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Lung cancer is the leading cause of cancer-related deaths worldwide, accounting for almost a fifth of all cancer-related deaths. Annual computed tomographic lung cancer screening (CTLS) detects lung cancer at earlier stages and reduces lung cancer-related mortality among high-risk individuals. Many medical organizations, including the U.S. Preventive Services Task Force, recommend annual CTLS in high-risk populations. However, fewer than 5% of individuals worldwide at high risk for lung cancer have undergone screening. In large part, this is owing to delayed implementation of CTLS in many countries throughout the world. Factors contributing to low uptake in countries with longstanding CTLS endorsement, such as the United States, include lack of patient and clinician awareness of current recommendations in favor of CTLS and clinician concerns about CTLS-related radiation exposure, false-positive results, overdiagnosis, and cost. This review of the literature serves to address these concerns by evaluating the potential risks and benefits of CTLS. Review of key components of a lung screening program, along with an updated shared decision aid, provides guidance for program development and optimization. Review of studies evaluating the population considered "high-risk" is included as this may affect future guidelines within the United States and other countries considering lung screening implementation.

Background Although preliminary evidence suggests that intermittent calorie restriction (ICR) exerts stronger effects on metabolic parameters, which may link obesity and major chronic diseases, compared with continuous calorie restriction (CCR), there is a lack of well-powered intervention studies. Objective We conducted a randomized controlled trial to test whether ICR, operationalized as the "5:2 diet," has stronger effects on adipose tissue gene expression, anthropometric and body composition measures, and circulating metabolic biomarkers than CCR and a control regimen. Design One hundred and fifty overweight and obese nonsmokers [body mass index (kg/m2) ≥25 to

Background A recent single-centre study demonstrated that MRI is sensitive to detect early abnormalities in the lung and response to therapy in infants and preschool children with cystic fibrosis (CF) supporting MRI as an outcome measure of early CF lung disease. However, the feasibility of multicentre standardisation remains unknown. Objective To determine the feasibility of multicentre standardisation of chest MRI in infants and preschool children with CF. Methods A standardised chest 1.5 T MRI protocol was implemented across four specialised CF centres. Following training and initiation visits, 42 infants and preschool children (mean age 3.2 ± 1.5 years, range 0–6 years) with clinically stable CF underwent MRI and chest X-ray (CXR). Image quality and lung abnormalities were assessed using a standardised questionnaire and an established CF MRI and CXR score. Results MRI was successfully performed with diagnostic quality in all patients (100%). Incomplete lung coverage was observed in 6% and artefacts also in 6% of sequence acquisitions, but these were compensated by remaining sequences in all patients. The range of the MRI score in CF patients was similar across centres with a mean global MRI score of 13.3 ± 5.8. Cross-validation of the MRI against the CXR score revealed a moderate correlation (r = 0.43–0.50, p Conclusion Our results demonstrate that multicentre standardisation of chest MRI is feasible and support its use as radiation-free outcome measure of lung disease in infants and preschool children with CF.

PURPOSE: To examine the performance of radiologists in differentiating COVID-19 from non-COVID-19 atypical pneumonia and to perform an analysis of CT patterns in a study cohort including viral, fungal and atypical bacterial pathogens. METHODS: Patients with positive RT-PCR tests for COVID-19 pneumonia (n = 90) and non-COVID-19 atypical pneumonia (n = 294) were retrospectively included. Five radiologists, blinded to the pathogen test results, assessed the CT scans and classified them as COVID-19 or non-COVID-19 pneumonia. For both groups specific CT features were recorded and a multivariate logistic regression model was used to calculate their ability to predict COVID-19 pneumonia. RESULTS: The radiologists differentiated between COVID-19 and non-COVID-19 pneumonia with an overall accuracy, sensitivity, and specificity of 88% ± 4 (SD), 79% ± 6 (SD), and 90% ± 6 (SD), respectively. The percentage of correct ratings was lower in the early and late stage of COVID-19 pneumonia compared to the progressive and peak stage (68 and 71% vs 85 and 89%). The variables associated with the most increased risk of COVID-19 pneumonia were band like subpleural opacities (OR 5.55, p

Background: Minimal residual disease (MRD) supports a more accurate assessment when children and adolescents with late bone marrow relapses of B-cell precursor (BCP) acute lymphoblastic leukaemia (ALL) will benefit from allogeneic haematopoietic stem cell transplantation (alloHSCT). A more detailed dissection of MRD heterogeneity, dynamics and the specific genetic aberrations involved promises to further improve treatment stratification. Methods: Patients treated according to the ALL-REZ BFM 2002 trial/registry protocol with late BCP ALL bone marrow relapses (n=413) were included. AlloHSCT was indicated for patients with MRD≥10-3 after induction treatment (poor response). Findings: Patients with good (MRD

