Publications by authors named "Jose Torrealba"

101 Publications

Intraoperative Cytology for Video-Assisted Thoracic Surgery. A Quality Improvement Analysis.

Ann Thorac Surg 2021 Mar 4. Epub 2021 Mar 4.

Department of Surgery, Thoracic, University of Rochester Medical Center, Rochester, NY.

Background: Frozen section is a standard of care procedure during thoracic surgery when an immediate diagnosis is needed. An alternative procedure is intraoperative cytology. Video-assisted thoracic surgery is currently widely used for thoracic surgical procedures. The aim of this study was to assess intraoperative cytology together with frozen section for accuracy, turnaround time, and total response time during video-assisted thoracic surgery.

Methods: Patients having video-assisted thoracic surgery between August 2018 and February 2019 at our institution were included. A cytopathologist and a surgical pathologist independently performed intraoperative cytology and frozen sections, respectively. Final histologic diagnosis was the gold standard. Intraoperative cytology, frozen section turnaround and total response times were analyzed.

Results: Fifty-two specimens from twenty-seven patients were included. The intraoperative cytology correlated with final histology in 98% of cases. Frozen section correlated with final histology in 100% of cases. The intraoperative cytology turnaround and total response times were equal with a mean of 4.35 minutes (range: 2-15). The mean frozen section turnaround and response times were 26.2 (range: 9-61) and 36.7 minutes (range: 16-90), respectively. A statistically significant difference between intraoperative cytology and frozen section turnaround time and total response times (p< 0.001) was found.

Conclusions: This study highlights that intraoperative cytology could be as accurate and considerably faster (p< 0.001) than frozen section during video-assisted thoracic surgery. Total response time could potentially be used as a quality metric for video-assisted thoracic surgery.
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http://dx.doi.org/10.1016/j.athoracsur.2021.02.043DOI Listing
March 2021

Uncommon Disease in a Rare Location: The Mystery of the Rapidly Progressive Cardiomyopathy.

Circulation 2020 Oct 19;142(16):1591-1595. Epub 2020 Oct 19.

Division of Cardiology (J.L.G.), University of Texas Southwestern Medical Center, Dallas.

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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.048323DOI Listing
October 2020

B-cell non-Hodgkin's lymphoma mimicking carotid body tumor.

Vasc Med 2021 Feb 2;26(1):86-88. Epub 2020 Sep 2.

Departamento de Cirugía Vascular y Endovascular, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile.

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http://dx.doi.org/10.1177/1358863X20948584DOI Listing
February 2021

Utility of Bronchoalveolar Lavage and Transbronchial Biopsy in Patients with Interstitial Lung Disease.

Lung 2020 10 1;198(5):803-810. Epub 2020 Sep 1.

Division of Pulmonary and Critical Care Medicine, University of Texas Southwestern Medical Center, UT Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX, 75219, USA.

Purpose: Bronchoalveolar lavage and transbronchial biopsy can be a useful tool in the evaluation of interstitial lung disease (ILD), but patient selection for this procedure remains poorly defined. Determining clinical characteristics that help with patient selection for bronchoscopy may improve confidence of ILD classification while limiting potential adverse outcomes associated with surgical lung biopsy. The purpose of this study is to identify factors that were associated with change in multidisciplinary ILD diagnosis (MDD) before and after incorporation of BAL and TBBx data.

Methods: We conducted a retrospective cohort study of ILD patients at a single center who underwent bronchoscopy in the diagnostic workup of ILD. We performed sequential MDD both pre- and post-bronchoscopy to calculate the frequency of change in diagnosis after incorporating information from BAL and TBBx and identify features associated with change in diagnosis.

Results: 245 patients were included in the study. Bronchoscopy led to a change in diagnosis in 58 patients (23.7%). The addition of TBBx to BAL increased diagnostic yield from 21.8 to 34.1% (p = 0.027). Identification of antigen, HRCT scan inconsistent with UIP, and absence of a pre-bronchoscopy diagnosis of CTD-ILD or IPAF were associated with a change in diagnosis after bronchoscopy.

Conclusion: Our study suggests clinical features that may assist with patient selection for bronchoscopy. We suggest bronchoscopy in patients with identified antigen or an HRCT that is consistent with a non-IPF diagnosis. Appropriate patient selection for bronchoscopy may improve ILD diagnostic confidence and avoid potential complications from more invasive and higher risk procedures.
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http://dx.doi.org/10.1007/s00408-020-00389-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7899290PMC
October 2020

Endovascular Management of a Ruptured Iliac Aneurysm With an Inferior Vena Cava Fistula.

