An exploration of knowledge-organizing technologies to advance transdisciplinary back pain research.

Chronic low back pain (LBP) is influenced by a broad spectrum of patient-specific factors as codified in domains of the biopsychosocial model (BSM). Operationalizing the BSM into research and clinical care is challenging because most investigators work in silos that concentrate on only one or two BSM domains. Furthermore, the expanding, multidisciplinary nature of BSM research creates practical limitations as to how individual investigators integrate current data into their processes of generating impactful hypotheses. The rapidly advancing field of artificial intelligence (AI) is providing new tools for organizing knowledge, but the practical aspects for how AI may advance LBP research and clinical are beginning to be explored. The goals of the work presented here are to: (1) explore the current capabilities of knowledge integration technologies (large language models (LLM), similarity graphs (SGs), and knowledge graphs (KGs)) to synthesize biomedical literature and depict multimodal relationships reflected in the BSM, and; (2) highlight limitations, implementation details, and future areas of research to improve performance. We demonstrate preliminary evidence that LLMs, like GPT-3, may be useful in helping scientists analyze and distinguish cLBP publications across multiple BSM domains and determine the degree to which the literature supports or contradicts emergent hypotheses. We show that SG representations and KGs enable exploring LBP's literature in novel ways, possibly providing, trans-disciplinary perspectives or insights that are currently difficult, if not infeasible to achieve. The SG approach is automated, simple, and inexpensive to execute, and thereby may be useful for early-phase literature and narrative explorations beyond one's areas of expertise. Likewise, we show that KGs can be constructed using automated pipelines, queried to provide semantic information, and analyzed to explore trans-domain linkages. The examples presented support the feasibility for LBP-tailored AI protocols to organize knowledge and support developing and refining trans-domain hypotheses.

First Observation of the ß3αp Decay of

The ß-delayed proton decay of ^{13}O has previously been studied, but the direct observation of ß-delayed 3αp decay has not been reported. Rare 3αp events from the decay of excited states in ^{13}N^{⋆} provide a sensitive probe of cluster configurations in ^{13}N. To measure the low-energy products following ß-delayed 3αp decay, the Texas Active Target (TexAT) time projection chamber was employed using the one-at-a-time ß-delayed charged-particle spectroscopy technique at the Cyclotron Institute, Texas A&M University. A total of 1.9×10^{5} ^{13}O implantations were made inside the TexAT time projection chamber. A total of 149 3αp events were observed, yielding a ß-delayed 3αp branching ratio of 0.078(6)%. Four previously unknown α-decaying excited states were observed in ^{13}N at 11.3, 12.4, 13.1, and 13.7 MeV decaying via the 3α+p channel.

Theoretical Schemas to Guide Back Pain Consortium (BACPAC) Chronic Low Back Pain Clinical Research.

BACKGROUND: Chronic low back pain (cLBP) is a complex with a heterogenous clinical presentation. A better understanding of the factors that contribute to cLBP is needed for accurate diagnosis, optimal treatment, and identification of mechanistic targets for new therapies. The Back Pain Consortium (BACPAC) Research Program provides a unique opportunity in this regard, as it will generate large clinical datasets, including a diverse set of harmonized measurements. The Theoretical Model Working Group was established to guide BACPAC research and to organize new knowledge within a mechanistic framework. This article summarizes the initial work of the Theoretical Model Working Group. It includes a three-stage integration of expert opinion and an umbrella literature review of factors that affect cLBP severity and chronicity. METHODS: During Stage 1, experts from across BACPAC established a taxonomy for risk and prognostic factors (RPFs) and preliminary graphical depictions. During Stage 2, a separate team conducted a literature review according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines to establish working definitions, associated data elements, and overall strength of evidence for identified RPFs. These were subsequently integrated with expert opinion during Stage 3. RESULTS: The majority (∼80%) of RPFs had little strength-of-evidence confidence, whereas seven factors had substantial confidence for either a positive association with cLBP (pain-related anxiety, serum C-reactive protein, diabetes, and anticipatory/compensatory postural adjustments) or no association with cLBP (serum interleukin 1-beta / interleukin 6, transversus muscle morphology/activity, and quantitative sensory testing). CONCLUSION: This theoretical perspective will evolve over time as BACPAC investigators link empirical results to theory, challenge current ideas of the biopsychosocial model, and use a systems approach to develop tools and algorithms that disentangle the dynamic interactions among cLBP factors.

