A keratinocyte-adipocyte signaling loop is reprogrammed by loss of BTG3 to augment skin carcinogenesis.

Obesity is endemic to many developed countries. Overweight or obesity is associated with an increased risk of developing cancer. Dysfunctional adipose tissue alters cancer cell proliferation and migration; however, whether and how neoplastic epithelial cells communicate with adipose tissue and the underlying mechanism are less clear. BTG3 is a member of the anti-proliferative BTG/Tob family and functions as a tumor suppressor. Here, we demonstrated that BTG3 levels are downregulated in basal cell carcinoma and squamous cell carcinoma compared to normal skin tissue, and Btg3 knockout in mice augmented the development of papilloma in a mouse model of DMBA/TPA-induced skin carcinogenesis. Mechanistically, BTG3-knockout keratinocytes promoted adipocyte differentiation mainly through the release of IL1α, IL10, and CCL4, as a result of elevated NF-κB activity. These adipocytes produced CCL20 and FGF7 in a feedback loop to promote keratinocyte migration. Thus, our findings showcased the role of BTG3 in guarding the interplay between keratinocytes and adjacent adipocytes, and identified the underlying neoplastic molecular mediators that may serve as possible targets in the treatment of skin cancer.

Cognitive Effects of Body Temperature During Hypothermic Circulatory Arrest Trial (GOT ICE): A Randomized Clinical Trial Comparing Outcomes After Aortic Arch Surgery.

BACKGROUND: Deep hypothermia has been the standard for hypothermic circulatory arrest (HCA) during aortic arch surgery. However, centers worldwide have shifted toward lesser hypothermia with antegrade cerebral perfusion. This has been supported by retrospective data, but there has yet to be a multicenter, prospective randomized study comparing deep versus moderate hypothermia during HCA. METHODS: This was a randomized single-blind trial (GOT ICE [Cognitive Effects of Body Temperature During Hypothermic Circulatory Arrest]) of patients undergoing arch surgery with HCA plus antegrade cerebral perfusion at 4 US referral aortic centers (August 2016-December 2021). Patients were randomized to 1 of 3 hypothermia groups: DP, deep (≤20.0 °C); LM, low-moderate (20.1-24.0 °C); and HM, high-moderate (24.1-28.0 °C). The primary outcome was composite global cognitive change score between baseline and 4 weeks postoperatively. Analysis followed the intention-to-treat principle to evaluate if: (1) LM noninferior to DP on global cognitive change score; (2) DP superior to HM. The secondary outcomes were domain-specific cognitive change scores, neuroimaging findings, quality of life, and adverse events. RESULTS: A total of 308 patients consented; 282 met inclusion and were randomized. A total of 273 completed surgery, and 251 completed the 4-week follow-up (DP, 85 [34%]; LM, 80 [34%]; HM, 86 [34%]). Mean global cognitive change score from baseline to 4 weeks in the LM group was noninferior to the DP group; likewise, no significant difference was observed between DP and HM. Noninferiority of LM versus DP, and lack of difference between DP and HM, remained for domain-specific cognitive change scores, except structured verbal memory, with noninferiority of LM versus DP not established and structured verbal memory better preserved in DP versus HM (P = 0.036). There were no significant differences in structural or functional magnetic resonance imaging brain imaging between groups postoperatively. Regardless of temperature, patients who underwent HCA demonstrated significant reductions in cerebral gray matter volume, cortical thickness, and regional brain functional connectivity. Thirty-day in-hospital mortality, major morbidity, and quality of life were not different between groups. CONCLUSIONS: This randomized multicenter study evaluating arch surgery HCA temperature strategies found low-moderate hypothermia noninferior to traditional deep hypothermia on global cognitive change 4 weeks after surgery, although in secondary analysis, structured verbal memory was better preserved in the deep group. The verbal memory differences in the low- and high-moderate groups and structural and functional connectivity reductions from baseline merit further investigation and suggest opportunities to further optimize brain perfusion during HCA. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02834065.

Serum proteomic biomarkers diagnostic of knee osteoarthritis.

OBJECTIVE: To better understand the pathogenesis of knee osteoarthritis (OA) through identification of serum diagnostics. DESIGN: We conducted multiple reaction monitoring mass spectrometry analysis of 107 peptides in baseline sera of two cohorts: the Foundation for National Institutes of Health (NIH) (n = 596 Kellgren-Lawrence (KL) grade 1-3 knee OA participants); and the Johnston County Osteoarthritis Project (n = 127 multi-joint controls free of radiographic OA of the hands, hips, knees (bilateral KL=0), and spine). Data were split into (70%) training and (30%) testing sets. Diagnostic peptide and clinical data predictors were selected by random forest (RF); selection was based on association (p < 0.05) with OA status in multivariable logistic regression models. Model performance was based on area under the curve (AUC) of receiver operating characteristic (ROC) and precision-recall (PR) curves. RESULTS: RF selected 23 peptides (19 proteins) and body mass index (BMI) as diagnostic of OA. BMI weakly diagnosed OA (ROC-AUC 0.57, PR-AUC 0.812) and only symptomatic OA cases. ACTG was the strongest univariable predictor (ROC-AUC 0.705, PR-AUC 0.897). The final model (8 serum peptides) was highly diagnostic (ROC-AUC 0.833, 95% confidence interval [CI] 0.751, 0.905; PR-AUC 0.929, 95% CI 0.876, 0.973) in the testing set and equally diagnostic of non-symptomatic and symptomatic cases (AUCs 0.830-0.835), and not significantly improved with addition of BMI. The STRING database predicted multiple high confidence interactions of the 19 diagnostic OA proteins. CONCLUSIONS: No more than 8 serum protein biomarkers were required to discriminate knee OA from non-OA. These biomarkers lend strong support to the involvement and cross-talk of complement and coagulation pathways in the development of OA.

