The Mechanism of Death in Electrocution: A Historical Review of the Literature.

ABSTRACT: Our present understanding of electrocution followed a long path of detours and speculation. It is now hard to appreciate how mysterious was an unexpected sudden death-without visible trauma-and we should be sympathetic to the surprising theories that came from well-intentioned attempts to find something in the autopsy of an electrocution victim.The early hypotheses (1880s) tended to favor effects on the central nervous system, but the emphasis switched to arterial and hematological mechanisms as well as respiratory arrest (ie, asphyxia) along with a widespread publication debate. While careful animal experimentation slowly established that electrocution was due to the induction of VF (ventricular fibrillation), the older hypotheses held sway for many decades. Even today, the neurogenic and asphyxial explanations reappear occasionally.Despite 170 years of research, the phenomenon of electrocution continues to generate new hypotheses for its mechanism.

Measuring air metagenomic diversity in an agricultural ecosystem.

All species shed DNA during life or in death, providing an opportunity to monitor biodiversity via environmental DNA (eDNA). In recent years, combining eDNA, high-throughput sequencing technologies, bioinformatics, and increasingly complete sequence databases has promised a non-invasive and non-destructive environmental monitoring tool. Modern agricultural systems are often large monocultures and so are highly vulnerable to disease outbreaks. Pest and pathogen monitoring in agricultural ecosystems is key for efficient and early disease prevention, lower pesticide use, and better food security. Although the air is rich in biodiversity, it has the lowest DNA concentration of all environmental media and yet is the route for windborne spread of many damaging crop pathogens. Our work suggests that ecosystems can be monitored efficiently using airborne nucleic acid information. Here, we show that the airborne DNA of microbes can be recovered, shotgun sequenced, and taxonomically classified, including down to the species level. We show that by monitoring a field growing key crops we can identify the presence of agriculturally significant pathogens and quantify their changing abundance over a period of 1.5 months, often correlating with weather variables. We add to the evidence that aerial eDNA can be used as a source for biomonitoring in terrestrial ecosystems, specifically highlighting agriculturally relevant species and how pathogen levels correlate with weather conditions. Our ability to detect dynamically changing levels of species and strains highlights the value of airborne eDNA in agriculture, monitoring biodiversity changes, and tracking taxa of interest.

Improving uptake of population health management through scalable analysis of linked electronic health data.

Population Health Management - often abbreviated to PHM - is a relatively new approach for healthcare planning, requiring the application of analytical techniques to linked patient level data. Despite expectations for greater uptake of PHM, there is a deficit of available solutions to help health services embed it into routine use. This paper concerns the development, application and use of an interactive tool which can be linked to a healthcare system's data warehouse and employed to readily perform key PHM tasks such as population segmentation, risk stratification, and deriving various performance metrics and descriptive summaries. Developed through open-source code in a large healthcare system in South West England, and used by others around the country, this paper demonstrates the importance of a scalable, purpose-built solution for improving the uptake of PHM in health services.

Enhanced expression of the myogenic factor Myocyte enhancer factor-2 in imaginal disc myoblasts activates a partial, but incomplete, muscle development program.

The Myocyte enhancer factor-2 (MEF2) transcription factor plays a vital role in orchestrating muscle differentiation. While MEF2 cannot effectively induce myogenesis in naïve cells, it can potently accelerate myogenesis in mesodermal cells. This includes in Drosophila melanogaster imaginal disc myoblasts, where triggering premature muscle gene expression in these adult muscle progenitors has become a paradigm for understanding the regulation of the myogenic program. Here, we investigated the global consequences of MEF2 overexpression in the imaginal wing disc myoblasts, by combining RNA-sequencing with RT-qPCR and immunofluorescence. We observed the formation of sarcomere-like structures that contained both muscle and cytoplasmic myosin, and significant upregulation of muscle gene expression, especially genes essential for myofibril formation and function. These transcripts were functional since numerous myofibrillar proteins were detected in discs using immunofluorescence. Interestingly, muscle genes whose expression is restricted to the adult stages were not activated in these adult myoblasts. These studies confirm a broad activation of the myogenic program in response to MEF2 expression and suggest that additional regulatory factors are required for promoting the adult muscle-specific program. Our findings contribute to understanding the regulatory mechanisms governing muscle development and highlight the multifaceted role of MEF2 in orchestrating this intricate process.