Identifying the optimal developmental age of human pluripotent stem cell-derived midbrain dopaminergic progenitors for transplantation in a rodent model of Parkinson's disease.

Donor cell age can have a significant impact on transplantation outcomes. Despite the rapid advancement of human pluripotent stem cell (hPSC)-derived dopaminergic (DA) progenitors to the clinic for transplantation into Parkinson's Disease (PD), surprisingly limited data exists regarding the influence of cellular age on neural graft survival, composition, and integration. Here we examined the impact of transplanting ventral midbrain (VM) progenitors at varying days of differentiation (from day 13-30) into a rodent PD model, comparing two hPSC lines (an embryonic and an induced pluripotent cell line, hESC and hiPSC, respectively). Both hPSC lines expressed GFP under the promoter PITX3 enabling specific tracking of graft-derived DA neurons. Post-mortem analysis at 6 months revealed larger grafts from Day19 (D19), D22 and D25 progenitors, yet contained a higher proportion of non-DA and poorly specified (FOXA2-) cells. While D13 and D30 progenitors yielded smaller grafts. D13-derived grafts had the highest DA neuron proportion and proportionally more GIRK2+ DA neurons, the subpopulation critical for motor function. These younger progenitor grafts maintained their capacity to innervate developmentally relevant DA targets, with increased innervation capacity per DA neuron, collectively resulting in restoration of motor deficits with equal or greater proficiency than older donor cells. While donor age effects were reproducible for a given hPSC line and trends were similar between the two hPSC lines, grafts of D13 hiPSC-derived progenitors showed a 6-fold greater density of DA neurons compared to D13 hESC-derived grafts, highlighting between-line variability. These findings show that hPSC-derived VM donor age has a direct impact on graft survival, composition and maturation, and that careful assessment, on a line-to-line basis is required prior to translation.

Utilizing virtual experiments to increase understanding of discrepancies involving in vitro-to-in vivo predictions of hepatic clearance.

Predictions of xenobiotic hepatic clearance in humans using in vitro-to-in vivo extrapolation methods are frequently inaccurate and problematic. Multiple strategies are being pursued to disentangle responsible mechanisms. The objective of this work is to evaluate the feasibility of using insights gained from independent virtual experiments on two model systems to begin unraveling responsible mechanisms. The virtual culture is a software analog of hepatocytes in vitro, and the virtual human maps to hepatocytes within a liver within an idealized model human. Mobile objects (virtual compounds) map to amounts of xenobiotics. Earlier versions of the two systems achieved quantitative validation targets for intrinsic clearance (virtual culture) and hepatic clearance (virtual human). The major difference between the two systems is the spatial organization of the virtual hepatocytes. For each pair of experiments (virtual culture, virtual human), hepatocytes are configured the same. Probabilistic rules govern virtual compound movements and interactions with other objects. We focus on highly permeable virtual compounds and fix their extracellular unbound fraction at one of seven values (0.05-1.0). Hepatocytes contain objects that can bind and remove compounds, analogous to metabolism. We require that, for a subset of compound properties, per-hepatocyte compound exposure and removal rates during culture experiments directly predict corresponding measures made during virtual human experiments. That requirement serves as a cross-system validation target; we identify compound properties that enable achieving it. We then change compound properties, ceteris paribus, and provide model mechanism-based explanations for when and why measures made during culture experiments under- (or over-) predict corresponding measures made during virtual human experiments. The results show that, from the perspective of compound removal, the organization of hepatocytes within virtual livers is more efficient than within cultures, and the greater the efficiency difference, the larger the underprediction. That relationship is noteworthy because most in vitro-to-in vivo extrapolation methods abstract away the structural organization of hepatocytes within a liver. More work is needed on multiple fronts, including the study of an expanded variety of virtual compound properties. Nevertheless, the results support the feasibility of the approach and plan.

