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In Eurotransplant, relatively more females than males die while waiting for liver transplantation, and relatively fewer females undergo transplantation. With adult liver transplantation candidates listed between 2007 and 2019 (n = 21 170), we study whether sex disparity is inherent to the model for end-stage liver disease (MELD) scoring system, or the indirect result of a small candidate body size limiting access to transplantation. Cox proportional hazard models are used to quantify the direct effect of sex on waitlist mortality, independent of the effect of sex through MELD scores, and the direct effect of sex on the transplantation rate, independent of the effect of sex through MELD and candidate body size. Adjusted waitlist mortality hazard ratios (HRs) for female sex are insignificant (HR: 1.03, 95% CI: 0.88-1.20). We thus lack evidence that MELD systematically underestimates waitlist mortality rates for females. Transplantation rates are 25% lower for females than males in unadjusted analyses (HR: 0.74, 95% CI: 0.71-0.77), but HRs become insignificant with adjustment for mediators (HR: 0.98, 95% CI: 0.93-1.04), most importantly candidate body size. Sex disparity in Eurotransplant thus appears to be largely a consequence of lower transplantation rates for females, which are explained by sex differences in body size.

ObjectiveEndoscopic mucosal resection (EMR) is the preferred treatment for non-invasive large (≥20 mm) non-pedunculated colorectal polyps (LNPCPs) but is associated with an early recurrence rate of up to 30%. We evaluated whether standardised EMR training could reduce recurrence rates in Dutch community hospitals.DesignIn this multicentre cluster randomised trial, 59 endoscopists from 30 hospitals were randomly assigned to the intervention group (e-learning and 2-day training including hands-on session) or control group. From April 2019 to August 2021, all consecutive EMR-treated LNPCPs were included. Primary endpoint was recurrence rate after 6 months.ResultsA total of 1412 LNPCPs were included; 699 in the intervention group and 713 in the control group (median size 30 mm vs 30 mm, 45% vs 52% size, morphology, site and access (SMSA) score IV, 64% vs 64% proximal location). Recurrence rates were lower in the intervention group compared with controls (13% vs 25%, OR 0.43; 95% CI 0.23 to 0.78; p=0.005) with similar complication rates (8% vs 9%, OR 0.93; 95% CI 0.64 to 1.36; p=0.720). Recurrences were more often unifocal in the intervention group (92% vs 76%; p=0.006). In sensitivity analysis, the benefit of the intervention on recurrence rate was only observed in the 20–40 mm LNPCPs (5% vs 20% in 20–29 mm, p=0.001; 10% vs 21% in 30–39 mm, p=0.013) but less evident in ≥40 mm LNPCPs (24% vs 31%; p=0.151). In a post hoc analysis, the training effect was maintained in the study group, while in the control group the recurrence rate remained high.ConclusionA compact standardised EMR training for LNPCPs significantly reduced recurrences in community hospitals. This strongly argues for a national dedicated training programme for endoscopists performing EMR of ≥20 mm LNPCPs. Interestingly, in sensitivity analysis, this benefit was limited for LNPCPs ≥40 mm.Trial registration numberNTR7477.

IMPORTANCE: Despite guideline recommendations, clinicians do not systematically use prior screening or health history to guide colorectal cancer (CRC) screening decisions in older adults. OBJECTIVE: To evaluate the effect of a personalized multilevel intervention on screening orders in older adults due for average-risk CRC screening. DESIGN, SETTING, AND PARTICIPANTS: Interventional 2-group parallel unmasked cluster randomized clinical trial conducted from November 2015 to February 2019 at 2 US Department of Veterans Affairs (VA) facilities: 1 academic VA medical center and 1 of its connected outpatient clinics. Randomization at the primary care physician/clinician (PCP) level, stratified by study site and clinical full-time equivalency. Participants were 431 average-risk, screen-due US veterans aged 70 to 75 years attending a primary care visit. Data analysis was performed from August 2018 to August 2023. INTERVENTION: The intervention group received a multilevel intervention including a decision-aid booklet with detailed information on screening benefits and harms, personalized for each participant based on age, sex, prior screening, and comorbidity. The control group received a multilevel intervention including a screening informational booklet. All participants received PCP education and system-level modifications to support personalized screening. MAIN OUTCOMES AND MEASURES: The primary outcome was whether screening was ordered within 2 weeks of clinic visit. Secondary outcomes were concordance between screening orders and screening benefit and screening utilization within 6 months. RESULTS: A total of 436 patients were consented, and 431 were analyzed across 67 PCPs. Patients had a mean (SD) age of 71.5 (1.7) years; 424 were male (98.4%); 374 were White (86.8%); 89 were college graduates (21.5%); and 351 (81.4%) had undergone prior screening. A total of 258 (59.9%) were randomized to intervention, and 173 (40.1%) to control. Screening orders were placed for 162 of 258 intervention patients (62.8%) vs 114 of 173 control patients (65.9%) (adjusted difference, −4.0 percentage points [pp]; 95% CI, −15.4 to 7.4 pp). In a prespecified interaction analysis, the proportion receiving orders was lower in the intervention group than in the control group for those in the lowest benefit quartile (59.4% vs 71.1%). In contrast, the proportion receiving orders was higher in the intervention group than in the control group for those in the highest benefit quartile (67.6% vs 52.2%) (interaction P = .049). Fewer intervention patients (106 of 256 [41.4%]) utilized screening overall at 6 months than controls (96 of 173 [55.9%]) (adjusted difference, −13.4 pp; 95% CI, −25.3 to −1.6 pp). CONCLUSIONS AND RELEVANCE: In this cluster randomized clinical trial, patients who were presented with personalized information about screening benefits and harms in the context of a multilevel intervention were more likely to receive screening orders concordant with benefit and were less likely to utilize screening. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02027545

