Designing organometallic compounds for catalysis and therapy

Bioorganometallic chemistry is a rapidly developing area of research. In recent years organometallic compounds have provided a rich platform for the design of effective catalysts, e.g. for olefin metathesis and transfer hydrogenation. Electronic and steric effects are used to control both the thermodynamics and kinetics of ligand substitution and redox reactions of metal ions, especially Ru II. Can similar features be incorporated into the design of targeted organometallic drugs? Such complexes offer potential for novel mechanisms of drug action through incorporation of outer-sphere recognition of targets and controlled activation features based on ligand substitution as well as metal- and ligand-based redox processes. We focus here on η 6-arene, η 5-cyclopentadienyl sandwich and half-sandwich complexes of Fe II, Ru II, Os II and Ir III with promising activity towards cancer, malaria, and other conditions. © 2012 The Royal Society of Chemistry

Antiracism in leading public health universities, journals and funders: commitments, accountability and the decision-makers.

INTRODUCTION: Two years since the murder of George Floyd, there has been unprecedented attention to racial justice by global public health organisations. Still, there is scepticism that attention alone will lead to real change. METHODS: We identified the highest-ranked 15 public health universities, academic journals and funding agencies, and used a standardised data extraction template to analyse the organisation's governance structures, leadership dynamics and public statements on antiracism since 1 May 2020. RESULTS: We found that the majority of organisations (26/45) have not made any public statements in response to calls for antiracism actions, and that decision-making bodies are still lacking diversity and representation from the majority of the world's population. Of those organisations that have made public statements (19/45), we identified seven types of commitments including policy change, financial resources, education and training. Most commitments were not accompanied by accountability measures, such as setting goals or developing metrics of progress, which raises concerns about how antiracism commitments are being tracked, as well as how they can be translated into tangible action. CONCLUSION: The absence of any kind of public statement paired with the greater lack of commitments and accountability measures calls into question whether leading public health organisations are concretely committed to racial justice and antiracism reform

Using critical information to strengthen pandemic preparedness: the role of national public health agencies.

COVID-19 has demonstrated that most countries' public health systems and capacities are insufficiently prepared to prevent a localised infectious disease outbreak from spreading. Strengthening national preparedness requires National Public Health Institutes (NPHIs), or their equivalent, to overcome practical challenges affecting timely access to, and use of, data that is critical to preparedness. Our situational analysis in collaboration with NPHIs in three countries-Ethiopia, Nigeria and Pakistan-characterises these challenges. Our findings indicate that NPHIs' role necessitates collection and analysis of data from multiple sources that do not routinely share data with public health authorities. Since initiating requests for access to new data sources can be a lengthy process, it is essential that NPHIs are routinely monitoring a broad set of priority indicators that are selected to reflect the country-specific context. NPHIs must also have the authority to be able to request rapid sharing of data from public and private sector organisations during health emergencies and to access additional human and financial resources during disease outbreaks. Finally, timely, transparent and informative communication of synthesised data from NPHIs will facilitate sustained data sharing with NPHIs from external organisations. These actions identified by our analysis will support the availability of robust information systems that allow relevant data to be collected, shared and analysed by NPHIs sufficiently rapidly to inform a timely local response to infectious disease outbreaks in the future

Metabolomic profiles predict individual multidisease outcomes

Publisher Copyright: © 2022, The Author(s).Risk stratification is critical for the early identification of high-risk individuals and disease prevention. Here we explored the potential of nuclear magnetic resonance (NMR) spectroscopy-derived metabolomic profiles to inform on multidisease risk beyond conventional clinical predictors for the onset of 24 common conditions, including metabolic, vascular, respiratory, musculoskeletal and neurological diseases and cancers. Specifically, we trained a neural network to learn disease-specific metabolomic states from 168 circulating metabolic markers measured in 117,981 participants with ~1.4 million person-years of follow-up from the UK Biobank and validated the model in four independent cohorts. We found metabolomic states to be associated with incident event rates in all the investigated conditions, except breast cancer. For 10-year outcome prediction for 15 endpoints, with and without established metabolic contribution, a combination of age and sex and the metabolomic state equaled or outperformed established predictors. Moreover, metabolomic state added predictive information over comprehensive clinical variables for eight common diseases, including type 2 diabetes, dementia and heart failure. Decision curve analyses showed that predictive improvements translated into clinical utility for a wide range of potential decision thresholds. Taken together, our study demonstrates both the potential and limitations of NMR-derived metabolomic profiles as a multidisease assay to inform on the risk of many common diseases simultaneously.Peer reviewe

Improving National Intelligence for Public Health Preparedness: a methodological approach to finding local multi-sector indicators for health security.