Inpatient comparison of wireless and wired pulse oximetry in neonates.

BACKGROUND: To compare oxygen saturation (SpO2) and heart rate (HR) recorded by a reference wired pulse oximeter to a wireless pulse oximeter in inpatient neonates. METHODS: Term infants born≥37 + 0 weeks and preterm infants born≤35 + 0 weeks gestation were enrolled and time-matched data pairs were obtained. The primary outcome was intraclass correlation coefficient and r-values between the two oximeters for heart rate and oxygen saturation. RESULTS: Thirty term and 20 preterm neonates were enrolled. There was a high degree of correlation between the two oximeters for HR (r = 0.926) among all 50 infants, and excellent interclass correlation (ICC = 0.961), but there were no bradycardia episodes in either term or preterm infants. There was a lesser degree of correlation for SpO2 values in the term and preterm groups (r = 0.242; 0.521, respectively) along with moderate interclass correlation (ICC = 0.719) but few episodes of hypoxemia≤90% occurred in enrolled subjects. CONCLUSIONS: There were no significant differences between the wireless and reference wired oximeters for assessing HR. There was less correlation between the two oximeters for monitoring SpO2 in both the term and preterm group. Wireless pulse oximetry may have practical advantages for use in inpatient neonates, but additional studies are needed that include bradycardia and desaturation events to delineate this question.

Calcified Pseudoneoplasm of the Neuraxis.

Calcified pseudoneoplasms of the neuraxis are extremely rare non-neoplastic lesions that can exist anywhere in the CNS. Although benign, the lesions can cause substantial neurologic symptoms, typically related to mass effect on adjacent structures. Calcified pseudoneoplasms of the neuraxis can also mimic other entities such as calcified oligodendrogliomas and meningiomas. Nevertheless, the lesions can usually be strongly suggested at the time of imaging due to a number of fairly unique imaging characteristics. Here, the clinical presentation of a patient with a posterior fossa calcified pseudoneoplasm of the neuraxis is described, along with its imaging and pathologic features.

Synoptic assessment of coastal total alkalinity through community science.

Comprehensive sampling of the carbonate system in estuaries and coastal waters can be difficult and expensive because of the complex and heterogeneous nature of near-shore environments. We show that sample collection by community science programs is a viable strategy for expanding estuarine carbonate system monitoring and prioritizing regions for more targeted assessment. 'Shell Day' was a single-day regional water monitoring event coordinating coastal carbonate chemistry observations by 59 community science programs and seven research institutions in the northeastern United States, in which 410 total alkalinity (TA) samples from 86 stations were collected. Field replicates collected at both low and high tides had a mean standard deviation between replicates of 3.6 ± 0.3 µmol kg-1 (σ mean ± SE, n = 145) or 0.20 ± 0.02%. This level of precision demonstrates that with adequate protocols for sample collection, handling, storage, and analysis, community science programs are able to collect TA samples leading to high-quality analyses and data. Despite correlations between salinity, temperature, and TA observed at multiple spatial scales, empirical predictions of TA had relatively high root mean square error >48 µmol kg-1. Additionally, ten stations displayed tidal variability in TA that was not likely driven by low TA freshwater inputs. As such, TA cannot be predicted accurately from salinity using a single relationship across the northeastern US region, though predictions may be viable at more localized scales where consistent freshwater and seawater endmembers can be defined. There was a high degree of geographic heterogeneity in both mean and tidal variability in TA, and this single-day snapshot sampling identified three patterns driving variation in TA, with certain locations exhibiting increased risk of acidification. The success of Shell Day implies that similar community science based events could be conducted in other regions to not only expand understanding of the coastal carbonate system, but also provide a way to inventory monitoring assets, build partnerships with stakeholders, and expand education and outreach to a broader constituency.

Changing paradigm of sacral neuromodulation and external anal sphincter repair for faecal incontinence in specialist centres.