ObjectivesTo examine the prognostic potential of repeated faecal haemoglobin (F-Hb) concentration measurements in faecal immunochemical test (FIT)-based screening for colorectal cancer (CRC).DesignPrognostic model.SettingDutch biennial FIT-based screening programme during 2014–2018.Participants265 881 participants completing three rounds of FIT, with negative test results (F-Hb <47 µg Hb/g faeces) in rounds 1 and 2.InterventionsColonoscopy follow-up in participants with a positive FIT (F-Hb ≥47 µg Hb/g faeces).Main outcomesWe evaluated prognostic models for detecting advanced neoplasia (AN) and CRC in round 3, with as predictors, participant age, sex, F-Hb in rounds 1 and 2, and categories/combinations/non-linear transformations of F-Hb. Primary evaluation criteria included: risk prediction accuracy (calibration), discrimination of participants with versus without AN or CRC (optimism-adjusted C-statistics, range 0.5–1.0), the degree of risk stratification and C-statistics in external validation.ResultsAmong study participants, 8806 (3.3%) had a positive FIT result, 3254 (1.2%) had AN detected and 557 (0.2%) had cancer. F-Hb concentrations in rounds 1 and 2 were the strongest outcome predictors, with adjusted ORs of up to 9.4 (95% CI 7.5 to 11.7) for the highest F-Hb category. Risk predictions matched the observed risk for most participants (calibration intercept −0.008 to −0.099; slope 0.982–0.998), and discriminated participants with versus without AN or CRC with C-statistics of 0.78 (95% CI 0.77 to 0.79) and 0.73 (95% CI 0.71 to 0.75), respectively. The predicted risk ranged from 0.4% to 36.7% for AN and from 0.0% to 5.5% for CRC across participants. In external validation, the model retained similar discrimination accuracy for AN (C-statistic 0.77, 95% CI 0.66 to 0.87) and CRC (C-statistic 0.78, 95% CI 0.66 to 0.91).ConclusionParticipants at lower versus higher risk of future AN or CRC can be accurately identified based on their age, sex and particularly, prior F-Hb concentrations. Risk stratification should be considered based on this information.

ObjectiveTo assess the impact of delayed invitation on screen-detected and interval colorectal cancers (CRC) within a faecal immunochemical testing (FIT)-based CRC screening programme.DesignAll individuals that participated in 2017 and 2018 with a negative FIT and were eligible for CRC screening in 2019 and 2020 were included using individual-level data. Multivariable logistic regression analyses were used to assess the association between either the different time periods (ie, ‘before’, ‘during’ and ‘after’ the first COVID-19 wave) or the invitation interval on screen-detected and interval CRCs.ResultsPositive predictive value for advanced neoplasia (AN) was slightly lower during(OR=0.91) and after(OR=0.95) the first COVID-19 wave, but no significant difference was observed for the different invitation intervals. Out of all individuals that previously tested negative, 84 (0.004%) had an interval CRC beyond the 24 months since their last invitation. The time period of invitation as well as the extended invitation interval was not associated with detection rates for AN and interval CRC rate.ConclusionThe impact of the first COVID-19 wave on screening yield was modest. A very small proportion of the FIT negatives had an interval CRC possibly due to an extended interval, which potentially could have been prevented if they had received the invitation earlier. Nonetheless, no increase in interval CRC rate was observed, indicating that an extended invitation interval up to 30 months had no negative impact on the performance of the CRC screening programme and a modest extension of the invitation interval seems an appropriate intervention.

Adenoma detection rate (ADR) is a well-established quality indicator for colonoscopy and is inversely associated with the incidence of interval post-colonoscopy colorectal cancer. However, interval post-colonoscopy colorectal cancers frequently develop from serrated polyps, which are not included in the ADR. Therefore, the proximal serrated polyp detection rate (PSPDR) has been proposed as a quality indicator, but its association with interval post-colonoscopy colorectal cancer has not been studied. We aimed to evaluate this potential association based on data collected in the Dutch colorectal cancer screening programme.

Classical approaches for the backbone cyclization of polypeptides require conditions that may compromise the chirality of the C-terminal residue during the activation step of the cyclization reaction. Here, we describe an efficient epimerization-free approach for the Fmoc-based synthesis of murepavadin using intramolecular native chemical ligation in combination with a concomitant desulfurization reaction. Using this approach, bioactive murepavadin was produced in a good yield in two steps. The synthetic peptide antibiotic showed potent activity against different clinical isolates of P. aeruginosa. This approach can be easily adapted for the production of murepavadin analogues and other backbone-cyclized peptides.

Liver function is measured regularly in liver transplantation (LT) candidates. Currently, these previous disease development data are not used for survival prediction. By constructing and validating joint models (JMs), we aimed to predict the outcome based on all available data, using both disease severity and its rate of change over time. Adult LT candidates listed in Eurotransplant between 2007 and 2018 (n= 16 283) and UNOS between 2016 and 2019 (n= 30 533) were included. Patients with acute liver failure, exception points, or priority status were excluded. Longitudinal MELD(‐Na) data were modeled using spline‐based mixed effects. Waiting list survival was modeled with Cox proportional hazards models. The JMs combined the longitudinal and survival analysis. JM 90‐day mortality prediction performance was compared to MELD(‐Na) in the validation cohorts. MELD(‐Na) score and its rate of change over time significantly influenced patient survival. The JMs significantly outperformed the MELD(‐Na) score at baseline and during follow‐up. At baseline, MELD‐JM AUC and MELD AUC were 0.94 (0.92–0.95) and 0.87 (0.85–0.89), respectively. MELDNa‐JM AUC was 0.91 (0.89–0.93) and MELD‐Na AUC was 0.84 (0.81–0.87). The JMs were significantly (p< .001) more accurate than MELD(‐Na). After 90 days, we ranked patients for LT based on their MELD‐Na and MELDNa‐JM survival rates, showing that MELDNa‐JM‐prioritized patients had three times higher waiting list mortality. Dynamic prediction of waitlist survival using joint modeling of liver disease development over time better predicts survival, compared to the model for end‐stage liver disease sodium score, for both Eurotransplant and UNOS liver transplant candidates. See Bittermann and Abt's editorial on page 3511‐3512.