Association of Dipeptidylpeptidase 4 (CD26) With Chondrocyte Senescence and Radiographic Progression in Knee Osteoarthritis.

OBJECTIVE: To evaluate the association of dipeptidylpeptidase 4 (DPP-4; also known as CD26) with cellular senescence of human cartilage and progression of knee osteoarthritis (OA). METHODS: Articular cartilage sections and chondrocytes were acquired from 35 individuals undergoing total knee replacement for OA to evaluate the following: 1) the association between OA severity and established senescence markers (senescence-associated ß-galactosidase activity and p16), which was quantified using immunohistochemistry and flow cytometry (n = 19 samples); 2) the coexpression of DPP-4 with established senescence markers, which was assessed using flow cytometry; and 3) expression levels of anabolic and catabolic genes, senescence-related genes, and senescence-associated secretory phenotypes in DPP-4+ and DPP-4- cells, which were isolated using fluorescence-activated cell sorting or magnetic-activated cell sorting (n = 16 samples). The concentration of soluble DPP-4 was measured in samples of synovial fluid and samples of plasma from the Prediction of Osteoarthritis Progression cohort and then evaluated for association with the severity of radiographic knee OA at baseline (n = 65 samples) and the progression of structural radiographic OA (n = 57 samples) over a 3-year period. RESULTS: DPP-4 expression was associated with higher senescence-associated ß-galactosidase activity, p16 expression, senescence-related gene and catabolic gene (ADAMTS5, MMP13, IL6, and IL8) expression, higher senescence-associated secretory phenotype secretion, and lower anabolic gene (COL2A1 and ACAN) expression in primary chondrocytes. Synovial fluid DPP-4 concentration was associated with radiographic OA progression (odds ratio 105.32; P = 0.015), proteases (synovial fluid matrix metalloproteinase 1 and matrix metalloproteinase 3), aggrecan degradation (synovial fluid sulfated glycosaminoglycan), indicators of activated macrophages (synovial fluid CD14 and CD163), and inflammation (synovial fluid interleukin-6). CONCLUSION: Our study identifies DPP-4 as a key surface marker in senescent chondrocytes and a predictor of radiographic OA progression.

Allopurinol hepatotoxicity is associated with human leukocyte antigen Class I alleles.

BACKGROUND/AIMS: Allopurinol can cause HLA class I-associated life-threatening severe skin reactions. However, HLA risk and association with clinical features in allopurinol hepatotoxicity are unknown. METHODS: Eleven of 17 patients with suspected allopurinol hepatotoxicity enrolled into the Drug-Induced Liver Injury Network were adjudicated as definite, highly likely, or probable. High-resolution HLA sequencing was undertaken in cases and compared with population and other DILI controls. RESULT: Median age was 60 years, 54% were male, and 63% African- American, 27% Caucasian, and 9% Hispanic. Patients presented at a median of 52 days after starting allopurinol, all were hospitalized and six were jaundiced. The median peak ALT, alkaline phosphatase, and total bilirubin were 525 U/L, 521 U/L, and 7.8 mg/dl, respectively, with a median R ratio of 2.7 at onset. During follow-up, nine patients were treated with corticosteroids including five of the six with suspected DRESS. Three patients died including two from liver failure at 38 and 45 days after onset, and the remaining eight recovered. Three HLA alleles were found to be overrepresented in allopurinol cases, particularly in African Americans: HLA-B*58:01, which has been previously linked to severe skin reactions, and HLA-B*53:01 and HLA-A*34:02, all of which are more frequently found in African Americans than European Americans or Latinos. CONCLUSIONS: Allopurinol hepatotoxicity is associated with systemic hypersensitivity, a short latency to onset, African-American race and three HLA risk alleles, HLA-B*58:01, HLA-B*53:01, and HLA-A*34:02-58:01 testing may help confirm a diagnosis of hepatotoxicity in allopurinol-treated patients.

Cerebrospinal Fluid Proteome Changes in Older Non-Cardiac Surgical Patients with Postoperative Cognitive Dysfunction.