Vasc Endovascular Surg 2020 Oct 14;54(7):638-642. Epub 2020 Jul 14.

28033Pontificia Universidad Católica de Chile, Santiago, Chile.

Aortocaval fistula is uncommon and often associated with a ruptured iliac or abdominal aortic aneurysm. It has a high mortality secondary to the aneurysmal rupture but also to a high output heart failure. Open surgery has been the standard; however, endovascular management has emerged with lower mortality. We present a patient with a ruptured iliac aneurysm and an inferior vena cava fistula successfully treated with an endograft with embolization of the right hypogastric artery. The patient arrested on induction and was resuscitated with aortic balloon inflation. Endovascular therapy can be safely used in the management of iliac/aortocaval fistula.
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http://dx.doi.org/10.1177/1538574420939724DOI Listing
October 2020

Phase II Study of Ensituximab, a Novel Chimeric Monoclonal Antibody, in Adults with Unresectable, Metastatic Colorectal Cancer.

Clin Cancer Res 2020 07 17;26(14):3557-3564. Epub 2020 Apr 17.

Department of Oncology, University of Texas Southwestern Medical Center of Dallas, Dallas, Texas.

Purpose: Patients with metastatic colorectal cancer refractory to chemotherapy have limited treatment options. Ensituximab (NEO-102) is a novel chimeric mAb targeting a variant of with specificity to colorectal cancer.

Patients And Methods: Single-arm, phase II trial assessed the efficacy and safety of ensituximab in patients with advanced, refractory cancer who expressed antigen in tumor tissue. Ensituximab was administered intravenously every 2 weeks with 3 mg/kg as recommended phase II dose (RP2D). A minimum sample size of 43 patients was required on the basis of the assumption that ensituximab would improve median overall survival (OS) by 7 months using a one-sided significance level of 10% and 80% power. Written informed consent was obtained from all patients.

Results: Sixty-three patients with advanced, refractory colorectal cancer were enrolled and 53 subjects were treated in phase II arm. Median age was 58 years and 46% of the patients were female. Among 57 evaluable patients, median OS was 6.8 months. No responses were observed, and stable disease was achieved in 21% of the patients. The most common treatment-related adverse events (AE) at RP2D included fatigue (38%), anemia (30%), nausea (15%), vomiting (11%), increased bilirubin (9%), constipation (8%), decreased appetite (6%), and diarrhea (6%). Serious AEs at least possibly related to ensituximab occurred in 4 patients and included anemia, nausea, increased bilirubin, and hypoxia. No patients discontinued treatment due to drug-related AEs.

Conclusions: Ensituximab was well tolerated and demonstrated modest antitumor activity in patients with heavily pretreated refractory colorectal cancer.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-0426DOI Listing
July 2020

Pathology of the kidney allograft.

Semin Diagn Pathol 2020 May 29;37(3):148-153. Epub 2020 Mar 29.

Department of Pathology, University of Texas Southwestern Medical Center, Professional Office Building I, 3rd Floor Suite HP3.370, Room HP3.392 ,5959 Harry Hines Blvd, Dallas, TX 75390, TX, United States. Electronic address:

The kidney biopsy still represents the best approach to diagnose renal transplant complications. It is considered the gold standard in the diagnosis of rejection and non-rejection complications. Although invasive, it is a safe procedure with a very low complication rate. With adequate sampling, changes related to antibody-mediated rejection (ABMR) and T-cell mediated rejection (TCMR) can be identified. However, the pathologist needs to be aware of the many other complications, not related to rejection, that can affect the allograft function. Examples include viral infections, drug toxicity, systemic diseases such as hypertension and diabetes, and recurrent or de novo glomerulopathy, among others. In this article, we review the recent classification of pathology of the kidney allograft, with reference to recent consensus reached at the most recent Banff renal allograft classification meetings, and also highlight common non-rejection complications of the kidney transplant.
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http://dx.doi.org/10.1053/j.semdp.2020.03.005DOI Listing
May 2020

Upregulation of Endothelial HLA Class II is a Marker of Antibody-Mediated Rejection in Heart Allograft Biopsies.

Transplant Proc 2020 May 18;52(4):1192-1197. Epub 2020 Mar 18.

