Considerations for using potential surrogate endpoints in cancer screening trials.

The requirement of large-scale expensive cancer screening trials spanning decades creates considerable barriers to the development, commercialisation, and implementation of novel screening tests. One way to address these problems is to use surrogate endpoints for the ultimate endpoint of interest, cancer mortality, at an earlier timepoint. This Review aims to highlight the issues underlying the choice and use of surrogate endpoints for cancer screening trials, to propose criteria for when and how we might use such endpoints, and to suggest possible candidates. We present the current landscape and challenges, and discuss lessons and shortcomings from the therapeutic trial setting. It is hugely challenging to validate a surrogate endpoint, even with carefully designed clinical studies. Nevertheless, we consider whether there are candidates that might satisfy the requirements defined by research and regulatory bodies.

Battle of the sections: Student outcomes and course feedback support combined prosection and dissection laboratory formats to maximize student success.

Gross anatomy laboratories frequently utilize dissection or prosection formats within medical curricula. Practical examination scores are consistent across the formats, yet these examinations assessed larger anatomical structures. In contrast, a single report noted improved scores when prosection was used in the hand and foot regions, areas that are more difficult to dissect. The incorporation of prosected donors within "Head and Neck" laboratories provided an opportunity to further characterize the impact of prosection in a structurally complex area. Retrospective analysis of 21 Head and Neck practical examination questions was completed to compare scores among cohorts that utilized dissection exclusively or incorporated prosection. Mean scores of practical examination questions were significantly higher in the prosection cohort (84.27% ± 12.69) as compared with the dissection cohort (75.59% ± 12.27) (p < 0.001). Of the 12 questions that performed better in the prosection cohort (88.42% ± 8.21), 10 items mapped to deeper anatomical regions. By comparison, eight of nine questions in the dissection cohort outperformed (88.44% ± 3.34) the prosection cohort (71.74% ± 18.11), and mapped to anatomically superficial regions. Despite the mean score increase with positional location of the questions, this effect was not statically significant across cohorts (p = 1.000), suggesting that structure accessibility in anatomically complex regions impacts performance. Student feedback cited structure preservation (71.5%) and time savings (55.8%) as advantages to prosection; however, dissection was the perceived superior and preferred laboratory format (88.6%). These data support combined prosection and dissection formats for improving student recognition of deeply positioned structures and maximizing student success.

Increased expression of long non-coding RNA FIRRE promotes hepatocellular carcinoma by HuR-CyclinD1 axis signaling.

There is a critical need to understand the disease processes and identify improved therapeutic strategies for hepatocellular carcinoma (HCC). The long noncoding RNAs (lncRNAs) display diverse effects on biological regulations. The aim of this study was to identify a lncRNA as a potential biomarker of HCC and investigate the mechanisms by which the lncRNA promotes HCC progression using human cell lines and in vivo. Using RNA-Seq analysis, we found that lncRNA FIRRE was significantly upregulated in hepatitis C virus (HCV) associated liver tissue and identified that lncRNA FIRRE is significantly upregulated in HCV-associated HCC compared to adjacent non-tumor liver tissue. Further, we observed that FIRRE is significantly upregulated in HCC specimens with other etiologies, suggesting this lncRNA has the potential to serve as an additional biomarker for HCC. Overexpression of FIRRE in hepatocytes induced cell proliferation, colony formation, and xenograft tumor formation as compared to vector-transfected control cells. Using RNA pull-down proteomics, we identified HuR as an interacting partner of FIRRE. We further showed that the FIRRE-HuR axis regulates cyclin D1 expression. Our mechanistic investigation uncovered that FIRRE is associated with an RNA-binding protein HuR for enhancing hepatocyte growth. Together, these findings provide molecular insights into the role of FIRRE in HCC progression.

Do risk scores improve use of faecal immunochemical testing for haemoglobin in symptomatic patients in primary care?

