Characterization and Implications of IncP-2A Plasmid pMAS152 Harboring Multidrug Resistance Genes in Extensively Drug-Resistant Pseudomonas aeruginosa.

Bacterial antimicrobial resistance (AMR) poses a significant global public health challenge. The escalation of AMR is primarily attributed to the horizontal gene transfer (HGT) of antibiotic resistance genes (ARGs), often facilitated by plasmids. This underscores the critical need for a comprehensive understanding of the resistance mechanisms and transmission dynamics of these plasmids. In this study, we utilized in vitro drug sensitivity testing, conjugation transfer assays, and whole-genome sequencing to investigate the resistance mechanism of an extensively drug-resistant (XDR) Pseudomonas aeruginosa clinical isolate, MAS152. We specifically focused on analyzing the drug-resistant plasmid pMAS152 it harbors and its potential for widespread dissemination. Bioinformatics analysis revealed that MAS152 carries a distinct IncpP-2A plasmid, pMAS152, characterized by a 44.8 kb multidrug resistance (MDR) region. This region houses a 16S rRNA methyltransferase (16S-RMTase) gene, rmtB, conferring high-level resistance to aminoglycoside antibiotics. Notably, this region also contains an extended-spectrum ß-Lactamase (ESBL) gene, blaPER-1, and an efflux pump operon, tmexCD-oprJ, which mediate resistance to ß-Lactams and quinolone antibiotics, respectively. Such a combination of ARGs, unprecedented in reported plasmids, could significantly undermine the effectiveness of first-line antibiotics in treating P. aeruginosa infections. Investigation into the genetic environment of the MDR region suggests that Tn2 and IS91 elements may be instrumental in the horizontal transfer of rmtB. Additionally, a complex Class I integron with an ISCR1 structure, along with TnAs1, seems to facilitate the horizontal transfer of blaPER-1. The conjugation transfer assay, coupled with the annotation of conjugation-related genes and phylogenetic analysis, indicates that the plasmid pMAS152 functions as a conjugative plasmid, with other genus Pseudomonas species as potential hosts. Our findings provide vital insights into the resistance mechanisms and transmission potential of the XDR P. aeruginosa isolate MAS152, underlining the urgent need for novel strategies to combat the spread of AMR. This study highlights the complex interplay of genetic elements contributing to antibiotic resistance and underscores the importance of continuous surveillance of emerging ARGs in clinical isolates.

Receptor-Independent Therapies for Forensic Detainees with Schizophrenia-Dementia Comorbidity.

Forensic institutions throughout the world house patients with severe psychiatric illness and history of criminal violations. Improved medical care, hygiene, psychiatric treatment, and nutrition led to an unmatched longevity in this population, which previously lived, on average, 15 to 20 years shorter than the public at large. On the other hand, longevity has contributed to increased prevalence of age-related diseases, including neurodegenerative disorders, which complicate clinical management, increasing healthcare expenditures. Forensic institutions, originally intended for the treatment of younger individuals, are ill-equipped for the growing number of older offenders. Moreover, as antipsychotic drugs became available in 1950s and 1960s, we are observing the first generation of forensic detainees who have aged on dopamine-blocking agents. Although the consequences of long-term treatment with these agents are unclear, schizophrenia-associated gray matter loss may contribute to the development of early dementia. Taken together, increased lifespan and the subsequent cognitive deficit observed in long-term forensic institutions raise questions and dilemmas unencountered by the previous generations of clinicians. These include: does the presence of neurocognitive dysfunction justify antipsychotic dose reduction or discontinuation despite a lifelong history of schizophrenia and violent behavior? Should neurolipidomic interventions become the standard of care in elderly individuals with lifelong schizophrenia and dementia? Can patients with schizophrenia and dementia meet the Dusky standard to stand trial? Should neurocognitive disorders in the elderly with lifelong schizophrenia be treated differently than age-related neurodegeneration? In this article, we hypothesize that gray matter loss is the core symptom of schizophrenia which leads to dementia. We hypothesize further that strategies to delay or stop gray matter depletion would not only improve the schizophrenia sustained recovery, but also avert the development of major neurocognitive disorders in people living with schizophrenia. Based on this hypothesis, we suggest utilization of both receptor-dependent and independent therapeutics for chronic psychosis.

Early Life Nutrition Factors and Risk of Acute Leukemia in Children: Systematic Review and Meta-Analysis.

