Antiplatelet therapy versus observation in low-risk essential thrombocythemia with CALR mutation

The role of antiplatelet therapy as primary prophylaxis of thrombosis in low-risk essential thrombocythemia has not been studied in randomized clinical trials. We assessed the benefit/risk of low-dose aspirin in 433 low-risk essential thrombocythemia patients (CALR-mutated n=271, JAK2V617F-mutated n=162) who were on antiplatelet therapy or observation only. After a 2215 person-years follow-up free from cytoreduction, 25 thrombotic and 17 bleeding episodes were recorded. In CALR-mutated patients, antiplatelet therapy did not affect the risk of thrombosis but was associated with a higher incidence of bleeding (12.9 vs. 1.8 x1000 patient-years, p=0.03). In JAK2V617F-mutated patients, low-dose aspirin was associated with a reduced incidence of venous thrombosis with no effect on the risk of bleeding. Coexistence of JAK2V617F-mutation and cardiovascular risk factors increased the risk of thrombosis, even after adjusting for treatment with low-dose aspirin (incidence rate ratio: 9.8; 95% confidence interval: 2.3-42.3; p=0.02). Time free from cytoreduction was significantly shorter in CALR-mutated than in JAK2V617F-mutated essential thrombocythemia (median time 5 years and 9.8 years, respectively; p=0.0002) usually to control extreme thrombocytosis. In conclusion, in patients with low-risk, CALR-mutated essential thrombocythemia, low-dose aspirin does not reduce the risk of thrombosis and may increase the risk of bleeding.

HER2 in high-risk rectal cancer patients treated in EXPERT-C, a randomized phase II trial of neoadjuvant capecitabine and oxaliplatin (CAPOX) and chemoradiotherapy (CRT) with or without cetuximab.

BACKGROUND: HER2 is an established therapeutic target in breast and gastric cancers. The role of HER2 in rectal cancer is unclear, as conflicting data on the prevalence of HER2 expression in this disease have been reported. We evaluated the prevalence of HER2 and its impact on the outcome of high-risk rectal cancer patients treated with neoadjuvant CAPOX and CRT±cetuximab in the EXPERT-C trial. PATIENTS AND METHODS: Eligible patients with available tumour tissue for HER2 analysis were included. HER2 expression was determined by immunohistochemistry (IHC) in pre-treatment biopsies and/or surgical specimens (score 0-3+). Immunostaining was scored according to the consensus panel recommendations on HER2 scoring for gastric cancer. Tumours with equivocal IHC result (2+) were tested for HER2 amplification by D-ISH. Tumours with IHC 3+ or D-ISH ratio ≥2.0 were classified as HER2+. The impact of HER2 on primary and secondary end points of the study was analysed. RESULTS: Of 164 eligible study patients, 104 (63%) biopsy and 114 (69%) surgical specimens were available for analysis. Only 3 of 104 (2.9%) and 3 of 114 (2.6%) were HER2+, respectively. In 77 patients with paired specimens, concordance for HER2 status was found in 74 (96%). Overall, 141 patients were assessable for HER2 and 6 out of 141 (4.3%) had HER2 overexpression and/or amplification. The median follow-up was 58.6 months. HER2 was not associated with a difference in the outcome for any of the study end points, including in the subset of 90 KRAS/BRAF wild-type patients treated±cetuximab. CONCLUSIONS: Based on the low prevalence of expression as recorded in the EXPERT-C trial, HER2 does not appear to represent a useful therapeutic target in high-risk rectal cancer. However, the role of HER2 as a potential predictive biomarker of resistance to anti-EGFR-based treatments and a therapeutic target in anti-EGFR refractory metastatic colorectal cancer (CRC) warrants further investigation. TRIAL REGISTRATION: ISRCTN Register: 99828560.

