Discrimination of grade 2 and 3 cervical intraepithelial neoplasia by means of analysis of water soluble proteins recovered from cervical biopsies

<p>Abstract</p> <p>Background</p> <p>Cervical intraepithelial neoplasia (CIN) grades 2 and 3 are usually grouped and treated in the same way as "high grade", in spite of their different risk to cancer progression and spontaneous regression rates. CIN2-3 is usually diagnosed in formaldehyde-fixed paraffin embedded (FFPE) punch biopsies. This procedure virtually eliminates the availability of water-soluble proteins which could have diagnostic and prognostic value.</p> <p>Aim</p> <p>To investigate whether a water-soluble protein-saving biopsy processing method followed by a proteomic analysis of supernatant samples using LC-MS/MS (LTQ Orbitrap) can be used to distinguish between CIN2 and CIN3.</p> <p>Methods</p> <p>Fresh cervical punch biopsies from 20 women were incubated in RPMI1640 medium for 24 hours at 4°C for protein extraction and subsequently subjected to standard FFPE processing. P16 and Ki67-supported histologic consensus review CIN grade (CIN2, n = 10, CIN3, n = 10) was assessed by independent gynecological pathologists. The biopsy supernatants were depleted of 7 high abundance proteins prior to uni-dimensional LC-MS/MS analysis for protein identifications.</p> <p>Results</p> <p>The age of the patients ranged from 25-40 years (median 29.7), and mean protein concentration was 0.81 mg/ml (range 0.55 - 1.14). After application of multistep identification criteria, 114 proteins were identified, including proteins like vimentin, actin, transthyretin, apolipoprotein A-1, Heat Shock protein beta 1, vitamin D binding protein and different cytokeratins. The identified proteins are annotated to metabolic processes (36%), signal transduction (27%), cell cycle processes (15%) and trafficking/transport (9%). Using binary logistic regression, Cytokeratin 2 was found to have the strongest independent discriminatory power resulting in 90% overall correct classification.</p> <p>Conclusions</p> <p>114 proteins were identified in supernatants from fresh cervical biopsies and many differed between CIN2 and 3. Cytokeratin 2 is the strongest discriminator with 90% overall correct classifications.</p

PSMA-RLT in Patients with Metastatic Hormone-Sensitive Prostate Cancer : A Retrospective Study

Background: Prostate-specific membrane antigen (PSMA)-directed radioligand therapy (RLT) is a novel treatment for patients with castration-resistant prostate cancer (CRPC). Given the mode of action, patients in an earlier disease stage, such as hormone-sensitive prostate cancer (HSPC), are also likely to benefit from [177Lu]Lu-PSMA- (177Lu-PSMA) or [225Ac]Ac-PSMA-radioligand treatment (225Ac-PSMA). In this retrospective study, we analyzed the safety and efficacy of PSMARLT in early-stage and hormone-sensitive metastatic prostate cancer patients. Methods: A retrospective study was performed in patients who received 177Lu-PSMA and/or 225Ac-PSMA with early-stage metastatic prostate cancer. The primary outcome parameter evaluated in this study was the progression-free survival (PFS) after PSMA-RLT and toxicity according to the Common Terminology Criteria for Adverse Events. Secondary outcome parameters were prostate-specific antigen (PSA) response and the date of onset of CRPC state. Results: In total, 20 patients were included of which 18 patients received 177Lu-PSMA radioligand and two patients received tandem treatment with both 177Lu-PSMA and 225Ac-PSMA radioligands. Patients received a median of 2 treatment cycles (range 1–6) and a median activity of 6.2 GBq 177Lu-PSMA per cycle (interquartile range (IQR) 5.2–7.4 GBq). PSMA-RLT was overall well-tolerated. The most common grade 1–2 side effects were xerostomia (n = 6) and fatigue (n = 8), which were only temporarily reported. One patient that received 225Ac-PSMA developed grade 3–4 bone marrow toxicity. The median PFS was 12 months (95% confidence interval (CI), 4.09–19.9 months). Seventeen (85%) patients had a ≥50% PSA response following PSMA-RLT. One patient developed CRPC 9 months following PSMA-RLT. Conclusions: In this small cohort study, PSMA-RLT appeared safe and showed encouraging efficacy for (metastasized) early-stage and hormone-sensitive prostate cancer patients. Prospective studies are awaited and should include long-term follow-up

