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TwoGram-stain-positive and rod-shaped actinomycetes (strains CDC186T and CDC192) were isolated from sputum samples of a patient in Chongqing, PR China, and were investigated to determine their taxonomic status. The results of phylogenetic analysis based on the 16S rRNA gene indicated that CDC186T and CDC192 represented members of the genus Nocardia, and the sequence similarity with Nocardia beijingensis DSM 44636T was the highest, at 99.71 and 99.78â%, respectively. The DNA G+C content of both CDC186T and CDC192 was 69.1â%. Genomic diversity analysis revealed that the average nucleotide identity and in silico DNAâDNA hybridisation values between the two novel strains and closely related species were significantly below the thresholds of 95-96 and 70â%, respectively, but these values between the two novel strains were 99.96 and 99.90â%, respectively. The phylogenetic relationship based on the dapb1 gene and the single-copy core genes further indicated that the two novel strains were clustered in separate branch adjacent to N. beijingensis DSM 44636T. Growth occurred within the ranges of 20-42â°C, pH 6.0-9.0 and NaCl concentrations of 0.5-4.5â% (w/v). The major fatty acids of CDC186T and CDC192 were C16â:â0 and C18â:â0 10-methyl [tuberculostearic acid (TBSA)]. The predominant respiratory menaquinone was MK-9. The polar lipid profile contained diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylinositol mannoside, one unidentified glycolipid, one unidentified phospholipid and one unidentified phosphoglycolipid. All the genomes of the studied strains were annotated with virulence factor (VF)-associated genes homologous to those of Mycobacterium tuberculosis, and the results of susceptibility testing indicated that CDC186T and CDC192 were resistant to amoxicillin-clavulanic acid and tigecycline. On the basis of chemotaxonomic characteristics and the results of phylogenetic analyses, strains CDC186T and CDC192 represent a novel species within the genus Nocardia, for which the name Nocardia implantans sp. nov. is proposed. The type strain is CDC186T (=GDMCC 4.206T= JCM 34959T).
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Técnicas de Tipagem Bacteriana , Composição de Bases , DNA Bacteriano , Ácidos Graxos , Nocardiose , Nocardia , Hibridização de Ácido Nucleico , Filogenia , RNA Ribossômico 16S , Análise de Sequência de DNA , Escarro , Nocardia/isolamento & purificação , Nocardia/genética , Nocardia/classificação , Humanos , RNA Ribossômico 16S/genética , China , DNA Bacteriano/genética , Ácidos Graxos/análise , Ácidos Graxos/química , Nocardiose/microbiologia , Escarro/microbiologia , Antibacterianos/farmacologia , Testes de Sensibilidade Microbiana , Genoma BacterianoRESUMO
The phenomenon of rectification describes the emergence of a DC current from the application of an oscillating voltage. Although the origin of this effect has been associated with the nonlinearity in the current-voltage I(V) relation, a rigorous understanding of the microscopic mechanisms for this phenomenon remains challenging. Here, we show the close connection between rectification and inelastic electron tunneling spectroscopy and microscopy for single molecules with a scanning tunneling microscope. While both techniques are based on nonlinear features in the I(V) curve, comprehensive line shape analyses reveal notable differences that highlight the two complementary techniques of nonlinear conductivity spectromicroscopy for probing nanoscale systems.