University of Texas Southwestern Medical Center, Dallas, Texas. Electronic address:

In 2013, the International Society of Heart and Lung Transplant (ISHLT) introduced the working classification for pathologic changes associated with antibody-mediated rejection (AMR) of the heart allograft, known as pathologic AMR (pAMR). With 2 components associated with AMR, histopathologic changes) and immunopathologic markers, the proposed classification also suggests the use of class II HLA as a marker of endothelial integrity. It is known that during allograft rejection, endothelial cells are activated, therefore, we hypothesized that endothelial class II HLA rather than a marker of mere endothelial presence, is a marker of endothelial activation and becomes upregulated in AMR. Eight hundred thirty-eight heart allograft biopsies, collected from January 2016 to September 2018 at a single institution from patients with a current or recent diagnosis of AMR, were evaluated for both histopathologic and immunopathologic changes of AMR. Biopsies were labeled with immunofluorescence with antibodies against C4d and for immunohistochemistry with antibodies against C3d, CD68, and class II HLA. ISHLT criteria were used to classify the biopsies, and for class II HLA, both the percentage and the stain intensity were evaluated. Biopsies (74.8%) from our cohort showed either histopathologic pAMR-1, immunopathologic pAMR-1, or combined histopathologic and immunopathologic pAMR-2 evidence of AMR. Expression of endothelial HLA class II was significantly correlated with the diagnosis of AMR by percentage area (P < .0001) and intensity of staining (P < .0001). The diagnosis of AMR significantly correlated with moderate (+2) and strong (+3) staining intensity for class II HLA as follows: histopathologic and immunopathologic pAMR-2 with odds ratio (OR) = 28.3 (P < .0001);histopathologic pAMR-1 alone with OR = 22.7 (P < .0001); and immunopathologic pAMR-1 alone with OR = 32.6 (P < .0001). Interestingly, our study also suggested that the inclusion of C4d focally positive cases also significantly correlates with the diagnosis of AMR (P < .003). We confirmed our hypothesis that in heart allograft biopsies, there is a spectrum of both percentage and intensity of HLA class II expression due to endothelial activation, and that class II HLA by immunohistochemistry is a marker significantly correlated with the diagnosis of AMR. In addition, the group of focally positive C4d biopsies (10%-50%) should be considered positive for the immunopathologic component of the 2013 ISHLT classification, as this group of biopsies also correlated with the diagnosis of AMR.
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http://dx.doi.org/10.1016/j.transproceed.2020.01.049DOI Listing
May 2020

Typical and atypical carcinoid tumors of the lung: a clinicopathological correlation of 783 cases with emphasis on histological features.

Hum Pathol 2020 04 5;98:98-109. Epub 2020 Mar 5.

Department of Thoracic Surgery, M D Anderson Cancer Center, Houston, TX, 77030, USA.

We present 783 surgical resections of typical and atypical carcinoid tumors of the lung identified in the pathology files of 20 different pathology departments. All cases were critically reviewed for clinical and pathological features and further correlated with clinical outcomes. Long-term follow-up was obtained in all the patients and statistically analyzed to determine significance of the different parameters evaluated. Of the histopathological features analyzed, the presence of mitotic activity of 4 mitoses or more per 2 mm, necrosis, lymphatic invasion, and lymph node metastasis were identified as statistically significant. Tumors measuring 3 cm or more were also identified as statistically significant and correlated with clinical outcomes. Based on our analysis, we consider that the separation of low- and intermediate-grade neuroendocrine neoplasms of the lung needs to be readjusted in terms of mitotic count as the risk of overgrading these neoplasms exceeds 10% under the current criteria. We also consider that tumor size is an important feature to be considered in the assessment of these neoplasms and together with the histological grade of the tumor offers important features that can be correlated with clinical outcomes.
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http://dx.doi.org/10.1016/j.humpath.2020.02.005DOI Listing
April 2020

Targeted donor complement blockade after brain death prevents delayed graft function in a nonhuman primate model of kidney transplantation.

Am J Transplant 2020 06 20;20(6):1513-1526. Epub 2020 Feb 20.

Department of Surgery, Division of Transplantation, University of Wisconsin, School of Medicine and Public Health, Madison, Wisconsin, USA.