Wind, waves, and acoustic background levels at Station ALOHA

Author Posting. © American Geophysical Union, 2012. This article is posted here by permission of American Geophysical Union for personal use, not for redistribution. The definitive version was published in Journal of Geophysical Research 117 (2012): C03017, doi:10.1029/2011JC007267.Frequency spectra from deep-ocean near-bottom acoustic measurements obtained contemporaneously with wind, wave, and seismic data are described and used to determine the correlations among these data and to discuss possible causal relationships. Microseism energy appears to originate in four distinct regions relative to the hydrophone: wind waves above the sensors contribute microseism energy observed on the ocean floor; a fraction of this local wave energy propagates as seismic waves laterally, and provides a spatially integrated contribution to microseisms observed both in the ocean and on land; waves in storms generate microseism energy in deep water that travels as seismic waves to the sensor; and waves reflected from shorelines provide opposing waves that add to the microseism energy. Correlations of local wind speed with acoustic and seismic spectral time series suggest that the local Longuet-Higgins mechanism is visible in the acoustic spectrum from about 0.4 Hz to 80 Hz. Wind speed and acoustic levels at the hydrophone are poorly correlated below 0.4 Hz, implying that the microseism energy below 0.4 Hz is not typically generated by local winds. Correlation of ocean floor acoustic energy with seismic spectra from Oahu and with wave spectra near Oahu imply that wave reflections from Hawaiian coasts, wave interactions in the deep ocean near Hawaii, and storms far from Hawaii contribute energy to the seismic and acoustic spectra below 0.4 Hz. Wavefield directionality strongly influences the acoustic spectrum at frequencies below about 2 Hz, above which the acoustic levels imply near-isotropic surface wave directionality.Funding for the ALOHA Cabled Observatory was provided by the National Science Foundation and the State of Hawaii through the School of Ocean and Earth Sciences and Technology at the University of Hawaii-Manoa (F. Duennebier, PI). Donations from AT&T and TYCOM and the cooperation of the U.S. Navy made this project possible. The WHOI-Hawaii Ocean Time series Station (WHOTS) mooring is maintained by Woods Hole Oceanographic Institution (PIs R. Weller and A. Plueddemann) with funding from the NOAA Climate Program Office/Climate Observation Division. NSF grant OCE- 0926766 supported R. Lukas (co-PI) to augment and collaborate on the maintenance of WHOTS. Lukas was also supported during this analysis by The National Ocean Partnership Program “Advanced Coupled Atmosphere-Wave-Ocean Modeling for Improving Tropical Cyclone Prediction Models” under contract N00014-10-1-0154 to the University of Rhode Island (I. Ginis, PI).2012-09-1

Modelling sustainability performance to achieve absolute reductions in socio-ecological systems

As the world’s natural resources dwindle and critical levels of environmental pollution are approached, sustainability becomes a key issue for governments, organisations and individuals. With the consequences of such an issue in mind, this paper introduces a unifying approach to measure the sustainability performance of socio-economic systems based on the interplay between two key variables: essentiality of consumption and environmental impact. This measure attributes to every system a ‘fitness’ value i.e. a quantity that reflects its ability to remain resilient/healthy by avoiding ecological, social and economic collapse as it consumes the available resources. This new measure is tested on a system where there is a limited supply of resources and four basic consumption types. The analysis has theoretical implications as well as practical importance as it can help countries, organisations or even individuals, in finding better ways to measure sustainability performance

The Corona Pandemic and Participatory Governance:: Responding to the Vulnerabilities of Secondary School Students in Europe