Adoptive parents' racial colorblindness and adopted Korean adolescents' experiences of discrimination.

OBJECTIVES: Using longitudinal data, this study investigated the association between parent racial colorblindness and discrimination toward children (reported by both parents and adolescents) in transracial, transnational adoptive families. METHOD: Eighty White adoptive parents with adopted Korean children (ages 5-12 years old) were surveyed in 2007 (Time 1 [T1]), and both parents and adolescents (ages 13-19 years old) were surveyed in 2014 (Time 2 [T2]). Parents completed a self-report measure of parent racial colorblindness toward their child at T1 and T2, and parents and adolescents completed a measure of discrimination experienced by adoptees at T2. RESULTS: Parent reports of racial colorblindness toward their child were not significantly different between T1 and T2. However, parent reports of discrimination increased between time points. Further, parent and adolescent reports of discrimination were not significantly different from one another. Using hierarchical regression models, racial colorblindness among parents at T1 (when children were in middle childhood) was significantly associated with parent reports of discrimination experienced by adolescent children at T2, even when controlling for T2 racial colorblindness. This association did not hold for adolescent reports of discrimination. CONCLUSION: Adoptive parents' acknowledgment of their children's race and ethnicity appears relatively stable from childhood into adolescence, and parent racial colorblindness toward their own child can affect their ability to recognize discrimination during adolescent development, a vital period when discrimination becomes more common and salient. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Peripheral PRP in the Operating Room vs Standard Clinic PRP for the Initial Treatment of PDR.

Purpose: To compare the long-term outcomes of standard panretinal photocoagulation (PRP) performed in the operating room (OR) with peripheral PRP performed in the clinic in treatment-naïve patients with proliferative diabetic retinopathy (PDR). Methods: Consecutive cases from 2017 to 2022 were retrospectively reviewed. Exclusion criteria included previous PRP, pars plana vitrectomy performed at the time of the initial PRP, PRP performed in another setting within 3 months of the initial treatment, a documented plan for future PRP at the time of the initial treatment, and less than 3 years of follow-up. Negative binomial regressions were used to compare the number of subsequent interventions between the 2 groups and t tests to compare the visual acuity (VA) outcomes. Results: Of the 961 eyes of 679 patients screened, 82 eyes of 53 patients met the inclusion criteria. The initial PRP was performed in the OR (OR cohort) in 57 eyes of 38 patients and in the clinic (clinic cohort) in 25 eyes of 15 patients. The OR cohort had a mean of 0.4 subsequent surgeries and 0.8 subsequent PRP treatments and the clinic cohort, 0.8 subsequent surgeries (P < .05) and 1.8 subsequent PRP treatments (P < .05). No significant between-group difference was found in the VA outcomes over the long-term follow-up (mean, 44.2 months). Conclusions: Peripheral PRP performed in the OR resulted in fewer subsequent interventions than standard PRP in the clinic and may afford better control of PDR.

Top-down Proteomics for the Characterization and Quantification of Calreticulin Arginylation.

Arginylation installed by arginyltransferase 1 (ATE1) features an addition of arginine (Arg) to the reactive amino acids ( e . g ., Glu and Asp) at the protein N -terminus or side chain. Systemic removal of arginylation after ATE1 knockout (KO) in mouse models resulted in heart defects leading to embryonic lethality. The biological importance of arginylation has motivated the discovery of arginylation sites on proteins using bottom-up approaches. While bottom-up proteomics is powerful in localizing peptide arginylation, it lacks the ability to quantify proteoforms at the protein level. Here we developed a top-down proteomics workflow for characterizing and quantifying calreticulin (CALR) arginylation. To generate fully arginylated CALR (R-CALR), we have inserted an R residue after the signaling peptide (AA1-17). Upon overexpression in ATE1 KO cells, CALR and R-CALR were purified by affinity purification and analyzed by LCMS in positive mode. Both proteoforms showed charge states ranging from 27-68 with charge 58 as the most intense charge state. Their MS2 spectra from electron-activated dissociation (EAD) showed preferential fragmentation at the protein N -terminals which yielded sufficient c ions facilitating precise localization of the arginylation sites. The calcium-binding domain (CBD) gave minimum characteristic ions possibly due to the abundant presence of >100 D and E residues. Ultraviolet photodissociation (UVPD) compared with EAD and ETD significantly improved the sequence coverage of CBD. This method can identify and quantify CALR arginylation at absence, endogenous (low), and high levels. To our knowledge, our work is the first application of top-down proteomics in characterizing post-translational arginylation in vitro and in vivo .