AIM: Faecal immunochemical testing (FIT) is used in the detection of colorectal cancer (CRC). FIT is invariably used at a single faecal haemoglobin (f-Hb) concentration threshold. The aim of this observational study was to explore risk scoring models (RSMs) with f-Hb and other risk factors for CRC in symptomatic patients attending primary care, potentially speeding diagnosis and saving endoscopy resources. METHOD: Records of patients completing FIT were linked with The Scottish Cancer Registry and with other databases with symptoms, full blood count and demographic variables, and randomized into derivation and validation cohorts. Stepwise multivariable logistic regression created RSMs assessed in the validation cohort. RESULTS: Of 18 805 unique patients, 9374 and 9431 were in the derivation and validation cohorts, respectively: f-Hb, male sex, increasing age, iron deficiency anaemia and raised systemic immune inflammation index created the final RSM. A risk score threshold of ≥2.363, generating the same number of colonoscopies as a f-Hb threshold of ≥10 µg Hb/g gave improved sensitivity for CRC in both cohorts. A RSM which excluded f-Hb was used to investigate the effect of raising the f-Hb threshold from ≥10 to ≥20 µg Hb/g in those with a low risk score. This approach would have generated 234 fewer colonoscopies but missed four CRCs. CONCLUSION: The RSM conferred no significant benefit to patients with very low f-Hb and CRC. Alternative strategies combining FIT with other variables may be more appropriate for safety-netting of symptomatic patients. Further work to develop and investigate the value of RSM for significant bowel disease other than CRC may also be beneficial.

Momordicine-I Suppresses Head and Neck Cancer Growth by Reprogrammimg Immunosuppressive Effect of the Tumor-Infiltrating Macrophages and B Lymphocytes.

Head and neck cancer (HNC) is prevalent worldwide, and treatment options are limited. Momordicine-I (M-I), a natural component from bitter melon, shows antitumor activity against these cancers, but its mechanism of action, especially in the tumor microenvironment (TME), remains unclear. In this study, we establish that M-I reduces HNC tumor growth in two different immunocompetent mouse models using MOC2 and SCC VII cells. We demonstrate that the anticancer activity results from modulating several molecules in the monocyte/macrophage clusters in CD45+ populations in MOC2 tumors by single-cell RNA sequencing. Tumor-associated macrophages (TAM) often pose a barrier to antitumor effects, but following M-I treatment, we observe a significant reduction in the expression of Sfln4, a myeloid cell differentiation factor, and Cxcl3, a neutrophil chemoattractant, in the monocyte/macrophage populations. We further find that the macrophages must be in close contact with the tumor cells to inhibit Sfln4 and Cxcl3, suggesting that these TAMs are impacted by M-I treatment. Coculturing macrophages with tumor cells shows inhibition of Agr1 expression following M-I treatment, which is indicative of switching from M2 to M1 phenotype. Furthermore, the total B-cell population in M-I-treated tumors is significantly lower, whereas spleen cells also show similar results when cocultured with MOC2 cells. M-I treatment also inhibits PD1, PD-L1, and FoxP3 expression in tumors. Collectively, these results uncover the potential mechanism of M-I by modulating immune cells, and this new insight can help to develop M-I as a promising candidate to treat HNCs, either alone or as adjuvant therapy.

A new look at the architecture and dynamics of the Hydra nerve net.

The Hydra nervous system is the paradigm of a 'simple nerve net'. Nerve cells in Hydra, as in many cnidarian polyps, are organized in a nerve net extending throughout the body column. This nerve net is required for control of spontaneous behavior: elimination of nerve cells leads to polyps that do not move and are incapable of capturing and ingesting prey (Campbell, 1976). We have re-examined the structure of the Hydra nerve net by immunostaining fixed polyps with a novel antibody that stains all nerve cells in Hydra. Confocal imaging shows that there are two distinct nerve nets, one in the ectoderm and one in the endoderm, with the unexpected absence of nerve cells in the endoderm of the tentacles. The nerve nets in the ectoderm and endoderm do not contact each other. High-resolution TEM (transmission electron microscopy) and serial block face SEM (scanning electron microscopy) show that the nerve nets consist of bundles of parallel overlapping neurites. Results from transgenic lines show that neurite bundles include different neural circuits and hence that neurites in bundles require circuit-specific recognition. Nerve cell-specific innexins indicate that gap junctions can provide this specificity. The occurrence of bundles of neurites supports a model for continuous growth and differentiation of the nerve net by lateral addition of new nerve cells to the existing net. This model was confirmed by tracking newly differentiated nerve cells.

