Inconsistencies in graft osteoconduction and osteoinduction present a clinical challenge in regeneration of large bone defects. Deposition of decellularized extracellular matrix (dECM) on tissue engineered scaffolds offers an alternative approach that can enhance these properties by mimicking bone's molecular complexity and direct infiltrating cells to repair damaged bone. However, dECMs derived from homogenous cell populations do not adequately simulate the heterogeneous and vascularized microenvironment of the bone. In this study, successive culture and decellularization of fibroblasts and endothelial cells (ECs) grown on polycaprolactone microfibers was used to develop a bioactive scaffold with heterogeneous dECM mimicking endothelial basement membrane. These scaffolds had greater amount of protein and minimally increased nucleic acid content than scaffolds with homogenous culture dECM. Coomassie Blue and antibody staining revealed extensive tube formation by ECs on fibroblast dECM. Fibroblast/endothelial dECM significantly enhanced osteoblast attachment, alkaline phosphatase activity, and osteocalcin-and osteopontin-positive extracellular mineral deposits. We demonstrated that the osteoconduction of dECMs can be tailored with the appropriate combination of cells to accelerate osteoblast mineral secretion. The overall concept can be expanded to generate increasingly more complex tissue constructs for regeneration of bone defects and other vascularized tissues. K E Y W O R D S bone tissue engineering, decellularization, extracellular matrix, osteoblasts, vascularization
RATIONALE Severe inflammation is thought to drive disease severity in patients with COVID-19. Proposed treatments include corticosteroids and tocilizumab. Corticosteroids have demonstrated outcome benefit in patients with severe ARDS 1,2 . Tocilizumab (an interleukin-6 receptor antibody) is theorized to block the inflammatory cascade 3 . Variable steroid administration for COVID-19 illness stemmed from the possibility of increased viral shedding and limited survival benefit noted from other Coronavirus strains 4 . Lack of standardization for tocilizumab and corticosteroid administration leaves retrospective study prone to confounding and bias; therefore, we proposed using causal analysis to better determine treatment efficacy. In clinical observational studies, it is only possible to observe an individual participant under one treatment scenario, whereas the counterfactual (alternate) outcome is unknown 5 . Targeted Maximum Likelihood Estimator (TMLE) generates two matched subject populations using assigned weights to create a pseudo-population that models counterfactual outcomes while limiting confounding bias 6 . The causal analysis objective was to elucidate the Average Treatment Effect (ATE) for steroids and tocilizumab to reduce mortality in adult patients with COVID-19. METHODS A retrospective review of adult patients with COVID-19 admitted to an ICU between March 2020 and June 2020. The primary outcome was ICU mortality. We used TMLE with an ensemble of machine learning algorithms as the primary model 7 . The machine learning ensemble included Logistic Regression, a Neural Network, Naive Bayes, and XGboost 8 . The analysis was performed on corticosteroid and tocilizumab administration separately. The covariates included for the corticosteroid group were age, ethnicity, oxygen support level, and tocilizumab treatment. The tocilizumab analysis covariates included age, ethnicity, oxygen support, ECMO, and treatment with corticosteroids. Our primary metric was Average Treatment Effect (ATE). Secondary metrics are Odds Ratio and Risk Ratio. RESULTS Using TMLE, mortality analysis on the corticosteroids group (n=199) demonstrated an ATE (RD) of -0.259, 95% CI [-0.387 , -0.13], risk ratio (RR) 0.512, 95% CI [0.364, 0.72] and odds ratio (OR) of 0.33 [0.188, 0.581]. The tocilizumab group (n=199) demonstrated an ATE (RD) of 0.104, 95% CI [-0.025, 0.232], RR 1.343, 95% CI [0.916, 1.97] and OR of 1.578 [0.885 -2.813].CONCLUSION Causal analysis is a useful analysis model to evaluate treatment effects. In this cohort of adult patients with COVID-19, tocilizumab did not demonstrate a mortality difference, whereas corticosteroids were associated with decreased mortality.
Thyrotoxic Periodic Paralysis (TPP) is a rare manifestation of thyrotoxicosis, resulting in periodic episodes of acute onset muscle weakness in the setting of hypokalemia. The thyrotoxic form of Hypokalemic Periodic Paralysis (HPP) is less studied than the more well-known familial form due to fewer reported cases and smaller prevalence. This case study presents a 30-year-old African American male with multiple episodes of acute lower extremity muscle weakness, tachycardia, and a history of heat intolerance. Abnormal findings on thyroid ultrasound coupled with increased thyroid related immunoglobulins led to a diagnosis of TPP related to exacerbation of newly-found Graves’ disease. The case study will further discuss the importance of imaging in assessing the etiology of TPP with review of relevant literature.
Bundled Payments for Care Improvement-Advanced Program (BPCI-A) is designed to pay a single payment covering services provided during an episode of care. Sepsis is associated with increased readmissions, mortality, and health care costs. The purpose of the study was to evaluate the BPCI program patients with sepsis who were readmitted within 90 days versus not readmitted. This was a retrospective cohort study including 271 (110 readmitted) patients enrolled in the BPCI program with Diagnostic-Related Grouping codes of septicemia or severe sepsis. Skin/soft tissue infection was the most common infection. There was a significant difference between the groups for resource needs at discharge including wound care (25.45% versus 11.18%; P = 0.002) and physical therapy (74.55% versus 57.14%; P = 0.004). Mortality was higher among readmissions, 43.64% versus 26.71% no readmission (P = 0.004). Identifying risk factors for readmission, providing appropriate resources, and follow-up may contribute to improved patient outcomes for patients with sepsis enrolled in the BPCI program.
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