A systematic comparison between FEBio and PolyFEM for biomechanical systems.

BACKGROUND AND OBJECTIVES: Finite element simulations are widely employed as a non-invasive and cost-effective approach for predicting outcomes in biomechanical simulations. However, traditional finite element software, primarily designed for engineering materials, often encountered limitations in contact detection and enforcement, leading to simulation failure when dealing with complex biomechanical configurations. Currently, a lot of model tuning is required to get physically accurate finite element simulations without failures. This adds significant human interaction to each iteration of a biomechanical model. This study addressed these issues by introducing PolyFEM, a novel finite element solver that guarantees inversion- and intersection-free solutions with completely automatic collision detection. The objective of this research is to validate PolyFEM's capabilities by comparing its results with those obtained from a well-established finite element solver, FEBio. METHODS: To achieve this goal, five comparison scenarios were formulated to assess and validate PolyFEM's performance. The simulations were reproduced using both PolyFEM and FEBio, and the final results were compared. The five comparison scenarios included: (1) reproducing simulations from the FEBio test suite, consisting of static, dynamic, and contact-driven simulations; (2) replicating simulations from the verification paper published alongside the original release of FEBio; (3) a biomechanically based contact problem; (4) creating a custom simulation involving high-energy collisions between soft materials to highlight the difference in collision methods between the two solvers; and (5) performing biomechanical simulations of biting and quasi-stance. RESULTS: We found that PolyFEM was capable of replicating all simulations previously conducted in FEBio. Particularly noteworthy is PolyFEM's superiority in high-energy contact simulations, where FEBio fell short, unable to complete over half of the simulations in Scenario 4. Although some of the simulations required significantly more simulation time in PolyFEM compared to FEBio, it is important to highlight that PolyFEM achieved these results without the need for any additional model tuning or contact declaration. DISCUSSION: Despite being in the early stages of development, PolyFEM currently provides verified solutions for hyperelastic materials that are consistent with FEBio, both in previously published workflows and novel finite element scenarios. PolyFEM exhibited the ability to tackle challenging biomechanical problems where other solvers fell short, thus offering the potential to enhance the accuracy and realism of future finite element analyses.

ß-Lactams plus doxycycline versus azithromycin for treatment of severe community-acquired pneumonia in critically ill patients.

OBJECTIVES: Community-acquired pneumonia (CAP) is a significant source of hospital admissions and mortality. Atypical organisms are implicated in up to 40% of cases of CAP diagnoses. We studied the difference in outcomes of severe CAP patients treated with doxycycline versus azithromycin in addition to ß-lactam therapy. PATIENTS AND METHODS: This was a prospective observational cohort study from March 2020 to July 2022 in a medical ICU (MICU) of an academic quaternary medical center. Adults ≥18 years admitted to the MICU receiving doxycycline or azithromycin in addition to ß-lactam therapy for the treatment of CAP were included for analysis. The primary outcomes were in-hospital and 30 day mortality. Secondary outcomes were ICU and hospital length-of-stay, 30 day readmission, days of mechanical ventilation, escalation and duration of antibiotics, adverse effects such as Clostridioides difficile infection and QTc prolongation. RESULTS: Sixty-three patients were in the azithromycin group and eighty-six patients in the doxycycline group. Both groups had similar APACHE IV and CURB-65 scores. The mean Charlson Comorbidity Index score was higher for the doxycycline group compared with the azithromycin group (P = 0.04). There was no statistically significant difference in in-hospital and 30 day mortality between the groups (P = 0.53, P = 0.57). There were no significant differences in any of the secondary outcomes. CONCLUSIONS: MICU patients with severe CAP who received doxycycline versus azithromycin in addition to ß-lactam treatment showed no significant differences in outcomes. These data offer support for inclusion of doxycycline as an alternative regimen in current IDSA recommendations.

Outcomes of Patients With Sepsis and Septic Shock Requiring Source Control: A Prospective Observational Single-Center Study.