Liver function is measured regularly in liver transplantation (LT) candidates. Currently, these previous disease development data are not used for survival prediction. By constructing and validating joint models (JMs), we aimed to predict the outcome based on all available data, using both disease severity and its rate of change over time. Adult LT candidates listed in Eurotransplant between 2007 and 2018 (n= 16 283) and UNOS between 2016 and 2019 (n= 30 533) were included. Patients with acute liver failure, exception points, or priority status were excluded. Longitudinal MELD(-Na) data were modeled using spline-based mixed effects. Waiting list survival was modeled with Cox proportional hazards models. The JMs combined the longitudinal and survival analysis. JM 90-day mortality prediction performance was compared to MELD(-Na) in the validation cohorts. MELD(-Na) score and its rate of change over time significantly influenced patient survival. The JMs significantly outperformed the MELD(-Na) score at baseline and during follow-up. At baseline, MELD-JM AUC and MELD AUC were 0.94 (0.92–0.95) and 0.87 (0.85–0.89), respectively. MELDNa-JM AUC was 0.91 (0.89–0.93) and MELD-Na AUC was 0.84 (0.81–0.87). The JMs were significantly (p< .001) more accurate than MELD(-Na). After 90 days, we ranked patients for LT based on their MELD-Na and MELDNa-JM survival rates, showing that MELDNa-JM-prioritized patients had three times higher waiting list mortality.

IMPORTANCE: In 2018, only half of US women obtained all evidence-based cancer screenings. This proportion may have declined during the COVID-19 pandemic because of social distancing, high-risk factors, and fear. OBJECTIVE: To evaluate optimal screening strategies in women who obtain some, but not all, US Preventive Services Task Force (USPSTF)–recommended cancer screenings. DESIGN, SETTING, AND PARTICIPANTS: This modeling study was conducted from January 31, 2017, to July 20, 2020, and used 4 validated mathematical models from the National Cancer Institute’s Cancer Intervention and Surveillance Modeling Network using data from 20 million simulated women born in 1965 in the US. INTERVENTIONS: Forty-five screening strategies were modeled that combined breast, cervical, colorectal, and/or lung cancer (LC) screenings; restricted to 1, 2, 3 or 4 screenings per year; or all eligible screenings once every 5 years. MAIN OUTCOMES AND MEASURES: Modeled life-years gained from restricted cancer screenings as a fraction of those attainable from full compliance with USPSTF recommendations (maximum benefits). Results were stratified by LC screening eligibility (LC-eligible/ineligible). We repeated the analysis with 2018 adherence rates, evaluating the increase in adherence required for restricted screenings to have the same population benefit as USPSTF recommendations. RESULTS: This modeling study of 20 million simulated US women found that it was possible to reduce screening intensity to 1 carefully chosen test per year in women who were ineligible for LC screening and 2 tests per year in eligible women while maintaining 94% or more of the maximum benefits. Highly ranked strategies screened for various cancers, but less often than recommended by the USPSTF. For example, among LC-ineligible women who obtained just 1 screening per year, the optimal strategy frequently delayed breast and cervical cancer screenings by 1 year and skipped 3 mammograms entirely. Among LC-eligible women, LC screening was essential; strategies omitting it provided 25% or less of the maximum benefits. The top-ranked strategy restricted to 2 screenings per year was annual LC screening and alternating fecal immunochemical test with mammography (skipping mammograms when due for cervical cancer screening, 97% of maximum benefits). If adherence in a population of LC-eligible women obtaining 2 screenings per year were to increase by 1% to 2% (depending on the screening test), this model suggests that it would achieve the same benefit as USPSTF recommendations at 2018 adherence rates. CONCLUSIONS AND RELEVANCE: This modeling study of 45 cancer screening strategies suggests that women who are noncompliant with cancer screening guidelines may be able to reduce USPSTF-recommended screening intensity with minimal reduction in overall benefits.

Colorectal cancer screening programmes worldwide have been disrupted during the COVID-19 pandemic. We aimed to estimate the impact of hypothetical disruptions to organised faecal immunochemical test-based colorectal cancer screening programmes on short-term and long-term colorectal cancer incidence and mortality in three countries using microsimulation modelling.

The MELD score is used in the Eurotransplant (ET) region to allocate liver grafts. Hyponatremia in cirrhotic patients is an important predictor of death but is not incorporated in MELD. This study investigated the performance of the MELD‐Na score for the ET region. All adult patients with chronic liver disease on the ET liver transplantation waiting list (WL) allocated through lab MELD scores were included. The MELD‐corrected effect of serum sodium (Na) concentration at listing on the 90‐day WL mortality was calculated using Cox regression. The MELD‐Na performance was assessed with c‐indices, calibration per decile and Brier scores. The reclassification from MELD to MELD‐Na score was calculated to estimate the impact of MELD‐Na‐based allocation in the ET region. For the 5223 included patients, the risk of 90‐day WL death was 2.9 times higher for hyponatremic patients. The MELD‐Na had a significantly higher c‐index of 0.847 (SE 0.007) and more accurate 90‐day mortality prediction compared to MELD (Brier score of 0.059 vs 0.061). It was estimated that using MELD‐Na would reduce WL mortality by 4.9%. The MELD‐Na score yielded improved prediction of 90‐day WL mortality in the ET region and using MELD‐Na for liver allocation will very likely reduce WL mortality. This study validates the MELD‐Na for the Eurotransplant region, showing that its implementation could reduce waitlist mortality.

According to Fourier’s law, a temperature difference across a material results in a linear temperature profile and a thermal conductance that decreases inversely proportional to the system length. These are the hallmarks of diffusive heat flow. Here, we report heat flow in ultrathin (25 nm) GaP nanowires in the absence of a temperature gradient within the wire and find that the heat conductance is independent of wire length. These observations deviate from Fourier’s law and are direct proof of ballistic heat flow, persisting for wire lengths up to at least 15 μm at room temperature. When doubling the wire diameter, a remarkably sudden transition to diffusive heat flow is observed. The ballistic heat flow in the ultrathin wires can be modeled within Landauer’s formalism by ballistic phonons with an extraordinarily long mean free path.

ABSTRACTThe Pacific coast of North America is a hypothesized route by which the earliest inhabitants of the Americas moved southwards around the western margin of the Cordilleran Ice Sheet just after the last glacial maximum. To test this hypothesis, we have been using a stepwise process to aid in late Pleistocene archaeological site discovery along the coast. The steps involved include: (1) creating localized sea level curves; (2) generating detailed bare earth digital elevation models; (3) creating archaeological predictive models; (4) ground truthing these models using archaeological prospection; and (5) demonstrating that archaeological materials found date to the late Pleistocene. Here, we consider the use of these steps and how they have been employed to find late Pleistocene archaeological sites along the Pacific Coast of North America.

