Rare cases of Talaromyces pneumonia in individuals with underlying cancer and no travel to endemic areas.

Introduction: Talaromyces marneffei causes a systemic fungal infection, referred to as talaromycosis, in immunocompromised individuals. Talaromycosis is an AIDS (acquired immunodeficiency syndrome) defining illness for patients living in the Southeast Asian region. Here we present two rarely reported cases of pulmonary talaromycosis in Southern California in patients with active cancer, negative HIV status, and no prior travel history to endemic regions. Case description: Case 1: A 76-year-old male with a past medical history of emphysema and latent tuberculosis status post rifampin treatment, presented with a necrotic lung mass. He was diagnosed with squamous cell lung carcinoma and bronchoalveolar lavage cultures grew Talaromyces marneffei. He had no animal exposure or prior travel history to Asia. Due to a transfusion reaction to liposomal amphotericin (the mainstay of treatment), he required a transition to posaconazole. He was HIV-negative and expired due to underlying cancer and infection complications.Case2: A 63-year-old male with a past medical history of tuberculosis, diabetes, and cavitary pneumonia with bronchoscopy positive for Talaromyces presented with worsening back pain and was found to have multiple sites of poorly differentiated adenocarcinoma likely originating from gastric adenocarcinoma. He was HIV-negative and expired due to complications from underlying cancer and infection. Conclusion: We demonstrate that patients with pulmonary Talaromyces are becoming more prominent outside of endemic areas even in the setting of no prior travel. In addition, since patients with this infection are severely immunosuppressed, they require extensive workup for other comorbidities such as possible underlying cancer or tuberculosis.

Patient-provider discussions of bariatric surgery and subsequent weight changes and receipt of bariatric surgery.

OBJECTIVE: The purpose of this study was to determine whether patients who discuss bariatric surgery with their providers are more likely to undergo the procedure and to lose weight. METHODS: A retrospective cohort study of adults with BMI ≥ 35 kg/m2 treated between 2000 and 2015 was conducted to analyze the relationship between a discussion of bariatric surgery in the first year after study entry and weight changes (primary outcome) and receipt of bariatric surgery (secondary outcome) over 2 years after study entry. Natural language processing was used to identify the documentation of bariatric surgery discussion in electronic provider notes. RESULTS: Out of 30,560 study patients, a total of 2,659 (8.7%) discussed bariatric surgery with their providers. The BMI of patients who discussed bariatric surgery decreased by 2.18 versus 0.21 for patients who did not (p < 0.001). In a multivariable analysis, patients who discussed bariatric surgery with their providers lost more weight (by 1.43 [change in BMI]; 95% CI: 1.29-1.57) and had greater odds (10.2; 95% CI: 9.0-11.6; p < 0.001) of undergoing bariatric surgery. CONCLUSIONS: Clinicians rarely discussed bariatric surgery with their patients. Patients who did have this discussion were more likely to lose weight and to undergo bariatric surgery.

CD248 enhances tissue factor procoagulant function, promoting arterial and venous thrombosis in mouse models.

BACKGROUND: CD248 is a pro-inflammatory, transmembrane glycoprotein expressed by vascular smooth muscle cells (VSMC), monocytes/macrophages, and other cells of mesenchymal origin. Its distribution and properties are reminiscent of those of the initiator of coagulation, tissue factor (TF). OBJECTIVE: We examined whether CD248 also participates in thrombosis. METHODS: We evaluated the role of CD248 in coagulation using mouse models of vascular injury, and by assessing its functional interaction with the TF-factor VIIa (FVIIa)-factor X (FX) complex. RESULTS: The time to ferric chloride-induced occlusion of the carotid artery in CD248 knockout (KO) mice was significantly longer than in wild-type (WT) mice. In an inferior vena cava (IVC) stenosis model of thrombosis, lack of CD248 conferred relative resistance to thrombus formation compared to WT mice. Levels of circulating cells and coagulation factors, prothrombin time, activated partial thromboplastin time, and tail bleeding times were similar in both groups. Proximity ligation assays revealed that TF and CD248 are <40 nm apart, suggesting a potential functional relationship. Expression of CD248 by murine and human VSMCs, and by a monocytic cell line, significantly augmented TF-FVIIa-mediated activation of FX, which was not due to differential expression or encryption of TF, altered exposure of phosphatidylserine or differences in tissue factor pathway inhibitor expression. Rather, conformation-specific antibodies showed that CD248 induces allosteric changes in the TF-FVIIa-FX complex that facilitates FX activation by TF-FVIIa. CONCLUSION: CD248 is a newly uncovered protein partner and potential therapeutic target in the TF-FVIIa-FX macromolecular complex that modulates coagulation.

