Hospital episode-of-care costs for hip fractures: an activity-based costing analysis.

Background: Despite the large impact of hip fracture care on hospital budgets, accurate episode-of-care costs (EOCC) calculations for this injury remains a challenge. The objective of this article was to assess EOCC for geriatric patients with hip fractures using an activity-based costing methodology and identify intraoperative, perioperative, and patient-specific factors associated with higher EOCC. Material and Methods: This is a retrospective cohort study involving a total of 109 consecutive patients with hip fracture treated surgically at a Canadian level-1 trauma center from April 2018 to February 2019. Clinical and demographic data were extracted through the institution's centralized data warehouse. Data acquisition also included direct and indirect costs per episode of care, adverse events, and precise temporal data. Results: The median total EOCC was $13,113 (interquartile range 6658), excluding physician fees. Out of the total cost, 75% was attributed to direct costs, which represented a median expenditure of $9941. The median indirect cost of the EOCC was $3322. Based on the multivariate analysis, patients not operated within the 48 hours guidelines had an increased length of stay by 5.7 days (P = 0.003), representing an increase in EOCC of close to 5000$. Higher American Society of Anesthesiology (ASA) scores were associated with elevated EOCC. Conclusion: The cost of managing a patient with geriatric hip fracture from arrival in the emergency department to discharge from surgical ward represented $13,113. Main factors influencing the EOCC included adherence to the 48-hour benchmark surgical delay and ASA score. High-quality costing data are vital in assessing health care spending, conducting cost effectiveness analyses, and ultimately in guiding policy decisions. Level of Evidence: Level III (3), retrospective cohort study.

Postfasciotomy Classification System for Acute Compartment Syndrome of the Leg.

OBJECTIVE: Acute compartment syndrome (ACS) is a true emergency. Even with urgent fasciotomy, there is often muscle damage and need for further surgery. Although ACS is not uncommon, no validated classification system exists to aid in efficient and clear communication. The aim of this study was to establish and validate a classification system for the consequences of ACS treated with fasciotomy. METHODS: Using a modified Delphi method, an international panel of ACS experts was assembled to establish a grading scheme for the disease and then validate the classification system. The goal was to articulate discrete grades of ACS related to fasciotomy findings and associated costs. A pilot analysis was used to determine questions that were clear to the respondents. Discussion of this analysis resulted in another round of cases used for 24 other raters. The 24 individuals implemented the classification system 2 separate times to compare outcomes for 32 clinical cases. The accuracy and reproducibility of the classification system were subsequently calculated based on the providers' responses. RESULTS: The Fleiss Kappa of all raters was at 0.711, showing a strong agreement between the 24 raters. Secondary validation was performed for paired 276 raters and correlation was tested using the Kendall coefficient. The median correlation coefficient was 0.855. All 276 pairs had statistically significant correlation. Correlation coefficient between the first and second rating sessions was strong with the median pair scoring at 0.867. All surgeons had statistically significant internal consistency. CONCLUSION: This new ACS classification system may be applied to better understand the impact of ACS on patient outcomes and economic costs for leg ACS.

ICOS costimulation is indispensable for the differentiation of T follicular regulatory cells.

ICOS is a T-cell costimulatory receptor critical for Tfh cell generation and function. However, the role of ICOS in Tfr cell differentiation remains unclear. Using Foxp3-Cre-mediated ICOS knockout (ICOS FC) mice, we show that ICOS deficiency in Treg-lineage cells drastically reduces the number of Tfr cells during GC reactions but has a minimal impact on conventional Treg cells. Single-cell transcriptome analysis of Foxp3+ cells at an early stage of the GC reaction suggests that ICOS normally inhibits Klf2 expression to promote follicular features including Bcl6 up-regulation. Furthermore, ICOS costimulation promotes nuclear localization of NFAT2, a known driver of CXCR5 expression. Notably, ICOS FC mice had an unaltered overall GC B-cell output but showed signs of expanded autoreactive B cells along with elevated autoantibody titers. Thus, our study demonstrates that ICOS costimulation is critical for Tfr cell differentiation and highlights the importance of Tfr cells in maintaining humoral immune tolerance during GC reactions.

Predictors of Foot Acute Compartment Syndrome: Big Data analysis.

Acute compartment syndrome (ACS) in the foot is a challenging diagnosis and can lead to significant disabilities to patients. The present study aims to investigate the incidence, risk factors, demographics and association in the analysis of acute compartment syndrome (ACS) of the foot. We performed a retrospective review of the Trauma Quality Programs data from the American College of Surgeons including 70,525 patients who sustained a fracture of the foot from 2015 to 2018 (4 calendar years). Fasciotomies were performed in 0.7% of all foot fractures. Open fractures, crush injuries and multiple foot fractures were the strongest predictors of fasciotomies, with odds ratios of 2.38, 2.38 and 2.33 respectively. Being a male was associated with an increased likelihood of fasciotomies of 64% (p < .0001 O.R. = [1.42-1.90]), while a dislocation in the foot increased likelihood of fasciotomies by 48% (p = .0008 O.R. = [1.18-1.86]). Trauma centre level III had higher rate of fasciotomy than Tertiary Trauma centers. Multiple other factors were addressed while controlling for cofounders. This big data analysis provided information not previously reported on the risk factors, demographics, and clinical association of ACS in the foot.