Faecal immunochemical test (FIT)-based colorectal cancer screening requires successive rounds for maximum preventive effect. Advanced neoplasia can bleed intermittently and thus might be missed by single faecal sampling. Few studies have been done on two sample FIT (2-FIT) screening over multiple rounds. Therefore, we compared multiple rounds of one sample FIT (1-FIT) with 2-FIT screening with respect to participation, positive predictive value (PPV), diagnostic yield, and interval colorectal cancer.

Faecal immunochemical tests (FITs) are recommended for colorectal cancer screening. Two frequently used FIT methods (FOB-Gold, Sentinel Diagnostics, Milan, Italy and OC-Sensor, Eiken Chemical, Tokyo, Japan) perform similarly in detecting advanced neoplasia (ie, colorectal cancer and advanced adenoma) at a fixed positivity cutoff for faecal haemoglobin concentration. It is unclear whether the performance of the two methods is also comparable at other thresholds. We compared the accuracy of the two assays in detecting advanced neoplasia across various thresholds.

The conceptual application of complex coacervate core micelles (C3Ms) as drug delivery vehicles has obtained significant interest over the past several decades. Although C3Ms show promise in targeting specific body areas and improving drug circulation times, their low reproducibility and limited stability have hindered their progression to clinical trials and commercial viability. One of the major obstacles is the lack of understanding of the formation and growth kinetics of C3Ms. Since their structure is often controlled kinetically rather than thermodynamically, this insight is essential for achieving good reproducibility and stability of C3M drug delivery vehicles. Time-resolved small-angle X-ray scattering (TR-SAXS) offers excellent insights by resolving spatiotemporal kinetic processes on nanometer/millisecond scales. Here, we investigate the formation kinetics of C3Ms comprised of the antimicrobial peptide, colistin, and poly(ethylene oxide)-b-poly(methacrylic acid) (PEO-b-PMAA). Using TR-SAXS coupled to stopped-flow mixing, we have identified three distinct steps in the mechanism of this complex coacervation system: nucleation, fusion, and single chain/ion-pair insertion. Nucleation cannot be experimentally resolved as it is completed during the mixing process. The fusion kinetics proceed as a first-order reaction with relaxation times of approximately 50–85 ms. The driving force for fusion is larger at increased concentrations. Chain/pair insertion occurs at relaxation times of 15–25 s, where larger remaining size mismatches (higher dispersity) drive the final equilibration process. As expected, the structural formation is concentration-dependent, providing a handle to acquire control over the size and dispersity of these kinetically trapped C3Ms. These findings contribute to a deeper understanding of C3M formation and stability, potentially advancing the development of C3M-based drug delivery systems.

To combat the ever-growing increase of multidrug-resistant (MDR) bacteria, action must be taken in the development of antibiotic formulations. Colistin, an effective antibiotic, was found to be nephrotoxic and neurotoxic, consequently leading to a ban on its use in the 1980s. A decade later, colistin use was revived and nowadays used as a last-resort treatment against Gram-negative bacterial infections, although highly regulated. If cytotoxicity issues can be resolved, colistin could be an effective option to combat MDR bacteria. Herein, we investigate the complexation of colistin with poly(ethylene oxide)-b-poly(methacrylic acid) (PEO-b-PMAA) block copolymers to form complex coacervate core micelles (C3Ms) to ultimately improve colistin use in therapeutics while maintaining its effectiveness. We show that well-defined and stable micelles can be formed in which the cationic colistin and anionic PMAA form the core while PEO forms a protecting shell. The resulting C3Ms are in a kinetically arrested and stable state, yet they can be made reproducibly using an appropriate experimental protocol. By characterization through dynamic light scattering (DLS) and small-angle X-ray scattering (SAXS), we found that the best C3M formulation, based on long-term stability and complexation efficiency, is at charge-matching conditions. This nanoparticle formulation was compared to noncomplexed colistin on its antimicrobial properties, enzymatic degradation, serum protein binding, and cytotoxicity. The studies indicate that the antimicrobial properties and cytotoxicity of the colistin-C3Ms were maintained while protein binding was limited, and enzymatic degradation decreased after complexation. Since colistin-C3Ms were found to have an equal effectivity but with increased cargo protection, such nanoparticles are promising components for the antibiotic formulation toolbox.

Colistin methanesulfonate (CMS) is the less-toxic prodrug of highly nephrotoxic colistin. To develop and understand highly necessary new antibiotic formulations, the hydrolysis of CMS to colistin must be better understood. Herein, with the addition of poly(ethylene oxide)-b-poly(methacrylic acid) (PEO-b-PMAA) to CMS, we show that we can follow the hydrolysis kinetics, employing small-angle X-ray scattering (SAXS) through complex coacervation. During this hydrolysis, hydroxy methanesulfonate (HMS) groups from CMS are cleaved, while the newly formed cationic amino groups complex with the anionic charge from the PMAA block. As the hydrolysis of HMS groups is slow, we can follow the complex coacervation process by the gradual formation of complex micelles containing activated antibiotics. Combining mass spectrometry (MS) with SAXS, we quantify the hydrolysis as a function of pH. Upon modeling the kinetic pathways, we found that complexation only happens after complete hydrolysis into colistin and that the process is accelerated under acidic conditions. At pH = 5.0, effective charge switching was identified as the slowest step in the CMS conversion, constituting the rate-limiting step in colistin formation.

ObjectiveFaecal immunochemical tests (FITs) are replacing guaiac faecal occult blood tests (gFOBTs) for colorectal cancer (CRC) screening. Incidence of interval colorectal cancer (iCRC) following a negative stool test result is not yet known. We aimed to compare incidence of iCRC following a negative FIT or gFOBT.DesignWe searched Ovid Medline, Embase, Cochrane Library, Science Citation Index, PubMed and Google Scholar from inception to 12 December 2017 for citations related to CRC screening based on stool tests. We included studies on FIT or gFOBT iCRC in average-risk screening populations. Main outcome was pooled incidence rate of iCRCs per 100 000 person-years (p-y). Pooled incidence rates were obtained by fitting random-effect Poisson regression models.ResultsWe identified 7 426 records and included 29 studies. Meta-analyses comprised data of 6 987 825 subjects with a negative test result, in whom 11 932 screen-detected CRCs and 5 548 gFOBT or FIT iCRCs were documented. Median faecal haemoglobin (Hb) positivity cut-off used was 20 (range 10–200) µg Hb/g faeces in the 17 studies that provided FIT results. Pooled incidence rates of iCRC following FIT and gFOBT were 20 (95% CI 14 to 29; I2=99%) and 34 (95% CI 20 to 57; I2=99%) per 100 000 p-y, respectively. Pooled incidence rate ratio of FIT versus gFOBT iCRC was 0.58 (95% CI 0.32 to 1.07; I2=99%) and 0.36 (95% CI 0.17 to 0.75; I2=10%) in sensitivity analysis. For every FIT iCRC, 2.6 screen-detected CRCs were found (ratio 1:2.6); for gFOBT, the ratio between iCRC and screen-detected CRC was 1:1.2. Age below 60 years and the third screening round were significantly associated with a lower iCRC rate.ConclusionA negative gFOBT result is associated with a higher iCRC incidence than a negative FIT. This supports the use of FIT over gFOBT as CRC screening tool.

