Obstructive sleep apnea as an independent predictor of postoperative delirium and pain: Protocol for an observational study of a surgical cohort [version 2; referees: 2 approved]

Introduction: Postoperative delirium and pain are common complications in adults, and are difficult both to prevent and treat. Obstructive sleep apnea (OSA) is prevalent in surgical patients, and has been suggested to be a risk factor for postoperative delirium and pain. OSA also might impact pain perception, and alter pain medication requirements. This protocol describes an observational study, with the primary aim of testing whether OSA is an independent predictor of postoperative complications, focusing on (i) postoperative incident delirium and (ii) acute postoperative pain severity. We secondarily hypothesize that compliance with prescribed treatment for OSA (typically continuous positive airway pressure or CPAP) might decrease the risk of delirium and the severity of pain. Methods and analysis: We will include data from patients who have been enrolled into three prospective studies: ENGAGES, PODCAST, and SATISFY-SOS. All participants underwent general anesthesia for a non-neurosurgical inpatient operation, and had a postoperative hospital stay of at least one day at Barnes Jewish Hospital in St. Louis, Missouri, from February 2013 to May 2018.  Patients included in this study have been assessed for postoperative delirium and pain severity as part of the parent studies. In the current study, determination of delirium diagnosis will be based on the Confusion Assessment Method, and the Visual Analogue Pain Scale will be used for pain severity. Data on OSA diagnosis, OSA risk and compliance with treatment will be obtained from the preoperative assessment record. Other variables that are candidate risk factors for delirium and pain will also be extracted from this record. We will use logistic regression to test whether OSA independently predicts postoperative delirium and linear regression to assess OSAs relationship to acute pain severity. We will conduct secondary analyses with subgroups to explore whether these relationships are modified by compliance with OSA treatment.</ns4:p

A Dendritic-Cell-Stromal Axis Maintains Immune Responses in Lymph Nodes

SummaryWithin secondary lymphoid tissues, stromal reticular cells support lymphocyte function, and targeting reticular cells is a potential strategy for controlling pathogenic lymphocytes in disease. However, the mechanisms that regulate reticular cell function are not well understood. Here we found that during an immune response in lymph nodes, dendritic cells (DCs) maintain reticular cell survival in multiple compartments. DC-derived lymphotoxin beta receptor (LTβR) ligands were critical mediators, and LTβR signaling on reticular cells mediated cell survival by modulating podoplanin (PDPN). PDPN modulated integrin-mediated cell adhesion, which maintained cell survival. This DC-stromal axis maintained lymphocyte survival and the ongoing immune response. Our findings provide insight into the functions of DCs, LTβR, and PDPN and delineate a DC-stromal axis that can potentially be targeted in autoimmune or lymphoproliferative diseases

Biomaterial Hypersensitivity: Is It Real? Supportive Evidence and Approach Considerations for Metal Allergic Patients following Total Knee Arthroplasty

The prospect of biomaterial hypersensitivity developing in response to joint implant materials was first presented more than 30 years ago. Many studies have established probable causation between first-generation metal-on-metal hip implants and hypersensitivity reactions. In a limited patient population, implant failure may ultimately be related to metal hypersensitivity. The examination of hypersensitivity reactions in current-generation metal-on-metal knee implants is comparatively limited. The purpose of this study is to summarize all available literature regarding biomaterial hypersensitivity after total knee arthroplasty, elucidate overall trends about this topic in the current literature, and provide a foundation for clinical approach considerations when biomaterial hypersensitivity is suspected

Biomaterial Hypersensitivity: Is It Real? Supportive Evidence and Approach Considerations for Metal Allergic Patients following Total Knee Arthroplasty

The prospect of biomaterial hypersensitivity developing in response to joint implant materials was first presented more than 30 years ago. Many studies have established probable causation between first-generation metal-on-metal hip implants and hypersensitivity reactions. In a limited patient population, implant failure may ultimately be related to metal hypersensitivity. The examination of hypersensitivity reactions in current-generation metal-on-metal knee implants is comparatively limited. The purpose of this study is to summarize all available literature regarding biomaterial hypersensitivity after total knee arthroplasty, elucidate overall trends about this topic in the current literature, and provide a foundation for clinical approach considerations when biomaterial hypersensitivity is suspected

Interim analysis results from the RESTORE-CLI, a randomized, double-blind multicenter phase II trial comparing expanded autologous bone marrow-derived tissue repair cells and placebo in patients with critical limb ischemia