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Elétrons , Microscopia de Tunelamento , Condutividade Elétrica , Microscopia de Tunelamento/métodos , Nanotecnologia , Análise Espectral/métodosRESUMO
BACKGROUND: We have developed hybrid nanoparticles (NPs) by co-loading copper sulfide (CuS) NPs and glucose oxidase (GOD) (CuS@GOD NPs) to explore their antitumor properties. PURPOSE: To investigate the feasibility of using multiparametric magnetic resonance imaging (MRI) including intravoxel incoherent motion diffusion-weighted imaging (IVIM-DWI) and R2 * mapping to quantitatively assess the early antitumor effect of CuS@GOD NPs. STUDY TYPE: Prospective. ANIMAL MODEL: The orthotopic BALB/c mice 4 T1 breast cancer model. The 4 T1 xenografts in group 1 mice received normal saline, group 2 received CuS@GOD NPs, group 3 received CuS NPs plus laser, and group 4 received CuS@GOD NPs plus laser (n = 28 for each group). FIELD STRENGTH/SEQUENCE: A 3.0 T/IVIM-DWI MRI single-shot echo-planar imaging, R2 * mapping spoiled gradient recalled echo (SPGR) sequence, T2-weighted images (T2WI) and T1-weighted images (T1WI) fast spin echo (FSE) sequence. ASSESSMENT: The IVIM-DWI and R2 * mapping were performed before and after treatment at 0 hour, 0.5 hour, 1 hour, 2 hours, 4 hours, and 24 hours in four groups and the MRI parameters were obtained. Correlation analysis between the MRI parameters and histological analyses was conducted. STATISTICAL TESTS: One-way ANOVA, Pearson's correlation analysis, two independent samples t test, intraclass correlation coefficient. P < 0.05 was considered to be statistically significant. RESULTS: In group 4, the tumoral D value was significantly higher than that of group 2 at 24 hours (0.541 ± 0.065 vs. 0.492 ± 0.051). The f value of group 4 was significantly lower than that of groups 1 and 2 at 2 hours (10.83 ± 2.16 vs. 14.28 ± 1.86, 16.67 ± 3.53, respectively). The R2 * value was significantly increased at 0 hour in group 4 compared to that of groups 1 and 2 (64.552 ± 4.663 vs. 42.441 ± 1.516, 43.165 ± 1.709, respectively). D, f, and R2 * were correlated with the histological staining results (r = 0.695-0.970). DATA CONCLUSION: The IVIM-DWI-derived D and f and R2 * mapping-derived R2 * could monitor early response to CuS@GOD NPs treatment in vivo. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 2.
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Imageamento por Ressonância Magnética Multiparamétrica , Nanopartículas , Neoplasias , Animais , Cobre , Glucose Oxidase , Xenoenxertos , Camundongos , Estudos ProspectivosRESUMO
The toxicity of microplastic particles (MPs) on aquatic environments has been widely reported; however, their effects on protists are still contradictory. For example, it is unclear if cell size and cell wall have a role in shaping the response of flagellates to MPs. In this study, seven marine flagellated microalgae (six Dinoflagellates and one Raphidophyceae) were incubated with 10 mg L-1 MPs (polystyrene plastic micro-spheres, 1 µm diameter) to address the above question by measuring different response variables, i.e., growth, optimal photochemical efficiency (Fv/Fm), chlorophyll-a (Chl-a) content, superoxide dismutase (SOD) activity, and cell morphology. The effect of MPs on growth and Fv/Fm showed species-specificity effects. Maximum and minimum MPs-induced inhibitions were detected in Karenia mikimotoi (76.43%) and Akashiwo sanguinea (10.16%), respectively, while the rest of the species showed intermediate responses. The presence of MPs was associated with an average reduction of Chl-a content in most cases and with a higher superoxide dismutase activity in all cases. Seven species were classified into two groups by the variation of Chl-a under MPs treatment. One group (Prorocentrum minimum and Karenia mikimotoi) showed increased Chl-a, while the other (P. donghaiense, P. micans, Alexandrium tamarense, Akashiwo sanguinea, Heterosigma akashiwo) showed decreased Chl-a content. The MPs-induced growth inhibition was negatively correlated with cell size in the latter group. SEM images further indicated that MPs-induced malformation in the smaller cells (e.g., P. donghaiense and K. mikimotoi) was more severe than the bigger cells (e.g., A. sanguinea and P. micans), probably due to a relatively higher ratio of the cell surface to cell volume in the former. These results implicate that the effect of MPs on marine flagellated microalgae was related to the cell size among most species but not cell wall. Thus plastic pollution may have size-dependent effects on phytoplankton in future scenarios.