ObjectiveThe incidence of colorectal cancer (CRC) declines among subjects aged 50 years and above. An opposite trend appears among younger adults. In Europe, data on CRC incidence among younger adults are lacking. We therefore aimed to analyse European trends in CRC incidence and mortality in subjects younger than 50 years.DesignData on age-related CRC incidence and mortality between 1990 and 2016 were retrieved from national and regional cancer registries. Trends were analysed by Joinpoint regression and expressed as annual percent change.ResultsWe retrieved data on 143.7 million people aged 20–49 years from 20 European countries. Of them, 187 918 (0.13%) were diagnosed with CRC. On average, CRC incidence increased with 7.9% per year among subjects aged 20–29 years from 2004 to 2016. The increase in the age group of 30–39 years was 4.9% per year from 2005 to 2016, the increase in the age group of 40–49 years was 1.6% per year from 2004 to 2016. This increase started earliest in subjects aged 20–29 years, and 10–20 years later in those aged 30–39 and 40–49 years. This is consistent with an age-cohort phenomenon. Although in most European countries the CRC incidence had risen, some heterogeneity was found between countries. CRC mortality did not significantly change among the youngest adults, but decreased with 1.1%per year between 1990 and 2016 and 2.4% per year between 1990 and 2009 among those aged 30–39 years and 40–49 years, respectively.ConclusionCRC incidence rises among young adults in Europe. The cause for this trend needs to be elucidated. Clinicians should be aware of this trend. If the trend continues, screening guidelines may need to be reconsidered.

Multiple sclerosis (MS) patients exhibit neuropsychological symptoms in early disease despite the immune attack occurring predominantly in white matter and spinal cord. It is unclear why neurodegeneration may start early in the disease and is prominent in later stages. We assessed cortical microcircuit activity by employing spiking-specific two-photon Ca2+imaging in proteolipid protein-immunized relapsing-remitting SJL/J mice in vivo. We identified the emergence of hyperactive cortical neurons in remission only, independent of direct immune-mediated damage and paralleled by elevated anxiety. High levels of neuronal activity were accompanied by increased caspase-3 expression. Cortical TNFα expression was mainly increased by excitatory neurons in remission; blockade with intraventricular infliximab restored AMPA spontaneous excitatory postsynaptic current frequencies, completely recovered normal neuronal network activity patterns and alleviated elevated anxiety. This suggests a dysregulation of cortical networks attempting to achieve functional compensation by synaptic plasticity mechanisms, indicating a link between immune attack and early start of neurodegeneration.

On the basis of randomized controlled screening trial data showing higher participation rates for CT colonography, CT colonography is more cost-effective than colonoscopy screening for colorectal cancer.

BackgroundIn approximately 10% of all gastric cancer (GC) cases, a heritable cause is suspected. A subset of these cases have a causative germline CDH1mutation; however, in most cases the cause remains unknown. Our objective was to assess to what extent these remaining cases may be explained by germline mutations in the novel candidate GC predisposing genes CTNNA1, MAP3K6or MYD88.MethodsWe sequenced a large cohort of unexplained young and/or familial patients with GC (n=286) without a CDH1germline mutation for germline variants affecting CTNNA1, MAP3K6and MYD88using a targeted next-generation sequencing approach based on single-molecule molecular inversion probes.ResultsPredicted deleterious germline variants were not encountered in MYD88, but recurrently observed in CTNNA1(n=2) and MAP3K6(n=3) in our cohort of patients with GC. In contrast to deleterious variants in CTNNA1, deleterious variants in MAP3K6also occur frequently in the general population.ConclusionsBased on our results MAP3K6should no longer be considered a GC predisposition gene, whereas deleterious CTNNA1variants are confirmed as an infrequent cause of GC susceptibility. Biallelic MYD88germline mutations are at most a very rare cause of GC susceptibility as no additional cases were identified.

Recognition of individuals with a genetic predisposition to gastric cancer (GC) enables preventive measures. However, the underlying cause of genetic susceptibility to gastric cancer remains largely unexplained. We performed germline whole-exome sequencing on leukocyte DNA of 54 patients from 53 families with genetically unexplained diffuse-type and intestinal-type GC to identify novel GC-predisposing candidate genes. As young age at diagnosis and familial clustering are hallmarks of genetic tumor susceptibility, we selected patients that were diagnosed below the age of 35, patients from families with two cases of GC at or below age 60 and patients from families with three GC cases at or below age 70. All included individuals were tested negative for germline CDH1 mutations before or during the study. Variants that were possibly deleterious according to in silico predictions were filtered using several independent approaches that were based on gene function and gene mutation burden in controls. Despite a rigorous search, no obvious candidate GC predisposition genes were identified. This negative result stresses the importance of future research studies in large, homogeneous cohorts.

Background Despite differences between men and women in incidence of colorectal cancer (CRC) and its precursors, screening programs consistently use the same strategy for both genders.Objective The objective of this article is to illustrate the effects of gender-tailored screening, including the effects on miss rates of advanced neoplasia (AN).Methods Participants (age 50–75 years) in a colonoscopy screening program were asked to complete a fecal immunochemical test (FIT) before colonoscopy. Positivity rates, sensitivity and specificity for detection of AN at multiple cut-offs were determined. Absolute numbers of detected and missed AN per 1000 screenees were calculated.Results In total 1,256 individuals underwent FIT and colonoscopy, 51% male (median age 61 years; IQR 56–66) and 49% female (median age 60 years; IQR 55–65). At all cut-offs men had higher positivity rates than women, ranging from 3.8% to 10.8% versus 3.2% to 4.8%. Sensitivity for AN was higher in men than women; 40%–25% and 35%–22%, respectively. More AN were found and missed in absolute numbers in men at all cut-offs.Conclusion More AN were both detected and missed in men compared to women at all cut-offs. Gender-tailored cut-offs could either level sensitivity in men and women (i.e., lower cut-off in women) or level the amount of missed lesions (i.e., lower cut-off in men).