ICOS-Deficient Regulatory T Cells Can Prevent Spontaneous Autoimmunity but Are Impaired in Controlling Acute Inflammation.

ICOS is induced in activated T cells and its main role is to boost differentiation and function of effector T cells. ICOS is also constitutively expressed in a subpopulation of Foxp3+ regulatory T cells under steady-state condition. Studies using ICOS germline knockout mice or ICOS-blocking reagents suggested that ICOS has supportive roles in regulatory T (Treg) cell homeostasis, migration, and function. To avoid any compounding effects that may arise from ICOS-deficient non-Treg cells, we generated a conditional knockout system in which ICOS expression is selectively abrogated in Foxp3-expressing cells (ICOS FC mice). Compared to Foxp3-Cre control mice, ICOS FC mice showed a minor numerical deficit of steady-state Treg cells but did not show any signs of spontaneous autoimmunity, indicating that tissue-protective Treg populations do not heavily rely on ICOS costimulation. However, ICOS FC mice showed more severe inflammation in oxazolone-induced contact hypersensitivity, a model of atopic dermatitis. This correlated with elevated numbers of inflammatory T cells expressing IFN-γ and/or TNF-α in ICOS FC mice compared with the control group. In contrast, elimination of ICOS in all T cell compartments negated the differences, confirming that ICOS has a dual positive role in effector and Treg cells. Single-cell transcriptome analysis suggested that ICOS-deficient Treg cells fail to mature into T-bet+CXCR3+ "Th1-Treg" cells in the draining lymph node. Our results suggest that regimens that preferentially stimulate ICOS pathways in Treg cells might be beneficial for the treatment of Th1-driven inflammation.

Big data insights into predictors of acute compartment syndrome.

BACKGROUND: There remain gaps in knowledge regarding the pathophysiology, initial diagnosis, treatment, and outcome of acute compartment syndrome (ACS). Most reported clinical outcomes are from smaller studies of heterogeneous patients. For a disease associated with a financial burden to society that represents billions of dollars worldwide the literature does not currently establish baseline diagnostic parameters and risk factors that may serve to predict treatment and outcomes. METHODS: This study looks at a very large cohort of trauma patients obtained from four recent years of the Trauma Quality Programs data from the American College of Surgeons. From 3,924,127 trauma cases - 203,500 patients with tibial fractures were identified and their records examined for demographic information, potential risk factors for compartment syndrome, an associated coded diagnosis of muscle necrosis, and presence of other outcomes associated with compartment syndrome. A recurrent multiple logistic regression model was used to identify factors predictive of fasciotomy. The results were compared to the reported results from the literature to validate the findings. RESULTS: The rate of fasciotomy treatment for ACS was 4.3% in the cohort of identified patients. The analysis identified several clinical predictors of fasciotomy. Proximal and midshaft tibial fractures (P <0.0001) showed highest increases in the likelihood of ACS. Open fractures were twice (O.R [2.20-2.42]) as likely to have ACS. Having a complex fracture (P<0.0001), substance abuse disorder (P<0.0002), cirrhosis (P = 0.002) or smoking (P<0.0051) all increased the likelihood of ACS. Age decreased the likelihood by 1% per year (OR= [0.99-0.993]). Crush and penetrating injuries showed an important increase in the likelihood of ACS (O.R of 1.83 and 1.37 respectively). Additionally, sex, BMI, cirrhosis, tobacco smoking and fracture pattern as defined by OTA group and OTA subgroup had predictive value on actual myonecrosis. Fasciotomies for open tibial fractures were more likely to uncover significant muscle necrosis compared to closed fractures. Amputation resulted after 5.4% of fasciotomies. CONCLUSION: This big data approach shows us that ACS is primarily linked to the extent of soft tissue damage. However, newfound effect of some comorbidities like cirrhosis and hypertension on the risk of ACS imply other mechanisms.

Acute Compartment Syndrome Modeling with Sequential Infusion Shows the Deep Posterior Compartment Is Not Functionally Discrete.