BACKGROUND: Postoperative cognitive dysfunction (POCD), a syndrome of cognitive deficits occurring 1-12 months after surgery primarily in older patients, is associated with poor postoperative outcomes. POCD is hypothesized to result from neuroinflammation; however, the pathways involved remain unclear. Unbiased proteomic analyses have been used to identify neuroinflammatory pathways in multiple neurologic diseases and syndromes but have not yet been applied to POCD. OBJECTIVE: To utilize unbiased mass spectrometry-based proteomics to identify potential neuroinflammatory pathways underlying POCD. METHODS: Unbiased LC-MS/MS proteomics was performed on immunodepleted cerebrospinal fluid (CSF) samples obtained before, 24 hours after, and 6 weeks after major non-cardiac surgery in older adults who did (n = 8) or did not develop POCD (n = 6). Linear mixed models were used to select peptides and proteins with intensity differences for pathway analysis. RESULTS: Mass spectrometry quantified 8,258 peptides from 1,222 proteins in > 50%of patient samples at all three time points. Twelve peptides from 11 proteins showed differences in expression over time between patients with versus withoutPOCD (q < 0.05), including proteins previously implicated in neurodegenerative disease pathophysiology. Additionally, 283 peptides from 182 proteins were identified with trend-level differences (q < 0.25) in expression over time between these groups. Among these, pathway analysis revealed that 50 were from 17 proteins mapping to complement and coagulation pathways (q = 2.44*10-13). CONCLUSION: These data demonstrate the feasibility of performing unbiased mass spectrometry on perioperative CSF samples to identify pathways associated with POCD. Additionally, they provide hypothesis-generating evidence for CSF complement and coagulation pathway changes in patients with POCD.

Disease Expression and Familial Transmission of Fuchs Endothelial Corneal Dystrophy With and Without CTG18.1 Expansion.

Purpose: To characterize inheritance, penetrance, and trinucleotide repeat expansion stability in Fuchs endothelial corneal dystrophy (FECD). Methods: One thousand unrelated and related subjects with and without FECD were prospectively recruited. CTG18.1 repeat length (CTG18.1L) was determined via short tandem repeat assay and Southern blotting of leukocyte DNA. Multivariable logistic regression and generalized estimating equation models were employed. Results: There were 546 unrelated FECD cases (67.6% female; 70 ± 10 years) and 235 controls (63.8% female; 73 ± 8 years; all ≥ 50 years). CTG18.1 expansion (CTG18.1exp+) was observed in 424 (77.7%) cases and 18 (7.7%) controls (P = 2.48 × 10-44). CTG18.1 expansion was associated with FECD severity (P = 5.62 × 10-7). The family arm of the study included 331 members from 112 FECD-affected families; 87 families were CTG18.1exp+. Autosomal dominant inheritance with variable expression of FECD was observed, regardless of expansion status. FECD penetrance of CTG18.1 expansion increased with age, ranging from 44.4% in the youngest (19-46 years) to 86.2% in the oldest (64-91 years) age quartiles. Among 62 parent-offspring transmissions of CTG18.1exp+, 48 (77.4%) had a change in CTG18.1L ≤ 10 repeats, and eight (12.9%) were ≥50 repeats, including five large expansions (∼1000-2000 repeats) that contracted. Among 44 offspring who did not inherit the CTG18.1exp+ allele, eight (18.2%) exhibited FECD. Conclusions: CTG18.1 expansion was highly associated with FECD but demonstrated incomplete penetrance. CTG18.1L instability occurred in a minority of parent-offspring transmissions, with large expansions exhibiting contraction. The observation of FECD without CTG18.1 expansion among family members in CTG18.1exp+ families highlights the complexity of the relationship between the FECD phenotype and CTG18.1 expansion.

Conventional Ultrafiltration During Elective Cardiac Surgery and Postoperative Acute Kidney Injury.

OBJECTIVE: Conventional ultrafiltration (CUF) during cardiopulmonary bypass (CPB) serves to hemoconcentrate blood volume to avoid allogeneic blood transfusions. Previous studies have determined CUF volumes as a continuous variable are associated with postoperative acute kidney injury (AKI) after cardiac surgery, but optimal weight-indexed volumes that predict AKI have not been described. DESIGN: Retrospective cohort. SETTING: Single-center university hospital. PARTICIPANTS: A total of 1,641 consecutive patients who underwent elective cardiac surgery between June 2013 and December 2015. INTERVENTIONS: The CUF volume was removed during CPB in all participants as part of routine practice. The authors investigated the association of dichotomized weight-indexed CUF volume removal with postoperative AKI development to provide pragmatic guidance for clinical practice at the authors' institution. MEASUREMENTS AND MAIN RESULTS: Primary outcomes of postoperative AKI were defined by the Kidney Disease: Improving Global Outcomes staging criteria and dichotomized, weight-indexed CUF volumes (mL/kg) were defined by (1) extreme quartiles (Q3) and (2) Youden's criterion that best predicted AKI development. Multivariate logistic regression models were developed to test the association of these dichotomized indices with AKI status. Postoperative AKI occurred in 827 patients (50.4%). Higher CUF volumes were associated with AKI development by quartiles (CUF >Q3 = 32.6 v CUF < Q1 = 10.4 mL/kg; odds ratio [OR] = 1.68, 95% CI: 1.19-2.3) and Youden's criterion (CUF ≥ 32.9 v CUF <32.9 mL/kg; OR = 1.60, 95% CI: 1.21-2.13). Despite similar intraoperative nadir hematocrits among groups (p = 0.8), higher CUF volumes were associated with more allogeneic blood transfusions (p = 0.002) and longer lengths of stay (p < 0.001). CONCLUSIONS: Removal of weight-indexed CUF volumes > 32 mL/kg increased the risk for postoperative AKI development. Importantly, CUF volume removal of any amount did not mitigate allogeneic blood transfusion during elective cardiac surgery. Prospective studies are needed to validate these findings.