AIM: The aim of this study was to determine whether the paradigm of surgical intervention for faecal incontinence (FI) has changed between 2000 and 2013. METHOD: This was a multi-centre retrospective study of patients who had undergone either sacral neuromodulation (SNM) or delayed sphincter repair or sphincteroplasty (SR) as a primary surgical intervention for FI in five centres in Europe and one in the United States. The flow of patients according to the intervention, sustainability of the treatment at a minimum follow-up of 5 years, complications and requirement for further interventions were recorded. RESULTS: A total of 461 patients (median age 56 years, range 24-90 years, 41 men) had either SNM or SR as an index operation during the study period [SNM 284 (61.6%), SR 177 (38.4%)]. Among SNM patients, there were 169 revisional operations (change of battery and/or lead, re-siting or removal). At the time of last follow-up 203 patients (71.4%) continued to use SNM. Among SR patients, 30 (16.9%) had complications, most notably wound infection (22, 12.4%). During follow-up 32 patients (18.1%) crossed over to SNM. Comparing two 4-year periods (2000-2003 and 2007-2010), the proportion of patients operated on who had a circumferential sphincter defect of less than 90° was 48 (68%) and 45 (46%), respectively (P = 0.03), while those who had SNM as the primary intervention increased from 29% to 89% (P < 0.05). CONCLUSION: The paradigm of surgical intervention for FI has changed with increasing use of SNM.

Genetic diversity of Ethiopian sorghum reveals signatures of climatic adaptation.

KEY MESSAGE: A large collection of Ethiopian sorghum landraces, characterized by agro-ecology and racial-group, was found to contain high levels of diversity and admixture, with significant SNP associations identified for environmental adaptation. Sorghum [Sorghum bicolor L. (Moench)] is a major staple food crop in Ethiopia, exhibiting extensive genetic diversity with adaptations to diverse agroecologies. The environmental and climatic drivers, as well as the genomic basis of adaptation, are poorly understood in Ethiopian sorghum and are critical elements for the development of climate-resilient crops. Exploration of the genome-environment association (GEA) is important for identifying adaptive loci and predicting phenotypic variation. The current study aimed to better understand the GEA of a large collection of Ethiopian sorghum landraces (n = 940), characterized with genome-wide SNP markers, to investigate key traits related to adaptation to temperature, precipitation and altitude. The Ethiopian sorghum landrace collection was found to consist of 12 subpopulations with high levels of admixture (47%), representing all the major racial groups of cultivated sorghum with the exception of kafir. Redundancy analysis indicated that agroecology explained up to 10% of the total SNP variation, and geographical location up to 6%. GEA identified 18 significant SNP markers for environmental variables. These SNPs were found to be significantly enriched (P < 0.05) for a priori QTL for drought and cold adaptation. The findings from this study improve our understanding of the genetic control of adaptive traits in Ethiopian sorghum. Further, the Ethiopian sorghum germplasm collection provides sources of adaptation to harsh environments (cold and/or drought) that could be deployed in breeding programs globally for abiotic stress adaptation.

High-Throughput Phenotyping of Dynamic Canopy Traits Associated with Stay-Green in Grain Sorghum.

Drought is a recurring phenomenon that puts crop yields at risk and threatens the livelihoods of many people around the globe. Stay-green is a drought adaption phenotype found in sorghum and other cereals. Plants expressing this phenotype show less drought-induced senescence and maintain functional green leaves for longer when water limitation occurs during grain fill, conferring benefits in both yield per se and harvestability. The physiological causes of the phenotype are postulated to be water saving through mechanisms such as reduced canopy size or access to extra water through mechanisms such as deeper roots. In sorghum breeding programs, stay-green has traditionally been assessed by comparing visual scores of leaf senescence either by identifying final leaf senescence or by estimating rate of leaf senescence. In this study, we compared measurements of canopy dynamics obtained from remote sensing on two sorghum breeding trials to stay-green values (breeding values) obtained from visual leaf senescence ratings in multienvironment breeding trials to determine which components of canopy development were most closely linked to the stay-green phenotype. Surprisingly, canopy size as estimated using preflowering canopy parameters was weakly correlated with stay-green values for leaf senescence while postflowering canopy parameters showed a much stronger association with leaf senescence. Our study suggests that factors other than canopy size have an important role in the expression of a stay-green phenotype in grain sorghum and further that the use of UAVs with multispectral sensors provides an excellent way of measuring canopy traits of hundreds of plots grown in large field trials.

