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Introduction: Endoscopy is still the gold, standard for assessing disease activity in Crohn's disease (CD). Its invasiveness, poor acceptability, and cost limit its use in the era of tight control and treat-to-target management. Fecal calprotectin (FC) and intestinal ultrasound (IUS) are non-invasive alternatives to colonoscopy to assess disease activity. We aimed to evaluate the performance of IUS and FC to assess mucosal healing in CD., Methods: All consecutive CD patients who underwent colonoscopy for mucosal healing assessment and IUS and/or FC within four weeks between September 2019 and April 2022 were included in a prospective cohort. The bowel-wall thickness (BWT) and color Doppler signal (CDS) were assessed for each segment. Endoscopic remission was defined by a CDEIS score < 3., Results: In total, 153 patients were included, of whom 122 showed endoscopic mucosal healing. Eighty-two (53.6 %) were female, the median was age 36 years (IQR, 28-46), and the median disease duration was 10 years (IQR, 4-19). The sensitivity (Se), specificity (Sp), positive predictive value (PPV), and negative predictive value (NPV) of a BWT < 3 mm to predict endoscopic mucosal healing were 56 %, 88 %, 95 %, and 36 %, respectively (patients misclassified as mucosal healing, 2.5 %). The best FC threshold (< 92.9 µg/g) provided similar results: 77 %, 89 %, 96 %, and 67 %, respectively (patients misclassified, 2.2 %). The association of an FC < 250 µg/g with a BWT < 3 mm and the absence of CDS increased the Sp and PPV: Se 58 %, Sp 95 %, PPV 97 %, VPN 43 %; patients misclassified, 1.3 %., Conclusion: Noninvasive evaluation of mucosal healing by IUS or calprotectin efficiently identifies patients with CD who have achieved endoscopic mucosal healing., Competing Interests: Declaration of competing interest CY: consultant and lecture fees from Abbvie, Takeda, Janssen, Amgen, and Galapagos MF: consultant and lecture fees from Abbvie, Takeda, Janssen, Amgen, Galapagos, Gilead, Biogen, Fresenius, Pfizer, Lilly, Celltrion, Ferring, Tillots, and Nordic Pharma VH: AAA, Merck KGaA, Amgen, Servier, Deciphera, Ipsen, and Pierre Fabre The other authors have nothing to declare., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Background: Artificial intelligence systems have been developed to improve polyp detection. We aimed to evaluate the effect of real-time computer-aided detection (CADe) on the adenoma detection rate (ADR) in routine colonoscopy., Methods: This single-centre randomised controlled trial (COLO-GENIUS) was done at the Digestive Endoscopy Unit, Pôle Digestif Paris-Bercy, Clinique Paris-Bercy, Charenton-le-Pont, France. All consecutive individuals aged 18 years or older who were scheduled for a total colonoscopy and had an American Society of Anesthesiologists score of 1-3 were screened for inclusion. After the caecum was reached and the colonic preparation was appropriate, eligible participants were randomly assigned (1:1; computer-generated random numbers list) to either standard colonoscopy or CADe-assisted colonoscopy (GI Genius 2.0.2; Medtronic). Participants and cytopathologists were masked to study assignment, whereas endoscopists were not. The primary outcome was ADR, which was assessed in the modified intention-to-treat population (all randomly assigned participants except those with misplaced consent forms). Safety was analysed in all included patients. According to statistical calculations, 20 endoscopists from the Clinique Paris-Bercy had to include approximately 2100 participants with 1:1 randomisation. The trial is complete and registered with ClinicalTrials.gov, NCT04440865., Findings: Between May 1, 2021, and May 1, 2022, 2592 participants were assessed for eligibility, of whom 2039 were randomly assigned to standard colonoscopy (n=1026) or CADe-assisted colonoscopy (n=1013). 14 participants in the standard group and ten participants in the CADe group were then excluded due to misplaced consent forms, leaving 2015 participants (979 [48·6%] men and 1036 [51·4%] women) in the modified intention-to-treat analysis. ADR was 33·7% (341 of 1012 colonoscopies) in the standard group and 37·5% (376 of 1003 colonoscopies) in the CADe group (estimated mean absolute difference 4·1 percentage points [95% CI 0·0-8·1]; p=0·051). One bleeding event without deglobulisation occurred in the CADe group after a large (>2 cm) polyp resection and resolved after a haemostasis clip was placed during a second colonoscopy., Interpretation: Our findings support the benefits of CADe, even in a non-academic centre. Systematic use of CADe in routine colonoscopy should be considered., Funding: None., Competing Interests: Declaration of interests DK is a consultant for Olympus and has received financial support for attending meetings from Alfasigma and Fujifilm. FV has recieved honoraria for lectures, presentations, and speaking at events from AbbVie, Takeda, Amgen, and Janssen-Cilag; financial support for attending meetings from AbbVie; and is on the advisory board for Janssen-Cilag and Biogen. MC is a consultant for Janssen-Cilag, AbbVie, and MSD; has received honoraria for lectures, presentations, and speaking at events for MSD France, Amgen, Takeda, Pfizer, Mylan, and Tillots; financial support for attending meetings from Ferring, Takeda, and MSD; is on the advisory board for Janssen-Cilag and AbbVie; and has received equipment and materials from Celtrion and Biosynex. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Drug development in oncology commonly exploits the tools of molecular biology to gain therapeutic benefit through reprograming of cellular responses. In immuno-oncology (IO) the aim is to direct the patient's own immune system to fight cancer. After remarkable successes of antibodies targeting PD1/PD-L1 and CTLA4 receptors in targeted patient populations, the focus of further development has shifted toward combination therapies. However, the current drug-development approach of exploiting a vast number of possible combination targets and dosing regimens has proven to be challenging and is arguably inefficient. In particular, the unprecedented number of clinical trials testing different combinations may no longer be sustainable by the population of available patients. Further development in IO requires a step change in selection and validation of candidate therapies to decrease development attrition rate and limit the number of clinical trials. Quantitative systems pharmacology (QSP) proposes to tackle this challenge through mechanistic modeling and simulation. Compounds' pharmacokinetics, target binding, and mechanisms of action as well as existing knowledge on the underlying tumor and immune system biology are described by quantitative, dynamic models aiming to predict clinical results for novel combinations. Here, we review the current QSP approaches, the legacy of mathematical models available to quantitative clinical pharmacologists describing interaction between tumor and immune system, and the recent development of IO QSP platform models. We argue that QSP and virtual patients can be integrated as a new tool in existing IO drug development approaches to increase the efficiency and effectiveness of the search for novel combination therapies., (© 2020 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Objective: Endocuff Vision (ECV) is the second generation of a device designed to improve polyp detection. The aim of this study was to evaluate its impact on adenoma detection rate (ADR) in routine colonoscopy., Design: This cluster-randomised crossover trial compared Endocuff-assisted (ECV+) with standard (ECV-) colonoscopy. Two teams of 11 endoscopists each with prior ECV experience, balanced in terms of basal ADR, gender and case volume were compared. In randomised fashion, the teams started with ECV+ or ECV- and switched group after inclusion of half of the cases. The main outcome criterion was ADR difference between ECV+ and ECV-. Subgroup analysis was done for physicians with low and high ADR (< or ≥ 25%)., Results: During two periods of 20 and 21 weeks, respectively, the 22 endoscopists included 2058 patients (1032 ECV- vs 1026 ECV+, both groups being comparable). Overall ADR for both groups taken together was higher with ECV (39.2%) than without (29.4%; p<0.001) irrespective of the sequence of use (ECV+ or ECV- first), but mostly in adenomas <1 cm. In the physician subgroup analysis, only high detectors showed a significant ADR increase (from 31% to 41%, p<0.001), while the increase in the low detectors was not significant (from 24% to 30%, p=0.11). ECV had a positive impact in all colonic locations, except for the rectum. No ECV- related complication was reported., Conclusion: We observed a significant ADR difference of approximately 10% by the use of ECV. By subgroup analysis, this increase was significant only in physicians classified as high detectors., Trial Registration Number: ClinicalTrials.gov (NCT03344055)., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Adenoma detection rate (ADR) is correlated with the risk of interval colorectal cancer and is considered as a quality benchmark for colonoscopy. Serrated polyp detection rate (SPDR) might be a more stringent indicator of quality in polyp detection., Aims: To evaluate in a 2-year monocentric observational study patient-dependent and endoscopist-dependent factors influencing ADR and SPDR in daily practice., Methods: We determined ADR and SPDR. We collected patient-dependent factors and endoscopist-dependent factors. Links between these data and detection rates were assessed by uni- and multivariate analysis., Results: A total of 11682 colonoscopies were performed (female: 54.3%; male: 45.7%; median age 58) by 30 endoscopists (female: 9; male: 21). ADR and SPDR were 29.2% and 8%, respectively. In multivariate analysis, ADR was associated with patient-dependent factors: age (OR 1.044, CI 95% 1.040-1.048), male gender (OR 1.7, CI 95% 1.56-1.85), personal history of polyp/cancer (OR 1.53, CI 95% 1.3-1.9), and positive fecal immunochemical test (OR 2.47, CI 95% 2.0-3.1). In multivariate analysis, SPDR was associated with withdrawal time (OR 1.25, CI 95% 1.17-1.32), low volume activity (OR 1.3, CI 95% 1.1-1.52), and personal history of polyp/cancer (OR 1.61, CI 95% 1.15-2.25)., Conclusion: In this large series of routine colonoscopies, we found that ADR was mainly driven by patient-dependent conditions, i.e., age, male gender, colonoscopy indication for positive FIT, and a personal history of polyp or cancer. In contrast, SPDR was mainly related to endoscopist-dependent factor, i.e., withdrawal time and low volume activity.

