Hyperhomocysteinemia increases intimal hyperplasia in a rat carotid endarterectomy model

AbstractPurpose: This preliminary study investigated the ability to elevate the serum homocysteine (H[e]) levels and investigated the increases in postoperative neointimal hyperplasia (IH) in an environment with hyperhomocysteinemia and the resultant restenosis in a rat carotid endarterectomy (CEA) model. Method: The 9 rats for the control group were fed rat chow, and the 8 rats for the H(e) group were fed H(e)-supplemented rat chow for 2 weeks before and after CEA. The animals underwent anesthesia, and a left common CEA was performed. After 14 days, the serum H(e) levels were measured and the left carotid artery was harvested and elastin stained. Morphometric measurements were used to calculate the area of stenosis of the lumen. The mean and the standard deviation of the mean were determined. The 2 groups were compared with the Mann-Whitney test and a linear regression model. Three additional rats per group were studied, with carotid artery sectioning with double immunohistochemical staining for 5-bromodeoxyuridine (BrdU) and α–smooth muscle (α-SM) actin. Results: The serum H(e) level in the H(e) group was 36.32 μmol/L ± 15.28, and in the control group the level was 5.53 μmol/L ± 2.06 (P = .0007). IH presented as percent lumen stenosis was 21.89% ± 4.82% in the H(e) group and 4.82% ± 1.64% in the control group (P = .0007). The linear regression model of the serum H(e) levels and the percent stenosis showed a linear relationship (r2 = .72). The α-SM actin staining revealed that nearly all of the cells in the IH area were of smooth muscle or myofibroblast origin and that 10.1% ± 2.6% of the cells were stained for BrdU in the control group versus 23% ± 7.1% in the H(e) group. Also, 9.3% ± 2.6% of the cells in the IH area were stained for BrdU and for α-SM actin versus 19.1% ± 5.6% stained for both BrdU and α-SM actin in the H(e) group. Conclusion: This is the first study to examine IH after CEA and hyperhomocysteinemia in rats. The study shows that the elevation of serum H(e) levels can be obtained by feeding rats modified diets with added H(e). The consistent elevation of serum H(e) levels was associated with more than 4 times the amount of IH after a CEA in a rat model. (J Vasc Surg 1998;28:909-18.

A Bare Molecular Cloud at z~0.45

Several neutral species (MgI, SiI, CaI, FeI) have been detected in a weak MgII absorption line system (W_r(2796)~0.15 Angstroms) at z~0.45 along the sightline toward HE0001-2340. These observations require extreme physical conditions, as noted in D'Odorico (2007). We place further constraints on the properties of this system by running a wide grid of photoionization models, determining that the absorbing cloud that produces the neutral absorption is extremely dense (~100-1000/cm^3), cold (<100 K), and has significant molecular content (~72-94%). Structures of this size and temperature have been detected in Milky Way CO surveys, and have been predicted in hydrodynamic simulations of turbulent gas. In order to explain the observed line profiles in all neutral and singly ionized chemical transitions, the lines must suffer from unresolved saturation and/or the absorber must partially cover the broad emission line region of the background quasar. In addition to this highly unusual cloud, three other ordinary weak MgII clouds (within densities of ~0.005/cm^3 and temperatures of ~10000K) lie within 500 km/s along the same sightline. We suggest that the "bare molecular cloud", which appears to reside outside of a galaxy disk, may have had in situ star formation and may evolve into an ordinary weak MgII absorbing cloud.Comment: 15 pages, 4 figures, 4 tables, ApJ accepte

Ensuring that COVID-19 research is inclusive: guidance from the NIHR INCLUDE project