Does a Recent Urinary Tract Infection Increase the Risk of Postprocedure Urinary Tract Infection After Onabotulinum Toxin A?

OBJECTIVES: The objective of this study was to evaluate the risk of postprocedure urinary tract infection (UTI) after injection of onabotulinum toxin A (BTX-A) in women who had a UTI within 30 days before procedure. METHODS: This was a retrospective cohort study of women who underwent their first injection of BTX-A from 2010 to 2016. Two cohorts were identified: (1) recent UTI (within 30 days before injection) and (2) no recent UTI. Our primary outcome was UTI within 90 days after BTX-A. Continuous variables were analyzed using the Wilcoxon rank sum test, and categorical variables were analyzed using Fisher exact or χ2 tests. RESULTS: One hundred sixty-six women underwent their first BTX-A injection. Twenty-five (15%) had a recent UTI and 141 (85%) did not. Women with a recent UTI were more likely to have a subsequent infection (52% vs 26%, P < 0.01). However, in a logistic regression model, controlling for history of recurrent UTI, age, history of diabetes mellitus, periprocedural antibiotics, and urinary retention requiring catheterization, the association between having a recent UTI, and a subsequent UTI was no longer significant (adjusted odds ratio, 1.98; 95% confidence interval, 0.60-6.50; P = 0.26). CONCLUSIONS: Performing a first injection of BTX-A within 30 days of a UTI does not increase the odds of postprocedure UTI. Therefore, BTX-A therapy does not need to be delayed after a recent UTI.

Human Leukocyte Antigen B*14:01 and B*35:01 Are Associated With Trimethoprim-Sulfamethoxazole Induced Liver Injury.

BACKGROUND AND AIMS: Trimethoprim (TMP)-sulfamethoxazole (SMX) is an important cause of idiosyncratic drug-induced liver injury (DILI), but its genetic risk factors are not well understood. This study investigated the relationship between variants in the human leukocyte antigen (HLA) class 1 and 2 genes and well-characterized cases of TMP-SMX DILI. APPROACH AND RESULTS: European American and African American persons with TMP-SMX DILI were compared with respective population controls. HLA sequencing was performed by Illumina MiSeq (Illumina, San Diego, CA) for cases. The HLA genotype imputation with attribute bagging program was used to impute HLA alleles for controls. The allele frequency difference between case patients and controls was tested by Fisher's exact tests for each ethnic group. For European Americans, multivariable logistic regression with Firth penalization was used to test the HLA allelic effect after adjusting for age and the top two principal components. Molecular docking was performed to assess HLA binding with TMP and SMX. The European American subset had 51 case patients and 12,156 controls, whereas the African American subset had 10 case patients and 5,439 controls. Four HLA alleles were significantly associated in the European American subset, with HLA-B*14:01 ranking at the top (odds ratio, 9.20; 95% confidence interval, 3.16, 22.35; P = 0.0003) after covariate adjustment. All carriers of HLA-B*14:01 with TMP-SMX DILI possessed HLA-C*08:02, another significant allele (P = 0.0026). This pattern was supported by HLA-B*14:01-HLA-C*08:02 haplotype association (P = 1.33 × 10-5 ). For the African American patients, HLA-B*35:01 had 2.8-fold higher frequency in case patients than in controls, with 5 of 10 patients carrying this allele. Molecular docking showed cysteine at position 67 in HLA-B*14:01 and phenylalanine at position 67 in HLA-B*35:01 to be the predictive binding sites for SMX metabolites. CONCLUSIONS: HLA-B*14:01 is associated with TMP-SMX DILI in European Americans, and HLA-B*35:01 may be a potential genetic risk factor for African Americans.

Unplanned hospital admission after ambulatory surgery: a retrospective, single cohort study.

PURPOSE: We estimated the rate of unplanned hospital and intensive care unit (ICU) admissions following ambulatory surgery centre (ASC) procedures, and identified factors associated with their occurrence. METHODS: This retrospective cohort included adult patients who underwent ASC procedures within a large community practice from January 2010 to December 2014. Patients were categorized into two groups: unplanned postoperative hospital/ICU admission within 24 hr of procedure or uneventful discharge. Demographics, comorbidities, anesthesia type, procedure type, procedure group, and ASC facility were assessed. RESULTS: Of the 211,389 patients included, there were 211,147 uneventful discharges (99.89%) and 242 unplanned hospital admissions (0.11%), of which 75 were ICU admissions (0.04%). The multivariable logistic regression model for hospital admission showed an increased risk associated with age > 50 yr (odds ratio [OR], 1.53); American Society of Anesthesiologists (ASA) physical status (III vs II: OR, 1.45; IV vs II: OR, 1.88), comorbidity (chronic obstructive pulmonary disease: OR, 2.63; diabetes mellitus: OR, 1.62; transient ischemic attack: OR, 2.48) procedure (respiratory: OR, 2.92; digestive: OR, 2.66; musculoskeletal system: OR, 2.53), anesthetic management (general anesthesia [GA] and peripheral nerve block vs GA: OR, 1.79), and ASC facility (189BB: OR, 2.29; 30E9A: OR, 7.41; and BD21F: OR, 1.69). The multivariable logistic regression model for ICU admission showed increased risk of unplanned ICU admission associated with ASA physical status (ASA III vs II: OR, 3.0; ASA IV vs II: OR, 8.52), procedure (musculoskeletal system: OR, 2.45), and ASC facility (00E6C: OR, 3.14; 189BB: OR, 2.77; 30E9A: OR, 2.59; and BD21F: OR, 3.71). CONCLUSION: While a small percentage of adult patients who underwent ASC procedures required unplanned hospital admission (0.07%), approximately one-third of these admissions were to the ICU (0.04%). Facility was at least as strong a predictor of hospital admission as the patient- and/or procedure-specific variables.