Human epithelial cell adhesion molecule (HEPCAM) is a tumor-associated antigen frequently expressed in carcinomas, which promotes proliferation after regulated intramembrane proteolysis. Here, we describe extracellular shedding of HEPCAM at two α-sites through a disintegrin and metalloprotease (ADAM) and at one β-site through BACE1. Transmembrane cleavage by γ-secretase occurs at three γ-sites to generate extracellular Aβ-like fragments and at two ϵ-sites to release human EPCAM intracellular domain HEPICD, which is efficiently degraded by the proteasome. Mapping of cleavage sites onto three-dimensional structures of HEPEX cis-dimer predicted conditional availability of α- and β-sites. Endocytosis of HEPCAM warrants acidification in cytoplasmic vesicles to dissociate protein cis-dimers required for cleavage by BACE1 at low pH values. Intramembrane cleavage sites are accessible and not part of the structurally important transmembrane helix dimer crossing region. Surprisingly, neither chemical inhibition of cleavage nor cellular knock-out of HEPCAM using CRISPR-Cas9 technology impacted the adhesion of carcinoma cell lines. Hence, a direct function of HEPCAM as an adhesion molecule in carcinoma cells is not supported and appears to be questionable.

This blinded prospective study was performed to optimise the risk assessment of children with a late isolated, combined or an early combined bone marrow (BM) relapse of precursor B-cell acute lymphoblastic leukaemia (ALL). The aim was to develop a reliable tool to identify patients with an intermediate risk relapse who are in need of haematopoietic stem cell transplantation (HSCT).Included were 80 children and adolescents with first intermediate risk BM relapse of ALL recruited in trial ALL-REZ BFM P95/96. We assessed the prognostic value of minimal residual disease (MRD) after induction therapy quantified by PCR using leukaemia clone-specific T-cell receptor/immunoglobulin gene rearrangements.Molecular good responders (MRD10(-3), n=46) had a probability of event-free survival (pEFS) at 10 years of 76% standard error (SE) ± 6% and a cumulative incidence of second relapse (CIR) at 10 years of 21% SE ± 6%; pEFS of molecular poor responders (MRD ≥ 10(-3), n=34) at 10 years was 18% SE ± 7% and CIR 61% SE ± 9% (p0.001). Cox regression analysis revealed MRD after induction to be the strongest independent prognostic parameter with a 6.6-fold increased risk (95% confidence interval 3.3-13.5, p0.001) for molecular poor responders to suffer a subsequent adverse event compared to good responders.In patients with intermediate risk BM relapse of ALL, low MRD after induction is associated with an excellent long-term prognosis with conventional chemo-/radiotherapy whereas patients with insufficient response have an extremely poor prognosis. Therefore, in the subsequent trial ALL-REZ BFM 2002, MRD is used to allocate molecular good responders to conventional post-induction therapy and molecular poor responders to allogeneic HSCT.

a b s t r a c t Detection of minimal residual disease (MRD) during the treatment of acute lymphoblastic leukemia (ALL) by RQ-PCR analysis of clonal Ig/TCR rearrangements is used for risk group stratification in European treatment protocols. In Belarus patients with childhood ALL are treated according to ALL-MB protocols, which do not use MRD-based risk stratification. To evaluate the prognostic significance of MRD for ALL- MB-2002/2008 protocols, MRD was quantified by RQ-PCR in 68 ALL patients at four time points: on day 15, on day 36, before and after maintenance therapy (MT). MRD positivity, as well as quantitative level of MRD were analyzed and compared between patients who stayed in remission and relapsed. Relapse-free survival revealed to be significantly associated with MRD levels at different time points. Unfavorable prognosis was shown for MRD ≥ 10 −3 on day 36 (p < 0.001), and any positive MRD before (p < 0.001) and after (p = 0.001) MT. Multivariate Cox regression analysis proved MRD as independent significant prognosis factor at day 36 (p = 0.005) and before MT (p = 0.001). We conclude, that MRD quantified by RQ-PCR in children with ALL treated with ALL-MB protocols is feasible and independently associated with outcome. MRD may be a suitable parameter for treatment stratification in MB protocols in future.