Source control is important in management of septic shock. We studied differences in outcomes of patients with sepsis and septic shock who required source control intervention compared with those who did not need such intervention and the effect of the timing of source control on various clinical outcomes. DESIGN: Prospective observational study from February 28, 2020, to March 31, 2021. SETTING: Medical ICU of academic quaternary medical center. PATIENTS: Two hundred five adult (≥18 yr) ICU patients. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Patients were divided into a medical treatment group and a source control group. Patients requiring source control were further divided into early (intervention performed < 24 hr) and late (≥ 24 hr) source control groups. The primary outcomes were 30-day and ICU mortality. Secondary outcomes were ICU and hospital length of stay (LOS), days on mechanical ventilation, and need for renal replacement therapy. A total of 45.9% patients underwent source control. Of these, early source control was performed in 44.7% and late source control in 55.3% of patients. There was no significant difference in 30-day mortality or ICU mortality in the medical versus source control groups or in early versus late source control groups. Compared with the medical group, mean hospital LOS (11.5 vs 17.4 d; p < 0.01) and ICU LOS (5.2 vs 7.7 d; p < 0.01) were longer in the source control group. The hospital LOS (12.5 vs 21.4 d; p < 0.01) and ICU LOS (5.2 vs 9.7 d; p < 0.01) were also longer in patients who had delayed source control than in patients who had early source control. There were no significant differences in other outcomes. CONCLUSIONS: Although mortality was similar, patients who had delayed source control had a longer ICU and hospital LOS. Early source control may improve health care utilization in septic shock patients.

Mitochondrial membranes modify mutant huntingtin aggregation.

Huntington's disease (HD) is a neurodegenerative disease caused by the expansion of a polyglutamine (polyQ) tract near the N-terminus of the huntingtin (htt) protein. Expanded polyQ tracts are prone to aggregate into oligomers and insoluble fibrils. Mutant htt (mhtt) localizes to variety of organelles, including mitochondria. Specifically, mitochondrial defects, morphological alteration, and dysfunction are observed in HD. Mitochondrial lipids, cardiolipin (CL) in particular, are essential in mitochondria function and have the potential to directly interact with htt, altering its aggregation. Here, the impact of mitochondrial membranes on htt aggregation was investigated using a combination of mitochondrial membrane mimics and tissue-derived mitochondrial-enriched fractions. The impact of exposure of outer and inner mitochondrial membrane mimics (OMM and IMM respectively) to mhtt was explored. OMM and IMM reduced mhtt fibrillization, with IMM having a larger effect. The role of CL in mhtt aggregation was investigated using a simple PC system with varying molar ratios of CL. Lower molar ratios of CL (<5%) promoted fibrillization; however, increased CL content retarded fibrillization. As revealed by in situ AFM, mhtt aggregation and associated membrane morphological changes at the surface of OMM mimics was markedly different compared to IMM mimics. While globular deposits of mhtt with few fibrillar aggregates were observed on OMM, plateau-like domains were observed on IMM. A similar impact on htt aggregation was observed with exposure to purified mitochondrial-enriched fractions. Collectively, these observations suggest mitochondrial membranes heavily influence htt aggregation with implication for HD.

Utility of FDG PET/CT for assessment of lung nodules identified during low dose computed tomography screening.

BACKGROUND: Many clinical guidelines recommend FDG PET/CT for the evaluation of pulmonary nodules ≥8 mm detected during low dose computed tomography (LDCT) lung cancer screening. However, its added value in this setting requires confirmation. We evaluated the clinical utility of FDG PET/CT, including incidental findings, during the evaluation of lung nodules detected on LDCT screening. METHODS: A retrospective cohort study was performed among 75 patients who completed FDG PET/CT between January 2010 and December 2017, after lung nodules > 8 mm had been detected on LDCT lung cancer screening. We report demographic variables, characteristics of the initial nodules on LDCT and FDG PET/CT, incidental findings on FDG PET/CT, as well as further work up performed and the influence of FDG PET/CT findings on management. RESULTS: Nodules were reported to be benign on FDG PET/CT in 38/75 (50.6%) patients. Physicians chose either radiological follow-up or no further work up in all 38. FDG PET/CT was indeterminate or suggested malignancy in 37 (49.3%) patients. Biopsy was performed in 32 (86%) of these patients. Incidental findings on FDG PET/CT were reported in 37/75 (49%) patients. Further work-up of incidental findings was performed in 21/75 (28%) of patients. CONCLUSIONS: In this study, for majority of individuals with lung nodules identified during LDCT lung cancer screening, FDG PET/CT results were able to guide physicians in choosing between routine follow up or invasive biopsies. Conversely, 28% of these patients required additional investigations to address incidental findings.

Sphingomyelin and GM1 Influence Huntingtin Binding to, Disruption of, and Aggregation on Lipid Membranes.