RéSUMé: OBJECTIF: Nous avons estimé le taux d'admissions non planifiées à l'hôpital et à l'unité de soins intensifs (USI) après des interventions dans des centres de chirurgie ambulatoire (CCA), et identifié les facteurs associés à leur survenue. MéTHODE: Cette étude de cohorte rétrospective a porté sur des patients adultes ayant subi une intervention dans un CCA appartenant à une grande pratique communautaire entre janvier 2010 et décembre 2014. Les patients ont été catégorisés en deux groupes : admission postopératoire non planifiée à l'hôpital/USI dans les 24 h suivant l'intervention ou congé sans incident. Les données démographiques, les comorbidités, le type d'anesthésie, le type d'intervention, le groupe d'intervention et l'établissement de CCA ont été évalués. RéSULTATS: Parmi les 211 389 patients inclus, il y a eu 211 147 congés sans incident (99,89 %) et 242 admissions non planifiées à l'hôpital (0,11 %), 75 desquelles étaient des admissions à l'USI (0,04 %). Le modèle de régression logistique multivariée des admissions hospitalières a montré un risque accru associé à un âge > 50 ans (rapport de cotes [RC], 1,53); au statut physique ASA (American Society of Anesthesiologists) (III vs II : RC, 1,45; IV vs II : RC, 1,88), aux comorbidités (maladie pulmonaire obstructive chronique : RC, 2,63; diabète: RC, 1,62; accident ischémique transitoire : RC, 2,48); à l'intervention (respiratoire : RC, 2,92; digestive : RC, 2,66; appareil locomoteur : RC, 2,53); à la prise en charge anesthésique (anesthésie générale [AG] et bloc nerveux périphérique vs AG : RC, 1,79) et établissement de CCA (189BB : RC, 2,29; 30E9A : RC, 7,41; et BD21F : RC, 1,69). Le modèle de régression logistique multivariée des admissions à l'USI a montré un risque accru d'admission non planifiée à l'USI associé au statut physique ASA (ASA III vs II: RC, 3,0; ASA IV vs II: RC, 8,52), à l'intervention (appareil locomoteur : RC, 2,45), et à l'établissement de CCA (00E6C: RC, 3,14; 189BB: RC, 2,77; 30E9A: RC, 2,59; et BD21F: RC, 3,71). CONCLUSION: Alors qu'un faible pourcentage de patients adultes ayant subi des interventions en CCA ont nécessité une admission non planifiée à l'hôpital (0,11 %), environ un tiers de ces admissions étaient à l'USI (0,04 %). L'établissement était un prédicteur au moins aussi puissant d'admission à l'hôpital que les variables spécifiques au patient et/ou à l'intervention.

Loss of the tumor suppressor BTG3 drives a pro-angiogenic tumor microenvironment through HIF-1 activation.

B-cell translocation gene 3 (BTG3) is a member of the antiproliferative BTG gene family and is a downstream target of p53. Here, we show that senescence triggered by BTG3 depletion was accompanied by a secretome enriched with cytokines, growth factors, and matrix-remodeling enzymes, which could promote angiogenesis and cell scattering in vitro. We present evidence that at least part of these activities can be explained by elevated HIF-1α activity. Mechanistically, the BTG3 C-terminal domain competes with the coactivator p300 for binding the HIF-1α transactivation domain. The angiogenic promoting effect of BTG3 knockdown was largely diminished upon co-depletion of HIF-1α, indicating that HIF-1α is a major downstream target of BTG3 in the control of angiogenesis. In vivo, ectopic expression of BTG3 suppresses angiogenesis in xenograft tumors; and syngenic tumor growth and metastasis were enhanced in Btg3-null mice. Moreover, analysis of clinical datasets revealed that a higher BTG3/VEGFA expression ratio correlates with improved patient survival in a number of cancer types. Taken together, our findings highlight the non-autonomous regulation of tumor microenvironment by BTG3 while suppressing tumor progression.

Apolipoprotein L1 (APOL1) Coding Variants Are Associated With Creatinine Rise After Cardiac Surgery.

