The performance of FIT-based and other risk prediction models for colorectal neoplasia in symptomatic patients: a systematic review.

Background: Colorectal cancer (CRC) incidence and mortality are increasing internationally. Endoscopy services are under significant pressure with many overwhelmed. Faecal immunochemical testing (FIT) has been advocated to identify a high-risk population of symptomatic patients requiring definitive investigation by colonoscopy. Combining FIT with other factors in a risk prediction model could further improve performance in identifying those requiring investigation most urgently. We systematically reviewed performance of models predicting risk of CRC and/or advanced colorectal polyps (ACP) in symptomatic patients, with a particular focus on those models including FIT. Methods: The review protocol was published on PROSPERO (CRD42022314710). Searches were conducted from database inception to April 2023 in MEDLINE, EMBASE, Cochrane libraries, SCOPUS and CINAHL. Risk of bias of each study was assessed using The Prediction study Risk Of Bias Assessment Tool. A narrative synthesis based on the guidelines for Synthesis Without Meta-Analysis was performed due to study heterogeneity. Findings: We included 62 studies; 23 included FIT (n = 22) or guaiac Faecal Occult Blood Testing (n = 1) combined with one or more other variables. Twenty-one studies were conducted solely in primary care. Generally, prediction models including FIT consistently had good discriminatory ability for CRC/ACP (i.e. AUC >0.8) and performed better than models without FIT although some models without FIT also performed well. However, many studies did not present calibration and internal and external validation were limited. Two studies were rated as low risk of bias; neither model included FIT. Interpretation: Risk prediction models, including and not including FIT, show promise for identifying those most at risk of colorectal neoplasia. Substantial limitations in evidence remain, including heterogeneity, high risk of bias, and lack of external validation. Further evaluation in studies adhering to gold standard methodology, in appropriate populations, is required before widespread adoption in clinical practice. Funding: National Institute for Health and Care Research (NIHR) [Health Technology Assessment Programme (HTA) Programme (Project number 133852).

A Comparison of Di- and Trinuclear Platinum Complexes Interacting with Glycosaminoglycans for Targeted Chemotherapy.

Heparan sulfate proteoglycans (HSPGs) and their associated proteins aid in tumor progression through modulation of biological events such as cell invasion, angiogenesis, metastasis, and immunological responses. Metalloshielding of the anionic heparan sulfate (HS) chains by cationic polynuclear platinum complexes (PPCs) prevents the HS from interacting with HS-associated proteins and thus diminishes the critical functions of HSPG. Studies herein exploring the PPC-HS interactions demonstrated that a series of PPCs varying in charge, nuclearity, distance between Pt centers, and hydrogen-bonding ability influence HS affinity. We report that the polyamine-linked complexes have high HS affinity and display excellent in vivo activity against breast cancer metastases and those arising in the bone and liver compared to carboplatin. Overall, the PPC-HS niche offers an attractive approach for targeting HSPG-expressing tumor cells.

Quality in colonoscopy: time to ensure national standards are implemented?

Background: High-quality colonoscopy is crucial to ensure complete mucosal visualisation and to maximise detection of pathology. Previous audits showing variable quality have prompted national and international colonoscopy improvement programmes, including the development of quality assurance standards and key performance indicators (KPIs). The most widely used marker of mucosal visualisation is the adenoma detection rate (ADR), however, histological confirmation is required to calculate this. We explored the relationship between core colonoscopy KPIs. Methods: Data were collected from colonoscopists in eight hospitals in North East England over a 6-month period, as part of a quality improvement study. Procedural information was collected including number of colonoscopies, caecal intubation rate (CIR), ADR and polyp detection rate (PDR). Associations between KPIs and colonoscopy performance were analysed. Results: 9265 colonoscopies performed by 118 endoscopists were included. Mean ADR and PDR per endoscopist were 16.6% (range 0-36.3, SD 7.4) and 27.2% (range 0-57.5, SD 9.3), respectively. Mean number of colonoscopies conducted in 6 months was 78.5 (range 4-334, SD 61). Mean CIR was 91.2% (range 55.5-100, SD 6.6). Total number of colonoscopies and ADR>15% were significantly associated (p=0.04). Undertaking fewer colonoscopies and using hyoscine butylbromide less frequently was significantly associated with ADR<15%. CIR, endoscopist grade, % male patients, mean patient age and CIR were not significantly related to ADR<15%. In adjusted analyses, factors which affected ADR were PDR and mean patient age. Conclusion: Colonoscopists who perform fewer than the nationally stipulated minimum of 100 procedures per year had significantly lower ADRs. This study demonstrates that PDR can be used as a marker of ADR; providing age is also considered.