The role of endoscopist adenoma detection rate in in sex differences in colonoscopy findings: cross-sectional analysis of the SCREESCO randomized controlled trial.

BACKGROUND: Fewer adenomas are detected at colonoscopy in women compared to men and failure to detect adenomas and sessile serrated polyps is associated with an increased risk of post-colonoscopy colorectal cancer. The aim of this study was to investigate whether this was in part due to the greater difficulty of conducting colonoscopy in women, with the difference being more apparent in colonoscopies conducted by less skilled endoscopists. MATERIAL AND METHODS: Cross-sectional exploratory analysis of data on 16,551 individuals undergoing a primary colonoscopy (PCOL group) or colonoscopy after positive faecal immunochemical test (FIT group) within the randomized controlled trial SCREESCO. Endoscopist adenoma detection rate (ADR; low or high) was determined based on each endoscopist's colonoscopies performed in SCREESCO. In each study group, the relationship between the sex difference in colonoscopy outcome and endoscopist ADR was assessed using multiplicative interaction tests. RESULTS: Endoscopists performed equally many colonoscopies in men and women (median 52% men). There were no signs of effect modification of the risk ratio of any finding (men vs women) by endoscopist ADR in the PCOL group (p = 0.33) or the FIT group (p = 0.30). The proportion of incomplete index colonoscopies was lower in men than in women in both groups and there was no effect modification by endoscopist ADR in either the PCOL group (p = 0.41) or the FIT group (p = 0.96). CONCLUSIONS: This study provides no evidence that endoscopist skill measured by ADR underlies the sex difference in adenoma detection at colonoscopy. This study has trial number NCT02078804 and is registered with ClinicalTrials.gov.

Interval cancers in a national colorectal screening programme based on faecal immunochemical testing: Implications for faecal haemoglobin concentration threshold and sex inequality.

OBJECTIVE: To compare interval cancer proportions (ICP) in the faecal immunochemical test (FIT)-based Scottish Bowel Screening Programme (SBoSP) with the former guaiac faecal occult blood test (gFOBT)-based SBoSP and investigate associations between interval cancer (IC) and faecal haemoglobin concentration (f-Hb) threshold, sex, age, deprivation, site, and stage. METHODS: The ICP data from first year of the FIT-based SBoSP and the penultimate year of the gFOBT-based SBoSP were compared in a prospective cohort design. RESULTS: With FIT, 801 colorectal cancers (CRCs) were screen detected (SDC), 802 were in non-participants, 548 were ICs, 39 were colonoscopy missed and 72 were diagnosed after incomplete screening; with gFOBT: 540, 904, 556, 45, and 13, respectively. FIT had a significantly higher proportion of SDC compared to IC than gFOBT. For FIT and gFOBT, ICP was significantly higher in women than men. As f-Hb threshold increased, ICP increased and, for any f-Hb threshold for men, a lower threshold was required for comparable ICP in women. In Scotland, the current threshold of ≥80 µg Hb/g faeces would have to be lowered to ≥40 µg Hb/g faeces for women to achieve sex equality for ICP. In the FIT-based SBoSP, there were four times as many stage I SDC than IC. This was reversed in advanced stages, with twice as many stage IV CRC diagnosed as IC versus SDC. CONCLUSIONS: Reducing the numbers of IC requires lowering the f-Hb threshold. Using different f-Hb thresholds for women and men could eliminate the sex disparity, but with additional colonoscopy.

The Development and Evaluation of a Cross-Context Employment Program for Autistic Adolescents.