OBJECTIVE: Acute kidney injury (AKI) is a complication of cardiac surgery that is considerably more common in African Americans (1.5-fold). Although homozygous status for apolipoprotein L1 (APOL1) risk alleles is associated with chronic kidney disease in individuals of African ancestry, whether these coding variants confer AKI risk is unknown. The present study examined whether APOL1 homozygous risk allele status was associated with AKI in African Americans after cardiac surgery. DESIGN: Retrospective analysis of a cohort. SETTING: Single-center university hospital. PARTICIPANTS: African American patients from the CATHeterization GENetics study cohort who underwent cardiac surgery with cardiopulmonary bypass. INTERVENTIONS: Genotyping of APOL1 alleles. MEASUREMENTS AND MAIN RESULTS: Data from 125 African American patients included 12 APOL1 risk (ie, homozygous for risk alleles) patients and 113 APOL1 control (ie, wildtype or heterozygous for risk alleles) patients. The primary outcome to reflect AKI was peak serum creatinine rise after surgery relative to the preoperative creatinine (%ΔCr). The secondary outcome was Kidney Disease: Improving Global Outcomes (KDIGO) AKI criteria. In the primary analysis, peak creatinine rise was higher in risk compared with control patients in both univariate (%ΔCr 69.1 v 29.6%; p = 0.005) and multivariate regression (%ΔCr 88.5 v 43.7%; p = 0.006) analyses. For the secondary outcome, a trend toward KDIGO AKI development was noted in APOL1 risk patients, but this was not statistically significant. CONCLUSIONS: African American cardiac surgery patients homozygous for APOL1 chronic kidney disease risk variants averaged a more than 2-fold higher postoperative creatinine rise even after adjustment for other risk factors, suggesting these alleles also are independent risk factors for AKI.

The Utility of the Early Postoperative Follow-up and Radiographs After Operative Treatment of Supracondylar Humerus Fractures in Children.

BACKGROUND: Supracondylar humerus (SCH) fractures are common elbow injuries in pediatric patients. The American Academy of Orthopedic Surgeons published guidelines for the standard of care in the treatment of displaced SCH fractures, however, no recommendations for follow-up care were made. With the recent push to eliminate unnecessary radiographs and decrease health care costs, many are questioning postoperative protocols. The purpose of our study was to evaluate the utility of the 1-week follow-up appointment after closed reduction and percutaneous pinning (CRPP) of displaced SCH fractures. METHODS: A retrospective review performed at a single institution from 2014 to 2016 included patients under 14 years of age with a closed, displaced SCH fracture treated with CRPP. Exclusion criteria included patients without complete clinical or radiographic follow-up. Variables examined included time to initial follow-up, change in treatment plan after 1-week x-rays, complications, demographics, fracture type, pin number and configuration, reduction parameters, immobilization, time to pin removal, duration of casting, and clinical outcome. RESULTS: A total of 412 patients were divided into 2 groups based on time to initial follow-up. Overall, 368 had an initial follow-up at 7 to 10 days (group 1) and 44 at 21 to 28 days (group 2). There was no difference in age, sex, fracture type, pin configuration, or a number of pins between groups. Statistically significant findings included time to initial follow-up and days to pin removal (group 1 at 26.2 d vs. group 2 at 23.8 d), type of immobilization (group 1 with 5% circumferential casts and group 2 with 70%), and time to surgery (26.2 vs. 62.9 h, respectively). There was no significant difference in complication rates and only a 0.5% rate of change in management in group 1. CONCLUSIONS: Early postoperative follow-up and radiographs did not change the patient outcome and might be eliminated in children with displaced SCH fractures treated with CRPP. Given the current focus of on efficiency and cost-effective care, eliminating the 1-week postoperative appointment would improve appointment availability and decrease medical cost. LEVEL OF EVIDENCE: Level III-Therapeutic.

Intraoperative renal resistive index threshold as an acute kidney injury biomarker.

STUDY OBJECTIVE: The lag in creatinine-mediated diagnosis of cardiac surgery-associated acute kidney injury (AKI) may be impeding the development of renoprotection therapies. Postoperative renal resistive index (RRI) measured by transabdominal Doppler ultrasound is a promising early AKI biomarker. RRI measured intraoperatively by transesophageal echocardiography (TEE) is available even earlier but is less evaluated. Therefore, we conducted an assessment of intraoperative RRI as an AKI biomarker using previously reported post-renal insult thresholds. DESIGN: Retrospective convenience sample. SETTING: Intraoperative. PATIENTS: 180 adult cardiac surgical patients between July 2013 and July 2014. INTERVENTION: None. MEASUREMENTS: Pre- and post-cardiopulmonary bypass (CPB) RRI thresholds, measured using intraoperative TEE, exceeding 0.74 or 0.79 were used to evaluate for an association with KDIGO AKI risk using the Chi-square test. Other consensus AKI criteria (AKIN, RIFLE) were similarly evaluated. Additional t-test analyses examined the relationship of pre- and pre-to-post (delta) CPB RRI with AKI. MAIN RESULTS: Post-CPB RRI for 99 patients included 36 and 23 with values exceeding 0.74 and 0.79, respectively. Analyses confirmed associations of both RRI thresholds with all consensus AKI definitions (0.74; KDIGO: p = 0.05, AKIN: p = 0.03, RIFLE: p = 0.03, 0.79; KDIGO: p = 0.002, AKIN: p = 0.001, RIFLE: p = 0.004). In contrast, pre-CPB and pre-to post-CPB RRI were not associated with AKI. CONCLUSIONS: RRI obtained intraoperatively in cardiac surgery patients, assessed using previously reported thresholds, is highly associated with AKI and warrants further evaluation as a promising "earliest" AKI biomarker. These significant findings suggest that RRI assessment should be included in the standard intraoperative TEE exam.