Huntington disease (HD) is an inherited neurodegenerative disease caused by the expansion beyond a critical threshold of a polyglutamine (polyQ) tract near the N-terminus of the huntingtin (htt) protein. Expanded polyQ promotes the formation of a variety of oligomeric and fibrillar aggregates of htt that accumulate into the hallmark proteinaceous inclusion bodies associated with HD. htt is also highly associated with numerous cellular and subcellular membranes that contain a variety of lipids. As lipid homeostasis and metabolism abnormalities are observed in HD patients, we investigated how varying both the sphingomyelin (SM) and ganglioside (GM1) contents modifies the interactions between htt and lipid membranes. SM composition is altered in HD, and GM1 has been shown to have protective effects in animal models of HD. A combination of Langmuir trough monolayer techniques, vesicle permeability and binding assays, and in situ atomic force microscopy (AFM) were used to directly monitor the interaction of a model, synthetic htt peptide and a full-length htt-exon1 recombinant protein with model membranes comprised of total brain lipid extract (TBLE) and varying amounts of exogenously added SM or GM1. The addition of either SM or GM1 decreased htt insertion into the lipid monolayers. However, TBLE vesicles with an increased SM content were more susceptible to htt-induced permeabilization, whereas GM1 had no effect on permeablization. Pure TBLE bilayers and TBLE bilayers enriched with GM1 developed regions of roughened, granular morphologies upon exposure to htt-exon1, but plateau-like domains with a smoother appearance formed in bilayers enriched with SM. Oligomeric aggregates were observed on all bilayer systems regardless of induced morphology. Collectively, these observations suggest that the lipid composition and its subsequent effects on membrane material properties strongly influence htt binding and aggregation on lipid membranes.

Cholesterol Modifies Huntingtin Binding to, Disruption of, and Aggregation on Lipid Membranes.

Huntington's disease (HD) is an inherited neurodegenerative disease caused by abnormally long CAG-repeats in the huntingtin gene that encode an expanded polyglutamine (polyQ) domain near the N-terminus of the huntingtin (htt) protein. Expanded polyQ domains are directly correlated to disease-related htt aggregation. Htt is found highly associated with a variety of cellular and subcellular membranes that are predominantly comprised of lipids. Since cholesterol homeostasis is altered in HD, we investigated how varying cholesterol content modifies the interactions between htt and lipid membranes. A combination of Langmuir trough monolayer techniques, vesicle permeability and binding assays, and in situ atomic force microscopy were used to directly monitor the interaction of a model, synthetic htt peptide and a full-length htt-exon1 recombinant protein with model membranes comprised of total brain lipid extract (TBLE) and varying amounts of exogenously added cholesterol. As the cholesterol content of the membrane increased, the extent of htt insertion decreased. Vesicles containing extra cholesterol were resistant to htt-induced permeabilization. Morphological and mechanical changes in the bilayer associated with exposure to htt were also drastically altered by the presence of cholesterol. Disrupted regions of pure TBLE bilayers were grainy in appearance and associated with a large number of globular aggregates. In contrast, morphological changes induced by htt in bilayers enriched in cholesterol were plateau-like with a smooth appearance. Collectively, these observations suggest that the presence and amount of cholesterol in lipid membranes play a critical role in htt binding and aggregation on lipid membranes.

Identification of novel polyglutamine-expanded aggregation species in spinal and bulbar muscular atrophy.

Polyglutamine-repeat disorders are part of a larger family of neurodegenerative diseases characterized by protein misfolding and aggregation. In spinal and bulbar muscular atrophy (SBMA), polyglutamine expansion within the androgen receptor (AR) causes progressive debilitating muscular atrophy and lower motor neuron loss in males. Although soluble polyglutamine-expanded aggregation species are considered toxic intermediates in the aggregation process, relatively little is known about the spectrum of structures that are formed. Here we identify novel polyglutamine-expanded AR aggregates that are SDS-soluble and bind the toxicity-predicting antibody 3B5H10. Soluble, 3B5H10-reactive aggregation species exist in low-density conformations and are larger by atomic force microscopy, suggesting that they may be less compact than later-stage, insoluble aggregates. We demonstrate disease-relevance in vivo and draw correlations with toxicity in vitro. This article is part of a Special Issue entitled SI: Neuroprotection.

Detection of Clostridium difficile toxin: comparison of enzyme immunoassay results with results obtained by cytotoxicity assay.

Several kinds of laboratory techniques are available to detect Clostridium difficile toxin in fecal samples. Because questions have been raised about the reliability of immunoassays compared to the accepted standard, cytotoxicity assay, we studied three enzyme immunoassays (EIAs) and one rapid EIA, which demonstrated relatively good sensitivities and specificities compared to cytotoxicity assay.