To architecturally support the programming of safety related control applications in the graphical language function block diagram and the verification of such software meeting the requirements of Safety Integrity Level SIL 3, a dedicated, low complexity execution platform is presented. Its hardware is fault detecting to immediately initiate emergency shut-downs in case of malfunctions. With their low processing speeds, currently available fail safe comparators constitute bottlenecks and, in case of malfunctions, do not distinguish between comparison errors and comparator errors. To solve these problems, a novel fail safe comparator of two binary inputs is presented, which does not only indicate a result, but also its status. Built in a modified CMOS technology, it can match the execution speed of digital computers. In contrast to all earlier designs of fail safe comparators, by employing ternary logic it provides three different output values, allowing to distinguish between the three indications “inputs equal and comparator working properly,” “inputs unequal and comparator working properly” as well as “comparator malfunctioning.” By design, there is no semantic gap between the programming and machine execution levels of the controller, enabling the safety licensing of application software by extremely simple, but rigorous methods, viz., diverse back translation and inspection. Operating in a strictly periodic fashion, the platform exhibits fully predictable real time behaviour.

In safety related computer control, redundancy is used to cope with errors of any kind. To detect errors, redundantly produced results must be compared imposing the responsibility for system safety on the comparators. Since comparison reduces the degree of redundancy, comparators are best implemented in form of hardware devices with fail safe behaviour. Currently available fail safe comparator circuits, however, constitute bottlenecks in safety related computing systems due to their low processing speeds. Moreover, in case of malfunctions, such comparators do not distinguish between comparison errors and comparator errors. To solve these problems, a novel fail safe comparator of two binary inputs is presented, which does not only indicate a result, but also its status. Built in a modified CM OS technology, it can match the execution speed of digital computers. In contrast to. all earlier designs of fail safe comparators, by employing ternary logic it provides three different output values, allowing to distinguish between the three indications "inputs equal and comparator working properly", "inputs unequal and comparator working properly" as well as "comparator malfunctioning". The comparator consists of 37 modules. Its circuitry structure ensures triple error protection at any time.

We investigated surficial sediments for physico-chemical composition from numerous sites of seven study areas in the manganese nodule field of the northern Peru Basin as part of a deep-sea environmental study. Major results from this study are strong variability with respect to water depth, productivity in surface waters, locality, bottom water flow, and seafloor topography. Sediment sites are located mostly in 3900 to 4300 m water depth between the lysocline and the carbonate compensation depth (CCD). Large fluctuations in carbonate content (0% to 80%) determine sediment density and compressional-wave velocity, and, by dilution, contents of opal and non-biogenic material. Mass accumulation rates of biogenic components as well as geochemical proxies (barium and phosphorus) distinguish areas of higher productivity in the northwest near equatorial upwelling and in the northeast close to coastal upwelling, from areas of lower productivity in the west and south. Comparisons between the central Peru Basin area (Discol) and western Peru Basin area (Sediperu) reveals, for the Sediperu area, a shallower CCD, more carbonate but less opal, organic carbon, and non-biogenic material in sediments at the same water depth as well as larger down-core fluctuations of organic carbon and MnO2. Bottom water flow in the abyssal hill topography causes winnowing of material from summits of seamounts and ridges, where organic carbon preservation is poor, to basins where organic carbon preservation is better. Down-core measurements in box cores indicate a three-fold division in the upper 50 cm of the sediment column. An uppermost semi-liquid top layer is dark brown, 5–15 cm thick and contains most of the ferro-manganese nodules. A 5–15 cm thick transition zone of light sediment color has increasing shear strength, lowest opal contents and compressional-wave velocities, but highest carbonate contents and sediment densities. The lowermost layer contains stiffer light gray sediments.

Since the late 1980s, polychemotherapy protocols for the treatment of childhood acute lymphoblastic leukaemia (ALL) derived from Western European and American regimens have been introduced in Russian paediatric oncology centres. Whereas treatment results were significantly improved compared with the results of former non-standard treatment strategies, the substantial toxicity of these protocols required a high standard of supportive care, and the high costs of treatment became a major problem. In 1991, a new protocol was developed with the aim of reducing toxicity and costs without affecting efficacy of the treatment. Since 1991, a single-centre study comparing the new Russian Protocol, Moscow-Berlin 91 (MB), with a modified version of the protocol ALL BFM 90 (BFM) of the Berlin-Frankfurt-Munster group was performed in Moscow to evaluate possible advantages of the new protocol under Russian conditions. The aim of the present analysis was to compare toxicity, need of supportive care and expense of both regimens (BFM, 25 pts; MB, 32 pts). Hepatotoxicity (liver enzymes), nephrotoxicity (creatinine), duration of neutropenia, and platelet transfusions were similar in both protocols. The median erythrocyte transfusion level was greater in the BFM (1000 ml/m2) than the MB patients (505 ml/m2, P < 0.01), as was the length of intravenous (i.v.) antibiotic therapy (22 days BFM versus 9 days MB, P < 0.01), treatment delays (39 days BFM versus 21 days MB, P < 0.001), and duration of in-patient treatment (47 days BFM versus 18 days MB, P < 0.001). Side-effects of the MB protocol occurred mainly during induction therapy. Total costs (mean cost/person/m2 body surface) of treatment including supportive care were 1.73-fold higher for the BFM protocol than MB, whereas costs of cytostatic drugs were comparable in both groups. In Russia both protocols were feasible. During consolidation therapy tolerance to treatment was better in MB 91 compared with BFM 90m, whereas toxicity during induction therapy was similar in both protocols. With respect to costs and side-effects, the MB 91 protocol appears to be an alternative to established protocols for countries with limited financial and clinical resources.