Synovial fluid biomarkers associated with osteoarthritis severity reflect macrophage and neutrophil related inflammation.

BACKGROUND: To identify a synovial fluid (SF) biomarker profile characteristic of individuals with an inflammatory osteoarthritis (OA) endotype. METHODS: A total of 48 knees (of 25 participants) were characterized for an extensive array of SF biomarkers quantified by Rules Based Medicine using the high-sensitivity multiplex immunoassay, Myriad Human InflammationMAP® 1.0, which included 47 different cytokines, chemokines, and growth factors related to inflammation. Multivariable regression with generalized estimating equations (GEE) and false discovery rate (FDR) correction was used to assess associations of SF RBM biomarkers with etarfolatide imaging scores reflecting synovial inflammation; radiographic knee OA severity (based on Kellgren-Lawrence (KL) grade, joint space narrowing, and osteophyte scores); knee joint symptoms; and SF biomarkers associated with activated macrophages and knee OA progression including CD14 and CD163 (shed by activated macrophages) and elastase (shed by activated neutrophils). RESULTS: Significant associations of SF biomarkers meeting FDR < 0.05 included soluble (s)VCAM-1 and MMP-3 with synovial inflammation (FDR-adjusted p = 0.025 and 1.06 × 10-7); sVCAM-1, sICAM-1, TIMP-1, and VEGF with radiographic OA severity (p = 1.85 × 10-5 to 3.97 × 10-4); and VEGF, MMP-3, TIMP-1, sICAM-1, sVCAM-1, and MCP-1 with OA symptoms (p = 2.72 × 10-5 to 0.050). All these SF biomarkers were highly correlated with macrophage markers CD163 and CD14 in SF (r = 0.43 to 0.90, FDR < 0.05); all but MCP-1 were also highly correlated with neutrophil elastase in SF (r = 0.62 to 0.89, FDR < 0.05). CONCLUSIONS: A subset of six SF biomarkers was related to synovial inflammation in OA, as well as radiographic and symptom severity. These six OA-related SF biomarkers were specifically linked to indicators of activated macrophages and neutrophils. These results attest to an inflammatory OA endotype that may serve as the basis for therapeutic targeting of a subset of individuals at high risk for knee OA progression. TRIAL REGISTRATION: Written informed consent was received from participants prior to inclusion in the study; the study was registered at ClinicalTrials.gov ( NCT01237405 ) on November 9, 2010, prior to enrollment of the first participant.

Three-factor prothrombin complex concentrates for refractory bleeding after cardiovascular surgery within an algorithmic approach to haemostasis.

BACKGROUND/OBJECTIVES: Prothrombin complex concentrates (PCC) are increasingly administered off-label in the United States to treat bleeding in cardiovascular surgical patients and carry the potential risk for acquired thromboembolic side-effects after surgery. Therefore, we hypothesized that the use of low-dose 3-factor (3F) PCC (20-30 IU/kg), as part of a transfusion algorithm, reduces bleeding without increasing postoperative thrombotic/thromboembolic complications. MATERIALS/METHODS: After IRB approval, we retrospectively analysed 114 consecutive, complex cardiovascular surgical patients (age > 18 years), between February 2014 and June 2015, that received low-dose 3F-PCC (Profilnine® ), of which seven patients met established exclusion criteria. PCC was dosed according to an institutional perioperative algorithm. Allogeneic transfusions were recorded before and after PCC administration (n = 107). The incidence of postoperative thromboembolic events was determined within 30 days of surgery, and Factor II levels were measured in a subset of patients (n = 20) as a quality control measure to avoid excessive PCC dosing. RESULTS: Total allogeneic blood product transfusion reached a mean of 12·4 ± 9·9 units before PCC and 5·0 ± 6·3 units after PCC administration (P < 0·001). The mean PCC dose was 15·8 ± 7·1 IU/kg. Four patients (3·8%) each experienced an ischaemic stroke on postoperative day 1, 2, 4 and 27. Seven patients (6·5%) had acquired venous thromboembolic disease within 10 days of surgery. Median factor II level after transfusion algorithm adherence and PCC administration was 87%. CONCLUSIONS: 3F-PCC use for refractory bleeding after cardiovascular surgery resulted in reduced transfusion of allogeneic blood and blood products. Adherence to this algorithmic approach was associated with an acceptable incidence of postoperative thrombotic/thromboembolic complications.

Exogenous GDF11 attenuates non-canonical TGF-ß signaling to protect the heart from acute myocardial ischemia-reperfusion injury.