Radiation induces ESCRT pathway dependent CD44v3+ extracellular vesicle production stimulating pro-tumor fibroblast activity in breast cancer.

Despite recent advances in radiotherapeutic strategies, acquired resistance remains a major obstacle, leading to tumor recurrence for many patients. Once thought to be a strictly cancer cell intrinsic property, it is becoming increasingly clear that treatment-resistance is driven in part by complex interactions between cancer cells and non-transformed cells of the tumor microenvironment. Herein, we report that radiotherapy induces the production of extracellular vesicles by breast cancer cells capable of stimulating tumor-supporting fibroblast activity, facilitating tumor survival and promoting cancer stem-like cell expansion. This pro-tumor activity was associated with fibroblast production of the paracrine signaling factor IL-6 and was dependent on the expression of the heparan sulfate proteoglycan CD44v3 on the vesicle surface. Enzymatic removal or pharmaceutical inhibition of its heparan sulfate side chains disrupted this tumor-fibroblast crosstalk. Additionally, we show that the radiation-induced production of CD44v3+ vesicles is effectively silenced by blocking the ESCRT pathway using a soluble pharmacological inhibitor of MDA-9/Syntenin/SDCBP PDZ1 domain activity, PDZ1i. This population of vesicles was also detected in the sera of human patients undergoing radiotherapy, therefore representing a potential biomarker for radiation therapy and providing an opportunity for clinical intervention to improve treatment outcomes.

Trial protocol for COLO-DETECT: A randomized controlled trial of lesion detection comparing colonoscopy assisted by the GI Genius™ artificial intelligence endoscopy module with standard colonoscopy.

AIM: Colorectal cancer is the second commonest cause of cancer death worldwide. Colonoscopy plays a key role in the control of colorectal cancer and, in that regard, maximizing detection (and removal) of pre-cancerous adenomas at colonoscopy is imperative. GI Genius™ (Medtronic Ltd) is a computer-aided detection system that integrates with existing endoscopy systems and improves adenoma detection during colonoscopy. COLO-DETECT aims to assess the clinical and cost effectiveness of GI Genius™ in UK routine colonoscopy practice. METHODS AND ANALYSIS: Participants will be recruited from patients attending for colonoscopy at National Health Service sites in England, for clinical symptoms, surveillance or within the national Bowel Cancer Screening Programme. Randomization will involve a 1:1 allocation ratio (GI Genius™-assisted colonoscopy:standard colonoscopy) and will be stratified by age category (<60 years, 60-<74 years, ≥74 years), sex, hospital site and indication for colonoscopy. Demographic data, procedural data, histology and post-procedure patient experience and quality of life will be recorded. COLO-DETECT is designed and powered to detect clinically meaningful differences in mean adenomas per procedure and adenoma detection rate between GI Genius™-assisted colonoscopy and standard colonoscopy groups. The study will close when 1828 participants have had a complete colonoscopy. An economic evaluation will be conducted from the perspective of the National Health Service. A patient and public representative is contributing to all stages of the trial. Registered at ClinicalTrials.gov (NCT04723758) and ISRCTN (10451355). WHAT WILL THIS TRIAL ADD TO THE LITERATURE?: COLO-DETECT will be the first multi-centre randomized controlled trial evaluating GI Genius™ in real world colonoscopy practice and will, uniquely, evaluate both clinical and cost effectiveness.

