Cutting out the middleman: measuring nuclear area in histopathology slides without segmentation

The size of nuclei in histological preparations from excised breast tumors is predictive of patient outcome (large nuclei indicate poor outcome). Pathologists take into account nuclear size when performing breast cancer grading. In addition, the mean nuclear area (MNA) has been shown to have independent prognostic value. The straightforward approach to measuring nuclear size is by performing nuclei segmentation. We hypothesize that given an image of a tumor region with known nuclei locations, the area of the individual nuclei and region statistics such as the MNA can be reliably computed directly from the image data by employing a machine learning model, without the intermediate step of nuclei segmentation. Towards this goal, we train a deep convolutional neural network model that is applied locally at each nucleus location, and can reliably measure the area of the individual nuclei and the MNA. Furthermore, we show how such an approach can be extended to perform combined nuclei detection and measurement, which is reminiscent of granulometry.Comment: Conditionally accepted for MICCAI 201

The effect of age on phosphatidylinositol kinase, phosphatidylinositol phosphate kinase and diacylglycerol kinase activities in rat brain cortex

A previous study, in which a lysed fraction was used with endogenous phospholipids as substrate, revealed age-related changes in PA and PIP2 formation but not in PIP formation (Bothmer et al., Neurochem. Int. 21, 223-228, 1992). To rule out the influence of substrate availability in the present study, the effect of age on PI kinase, PIP kinase and DAG kinase activities was studied with exogenous phospholipids as substrate in the cerebral cortex from 8-month-old, 14-month-old and 26-month-old Brown Norway rats. PI kinase activity was predominantly located in a tight membrane-bound protein fraction, DAG kinase activity in cytosolic and loosely membrane-bound protein fractions, and PIP kinase activity was present in all three protein preparations. The effects of age were limited to a small increase in kinase activity in the tight membrane-bound protein fraction in 14-month-old and 26-month-old rats compared to 8-month-old rats, and a 10% decrease in PIP kinase activity in the cytosolic protein fraction in 14-month-old and 26-month-old rats compared to 8-month-old rats. DAG kinase activity showed no age-related changes. In conclusion, one should take care in comparing rat aging with human aging as PI kinase activity shows an age-related decline in human brain cortex (Jolles et al., J. Neurochem. 58, 2326-2329, 1992). Furthermore, previously reported decreases in PA formation rates in rat brain are probably not due to changes in DAG kinase itself but to changes in DAG availability, although further experimental evidence is needed to confirm this conclusion

The Implementation of the Feedback Principle in Science and Technics

In this study positive and negative influence of the feedback have been examined. A feedback principle in the alternating current amplifier and in the speed regulator of the turbine rotation was described. The main conclusion of the positive and negative effect was obtained. Negative feedback worsens the properties of an object, reducing a strengthening factor, delaying regulatory action. Positive feedback considerably raises device work stability. This research will enable to identify the importance and effectiveness of the feedback principle in science and technics

Attitudes to a male contraceptive pill in a group of contraceptive users in the UK

BACKGROUND. Small scale trials of male hormonal contraception have produced encouraging results. Attitudes to and beliefs about a proposed male pill may affect uptake. METHODS. This paper examines attitudes towards a proposed ‘male contraceptive pill’ among a self selected sample of 54 men and 134 women, living in a non-metropolitan centre in the East of England, United Kingdom who were already users of contraception. Thirty four respondents were also interviewed and their views on the male pill were qualitatively analysed. RESULTS. The acceptability of a male pill was high with just under half (49.5%) of respondents indicating that they would use it. Gender, length of relationship, age and educational achievement did not affect the reported acceptability. 42% of respondents expressed concerns that men would forget to take a male pill. Women were significantly more likely to express this concern than men. 26% of respondents expressed health concerns. Willingness to take a male pill was associated with expressing the view that increased protection against pregnancy would be an advantage of such a method. Those unwilling or undecided were more likely to express concerns about the effect of a pill on future fertility. CONCLUSIONS. A male pill was accepted as a potential aid to increased fertility control by a large proportion of a convenience sample of contraceptive users in the East of England. If a male pill were to be marketed in the UK this study suggests that concerns about effects on future fertility and health risks may need to be addressed

