Crash Injury Prediction and Vehicle Damage Reporting by Paramedics

Objective: The accuracy of pre-hospital crash scene details and crash victim assessment has important implications for initial trauma care assessment and management. Similarly, it is known to influence physician perception of crash victim injury severity. The goal of this feasibility study was to examine paramedic accuracy in predicting crash victim injury profile, disability outcome at hospital discharge, and reporting vehicle damage with other crash variables.Methods: This prospective case series study was undertaken at a Southern California, Level I trauma center certified by the American College of Surgeons. Paramedics transporting crash injured motor vehicle occupants to our emergency department (ED)/trauma center were surveyed. We abstracted ED and in-patient records of injured vehicle occupants. Vehicle and crash scene data were obtained from a professional crash reconstruction, which included the assessment of deformation, crash forces, change in velocity, and the source of each injury.Results: We used survey, injury, and crash reconstruction data from 22 collision cases in the final analysis. The median Injury Severity Score (ISS) was five (range 1-24). No enrolled patients died, and none were severely disabled at the time of discharge from the hospital. The paramedic crash injury severity predictions were sensitive for an Abbreviated Injury Scale (AIS) of 2-4. Paramedics often agreed with the crash reconstruction on restraint use, ejection, and other fatalities at the scene, and had lower levels of agreement for front airbag deployment, steering wheel damage, and window/windshield impact. Paramedics had 80% accuracy in predicting any disability at the time of hospital discharge.Conclusion: Paramedic prediction of injury profile was sensitive, and prediction of disability outcome at discharge was accurate when compared to discharge diagnosis. Their reporting of vehicle specific crash variables was less accurate. Further study should be undertaken to assess the benefits of crash biomechanics education for paramedics and other pre-hospital care providers. [WestJEM. 2009;10:62-67.

Schmallenberg virus pathogenesis, tropism and interaction with the innate immune system of the host

Schmallenberg virus (SBV) is an emerging orthobunyavirus of ruminants associated with outbreaks of congenital malformations in aborted and stillborn animals. Since its discovery in November 2011, SBV has spread very rapidly to many European countries. Here, we developed molecular and serological tools, and an experimental in vivo model as a platform to study SBV pathogenesis, tropism and virus-host cell interactions. Using a synthetic biology approach, we developed a reverse genetics system for the rapid rescue and genetic manipulation of SBV. We showed that SBV has a wide tropism in cell culture and “synthetic” SBV replicates in vitro as efficiently as wild type virus. We developed an experimental mouse model to study SBV infection and showed that this virus replicates abundantly in neurons where it causes cerebral malacia and vacuolation of the cerebral cortex. These virus-induced acute lesions are useful in understanding the progression from vacuolation to porencephaly and extensive tissue destruction, often observed in aborted lambs and calves in naturally occurring Schmallenberg cases. Indeed, we detected high levels of SBV antigens in the neurons of the gray matter of brain and spinal cord of naturally affected lambs and calves, suggesting that muscular hypoplasia observed in SBV-infected lambs is mostly secondary to central nervous system damage. Finally, we investigated the molecular determinants of SBV virulence. Interestingly, we found a biological SBV clone that after passage in cell culture displays increased virulence in mice. We also found that a SBV deletion mutant of the non-structural NSs protein (SBVΔNSs) is less virulent in mice than wild type SBV. Attenuation of SBV virulence depends on the inability of SBVΔNSs to block IFN synthesis in virus infected cells. In conclusion, this work provides a useful experimental framework to study the biology and pathogenesis of SBV