The COLO-COHORT (Colorectal Cancer Cohort) study: Protocol for a multi-centre, observational research study and development of a consent-for-contact research platform.

AIM: The COLO-COHORT study aims to produce a multi-factorial risk prediction model for colorectal neoplasia that can be used to target colonoscopy to those at greatest risk of colorectal neoplasia, ensuring that people are not investigated unnecessarily and maximizing the use of limited endoscopy resources. The study will also explore the link between neoplasia and the human gut microbiome. Additionally, the study aims to generate a cohort of colonoscopy patients who are 'research ready' through the development of a consent-for-contact (C4C) platform, to facilitate a range of colorectal cancer prevention studies to be conducted at scale and speed. METHODS AND ANALYSIS: This is a multi-centre observational study involving sites across the UK. Recruitment is over a 6-year period (2019-2025). Patients recruited to the study are those attending for colonoscopy. Patients are recruited into two groups, namely observational group A (10 000 patients) and C4C group B (10 000 patients), known as COLO-SPEED (Colorectal Cancer Screening Prevention Endoscopy and Early Diagnosis; https://colospeed.uk). Patients complete a health questionnaire, provide anthropometric measurements and submit biosamples (blood and stool-depending on the part of the study they are recruited into). Patients' colonoscopy and histology findings are also recorded. Models of factors associated with the presence of neoplasia at colonoscopy will be developed using logistic or multinomial regression. For internal validation, model discrimination and calibration will be assessed and bootstrapping and cross-validation approaches used. To enable long-term follow-up for outcomes related to colorectal cancer and polyps, patients are asked to consent to follow-up through data linkage with national databases. DISSEMINATION: In keeping with good research practice, following analysis by the study team the study investigators will make the anonymized dataset available to other researchers. The C4C platform will also be accessible to other researchers. The study findings will be submitted for publication in peer-reviewed journals and lay summaries will be disseminated to participants and the wider public.

Is Concept Appraisal Modulated by Procedural or Declarative Manipulations?

A recent study has established that thinkers reliably engage in epistemic appraisals of concepts of natural categories. Here, five studies are reported which investigated the effects of different manipulations of category learning context on appraisal of the concepts learnt. It was predicted that dimensions of concept appraisal could be affected by manipulating either procedural factors (spacing of learning, perceptual fluency) or declarative factors (causal knowledge about categories). While known effects of these manipulations on metacognitive judgements such as category learning judgements and confidence at test were replicated, procedural factors had no reliable effects on the dimensions of concept appraisal. Effects of declarative manipulations on some forms of concept appraisal were observed.

Context effects in similarity judgments.

Tversky's (1977) famous demonstration of a diagnosticity effect indicates that the similarity between the same two stimuli depends on the presence of contextual stimuli. In a forced choice task, the similarity between a target and a choice, appears to depend on the other choices. Specifically, introducing a distractor grouped with one of the options would reduce preference for the grouped option. However, the diagnosticity effect has been difficult to replicate, casting doubt on its robustness and our understanding of contextual effects in similarity generally. We propose that the apparent brittleness of the diagnosticity effect is because it is in competition with an opposite attraction effect. Even though in both the similarity and decision-making literatures there are indications for such a competition, we provide the first direct experimental demonstration of how an attraction effect can give way to a diagnosticity one, as a distractor option is manipulated. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Exploitation of Sulfated Glycosaminoglycan Status for Precision Medicine of Triplatin in Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is a subtype of breast cancer lacking targetable biomarkers. TNBC is known to be most aggressive and when metastatic is often drug-resistant and uncurable. Biomarkers predicting response to therapy improve treatment decisions and allow personalized approaches for patients with TNBC. This study explores sulfated glycosaminoglycan (sGAG) levels as a predictor of TNBC response to platinum therapy. sGAG levels were quantified in three distinct TNBC tumor models, including cell line-derived, patient-derived xenograft (PDX) tumors, and isogenic models deficient in sGAG biosynthesis. The in vivo antitumor efficacy of Triplatin, a sGAG-directed platinum agent, was compared in these models with the clinical platinum agent, carboplatin. We determined that >40% of TNBC PDX tissue microarray samples have high levels of sGAGs. The in vivo accumulation of Triplatin in tumors as well as antitumor efficacy of Triplatin positively correlated with sGAG levels on tumor cells, whereas carboplatin followed the opposite trend. In carboplatin-resistant tumor models expressing high levels of sGAGs, Triplatin decreased primary tumor growth, reduced lung metastases, and inhibited metastatic growth in lungs, liver, and ovaries. sGAG levels served as a predictor of Triplatin sensitivity in TNBC. Triplatin may be particularly beneficial in treating patients with chemotherapy-resistant tumors who have evidence of residual disease after standard neoadjuvant chemotherapy. More effective neoadjuvant and adjuvant treatment will likely improve clinical outcome of TNBC.