Imaging Review of Paraneoplastic Neurologic Syndromes.

Paraneoplastic syndromes are systemic reactions to neoplasms mediated by immunologic or hormonal mechanisms. The most well-recognized paraneoplastic neurologic syndrome, both clinically and on imaging, is limbic encephalitis. However, numerous additional clinically described syndromes affect the brain, spinal cord, and peripheral nerves. Many of these syndromes can have imaging findings that, though less well described, are important in making the correct diagnosis. Moreover, imaging in these syndromes frequently mimics more common pathology, which can be a diagnostic challenge for radiologists. Our goal is to review the imaging findings of paraneoplastic neurologic syndromes, including less well-known entities and atypical presentations of common entities. Specifically, we discuss limbic encephalitis, paraneoplastic cerebellar degeneration, paraneoplastic brain stem encephalitis, cranial neuropathy, myelitis, and polyneuropathy. We also demonstrate common diagnostic pitfalls that can be encountered when imaging these patients.

Mitochondrial DNA damage as a potential biomarker of LRRK2 kinase activity in LRRK2 Parkinson's disease.

Leucine-rich repeat kinase 2 (LRRK2) is a promising therapeutic target for the treatment of Parkinson's disease (PD) and LRRK2 kinase inhibitors are currently being tested in early phase clinical trials. In order to ensure the highest chance of success, a biomarker-guided entry into clinical trials is key. LRRK2 phosphorylation, and phosphorylation of the LRRK2 substrate Rab10, have been proposed as target engagement biomarkers for LRRK2 kinase inhibition. However, a pharmacodynamic biomarker to demonstrate that a biological response has occurred is lacking. We previously discovered that the LRRK2 G2019S mutation causes mitochondrial DNA (mtDNA) damage and is LRRK2 kinase activity-dependent. Here, we have explored the possibility that measurement of mtDNA damage is a "surrogate" for LRRK2 kinase activity and consequently of kinase inhibitor activity. Mitochondrial DNA damage was robustly increased in PD patient-derived immune cells with LRRK2 G2019S mutations as compared with controls. Following treatment with multiple classes of LRRK2 kinase inhibitors, a full reversal of mtDNA damage to healthy control levels was observed and correlated with measures of LRRK2 dephosphorylation. Taken together, assessment of mtDNA damage levels may be a sensitive measure of altered kinase activity and provide an extended profile of LRRK2 kinase modulation in clinical studies.

Contrasting model mechanisms of alanine aminotransferase (ALT) release from damaged and necrotic hepatocytes as an example of general biomarker mechanisms.

Interpretations of elevated blood levels of alanine aminotransferase (ALT) for drug-induced liver injury often assume that the biomarker is released passively from dying cells. However, the mechanisms driving that release have not been explored experimentally. The usefulness of ALT and related biomarkers will improve by developing mechanism-based explanations of elevated levels that can be expanded and elaborated incrementally. We provide the means to challenge the ability of closely related model mechanisms to generate patterns of simulated hepatic injury and ALT release that scale (or not) to be quantitatively similar to the wet-lab validation targets, which are elevated plasma ALT values following acetaminophen (APAP) exposure in mice. We build on a published model mechanism that helps explain the generation of characteristic spatiotemporal features of APAP hepatotoxicity within hepatic lobules. Discrete event and agent-oriented software methods are most prominent. We instantiate and leverage a small constellation of concrete model mechanisms. Their details during execution help bring into focus ways in which particular sources of uncertainty become entangled with cause-effect details within and across several levels. We scale ALT amounts in virtual mice directly to target plasma ALT values in individual mice. A virtual experiment comprises a set of Monte Carlo simulations. We challenge the sufficiency of four potentially explanatory theories for ALT release. The first of the tested model theories failed to achieve the initial validation target, but each of the three others succeeded. Results for one of the three model mechanisms matched all target ALT values quantitatively. It explains how ALT externalization is the combined consequence of lobular-location-dependent drug-induced cellular damage and hepatocyte death. Falsification of one (or more) of the model mechanisms provides new knowledge and incrementally shrinks the constellation of model mechanisms. The modularity and biomimicry of our explanatory models enable seamless transition from mice to humans.