SANEAMENTO BÁSICO COMO CONDICIONANTE À EXPANSÃO URBANA DE FAXINAL DOS GUEDES, SC

Este estudo visou traçar um perfil do crescimento urbano do Município de Faxinal dos Guedes, no Oeste do Estado de Santa Catarina, com aproximadamente 11 mil habitantes, a partir da instalação de infraestrutura urbana de saneamento básico: rede de coleta e tratamento de esgotos. O projeto, cuja execução foi iniciada em 1989 e concluída em 2004, teve um amplo investimento por parte dos entes federativo, estadual e do próprio Município, que totalizou um total de 15 milhões de reais. Desde 2010, os serviços de saneamento básico atendem 100% da área urbana, o que confere a maior cobertura de esgoto do Sul do Brasil, colocando a cidade em destaque nacional. Por meio de pesquisas documentais e elaboração de mapas com a evolução da malha urbana, conclui-se que a estação de tratamento serviu como polo gerador do espaço urbano, já que a partir dela localizaram-se diversos empreendimentos. Do mesmo modo, a rede de coleta tornou-se um condicionante de expansão da malha urbana, já que as conexões com ela definem o surgimento de novos loteamentos, evitando vazios urbanos. Junto ao processo de “eliminar as fossas”, como os próprios moradores do Município se referem, outros projetos foram conciliados, tecendo uma gama de benefícios na infraestrutura urbana: recuperação de toda a pavimentação das vias urbanas e a implantação de outros projetos de cunho ambiental, os quais contribuíram para o êxito do projeto de saneamento básico e o desenvolvimento sustentável de Faxinal do Guedes.Palavras-chave: Faxinal dos Guedes.  Saneamento básico. Evolução urbana

Interpersonal neural synchrony and mental disorders: unlocking potential pathways for clinical interventions

Introduction: Interpersonal synchronization involves the alignment of behavioral, affective, physiological, and brain states during social interactions. It facilitates empathy, emotion regulation, and prosocial commitment. Mental disorders characterized by social interaction dysfunction, such as Autism Spectrum Disorder (ASD), Reactive Attachment Disorder (RAD), and Social Anxiety Disorder (SAD), often exhibit atypical synchronization with others across multiple levels. With the introduction of the “second-person” neuroscience perspective, our understanding of interpersonal neural synchronization (INS) has improved, however, so far, it has hardly impacted the development of novel therapeutic interventions. Methods: To evaluate the potential of INS-based treatments for mental disorders, we performed two systematic literature searches identifying studies that directly target INS through neurofeedback (12 publications; 9 independent studies) or brain stimulation techniques (7 studies), following PRISMA guidelines. In addition, we narratively review indirect INS manipulations through behavioral, biofeedback, or hormonal interventions. We discuss the potential of such treatments for ASD, RAD, and SAD and using a systematic database search assess the acceptability of neurofeedback (4 studies) and neurostimulation (4 studies) in patients with social dysfunction. Results: Although behavioral approaches, such as engaging in eye contact or cooperative actions, have been shown to be associated with increased INS, little is known about potential long-term consequences of such interventions. Few proof-of-concept studies have utilized brain stimulation techniques, like transcranial direct current stimulation or INS-based neurofeedback, showing feasibility and preliminary evidence that such interventions can boost behavioral synchrony and social connectedness. Yet, optimal brain stimulation protocols and neurofeedback parameters are still undefined. For ASD, RAD, or SAD, so far no randomized controlled trial has proven the efficacy of direct INS-based intervention techniques, although in general brain stimulation and neurofeedback methods seem to be well accepted in these patient groups. Discussion: Significant work remains to translate INS-based manipulations into effective treatments for social interaction disorders. Future research should focus on mechanistic insights into INS, technological advancements, and rigorous design standards. Furthermore, it will be key to compare interventions directly targeting INS to those targeting other modalities of synchrony as well as to define optimal target dyads and target synchrony states in clinical interventions

A plasmid DNA-launched SARS-CoV-2 reverse genetics system and coronavirus toolkit for COVID-19 research

The recent emergence of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the underlying cause of Coronavirus Disease 2019 (COVID-19), has led to a worldwide pandemic causing substantial morbidity, mortality, and economic devastation. In response, many laboratories have redirected attention to SARS-CoV-2, meaning there is an urgent need for tools that can be used in laboratories unaccustomed to working with coronaviruses. Here we report a range of tools for SARS-CoV-2 research. First, we describe a facile single plasmid SARS-CoV-2 reverse genetics system that is simple to genetically manipulate and can be used to rescue infectious virus through transient transfection (without in vitro transcription or additional expression plasmids). The rescue system is accompanied by our panel of SARS-CoV-2 antibodies (against nearly every viral protein), SARS-CoV-2 clinical isolates, and SARS-CoV-2 permissive cell lines, which are all openly available to the scientific community. Using these tools, we demonstrate here that the controversial ORF10 protein is expressed in infected cells. Furthermore, we show that the promising repurposed antiviral activity of apilimod is dependent on TMPRSS2 expression. Altogether, our SARS-CoV-2 toolkit, which can be directly accessed via our website at https://mrcppu-covid.bio/, constitutes a resource with considerable potential to advance COVID-19 vaccine design, drug testing, and discovery science