Ducks lay eggs and lions have manes: The acceptability of gender-specific minority generic sentences.

Minority characteristic generic statements such as ducks lay eggs are judged to be generally true of the class, despite being true of a minority of cases, such as healthy female ducks of egg-laying age. Five studies explored the factors responsible for the acceptance of minority generic statements about biological kinds. Studies 1 and 2 found that minority generic statements about animals that are true of just 1 sex were no more likely to be accepted as true of the class than were statements true of just 1 of 2 subtypes, not differentiated by sex. Further studies showed that gender-specific properties are more often accepted when related to reproduction (ducks lay eggs) than to appearance (deer have antlers). It is proposed that reproductive properties are more easily interpreted as referring to the kinds themselves, on account of their role in naïve biological theories of the kinds. The result supports the view that minority generics are accepted to the degree that they are embedded in naïve theories of a biological kind. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Concept Appraisal.

This paper reports the first empirical investigation of the hypothesis that epistemic appraisals form part of the structure of concepts. To date, studies of concepts have focused on the way concepts encode properties of objects and the way those features are used in categorization and in other cognitive tasks. Philosophical considerations show the importance of also considering how a thinker assesses the epistemic value of beliefs and other cognitive resources and, in particular, concepts. We demonstrate that there are multiple, reliably judged, dimensions of epistemic appraisal of concepts. Four of these dimensions are accounted for by a common underlying factor capturing how well people believe they understand a concept. Further studies show how dimensions of concept appraisal relate to other aspects of concepts. First, they relate directly to the hierarchical organization of concepts, reflecting the increase in specificity from superordinate to basic and subordinate levels. Second, they predict inductive choices in category-based induction. Our results suggest that epistemic appraisals of concepts form a psychologically important yet previously overlooked aspect of the structure of concepts. These findings will be important in understanding why individuals sometimes abandon and replace certain concepts; why social groups do so, for example, during a "scientific revolution"; and how we can facilitate such changes when we engage in deliberate "conceptual engineering" for epistemic, social, and political purposes.

Colorectal Cancer Screening and Surveillance for Non-Hereditary High-Risk Groups-Is It Time for a Re-Think?

PURPOSE OF REVIEW: Colorectal cancer (CRC) is the second most common cause of cancer death worldwide, killing approximately 900,000 people each year. An individual's risk of developing CRC is multi-factorial with known risk factors including increasing age, male sex, family history of CRC and raised body mass index. Population-based screening programmes for CRC exist in many countries, and in the United Kingdom (UK), screening is performed through the NHS Bowel Cancer Screening Programme (BCSP). Screening programmes offer a population-based approach for those at "average risk", and do not typically offer enhanced screening for groups at increased risk. In the UK, such patients are managed via non-screening symptomatic services but in a non-systematic way. RECENT FINDINGS: There is growing evidence that conditions such as cystic fibrosis and a history of childhood cancer are associated with higher risk of CRC, and surveillance of these groups is advocated by some organizations; however, national recommendations do not exist in most countries. SUMMARY: We review the evidence for screening "high risk" groups not covered within most guidelines and discuss health economic issues requiring consideration acknowledging that the demand on colonoscopy services is already overwhelming.

