The undetected murder? Evaluation and validation of a practicable and rapid inductively coupled plasma-mass spectrometry method for the detection of arsenic, lead, and thallium intoxications in postmortem blood.

Homicide, suicide, or accident - elemental intoxication may be a cause in each of these types of deaths. Inductively coupled plasma mass spectrometry (ICP-MS) has emerged as the gold standard analytical method for toxic metal analysis in both clinical and forensic settings. An ICP-MS method was developed using a modified acidic workup for the quantitative determination of arsenic, lead, and thallium. Method validation focused on the assessment of linearity, between- and within-day precisions, limits of detection (LoD) and lower limits of quantification (LLoQ), and carryover. The method was applied to analysis of postmortem peripheral blood samples from 279 forensic cases for which orders for chemical-toxicological examination had been received from the public prosecutor's office. Using six-point and one-point calibrations (latter for rapid screening purposes), precisions and accuracies ranged from -4.8 to 5.8% and -6.4 to 7.5%. Analytical sensitivities for As, Pb, and Tl were 0.08, 0.18, and 0.01 µg/l (LoD) and 0.23, 0.66, and 0.03 µg/l (LLoQ), respectively. Observed postmortem peripheral blood concentrations were As, 1.31 ± 3.42 µg/L; Pb, 17.4 ± 13.1 µg/L; and Tl, 0.11 ± 0.07 µg/L (mean ± standard deviation [SD]). Elemental concentrations, determined in additional quality control samples, were in good agreement to those obtained with an external ICP-MS method based on alkaline sample processing. The current method is practicable and compatible with an ICP-MS system used for trace element analysis in an accredited medical laboratory. It allows for implementation of low-threshold investigations when metal intoxications are suspected in forensic routine.

Measuring the global response to antimicrobial resistance, 2020-21: a systematic governance analysis of 114 countries.

BACKGROUND: Understanding strategic commitments and policy responses to overcome antimicrobial resistance at the national, regional, and global levels is required to evaluate current progress and direct future planning. National action plans (NAPs) are the primary mechanism for guiding national strategy and action for antimicrobial resistance governance. Although several NAPs have been developed, no comprehensive content analysis of these plans exists. Using a governance framework, we aimed to assess all publicly available NAPs on antimicrobial resistance. METHODS: We systematically reviewed the contents of NAPs on antimicrobial resistance from 114 countries, applying a governance framework containing 18 domains and 54 indicators in three integral areas: policy design, implementation tools, and monitoring and evaluation. As well as manually searching NAPs and doing online and literature searches that were relevant to specific indicators from repository inception to June 1, 2022, several data sources were used to generate scores, including the Tripartite Antimicrobial Resistance Country Self-Assessment Survey, the Global Antimicrobial Resistance and Use Surveillance System, the Global Antimicrobial Resistance Research and Development Hub, and various WHO datasets. NAPs were included if the country had also submitted the NAP to the Tripartite Antimicrobial Resistance Country Self-Assessment Survey 2020-21, if the NAP was retrievable through a publicly accessible database or website, and if the NAP was either published in English or eligible for machine translation. Three researchers independently reviewed each NAP and were initially blinded to the evaluations of other researchers. They generated a score using a quantification system for each of 54 indicators. The Cochrane protocol for ensuring reliability was followed. The three researchers were then unblinded and met to resolve any disagreements in scoring to reach a consensus agreement. In each case of discrepancy, consensus was reached between the researchers. We developed criteria to standardise the process of quantifying each indicator. We also weighted and collated relevant national data from various sources to generate composite scores concordant with the key governance areas. We transformed these data to a scale of 0 (worst) to 100 (best), ranked countries on the basis of their mean scores, and used descriptive statistics to analyse global and regional trends. FINDINGS: 306 NAPs were identified and 114 were eligible for analysis. Between 2020 and 2021, the mean antimicrobial resistance governance score was 51 (SD 14). Norway had the highest governance score (mean 85 [SD 32]), and the Federated States of Micronesia had the lowest governance score (28 [37]). The highest scoring domain was participation (83 [16]), and the lowest scoring domains were accountability (30 [18]) and feedback mechanism (30 [25]). Domains relating to policy design (55 [13]) and implementation tools (54 [17]) scored similarly, whereas monitoring and evaluation (38 [20]) efforts were lower. INTERPRETATION: International efforts to control antimicrobial resistance varied considerably between countries. Monitoring and evaluation efforts need improving for continuous understanding of national and international progress. International response might not be commensurate with the scale and severity of antimicrobial resistance. FUNDING: None.