Objective: To provide guidance to researchers, funders, regulators and study delivery teams to ensure that research on COVID-19 is inclusive, particularly of groups disproportionately affected by COVID-19 and who may have been historically under-served by research. Summary of key points: Groups who are disproportionately affected by COVID-19 include (but are not limited to) older people, people with multiple long-term conditions, people with disabilities, people from Black, Asian and Ethnic minority groups, people living with obesity, people who are socioeconomically deprived and people living in care homes. All these groups are under-served by clinical research, and there is an urgent need to rectify this if COVID-19 research is to deliver relevant evidence for these groups who are most in need. We provide a framework and checklists for addressing key issues when designing and delivering inclusive COVID-19 research, based on the National Institute for Health Research INnovations in CLinical trial design and delivery for the UnDEr-served project roadmap. Strong community engagement, codevelopment and prioritisation of research questions and interventions are essential. Under-served groups should be represented on funding panels and ethics committees, who should insist on the removal of barriers to participation. Exclusion criteria should be kept to a minimum; intervention delivery and outcome measurement should be simple, flexible and tailored to the needs of different groups, and local advice on the best way to reach and engage with under-served communities should be taken by study delivery teams. Data on characteristics that allow identification of under-served groups must be collected, analyses should include these data to enable subgroup comparisons and results should be shared with under-served groups at an early stage. Conclusion: Inclusive COVID-19 research is a necessity, not a luxury, if research is to benefit all the communities it seeks to serve. It requires close engagement with under-served groups and attention to aspects of study topic, design, delivery, analysis and dissemination across the research life cycle

Молекуларно-дијагностички методи, ризици и превенција на фамилијарната хиперхолестеролемија

методи, ризици и превенција на фамилијарната хиперхолестеролемија Апстракт Фамилијарната хиперхолестеролемија (FH – Familiar Hypercholesterolemia) претставува генетичко заболување на организмот предизвикана најчесто од мутација во генот за рецепторот за липопротеини со мала густина (LDLR) и аполипопротеин Б генот (apoB). Претставува наследно заболување и како такво се карактеризира со покачени количества на вкупен холестерол и LDL – холестерол, како резултат на присуство на дисфункционални рецептори за LDL – холестерол или недостаток од рецептори за LDL- холестерол во црниот дроб со кои организмот, поточно црниот дроб, би го чистел LDL – холестеролот од циркулацијата во организмот. Пациентите со оваа болест се со голем ризик на многу млада возраст да развијат кардиоваскуларна, цереброваскуларна или периферна васкуларна болест како резултат на атероматозни промени во крвните садови, а со тоа и голем ризик од фатален исход доколку состојбата не се открие и третира соодветно. Во овој истражувачки труд се користени резултатите од лабораториски испитувања од амбулантскиот дневник на ПЗУ ДЛ „Павлина” – Виница, во временски период од две години 2010-2011 година. Трудот има за цел да ја прикаже преваленцата и ризикот од појава на можна хиперхолестеролемија, дефинирана по пол и возраст. Според анализираните резултати, заклучивме дека кај машката популација најмногу пациенти со високи концентрации на холестерол има во возрасната група од 40 до 60 години, додека кај женскиот пол во возрасната групата на жени над 60 години има најмногу пациенти со покачени концентрации на холестерол. Утврдено е и генерациска врска, т.е. покачени концентрации на холестерол во две генерации во една фамилија. Фамилијарната хиперхолестеролемија е болест која е проценето дека е присутна кај најмалку 250 милиони луѓе во светот и е од особена важност нејзината брза и рана детекција. Тоа се прави со помош на клиничко лабораториски методи и критериуми и молекуларно-дијагностички методи за откривање на генетската причина за појава на оваа болест

Developing the INCLUDE Ethnicity Framework—a tool to help trialists design trials that better reflect the communities they serve