Cryopreservation of the common carotid artery of the rabbit: Optimization of dimethyl sulfoxide concentration and cooling rate.

This paper describes the continuation of studies that demonstrated the suitability of CP-Tes solution as a medium for the introduction and removal of dimethyl sulfoxide in rabbit common carotid arteries and established the kinetics of cryoprotectant permeation in that tissue. In this paper we report the tolerance of rabbit common carotid artery to dimethyl sulfoxide, in concentrations up to 30% (w/w), using a technique of exposure that was designed to control osmotic stress. The maximum concentration achieved without damage was 15% (w/w). Vessels were then equilibrated with 15% dimethyl sulfoxide and cooled to -80 °C at 0.22, 0.69, 2.15, or 9.63 °C/min: they were then transferred to the gas phase of a liquid nitrogen refrigerator {temperature below -160 °C) for storage. Thawing was carried out in a 37 °C water bath. The optimum rate of cooling for these conditions was found to be 0.69 °C/min. The maximal recovery of contractile force in response to 10-6 M norepinephrine was 30-40%; relaxation to acetylcholine (an endothelium-mediated function) was 80% of control, and an estimated 71% of endothelial cells survived with minimal ultrastructural change.

A case study approach to high-containment laboratory workflows promoting sustainability, networking and innovation.

Advances in information technologies (ITs) and operational technologies (OTs) offer high-containment laboratories opportunities to evolve scientific and operational approaches, while increasing efficiency. Emerging technologies steadily introduce changes in data generation and management practices. United States (US) government agencies and partners operate high-containment laboratories that rely on ITs/OTs to provide critical scientific functions that support prevention, detection, response and recovery for catastrophic events. These unique operating environments provide an opportunity for implementation of ITs/OTs that can facilitate both efficiency and deeper or parallel study of disease and associated biological phenomena. Operational study by subject matter experts can aid in identification of requirements and challenges pertaining to emerging ITs/OTs, examination of use cases, refinement of technical specifications and optimisation of workflows. The National Bio and Agro-Defense Facility (NBAF) in the United States of America (USA), slated to be fully operational by 2023, will be a state-of-the-art research and diagnostic facility with Biosafety Level 2, 3 and 4 laboratories for the study of high-consequence transboundary animal pathogens and zoonotic diseases impacting public health. The NBAF will support the diagnosis of emerging diseases, development of countermeasures and transboundary animal disease training. Given the rapid emergence of IT/OT solutions, the authors used a case study approach to analyse and assess real-world, high-containment laboratory functions to help maximise efficiency in mission delivery for the NBAF and the broader high-containment laboratory network. The case study approach described here could be widely adapted to diverse situations characterised by a high rate of change to provide accurate, relevant workflow analyses and optimised recommendations.