Despite differences between men and women in incidence of colorectal cancer (CRC) and its precursors, screening programs consistently use the same strategy for both genders. The objective of this article is to illustrate the effects of gender-tailored screening, including the effects on miss rates of advanced neoplasia (AN). Participants (age 50–75 years) in a colonoscopy screening program were asked to complete a fecal immunochemical test (FIT) before colonoscopy. Positivity rates, sensitivity and specificity for detection of AN at multiple cut-offs were determined. Absolute numbers of detected and missed AN per 1000 screenees were calculated. In total 1,256 individuals underwent FIT and colonoscopy, 51% male (median age 61 years; IQR 56–66) and 49% female (median age 60 years; IQR 55–65). At all cut-offs men had higher positivity rates than women, ranging from 3.8% to 10.8% versus 3.2% to 4.8%. Sensitivity for AN was higher in men than women; 40%–25% and 35%–22%, respectively. More AN were found and missed in absolute numbers in men at all cut-offs. More AN were both detected and missed in men compared to women at all cut-offs. Gender-tailored cut-offs could either level sensitivity in men and women (i.e., lower cut-off in women) or level the amount of missed lesions (i.e., lower cut-off in men).

ObjectiveColorectal cancer (CRC) screening programmes based on faecal immunochemical testing for haemoglobin (FIT) typically use a screening interval of 2 years. We aimed to estimate how alternative FIT strategies that use a lower than usual positivity threshold followed by a longer screening interval compare with conventional strategies.MethodsWe analysed longitudinal data of 4523 Dutch individuals (50–74 years at baseline) participating in round I of a one-sample FIT screening programme, of which 3427 individuals also participated in round II after 1–3 years. The cohort was followed until 2 years after round II. In both rounds, a cut-off level of ≥50 ng haemoglobin (Hb)/mL buffer (corresponding to 10 µg Hb/g faeces) was used, representing the standard scenario. We determined the cumulative positivity rate (PR) and the numbers of subjects diagnosed with advanced adenomas (N_AdvAd) and early stage CRC (N_earlyCRC) in the cohort over two rounds of screening (standard scenario) and compared it with hypothetical single-round screening with use of a lower cut-off and omission of the second round (alternative scenario).ResultsIn the standard scenario, the cumulative (ie, round I and II combined) PR, N_AdvAd and N_earlyCRC were 13%, 180% and 26%, respectively. In alternative scenarios using a cut-off level of respectively ≥11 and ≥22 ng/HbmL buffer (corresponding to 2 and 4 µg Hb/g faeces), the PRs were 18% and 13%, the N_AdvAd were 180 and 162 and the N_earlyCRC ranged between 22–27 and 22–26.ConclusionsThe diagnostic yield of FIT screening using a lowered positivity threshold in combination with an extended screening interval (up to 5 years) may be similar to conventional FIT strategies. This justifies and motivates further research steps in this direction.

ObjectiveLimited data exist on attendance and additional yield of 2-sample faecal immunochemical testing (FIT) screening during multiple rounds. We therefore conducted a population-based colorectal cancer screening trial comparing attendance and yield of repeated 1-sample and 2-sample FIT screenings.DesignTwo randomly selected groups of average-risk subjects aged 50–74 years were invited for two rounds of either 1-sample (n=5007) or 2-sample (n=3197) FIT (OC-sensor Micro) screening. The test was considered positive if at least one sample was positive (cut-off 50 ng/mL; 10 µg haemoglobin/g).ResultsThe cumulative attendance rate was similar for repeated 1-sample and 2-sample FIT screenings (1-sample FIT: 68.1%; 2-sample FIT: 67.1%, p=0.368). The positivity rate in the second round was lower for 1-sample FIT (6.2%, 95% CI 5.4% to 7.2%) than for 2-sample FIT (8.4%, 95% CI 7.1% to 9.8%, p=0.007), whereas the detection rate of advanced neoplasia (AN, 1-sample FIT: 1.9%, 95% CI 1.2% to 2.2%; 2-sample FIT: 1.7%, 95% CI 1.2% to 2.5%, p=0.861) and the positive predictive value (1-sample FIT: 32%, 95% CI 24% to 40%; 2-sample FIT: 21%, 95% CI 15% to 29%, p=0.075) did not differ. After two rounds of screening, the cumulative diagnostic yield of AN for 1-sample FIT was 29.3 per 1000 invitees, compared with 34.0 for 2-sample FIT (p=0.241).ConclusionsUsing 2-sample FIT instead of 1-sample FIT does not result in a higher detection rate of AN in the second round of repeated FIT screening. Furthermore, both strategies lead to a similar yield of AN over two rounds. These findings imply that 1-sample FIT screening is preferred over 2-sample FIT screening.

ObjectiveColorectal cancer screening programmes are implemented worldwide; many are based on faecal immunochemical testing (FIT). The aim of this study was to evaluate two frequently used FITs on participation, usability, positivity rate and diagnostic yield in population-based FIT screening.DesignComparison of two FITs was performed in a fourth round population-based FIT-screening cohort. Randomly selected individuals aged 50–74 were invited for FIT screening and were randomly allocated to receive an OC -Sensor (Eiken, Japan) or faecal occult blood (FOB)-Gold (Sentinel, Italy) test (March–December 2014). A cut-off of 10 µg haemoglobin (Hb)/g faeces (ie, 50 ng Hb/mL buffer for OC-Sensor and 59 ng Hb for FOB-Gold) was used for both FITs.ResultsIn total, 19 291 eligible invitees were included (median age 61, IQR 57–67; 48% males): 9669 invitees received OC-Sensor and 9622 FOB-Gold; both tests were returned by 63% of invitees (p=0.96). Tests were non-analysable in 0.7% of participants using OC-Sensor vs 2.0% using FOB-Gold (p<0.001). Positivity rate was 7.9% for OC-Sensor, and 6.5% for FOB-Gold (p=0.002). There was no significant difference in diagnostic yield of advanced neoplasia (1.4% for OC-Sensor vs 1.2% for FOB-Gold; p=0.15) or positive predictive value (PPV; 31% vs 32%; p=0.80). When comparing both tests at the same positivity rate instead of cut-off, they yielded similar PPV and detection rates.ConclusionsThe OC-Sensor and FOB-Gold were equally acceptable to a screening population. However, FOB-Gold was prone to more non-analysable tests. Comparison between FIT brands is usually done at the same Hb stool concentration. Our findings imply that for a fair comparison on diagnostic yield between FIT's positivity rate rather than Hb concentration should be used.Trial registration numberNTR5385; Results.