Phonic skills mediate improved literacy outcomes in at-risk primary school children: results from the Ready-to-Learn Programme

Background
Learning to read is a key goal during primary school: reading difficulties may curtail children’s learning trajectories. Controversy remains regarding what types of interventions are effective for children at risk for academic failure, such as children in disadvantaged areas. We present data from a complex intervention to test the hypothesis that phonic skills and word recognition abilities are a pivotal and specific causal mechanism for the development of reading skills in children at risk for poorer literacy outcomes.
Method
Over 500 pupils across 16 primary schools took part in a Cluster Randomised Controlled Trial from school year 1 to year 3. Schools were randomly allocated to the intervention or the control arm. The intervention involved a literacy-rich after-school programme. Children attending schools in the control arm of the study received the curriculum normally provided. Children in both arms completed batteries of language, phonic skills, and reading tests every year. We used multilevel mediation models to investigate mediating processes between intervention and outcomes.
Findings
Children who took part in the intervention displayed improvements in reading skills compared to those in the control arm. Results indicated a significant indirect effect of the intervention via phonics encoding.
Discussion
The results suggest that the intervention was effective in improving reading abilities of children at risk, and this effect was mediated by improving children’s phonic skills. This has relevance for designing interventions aimed at improving literacy skills of children exposed to socio-economic disadvantage. Results also highlight the importance of methods to investigate causal pathways from intervention to outcomes.

Establishing continental sovereignty in Africa: risk and opportunity in financial integration - lessons for Africa from a legal perspective

This thesis identifies and defines the new African sovereignty. It establishes a modern sovereignty in Africa hatched from the changing nature of sovereignty in which countries come together at various levels or grades of partial surrender of national sovereignty in order to work closer together for their mutual advantage and benefit. To this end, the narrative zooms in on the central issues within the realms of money matters whereby a new model of monetary sovereignty and monetary solutions is designed in an attempt to ease the recurring tensions and challenges of modern national sovereignty in the continent of Africa. As such, this discussion will offer a historical journey through the constitution of sovereignty, to the birth of the nation state and international public law. It develops the theory of the changing nature of sovereignty within the modern state and opens new lines of inquiry for Africa. In this regard, it draws from juxtaposing and mixing elements of regional and global financial integration as well as retaining national financial sovereignty features to form this new design which I dub continental sovereignty. At its core, the thesis will deal with the legal aspects that stem from the co-mingling of legal systems of nation states and communities at the regional and global levels within the context of financial integration. The argument is that the rule of law remains sacrosanct in monetary management. Effective financial integration is the result of properly structured and managed legal frameworks with robust laws and institutions whether at a national, regional or global level. However, the thesis reveals that in order to avoid undermining the progress of Africa’s financial integration project, any solution for Africa must be immersed within a broader global solution where development issues are addressed and resolved and Africa can form a more central part in all relevant international discussion fora. The work will expound these issues by applying them within a regional and global context, with the state of affairs in Africa forming the nucleus. This application consequently presents the six key themes of the thesis which will be considered therein. They are: a.) regional advantage: which exploits the possibilities of deeper and further financial integration between smaller communal arrangements; b.) regional risk and exposure: the extent to which this deeper form of financial integration can spiral out of control if effected too quickly and too ambitiously; c.) global advantage: which considers the merits of global financial integration and the influence exerted by financial laws on the global financial architecture; d.) global risk and exposure: which considers the challenges of global financial integration especially within the background of the Global Financial Crisis 2007-2008; e.) African challenge: which considers the extent to which this analysis impacts the African economic and financial integration agenda; and f.) development challenge: which examines the extent to which global development issues impact the African solution (continental sovereignty) and the need for any solution for the continent to be roped into a broader global solution within which Africa can form an important part. Even though the thesis requests an optimistic undertone on the progress made so far, it unearths the African problem of multiple national sovereignty and multiple overlapping regional sovereignty constituted as the ‘spaghetti bowl’ dilemma. As such, the unique contribution to knowledge on financial integration in Africa can be echoed in these words: Africa‘s financial integration agenda has had little success in authenticating a systematic and dependable legal framework for monetary management. Efforts made have been incomplete, substandard, and not carefully followed through particularly reflected in the impuissant nature of the judicial enforcement mechanisms. Thus, the thesis argues that, any meaningful answer to the problems dogging the continent is inter alia deeply entrenched within a new form of cooperative monetary sovereignty. In other words, the thesis does not prescribe the creation of new laws; rather it advocates the effective enforcement of existing laws.