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Microalgas , Poluentes Químicos da Água , Parede Celular/química , Dinoflagellida , Microplásticos , Plásticos/toxicidade , Poluentes Químicos da Água/análiseRESUMO
AIMS: Beta-blockers are commonly used to treat hypertension that arises during pregnancy. However, reproductive safety concerns have been expressed. Here, we investigated whether the use of ß-blockers during early pregnancy increased the risk of congenital malformations. METHODS: A systematic literature search was performed in PubMed, Embase and Cochrane Library to identify relevant studies published from database inception until February 2020. Observational studies evaluating associations between maternal ß-blocker use and congenital malformations were included in this meta-analysis. Two reviewers independently extracted data and assessed study quality. Meta-analysis of outcomes was performed and a summary odds ratio (OR) was calculated with consideration of heterogeneity. RESULTS: Twenty observational studies were identified. Beta-blocker use during early pregnancy was not associated with an increased risk of congenital malformations (OR = 1.01, 95% confidence interval [CI] = 0.93-1.09). Subgroup analysis of organ-specific malformations revealed that ß-blocker use was associated with an increased risk of heart malformations (OR = 1.29, 95% CI = 1.02-1.63) and an increased risk of cleft lip or palate (OR = 1.5, 95% CI = 1.18-1.91); however, these associations (OR = 1.11, 95% CI = 0.94-1.32 for heart malformations; OR = 1.34, 95% CI = 0.98-1.85 for cleft lip or palate) disappeared when the adjusted data were pooled. Beta-blocker use was not associated with increased risks of central nervous system malformations, neural tube defects or hypospadias. CONCLUSION: Exposure to ß-blockers during early pregnancy does not appear to be associated with congenital malformations or heart malformations in offspring. Other organ-specific congenital malformations should be evaluated in further studies.
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Cardiopatias Congênitas , Hipertensão , Antagonistas Adrenérgicos beta/efeitos adversos , Feminino , Cardiopatias Congênitas/induzido quimicamente , Cardiopatias Congênitas/epidemiologia , Humanos , Masculino , Estudos Observacionais como Assunto , Razão de Chances , GravidezRESUMO
BACKGROUND: Myeloid sarcoma (MS) is a tumor secondary to myeloid leukemia that consists of immature granulocytes with or without mature granulocytes and is a rare extramedullary manifestation of acute myeloid leukemia (AML). CASE PRESENTATION: We report a case of a 34-year-old woman diagnosed with AML-M4 who achieved remission after chemotherapy and received allogeneic stem cell transplantation (allo-SCT) for consolidation. Her past medical history showed that she received bilateral breast implants 7 years ago. This patient underwent ultrasound examination of the breast and multiple bilateral breast nodules were revealed that were not considered by clinicians to be concerning. Several months later, the patient's bilateral nodules rapidly progressed to large palpable masses. Ultrasound-guided biopsy revealed diffuse infiltration of undifferentiated tumor cells and immunohistochemistry (IHC) indicated that the tumor was positive for myeloperoxidase (MPO), cluster of differentiation (CD) 34, CD43, CD68, CD117, and Ki67. The pathological diagnosis was extramedullary recurrence of AML as MS of breast. After the diagnosis, the patient received systemic chemotherapy and drugs containing cytarabine, azacitidine, and methotrexate. However, 1 year after achieving partial remission, the patient died from intracranial invasion of leukemia, brain herniation, and respiratory failure. CONCLUSION: It is necessary for the specialist to have a high suspicion index by careful inquiry of the patient's medical history if a patient presents at the breast clinic with a breast tumor as the chief complaint. Combining information from the patient's medical history with a tumor biopsy is critical for obtaining the correct diagnosis of the disease.
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Transplante de Células-Tronco Hematopoéticas , Leucemia Mielomonocítica Aguda , Sarcoma Mieloide , Adulto , Feminino , Humanos , Biópsia Guiada por Imagem , Prognóstico , Sarcoma Mieloide/diagnóstico por imagem , Sarcoma Mieloide/terapiaRESUMO
Post-traumatic osteomyelitis (PTO) is a worldwide problem in the field of orthopaedic trauma. So far, there is no ideal treatment or consensus-based gold standard for its management. This paper reviews the representative literature focusing on PTO, mainly from the following four aspects: (1) the pathophysiological mechanism of PTO and the interaction mechanism between bacteria and the body, including fracture stress, different components of internal fixation devices, immune response, occurrence and development mechanisms of inflammation in PTO, as well as the occurrence and development mechanisms of PTO in skeletal system; (2) clinical classification, mainly the etiological classification, histological classification, anatomical classification and the newly proposed new classifications (a brief analysis of their scope and limitations); (3) imaging diagnosis, including non-invasive examination and invasive examination (this paper discusses their advantages and disadvantages respectively, and briefly compares the sensitivity and effectiveness of the current examinations); and (4) strategies, including antibiotic administration, surgical choices and other treatment programs. Based on the above-mentioned four aspects, we try to put forward some noteworthy sections, in order to make the existing opinions more specific.