Delayed graft function (DGF) in renal transplant is associated with reduced graft survival and increased immunogenicity. The complement-driven inflammatory response after brain death (BD) and posttransplant reperfusion injury play significant roles in the pathogenesis of DGF. In a nonhuman primate model, we tested complement-blockade in BD donors to prevent DGF and improve graft survival. BD donors were maintained for 20 hours; kidneys were procured and stored at 4°C for 43-48 hours prior to implantation into ABO-compatible, nonsensitized, MHC-mismatched recipients. Animals were divided into 3 donor-treatment groups: G1 - vehicle, G2 - rhC1INH+heparin, and G3 - heparin. G2 donors showed significant reduction in classical complement pathway activation and decreased levels of tumor necrosis factor α and monocyte chemoattractant protein 1. DGF was diagnosed in 4/6 (67%) G1 recipients, 3/3 (100%) G3 recipients, and 0/6 (0%) G2 recipients (P = .008). In addition, G2 recipients showed superior renal function, reduced sC5b-9, and reduced urinary neutrophil gelatinase-associated lipocalin in the first week posttransplant. We observed no differences in incidence or severity of graft rejection between groups. Collectively, the data indicate that donor-management targeting complement activation prevents the development of DGF. Our results suggest a pivotal role for complement activation in BD-induced renal injury and postulate complement blockade as a promising strategy for the prevention of DGF after transplantation.
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http://dx.doi.org/10.1111/ajt.15777DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7261643PMC
June 2020

Does Tumor FDG-PET Avidity Represent Enhanced Glycolytic Metabolism in Non-Small Cell Lung Cancer?

Ann Thorac Surg 2020 04 14;109(4):1019-1025. Epub 2019 Dec 14.

Children's Medical Center Research Institute, University of Texas Southwestern, Dallas, Texas; Department of Pediatrics, University of Texas Southwestern, Dallas, Texas; Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern, Dallas, Texas; Howard Hughes Medical Institute, Chevy Chase, Maryland.

Background: In non-small cell lung cancer (NSCLC), fluoro-2-deoxyglucose-positron emission tomography (FDG-PET) assists in diagnosis, staging, and evaluating treatment response. One variable of FDG-PET, the maximum standard uptake value (SUV), is considered an objective measure of glucose uptake. However, little is known about the fate of glucose in FDG-avid lung tumors in vivo. This study used stable glucose isotope tracing to determine whether the SUV predicts glycolytic metabolism or other glucose fates in tumors.

Methods: In this prospective Institutional Review Board-approved clinical trial, 52 untreated potentially resectable confirmed NSCLC patients underwent FDG-PET computed tomography. During the surgical procedure, the patients were infused with C-labeled glucose. Blood, tumor, and normal lung samples were analyzed by mass spectrometry to determine C enrichment in glycolytic intermediates. These values were compared with clinical variables, including SUV, maximum tumor diameter, stage, grade, and MIB-1/Ki67 proliferation index.

Results: For each patient, C enrichment in each metabolite was compared between tumor and adjacent lung. Although all tumors metabolized glucose, SUV did not correlate with glycolytic intermediate labeling. Rather, SUV correlated with markers indicating the use of other respiratory substrates, including lactate, and with the proliferation index.

Conclusions: SUV does not correlate with glycolytic metabolism in human NSCLC but does correlate with the proliferation index, suggesting that SUV predicts glucose use by pathways other than glycolysis. These pathways may offer alternative therapeutic targets, including biosynthetic pathways required for cell proliferation. The research techniques in this study offer the opportunity to understand the relationships between SUV, tumor metabolism, and therapeutic vulnerabilities in human NSCLCs.
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http://dx.doi.org/10.1016/j.athoracsur.2019.10.061DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7370816PMC
April 2020

Clinicopathological features of C3 glomerulopathy in children: a single-center experience.

Pediatr Nephrol 2020 01 30;35(1):153-162. Epub 2019 Oct 30.

Department of Pathology, UT Southwestern Medical Center, 5959 Harry Hines Blvd., Suite HP3-378, Dallas, TX, 75390-9234, USA.

Background: C3 glomerulopathy (C3G) is defined by dominant glomerular deposition of C3 and minimal or no immunoglobulin, with two subtypes-dense deposit disease (DDD) and C3 glomerulonephritis (C3GN)-distinguished by features on electron microscopy (EM). Given that this rare disease has generally unfavorable yet highly variable outcomes, we sought out to review the histopathology, complement/genetic studies, and renal outcomes of pediatric patients with C3G at our institution.