Home and group-based implementation of the "Growing Up Happily in the Family" program in at-risk psychosocial contexts

"Growing Up Happily in the Family" is a program to prevent child maltreatment targeted at parents of children aged 0-5 years old in at-risk psychosocial contexts. The program is delivered via either a group-based or a home-visit format. The objective of this study was to evaluate the impact of various implementation components in the home and group versions on changes in parental attitudes about child development and education. At-risk and non at-risk parents participated in the group-based (196 participants in 26 groups) and home-visit (95 participants) versions of the program delivered through local social services. We analyzed program adherence, adaptations, participant responsiveness, quality of delivery, and implementation barriers as predictors of changes in parental attitudes. The results showed that greater program adherence, better quality of delivery and participant responsiveness, and positive climate predicted changes in parental attitudes in both formats. Therefore, it is important to take into account the quality of the implementation process when testing the effectiveness of early group-based and home-visit interventions in at-risk families.

Geometrical Methods in Multivariate Risk Management: Algorithms and Applications

This thesis builds a framework for evaluating downside risk from multivariate data via a special class of risk measures (RM). The peculiarity of the analysis lies in getting rid of strong data distributional assumptions and in orientation towards the most critical data in risk management: those with asymmetries and heavy tails. At the same time, under typical assumptions, such as the ellipticity of the data probability distribution, the conformity with classical methods is shown. The constructed class of RM is a multivariate generalization of the coherent distortion RM, which possess valuable properties for a risk manager. The design of the framework is twofold. The first part contains new computational geometry methods for the high-dimensional data. The developed algorithms demonstrate computability of geometrical concepts used for constructing the RM. These concepts bring visuality and simplify interpretation of the RM. The second part develops models for applying the framework to actual problems. The spectrum of applications varies from robust portfolio selection up to broader spheres, such as stochastic conic optimization with risk constraints or supervised machine learning.

Noninvasive Ventilation and Droplet dispersion. Health professional protocols. Nurse perspective. in: Noninvasive Ventilation in High-Risk Infections and Mass Casualty Events,

The past few decades have seen major impacts of different pandemics and mass casualty events on health resource use in terms of rising health cost and increased mortality.

Research, development, and innovations in health risk assessment for brazilian agriculture.

Agriculture and livestock are key sectors of the Brazilian economy, which are essential for the country?s economic growth and for the equality between the domestic currency?s supply and demand. Agribusiness answered for about 23% of the gross domestic product (GDP) in 2015, according to Confederação Nacional da Agricultura (CNA), and reached 50.3% of total exports in February 2016, according to Secretaria de Relações Internacionais do Agronegócio (SRI) of Ministério da Agricultura, Pecuária e Abastecimento (Mapa) (Brasil, 2016). Currently, this sector is recognized as the most competitive and efficient in Brazil, considering the global scenario.

The environmental DNA in the risk assessment and decision making processes for the invasive species management in agri-food sector, hydraulic security and biodiversity conservation