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Fraturas Ósseas , Osteomielite , Antibacterianos/uso terapêutico , Fraturas Ósseas/complicações , Fraturas Ósseas/diagnóstico por imagem , Humanos , Osteomielite/diagnóstico por imagem , Osteomielite/terapiaRESUMO
BACKGROUND: At present, there remains a lack of a reliable indicator for monitoring renal function in patients with hyperuricemia. PURPOSE: This study aimed to evaluate the feasibility of diffusion kurtosis imaging in the assessment of renal function in patients with hyperuricemia. MATERIAL AND METHODS: A total of 75 male participants, including 25 with asymptomatic hyperuricemia, 25 with gouty arthritis, and 25 age-matched male healthy controls, were enrolled in this study. Diffusion kurtosis imaging data were acquired to derive axial (Ka), radial (Kr), and mean kurtosis (MK), fractional anisotropy, axial (Da), radial (Dr), and mean diffusivity (MD) for comparisons among the three groups. They were also correlated with estimated glomerular filtration rate (eGFR). RESULTS: The MK values of the renal cortex and medulla and Kr value of the renal medulla in patients with asymptomatic hyperuricemia and gouty arthritis significantly increased compared with those in the controls (P < 0.05). Patients with gouty arthritis showed significant higher cortical and medullary Ka values compared with the other two groups (P < 0.05). The cortical Kr values of the asymptomatic hyperuricemia and gouty arthritis patients were significantly higher than that of the controls (P < 0.05). The medullary fractional anisotropy value showed a significant difference between the control and gouty arthritis groups (P < 0.05). No correlation was found between any diffusion kurtosis imaging parameters and eGFR value. CONCLUSION: Diffusion kurtosis imaging is feasible in the assessment of the early changes of renal cortex and medulla in patients with hyperuricemia.
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Imagem de Tensor de Difusão/métodos , Hiperuricemia/diagnóstico por imagem , Adulto , Estudos de Viabilidade , Humanos , Hiperuricemia/fisiopatologia , Rim/diagnóstico por imagem , Rim/fisiopatologia , Masculino , Reprodutibilidade dos Testes , Adulto JovemRESUMO
The spin states of magnetic molecules have advantageous attributes as carriers of quantum information. However, spin-vibration coupling in molecules causes a decay of excited spin states and a loss of spin coherence. Here, we detect excitations of spin-vibration states in single nickelocene molecules on Ag(110) with a scanning tunneling microscope. By transferring a nickelocene to the tip, the joint spin-vibration states with an adsorbed nickelocene were measured. Chemical variations in magnetic molecules offer the opportunity to tune spin-vibration coupling for controlling the spin coherence.
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Prolonged QT intervals are a major risk factor for ventricular arrhythmias and a leading cause of sudden cardiac death. Various drugs are known to trigger QT interval prolongation and increase the proarrhythmic potential. Yet, how precisely the action of drugs on the cellular level translates into QT interval prolongation on the whole organ level remains insufficiently understood. Here we use machine learning techniques to systematically characterize the effect of 30 common drugs on the QT interval. We combine information from high fidelity three-dimensional human heart simulations with low fidelity one-dimensional cable simulations to build a surrogate model for the QT interval using multi-fidelity Gaussian process regression. Once trained and cross-validated, we apply our surrogate model to perform sensitivity analysis and uncertainty quantification. Our sensitivity analysis suggests that compounds that block the rapid delayed rectifier potassium current I Kr have the greatest prolonging effect of the QT interval, and that blocking the L-type calcium current I CaL and late sodium current I NaL shortens the QT interval. Our uncertainty quantification allows us to propagate the experimental variability from individual block-concentration measurements into the QT interval and reveals that QT interval uncertainty is mainly driven by the variability in I Kr block. In a final validation study, we demonstrate an excellent agreement between our predicted QT interval changes and the changes observed in a randomized clinical trial for the drugs dofetilide, quinidine, ranolazine, and verapamil. We anticipate that both the machine learning methods and the results of this study will have great potential in the efficient development of safer drugs.