Background: Colonoscopy is considered a valid primary screening tool for colorectal cancer (CRC). The decreasing risk of CRC observed in patients undergoing colonoscopy is correlated with the adenoma detection rate (ADR). Due to the fact that screening programs usually start from the age of 50, very few data are available on the risk of adenoma between 40 and 49 years. However, the incidence of CRC is increasing in young populations and it is not uncommon in routine practice to detect adenomas or even advanced neoplasia during colonoscopy in patients under 50 years., Aim: To compare the ADR and advanced neoplasia detection rate (ANDR) according to age in a large series of patients during routine colonoscopy., Methods: All consecutive patients who were scheduled for colonoscopy were included. Exclusion criteria were as follows: patients scheduled for partial colonoscopy or interventional colonoscopy (for stent insertion or stenosis dilation). Colonoscopies were performed in our unit by a team of 30 gastroenterologists in 2016. We determined the ADR and ANDR in each age group in the whole population and in the population with an average risk of CRC (excluding patients with personal or family history of advanced adenoma or cancer)., Results: 6027 colonoscopies were performed in patients with a median age of 57 years (range, 15-96). The ADR and ANDR were 28.6% and 9.7%, respectively, in the whole population. When comparing patients aged 40-44 ( n = 382) and 45-49 years ( n = 515), a strong increase in all parameters from 45 years was observed, with the ADR rising from 9.7% in patients aged 40-44 to 21.2% between 45 and 49 ( P < 0.001) and the ANDR increasing from 3.1% in patients aged 40-44 to 6.4% in those aged 45-49 years ( P < 0.03). With regard to patients aged 50-54 ( n = 849), a statistically significant increase in the ADR and ANDR was not observed between patients aged 45-49 and those aged 50-54 years. In the population with an average risk of CRC, the ADR and ANDR were still significantly higher in patients aged 45-49 compared with those aged 40-44 years., Conclusion: This study shows a significant two-fold increase in the ADR and ANDR in patients aged 45 years and over., Competing Interests: Conflict-of-interest statement: All the Authors have no conflict of interest related to the manuscript.