Acute leukemia commonly occurs in young children with peak incidence at the age of 2-5 years. However, the etiology is still unclear and many preventable risk factors still deserve to be reviewed. The focus of this systematic review and meta-analysis is to summarize the evidence concerning early life nourishment (breastfeeding, early life diet), neonatal vitamin K administration and the risk of acute leukemia. All epidemiological studies published up to June 2023 and assessing diet-related risk factors for childhood acute leukemia were identified in two electronic databases (PubMed and Web of Science), with no limits on publication year or language. A total of 38 studies (37 case-control studies and 1 study with pooled analysis) were included. The published risk estimates were combined into a meta-analysis using the Generic Inverse Variance method. The current evidence shows that breastfeeding (yes vs. no) has a protective effect against acute lymphoblastic leukemia (odds ratio = 0.85; 95% CI, 0.76-0.94). Evidence related to the role of other studied factors (foods and supplements) is inconclusive. Further research into the potential role of diet in early life and the risk of acute leukemia is needed to develop prevention strategies at population level. Review Registration: PROSPERO registration no. CRD42019128937.

The intratumor mycobiome promotes lung cancer progression via myeloid-derived suppressor cells.

Although polymorphic microbiomes have emerged as hallmarks of cancer, far less is known about the role of the intratumor mycobiome as living microorganisms in cancer progression. Here, using fungi-enriched DNA extraction and deep shotgun metagenomic sequencing, we have identified enriched tumor-resident Aspergillus sydowii in patients with lung adenocarcinoma (LUAD). By three different syngeneic lung cancer mice models, we find that A. sydowii promotes lung tumor progression via IL-1ß-mediated expansion and activation of MDSCs, resulting in suppressed activity of cytotoxic T lymphocyte cells and accumulation of PD-1+ CD8+ T cells. This is mediated by IL-1ß secretion via ß-glucan/Dectin-1/CARD9 pathway. Analysis of human samples confirms that enriched A. sydowii is associated with immunosuppression and poor patient outcome. Our findings suggest that intratumor mycobiome, albeit at low biomass, promotes lung cancer progression and could be targeted at the strain level to improve patients with LUAD outcome.

What went right during the COVID crisis: The capabilities of local actors and lasting innovations in oncology care and research.

This article will elaborate how oncology care and research was adapted during the COVID pandemic in the Metropole of Lyon (France), including the lasting innovations that came out of the crisis. The research method involved 22 semi-structured qualitative interviews of healthcare professionals, managers, and researchers in the Lyon, France region coming from both public and private academic hospitals. The interviews took place from February 2021-December 2022 in order to assess the long-term adaptations and innovations in cancer care organization in the post-COVID era. The main results show adaptations and innovations in 1) new processes and resources to facilitate disciplinary and interdisciplinary work; 2) harmonization and streamlining of patient journeys. In the discussion section, we will mobilize the capabilities approach, an interdisciplinary social sciences approach that focuses on the capabilities of persons to be and to do, to elaborate the conditions by which local actors were able to be agile, to adapt and to innovate in spite of the healthcare emergency and in coherence with their professional and personal values.

Long COVID as a Tauopathy: Of "Brain Fog" and "Fusogen Storms".

Long COVID, also called post-acute sequelae of SARS-CoV-2, is characterized by a multitude of lingering symptoms, including impaired cognition, that can last for many months. This symptom, often called "brain fog", affects the life quality of numerous individuals, increasing medical complications as well as healthcare expenditures. The etiopathogenesis of SARS-CoV-2-induced cognitive deficit is unclear, but the most likely cause is chronic inflammation maintained by a viral remnant thriving in select body reservoirs. These viral sanctuaries are likely comprised of fused, senescent cells, including microglia and astrocytes, that the pathogen can convert into neurotoxic phenotypes. Moreover, as the enteric nervous system contains neurons and glia, the virus likely lingers in the gastrointestinal tract as well, accounting for the intestinal symptoms of long COVID. Fusogens are proteins that can overcome the repulsive forces between cell membranes, allowing the virus to coalesce with host cells and enter the cytoplasm. In the intracellular compartment, the pathogen hijacks the actin cytoskeleton, fusing host cells with each other and engendering pathological syncytia. Cell-cell fusion enables the virus to infect the healthy neighboring cells. We surmise that syncytia formation drives cognitive impairment by facilitating the "seeding" of hyperphosphorylated Tau, documented in COVID-19. In our previous work, we hypothesized that the SARS-CoV-2 virus induces premature endothelial senescence, increasing the permeability of the intestinal and blood-brain barrier. This enables the migration of gastrointestinal tract microbes and/or their components into the host circulation, eventually reaching the brain where they may induce cognitive dysfunction. For example, translocated lipopolysaccharides or microbial DNA can induce Tau hyperphosphorylation, likely accounting for memory problems. In this perspective article, we examine the pathogenetic mechanisms and potential biomarkers of long COVID, including microbial cell-free DNA, interleukin 22, and phosphorylated Tau, as well as the beneficial effect of transcutaneous vagal nerve stimulation.