Background Ensuring that a trial is designed so that its participants reflect those who might benefit from the results, or be spared harms, is key to the potential benefits of the trial reaching all they should. This paper describes the process, facilitated by Trial Forge, that was used between July 2019 and October 2020 to develop the INCLUDE Ethnicity Framework, part of the wider INCLUDE initiative from the National Institute for Health Research to improve inclusion of under-served groups in clinical research studies. Methods Development of the Framework was done in seven phases: (1) outline, (2) initial draft, (3) stakeholder meeting, (4) modify draft, (5) Stakeholder feedback, (6) applying the Framework and (7) packaging. Phases 2 and 3 were face-to-face meetings. Consultation with stakeholders was iterative, especially phases 4 to 6. Movement to the next phase was done once all or most stakeholders were comfortable with the results of the current phase. When there was a version of the Framework that could be considered final, the Framework was applied to six trials to create a set of examples (phase 6). Finally, the Framework, guidance and examples were packaged ready for dissemination (phase 7). Results A total of 40 people from stakeholder groups including patient and public partners, clinicians, funders, academics working with various ethnic groups, trial managers and methodologists contributed to the seven phases of development. The Framework comprises two parts. The first part is a list of four key questions: 1.Who should my trial apply to? 2.Are the groups identified likely to respond in different ways? 3.Will my study intervention make it harder for some groups to engage? 4.Will the way I have designed the study make it harder for some groups to engage? The second part is a set of worksheets to help trial teams address these questions. The Framework can be used for any stage of trial, for a healthcare intervention in any disease area. The Framework was launched on 1st October 2020 and is available open access at the Trial Forge website: https://www.trialforge.org/trial-forge-centre/include/. Conclusion Thinking about the number of people in our trials is not enough: we need to start thinking more carefully about who our participants are

Developing a roadmap to improve trial delivery for under-served groups: results from a UK multi-stakeholder process

Abstract: Background: Participants in clinical research studies often do not reflect the populations for which healthcare interventions are needed or will be used. Enhancing representation of under-served groups in clinical research is important to ensure that research findings are widely applicable. We describe a multicomponent workstream project to improve representation of under-served groups in clinical trials. Methods: The project comprised three main strands: (1) a targeted scoping review of literature to identify previous work characterising under-served groups and barriers to inclusion, (2) surveys of professional stakeholders and participant representative groups involved in research delivery to refine these initial findings and identify examples of innovation and good practice and (3) a series of workshops bringing together key stakeholders from funding, design, delivery and participant groups to reach consensus on definitions, barriers and a strategic roadmap for future work. The work was commissioned by the UK National Institute for Health Research Clinical Research Network. Output from these strands was integrated by a steering committee to generate a series of goals, workstream plans and a strategic roadmap for future development work in this area. Results: ‘Under-served groups’ was identified and agreed by the stakeholder group as the preferred term. Three-quarters of stakeholders felt that a clear definition of under-served groups did not currently exist; definition was challenging and context-specific, but exemplar groups (e.g. those with language barriers or mental illness) were identified as under-served. Barriers to successful inclusion of under-served groups could be clustered into communication between research teams and participant groups; how trials are designed and delivered, differing agendas of research teams and participant groups; and lack of trust in the research process. Four key goals for future work were identified: building long-term relationships with under-served groups, developing training resources to improve design and delivery of trials for under-served groups, developing infrastructure and systems to support this work and working with funders, regulators and other stakeholders to remove barriers to inclusion. Conclusions: The work of the INCLUDE group over the next 12 months will build on these findings by generating resources customised for different under-served groups to improve the representativeness of trial populations