Fighting Antimicrobial Resistance: Development and Implementation of the Ghanaian National Action Plan (2017-2021).

In recent years, Ghana has been recognised as a leading player in addressing antimicrobial resistance (AMR) in Africa. However, based on our literature review, we could not ascertain whether the core elements of the national action plan (NAP) were implemented in practice. In this paper, we present a qualitative analysis of the development of AMR-related policies in Ghana, including the NAP. We conducted 13 semi-structured expert interviews to obtain at a more thorough understanding of the implementation process for the AMR NAP and to highlight its accomplishments and shortcomings. The results show that AMR policies, as embodied in the NAP, have led to an extended network of cooperation between stakeholders in many political fields. Broadly, limited allocation of financial resources from the government and from international cooperation have been deplored. Furthermore, the opportunity for using the NAP in mainstreaming the response to the threat of AMR has not been seized. To the general public, this remained hidden behind a number of other relevant health topics such as infection prevention, veterinary services and pharmaceutical regulation. As a One Health (OH) challenge, developing countries could integrate AMR NAPs into other health and environmental programmes to improve its implementation in practice.

Critical prerequisites for Covid-19 vaccine acceleration: A developing economy perspective.

This study aims to explore the critical prerequisites for accelerating the distribution of the COVID-19 vaccine in developing countries by using Ghana as a case study. A qualitative study method and content analysis approach was used. In-depth interviews were conducted with health experts from the Ghana Health Service, World Health Organization (WHO), AstraZeneca, Novartis, and Medtronic Inc. in Ghana. Our analysis of data revealed that new structures, committees, advisory bodies and lines of communication in government evolved during this pandemic and are underlying the current strategy development and decision-making on COVID-19 vaccines. The interviews gave insights into six major factors that will aid COVID-19 vaccine acceleration in Ghana. These factors are: (1) Access to vaccines through delivery, (2) national manufacturing of vaccines, (3) choosing the best vaccine candidates, (4) financial resources, (5) transparency, and (6) vaccine roll-out and administration. These results could guide policymakers and other relevant stakeholders in prioritizing activities that will aid COVID-19 vaccine acceleration in Ghana and other lower-middle-income countries, tailored to their specific context. As a recommendation, the Ghanaian government should embrace a multisectoral synergy approach to fight the disease. The study also provides insights into how vaccine adoption can be accelerated in the case of future pandemics.

The global health concept of the German government: strengths, weaknesses, and opportunities.

Recognising global health as a rapidly emerging policy field, the German federal government recently released a national concept note for global health politics (July 10, 2013). As the German government could have a significant impact on health globally by making a coherent, evidence-informed, and long-term commitment in this field, we offer an initial appraisal of the strengths, weaknesses, and opportunities for development recognised in this document. We conclude that the national concept is an important first step towards the implementation of a coherent global health policy. However, important gaps were identified in the areas of intellectual property rights and access to medicines. In addition, global health determinants such as trade, economic crises, and liberalisation as well as European Union issues such as the health of migrants, refugees, and asylum seekers are not adequately addressed. Furthermore, little information is provided about the establishment of instruments to ensure an effective inter-ministerial cooperation. Finally, because implementation aspects for the national concept are critical for the success of this initiative, we call upon the newly elected 2013 German government to formulate a global health strategy, which includes a concrete plan of action, a time scale, and measurable goals.

Fragmentation of salivary stones with a 980nm diode laser.