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We review the representatives literatures on chronic osteomyelitis, sum up the new insights in recent years into diagnostic options and treatment regimens, analyze the advantages and disadvantages of various diagnostic approaches and treatment strategies, and propose areas of interest to make current diagnostic and treatment strategies more specific.
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Osteomielite/diagnóstico , Osteomielite/metabolismo , Osteomielite/terapiaRESUMO
Untreated tricuspid valve regurgitation (TR) is associated with increased rates of mortality, morbidity, and hospitalization. Current pharmacological and surgical treatment options for TR are limited. MitraClip (MC), an edge-to-edge percutaneous intervention, has been reported to be effective for treatment of TR. The goal of this study was to examine the effects of MC position on TR, using a multiphysics fluid-structure-interaction (FSI) analysis. The computational set up included the tricuspid valve (TV), the chordae tendineae, the blood particles, and a tube that surrounded the leaflets and blood particles. The leaflets and chordae were modeled as hyperelastic materials, and blood was modeled using smoothed particle hydrodynamics. FSI analysis was conducted for blood flow through the closed valve for multiple simulations that account for normal, diseased, and treated conditions of the TV. To simulate the diseased TV, a group of chordae between septal and pulmonary leaflets were removed from the normal TV, which produced increased regurgitation. Four MC treated scenarios were considered: i) one MC near the annulus, ii) one MC approximately midway between the annulus and leaflet tip, iii) one MC near the leaflet tip, iv) two MCs: one approximately midway between the annulus and leaflet tip, and one close to the leaflet tip. The TR increased in diseased TV (7.5%) compared to normal TV (2.5%). All MC treated scenarios decreased TR. The MC located near the midway point between the annulus and leaflet tip led to largest decrease in TR (75.2% compared to the untreated condition). The MC located near the leaflet tip was associated with lowest reduction in TR (2.2% compared to the untreated condition). When two MCs were used, reduction in TR was relatively high (68.7%), but TR was not improved compared to the optimal single MC. MC caused high stresses in the vicinity of the clipping area in all conditions; the highest occurred when the MC was near the leaflet tips. Using a quantitative computational approach, we confirm previous clinical reports on the efficacy of MC for treatment of TR. The results of this study could lead to the design of more efficient MC interventions for TR.
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In the early embryo, the primitive heart tube (HT) undergoes the morphogenetic process of c-looping as it bends and twists into a c-shaped tube. Despite intensive study for nearly a century, the physical forces that drive looping remain poorly understood. This is especially true for the bending component, which is the focus of this paper. For decades, experimental measurements of mitotic rates had seemingly eliminated differential growth as the cause of HT bending, as it has commonly been thought that the heart grows almost exclusively via hyperplasia before birth and hypertrophy after birth. Recently published data, however, suggests that hypertrophic growth may play a role in looping. To test this idea, we developed finite-element models that include regionally measured changes in myocardial volume over the HT. First, models based on idealized cylindrical geometry were used to simulate the bending process in isolated hearts, which bend without the complicating effects of external loads. With the number of free parameters in the model reduced to the extent possible, stress and strain distributions were compared to those measured in embryonic chick hearts that were isolated and cultured for 24 h. The results show that differential growth alone yields results that agree reasonably well with the trends in our data, but adding active changes in myocardial cell shape provides closer quantitative agreement with stress measurements. Next, the estimated parameters were extrapolated to a model based on realistic 3D geometry reconstructed from images of an actual chick heart. This model yields similar results and captures quite well the basic morphology of the looped heart. Overall, our study suggests that differential hypertrophic growth in the myocardium (MY) is the primary cause of the bending component of c-looping, with other mechanisms possibly playing lesser roles.