Creating personas for exposome research: the experience from the HEAP project.

The exposome is a complex scientific field that has enjoyed consistent growth over the last two decades, defined as the composite of every exposure to which an individual is subjected from conception to death. The study of the exposome requires consideration of both the nature of those exposures and their changes over time, and as such necessitates high quality data and software solutions. As the exposome is both a broad and a recent concept, it is challenging to define or to introduce in a structured way. Thus, an approach to assist with clear definitions and a structured framework is needed for the wider scientific and public communication. Results: A set of 14 personas were developed through three focus groups and a series of 14 semi-structured interviews. The focus groups defined the broad themes specific to exposome research, while the sub-themes emerged to saturation via the interviews process. Personas are imaginary individuals that represent segments/groups of real people within a population. Within the context of the HEAP project, the created personas represented both exposome data generators and users. Conclusion: Personas have been implemented successfully in computer science, improving the understanding of human-computer interaction. The creation of personas specific to exposome research adds a useful tool supporting education and outreach activities for a complex scientific field.

Promoting Health for Adolescents: An Editorial.

The research area of adolescent health corresponds to the summary of a wide range of scientific interests and investigations, focusing on the first years of life of an individual [...].

Immunological considerations for laboratory staff and COVID-19 biosafety.

The vulnerability of healthcare and laboratory to potential infection by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus has thus far been analyzed through the lens of the acute phase of the pandemic, including remote-based work, as well as emergency settings that are different from routine healthcare operations. However, as lockdowns ease and activities return to an identifiable pre-pandemic routine, the safety considerations also require to shift accordingly. As laboratory workers are likely to continue being exposed to unidentified SARS-CoV-2 positive samples through routine blood collection and processing operations, coronavirus disease 2019 (COVID-19) might have to be re-considered as an occupational disease within this context. Additionally, as per many such occupational diseases, a surveillance system is implemented for the medium- and long-term. This manuscript presents the views on the possible surveillance scenarios for laboratory staff, viewed from an immunological and biosafety perspective.

Recent Developments in Protein Lactylation in PTSD and CVD: Novel Strategies and Targets.

In 1938, Corneille Heymans received the Nobel Prize in physiology for discovering that oxygen sensing in the aortic arch and carotid sinus was mediated by the nervous system. The genetics of this process remained unclear until 1991 when Gregg Semenza while studying erythropoietin, came upon hypoxia-inducible factor 1, for which he obtained the Nobel Prize in 2019. The same year, Yingming Zhao found protein lactylation, a posttranslational modification that can alter the function of hypoxia-inducible factor 1, the master regulator of cellular senescence, a pathology implicated in both post-traumatic stress disorder (PTSD) and cardiovascular disease (CVD). The genetic correlation between PTSD and CVD has been demonstrated by many studies, of which the most recent one utilizes large-scale genetics to estimate the risk factors for these conditions. This study focuses on the role of hypertension and dysfunctional interleukin 7 in PTSD and CVD, the former caused by stress-induced sympathetic arousal and elevated angiotensin II, while the latter links stress to premature endothelial cell senescence and early vascular aging. This review summarizes the recent developments and highlights several novel PTSD and CVD pharmacological targets. They include lactylation of histone and non-histone proteins, along with the related biomolecular actors such as hypoxia-inducible factor 1α, erythropoietin, acid-sensing ion channels, basigin, and Interleukin 7, as well as strategies to delay premature cellular senescence by telomere lengthening and resetting the epigenetic clock.

Microbiota-derived psychedelics: Lessons from COVID-19.

Emil Kraepelin believed that dementia praecox, the disorder we now call schizophrenia, was caused by the brain being poisoned with toxins generated in other parts of the body, especially the mouth, intestine or genitals. In this regard, Kraepelin hinted at the microbiome and conceptualized microbial molecules as drivers of severe psychiatric illness. However, it was not until the coronavirus disease (COVID-19) pandemic that Kraepelin's paradigm gained traction, particularly because this virus was associated with both gut barrier disruption and new-onset psychosis.Likewise, despite numerous studies linking severe psychiatric illness to genomic damage and dysfunctional DNA repair, this pathogenetic mechanism was underappreciated before the COVID-19 pandemic. The use of the psychotomimetic anesthetic, ketamine, for treatment-resistant depression has reawakened the interest in endogenous serotonergic hallucinogens, especially tryptamine and N,N-dimethyltryptamine (DMT), which are beneficial for depression but associated with psychosis.In this editorial, we take a closer look at the role of the microbiome in psychopathology, attempting to answer 2 questions:1. Why may psychosis-predisposing serotonergic hallucinogens alleviate depression?2. Are microbiota-derived psychedelics part of an inbuilt antidepressant system similar to endogenous opioids?