Vocational programs typically focus on building the skills of autistic youth. However, there is growing recognition that the supportive environment (or ecosystem) around an individual plays an important role in finding and maintaining work. Programs at the ecosystem-level can be established by coordinating support before high school ends. Cocreation of a vocational program by support providers can facilitate an integrated effort to prepare autistic youth for employment. In this study, we describe and evaluate the Job-Train Program (JTP), a vocational program for autistic high school students codesigned with educators and a community-based social services agency. A school board, community-based social services agency, and academics partnered to cocreate JTP. JTP combined skill teaching and paid supported employment on a university campus. This pilot study evaluated JTP using qualitative and quantitative data. Twelve autistic youth were recruited, aged 15-18 years (10 males, 2 females) with an average intelligence quotient of 101.9 (standard deviation = 14.4), from the Wechsler Abbreviated Scale of Intelligence-2. Youth and parents completed self-report measures (pre-post), including the primary outcome, Canadian Occupational Performance Measure (COPM). Post-JTP, interviews, focus groups, and surveys collected additional information from youth (n = 11), parents (n = 10), job coaches (n = 5), and employers (n = 8). Youth COPM scores indicated significant improvements in self-perceived ratings of skill performance (z = -2.5, p = 0.01) and satisfaction (z = -2.6, p = 0.01). Qualitative data corroborated COPM results noting youth skill improvements in self-esteem, independence, communication, and understanding work. Findings demonstrated a promising vocational training model for autistic high school students informing the development of integrated service pathways to support preparation for employment.

Why was this program developed?: When autistic young people leave school, they can experience difficulties in getting a job. We need to test whether job training might be helpful for autistic young people when they are leaving school. Current support focuses mostly on developing educational skills, but it is important that we think about the strengths and abilities of the individual within their environment. In this study, we worked with educators from schools and a community service agency (who support autistic adults) to develop a job training support program for autistic youth. What does this program do?: We designed the 13-week Job-Train Program (JTP) to provide training and paid work experience, develop work abilities, and increase support around the autistic youth. Participants took part in weekly group sessions about work skills, and they did 8 weeks of paid work, supported by a job coach on a university campus. How did researchers evaluate the program?: Twelve autistic high school students (age 15­18) took part, and eight university departments hosted work experiences. We used several approaches to see if the program was helping and to identify areas where we could improve the program in the future. Ten parents and 11 autistic youth completed the Canadian Occupational Performance Measure (COPM) before and after the program, so we could see if there were any changes in work-related skills. We also completed interviews with youth, focus groups with parents, and surveys with job coaches to gather feedback. What were the early findings?: Scores on the COPM questionnaire showed that the young people rated themselves as more skilled and they were more satisfied with their skills after the program. Parent ratings showed a similar pattern. When we spoke to youth, parents, and job coaches, they mentioned improvements in responsibility and independence. Eight employers in university departments gained awareness of autistic youth as employees and all were willing to be part of the program again. Parents suggested that having more training of advocacy skills would help youth with gaining work in the future. What were the weaknesses of this project?: We did not assess how well the job coaches did in delivering the program or exactly how they made accommodations within the work experience jobs. Autistic individuals and their parents were not included in program development. What are the next steps?: We now plan to include autistic youth and their parents in further refining the program. We also plan to follow up with the youth who took part, to see how they are doing in the long term. We also will improve the support provided by job coaches. How will this work help autistic adults now or in future?: The JTP approach may help autistic youth as they go into employment and could provide high-quality support for the transition to adulthood. We also show that university campuses could be great places for autistic youth to gain experience, so in the future hope that universities and schools work together more to help support autistic youth.

Air Quality Implications of Using Ammonia as a Renewable Fuel: How Low Can NOx Emissions Go?

In addition to their lifecycle carbon emissions, another important issue with decarbonized energy pathways is their air quality, water, or land use implications. This paper considers the air quality issue for ammonia combustion. When directly combusting ammonia, reactions of its N atom with atmospheric oxygen lead to NOx emissions that are O(103) ppm, 2 orders of magnitude higher than EPA limits or the amount emitted by current natural-gas-fired technologies. In order to provide guidance to policymakers and technologists on what is fundamentally possible, this Perspective analyzes the fundamental minimum NOx emissions that can be produced from ammonia combustion. The analysis shows that it is possible to achieve quite low NOx emission levels of O(10) ppm, but these designs differ markedly from those used in today's lean, premixed combustion systems.