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Análise de Elementos Finitos , Coração/embriologia , Fenômenos Mecânicos , Animais , Fenômenos Biomecânicos , Forma Celular , Embrião de Galinha , Coração/anatomia & histologia , Morfogênese , Miocárdio/citologia , Estresse MecânicoRESUMO
To deal with nonlinear characteristics of spectra data for the thermal power plant flue, a nonlinear partial least square (PLS) analysis method with internal model based on neural network is adopted in the paper. The latent variables of the independent variables and the dependent variables are extracted by PLS regression firstly, and then they are used as the inputs and outputs of neural network respectively to build the nonlinear internal model by train process. For spectra data of flue gases of the thermal power plant, PLS, the nonlinear PLS with the internal model of back propagation neural network (BP-NPLS), the non-linear PLS with the internal model of radial basis function neural network (RBF-NPLS) and the nonlinear PLS with the internal model of adaptive fuzzy inference system (ANFIS-NPLS) are compared. The root mean square error of prediction (RMSEP) of sulfur dioxide of BP-NPLS, RBF-NPLS and ANFIS-NPLS are reduced by 16.96%, 16.60% and 19.55% than that of PLS, respectively. The RMSEP of nitric oxide of BP-NPLS, RBF-NPLS and ANFIS-NPLS are reduced by 8.60%, 8.47% and 10.09% than that of PLS, respectively. The RMSEP of nitrogen dioxide of BP-NPLS, RBF-NPLS and ANFIS-NPLS are reduced by 2.11%, 3.91% and 3.97% than that of PLS, respectively. Experimental results show that the nonlinear PLS is more suitable for the quantitative analysis of glue gas than PLS. Moreover, by using neural network function which can realize high approximation of nonlinear characteristics, the nonlinear partial least squares method with internal model mentioned in this paper have well predictive capabilities and robustness, and could deal with the limitations of nonlinear partial least squares method with other internal model such as polynomial and spline functions themselves under a certain extent. ANFIS-NPLS has the best performance with the internal model of adaptive fuzzy inference system having ability to learn more and reduce the residuals effectively. Hence, ANFIS-NPLS is an accurate and useful quantitative thermal power plant flue gas analysis method.
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Studying the photoinduced changes of materials with atomic-scale spatial resolution can provide a fundamental understanding of light-matter interaction. A long-standing impediment has been the detrimental thermal effects on the stability of the tunneling gap from intensity-modulated laser irradiation of the scanning tunneling microscope junction. Photoinduced DC current transduces photons to an electric current and is widely applied in optoelectronics as switches and signal transmission. Our results revealed the origin of the light-induced DC current and related it to the two-level population dynamics and related nonlinearity in the conductance of a single molecule. Here, we compensated for the near-visible laser-induced thermal effects to demonstrate photoinduced DC current spectroscopy and microscopy and to observe the persistent photoconductivity of a two-level pyrrolidine molecule. The methodology can be generally applied to the coupling of light to scan probes to investigate light-matter interactions at the atomic scale.
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Ni-rich cathode materials exhibit superior energy densities and have attracted interest among both research and industrial fields; whereas, their practical application is hindered by the intrinsic drawbacks brought by the high nickel content such as structural instability and rapid capacity fading. Herein, in situ formation of a LiBO2 coating layer and spinel phase layer is achieved on the surface of a Ni-rich cathode material via a boric acid etching method at the precursor state. The spinel phase is considered to have a 3D lithium diffusion tunnel and hence faster diffusion kinetics. Moreover, the LiBO2 layer possesses excellent (electro)chemical inertness and can suppress electrolyte decomposition, resulting in a more inorganic and stable cathode-electrolyte interface. The surface reconstructed sample exhibits better cyclic stability (93.3% capacity retention vs 85.3% for the pristine sample at 1 C for 100 cycles) and rate performance. The superiority of this surface reconstruction is demonstrated by a series of electrochemical techniques and characterization methods including high-angle annular dark-field scanning transmission electron microscopy (HAADF-STEM), post-mortem X-ray photoelectron spectroscopy (XPS) analysis, and density functional theory (DFT) calculations.
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Left ventricular (LV) longitudinal function is mechanically coupled to the elasticity of the ascending aorta (AA). The pathophysiologic link between a stiff AA and reduced longitudinal strain and the subsequent deterioration in longitudinal LV systolic function is likely relevant in heart failure with preserved ejection fraction (HFpEF). The proposed therapeutic effect of freeing the LV apex and allowing for LV inverse longitudinal shortening was studied in silico utilizing the Living Left Heart Human Model (Dassault Systémes Simulia Corporation). LV function was evaluated in a model with (A) an elastic AA, (B) a stiff AA, and (C) a stiff AA with a free LV apex. The cardiac model simulation demonstrated that freeing the apex caused inverse LV longitudinal shortening that could abolish the deleterious mechanical effect of a stiff AA on LV function. A stiff AA and impairment of the LV longitudinal strain are common in patients with HFpEF. The hypothesis-generating model strongly suggests that freeing the apex and inverse longitudinal shortening may improve LV function in HFpEF patients with a stiff AA.