Digital public health leadership in the global fight for health security.

The COVID-19 pandemic highlighted the need to prioritise mature digital health and data governance at both national and supranational levels to guarantee future health security. The Riyadh Declaration on Digital Health was a call to action to create the infrastructure needed to share effective digital health evidence-based practices and high-quality, real-time data locally and globally to provide actionable information to more health systems and countries. The declaration proposed nine key recommendations for data and digital health that need to be adopted by the global health community to address future pandemics and health threats. Here, we expand on each recommendation and provide an evidence-based roadmap for their implementation. This policy document serves as a resource and toolkit that all stakeholders in digital health and disaster preparedness can follow to develop digital infrastructure and protocols in readiness for future health threats through robust digital public health leadership.

The Use of Digital Technology for COVID-19 Detection and Response Management in Indonesia: Mixed Methods Study.

BACKGROUND: The COVID-19 pandemic has triggered a greater use of digital technologies as part of the health care response in many countries, including Indonesia. It is the world's fourth-most populous nation and Southeast Asia's most populous country, with considerable public health pressures. OBJECTIVE: The aim of our study is to identify and review the use of digital health technologies in COVID-19 detection and response management in Indonesia. METHODS: We conducted a literature review of publicly accessible information in technical and scientific journals, as well as news articles from September 2020 to August 2022 to identify the use case examples of digital technologies in COVID-19 detection and response management in Indonesia. RESULTS: The results are presented in 3 groups, namely (1) big data, artificial intelligence, and machine learning (technologies for the collection or processing of data); (2) health care system technologies (acting at the public health level); and (3) COVID-19 screening, population treatment, and prevention population treatment (acting at the individual patient level). Some of these technologies are the result of government-academia-private sector collaborations during the pandemic, which represent a novel, multisectoral practice in Indonesia within the public health care ecosystem. A small number of the identified technologies pre-existed the pandemic but were upgraded and adapted for current needs. CONCLUSIONS: Digital technologies were developed in Indonesia during the pandemic, with a direct impact on supporting COVID-19 management, detection, response, and treatment. They addressed different areas of the technological spectrum and with different levels of adoption, ranging from local to regional to national. The indirect impact of this wave of technological creation and use is a strong foundation for fostering future multisectoral collaboration within the national health care system of Indonesia.

Integrating research infrastructures into infectious diseases surveillance operations: Focus on biobanks.

Technological advances in the first two decades of the 21st century have profoundly impacted medical research in many ways, with large population cohorts, biological sample collections and datasets through biobanks becoming valued global resources to guide biomedical research, drug development, and medical practice. However, in order for biobanks to maximize their impact and scientific reach of their resources, they would need to act within a complex network of infrastructures and activities. Therefore, different ways have emerged in which biobanks, including those for infectious diseases, can emerge as (part of) infrastructures, integrate within existing ones, or become an independent, yet an interoperable component of the existing infrastructural landscape. However, there has been a limited understanding and study of such mechanisms to date. This perspective aims to address this knowledge gap and illustrates these three high-level ways in which such infrastructures could integrate their activities and identifies the necessary key pre-conditions for doing so, while drawing from specific examples.

Paediatric biobanking for health: The ethical, legal, and societal landscape.

Biobanks play a central role in pediatric translational research, which deals primarily with genetic data from sample-based research. However, participation of children in biobanking has received only limited attention in the literature, even though research in general and in clinical trials in particular have a long history in involving minors. So, we resolved to explore specific challenging ethical, legal, and societal issues (ELSI) in the current pediatric biobanking landscape to propose a way forward for biobanking with children as partners in research. Methodologically, we first established the accessibility and utilization of pediatric biobanks, mainly in Europe. This was supported by a literature review related to children's participation, taking into account not only academic papers but also relevant guidelines and best-practices. Our findings are discussed under five themes: general vulnerability; ethical issues-balancing risks and benefits, right to an open future, return of results including secondary findings; legal issues-capacity and legal majority; societal issues-public awareness and empowerment; and responsible research with children. Ultimately, we observed an on-going shift from the parents'/guardians' consent being a sine-qua-non condition to the positive minor's agreement: confirming that the minor is the participant, not the parent(s)/guardian(s). This ethical rethinking is paving the way toward age-appropriate, dynamic and participatory models of involving minors in decision-making. However, we identified a requirement for dynamic tools to assess maturity, a lack of co-produced engagement tools and paucity of shared best practices. We highlight the need to provide empowerment and capability settings to support researchers and biobankers, and back this with practical examples. In conclusion, equipping children and adults with appropriate tools, and ensuring children's participation is at the forefront of responsible pediatric biobanking, is an ethical obligation, and a cornerstone for research integrity.