Clinical and functional outcomes of reverse total shoulder arthroplasty supplemented with latissimus dorsi transfer: a systematic review and meta-analysis.

Background: To optimize patients' functional external rotation outcomes, reverse total shoulder arthroplasties (rTSAs) including a latissimus dorsi tendon transfer were undertaken with promising early results and no significant increase in complications in comparison to traditional rTSAs. This was especially utilized for patients with a pronounced combined loss of elevation and external rotation. The purpose of this study is to evaluate and synthesize the findings of all relevant publications assessing the outcomes of rTSAs with associated latissimus dorsi transfer. Methods: We thoroughly searched the literature within the PubMed database using a standardized methodology. For our inclusion criteria, we included any study regarding rTSAs that contained functional outcome scores for postoperative range of motion (such as elevation, external rotation, etc.) or postoperative outcomes such as complications (reoperation, infection, etc.) and patient satisfaction. For the extraction of data, we used pilot-tested Google Forms to record extracted data. These data were then converted to spreadsheets (Microsoft Excel [Microsoft, Redmond, WA, USA]). This was done on 2 separate scenarios by 2 authors to ensure accuracy. We used the modified Coleman Methodology Score to assess the methodological quality of the studies in our samples. Meta-analysis mathematics and statistical analysis were performed using Stata software 17 (StataCorp, College Station, TX, USA). Results: Our search returned a total of 12 studies containing data of 213 shoulders receiving RTSAs with a latissimus dorsi transfer. Functional outcomes were available for 160 shoulders. The mean preoperative elevation of the affected shoulder was 73.57 degrees, and the mean postoperative elevation was 141.80 degrees. For external rotation, the mean preoperative average was -6.71 degrees, and the mean postoperative average was 22.73 degrees. The absolute Constant score average was 31.56 preoperatively, while the postoperative value was 68.93. In our sample, 25 patients (11.73%) required a revision of the RTSA implant due to complications. Discussion: Combined loss of elevation and external rotation can be a severely debilitating condition for those with a glenohumeral pathology. Latissimus dorsi transfer for this condition has been proven to be an effective modality. The reoperation and complication rate appears to be sizable, and as such surgeons should consider this when considering this modality for their patients.

Coevolution of the Tlx homeobox gene with medusa development (Cnidaria: Medusozoa).

Cnidarians display a wide diversity of life cycles. Among the main cnidarian clades, only Medusozoa possesses a swimming life cycle stage called the medusa, alternating with a benthic polyp stage. The medusa stage was repeatedly lost during medusozoan evolution, notably in the most diverse medusozoan class, Hydrozoa. Here, we show that the presence of the homeobox gene Tlx in Cnidaria is correlated with the presence of the medusa stage, the gene having been lost in clades that ancestrally lack a medusa (anthozoans, endocnidozoans) and in medusozoans that secondarily lost the medusa stage. Our characterization of Tlx expression indicate an upregulation of Tlx during medusa development in three distantly related medusozoans, and spatially restricted expression patterns in developing medusae in two distantly related species, the hydrozoan Podocoryna carnea and the scyphozoan Pelagia noctiluca. These results suggest that Tlx plays a key role in medusa development and that the loss of this gene is likely linked to the repeated loss of the medusa life cycle stage in the evolution of Hydrozoa.

An efficient strategy for evaluating new non-invasive screening tests for colorectal cancer: the guiding principles.

