue to be collected. Accurate data collection and efficient management methods are required to ensure high-quality data and valid and consistent analyses of trial outcomes. Information Management Services (IMS) was and continues to be responsible for processing and converting the collected raw PLCO data into comprehensive and accessible datasets. IMS also continues to provide a wide spectrum of analytic support including support for trial monitoring, data sharing, and epidemiologic research. In this paper, we describe the data processing and management requirements from the analytic team perspective, highlighting the various data sources and their complexity. We also illustrate the construction of usable analytic data files and discuss the wide range of analytic support provided. Instructions for accessing PLCO data also are provided.

Managing Multi-Center Recruitment in the PLCO Cancer Screening Trial.

There were significant recruitment challenges specific to the PLCO Cancer Screening Trial. Large numbers of participants were to be randomized from ten catchment areas nationwide within time and budgetary constraints. The eligible population was elderly and had to meet health and behavioral thresholds. Informed consent was required to participate and be randomized to screening for three cancers at periodic clinic visits or to a usual care arm that included no clinical visits. Consenting required special efforts to fully explain the trial and its potential scientific benefit to future patients with potentially no benefits but possible harms to PLCO participants. Participation would include continued follow-up for at least 13 years after randomization. Strong collaborative investments were required by the NCI and screening centers (SCs) to assure timely recruitment and appropriate racial participation. A trial-wide pilot phase tested recruitment and protocol follow through at SCs and produced a vanguard population of 11,406 participants. NCI announced the trial nationally in advance of the pilot and followed with an even more intense collaborative role with SCs for the main phase to facilitate trial-wide efficient and timely recruitment. Special efforts to enhance recruitment in the main phase included centralized and local monitoring of progress, cross-linking SCs to share experiences in problem solving, centralized training, substantial additional funding dedicated to recruitment and retention, including specialized programs for minority recruitment, obtaining national endorsement by the American Cancer Society, launching satellite recruitment and screening centers, including minority focused satellites, and adding a new SC dedicated to minority recruitment.

PLCO: Evolution of an Epidemiologic Resource and Opportunities for Future Studies.

The Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO), a large-scale, multi-institutional, randomized controlled trial, was launched in 1992 to evaluate the effectiveness of screening modalities for prostate, lung, colorectal, and ovarian cancer. However, PLCO was additionally designed to serve as an epidemiologic resource and the National Cancer Institute has invested substantial resources over the years to accomplish this goal. In this report, we provide a summary of changes to PLCO's follow-up after conclusion of the screening phase of the trial and highlight recent data and biospecimen collections, including ancillary studies, geocoding, administration of a new medication use questionnaire, consent for linkage to Medicare, and additional tissue collection that enhance the richness of the PLCO resource and provide further opportunities for scientific investigation into the prevention, early detection, etiology and treatment of cancer.

Diagnostic evaluation following a positive lung screening chest radiograph in the Prostate, Lung, Colorectal, Ovarian (PLCO) Cancer Screening Trial.

Lung cancer is the major cause of cancer mortality. One of the aims of the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO) was to determine if annual screening chest radiographs reduce lung cancer mortality. We enrolled 154,900 individuals, aged 55-74 years; 77,445 were randomized to the intervention arm and received an annual chest radiograph for 3 or 4 years. Participants with a positive screen underwent diagnostic evaluation under guidance of their primary physician. Methods of diagnosis or exclusion of cancer, interval from screen to diagnosis, and factors predicting diagnostic testing were evaluated. One or more positive screens occurred in 17% of participants. Positive screens resulted in biopsy in 3%, with 54% positive for cancer. Biopsy likelihood was associated with a mass, smoking, age, and family history of lung cancer. Diagnostic testing stopped after a chest radiograph or computed tomography/magnetic resonance imaging in over half. After a second or subsequent positive screen, evaluation stopped after comparison to prior radiographs in over half. Of 308 screen-detected cancers, the diagnosis was established by thoracotomy/thoracoscopy in 47.7%, needle biopsy in 27.6%, bronchoscopy in 20.1% and mediastinoscopy in 2.9%. Eighty-four percent of screen-detected lung cancers were diagnosed within 6 months. Diagnostic evaluations following a positive screen were conducted in a timely fashion. Lung cancer was diagnosed by tissue biopsy or cytology in all cases. Lung cancer was excluded during evaluation of positive screening examinations by clinical or radiographic evaluation in all but 1.4% who required a tissue biopsy.

Emergence and global spread of epidemic healthcare-associated Clostridium difficile.

Epidemic C. difficile (027/BI/NAP1) has rapidly emerged in the past decade as the leading cause of antibiotic-associated diarrhea worldwide. However, the key events in evolutionary history leading to its emergence and the subsequent patterns of global spread remain unknown. Here, we define the global population structure of C. difficile 027/BI/NAP1 using whole-genome sequencing and phylogenetic analysis. We show that two distinct epidemic lineages, FQR1 and FQR2, not one as previously thought, emerged in North America within a relatively short period after acquiring the same fluoroquinolone resistance-conferring mutation and a highly related conjugative transposon. The two epidemic lineages showed distinct patterns of global spread, and the FQR2 lineage spread more widely, leading to healthcare-associated outbreaks in the UK, continental Europe and Australia. Our analysis identifies key genetic changes linked to the rapid transcontinental dissemination of epidemic C. difficile 027/BI/NAP1 and highlights the routes by which it spreads through the global healthcare system.

FlyMine: an integrated database for Drosophila and Anopheles genomics.

FlyMine is a data warehouse that addresses one of the important challenges of modern biology: how to integrate and make use of the diversity and volume of current biological data. Its main focus is genomic and proteomics data for Drosophila and other insects. It provides web access to integrated data at a number of different levels, from simple browsing to construction of complex queries, which can be executed on either single items or lists.