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During systole, longitudinal shortening of the left ventricle (LV) displaces the aortic root toward the apex of the heart and stretches the ascending aorta (AA). An in silico study (Living Left Heart Human Model, Dassault Systèmes Simulia Corporation) demonstrated that stiffening of the AA affects myocardial stress and LV strain patterns. With AA stiffening, myofiber stress increased overall in the LV, with particularly high-stress areas at the septum. The most pronounced reduction in strain was noted along the septal longitudinal region. The pressure-volume loops showed that AA stiffening caused a deterioration in LV function, with increased end-systolic volume, reduced systolic LV pressure, decreased stroke volume and effective stroke work, but elevated end-diastolic pressure. An increase in myofiber contractility indicated that stroke volume and effective stroke work could be recovered, with an increase in LV end-systolic pressure and a decrease in end-diastolic pressure. Longitudinal and radial strains remained reduced, but circumferential strains increased over baseline, compensating for lost longitudinal LV function. Myofiber stress increased overall, with the most dramatic increase in the septal region and the LV apex. We demonstrate a direct mechanical pathophysiologic link between stiff AA and reduced longitudinal left ventricular strain which are common in patients with HFpEF.
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Computational models of patients and medical devices can be combined to perform an in silico clinical trial (ISCT) to investigate questions related to device safety and/or effectiveness across the total product life cycle. ISCTs can potentially accelerate product development by more quickly informing device design and testing or they could be used to refine, reduce, or in some cases to completely replace human subjects in a clinical trial. There are numerous potential benefits of ISCTs. An important caveat, however, is that an ISCT is a virtual representation of the real world that has to be shown to be credible before being relied upon to make decisions that have the potential to cause patient harm. There are many challenges to establishing ISCT credibility. ISCTs can integrate many different submodels that potentially use different modeling types (e.g., physics-based, data-driven, rule-based) that necessitate different strategies and approaches for generating credibility evidence. ISCT submodels can include those for the medical device, the patient, the interaction of the device and patient, generating virtual patients, clinical decision making and simulating an intervention (e.g., device implantation), and translating acute physics-based simulation outputs to health-related clinical outcomes (e.g., device safety and/or effectiveness endpoints). Establishing the credibility of each ISCT submodel is challenging, but is nonetheless important because inaccurate output from a single submodel could potentially compromise the credibility of the entire ISCT. The objective of this study is to begin addressing some of these challenges and to identify general strategies for establishing ISCT credibility. Most notably, we propose a hierarchical approach for assessing the credibility of an ISCT that involves systematically gathering credibility evidence for each ISCT submodel in isolation before demonstrating credibility of the full ISCT. Also, following FDA Guidance for assessing computational model credibility, we provide suggestions for ways to clearly describe each of the ISCT submodels and the full ISCT, discuss considerations for performing an ISCT model risk assessment, identify common challenges to demonstrating ISCT credibility, and present strategies for addressing these challenges using our proposed hierarchical approach. Finally, in the Appendix we illustrate the many concepts described here using a hypothetical ISCT example.
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ISCR28 is a fully functional and active member of the IS91-like family of insertion sequences. ISCR28 is 1,708-bp long and contains a 1,293-bp long putative open reading frame that codes a transposase. Sixty ISCR28-containing sequences from GenBank generated 27 non-repeat genetic contexts, all of which represented naturally occurring biological events that had occurred in a wide range of gram-negative organisms. Insertion of ISCR28 into target DNA preferred the presence of a 5'-GXXT-3' sequence at its terIS (replication terminator) end. Loss of the first 4 bp of its oriIS (origin of replication) likely caused ISCR28 to be trapped in ISApl1-based transposons or similar structures. Loss of terIS and fusion with a mobile element upstream likely promoted co-transfer of ISCR28 and the downstream resistance genes. ArmA and its downstream intact ISCR28 can be excised from recombinant pKD46 plasmids forming circular intermediates, further elucidating its activity as a transposase.