CLINICAL REASONING AND ARTIFICIAL INTELLIGENCE: CAN AI REALLY THINK?

Artificial intelligence (AI) in the form of ChatGPT has rapidly attracted attention from physicians and medical educators. While it holds great promise for more routine medical tasks, may broaden one's differential diagnosis, and may be able to assist in the evaluation of images, such as radiographs and electrocardiograms, the technology is largely based on advanced algorithms akin to pattern recognition. One of the key questions raised in concert with these advances is: What does the growth of artificial intelligence mean for medical education, particularly the development of critical thinking and clinical reasoning? In this commentary, we will explore the elements of cognitive theory that underlie the ways in which physicians are taught to reason through a diagnostic case and compare hypothetico-deductive reasoning, often employing illness scripts, with inductive reasoning, which is based on a deeper understanding of mechanisms of health and disease. Issues of cognitive bias and their impact on diagnostic error will be examined. The constructs of routine and adaptive expertise will also be delineated. The application of artificial intelligence to diagnostic problem solving, along with concerns about racial and gender bias, will be delineated. Using several case examples, we will demonstrate the limitations of this technology and its potential pitfalls and outline the direction medical education may need to take in the years to come.

Use of tRNA gene barriers improves stability of transgene expression in CHO cells.

Instability of transgene expression is a major challenge for the biopharmaceutical industry, which can impact yields and regulatory approval. Some tRNA genes (tDNAs) can resist epigenetic silencing, the principal mechanism of expression instability, and protect adjacent genes against the spread of repressive heterochromatin. We have taken two naturally occurring clusters of human tDNAs and tested their ability to reduce epigenetic silencing of transgenes integrated into the genome of Chinese hamster ovary (CHO) cells. We find sustained improvements in productivity both in adherent CHO-K1 cells and in an industrially relevant CHO-DG44 expression system (Apollo X, FUJIFILM Diosynth Biotechnologies). We conclude that specific tDNA clusters offer potential to mitigate the widespread problem of production instability.

Multiple promoter and enhancer differences likely contribute to augmented G6PC2 expression in human versus mouse pancreatic islet alpha cells.

G6PC2 encodes a glucose-6-phosphatase catalytic subunit that opposes the action of glucokinase in pancreatic islets thereby modulating the sensitivity of insulin and glucagon secretion to glucose. In mice, G6pc2 is expressed at ~20-fold higher levels in ß-cells versus α-cells, whereas in humans G6PC2 is expressed at only ~5-fold higher levels in ß-cells. We therefore hypothesize that G6PC2 likely influences glucagon secretion to a greater degree in humans. With a view to generating a humanized mouse that re-capitulates augmented G6PC2 expression levels in α-cells, we sought to identify the genomic regions that confer differential mouse G6pc2 expression in α-cells versus ß-cells as well as the evolutionary changes that have altered this ratio in humans. Studies in islet-derived cell lines suggest that the elevated G6pc2 expression in mouse ß-cells versus α-cells is mainly due to a difference in the relative activity of the proximal G6pc2 promoter in these cell types. Similarly, the smaller difference in G6PC2 expression between α-cells versus ß-cells in humans is potentially explained by a change in relative proximal G6PC2 promoter activity. However, we show that both glucocorticoid levels and multiple differences in the relative activity of eight transcriptional enhancers between mice and humans likely contribute to differential G6PC2 expression. Finally, we show that a mouse-specific non-coding RNA, Gm13613, whose expression is controlled by G6pc2 enhancer I, does not regulate G6pc2 expression, indicating that altered expression of Gm13613 in a humanized mouse that contains both the human promoter and enhancers, should not affect G6PC2 function.

The CIMMYT Australia ICARDA Germplasm Evaluation concept: a model for international cooperation and impact.