Improving Identification of Patients at Low Risk for Major Cardiac Events After Noncardiac Surgery Using Intraoperative Data.

BACKGROUND/OBJECTIVE: Risk-stratification tools for cardiac complications after noncardiac surgery based on preoperative risk factors are used to inform postoperative management. However, there is limited evidence on whether risk stratification can be improved by incorporating data collected intraoperatively, particularly for low-risk patients. METHODS: We conducted a retrospective cohort study of adults who underwent noncardiac surgery between 2014 and 2018 at four hospitals in the United States. Logistic regression with elastic net selection was used to classify in-hospital major adverse cardiovascular events (MACE) using preoperative and intraoperative data ("perioperative model"). We compared model performance to standard risk stratification tools and professional society guidelines that do not use intraoperative data. RESULTS: Of 72,909 patients, 558 (0.77%) experienced MACE. Those with MACE were older and less likely to be female. The perioperative model demonstrated an area under the receiver operating characteristic curve (AUC) of 0.88 (95% CI, 0.85-0.92). This was higher than the Lee Revised Cardiac Risk Index (RCRI) AUC of 0.79 (95% CI, 0.74-0.84; P < .001 for AUC comparison). There were more MACE complications in the top decile (n = 1,465) of the perioperative model's predicted risk compared with that of the RCRI model (n = 58 vs 43). Additionally, the perioperative model identified 2,341 of 7,597 (31%) patients as low risk who did not experience MACE but were recommended to receive postoperative biomarker testing by a risk factor-based guideline algorithm. CONCLUSIONS: Addition of intraoperative data to preoperative data improved prediction of cardiovascular complication outcomes after noncardiac surgery and could potentially help reduce unnecessary postoperative testing.

Risk Stratification for Postoperative Acute Kidney Injury in Major Noncardiac Surgery Using Preoperative and Intraoperative Data.

Importance: Acute kidney injury (AKI) is one of the most common complications after noncardiac surgery. Yet current postoperative AKI risk stratification models have substantial limitations, such as limited use of perioperative data. Objective: To examine whether adding preoperative and intraoperative data is associated with improved prediction of noncardiac postoperative AKI. Design, Setting, and Participants: A prognostic study using logistic regression with elastic net selection, gradient boosting machine (GBM), and random forest approaches was conducted at 4 tertiary academic hospitals in the United States. A total of 42 615 hospitalized adults with serum creatinine measurements who underwent major noncardiac surgery between January 1, 2014, and April 30, 2018, were included in the study. Serum creatinine measurements from 365 days before and 7 days after surgery were used in this study. Main Outcomes and Measures: Postoperative AKI (defined by the Kidney Disease Improving Global Outcomes within 7 days after surgery) was the primary outcome. The area under the receiver operating characteristic curve (AUC) was used to assess discrimination. Results: Among 42 615 patients who underwent noncardiac surgery, the mean (SD) age was 57.9 (15.7) years, 23 943 (56.2%) were women, 27 857 (65.4%) were white, and the most frequent surgery types were orthopedic (15 718 [36.9%]), general (8808 [20.7%]), and neurologic (6564 [15.4%]). The rate of postoperative AKI was 10.1% (n = 4318). The progressive addition of clinical data improved model performance across all modeling approaches, with GBM providing the highest discrimination by AUC. In GBM models, the AUC increased from 0.712 (95% CI, 0.694-0.731) using prehospitalization variables to 0.804 (95% CI, 0.788-0.819) using preoperative variables (inclusive of prehospitalization variables) (P < .001 for AUC comparison). The AUC further increased to 0.817 (95% CI, 0.802-0.832) when adding intraoperative variables (P < .001 for comparison vs model using preoperative variables). However, the statistically significant improvements in discrimination did not appear to be clinically significant. In particular, the AKI rate among patients classified as high risk improved from 29.1% to 30.0%, a net of 15 patients were appropriately reclassified as high risk, and an additional 15 patients were appropriately reclassified as low risk. Conclusions and Relevance: The findings of the study suggest that electronic health record data may be used to accurately stratify patients at risk of perioperative AKI, but the modest improvements from adding intraoperative data should be weighed against challenges in using intraoperative data.