Сутність адміністративного права за новою класифікацією юриспруденції

На основі новітніх підходів до розумінні завдань, об’єктів і класифікації юридичних наук запропонована перспектива розвитку адміністративного права і процесу, які повинні трансформуватися в нові юридичні науки: базисноантиделыктне «Адміністра­тивне право України», процедурне «Админо­регламентное право України» та у низку регулятивних юридичних наук, а також розробити Адміністративний кодекс України, Адміно-регламентній кодекс України, відповідні регулятивні кодекси.На основе новейших подходов к понимании задач, объектов и классификации юридических наук предложена перспектива развития административного права и процес­са, которые должны трансформироваться в новые юридические науки: базисноанти­деликтное «Административное право Украины», процедурное «Админо­регламентное право Украины» и ряд регулятивных юридических наук, а также разработать Административный кодекс Украины, Админо-регламентный кодекс Украины, соответствую­щие регулятивные кодексы.On the basis of the newest fittings to for understanding of tasks, objects and classification of legal sciences the prospect of development of administrative law and process is offered, which must be transformed in new legal sciences: basisuntidelictical the «Administrative law of Ukraine», procedural «Administrative-reglamental law of Ukraine» and the row of regulative legal sciences, and also to develop the Administrative code of Ukraine, Administrative­-reglamental code of Ukraine, proper regulative codes

Transient early wheeze and lung function in early childhood associated with chronic obstructive pulmonary disease genes

Background It has been hypothesized that a disturbed early lung development underlies the susceptibility to chronic obstructive pulmonary disease (COPD). Little is known about whether subjects genetically predisposed to COPD show their first symptoms or reduced lung function in c

Mode of Delivery and Asthma at School Age in 9 European Birth Cohorts

Evidence on the association between mode of delivery and asthma at school age is inconclusive. We assessed the associations between specific modes of delivery and asthma in children from 9 European birth cohorts that enrolled participants between 1996 and 2006. Cohort-specific crude and adjusted risk ratios for asthma at ages 5–9 years were calculated using Poisson regression models and pooled. A sensitivity analysis was carried out in children born at term to reduce confounding due to perinatal factors. The study included 67,613 participants. Cohortspecific rates of cesarean delivery varied from 9.4% to 37.5%. Cesarean delivery, as opposed to vaginal delivery, was associated with an increased risk of asthma (adjusted risk ratio (aRR) = 1.22, 95% confidence interval (CI): 1.02, 1.46). Compared with spontaneous vaginal delivery, the adjusted risk ratio was 1.33 (95% CI: 1.02, 1.75) for elective cesarean delivery, 1.07 (95% CI: 0.94, 1.22) for emergency cesarean delivery, and 0.97 (95% CI: 0.84, 1.12) for operative vaginal delivery. In children born at term, the associations were strengthened only for elective cesarean delivery (aRR = 1.49, 95% CI: 1.13, 1.97). The large sample size allowed analysis of the associations between specific modes of delivery and asthma at school age. The increased risk of asthma associated with elective cesarean delivery, especially among children born at term, is relevant in counteracting the increasing use of this procedure, which is often performed without a clear medical indication.This work was supported by the European Community’s Seventh Framework Programme (FP7/2009–2013) under a grant agreement (grant 241604) and by the University of Turin and the San Paolo Foundation (Turin, Italy). Data collection was funded and the study teams of all participating birth cohorts were supported by local and/or national research organizations

Trastuzumab duocarmazine in locally advanced and metastatic solid tumours and HER2-expressing breast cancer: a phase 1 dose-escalation and dose-expansion study