Bread wheat germplasm is accessed from the International Maize and Wheat Improvement Centre (CIMMYT) and the International Centre for Agricultural Research in the Dry Areas (ICARDA) by Australian wheat breeders and researchers through the CIMMYT Australia ICARDA Germplasm Evaluation (CAIGE) program. The CAIGE program coordinates the selection, importation, quarantine, dissemination, and evaluation of the imported bread wheat germplasm and the management of associated data and information. This paper describes the CAIGE model and assesses both the genetic and economic impacts of these materials on the Australian wheat industry after commercialisation of wheat breeding in the early 21st century and the establishment of CAIGE. The CAIGE concept was validated using data collected and analysed from multi-environment trials between 2017 and 2020. The impact of cultivars with and without CAIGE contribution to pedigree on yield was estimated using production-by-variety statistics. Net gain in yield, estimated as the yield difference between CAIGE and Non-CAIGE varieties, was multiplied by the percentage contribution to pedigree to estimate the additional yield. The CAIGE bread wheat program identified diverse, high-yielding, and disease-resistant germplasm and significantly improved the capture and dissemination of information. The benefit-cost ratio, calculated as the sum of benefits divided by investments, indicated that, for every dollar invested in CAIGE, a further $20 was generated in benefits. The internal rate of return was estimated at 163% and the modified rate at 18%. The benefits of these international materials to Australian wheat breeding remained significant.

Apixaban vs Aspirin in Patients With Cancer and Cryptogenic Stroke: A Post Hoc Analysis of the ARCADIA Randomized Clinical Trial.

Importance: Approximately 10% to 15% of ischemic strokes are associated with cancer; cancer-associated stroke, particularly when cryptogenic, is associated with high rates of recurrent stroke and major bleeding. Limited data exist on the safety and efficacy of different antithrombotic strategies in patients with cancer and cryptogenic stroke. Objective: To compare apixaban vs aspirin for the prevention of adverse clinical outcomes in patients with history of cancer and cryptogenic stroke. Design, Setting, and Participants: Post hoc analysis of data from 1015 patients with a recent cryptogenic stroke and biomarker evidence of atrial cardiopathy in the Atrial Cardiopathy and Antithrombotic Drugs in Prevention After Cryptogenic Stroke (ARCADIA) trial, a multicenter, randomized, double-blind clinical trial conducted from 2018 to 2023 at 185 stroke centers in North America. Data analysis was performed from October 15, 2023, to May 23, 2024. Exposures: Oral apixaban, 5 mg (or 2.5 mg if criteria met), twice daily vs oral aspirin, 81 mg, once daily. Subgroups of patients with and without cancer at baseline were examined. Main Outcomes and Measures: The primary outcome for this post hoc analysis was a composite of major ischemic or major hemorrhagic events. Major ischemic events were recurrent ischemic stroke, myocardial infarction, systemic embolism, and symptomatic deep vein thrombosis or pulmonary embolism. Major hemorrhagic events included symptomatic intracranial hemorrhage and any major extracranial hemorrhage. Results: Among 1015 participants (median [IQR] age, 68 [60-76] years; 551 [54.3%] female), 137 (13.5%) had a history of cancer. The median (IQR) follow-up was 1.5 (0.6-2.5) years for patients with history of cancer and 1.5 (0.6-3.0) years for those without history of cancer. Participants with history of cancer, compared with those without history of cancer, had a higher risk of major ischemic or major hemorrhagic events (hazard ratio [HR], 1.73; 95% CI, 1.10-2.71). Among those with history of cancer, 8 of 61 participants (13.1%) randomized to apixaban and 16 of 76 participants (21.1%) randomized to aspirin had a major ischemic or major hemorrhagic event; however, the risk was not significantly different between groups (HR, 0.61; 95% CI, 0.26-1.43). Comparing participants randomized to apixaban vs aspirin among those with cancer, events included recurrent stroke (5 [8.2%] vs 9 [11.8%]), major ischemic events (7 [11.5%] vs 14 [18.4%]), and major hemorrhagic events (1 [1.6%] vs 2 [2.6%]). Conclusions and Relevance: Among participants in the ARCADIA trial with history of cancer, the risk of major ischemic and hemorrhagic events did not differ significantly with apixaban compared with aspirin. Trial Registration: ClinicalTrials.gov Identifier: NCT03192215.

Itaconate suppresses house dust mite-induced allergic airways disease and Th2 cell differentiation.