OBJECTIVE: New screening tests for colorectal cancer (CRC) are rapidly emerging. Conducting trials with mortality reduction as the end point supporting their adoption is challenging. We re-examined the principles underlying evaluation of new non-invasive tests in view of technological developments and identification of new biomarkers. DESIGN: A formal consensus approach involving a multidisciplinary expert panel revised eight previously established principles. RESULTS: Twelve newly stated principles emerged. Effectiveness of a new test can be evaluated by comparison with a proven comparator non-invasive test. The faecal immunochemical test is now considered the appropriate comparator, while colonoscopy remains the diagnostic standard. For a new test to be able to meet differing screening goals and regulatory requirements, flexibility to adjust its positivity threshold is desirable. A rigorous and efficient four-phased approach is proposed, commencing with small studies assessing the test's ability to discriminate between CRC and non-cancer states (phase I), followed by prospective estimation of accuracy across the continuum of neoplastic lesions in neoplasia-enriched populations (phase II). If these show promise, a provisional test positivity threshold is set before evaluation in typical screening populations. Phase III prospective studies determine single round intention-to-screen programme outcomes and confirm the test positivity threshold. Phase IV studies involve evaluation over repeated screening rounds with monitoring for missed lesions. Phases III and IV findings will provide the real-world data required to model test impact on CRC mortality and incidence. CONCLUSION: New non-invasive tests can be efficiently evaluated by a rigorous phased comparative approach, generating data from unbiased populations that inform predictions of their health impact.

Chromosome-level genome assembly of Hydractinia symbiolongicarpus.

Hydractinia symbiolongicarpus is a pioneering model organism for stem cell biology, being one of only a few animals with adult pluripotent stem cells (known as i-cells). However, the unavailability of a chromosome-level genome assembly has hindered a comprehensive understanding of global gene regulatory mechanisms underlying the function and evolution of i-cells. Here, we report the first chromosome-level genome assembly of H. symbiolongicarpus (HSymV2.0) using PacBio HiFi long-read sequencing and Hi-C scaffolding. The final assembly is 483 Mb in total length with 15 chromosomes representing 99.8% of the assembly. Repetitive sequences were found to account for 296 Mb (61%) of the total genome; we provide evidence for at least two periods of repeat expansion in the past. A total of 25,825 protein-coding genes were predicted in this assembly, which include 93.1% of the metazoan Benchmarking Universal Single-Copy Orthologs (BUSCO) gene set. 92.8% (23,971 genes) of the predicted proteins were functionally annotated. The H. symbiolongicarpus genome showed a high degree of macrosynteny conservation with the Hydra vulgaris genome. This chromosome-level genome assembly of H. symbiolongicarpus will be an invaluable resource for the research community that enhances broad biological studies on this unique model organism.

Increasing uptake of FIT colorectal screening: protocol for the TEMPO randomised controlled trial testing a suggested deadline and a planning tool.

INTRODUCTION: Screening can reduce deaths from colorectal cancer (CRC). Despite high levels of public enthusiasm, participation rates in population CRC screening programmes internationally remain persistently below target levels. Simple behavioural interventions such as completion goals and planning tools may support participation among those inclined to be screened but who fail to act on their intentions. This study aims to evaluate the impact of: (a) a suggested deadline for return of the test; (b) a planning tool and (c) the combination of a deadline and planning tool on return of faecal immunochemical tests (FITs) for CRC screening. METHODS AND ANALYSIS: A randomised controlled trial of 40 000 adults invited to participate in the Scottish Bowel Screening Programme will assess the individual and combined impact of the interventions. Trial delivery will be integrated into the existing CRC screening process. The Scottish Bowel Screening Programme mails FITs to people aged 50-74 with brief instructions for completion and return. Participants will be randomised to one of eight groups: (1) no intervention; (2) suggested deadline (1 week); (3) suggested deadline (2 weeks); (4) suggested deadline (4 weeks); (5) planning tool; (6) planning tool plus suggested deadline (1 week); (7) planning tool plus suggested deadline (2 weeks); (8) planning tool plus suggested deadline (4 weeks). The primary outcome is return of the correctly completed FIT at 3 months. To understand the cognitive and behavioural mechanisms and to explore the acceptability of both interventions, we will survey (n=2000) and interview (n=40) a subgroup of trial participants. ETHICS AND DISSEMINATION: The study has been approved by the National Health Service South Central-Hampshire B Research Ethics Committee (ref. 19/SC/0369). The findings will be disseminated through conference presentations and publication in peer-reviewed journals. Participants can request a summary of the results. TRIAL REGISTRATION NUMBER: clinicaltrials.govNCT05408169.