Model Performance Metrics in Assessing the Value of Adding Intraoperative Data for Death Prediction: Applications to Noncardiac Surgery.

We tested the value of adding data from the operating room to models predicting in-hospital death. We assessed model performance using two metrics, the area under the receiver operating characteristic curve (AUROC) and the area under the precision-recall curve (AUPRC), to illustrate the differences in information they convey in the setting of class imbalance. Data was collected on 74,147 patients who underwent major noncardiac surgery and 112 unique features were extracted from electronic health records. Sets of features were incrementally added to models using logistic regression, naïve Bayes, random forest, and gradient boosted machine methods. AUROC increased as more features were added, but changes were small for some modeling approaches. In contrast, AUPRC, which reflects positive predicted value, exhibited improvements across all models. Using AUPRC highlighted the added value of intraoperative data, not seen consistently with AUROC, and that with class imbalance AUPRC may serve as the more clinically relevant criterion.

Specific loss of adipocyte CD248 improves metabolic health via reduced white adipose tissue hypoxia, fibrosis and inflammation.

BACKGROUND: A positive energy balance promotes white adipose tissue (WAT) expansion which is characterized by activation of a repertoire of events including hypoxia, inflammation and extracellular matrix remodelling. The transmembrane glycoprotein CD248 has been implicated in all these processes in different malignant and inflammatory diseases but its potential impact in WAT and metabolic disease has not been explored. METHODS: The role of CD248 in adipocyte function and glucose metabolism was evaluated by omics analyses in human WAT, gene knockdowns in human in vitro differentiated adipocytes and by adipocyte-specific and inducible Cd248 gene knockout studies in mice. FINDINGS: CD248 is upregulated in white but not brown adipose tissue of obese and insulin-resistant individuals. Gene ontology analyses showed that CD248 expression associated positively with pro-inflammatory/pro-fibrotic pathways. By combining data from several human cohorts with gene knockdown experiments in human adipocytes, our results indicate that CD248 acts as a microenvironmental sensor which mediates part of the adipose tissue response to hypoxia and is specifically perturbed in white adipocytes in the obese state. Adipocyte-specific and inducible Cd248 knockouts in mice, both before and after diet-induced obesity and insulin resistance/glucose intolerance, resulted in increased microvascular density as well as attenuated hypoxia, inflammation and fibrosis without affecting fat cell volume. This was accompanied by significant improvements in insulin sensitivity and glucose tolerance. INTERPRETATION: CD248 exerts detrimental effects on WAT phenotype and systemic glucose homeostasis which may be reversed by suppression of adipocyte CD248. Therefore, CD248 may constitute a target to treat obesity-associated co-morbidities.

Stand-alone lateral lumbar interbody fusion for the treatment of symptomatic adjacent segment degeneration following previous lumbar fusion.

BACKGROUND CONTEXT: Revision posterior decompression and fusion surgery for patients with symptomatic adjacent segment degeneration (ASD) is associated with significant morbidity and is technically challenging. The use of a stand-alone lateral lumbar interbody fusion (LLIF) in patients with symptomatic ASD may prevent many of the complications associated with revision posterior surgery. PURPOSE: The objective of this study was to assess the clinical and radiographic outcomes of patients who underwent stand-alone LLIF for symptomatic ASD. STUDY DESIGN: This is a retrospective case series. PATIENT SAMPLE: We retrospectively reviewed patients with a prior posterior instrumented fusion who underwent a subsequent stand-alone LLIF for ASD by a single surgeon. All patients had at least 18 months of follow-up. Patients were diagnosed with symptomatic ASD if they had a previous lumbar fusion with the subsequent development of back pain, neurogenic claudication, or lower extremity radiculopathy in the setting of imaging, which demonstrated stenosis, spondylolisthesis, kyphosis, or scoliosis at the adjacent level. OUTCOME MEASURES: Patient-reported outcomes were obtained at preoperative and final follow-up visits using the Oswestry Disability Index [ODI], visual analog scale (VAS)-back, and VAS-leg. Radiographic parameters were measured, including segmental and overall lordoses, pelvic incidence-lumbar lordosis mismatch, coronal alignment, and intervertebral disc height. METHODS: Clinical and radiographic outcomes were compared between preoperative and final follow-up using paired t tests. RESULTS: Twenty-five patients met inclusion criteria. The mean age was 62.0±11.3 years. The average follow-up was 34.8±22.4 months. Fifteen (60%) underwent stand-alone LLIF surgery for radicular leg pain, 7 (28%) for symptoms of claudication, and 25 (100.0%) for severe back pain. Oswestry Disability Index scores significantly improved from preoperative values (46.6±16.4) to final follow-up (30.4±16.8, p=.002). Visual analog scale-back (preop 8.4±1.0, postop 3.2±1.9; p<.001), and VAS-leg (preop 3.6±3.4, postop 1.9±2.6; p<.001) scores significantly improved following surgery. Segmental and regional lordoses, as well as intervertebral disc height, significantly improved (p<.001) and remained stable (p=.004) by the surgery. Pelvic incidence-lumbar lordosis mismatch significantly improved at the first postoperative visit (p=.029) and was largely maintained at the most recent follow-up (p=.45). Six patients suffered from new-onset thigh weakness following LLIF surgery, but all showed complete resolution within 6 weeks. Three patients required subsequent additional surgeries, all of which were revised to include posterior instrumentation. CONCLUSIONS: Stand-alone LLIF is a safe and effective approach with low morbidity and acceptable complication rates for patients with symptomatic ASD following a previous lumbar fusion.