Growth differentiation factor 11 (GDF11) is a member of the transforming growth factor beta 1 (TGF-ß1) superfamily that reverses age-related cardiac hypertrophy, improves muscle regeneration and angiogenesis, and maintains progenitor cells in injured tissue. Recently, targeted myocardial delivery of the GDF11 gene in aged mice was found to reduce heart failure and enhance the proliferation of cardiac progenitor cells after myocardial ischemia-reperfusion (I-R). No investigations have as yet explored the cardioprotective effect of exogenous recombinant GDF11 in acute I-R injury, despite the convenience of its clinical application. We sought to determine whether exogenous recombinant GDF11 protects against acute myocardial I-R injury and investigate the underlying mechanism in Sprague-Dawley rats. We found that GDF11 reduced arrhythmia severity and successfully attenuated myocardial infarction; GDF11 also increased cardiac function after I-R, enhanced HO-1 expression and decreased oxidative damage. GDF11 activated the canonical TGF-ß signaling pathway and inactivated the non-canonical pathways, ERK and JNK signaling pathways. Moreover, administration of GDF11 prior to reperfusion protected the heart from reperfusion damage. Notably, pretreatment with the activin-binding protein, follistatin (FST), inhibited the cardioprotective effects of GDF11 by blocking its activation of Smad2/3 signaling and its inactivation of detrimental TGF-ß signaling. Our data suggest that exogenous GDF11 has cardioprotective effects and may have morphologic and functional recovery in the early stage of myocardial I-R injury. GDF11 may be an innovative therapeutic approach for reducing myocardial I-R injury.

Effects of Delivering SLCO1B1 Pharmacogenetic Information in Randomized Trial and Observational Settings.

BACKGROUND: Outcomes of tailoring statin-type based on solute carrier organic anion transporterfamily member 1B1 ( SLCO1B1)pharmacogenetic toxicity information on patient, provider, and pharmacological outcomes are unknown. METHODS: The trial randomized 159 patients not taking statins because of prior statin myalgia 1:1 to receiving SLCO1B1 GIST (Genotype Informed Statin Therapy) versus usual care (UC) and followed for up to 8 months. The UC arm received their SLCO1B1 results post-trial. The primary outcome was statin adherence using the Morisky Medication Adherence Scale, which was assessed in those patients who reinitiated statins. Secondary outcomes assessed in all participants included statin reinitiation and LDLc (low-density lipoprotein cholesterol), within and post-trial. Using commercial laboratory data, serial LDLc were compared between 1907 patients receiving SLCO1B1 testing and propensity-matched, untested controls. RESULTS: Trial participants were 25% SLCO1B1*5 carriers. Statin adherence was similar between arms (Morisky Medication Adherence Scale in GIST versus UC, 6.8±1.5 versus 6.9±1.6, P=0.96). GIST led to more new statin prescriptions (55.4% versus 38.0%, P=0.04) and lower LDLc at 3 months (131.9±42.0 versus 144.4±43.0 mg/dL; P=0.048) with similar magnitude at 8 months (128.6±37.9 versus 141.0±44.4; P=0.12). SLCO1B1*5 carriers exhibited a greater drop in LDLc with GIST versus UC (interaction P=0.048). Post-trial, LDLc decreased in UC participants who crossed over to GIST compared with those allocated to GIST (-14.9±37.8 versus +9.0±37.3 mg/dL, P=0.03). Patients tested for SLCO1B1 though a commercial laboratory had a greater LDLc decrease ( P=0.04) compared with controls. CONCLUSIONS: Delivery of SLCO1B1 pharmacogenetic testing that addresses statin myalgia improved statin reinitiation and LDLc but did not improve self-reported statin adherence. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01894230.

Genome-Wide Association Study Links Receptor Tyrosine Kinase Inhibitor Sprouty 2 to Thrombocytopenia after Coronary Artery Bypass Surgery.

INTRODUCTION: Thrombocytopenia after cardiac surgery independently predicts stroke, acute kidney injury and death. To understand the underlying risks and mechanisms, we analysed genetic variations associated with thrombocytopenia in patients undergoing coronary artery bypass grafting (CABG) surgery. MATERIALS AND METHODS: Study subjects underwent isolated on-pump CABG surgery at Duke University Medical Center. Post-operative thrombocytopenia was defined as platelet count < 100 × 109/L. Using a logistic regression model adjusted for clinical risk factors, we performed a genome-wide association study in a discovery cohort (n = 860) and validated significant findings in a replication cohort (n = 296). Protein expression was assessed in isolated platelets by immunoblot. RESULTS: A total of 63 single-nucleotide polymorphisms met a priori discovery thresholds for replication, but only 1 (rs9574547) in the intergenic region upstream of sprouty 2 (SPRY2) met nominal significance in the replication cohort. The minor allele of rs9574547 was associated with a lower risk for thrombocytopenia (discovery cohort, odds ratio, 0.45, 95% confidence interval, 0.30-0.67, p = 9.76 × 10-5) with the overall association confirmed by meta-analysis (meta-p = 7.88 × 10-6). Immunoblotting demonstrated expression of SPRY2 and its dynamic regulation during platelet activation. Treatment with a functional SPRY2 peptide blunted platelet extracellular signal-regulated kinase (ERK) phosphorylation after agonist stimulation. CONCLUSION: We identified the association of a genetic polymorphism in the intergenic region of SPRY2 with a decreased incidence of thrombocytopenia after CABG surgery. Because SPRY2-an endogenous receptor tyrosine kinase inhibitor-is present in platelets and modulates essential signalling pathways, these findings support a role for SPRY2 as a novel modulator of platelet responses after cardiac surgery.