Trigeminocardiac Reflex: A Review and Key Implications to Dermatologic Surgery.

BACKGROUND: The trigeminocardiac reflex is a common but underreported occurrence that can vary from benign to life threatening. This reflex can be elicited by placing direct pressure on the globe of the eye or from traction of the extraocular muscles, stimulating the trigeminal nerve. OBJECTIVE: To provide a review of potential stimuli for the trigeminocardiac reflex within dermatologic surgery and to discuss management options for the treatment of the trigeminocardiac reflex. METHODS: PubMed and Cochrane were used to identify articles and case reports that established scenarios in which the trigeminocardiac reflex was provoked and subsequently how the reflex was managed. RESULTS: Within the field of dermatologic surgery, the trigeminocardiac reflex can be stimulated during biopsies, cryoablations, injections, laser treatments, Mohs micrographic surgery, and oculoplastic interventions, most often occurring in an office setting. The most common presentations include significant bradycardia, hypotension, gastric hypermobility, and lightheadedness. The most definitive treatment is cessation of the inciting stimulus, monitoring, and symptomatic management. Glycopyrrolate and atropine are common treatments for severe, intractable cases of the trigeminocardiac reflex. CONCLUSION: The trigeminocardiac reflex, while underreported and underrepresented in dermatologic literature and dermatologic surgery settings, should be considered in the setting of bradycardia and hypotension during dermatologic procedures.

Improved use of faecal immunochemical tests for haemoglobin in the Scottish bowel screening programme.

OBJECTIVES: This study aimed to develop a risk-scoring model in the Scottish Bowel Screening Programme incorporating faecal haemoglobin concentration with other risk factors for colorectal cancer. METHODS: Data were collected for all individuals invited to participate in the Scottish Bowel Screening Programme between November 2017 and March 2018 including faecal haemoglobin concentration, age, sex, National Health Service Board, socioeconomic status, and screening history. Linkage with The Scottish Cancer Registry identified all screening participants diagnosed with colorectal cancer. Logistic regression was performed to identify which factors demonstrated significant association with colorectal cancer and could be used in the development of a risk-scoring model. RESULTS: Of 232,076 screening participants, 427 had colorectal cancer: 286 diagnosed following a screening colonoscopy and 141 arising after a negative screening test result giving an interval cancer proportion of 33.0%. Only faecal haemoglobin concentration and age showed a statistically significant association with colorectal cancer. Interval cancer proportion increased with age and was higher in women (38.1%) than men (27.5%). If positivity in women were mirrored in men at each age quintile interval cancer proportion would still have remained higher in women (33.2%). Moreover, an additional 1201 colonoscopies would be required to detect 11 colorectal cancers. CONCLUSIONS: Development of a risk scoring model using early data from the Scottish Bowel Screening Programme was not feasible due to most variables showing insignificant association with colorectal cancer. Tailoring the faecal haemoglobin concentration threshold according to age could help to diminish some of the disparity in interval cancer proportion between women and men. Strategies to achieve sex equality using faecal haemoglobin concentration thresholds depend considerably on which variable is selected for equivalency and this requires further exploration.

Faecal haemoglobin concentration predicts all-cause mortality.