Evenness mediates the global relationship between forest productivity and richness

Biodiversity is an important component of natural ecosystems, with higher species richness often correlating with an increase in ecosystem productivity. Yet, this relationship varies substantially across environments, typically becoming less pronounced at high levels of species richness. However, species richness alone cannot reflect all important properties of a community, including community evenness, which may mediate the relationship between biodiversity and productivity. If the evenness of a community correlates negatively with richness across forests globally, then a greater number of species may not always increase overall diversity and productivity of the system. Theoretical work and local empirical studies have shown that the effect of evenness on ecosystem functioning may be especially strong at high richness levels, yet the consistency of this remains untested at a global scale. 2. Here, we used a dataset of forests from across the globe, which includes composition, biomass accumulation and net primary productivity, to explore whether productivity correlates with community evenness and richness in a way that evenness appears to buffer the effect of richness. Specifically, we evaluated whether low levels of evenness in speciose communities correlate with the attenuation of the richness–productivity relationship. 3. We found that tree species richness and evenness are negatively correlated across forests globally, with highly speciose forests typically comprising a few dominant and many rare species. Furthermore, we found that the correlation between diversity and productivity changes with evenness: at low richness, uneven communities are more productive, while at high richness, even communities are more productive. 4. Synthesis. Collectively, these results demonstrate that evenness is an integral component of the relationship between biodiversity and productivity, and that the attenuating effect of richness on forest productivity might be partly explained by low evenness in speciose communities. Productivity generally increases with species richness, until reduced evenness limits the overall increases in community diversity. Our research suggests that evenness is a fundamental component of biodiversity–ecosystem function relationships, and is of critical importance for guiding conservation and sustainable ecosystem management decisions. © 2023 The Authors. Journal of Ecology published by John Wiley & Sons Ltd on behalf of British Ecological Society

The 2021 WHO catalogue of Mycobacterium tuberculosis complex mutations associated with drug resistance: a genotypic analysis.

Background: Molecular diagnostics are considered the most promising route to achievement of rapid, universal drug susceptibility testing for Mycobacterium tuberculosis complex (MTBC). We aimed to generate a WHO-endorsed catalogue of mutations to serve as a global standard for interpreting molecular information for drug resistance prediction. Methods: In this systematic analysis, we used a candidate gene approach to identify mutations associated with resistance or consistent with susceptibility for 13 WHO-endorsed antituberculosis drugs. We collected existing worldwide MTBC whole-genome sequencing data and phenotypic data from academic groups and consortia, reference laboratories, public health organisations, and published literature. We categorised phenotypes as follows: methods and critical concentrations currently endorsed by WHO (category 1); critical concentrations previously endorsed by WHO for those methods (category 2); methods or critical concentrations not currently endorsed by WHO (category 3). For each mutation, we used a contingency table of binary phenotypes and presence or absence of the mutation to compute positive predictive value, and we used Fisher's exact tests to generate odds ratios and Benjamini-Hochberg corrected p values. Mutations were graded as associated with resistance if present in at least five isolates, if the odds ratio was more than 1 with a statistically significant corrected p value, and if the lower bound of the 95% CI on the positive predictive value for phenotypic resistance was greater than 25%. A series of expert rules were applied for final confidence grading of each mutation. Findings: We analysed 41 137 MTBC isolates with phenotypic and whole-genome sequencing data from 45 countries. 38 215 MTBC isolates passed quality control steps and were included in the final analysis. 15 667 associations were computed for 13 211 unique mutations linked to one or more drugs. 1149 (7·3%) of 15 667 mutations were classified as associated with phenotypic resistance and 107 (0·7%) were deemed consistent with susceptibility. For rifampicin, isoniazid, ethambutol, fluoroquinolones, and streptomycin, the mutations' pooled sensitivity was more than 80%. Specificity was over 95% for all drugs except ethionamide (91·4%), moxifloxacin (91·6%) and ethambutol (93·3%). Only two resistance mutations were identified for bedaquiline, delamanid, clofazimine, and linezolid as prevalence of phenotypic resistance was low for these drugs. Interpretation: We present the first WHO-endorsed catalogue of molecular targets for MTBC drug susceptibility testing, which is intended to provide a global standard for resistance interpretation. The existence of this catalogue should encourage the implementation of molecular diagnostics by national tuberculosis programmes. Funding: Unitaid, Wellcome Trust, UK Medical Research Council, and Bill and Melinda Gates Foundation