Les progrès enregistrés dans les domaines des technologies de l'information (IT) et des technologies opérationnelles (OT) offrent aux laboratoires de confinement à haute sécurité la possibilité de faire évoluer leurs approches scientifiques et opérationnelles tout en gagnant en efficacité. Grâce à ces technologies émergentes, les pratiques de production et de gestion des données sont régulièrement affinées. Les organismes gouvernementaux étatsuniens et leurs partenaires exploitent des laboratoires de confinement à haute sécurité qui font appel aux IT/OT pour mettre en oeuvre des fonctionnalités scientifiques cruciales en appui de la prévention, la détection, l'intervention et le rétablissement en cas de catastrophes. Ces environnements opérationnels uniques offrent la possibilité d'introduire des applications IT/OT afin de faciliter aussi bien l'efficacité des opérations que l'étude plus approfondie ou concomitante d'une maladie et des phénomènes biologiques qui lui sont associés. Des études opérationnelles menées par des spécialistes peuvent contribuer à identifier les exigences et les défis liés aux IT/OT émergentes, à vérifier leurs utilisations concrètes, à affiner les spécifications techniques et à optimiser l'ordonnancement des opérations. Le National Bio and Agro-Defense Facility (NBAF) des états-Unis d'Amérique, qui devrait être pleinement opérationnel d'ici 2023, sera une institution de recherche et de diagnostic de pointe dotée de laboratoires de niveaux de biosécurité 2, 3 et 4 pour l'étude des agents pathogènes responsables de maladies animales transfrontalières à haut risque et des agents zoonotiques à fort impact sur la santé publique. Le NBAF contribuera au diagnostic des maladies émergentes et à l'élaboration de mesures de lutte ; il dispensera également des formations sur les maladies animales transfrontalières. Compte tenu du développement rapide des nouvelles solutions IT/OT, les auteurs ont mis au point une méthode d'études de cas pour l'analyse et l'évaluation des fonctionnalités concrètes des laboratoires de confinement à haute sécurité, destinée à maximiser l'efficacité des prestations du NBAF et du réseau plus large de laboratoires de confinement à haute sécurité. La méthode par études de cas décrite ici pourrait être largement adaptée à diverses situations caractérisées par un niveau élevé de changement, afin de fournir des analyses précises et pertinentes de l'ordonnancement des opérations et d'élaborer des recommandations optimisées.

Los adelantos de las tecnologías de la información (TI) y las tecnologías operativas (TO) ofrecen a los laboratorios de alta contención la posibilidad de transformar sus lógicas y procedimientos de trabajo científico y al mismo tiempo ganar en eficiencia. Progresivamente, a la estela de las nuevas tecnologías, los métodos empleados para generar y gestionar datos van evolucionando. Ciertos organismos públicos estadounidenses administran, junto con entidades colaboradoras, laboratorios de alta contención que dependen de las TI/TO para cumplir una serie de cometidos científicos fundamentales en apoyo de la prevención y detección de sucesos catastróficos, de la respuesta a ellos y de los subsiguientes procesos de recuperación. Estos excepcionales entornos de trabajo ofrecen la posibilidad de implantar TI/TO que a la vez aporten más eficiencia y faciliten un estudio más a fondo o en paralelo de as enfermedades y los fenómenos biológicos asociados a ellas. La realización de estudios operativos a cargo de especialistas en el tema puede ayudar a determinar las necesidades y dificultades que plantean las nuevas TI/TO, a examinar ejemplos de utilización, a afinar las especificaciones técnicas y a optimizar los procesos de trabajo. El órgano nacional de defensa biológica y agrícola (National Bio and Agro-Defense Facility, NBAF) de los Estados Unidos de América, que según las previsiones funcionará a pleno rendimiento en 2023, constituirá un avanzado dispositivo de investigación y diagnóstico al que estarán adscritos laboratorios de nivel 2, 3 y 4 de seguridad biológica para el estudio de agentes patógenos de los animales y enfermedades zoonóticas de carácter transfronterizo y de gran repercusión que afecten a la salud pública. El NBAF secundará el diagnóstico de enfermedades emergentes, la preparación de medidas de lucha y la formación sobre enfermedades animales transfronterizas. Teniendo en cuenta la velocidad a la que surgen soluciones de TI/TO, los autores recurrieron al estudio de ejemplos concretos para analizar y evaluar las funciones que cumplen en el mundo real los laboratorios de alta contención con el objetivo de ayudar al NBAF y a la red general de laboratorios de alta contención a ejercer su cometido con la máxima eficiencia. El método de trabajo aquí descrito, basado en el estudio de casos concretos, podría ser adaptado a diversas situaciones que se caractericen por un alto ritmo de transformaciones para efectuar análisis precisos y pertinentes de los procesos de trabajo y formular recomendaciones optimizadas.

Propagation of Pericentral Necrosis During Acetaminophen-Induced Liver Injury: Evidence for Early Interhepatocyte Communication and Information Exchange.