Gastrointestinal (GI) diseases are among the leading causes of death in the world. To reduce the burden of GI diseases, surveillance is recommended for some diseases, including for patients with inflammatory bowel diseases, Barrett's oesophagus, precancerous gastric lesions, colorectal adenoma, and pancreatic neoplasms. This review aims to provide an overview of the evidence on cost-effectiveness of surveillance of individuals with GI conditions predisposing them to cancer, specifically focussing on the aforementioned conditions. We searched the literature and reviewed 21 studies. Despite heterogeneity of studies in terms of settings, study populations, surveillance strategies and outcomes, most reviewed studies suggested at least some surveillance of patients with these GI conditions to be cost-effective. For some high-risk conditions frequent surveillance with 3-month intervals was warranted, while for other conditions, surveillance may only be cost-effective every 10 years. Further studies based on more robust effectiveness evidence are needed to inform and optimise surveillance programmes for GI cancers.

Aspergillus fumigatusis an opportunistic fungal pathogen and the most common causative agent of fatal invasive mycoses. The flavin-dependent monooxygenase siderophore A (SidA) catalyzes the oxygen and NADPH dependent hydroxylation of l-ornithine (l-Orn) to N5-l-hydroxyornithine in the biosynthetic pathway of hydroxamate-containing siderophores in A. fumigatus. Deletion of the gene that codes for SidA has shown that it is essential in establishing infection in mice models. Here, a fluorescence polarization high-throughput assay was used to screen a 2320 compound library for inhibitors of SidA. Celastrol, a natural quinone methide, was identified as a noncompetitive inhibitor of SidA with a MIC value of 2 μM. Docking experiments suggest that celastrol binds across the NADPH and l-Orn pocket. Celastrol prevents A. fumigatusgrowth in blood agar. The addition of purified ferric-siderophore abolished the inhibitory effect of celastrol. Thus, celastrol inhibits A. fumigatusgrowth by blocking siderophore biosynthesis through SidA inhibiton.

IMPORTANCE: Although some countries have implemented widespread colonoscopy screening, most European countries have not introduced it because of uncertainty regarding participation rates, procedure-related pain and discomfort, endoscopist performance, and effectiveness. To our knowledge, no randomized trials on colonoscopy screening currently exist. OBJECTIVE: To investigate participation rate, adenoma yield, performance, and adverse events of population-based colonoscopy screening in several European countries. DESIGN, SETTING, AND POPULATION: A population-based randomized clinical trial was conducted among 94 959 men and women aged 55 to 64 years of average risk for colon cancer in Poland, Norway, the Netherlands, and Sweden from June 8, 2009, to June 23, 2014. INTERVENTIONS: Colonoscopy screening or no screening. MAIN OUTCOMES AND MEASURES: Participation in colonoscopy screening, cancer and adenoma yield, and participant experience. Study outcomes were compared by country and endoscopist. RESULTS: Of 31 420 eligible participants randomized to the colonoscopy group, 12 574 (40.0%) underwent screening. Participation rates were 60.7% in Norway (5354 of 8816), 39.8% in Sweden (486 of 1222), 33.0% in Poland (6004 of 18 188), and 22.9% in the Netherlands (730 of 3194) (P &lt; .001). The cecum intubation rate was 97.2% (12 217 of 12 574), with 9726 participants (77.4%) not receiving sedation. Of the 12 574 participants undergoing colonoscopy screening, we observed 1 perforation (0.01%), 2 postpolypectomy serosal burns (0.02%), and 18 cases of bleeding owing to polypectomy (0.14%). Sixty-two individuals (0.5%) were diagnosed with colorectal cancer and 3861 (30.7%) had adenomas, of which 1304 (10.4%) were high-risk adenomas. Detection rates were similar in the proximal and distal colon. Performance differed significantly between endoscopists; recommended benchmarks for cecal intubation (95%) and adenoma detection (25%) were not met by 6 (17.1%) and 10 of 35 endoscopists (28.6%), respectively. Moderate or severe abdominal pain after colonoscopy was reported by 601 of 3611 participants (16.7%) examined with standard air insufflation vs 214 of 5144 participants (4.2%) examined with carbon dioxide (CO2) insufflation (P &lt; .001). CONCLUSIONS AND RELEVANCE: Colonoscopy screening entails high detection rates in the proximal and distal colon. Participation rates and endoscopist performance vary significantly. Postprocedure abdominal pain is common with standard air insufflation and can be significantly reduced by using CO2. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00883792

The Borexino detector has convincingly shown its outstanding performance in the in the sub-MeV regime through its unprecedented accomplishments in the solar and geo-neutrinos detection, which make it the ideal tool to unambiguously test the long-standing issue of the existence of a sterile neutrino, as suggested by several anomalies: the outputs of the LSND and Miniboone experiments, the results of the source calibration of the two Gallium solar νexperiments, and the recently hinted reactor anomaly. The SOX project will exploit two sources, based on chromium and cerium, which deployed under the experiment will emit two intense beams of νe(Cr) and νe‾(Ce). Interacting in the active volume of the liquid scintillator, each beam would create a spatial wave pattern in case of oscillation of the νe(or νe‾) into the sterile state, which would be the smoking gun proving the existence of the new sterile member of the neutrino family. Otherwise, its absence will allow setting very stringent limit on its existence.

The Borexino detector was built starting from 1996 in the underground hall C of Gran Sasso National Laboratory (LNGS) in Italy under about 1400 m of rock (3800 m.w.e) and it is mostly aimed to the study in real-time of the low-energy solar neutrinos.