A novel 2-stage approach that detects complement activation in patients with antiphospholipid antibody syndrome.

INTRODUCTION: The antiphospholipid syndrome (APS) is marked by autoantibodies that recognize anionic phospholipids in a cofactor-dependent manner. A role for complement has been implicated in the pathophysiology, however, elevations of complement activation markers have not been consistently demonstrated in clinical studies. We therefore designed a proof-of-principle study to determine whether complement activation might be detectable in APS by first exposing plasmas to phospholipid vesicles. METHODS: We examined complement activation markers in patients with APS, non-APS thrombosis, systemic lupus erythematosus, cancer, patients with antiphospholipid antibodies without thrombosis (APL) and healthy controls. Direct measurements of plasma C5a and sC5b-9 levels were compared to levels that were generated in normal serum by phospholipid vesicles that had been pre-incubated with the same plasmas. We then determined the effects of the C5 inhibitor, eculizumab, examined the complement pathways involved, and determined whether the effects could be reproduced with purified IgGs and ß2-glycoprotein I (ß2GPI). RESULTS: Plasma levels of C5a and sC5b-9 were higher, but not significantly increased in APS patients compared to healthy controls. In contrast, phospholipid vesicles pre-incubated with APS plasmas generated significantly higher levels than healthy controls and the other groups, except for APL patients. Complement activation was abrogated by addition of eculizumab. The results with substrate sera indicated that the alternative and classical/lectin pathways were involved. The results were reproducible with purified IgGs and ß2GPI. CONCLUSION: This proof-of-principle study confirms a role for complement in APS and opens the possibility of monitoring complement activation by including phospholipid vesicles in assay systems.

Polyphosphate is a novel cofactor for regulation of complement by a serpin, C1 inhibitor.

The complement system plays a key role in innate immunity, inflammation, and coagulation. The system is delicately balanced by negative regulatory mechanisms that modulate the host response to pathogen invasion and injury. The serpin, C1-esterase inhibitor (C1-INH), is the only known plasma inhibitor of C1s, the initiating serine protease of the classical pathway of complement. Like other serpin-protease partners, C1-INH interaction with C1s is accelerated by polyanions such as heparin. Polyphosphate (polyP) is a naturally occurring polyanion with effects on coagulation and complement. We recently found that polyP binds to C1-INH, prompting us to consider whether polyP acts as a cofactor for C1-INH interactions with its target proteases. We show that polyP dampens C1s-mediated activation of the classical pathway in a polymer length- and concentration-dependent manner by accelerating C1-INH neutralization of C1s cleavage of C4 and C2. PolyP significantly increases the rate of interaction between C1s and C1-INH, to an extent comparable to heparin, with an exosite on the serine protease domain of the enzyme playing a major role in this interaction. In a serum-based cell culture system, polyP significantly suppressed C4d deposition on endothelial cells, generated via the classical and lectin pathways. Moreover, polyP and C1-INH colocalize in activated platelets, suggesting that their interactions are physiologically relevant. In summary, like heparin, polyP is a naturally occurring cofactor for the C1s:C1-INH interaction and thus an important regulator of complement activation. The findings may provide novel insights into mechanisms underlying inflammatory diseases and the development of new therapies.