Background: Trastuzumab duocarmazine is a novel HER2-targeting antibody-drug conjugate comprised of trastuzumab covalently bound to a linker drug containing duocarmycin. Preclinical studies showed promising antitumour activity in various models. In this first-in-human study, we assessed the safety and activity of trastuzumab duocarmazine in patients with advanced solid tumours. Methods: We did a phase 1 dose-escalation and dose-expansion study. The dose-escalation cohort comprised patients aged 18 years or older enrolled from three academic hospitals in Belgium, the Netherlands, and the UK with locally advanced or metastatic solid tumours with variable HER2 status who were refractory to standard cancer treatment. A separate cohort of patients were enrolled to the dose-expansion phase from 15 hospitals in Belgium, the Netherlands, Spain, and the UK. Dose-expansion cohorts included patients aged 18 years or older with breast, gastric, urothelial, or endometrial cancer with at least HER2 immunohistochemistry 1+ expression and measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST). Trastuzumab duocarmazine was administered intravenously on day 1 of each 3-week cycle. In the dose-escalation phase, trastuzumab duocarmazine was given at doses of 0.3 mg/kg to 2.4 mg/kg (3 + 3 design) until disease progression or unacceptable toxicity. The primary endpoint of the dose-escalation phase was to assess safety and ascertain the recommended phase 2 dose, which would be the dose used in the dose-expansion phase. The primary endpoint of the dose-expansion phase was the proportion of patients achieving an objective response (complete response or partial response), as assessed by the investigator using RECIST version 1.1. This ongoing study is registered with ClinicalTrials.gov, number NCT02277717, and is fully recruited. Findings: Between Oct 30, 2014, and April 2, 2018, 39 patients were enrolled and treated in the dose-escalation phase and 146 patients were enrolled and treated in the dose-expansion phase. One dose-limiting toxic effect (death from pneumonitis) occurred at the highest administered dose (2.4 mg/kg) in the dose-escalation phase. One further death occurred in the dose-escalation phase (1.5 mg/kg cohort) due to disease progression, which was attributed to general physical health decline. Grade 3-4 treatment-related adverse events reported more than once in the dose-escalation phase were keratitis (n=3) and fatigue (n=2). Based on all available data, the recommended phase 2 dose was set at 1.2 mg/kg. In the dose-expansion phase, treatment-related serious adverse events were reported in 16 (11%) of 146 patients, most commonly infusion-related reactions (two [1%]) and dyspnoea (two [1%]). The most common treatment-related adverse events (grades 1-4) were fatigue (48 [33%] of 146 patients), conjunctivitis (45 [31%]), and dry eye (45 [31%]). Most patients (104 [71%] of 146) had at least one ocular adverse event, with grade 3 events reported in ten (7%) of 146 patients. No patients died from treatment-related adverse events and four patients died due to disease progression, which were attributed to hepatic failure (n=1), upper gastrointestinal haemorrhage (n=1), neurological decompensation (n=1), and renal failure (n=1). In the breast cancer dose-expansion cohorts, 16 (33%, 95% CI 20.4-48.4) of 48 assessable patients with HER2-positive breast cancer achieved an objective response (all partial responses) according to RECIST. Nine (28%, 95% CI 13.8-46.8) of 32 patients with HER2-low, hormone receptor-positive breast cancer and six (40%, 16.3-67.6) of 15 patients with HER2-low, hormone receptor-negative breast cancer achieved an objective response (all partial responses). Partial responses were also observed in one (6%, 95% CI 0.2-30.2) of 16 patients with gastric cancer, four (25%, 7.3-52.4) of 16 patients with urothelial cancer, and five (39%, 13.9-68.4) of 13 patients with endometrial cancer. Interpretation: Trastuzumab duocarmazine shows notable clinical activity in heavily pretreated patients with HER2-expressing metastatic cancer, including HER2-positive trastuzumab emtansine-resistant and HER2-low breast cancer, with a manageable safety profile. Further investigation of trastuzumab duocarmazine for HER2-positive breast cancer is ongoing and trials for HER2-low breast cancer and other HER2-expressing cancers are in preparation. Copyright (C) 2019 Elsevier Ltd. All rights reserved