The use of environmental DNA (eDNA) analysis as a monitoring tool is becoming more and more widespread. The eDNA metabarcoding methods allow rapid community assessments of different target taxa. This work is focused on the validation of the environmental DNA metabarcoding protocol for biodiversity assessment of freshwater habitats. Scolo Dosolo was chosen as study area and three sampling points were defined for traditional and eDNA analyses. The gutter is a 205 m long anthropic canal located in Sala Bolognese (Bologna, Italy). Fish community and freshwater invertebrate metazoans were the target groups for the analysis. After a preliminary study in summer 2019, 2020 was devoted to the sampling campaign with winter (January), spring (May), summer (July) and autumn (October) surveys. Alongside with the water samplings for the eDNA study, also traditional fish surveys using the electrofishing technique were performed to assess fish community composition; census on invertebrates was performed using an entomological net and a surber sampler. After in silico analysis, the MiFish primer set amplifying a fragment of the 12s rRNA gene was selected for bony fishes. For invertebrates the FWHF2 + FWHR2N primer combination, that amplifies a region of the mitochondrial coi gene, was chosen. Raw reads were analyzed through a bioinformatic pipeline based on OBITools metabarcoding programs package and QIIME2. The OBITools pipeline retrieved seven fish taxa and 54 invertebrate taxa belonging to six different phyla, while QIIME2 recovered eight fish taxa and 45 invertebrate taxa belonging to the same six phyla as the OBITools pipeline. The metabarcoding results were then compared with the traditional surveys data and bibliographic records. Overall, the validated protocol provides a reliable picture of the biodiversity of the study area and an efficient support to the traditional methods.

The metabolic syndrome in hypertension: European society of hypertension position statement.

The metabolic syndrome considerably increases the risk of cardiovascular and renal events in hypertension. It has been associated with a wide range of classical and new cardiovascular risk factors as well as with early signs of subclinical cardiovascular and renal damage. Obesity and insulin resistance, beside a constellation of independent factors, which include molecules of hepatic, vascular, and immunologic origin with proinflammatory properties, have been implicated in the pathogenesis. The close relationships among the different components of the syndrome and their associated disturbances make it difficult to understand what the underlying causes and consequences are. At each of these key points, insulin resistance and obesity/proinflammatory molecules, interaction of demographics, lifestyle, genetic factors, and environmental fetal programming results in the final phenotype. High prevalence of end-organ damage and poor prognosis has been demonstrated in a large number of cross-sectional and a few number of prospective studies. The objective of treatment is both to reduce the high risk of a cardiovascular or a renal event and to prevent the much greater chance that metabolic syndrome patients have to develop type 2 diabetes or hypertension. Treatment consists in the opposition to the underlying mechanisms of the metabolic syndrome, adopting lifestyle interventions that effectively reduce visceral obesity with or without the use of drugs that oppose the development of insulin resistance or body weight gain. Treatment of the individual components of the syndrome is also necessary. Concerning blood pressure control, it should be based on lifestyle changes, diet, and physical exercise, which allows for weight reduction and improves muscular blood flow. When antihypertensive drugs are necessary, angiotensin-converting enzyme inhibitors, angiotensin II-AT1 receptor blockers, or even calcium channel blockers are preferable over diuretics and classical beta-blockers in monotherapy, if no compelling indications are present for its use. If a combination of drugs is required, low-dose diuretics can be used. A combination of thiazide diuretics and beta-blockers should be avoided.

Beyond the Threshold: Life in the New Russia

Amanda Sprang spent nine months, from September of 1995 to May of 1996, studying at Colby College's program in St. Petersburg, Russia. Through contacts made during previous trips to Russia in middle and high school, Amanda was able to quickly rekindle her old friendships and make new ones with many young Russians from different backgrounds. The following work is a collection of twelve essays about life in the New Russia. The essays are framed by a foreword and an epilogue that help place the entire work in a historical context. Although the theme of each essay emerges from a particular incident, within every story Amanda has addressed numerous topics relating to Russian life in today’s changing society. Her first essay, “Art Klinika," takes place in an avant-garde night club in St. Petersburg, and includes a brief yet impressionable, encounter with three young Russian men. “The Birthday Party” recalls a wild evening at the home of her close friend, showing how the Russians greet special occasions. Both the third and fourth essays take place in Moscow, where Amanda returns to visit old friends. These two essays portray the lives of the new economic elite in comparison with the average citizen, as well as show how young Russians face the new challenges that greet them. "Politics Russian Style" recalls a political rally in St. Petersburg, and attempts to shed light on the wacky political world of an infant democracy. Chapters Six through Ten take place away from the western cities of St. Petersburg and Moscow, as Amanda brings us to the cold, mysterious land of Siberia in the dead of winter. She recounts her five day train ride with a retired, high-powered, Communist party official, her experiences in the provincial city of Irkutsk, and a brief trip to a Buddhist monastery and, later, an excursion to Lake Baikal. Back in St. Petersburg, Chapter Eleven gives a humorous account of a ski trip with several Russian friends. Amanda finishes her work with her final chapter, “The Dacha," which describes a weekend spent at a Russian country home with her friend's family.