Conformational Modulation of Iduronic Acid-Containing Sulfated Glycosaminoglycans by a Polynuclear Platinum Compound and Implications for Development of Antimetastatic Platinum Drugs.

1 H NMR spectroscopic studies on the 1:1 adduct of the pentasaccharide Fondaparinux (FPX) and the substitution-inert polynuclear platinum complex TriplatinNC show significant modulation of geometry around the glycosidic linkages of the FPX constituent monosaccharides. FPX is a valid model for the highly sulfated cell signalling molecule heparan sulfate (HS). The conformational ratio of the 1 C4 :2 S0 forms of the FPX residue IdoA(2S) is altered from ca. 35:65 (free FPX) to ca. 75:25 in the adduct; the first demonstration of a small molecule affecting conformational changes on a HS oligosaccharide. Functional consequences of such binding are suggested to be inhibition of HS cleavage in MDA-MB-231 triple-negative breast cancer (TNBC) cells. We further describe inhibition of metastasis by TriplatinNC in the TNBC 4T1 syngeneic tumour model. Our work provides insight into a novel approach for design of platinum drugs (and coordination compounds in general) with intrinsic anti-metastatic potential.

What Makes Some Diseases More Typical than Others? A Survey on the Impact of Disease Characteristics and Professional Background on Disease Typicality.

Health professionals tend to perceive some diseases as more typical than others. If disease typicalities have implications for health professionals or health policy makers' handling of different diseases, then it is of great social, epistemic, and ethical interest. Accordingly, it is important to find out what makes health professionals rank diseases as more or less typical. This study investigates the impact of various factors on how typical various diseases are perceived to be by health professionals. In particular, we study the influence of broad disease categories, such as somatic versus psychological/behavioral conditions, and a wide range of more specific disease characteristics, as well as the health professional's own background. We find that professional background strongly impacted disease typicality. All professionals (MD, RN, physiotherapists and psychologists) considered somatic conditions to be more typical than psychological/behavioral. As expected, psychologists also found psychological/behavioral conditions to be more typical than did other groups. Professions of respondents could be well predicted from their individual typicality judgments, with the exception of physiotherapists and nurses who had very similar judgment profiles. We also demonstrate how various disease characteristics impact typicality for the different professionals. Typicality showed moderate to strong positive correlations with condition severity and mortality, and only non-severe conditions were rated as atypical. Hence, studying how different disease characteristics and occupational background influences health professionals' perception of disease typicality is the first and important step toward a more general study of how typicality influences disease handling.

Declarative Memory and Structural Language Impairment in Autistic Children and Adolescents.

Two experiments tested the hypothesis that a plausible contributory factor of structural language impairment in Autism Spectrum Disorder (ASD) is impaired declarative memory. We hypothesized that familiarity and recollection (subserving semantic and episodic memory, respectively) are both impaired in autistic individuals with clinically significant language impairment and learning disability (ASDLI/LD ); whereas recollection is selectively impaired in autistic individuals with typical language (ASDTL ). Teenagers with ASDLI/LD (n = 19) and primary school age children with ASDTL (n = 26) were compared with teenagers with learning disability (LD) (n = 26) without autism, and primary school aged typically developing (TD) children (n = 32). Both experiments provided strong support for the hypothesized links between declarative memory processes and lexical-semantic facets of language in the two autistic groups, but not in the TD group. Additional findings of interest were that declarative memory processes and lexical-semantic knowledge were also linked in the LD group and that the ASD groups-and to a lesser extent the LD group-may have compensated for declarative memory impairments using spared visual-perceptual abilities, a finding with potential educational implications. Relative difficulties with familiarity and recollection in ASDLI/LD and LD may help explain structural language impairment, as investigated here, but also the broader learning disabilities found in these populations. Autism Res 2020. © 2020 International Society for Autism Research, Wiley Periodicals, Inc. Autism Res 2020, 13: 1947-1958. © 2020 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Language impairment and learning disability affect 45% of the autistic population yet the factors that may be contributing to them is remarkably under-researched. To date there are no explanations of the lexical semantic (word meaning) abnormalities observed in ASD. We found that declarative memory is associated with lexical semantic knowledge in autism and learning disability but not in typical development. Difficulties with declarative memory may also be compensated for using visual-perceptual abilities by autistic and learning-disabled adolescents, which has positive implications for educationalists.