BACKGROUND: Clinical case series have indicated that 1 or 2-compartment decompression of the anterior or lateral leg may be sufficient for release, but, currently, no cadaveric model has verified that approach. The objective of this study was to investigate the functional relationship between compartments by alternating sequences of infusion and fasciotomy release. METHODS: This study utilized multicompartment sequential pressurization with simultaneous monitoring by continuous pressure sensors to model compartment syndrome in a human cadaver leg. Subsequent sequential release of compartments and continuous streaming of pressure readings permitted unique insights. RESULTS: A leg model allowed the examination of pressure changes in all 4 compartments as treated with sequential fasciotomies. The successful modeling of lower-leg pressures consistent with compartment syndrome showed that discrepancies relative to accepted concepts were seen when the deep posterior compartment was pressurized in isolation. Also, release of 1 of the 2 of either the anterior or lateral compartments seems to be sufficient for decompression to acceptable pressure levels. CONCLUSIONS: The deep posterior compartment does not appear to be completely discrete and instead follows the pressurization curve of the posterior muscle group. This indicates that release of the deep posterior compartment may not be needed in all acute compartment syndrome scenarios. CLINICAL RELEVANCE: Surgical techniques can be modified for treatment of acute compartment syndrome to avoid large scar lengths, deep dissection, and multiple exposures that could improve patient outcomes.

Hippo Signal Transduction Mechanisms in T Cell Immunity.

Hippo signaling pathways are evolutionarily conserved signal transduction mechanisms mainly involved in organ size control, tissue regeneration, and tumor suppression. However, in mammals, the primary role of Hippo signaling seems to be regulation of immunity. As such, humans with null mutations in STK4 (mammalian homologue of Drosophila Hippo; also known as MST1) suffer from recurrent infections and autoimmune symptoms. Although dysregulated T cell homeostasis and functions have been identified in MST1-deficient human patients and mouse models, detailed cellular and molecular bases of the immune dysfunction remain to be elucidated. Although the canonical Hippo signaling pathway involves transcriptional co-activator Yes-associated protein (YAP) or transcriptional coactivator with PDZ motif (TAZ), the major Hippo downstream signaling pathways in T cells are YAP/TAZ-independent and they widely differ between T cell subsets. Here we will review Hippo signaling mechanisms in T cell immunity and describe their implications for immune defects found in MST1-deficient patients and animals. Further, we propose that mutual inhibition of Mst and Akt kinases and their opposing roles on the stability and function of forkhead box O and ß-catenin may explain various immune defects discovered in mutant mice lacking Hippo signaling components. Understanding these diverse Hippo signaling pathways and their interplay with other evolutionarily-conserved signaling components in T cells may uncover molecular targets relevant to vaccination, autoimmune diseases, and cancer immunotherapies.

HOX13-dependent chromatin accessibility underlies the transition towards the digit development program.

Hox genes encode transcription factors (TFs) that establish morphological diversity in the developing embryo. The similar DNA-binding motifs of the various HOX TFs contrast with the wide-range of HOX-dependent genetic programs. The influence of the chromatin context on HOX binding specificity remains elusive. Here, we used the developing limb as a model system to compare the binding specificity of HOXA13 and HOXD13 (HOX13 hereafter), which are required for digit formation, and HOXA11, involved in forearm/leg development. We find that upon ectopic expression in distal limb buds, HOXA11 binds sites normally HOX13-specific. Importantly, these sites are loci whose chromatin accessibility relies on HOX13. Moreover, we show that chromatin accessibility specific to the distal limb requires HOX13 function. Based on these results, we propose that HOX13 TFs pioneer the distal limb-specific chromatin accessibility landscape for the proper implementation of the distal limb developmental program.

Progression of AITL-like tumors in mice is driven by Tfh signature proteins and T-B cross talk.

Angioimmunoblastic T-cell lymphoma (AITL) is an aggressive peripheral T-cell lymphoma driven by a pool of neoplastic cells originating from T follicular helper (Tfh) cells and concomitant expansion of B cells. Conventional chemotherapies for AITL have shown limited efficacy, and as such, there is a need for improved therapeutic options. Because AITL originates from Tfh cells, we hypothesized that AITL tumors continue to rely on essential Tfh components and intimate T-cell-B-cell (T-B) interactions. Using a spontaneous AITL mouse model (Roquinsan/+ mice), we found that acute loss of Bcl6 activity in growing tumors drastically reduced tumor size, demonstrating that AITL-like tumors critically depend on the Tfh lineage-defining transcription factor Bcl6. Because Bcl6 can upregulate expression of signaling lymphocytic activation molecule-associated protein (SAP), which is known to promote T-B conjugation, we next targeted the SAP-encoding Sh2d1a gene. We observed that Sh2d1a deletion from CD4+ T cells in fully developed tumors also led to tumor regression. Further, we provide evidence that tumor progression depends on T-B cross talk facilitated by SAP and high-affinity LFA-1. In our study, AITL-like tumors relied heavily on molecular pathways that support Tfh cell identity and T-B collaboration, revealing potential therapeutic targets for AITL.