Ethics in a capitalistic society

The problem of semantics is inherent in any discussion of ethics. The general term "ethics" is itself commonly confused. In addition, systems of ethics must be built upon assumptions, and assumptions are necessarily subject to lengthy debate. These two problems are encountered in my investigation of the ethical practices of the modern business community and to remedy the situation I have taken two steps: the first being an attempt to clarify the meaning of terms used therein;-and the second being a clear description of the assumptions utilized to further my analysis. To satisfy those who would disagree with these assumptions, I have attempted to outline the consequences of differing premises. The first assumption in my discussion is that the capitalistic economy is powered by the motivation supplied by man's self-interest. We are conditioned to basing our courses of action upon an orientation toward gratifying this self-interest. Careers are chosen by blending aptitude, interest, and remuneration. of course, some people are less materially inclined than others, but the average member of our capitalistic society is concerned with the physical rewards derived from his employment. Status and happiness are all-important considerations in pursuing a chosen course of action, yet all too often they are measured in physical terms. The normal self-interest natural to mankind is heightened in capitalism, due to the emphasis placed upon material compensation. Our thinking becomes mechanistic as life devolves into a complex game played by the rules. We are accustomed to performing meaningless or unpleasant duties to fulfill our gratifications. Thought, consequently, interferes with the completion of our everyday routines. We learn quickly not to be outspoken, as the outspoken one threatens the security of his fellow man. The majority of the people are quite willing to accept others views on morality, and indeed this is the sensible thing to do as one does not risk his own neck. The unfortunate consequence of this situation has been the substitution of the legal and jural for the moral and ethical. Our actions are guided by legal considerations and nowhere has this been more evident than in the business community. The large legal departments of modern corporations devote full time to inspecting the legality of corporate actions. The business community has become preoccupied with the law, yet this is necessarily so. Complex, modern, capitalistic society demands an elaborate framework of rules and regulations. Without this framework it would be impossible to have an orderly economy, to say nothing of protecting the best interests of the people. However, the inherent complexities, contradictions, and sometimes unfair aspects of our legal system can tempt men to take things into their own hands. From time to time cases arise where men have broken laws while acting in good faith, and other cases where men have been extremely unethical without being illegal. Examples such as these foster the growth of cynicism, and generally create an antagonistic attitude toward the law on the part of business. My second assumption is that the public, on the whole, has adopted an apathetic attitude toward business morality. when faced with an ethical problem, far too many people choose to cynically assume that, if I don't do it someone else will. "The danger of such an assumption lies in that it eliminates many of the inhibitions that normally would preclude unethical action. The preventative factor in contemplating an unethical act not only lies in it going against the "right course of action", but also in that it would display the actor as one of the few, immoral practitioners. However, if the contemplator feels that many other people follow the same course of action, he would not feel himself to be so conspicuous. These two assumptions underly my entire discussion of modern business ethics., and in my judgment are the two most important causal factors in unethical acts perpetrated by the business community. The future elimination of these factors seems improbable, if not futile, yet there is no reason to consider things worse than they ever have been before. The heightened public interest in business morality undoubtedly lies in part in the fact that examples of corporate malpractice are of such magnitude in scope, and hence more newsworthy.