Cell therapy is a novel experimental treatment modality for patients with critical limb ischemia (CLI) of the lower extremities and no other established treatment options. This study was conducted to assess the safety and clinical efficacy of intramuscular injection of autologous tissue repair cells (TRCs).A prospective, randomized double-blinded, placebo controlled, multicenter study (RESTORE-CLI) was conducted at 18 centers in the United States in patients with CLI and no option for revascularization. Enrollment of 86 patients began in April 2007 and ended in February 2010. For the prospectively planned interim analysis, conducted in February 2010, 33 patients had the opportunity to complete the trial (12 months of follow-up), and 46 patients had completed at least 6 months of follow-up. The interim analysis included analysis of both patient populations. An independent physician performed the bone marrow or sham control aspiration. The aspirate was processed in a closed, automated cell manufacturing system for approximately 12 days to generate the TRC population of stem and progenitor cells. An average of 136 ± 41 × 10 total viable cells or electrolyte (control) solution were injected into 20 sites in the ischemic lower extremity. The primary end point was safety as evaluated by adverse events, and serious adverse events as assessed at multiple follow-up time points. Clinical efficacy end points included major amputation-free survival and time to first occurrence of treatment failure (defined as any of the following: major amputation, death, de novo gangrene, or doubling of wound size), as well as major amputation rate and measures of wound healing.There was no difference in adverse or serious adverse events between the two groups. Statistical analysis revealed a significant increase in time to treatment failure (log-rank test, = .0053) and amputation-free survival in patients receiving TRC treatment, (log-rank test, = .038). Major amputation occurred in 19% of TRC-treated patients compared to 43% of controls ( = .14, Fisher exact test). There was evidence of improved wound healing in the TRC-treated patients when compared with controls at 12 months.Intramuscular injection of autologous bone marrow-derived TRCs is safe and decreases the occurrence of clinical events associated with disease progression when compared to placebo in patients with lower extremity CLI and no revascularization options

Phase I Trial of Single-Photon Emission Computed Tomography-Guided Liver-Directed Radiotherapy for Patients With Low Functional Liver Volume

BACKGROUND: Traditional constraints specify that 700 cc of liver should be spared a hepatotoxic dose when delivering liver-directed radiotherapy to reduce the risk of inducing liver failure. We investigated the role of single-photon emission computed tomography (SPECT) to identify and preferentially avoid functional liver during liver-directed radiation treatment planning in patients with preserved liver function but limited functional liver volume after receiving prior hepatotoxic chemotherapy or surgical resection. METHODS: This phase I trial with a 3 + 3 design evaluated the safety of liver-directed radiotherapy using escalating functional liver radiation dose constraints in patients with liver metastases. Dose-limiting toxicities were assessed 6-8 weeks and 6 months after completing radiotherapy. RESULTS: All 12 patients had colorectal liver metastases and received prior hepatotoxic chemotherapy; 8 patients underwent prior liver resection. Median computed tomography anatomical nontumor liver volume was 1584 cc (range = 764-2699 cc). Median SPECT functional liver volume was 1117 cc (range = 570-1928 cc). Median nontarget computed tomography and SPECT liver volumes below the volumetric dose constraint were 997 cc (range = 544-1576 cc) and 684 cc (range = 429-1244 cc), respectively. The prescription dose was 67.5-75 Gy in 15 fractions or 75-100 Gy in 25 fractions. No dose-limiting toxicities were observed during follow-up. One-year in-field control was 57%. One-year overall survival was 73%. CONCLUSION: Liver-directed radiotherapy can be safely delivered to high doses when incorporating functional SPECT into the radiation treatment planning process, which may enable sparing of lower volumes of liver than traditionally accepted in patients with preserved liver function. TRIAL REGISTRATION: NCT02626312

Normalization of the Lymph Node T Cell Stromal Microenvironment in lpr/lpr Mice Is Associated with SU5416-Induced Reduction in Autoantibodies

The vascular-stromal elements of lymph nodes can play important roles in regulating the activities of the lymphocytes within. During model immune responses, the vascular-stromal compartment has been shown to undergo proliferative expansion and functional alterations. The state of the vascular-stromal compartment and the potential importance of this compartment in a spontaneous, chronic model of autoimmunity have not been well studied. Here, we characterize the vascular expansion in MRL-lpr/lpr lymph nodes and attempt to ask whether inhibiting this expansion can interfere with autoantibody generation. We show that characteristics of vascular expansion in enlarging MRL-lpr/lpr lymph nodes resemble that of the VEGF-dependent expansion that occurs in wild-type mice after model immunization. Surprisingly, treatment with SU5416, an inhibitor of VEGF and other receptor tyrosine kinases, did not have sustained effects in inhibiting vascular growth, but attenuated the anti-dsDNA response and altered the phenotype of the double negative T cells that are expanded in these mice. In examining for anatomic correlates of these immunologic changes, we found that the double negative T cells are localized within ectopic follicles around a central B cell patch and that these T cell-rich areas lack the T zone stromal protein ER-TR7 as well as other elements of a normal T zone microenvironment. SU5416 treatment disrupted these follicles and normalized the association between T zone microenvironmental elements and T cell-rich areas. Recent studies have shown a regulatory role for T zone stromal elements. Thus, our findings of the association of anti-dsDNA responses, double negative T cell phenotype, and altered lymphocyte microenvironment suggest the possibility that lymphocyte localization in ectopic follicles protects them from regulation by T zone stromal elements and functions to maintain autoimmune responses. Potentially, altering the lymphocyte microenvironment that is set up by the vascular-stromal compartment can be a means by which to control undesired autoimmune responses