Multimorbidity: What do we know? What should we do?

Multimorbidity, which is defined as the co-occurrence of two or more chronic conditions, has moved onto the priority agenda for many health policymakers and healthcare providers. Patients with multimorbidity are high utilizers of healthcare resources and are some of the most costly and difficult-to-treat patients in Europe. Preventing and improving the way multimorbidity is managed is now a key priority for many countries, and work is at last underway to develop more sustainable models of care. Unfortunately, this effort is being hampered by a lack of basic knowledge about the aetiology, epidemiology, and risk factors for multimorbidity, and the efficacy and cost-effectiveness of different interventions. The European Commission recognizes the need for reform in this area and has committed to raising awareness of multimorbidity, encouraging innovation, optimizing the use of existing resources, and coordinating the efforts of different stakeholders across the European Union. Many countries have now incorporated multimorbidity into their own healthcare strategies and are working to strengthen their prevention efforts and develop more integrated models of care. Although there is some evidence that integrated care for people with multimorbidity can create efficiency gains and improve health outcomes, the evidence is limited, and may only be applicable to high-income countries with relatively strong and well-resourced health systems. In low- to middle-income countries, which are facing the double burden of infectious and chronic diseases, integration of care will require capacity building, better quality services, and a stronger evidence base. Journal of Comorbidity 2016;6(1):4–1

Massive X-ray screening reveals two allosteric drug binding sites of SARS-CoV-2 main protease

The coronavirus disease (COVID-19) caused by SARS-CoV-2 is creating tremendous health problems and economical challenges for mankind. To date, no effective drug is available to directly treat the disease and prevent virus spreading. In a search for a drug against COVID-19, we have performed a massive X-ray crystallographic screen of repurposing drug libraries containing 5953 individual compounds against the SARS-CoV-2 main protease (Mpro), which is a potent drug target as it is essential for the virus replication. In contrast to commonly applied X-ray fragment screening experiments with molecules of low complexity, our screen tested already approved drugs and drugs in clinical trials. From the three-dimensional protein structures, we identified 37 compounds binding to Mpro. In subsequent cell-based viral reduction assays, one peptidomimetic and five non-peptidic compounds showed antiviral activity at non-toxic concentrations. Interestingly, two compounds bind outside the active site to the native dimer interface in close proximity to the S1 binding pocket. Another compound binds in a cleft between the catalytic and dimerization domain of Mpro. Neither binding site is related to the enzymatic active site and both represent attractive targets for drug development against SARS-CoV-2. This X-ray screening approach thus has the potential to help deliver an approved drug on an accelerated time-scale for this and future pandemics

X-ray screening identifies active site and allosteric inhibitors of SARS-CoV-2 main protease

The coronavirus disease (COVID-19) caused by SARS-CoV-2 is creating tremendous human suffering. To date, no effective drug is available to directly treat the disease. In a search for a drug against COVID-19, we have performed a high-throughput X-ray crystallographic screen of two repurposing drug libraries against the SARS-CoV-2 main protease (M^(pro)), which is essential for viral replication. In contrast to commonly applied X-ray fragment screening experiments with molecules of low complexity, our screen tested already approved drugs and drugs in clinical trials. From the three-dimensional protein structures, we identified 37 compounds that bind to M^(pro). In subsequent cell-based viral reduction assays, one peptidomimetic and six non-peptidic compounds showed antiviral activity at non-toxic concentrations. We identified two allosteric binding sites representing attractive targets for drug development against SARS-CoV-2