Cybersecurity, our digital anchor: A European perspective

The Report ‘Cybersecurity – Our Digital Anchor’ brings together research from different disciplinary fields of the Joint Research Centre (JRC), the European Commission's science and knowledge service. It provides multidimensional insights into the growth of cybersecurity over the last 40 years, identifying weaknesses in the current digital evolution and their impacts on European citizens and industry. The report also sets out the elements that potentially could be used to shape a brighter and more secure future for Europe’s digital society, taking into account the new cybersecurity challenges triggered by the COVID-19 crisis. According to some projections, cybercrime will cost the world EUR 5.5 trillion by the end of 2020, up from EUR 2.7 trillion in 2015, due in part to the exploitation of the COVID-19 pandemic by cyber criminals. This figure represents the largest transfer of economic wealth in history, more profitable than the global trade in all major illegal drugs combined, putting at risk incentives for innovation and investment. Furthermore, cyber threats have moved beyond cybercrime and have become a matter of national security. The report addresses relevant issues, including: - Critical infrastructures: today, digital technologies are at the heart of all our critical infrastructures. Hence, their cybersecurity is already – and will become increasingly – a matter of critical infrastructure protection (see the cases of Estonia and Ukraine). - Magnitude of impact: the number of citizens, organisations and businesses impacted simultaneously by a single attack can be huge. - Complexity and duration of attacks: attacks are becoming more and more complex, demonstrating attackers’ enhanced planning capabilities. Moreover, attacks are often only detected post-mortem . - Computational power: the spread of malware also able to infect mobile and Internet of Things (IoT) devices (as in the case of Mirai botnet), hugely increases the distributed computational power of the attacks (especially in the case of denial of services (DoS)). The same phenomenon makes the eradication of an attack much more difficult. - Societal aspects: cyber threats can have a potentially massive impact on society, up to the point of undermining the trust citizens have in digital services. As such services are intertwined with our daily life, any successful cybersecurity strategy must take into consideration the human and, more generally, societal aspects. This report shows how the evolution of cybersecurity has always been determined by a type of cause-and-effect trend: the rise in new digital technologies followed by the discovery of new vulnerabilities, for which new cybersecurity measures must be identified. However, the magnitude and impacts of today's cyber attacks are now so critical that the digital society must prepare itself before attacks happen. Cybersecurity resilience along with measures to deter attacks and new ways to avoid software vulnerabilities should be enhanced, developed and supported. The ‘leitmotiv’ of this report is the need for a paradigm shift in the way cybersecurity is designed and deployed, to make it more proactive and better linked to societal needs. Given that data flows and information are the lifeblood of today’s digital society, cybersecurity is essential for ensuring that digital services work safely and securely while simultaneously guaranteeing citizens’ privacy and data protection. Thus, cybersecurity is evolving from a technological ‘option’ to a societal must. From big data to hyperconnectivity, from edge computing to the IoT, to artificial intelligence (AI), quantum computing and blockchain technologies, the ‘nitty-gritty’ details of cybersecurity implementation will always remain field-specific due to specific sectoral constraints. This brings with it inherent risks of a digital society with heterogeneous and inconsistent levels of security. To counteract this, we argue for a coherent, cross-sectoral and cross-societal cybersecurity strategy which can be implemented across all layers of European society. This strategy should cover not only the technological aspects but also the societal dimensions of ‘behaving in a cyber-secure way’. Consequently, the report concludes by presenting a series of possible actions instrumental to building a European digital society secure by design.JRC.E.3-Cyber and Digital Citizens' Securit

Monitoring biodiversity change through effective global coordination

The ability to monitor changes in biodiversity, and their societal impact, is critical to conserving species and managing ecosystems. While emerging technologies increase the breadth and reach of data acquisition, monitoring efforts are still spatially and temporally fragmented, and taxonomically biased. Appropriate long-term information remains therefore limited. The Group on Earth Observations Biodiversity Observation Network (GEO BON) aims to provide a general framework for biodiversity monitoring to support decision makers. Here, we discuss the coordinated observing system adopted by GEO BON, and review challenges and advances in its implementation, focusing on two interconnected core components — the Essential Biodiversity Variables as a standard framework for biodiversity monitoring, and the Biodiversity Observation Networks that support harmonized observation systems — while highlighting their societal relevance

The Science Performance of JWST as Characterized in Commissioning

This paper characterizes the actual science performance of the James Webb Space Telescope (JWST), as determined from the six month commissioning period. We summarize the performance of the spacecraft, telescope, science instruments, and ground system, with an emphasis on differences from pre-launch expectations. Commissioning has made clear that JWST is fully capable of achieving the discoveries for which it was built. Moreover, almost across the board, the science performance of JWST is better than expected; in most cases, JWST will go deeper faster than expected. The telescope and instrument suite have demonstrated the sensitivity, stability, image quality, and spectral range that are necessary to transform our understanding of the cosmos through observations spanning from near-earth asteroids to the most distant galaxies.Comment: 5th version as accepted to PASP; 31 pages, 18 figures; https://iopscience.iop.org/article/10.1088/1538-3873/acb29

Canagliflozin and renal outcomes in type 2 diabetes and nephropathy

BACKGROUND Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium–glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to &lt;90 ml per minute per 1.73 m2 of body-surface area and albuminuria (ratio of albumin [mg] to creatinine [g], &gt;300 to 5000) and were treated with renin–angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of &lt;15 ml per minute per 1.73 m2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P=0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P&lt;0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P=0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P&lt;0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years