TGFß-mediated suppression of CD248 in non-cancer cells via canonical Smad-dependent signaling pathways is uncoupled in cancer cells.

BACKGROUND: CD248 is a cell surface glycoprotein, highly expressed by stromal cells and fibroblasts of tumors and inflammatory lesions, but virtually undetectable in healthy adult tissues. CD248 promotes tumorigenesis, while lack of CD248 in mice confers resistance to tumor growth. Mechanisms by which CD248 is downregulated are poorly understood, hindering the development of anti-cancer therapies. METHODS: We sought to characterize the molecular mechanisms by which CD248 is downregulated by surveying its expression in different cells in response to cytokines and growth factors. RESULTS: Only transforming growth factor (TGFß) suppressed CD248 protein and mRNA levels in cultured fibroblasts and vascular smooth muscle cells in a concentration- and time-dependent manner. TGFß transcriptionally downregulated CD248 by signaling through canonical Smad2/3-dependent pathways, but not via mitogen activated protein kinases p38 or ERK1/2. Notably, cancer associated fibroblasts (CAF) and cancer cells were resistant to TGFß mediated suppression of CD248. CONCLUSIONS: The findings indicate that decoupling of CD248 regulation by TGFß may contribute to its tumor-promoting properties, and underline the importance of exploring the TGFß-CD248 signaling pathway as a potential therapeutic target for early prevention of cancer and proliferative disorders.

Polyphosphate suppresses complement via the terminal pathway.

Polyphosphate, synthesized by all cells, is a linear polymer of inorganic phosphate. When released into the circulation, it exerts prothrombotic and proinflammatory activities by modulating steps in the coagulation cascade. We examined the role of polyphosphate in regulating the evolutionarily related proteolytic cascade complement. In erythrocyte lysis assays, polyphosphate comprising more than 1000 phosphate units suppressed total hemolytic activity with a concentration to reduce maximal lysis to 50% that was 10-fold lower than with monophosphate. In the ion- and enzyme-independent terminal pathway complement assay, polyphosphate suppressed complement in a concentration- and size-dependent manner. Phosphatase-treated polyphosphate lost its ability to suppress complement, confirming that polymer integrity is required. Sequential addition of polyphosphate to the terminal pathway assay showed that polyphosphate interferes with complement only when added before formation of the C5b-7 complex. Physicochemical analyses using native gels, gel filtration, and differential scanning fluorimetry revealed that polyphosphate binds to and destabilizes C5b,6, thereby reducing the capacity of the membrane attack complex to bind to and lyse the target cell. In summary, we have added another function to polyphosphate in blood, demonstrating that it dampens the innate immune response by suppressing complement. These findings further establish the complex relationship between coagulation and innate immunity.

The Bacillus subtilis chemoreceptor McpC senses multiple ligands using two discrete mechanisms.

Bacillus subtilis can perform chemotaxis toward all 20 L-amino acids normally found in proteins. Loss of a single chemoreceptor, McpC, was previously found to reduce chemotaxis to 19 of these amino acids. In this study, we investigated the amino acid-sensing mechanism of McpC. We show that McpC alone can support chemotaxis to 17 of these amino acids to varying degrees. Eleven amino acids were found to directly bind the amino-terminal sensing domain of McpC in vitro. Sequence analysis indicates that the McpC sensing domain exhibits a dual Per-Arnt-Sim (PAS) domain structure. Using this structure as a guide, we were able to isolate mutants that suggest that four amino acids (arginine, glutamine, lysine, and methionine) are sensed by an indirect mechanism. We identified four candidate binding lipoproteins associated with amino acid transporters that may function in indirect sensing: ArtP, GlnH, MetQ, and YckB. ArtP was found to bind arginine and lysine; GlnH, glutamine; MetQ, methionine; and YckB, tryptophan. In addition, we found that ArtP, MetQ, and YckB bind the sensing domain of McpC, suggesting that the three participate in the indirect sensing of arginine, lysine, methionine, and possibly tryptophan as well. Taken together, these results further our understanding of amino acid chemotaxis in B. subtilis and gain insight into how a single chemoreceptor is able to sense many amino acids.