Synthetische Letalität von PARP- und APE1-Inhibitoren bei hämatologischen Neoplasien

Die Prognose bei Hochrisiko-MDS und AML Patienten ist ungünstig, was die Erforschung neuer Therapien notwendig macht. Ein Ansatz beruht auf der Inhibition wichtiger Enzyme in der DNA-Schadensreparatur. Zwei dieser Enzyme sind APE1 und PARP. In vorangegangen Studien konnte bereits gezeigt werden, dass PARP Inhibitoren besonders effektiv bei Tumoren mit Defekten in BRCA1/2 wirken. Dieser Effekt wird als synthetische Letalität bezeichnet. Im Rahmen dieser Arbeit sollte untersucht werden, ob der APE1 Inhibitor III und der PARP-Inhibitor Talazoparib bei CMML, MDS und AML Patientenzellen eine antileukämische Wirkung zeigen. Es wurden insgesamt 28 Patientenproben untersucht, von denen 6 auf Talazoparib (21%) und 8 auf den APE1 Inhibitor III (30%) angesprochen haben. Ziel war es zu überprüfen, ob es Marker gibt, die ein Ansprechen auf die Inhibitoren prognostizieren können. Bei möglichen Markern, wie dem Proliferationsverhalten der Zellen, der Menge an γH2AX Foci und der APE1 beziehungsweise PARP Expression gab es keine signifikanten Unterschiede zwischen ‚Ansprechern‘ und ‚Nicht Ansprechern‘. Auch spezifische chromosomale Aberrationen mit einem prognosefähigen Einfluss wurden nicht detektiert. Das molekulargenetische Profil der Patienten war heterogen und Mutationen, die ausschließlich in der Gruppe der ‚Ansprechern‘ auftraten, wurden nicht detektiert. Es konnten aber Mutationen in Genen bei den ‚Nicht Ansprechern‘ detektiert werden: IDH1 (2), IDH2 (5), PTPN11 (2), KRAS (2), NPM1 (4). Bei den Laborparametern war die Laktat-Dehydrogenase sowohl bei den APE1 Inhibitor III ‚Ansprechern‘ als auch bei den Talazoparib ‚Ansprechern‘ signifikant erhöht. Zusätzlich wurden noch Kombinationsversuche mit Decitabin± Talazoparib, Decitabin± APE1 Inhibitor III sowie Talazoparib± APE1 Inhibitor III durchgeführt. Hierbei war besonders die Kombination von Decitabin mit Talazoparib hervorzuheben, bei der durch die Kombination beider Inhibitoren die Zahl der ‚Ansprecher‘ von 7 (28%) mit Decitabin alleine auf 17 (60%) ‚Ansprecher‘ erhöht wurde. Dies könnte bei der Therapie Decitabin-resistenter Patienten ein interessanter Ansatz sein. Des Weiteren konnte beobachtet werden, dass Patienten, die im klinischen Verlauf resistent gegenüber Decitabin waren, auch in vitro nicht auf das Medikament ansprachen. In der vorliegenden Arbeit konnte gezeigt werden, dass sowohl der APE1 Inhibitor III als auch Talazoparib einen anti-leukämischen Effekt aufweisen. Beide Inhibitoren können in Kombination mit Decitabin dessen Wirkung verstärken. Die hier gewonnen Erkenntnisse liefern Daten für mögliche zukünftige klinische Studien

The Virtual Physiological Human

The Virtual Physiological Human is synonymous with a programme in computational biomedicine that aims to develop a framework of methods and technologies to investigate the human body as a whole. It is predicated on the transformational character of information technology, brought to bear on that most crucial of human concerns, our own health and well-being

Integrative approaches to computational biomedicine Subject collections http://rsfs.royalsocietypublishing.org/subscriptions go to: Interface Focus To subscribe to Introduction Integrative approaches to computational biomedicine

One contribution of 25 to a Theme Issue 'The virtual physiological human: integrative approaches to computational biomedicine'. The new discipline of computational biomedicine is concerned with the application of computer-based techniques and particularly modelling and simulation to human health. Since 2007, this discipline has been synonymous, in Europe, with the name given to the European Union's ambitious investment in integrating these techniques with the eventual aim of modelling the human body as a whole: the virtual physiological human. This programme and its successors are expected, over the next decades, to transform the study and practice of healthcare, moving it towards the priorities known as '4P's': predictive, preventative, personalized and participatory medicine