Agriculture adaptation in climate change : adaptation report

There is the need for a legal instrument that would first and foremost establish the executive powers of a new entity with overarching responsibilities and powers over all the authorities that have sectoral responsibilities for climate change. Such a legal instrument should also identify these sectoral authorities and their responsibilities, preferably within an Annex which could be amended and adjusted in a flexible manner. This instrument should be managed by a new unit on climate change within MRA and it should ensure integration without causing fragmentation between the sectors. At the same time, retaining the sectoral input would ensure that there is no duplication of roles, that the institutions are specialised within their own field and that the overarching institution does not becomes a bottle neck. In other words, different competent authorities responsible for the different sectoral policies and obligations should remain, but these must be answerable to an institution that has executive powers to ensure compliance and to coordinate long and short term planning with respect to climate change targets and impacts. By way of recommendation therefore, a legal instrument of this sort should seek to intervene as little as possible in the daily running of the sectoral policies and only apply its powers in situations of emergency when non compliance by the different sectors stalls the fulfilment of Malta’s obligations. Its main role should be to ensure implementation of a National Strategy on Mitigation and Adaptation. This legal instrument would not duplicate the role of public institutions that are already regulators for various sectors on climate change. It would however empower the new entity to take enforcement measures against the said institutions if they fail to do so. It would also ensure the implementation and enforcement of existing legislation that regulates the various sectors in order to rationalize their sustainable use and provide for conservation measures. This would benefit both the implementation of mitigation and adaptation measures. An entity entrusted with the overall responsibility for climate change law and policy must be legally empowered to ensure the implementation of national adaptation programmes. It must also coordinate the various sectors to carry out the necessary research to adopt and implement mitigation and adaptation measures. It must necessarily be supported by a parallel capacity building process in the various entities that run the day-to- day implementation functions. On an administrative level, without necessarily being included in a legal instrument, memoranda of understanding and stakeholder dialogue are indispensable tools to ensure cooperation. This will facilitate reaching mitigation and adaptation targets within the stipulated time frames. The mainstreaming of climate change impacts in national policies ensures the adoption of mitigation and adaptation measures and guarantees synergy and linkages amongst various public plans and programmes. Response to climate change should take place at a strategic level to assess beforehand the socio-economic impacts of any mitigation and adaptation measures adopted as a consequence prior to mainstreaming into national policy making. The existing Regulations on the Strategic Environment Assessment already include climate change impacts as one of the issues that needs to be taken into consideration in an SEA. Furthermore, for all those situations where an SEA is not required, Maltese authorities should promote pro-active adaptation measures such as, for example, in development planning, rather than take reactive adaptation measures. The new climate change legal instrument must ensure effective monitoring and stakeholder engagement, particularly the involvement of NGOS and Local Councils which increases public awareness on climate change issues. The new law should also take into consideration national security issues relating to climate change when formulating mitigation and adaptation strategies. The new law should also target the development of a research programme for climate change, including access to funding programmes. It is vital that Investment in research and development in all sectors should not remain on a voluntary basis. It will provide local industry with the necessary technology and it will generate specialised local expertise in a rapidly growing sector that is assuming a tremendous economic potential. Procrastination is detrimental on two main fronts. First because Malta will miss out in securing a place in this niche-market and second because we will keep relying upon foreign technology and expertise. Since Malta can rely on and pool from the scientific and technical advice of the European Environmental agency, it is best to concentrate on investing in scientific and technical research that addresses the local scenario. This should be earmarked as a priority for EU funded projects and care should be taken not to duplicate research conducted by EU agencies to which Malta has access, but rather to build upon it and apply it at the local level. It is also essential to include as a legal obligation the publication to civil society of information acquired as a result of research conducted at the EU level or carried out locally. It must be ensured that all sectors surmount the constraints due to the lack of a sound knowledge base on local ecosystem dynamics. Filling such a gap would serve to build local scientific evidence that would identify to what extent marine, terrestrial and aquatic flora and fauna groups are vulnerable to the impacts of climate change. Emphasis should be placed on minor and already vulnerable groups. All sectors should be legally bound to maintain a Geographic Information System to integrate data related to climate change, and any other data required apart from spatial information. Adopting and implementing the recommendations suggested by the National Sustainable Development Strategy for Malta would greatly enhance the implementation of adaptation measures relating to climate change, both on a cross-sectoral and sectoral level. At present it is envisaged that the government is currently preparing a new Bill on sustainable development, in the meantime the applicable provisions of the EPA by virtue of which the sustainable development strategy was published should continue to apply. Malta should also endeavour to promote more regional cooperation in the Mediterranean under the Barcelona Convention framework and Euro Med, to identify the adaptation needs of the Mediterranean littoral to the impacts of climate change. Authorities should initiate immediately, even at the regional Mediterranean level, studies to assess vulnerability due to climate change, how new opportunities may be tapped, how to meet with the negative consequences of climate change in the sector, how to ensure that local operators adapt to the shift in tourism trends as a result of climate change. There is the need of systematic and sustained awareness building programmes to educate all. This will intensify awareness and promote a change in behavioural patterns to improve adaptation to climate change. Increasing awareness of climate change impacts within the government, industry, and community sectors will support cultural change transitions that are required for the adoption of more climate change friendly technologies, designs, and operations by public and private operators. The new climate change law should also obligate the various sectors to formulate contingency plans. This serves to: address the negative impacts envisaged as a result of climate change particularly upon vulnerable groups. assess socio-economic implications, with increased insurance covers for risks resulting from the likely impacts of climate change. identify financial guarantees and incentives amongst the various stakeholders in all sectors.peer-reviewe