Spatial relocalization of proteins is crucial for the correct functioning of living cells. An interesting example of spatial ordering is the light-induced clustering of plant photoreceptor proteins. Upon irradiation by white or red light, the red light-active phytochrome, phytochrome B, enters the nucleus and accumulates in large nuclear bodies (NBs). The underlying physical process of nuclear body formation remains unclear, but phytochrome B is thought to coagulate via a simple protein-protein binding process. We measure, for the first time, the distribution of the number of phytochrome B-containing NBs as well as their volume distribution. We show that the experimental data cannot be explained by a stochastic model of nuclear body formation via simple protein-protein binding processes using physically meaningful parameter values. Rather modelling suggests that the data is consistent with a two step process: a fast nucleation step leading to macroparticles followed by a subsequent slow step in which the macroparticles bind to form the nuclear body. An alternative explanation for the observed nuclear body distribution is that the phytochromes bind to a so far unknown molecular structure. We believe it is likely this result holds more generally for other nuclear body-forming plant photoreceptors and proteins.

Phytochromes are red/far-red-light detecting photoreceptors that regulate plant growth and development. They photo-interconvert between an inactive Pr (red-light absorbing) and a physiologically active Pfr (far-red-light absorbing) form, acting as light-controlled molecular switches. Although the two major plant phytochromes A (phyA) and B (phyB) share similar absorption properties, they exhibit dramatic differences in their action spectra. Since both phytochromes antagonistically regulate seedling development under vegetative shade, it is essential for plants to clearly distinguish between phyA and phyB action. This discrimination is not comprehensible solely by the molecular properties of the phytochromes, but is evidently due to the dynamics of the phytochrome system. Using an integrated experimental and mathematical modelling approach we show that phytochrome dimerization is an essential element for phyB function. Our findings reveal that light-independent Pfr to Pr relaxation (dark reversion) and association/dissociation to nuclear bodies (NBs) severely depend on the conformational state of the phyB dimer. We conclude that only Pfr-Pfr homodimers of phyB can be responsible for triggering physiological responses, leading to a suppression of phyB function in the far-red range of the light spectrum.

Normal human peripheral blood lymphocytes were irradiated for 10 or 5 min with frequencies from 1.5 to 2.0 GHz. The frequency of 1.8 GHz overlaps that of mobile phones and leads to a significant reduction of the T-cell mediated antibacterial activity.

In centers without hemodynamic laboratories the quality of medical care may be suboptimal since the unavailability of these technologies may reduce medical experience in the treatment of heart disease, mostly in acute coronary syndromes, and may increase the need for referring some patients to other hospitals. The problem will be of great relevance in the case of expansion of the aggressive approach in the treatment of acute ischemic syndromes such as acute myocardial infarction and unstable angina. The impelling need for small centers of improving medical care may promote the spontaneous and uncontrolled proliferation of hemodynamic laboratories. The high number of hemodynamic laboratories may lead to a low institutional volume and, as a consequence, may negatively influence the outcome of coronary intervention and increase health care costs. The experience of operators and the costs are probably more relevant as regards angioplasty than coronary angiography. Therefore we propose the implementation of departments of interventional hemodynamic laboratories including different hospitals: diagnostic laboratories will be allocated in hospitals with coronary care units, while interventional laboratories will be allocated in referring hospitals.