Effectiveness of a Digital Lifestyle Change Program in Obese and Type 2 Diabetes Populations: Service Evaluation of Real-World Data.

BACKGROUND: The prevalence of type 2 diabetes mellitus (T2DM) and obesity is increasing, and the way people interact with health care is evolving. People traditionally access advice and support to improve their lifestyle and learn more about the self-management of T2DM in a face-to-face setting. Although these services have a strong evidence base, they have limitations for reaching specific groups of people. Digital programs could provide a new delivery model to help more people access health education and behavior change support, but long-term data supporting these programs are limited. OBJECTIVE: The purpose of this service evaluation was to analyze the weight change of people who participated in OurPath (also known as Second Nature), a UK-based digital lifestyle change program, for either weight management or diabetes-related weight management and structured education at 6 and 12 months. METHODS: Participants either paid to access the program privately (self-funded clients) or were referred by their general practitioner to participate in the program free of charge (funded by the National Health Service). Additional follow-up support was provided to help people to maintain lifestyle changes. To retrospectively assess potential weight loss, the analysis included data from participants who submitted weight readings at baseline and 6 and 12 months after starting the program. Changes in weight after 6 and 12 months were primary outcome measures. RESULTS: For the 896 participants who submitted baseline and 6- and 12-month data, a significant change in mean weight of -7.12 kg (-7.50%; SD 6.37; P<.001) was observed at 6 months. Data from the same participants at 12 months showed a change in mean weight when compared with a baseline of -6.14 kg (-6.48%; SD 6.97; P<.001). CONCLUSIONS: The data presented here had several limitations, and there were too many uncertainties to make any reliable conclusions. However, these results suggest that digital lifestyle change programs could provide a new way to help people to access nutritional advice and support to achieve weight loss. Further research into digital education and coaching platforms is needed to establish their effectiveness.

Using the validated Reflective Functioning Questionnaire to investigate mentalizing in individuals presenting with eating disorders with and without self-harm.

BACKGROUND: The present study builds on previous research which explored the relationship between mentalizing and eating disorders (ED) in a subgroup of patients with comorbid self-harm (SH). Whereas previous literature had linked this comorbidity to impulse-control difficulties, more recent advances have suggested that a lack of a mentalizing stance might be responsible for a more treatment-resistant and severe symptomatology in this subgroup of clients. METHODS: A cross-sectional, quasi-experimental, questionnaire-based, between-groups design was employed and a measure of mentalizing was compared in individuals presenting with ED only, individuals presenting with ED and concurrent SH and a control group. RESULTS: Individuals with ED with concurrent SH reported significantly more mentalizing ability impairment than individuals without concurrent SH. In addition, both groups differed significantly from the control group. Opposite scoring patterns were identified in hypo- and hypermentalizing with the comorbid group reporting the lowest scores in hypermentalizing and the highest scores in hypomentalizing. CONCLUSIONS: The current findings confirm that individuals with concurrent ED and SH report more severe impairments in mentalizing ability. Such impairments entail difficulties in symbolic capacity and abstract thinking and a concretisation of inner life, exemplified by a rigid, often inflexible focus on the physical world. The clinical implications that a lack of a mentalizing stance can have on individuals' ability to engage with the therapeutic process and to initiate change are reflected upon.