OBJECTIVE: Intraductal laser lithotripsy is a preferred method to fragment large, immobile intraglandular salivary stones. A number of different laser systems has been investigated for this purpose. It was our aim to study the effectiveness of a 980nm diode laser when fragmenting salivary stones in an experimental set up. METHODS: In an experimental set up we used a 980nm diode laser for the lithotripsy of 9 salivary stones. The temperature circle around the laser fibre tip was measured and stone remnants were chemically analysed for their composition. RESULTS: The salivary stones had a mean diameter of 6.7mm×5.6mm×3.0mm. Laser fragmentation with the diode laser was successful at all stones. The temperature next to the salivary stone increased to around 30°C during the active lithotripsy with continuous rinsing (fluid temperature 21°C). At a distance of 2mm the temperature around the laser fibre's tip is reduced by already about 50%. The salivary stones mainly consisted of carbonate apatite, followed by ß-calcium phosphate and other calcium phosphates. CONCLUSION: The fragmentation of salivary stones with a 980nm diode laser is possible in principle. Under a continuous irrigation with a positioning of the laser fibre's tip at the centre of the stone, no relevant temperature increase in the vicinity of the stone occurs. However, before the laser is used in humans, in vivo experiments on animal material seem to be advisable.

Addressing global health governance challenges through a new mechanism: the proposal for a Committee C of the World Health Assembly.

The field of global health has reached a critical juncture, where both its visibility and the complexity of its challenges are unprecedented. The World Health Organization, as the only global health actor possessing both democratic and formal legal legitimacy, is best positioned to capitalize on this new, precarious situation in public health and respond with the governance innovation that is needed to bring the increasingly chaotic network of activities and entities affecting health outcomes under the fold of a centralized, standard-setting agency. One such proposed innovation to guide normative and strategic coordination in global health is the creation of a Committee C of the World Health Assembly that would promote consensus building and multi-stakeholder decision-making within the unique convening power of the World Health Organization.

Do activities of cytochrome P450 (CYP)3A, CYP2D6 and P-glycoprotein differ between healthy volunteers and HIV-infected patients?

BACKGROUND: In inflammation and infection, cytochrome P450 (CYP) enzyme activities are down-regulated. Information on possible discrepancies in activities of CYP enzymes and drug transporters between HIV-infected patients and healthy people is limited. METHODS: We used midazolam, dextromethorphan and digoxin as in vivo phenotyping probes for CYP3A (CYP3A4/5), CYP2D6 and P-glycoprotein activities, respectively, and compared these activities between 12 healthy Caucasian volunteers and 30 treatment-naive HIV-infected patients. RESULTS: Among the HIV-infected patients, the overall CYP3A activity (apparent oral midazolam clearance) was approximately 50% of the activity observed in healthy volunteers (point estimate 0.490, 90% confidence interval [CI] 0.377-0.638). The CYP2D6 activity (plasma ratio area under the curve [AUC]; AUC(dextromethorphan)/AUC(dextrorphan)) was essentially unchanged (point estimate 1.289, 90% CI 0.778-2.136). P-glycoprotein activity was slightly lower in patients (digoxin maximum concentration point estimate 1.304, 90% CI 1.034-1.644). CONCLUSIONS: The overall CYP3A activity was approximately 50% lower in HIV-infected patients than in healthy volunteers. The CYP2D6 activity was highly variable, but, on average was not different between groups, whereas a marginally lower P-glycoprotein activity was observed in treatment-naive HIV-infected patients.

Impaired mitochondrial Ca2+ homeostasis in respiratory chain-deficient cells but efficient compensation of energetic disadvantage by enhanced anaerobic glycolysis due to low ATP steady state levels.

Energy-producing pathways, adenine nucleotide levels, oxidative stress response and Ca(2+) homeostasis were investigated in cybrid cells incorporating two pathogenic mitochondrial DNA point mutations, 3243A>G and 3302A>G in tRNA(Leu(UUR)), as well as Rho(0) cells and compared to their parental 143B osteosarcoma cell line. All cells suffering from a severe respiratory chain deficiency were able to proliferate as fast as controls. The major defect in oxidative phosphorylation was efficiently compensated by a rise in anaerobic glycolysis, so that the total ATP production rate was preserved. This enhancement of glycolysis was enabled by a considerable decrease of cellular total adenine nucleotide pools and a concomitant shift in the AMP+ADP/ATP ratios, while the energy charge potential was still in the normal range. Further important consequences were an increased production of superoxide which, however, was neither escorted by major changes in the antioxidative defence systems nor was it leading to substantial oxidative damage. Most interestingly, the lowered mitochondrial membrane potential led to a disturbed intramitochondrial calcium homeostasis, which most likely is a major pathomechanism in mitochondrial diseases.