Acetaminophen (APAP)-induced liver injury is clinically significant, and APAP overdose in mice often serves as a model for drug-induced liver injury in humans. By specifying that APAP metabolism, reactive metabolite formation, glutathione depletion, and mitigation of mitochondrial damage within individual hepatocytes are functions of intralobular location, an earlier virtual model mechanism provided the first concrete multiattribute explanation for how and why early necrosis occurs close to the central vein (CV). However, two characteristic features could not be simulated consistently: necrosis occurring first adjacent to the CV, and subsequent necrosis occurring primarily adjacent to hepatocytes that have already initiated necrosis. We sought parsimonious model mechanism enhancements that would manage spatiotemporal heterogeneity sufficiently to enable meeting two new target attributes and conducted virtual experiments to explore different ideas for model mechanism improvement at intrahepatocyte and multihepatocyte levels. For the latter, evidence supports intercellular communication via exosomes, gap junctions, and connexin hemichannels playing essential roles in the toxic effects of chemicals, including facilitating or counteracting cell death processes. Logic requiring hepatocytes to obtain current information about whether downstream and lateral neighbors have triggered necrosis enabled virtual hepatocytes to achieve both new target attributes. A virtual hepatocyte that is glutathione-depleted uses that information to determine if it will initiate necrosis. When a less-stressed hepatocyte is flanked by at least two neighbors that have triggered necrosis, it too will initiate necrosis. We hypothesize that the resulting intercellular communication-enabled model mechanism is analogous to the actual explanation for APAP-induced hepatotoxicity at comparable levels of granularity.

A Psychosexual Rehabilitation Booklet Increases Vaginal Dilator Adherence and Knowledge in Women Undergoing Pelvic Radiation Therapy for Gynaecological or Anorectal Cancer: A Randomised Controlled Trial.

AIMS: Women treated with pelvic radiation therapy (PRT) for gynaecological or anorectal cancer report a high number of sexual problems and unmet post-treatment psychosexual information needs. Currently, there is suboptimal adherence to recommended rehabilitation aids, such as vaginal dilators, and a paucity of resources to facilitate post-radiation rehabilitation and reduce distress in this population. This randomised controlled trial aimed to evaluate the effectiveness of a study-developed psychosexual rehabilitation booklet in this setting. MATERIALS AND METHODS: Eighty-two women scheduled for PRT to treat gynaecological/anorectal cancer were randomised to receive the intervention booklet (n = 44) or standard information materials (n = 38). Self-report questionnaires administered at pre-treatment baseline and at 3, 6 and 12 months post-treatment assessed adherence with rehabilitation aids, booklet knowledge, anxiety, depression and sexual functioning/satisfaction. RESULTS: Dilator adherence and booklet knowledge were significantly higher in the intervention group than in the control group (averaged over time points), with scores significantly increasing over time. Younger age and gynaecological cancer were significant predictors of greater dilator adherence. No significant group differences were found on psychological and sexual measures. CONCLUSIONS: The psychosexual rehabilitation booklet was effective in educating women with gynaecological and anorectal cancers about PRT-related psychosexual side-effects and rehabilitation options, as well as promoting uptake of vaginal dilator use. Future research should elucidate the effectiveness of this booklet in women with greater psychological and sexual functioning needs.

Credibility, Replicability, and Reproducibility in Simulation for Biomedicine and Clinical Applications in Neuroscience.

Modeling and simulation in computational neuroscience is currently a research enterprise to better understand neural systems. It is not yet directly applicable to the problems of patients with brain disease. To be used for clinical applications, there must not only be considerable progress in the field but also a concerted effort to use best practices in order to demonstrate model credibility to regulatory bodies, to clinics and hospitals, to doctors, and to patients. In doing this for neuroscience, we can learn lessons from long-standing practices in other areas of simulation (aircraft, computer chips), from software engineering, and from other biomedical disciplines. In this manuscript, we introduce some basic concepts that will be important in the development of credible clinical neuroscience models: reproducibility and replicability; verification and validation; model configuration; and procedures and processes for credible mechanistic multiscale modeling. We also discuss how garnering strong community involvement can promote model credibility. Finally, in addition to direct usage with patients, we note the potential for simulation usage in the area of Simulation-Based Medical Education, an area which to date has been primarily reliant on physical models (mannequins) and scenario-based simulations rather than on numerical simulations.