Catalytic cleavage of HEAT and subsequent covalent binding of the tetralone moiety by the SARS-CoV-2 main protease

Here we present the crystal structure of SARS-CoV-2 main protease (Mpro) covalently bound to 2-methyl-1-tetralone. This complex was obtained by co-crystallization of Mpro with HEAT (2-(((4-hydroxyphenethyl)amino)methyl)-3,4-dihydronaphthalen-1(2H)-one) in the framework of a large X-ray crystallographic screening project of Mpro against a drug repurposing library, consisting of 5632 approved drugs or compounds in clinical phase trials. Further investigations showed that HEAT is cleaved by Mpro in an E1cB-like reaction mechanism into 2-methylene-1-tetralone and tyramine. The catalytic Cys145 subsequently binds covalently in a Michael addition to the methylene carbon atom of 2-methylene-1-tetralone. According to this postulated model HEAT is acting in a pro-drug-like fashion. It is metabolized by Mpro, followed by covalent binding of one metabolite to the active site. The structure of the covalent adduct elucidated in this study opens up a new path for developing non-peptidic inhibitors

Inhibition of SARS-CoV-2 main protease by allosteric drug-binding

The coronavirus disease (COVID-19) caused by SARS-CoV-2 is creating tremendous health problems and economical challenges for mankind. To date, no effective drug is available to directly treat the disease and prevent virus spreading. In a search for a drug against COVID-19, we have performed a massive X-ray crystallographic screen of two repurposing drug libraries against the SARS-CoV-2 main protease (Mpro), which is essential for the virus replication and, thus, a potent drug target. In contrast to commonly applied X-ray fragment screening experiments with molecules of low complexity, our screen tested already approved drugs and drugs in clinical trials. From the three-dimensional protein structures, we identified 37 compounds binding to M$^{pro}$. In subsequent cell-based viral reduction assays, one peptidomimetic and five non-peptidic compounds showed antiviral activity at non-toxic concentrations. We identified two allosteric binding sites representing attractive targets for drug development against SARS-CoV-2

X-ray screening identifies active site and allosteric inhibitors of SARS-CoV-2 main protease

The coronavirus disease (COVID-19) caused by SARS-CoV-2 is creating tremendous human suffering. To date, no effective drug is available to directly treat the disease. In a search for a drug against COVID-19, we have performed a high-throughput X-ray crystallographic screen of two repurposing drug libraries against the SARS-CoV-2 main protease (Mpro), which is essential for viral replication. In contrast to commonly applied X-ray fragment screening experiments with molecules of low complexity, our screen tested already approved drugs and drugs in clinical trials. From the three-dimensional protein structures, we identified 37 compounds that bind to Mpro. In subsequent cell-based viral reduction assays, one peptidomimetic and six non-peptidic compounds showed antiviral activity at non-toxic concentrations. We identified two allosteric binding sites representing attractive targets for drug development against SARS-CoV-2