The COVID-19 epidemic is the latest evidence of critical gaps in our collective ability to monitor country-level preparedness for health emergencies. The global frameworks that exist to strengthen core public health capacities lack coverage of several preparedness domains and do not provide mechanisms to interface with local intelligence. We designed and piloted a process, in collaboration with three National Public Health Institutes (NPHIs) in Ethiopia, Nigeria and Pakistan, to identify potential preparedness indicators that exist in a myriad of frameworks and tools in varying local institutions. Following a desk-based systematic search and expert consultations, indicators were extracted from existing national and subnational health security-relevant frameworks and prioritised in a multi-stakeholder two-round Delphi process. Eighty-six indicators in Ethiopia, 87 indicators in Nigeria and 51 indicators in Pakistan were assessed to be valid, relevant and feasible. From these, 14-16 indicators were prioritised in each of the three countries for consideration in monitoring and evaluation tools. Priority indicators consistently included private sector metrics, subnational capacities, availability and capacity for electronic surveillance, measures of timeliness for routine reporting, data quality scores and data related to internally displaced persons and returnees. NPHIs play an increasingly central role in health security and must have access to data needed to identify and respond rapidly to public health threats. Collecting and collating local sources of information may prove essential to addressing gaps; it is a necessary step towards improving preparedness and strengthening international health regulations compliance

Is Africa prepared for tackling the COVID-19 (SARS-CoV-2) epidemic. Lessons from past outbreaks, ongoing pan-African public health efforts, and implications for the future

Soon after the novel coronavirus, SARS-CoV-2 (2019-nCoV), was first identified in a cluster of patients with pneumonia (Li et al., 2020), in the Chinese city of Wuhan on 31 December 2019, rapid human to human transmission was anticipated (Hui et al., 2020). The fast pace of transmission is wreaking havoc and stirring media hype and public health concern (Ippolito et al., 2020) globally. When the World Health Organization (WHO) declared the disease, (now officially named COVID-19) a Public Health Emergency of International Concern (PHEIC) on 31st January 2020 (WHO, 2020a), the Director General Dr Tedros Ghebreyesus justified the decision by stating that WHOs greatest concern was the potential for the virus to spread to countries with weaker health systems. Repeated outbreaks of other preventable emerging and re-emerging infectious diseases with epidemic potential have taken their toll on the health systems of many African countries. The devastating 2014–2016 Ebola Virus Epidemic (WHO, 2020b) in West Africa, demonstrated how ill-prepared the affected countries were to rapidly identify the infection and halt transmission (WHO, 2020d, Largent, 2016, Hoffman and Silverberg, 2018, Omoleke et al., 2016). Similarly, the smoldering remnants of the 2018–19 Ebola Virus outbreak in the Democratic Republic of Congo, have demonstrated even for health services with considerable experience of dealing with a certain emerging pathogen, geography and sociopolitical instability, can hamper the response (Aruna et al., 2019)

Mapping HIV in Uganda

Over the course of almost four decades the world has been left vulnerable by the HIV epidemic. Displaying the biggest public health challenge currently, many scholars aim to further the understanding of the mechanisms of the spread of HIV. This study aims to contribute to the existing body of literature through adding a spatial aspect to research performed on HIV key drivers in Uganda. Furthermore, the aim of this research is to explore the geographical aspects of the HIV epidemic on a district-level in Uganda in order to examine the relationship between the geographical distribution of HIV cases and their socioeconomic background. This was assessed using a quantitative cross-sectional study design relying on Multiple Linear Regression and Geographically Weighted Regression analysis. The analysis was performed using SPSS and ArcGIS. Prior to this, the conceptual framework in the shape of a risk-chain framework led by the concept of vulnerability, identified seven socioeconomic factors based on a thorough literature review which were measured in eight variables. The study assessed that HIV and the identified socioeconomic factors have a global and stationary relationship which accounts for 26.1% of the variance in HIV rates. The variables for conflict, wealth, access to health care and gender equality were assessed to be statistically significant. However, this was not enough to create a properly specified statistical model, hence potential key factors which could improve the analysis were discussed