DarkSide-50 (DS-50) at Gran Sasso underground laboratory (LNGS), Italy, is a direct dark matter search experiment based on a TPC with liquid argon. DS-50 has completed its first dark matter run using atmospheric argon as target. The DS-50 detector performances and the results of the first physics run are reviewed in this proceeding.

In 2014, a nation-wide colorectal cancer (CRC) screening program was launched in The Netherlands. Every 2 years, men and women aged 55–75 years will be invited to participate in fecal immunochemical test screening. Participants with a positive test result will be scheduled for colonoscopy. Starting from 2006, screening pilots have been performed to ascertain the choice of an optimal screening modality, population acceptance, logistics and cost effectiveness, in order to ensure that a screening program with maximal benefits and the least amount of harms was offered to the Dutch population. In this overview, we will discuss the results of Dutch CRC screening pilots in which different screening modalities were studied, the preparations made before the launch of the nation-wide screening program, and finally the initial results and lessons learned so far from the Dutch CRC screening program.

Colorectal cancer (CRC) is a major health problem and it is expected that the number of persons diagnosed with CRC and CRC-related deaths will continue to increase. However, recent years have shown reductions in CRC incidence and mortality particularly among individuals aged 50 years and older which can be attributed to screening, improvements in patients’ management, closer adherence to treatment guideline recommendations and a higher utilization of curative surgery, chemotherapy and radiotherapy. The International Agency for Research on Cancer has concluded that there has been sufficient evidence that biennially screening using a stool-test or once-only endoscopy screening reduces CRC-related mortality. In Europe, between 2008 and 2018, nine countries have successfully implemented a population-based organized program and another six are in the roll-out phase. Population-based organized programs show higher screening participation rates and lower lack of compliance to follow-up testing after a positive screen test compared to opportunistic screening. Moreover, organized programs aim to provide high quality screening thereby reducing the risk of the harms of screening, including over-screening, and complications of screening, and poor follow-up of those who test positive. We describe how population-based organized CRC screening programs are preferred, since they reflect a more appropriate utilization of available resources, reduce inequities in access, and can integrate interventions addressing barriers to screening at the individual and health system levels.

Management of rectal cancer has advanced, with an increasing use of neoadjuvant chemoradiotherapy (nCRT). This opens options for organ preserving treatment for those with a major response to nCRT. However, the degree of clinical response, based on MRI and post-treatment biopsies, only poorly matches the degree of actual pathological response. In order to select patients with major pathological response without surgical resection, it is of importance to define tumour markers predicting the degree of pathological response to nCRT. The intra-tumoural tumour-stroma ratio (TSR) might be this marker.

Several Asian countries are implementing nationwide cancer screening programs. Assessment of the effectiveness of these programs is critical to their success as this is the only way to ensure that the benefits of screening outweigh the harms. In this paper we focus on colorectal cancer (CRC) screening to illustrate the principles of screening program assessment. The International Agency for Research on Cancer (IARC) has defined organized screening, distinguishing it from opportunistic screening. The key advantage of organized screening is that it provides greater protection against the possible harms of screening. Since screening is a process, not simply a test, the effectiveness of a program depends on the quality of each step in the cancer screening process. The evaluation of long-term screening program outcomes (CRC incidence and mortality) will not be observable for many years, given the time it takes to plan, pilot and implement a program. However, early performance indicators of the impact of screening should be monitored to give an early indication whether the program is on track. The European Union (EU) has recommended a minimum dataset to be collected and reported regularly by a screening program. Using information from these data tables, early performance indicators can be generated (e.g., participation rate, proportion of screen-detected cancers that are early-stage). Subsequently, modeling the natural history of the disease can be very helpful to estimate long-term outcomes, making use of these directly measured early performance indicators. Modeling can also be used to estimate the cost-effectiveness of a screening program and the potential impact of changes in policy, as illustrated by its recent use in the Netherlands to change the definition of a positive fecal immunochemical test (FIT) for the CRC screening program. Programs should consider modeling as an important component of screening program evaluation.

Recent advances in Differential Acoustic Resonance Spectroscopy (DARS) techniques have given rise to applications in the field of poromechanics. We report on the experimental demonstration of bulk modulus measurements on poroelastic samples at sonic frequencies (1 kHz) with DARS. Normal mode perturbation is due to scattering of a foreign object (i.e., a rock sample) within an otherwise fluid‐filled resonator. The perturbation theory on an elastic object determines its bulk modulus (inverse compressibility). The experimental bulk modulus of medium‐ to high‐permeability (>10 mD) poroelastic samples is in agreement with predictions from quasi‐static loading of a porous sphere using the Biot theory. This result demonstrates that pore fluid flow governs the dominant relaxation process of the rock during compression. For low‐permeability samples (<10 mD), pressure equilibration via slow wave diffusion is limited, and only qualitative agreement is found between the upper bound (Gassmann undrained modulus) and the lower bound (volume‐weighted compressibilities of the two constituents). DARS experiments, in conjunction with the poroelastic theory presented here, allow one to infer such rock physical properties as the effective bulk modulus at sonic frequencies. A variety of rock samples are measured in DARS experimentsA quasi‐static poroelastic model is derivedPredictions agree with experiments on medium to high permeable rocks

Purpose:Family history of colorectal cancer (CRC) is a known risk factor for CRC and encompasses both genetic and shared environmental risks.Methods:We conducted a systematic review to estimate the impact of family history on the natural history of CRC and adherence to screening.Results:We found high heterogeneity in family-history definitions, the most common definition being one or more first-degree relatives. The prevalence of family history may be lower than the commonly cited 10%, and confirms evidence for increasing levels of risk associated with increasing family-history burden. There is evidence for higher prevalence of adenomas and of multiple adenomas in people with family history of CRC but no evidence for differential adenoma location or adenoma progression by family history. Limited data regarding the natural history of CRC by family history suggest a differential age or stage at cancer diagnosis and mixed evidence with respect to tumor location. Adherence to recommended colonoscopy screening was higher in people with a family history of CRC.Conclusion:Stratification based on polygenic and/or multifactorial risk assessment may mature to the point of displacing family history–based approaches, but for the foreseeable future, family history may remain a valuable clinical tool for identifying individuals at increased risk for CRC.Genet Med 17 9, 702–712.