BACKGROUND: Population-based screening for colorectal cancer by a faecal immunochemical test (FIT) is recommended by the European Union. Detectable faecal haemoglobin can indicate colorectal neoplasia as well as other conditions. A positive FIT predicts an increased risk of death from colorectal cancer but might also predict an increased risk of all-cause mortality. METHODS: A cohort of screening participants was followed using the Danish National Register of Causes of Death. Data were retrieved from the Danish Colorectal Cancer Screening Database supplemented with FIT concentrations. Colorectal cancer specific and all-cause mortality were compared between FIT concentration groups using multivariate cox proportional hazards regression models. FINDINGS: In 444,910 Danes invited for the screening program, 25,234 (5·7%) died during a mean follow-up of 56·5 months. Colorectal cancer caused 1120 deaths. The risk of colorectal cancer death increased with the increasing FIT concentration. The hazard ratios ranged from 2·6 to 25·9 compared to individuals with FIT concentrations <4 µg hb/g faeces. Causes other than colorectal cancer caused 24,114 deaths. The risk of all-cause death increased with the increasing FIT concentration, with the hazard ratios ranging from 1·6 to 5·3 compared to individuals with FIT concentrations <4 µg hb/g faeces. INTERPRETATION: The risk of colorectal cancer mortality increased with the increasing FIT concentrations even for FIT concentrations considered negative in all European screening programs. The risk of all-cause mortality was also increased for individuals with detectable faecal blood. For colorectal cancer specific mortality and all-cause mortality, the risk was increased at the FIT concentrations as low as 4-9 µg hb/g faeces. FUNDING: The study was funded by the Odense University Hospital grants A3610 and A2359.

Sex variation in colorectal cancer mortality: trends and implications for screening.

BACKGROUND: Colorectal cancer (CRC) screening using faecal tests reduces disease-specific mortality. To investigate mortality and its association with sex, rates in women and men, and in different age ranges, were examined, before and after screening began in Scotland. METHODS: From 1990-99, no structured screening existed. Three pilots ran from 2000 to 2007 and subsequent full roll-out completed in 2009. Crude mortality rates for 1990-2020 were calculated relative to Scottish population estimates, and age-sex standardized rates calculated for all, pre-screening (<50 years), screening (5-74 years) and post-screening (>74 years) age ranges. RESULTS: CRC mortality declined from 1990 to 2020, but not linearly, and differed between sexes. In women, 1990-99 showed a steady decline [average annual percentage change (AAPC): -2.1%, 95% confidence interval (CI): -2.8% to -1.4%], but a less marked decline after 2000 (AAPC: -0.7%, 95% CI: -0.9% to -0.4%). In men, no clear decline was seen from 1990 to 1999 (AAPC: -0.4%, 95% CI: -1.1% to 0.4%), but mortality declined from 2000 to 2020 (AAPC: -1.7%, 95% CI: -1.9% to -1.5%). This pattern was exaggerated in the screening age ranges. For 2000-20, the overall reduction in mortality was less in women and in the screening age range. In the post-screening age range, reductions were smaller, but an increase was seen in the pre-screening age range, greater in women. CONCLUSIONS: CRC mortality fell during 1990-2020, but the decline differed markedly between sexes, indicating a larger beneficial effect of screening on CRC mortality in men compared to women: use of different thresholds for the sexes might lead to equality.

SPIM-Flow: An Integrated Light Sheet and Microfluidics Platform for Hydrodynamic Studies of Hydra.

Selective plane illumination microscopy (SPIM), or light sheet microscopy, is a powerful imaging approach. However, access to and interfacing microscopes with microfluidics have remained challenging. Complex interfacing with microfluidics has limited the SPIM's utility for studying the hydrodynamics of freely moving multicellular organisms. We developed SPIM-Flow, an inexpensive light sheet platform that enables easy integration with microfluidics. We used SPIM-Flow to investigate the hydrodynamics of a freely moving Hydra polyp via particle tracking in millimeter-sized chambers. Initial experiments across multiple animals, feeding on a chip (Artemia franciscana nauplii used as food), and baseline behaviors (tentacle swaying, elongation, and bending) indicated the organisms' health inside the system. Fluidics were used to investigate Hydra's response to flow. The results suggested that the animals responded to an established flow by bending and swaying their tentacles in the flow direction. Finally, using SPIM-Flow in a proof-of-concept experiment, the shear stress required to detach an animal from a surface was demonstrated. Our results demonstrated SPIM-Flow's utility for investigating the hydrodynamics of freely moving animals.