Influence of hyperglycemia and diabetes on cardioprotection by humoral factors released after remote ischemic preconditioning (RIPC)

Remote ischemic preconditioning (RIPC) protects hearts from ischemia–reperfusion (I/R) injury in experimental studies; however, clinical RIPC trials were unsatisfactory. This discrepancy could be caused by a loss of cardioprotection due to comorbidities in patients, including diabetes mellitus (DM) and hyperglycemia (HG). RIPC is discussed to confer protective properties by release of different humoral factors activating cardioprotective signaling cascades. Therefore, we investigated whether DM type 1 and/or HG (1) inhibit the release of humoral factors after RIPC and/or (2) block the cardioprotective effect directly at the myocardium. Experiments were performed on male Wistar rats. Animals in part 1 of the study were either healthy normoglycemic (NG), type 1 diabetic (DM1), or hyperglycemic (HG). RIPC was implemented by four cycles of 5 min bilateral hind-limb ischemia/reperfusion. Control (Con) animals were not treated. Blood plasma taken in vivo was further investigated in isolated rat hearts in vitro. Plasma from diseased animals (DM1 or HG) was administered onto healthy (NG) hearts for 10 min before 33 min of global ischemia and 60 min of reperfusion. Part 2 of the study was performed vice versa—plasma taken in vivo, with or without RIPC, from healthy rats was transferred to DM1 and HG hearts in vitro. Infarct size was determined by TTC staining. Part 1: RIPC plasma from NG (NG Con: 49 ± 8% vs. NG RIPC 29 ± 6%; p < 0.05) and DM1 animals (DM1 Con: 47 ± 7% vs. DM1 RIPC: 38 ± 7%; p < 0.05) reduced infarct size. Interestingly, transfer of HG plasma showed comparable infarct sizes independent of prior treatment (HG Con: 34 ± 9% vs. HG RIPC 35 ± 9%; ns). Part 2: No infarct size reduction was detectable when transferring RIPC plasma from healthy rats to DM1 (DM1 Con: 54 ± 13% vs. DM1 RIPC 53 ± 10%; ns) or HG hearts (HG Con: 60 ± 16% vs. HG RIPC 53 ± 14%; ns). These results suggest that: (1) RIPC under NG and DM1 induces the release of humoral factors with cardioprotective impact, (2) HG plasma might own cardioprotective properties, and (3) RIPC does not confer cardioprotection in DM1 and HG myocardium

Validation of DEVS Models Using AGILE-Based Methods

International audienc

Milrinone-Induced Postconditioning Requires Activation of Mitochondrial Ca2+-sensitive Potassium (mBKCa) Channels

Cardioprotection by postconditioning requires activation of mitochondrial large-conductance Ca2+-sensitive potassium (mBKCa) channels. The involvement of these channels in milrinone-induced postconditioning is unknown. The authors determined whether cardioprotection by milrinone-induced postconditioning involves activation of mBKCa channels in the rat heart in vitro. Randomized, prospective, blinded laboratory investigation. Experimental laboratory. Male Wistar rats. Hearts of male Wistar rats were randomized, placed on a Langendorff system, and perfused with Krebs-Henseleit buffer at a constant pressure of 80 mmHg. All hearts were subjected to 33 minutes of global ischemia and 60 minutes of reperfusion. At the onset of reperfusion, hearts were perfused with different concentrations of milrinone (0.3-100 μM) for determination of a dose-effect curve. In a second set of experiments, 3 μM milrinone was administered in combination with the mBKCa channel inhibitor paxilline (1 μM). Infarct size was determined by triphenyltetrazoliumchloride staining. In control animals, infarct size was 37 ± 7%. Milrinone at a concentration of 3 μM reduced infarct size to 22 ± 7% (p < 0.05 v control). Higher milrinone concentrations did not confer stronger protection. Paxilline completely blocked milrinone-induced cardioprotection whereas paxilline alone had no effect on infarct size. This study shows that activation of mBKCa channels plays a pivotal role in milrinone-induced postconditionin