Adolescents in secondary schools have limited susceptibility to the SARS-COV-2 virus, but paradoxically are considered to be carrying the highest psychosocial burden during this pandemic. The aim of our European multi-country qualitative research was to investigate the COVID-19 crisis response in secondary schools and the role of national, regional, and local stakeholders in contributing to a participatory governance approach. We carried out 11 months of qualitative fieldwork, which included 90 respondents from the Netherlands, Ireland, and Finland for in-depth interviews and/or group discussions. Participant observation was conducted in four secondary schools to explore the interplay of day-to-day formal and informal practices of crisis governance. Our findings contribute to a better understanding of what efforts were made to facilitate participatory governance and where a bottom-up approach would have served useful in successfully implementing the COVID-19 mitigation strategies. Moreover, we show how these mitigation strategies have led to unintended consequences, such as students’ difficulties with isolation and associated mental health problems, and the struggles of socialization when returning to a physical school environment. Our findings highlight the importance of the school environment in the socio-emotional developments of adolescents. We introduce the TAPIC-R model to analyze good governance, advancing the existing TAPIC model with an emphasis on the role of resilience in shaping participatory governance. We argue this is urgently needed during crises to strengthen engagement of the community, including vulnerable groups and achieve positive outcomes within and across policy structures and action domains

Multinational Observational Cohort Study of COVID-19-Associated Pulmonary Aspergillosis(1)

Contains fulltext : 241443.pdf (Publisher’s version ) (Open Access

D1.2 – Lessons learned and best practices COVID-19 response: Health Emergency Response in Interconnected Systems