Products of low temperature hydrothermal activity are widespread in the Peru Basin and are associated with late Tertiary oceanic island type intraplate volcanics. Hydrothermal activity is still taking place as indicated by a series of sharp, high and narrow temperature anomalies over one of the volcanic cones. Submarine hydrothermal activity associated with off-axis volcanism has been frequently observed elsewhere, but was usually found to be limited to seamounts. In the Peru Basin a hydrothermal halo was found in sediments surrounding hydrothermally active seamounts in addition to hydrothermal precipitates on the tops of the seamounts. Todorokite, birnessite, Fe-nontronite, goethite, and silica were found on top of young volcanic edifices and occur as coatings on volcanic rocks and in nuclei of manganese nodules. The hydrothermal precipitates in the sediments are Mg–Fe silicates, as is the case in the adjacent Bauer Basin. The proportion of hydrothermal precipitates in the sediments increases with depth in the cores, down to the appearance of the basalt that indicates the beginning of intraplate volcanism 5 million years ago. Sediments overlying Late Tertiary volcanic rocks are locally enriched in hydrothermal material by solutions percolating upwards directly into the sediment. In these sediments, apatite and phillipsite appear to have been precipitated directly from these ascending hydrothermal solutions.

Risk assessment provides a methodology for estimating human exposure and risk from contaminated sites as part of a human health impact assessment (HHIA). All risk assessments follow a common outline and require the use of site-specific data and modeling at each of the steps in the process. Assumptions are made regarding the conditions under which exposure to contamination will take place. Deterministic risk assessment quantifies each of these assumptions as point estimates, whereas probabilistic risk assessment incorporates probability distributions for each variable, providing a context for the point estimates that shows the full range of risks likely to be experienced under specific exposure conditions. Once the risks have been estimated, risk managers communicate this information to decision-makers, site developers, and interested members of the public. Risk assessors must answer the question, “what is the chance that a hypothetical individual will develop cancer over the course of a lifetime as a result of living in the vicinity of a given site?” This article presents an overview of the individual steps in a risk assessment, with an emphasis on the use of probabilistic methods. Risk assessment is distinguished from risk management, and a brief discussion of computer desktop/video presentation tools is provided.

Three areas in the equatorial North Pacific between the Clarion and Clipperton fracture zones were investigated regarding depositional and diagenetic processes during manganese nodule formation. The areas lie on a NW-SE trending trace of the Pacific plate southeast of Hawaii. The manganese nodule facies shows low nodule abundance and low-grade (Cu+Ni+Co) nodules in the northwest but high abundance and high grade nodules in the southeast. The abundance, size, structure and composition of the nodules are determined by the nature of the underlying sediment. Breaks in sedimentation during the Oligocene and Miocene play a highly significant role in the formation of manganese nodules. This was the time when the growth of most nodules began, favoured by an abundance of potential nuclei. Ample supply of organic matter and of skeletal material was important for the diagenetic growth of nodules rich in Cu, Ni and Co. A large amount of organic matter stimulated bioturbation and hence lifting by benthic organisms, which in turn kept the nodules on top of the sediment. Even during the post-hiatus periods, the two areas in the southeast were always located in a zone of high biological productivity and hence much organic matter was supplied to the seafloor. As a consequence, most of the fields containing a great abundance of nodules rich in Cu, Ni and Co are found there. Due to the northwestward motion of the Pacific plate the northwestern area has been located, at least since the Early Miocene, outside the region with such favourable conditions. Nodules of low abundance and poor in Cu, Ni and Co are dominant. In spite of this distinct differentiation into two major or regional nodule facies areas, each area within itself is very complex. The development of the minor or local nodule facies is determined mainly by the position of the nodules in relation to the calcite compensation depth, the post-hiatus sediment thickness, the degree of reworking, the potential for formation of nuclei during hiatus periods and the rate of supply or decomposition of organic matter. These factors are in turn strongly controlled by the morphology of the seafloor and the activity of bottom currents.

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