Itaconate was initially identified as an antimicrobial compound produced by myeloid cells. Beyond its antimicrobial role, itaconate may also serve as a crucial metabolic and immune modulator. We therefore examined the roles of aconitate decarboxylase 1 (Acod1) and itaconate in house dust mite (HDM)-sensitized and -challenged mice, a model of T helper 2 (Th2)-driven allergic airways disease. HDM treatment induced lung Acod1 mRNA expression and bronchoalveolar lavage (BAL) itaconate levels in wild-type C57BL/6 mice. Acod1 knockout mice (Acod1-KO) with negligible BAL itaconate showed heightened HDM-induced type 2 cytokine expression, increased serum IgE, and enhanced recruitment of Th2 cells in the lung, indicating a shift towards a more pronounced Th2 immune response. Acod1-KO mice also showed increased eosinophilic airway inflammation and hyperresponsiveness. Experiments in chimeric mice demonstrated that bone marrow from Acod1-KO mice is sufficient to increase type 2 cytokine expression in wild-type mice, and that restitution of bone marrow from wild type mice attenuates mRNA expression of Th2 cytokines in Acod1-KO mice. Specific deletion of Acod1 in lysozyme-secreting macrophages (LysM-cre+Acod1flox/flox) recapitulated the exaggerated phenotype observed in whole-body Acod1-KO mice. Adoptive transfer of Acod1-KO bone marrow-derived macrophages also increased lung mRNA expression of Th2 cytokines. In addition, treatment of Th2-polarized CD4 cells with itaconate impeded Th2 cell differentiation, as shown by reduced expression of Gata3 and decreased release of IL-5 and IL-13. Finally, public datasets of human samples show lower Acod1 expression in subjects with allergic asthma, consistent with a protective role of itaconate in asthma pathogenesis. Together, these data suggest that itaconate plays a protective, immunomodulatory role in limiting airway type 2 inflammation after allergen challenge by attenuating T cell responses.

A randomised trial of malaria vaccine R21/Matrix-M™ with and without antimalarial drugs in Thai adults.

In preparation for mass vaccinations with R21/Matrix-M™ combined with mass administrations of dihydroartemisinin, piperaquine, and a single low dose primaquine we assessed the tolerability, safety, and potential interactions of this combination affecting immunogenicity or pharmacokinetics. 120 healthy Thai volunteers were randomised to receive either antimalarials combined with vaccinations (n = 50), vaccinations alone (n = 50), or antimalarials only (n = 20). Three rounds of vaccines and antimalarials were administered one month apart. The vaccine was well tolerated alone and in combination with the antimalarials. None of the participants failed completion of the 3-dose vaccine course. There was no significant difference in the vaccine immunogenicity or in the pharmacokinetics of piperaquine given individually or in combination. This study supports proceeding to a large trial of mass vaccinations with R21/Matrix-M™ combined with mass antimalarial administration in Bangladesh.

Hydrazinated geraniol derivatives as potential broad-spectrum antiprotozoal agents.

Geraniol, a primary component of several essential oils, has been associated with broad-spectrum antiprotozoal activities, although moderate to weak. This study primarily concentrated on the synthesis of hydrazinated geraniol derivatives as potential antiprotozoal agents. The synthesised compounds were tested in vitro against different parasitic protozoans of clinical relevance, including Trypanosoma brucei brucei, Trypanosoma brucei rhodesiense, Trypanosoma cruzi and Leishmania infantum. Compounds 6, 8, 13, 14 and 15 demonstrated low micromolar activity against the different parasites. Compounds 8, 13, 14 and 15 had the highest efficacy against Trypanosoma brucei rhodesiense, as indicated by their respective IC50 values of 0.74, 0.56, 1.26 and 1.00 µM. Compounds 6, 14 and 15 displayed the best activity against Trypanosoma brucei brucei, with IC50 values of 1.49, 1.48 and 1.85 µM, respectively. The activity of compounds 6, 14 and 15 also extended to intracellular Trypanosoma cruzi, with IC50 values of 5.14, 6.30 and 4.90 µM, respectively. Compound 6, with an IC50 value of 11.73 µM, and compound 14, with an IC50 value of 8.14 µM, demonstrated some modest antileishmanial activity.