This report on COVID-19 Crisis Governance is Deliverable 1.2 ‘Lessons learned and best practices’ of the project HERoS - Health Emergency Response in Interconnected Systems. It builds on HERoS’ Deliverable 1.1 ‘Recommendations for governance and policies in the COVID-2019 response’. This Deliverable contains three parts. Part A drives on extensive qualitative research in three European countries (the Netherlands, Finland, and Ireland). Part B presents best governance practices and challenges in cross-border medical supply chain. It takes lessons learned from the EU joint procurement and the COVAX initiative for the purchase and distribution of COVID-19 vaccines. Part C reflects on the social network Municipio Solidale in Rome the charity work in the years of the COVID-19 pandemic. Part D provides the best practices from deployment of UK-MED and PCPM’s Emergency Medical Teams (EMTs). Part A presents collected evidence and share best practices and lessons learned related to the governance of the COVID-19 crisis within nursing homes and secondary schools in Europe. Using a whole-of-society approach which we presented in Deliverable 1.1, we looked at three analytical layers: (1) the state and the institutional landscape, (2) established and emerging response organizations and networks, (3) societal resilience and participation. We conducted in-depth interviews, observations, and focus group discussions, and in the Netherlands, we additionally made use of a participatory action research approach wherein we used visual ethnography, photovoice, video diary and arts-based engagement research. Regarding nursing homes, three main themes emerged from our data. First, we found high levels of trauma among nursing home workers and supporting organisations. Therefore, on-site group therapy is the envisioned response needed. Second, we found a major workforce outflow of the sector. This could be mitigated by a structural wage development that is in line with the value of performing essential work duties and would additionally heighten the attractiveness of the nursing profession. Third, due to lack of governmental and public appreciation we have found diminished levels of professional pride, which could be addressed with aligning nursing home working conditions with national hospital standards. In conclusion, we warn about the possible uprising of a European social care crisis which could be mediated by rapid policy-level action in line with our findings. For secondary schools, we also derived three main themes from our data. First, we argue that there is a need in European countries for leadership that facilitates action towards the well-being of our young populations. Experts stressed the importance of strengthening adolescents’ lobbies and advocacy groups in decision making processes. Second, there is an urgent need for funding into tackling COVID-19 associated increases in inequalities among adolescents. Extra time and attention should be allocated to adolescents who have fallen behind with their studies during the past two years. Lastly, we discovered many adolescent accounts of depressive and anxiety symptoms and we emphasise the urgency of closing Europe’s biggest treatment gap within mental health services for youth by reducing waiting times. There is no doubt that the COVID-19 pandemic has caused long-lasting, and in some cases even life-long difficulties to young people. In conclusion, nursing homes and secondary schools are dealing with different vulnerable groups, risks, and priorities and hence, this fuelled variations in crisis response. General measures (e.g. school closures/visitor ban) should be decided upon by central authorities supported by proper coordination mechanisms, while more specific guidelines that depend on the individual attributes of the field needs to be decentralized and bottom-up. Deepening citizens’ participation into the crisis response gives them ownership and control to influence public decision-making that affects their lives. Part B presents the desk review on the European Union’s joint procurement for personal protective equipment, ventilators, laboratory equipment, therapeutic remdesivir and ICU medicines and vaccines, and the COVAX Facility for equitable access to COVID-19 vaccines. Since the COVID-19 pandemic has changed how we govern global medical supply chains unprecedented joint procurement and collaboration initiatives have been set up during the pandemic. In this part we refelct on such cross-border governance mechanisms of joint procurement initiatives in medical supply chains. It examines challenges and best practises by collaborative initiatives from both the EU and the COVAX’ COVID-19 vaccine procurement and distribution. Both comprise innovative cross-border collaborative mechanisms for vaccine procurement and distribution, yet differ across membership, geographic scale, policies, and organizational governance arrangements. They were both values-driven initiatives, inspired by calls for solidarity, but also stemming from necessity. The EU’s procurement for innovation mechanism required the adoption of novel practices in contract development and management, plus new governing institutions (first RescEU, now also HERA). This Part 2 shows how the EU faced unique challenges with one of their co-funded vaccine developers that resulted in disputes over delivery volumes and schedules. However, the joint purchasing of COVID-19 vaccines using Advance Purchase Agreements with vaccine manufacturers through funds under the European Commission´s Emergency Support instrument has been an innovative cross-border governance initiative that could inspire similar collaboration in other domains (e.g., energy). It comprised a centralised or ‘centre-out’ governance arrangement co-ordinated by the European Commission with formal rules within a fragmented bureaucracy, pursuing legal and political alignment among member states of a tightly connected union. It is characterised by broad regional scope, being far more ambitious than earlier EU procurement strategies. Part C is a presentation of the case Municipio Solidale, a local solidarity project in Rome that started at the beginning of the pandemic in March 2020 and lasted until the end of July 2020. The case is about the distribution of food in a municipality in Rome by spontaneous volunteers and social networks. The case presents the challenges the social network had to overcome. The fact that most of the planned activities are still ongoing in 2020 and are permanently included in the territorial offers, shows not only how urgent these measures were in the most difficult period of the pandemic crisis, but above all how necessary they were in general. The response of the territorial community itself, the degree of mobilization and passion that characterized all the activities of the project, as well as the welcome of citizens tell us that Municipio Solidale has managed to respond to a complex request already present in the VIII Municipality, which are further amplified by the COVID-19 pandemic: a demand for primary goods and relational goods among the most vulnerable. The case shows that local initiatives will last and grew into stable charity mechanisms and have the potential to become part of whole of society governance mechanisms. Part D describes PCPM part in EMTs that were one of few emergency response mechanisms that were of relevance in the COVID-19 pandemic. The teams of highly specialized medical staff, with considerable international experience and working under the auspices of the WHO, could have and in many instances were, a very meaningful support to the developing countries facing the worst brunt of the pandemics, coupled with shortages of skills, experienced personnel and equipment. This part summarizes main operational difficulties faced by UK-Med and Polish PCPM’s Emergency Medical Teams, stemming from 25 and 7 COVID-19 deployments respectively. In particular it discusses the changing role of EMTs, as well as challenges faced in meeting high expectations of the respective ministries of health