Methods: All native kidney biopsies performed in a single pediatric hospital over a 10-year period were reviewed for features of C3G. Of 589 biopsy reports, we identified 9 patients fulfilling the diagnostic criteria for C3G and retrospectively reviewed their clinical chart and renal biopsy findings.

Results: We identified 4 patients with DDD, 4 with C3GN, and 1 indeterminate case, with features of both C3GN and DDD. Five patients were positive for one or more nephritic factors (C3NeF, C4NeF, C5NeF) with 1 patient additionally positive for complement factor H (CFH) autoantibody. Genetic testing done in 5 of the 9 patients failed to identify any causative mutations. Three patients showed progressive renal dysfunction over a mean follow-up period of 33 months.

Conclusions: Complement and genetic studies are now routinely recommended for patients with a histopathological diagnosis of C3G. Careful interpretation of these studies and their prognostic and therapeutic implications in conjunction with biopsy findings is needed to further understand the pathophysiology of this rare disease in children.
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http://dx.doi.org/10.1007/s00467-019-04388-3DOI Listing
January 2020

Open Surgery for Ruptured Abdominal Aortic Aneurysm - 38 Years Experience at an Academic Center in Chile.

Ann Vasc Surg 2020 Apr 18;64:71-79.e1. Epub 2019 Oct 18.

Departamento de Cirugía Vascular y Endovascular, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile.

Background: Few series of ruptured abdominal aortic aneurysm (RAAA) from Latin America have been published.

Objectives: To report the outcomes of RAAA treated with open surgical repair (OSR) in a University Hospital in Chile. Secondary objectives are the identification of prognostic factors and survival rates.

Methods: Retrospective review of consecutive RAAA patients treated with OSR between September 1979 and December 2017. Medical records, diagnostic images, and follow-up details were obtained. Statistical methods include multiple logistic regression analysis.

Results: One hundred and sixteen patients underwent OSR for RAAA. The average age was 72.3 years (54-95), 62.9% ≥ 70 years, and 81.9% male. Preoperative systolic pressure <90 mm Hg was present in 74 patients (63.8%), and 10 (8.6%) experienced cardiac arrest before surgery. Only 30.2% were known to have an AAA before rupture. The mean aortic diameter was 7.9 cm. Sixteen patients had juxtarenal aneurysms (13.8%). The rupture was intra or retroperitoneal in 111 cases (95.7%), there were 4 fistulas to neighboring veins and one into the duodenum. Reconstruction included tubular graft in 39.7% and bifurcated in 58.6%. The estimated mean blood loss was 3,456 ± 2,768 mL (median 3,000). Mean mechanical ventilation was 7.4 ± 12.0 days and hemodialysis requirement in 21.8%. Six patients died during surgery and other 24 during the first postoperative month or in hospital, for an overall mortality rate of 25.9%. Age ≥70 years (P < 0.01), blood pressure less than 90 mm Hg (P = 0.03) and dialysis (P < 0.01) were associated with higher 30-day mortality rates. The survival rate was 68.0, 65.3, 44.3, and 25.2% at 1, 2, 5, and 10 years, respectively.

Conclusions: EVAR for RAAA is not affordable in every country. Outcomes of open RAAA repair at our institution are similar to results reported recently for OSR by the USA and European Medical centers.
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http://dx.doi.org/10.1016/j.avsg.2019.09.034DOI Listing
April 2020

Allograft outcomes of treated children with kidney transplant who developed plasma cell-rich acute rejection (PCAR): A single center's experience.

Pediatr Transplant 2019 09;23(6):e13500

Division of Pediatric Nephrology, University of Texas Southwestern Medical Center, Dallas, Texas.

Introduction: PCAR is a rare form of ACR that may compromise renal allografts. This review evaluates the outcomes of a protocol used to treat PCAR (Study group), and compares these outcomes with a matched cohort with ACR (Control group).

Methods: A retrospective analysis of 138 of pRTRs who underwent renal allograft biopsies between January 2008 and November 2016.

Results: Seven biopsies revealed in situ hybridization of EBER-negative PCAR (5%). Three Study group pRTRs lost their grafts within 3 months after rejection (43%). None of the Control group pRTRs lost their graft during this period. At the time of rejection, eGFR was different between the Control and Study groups (27.0 ± 19.9 mL/min per m vs 40.0 ± 10.6 mL/min/1.73 m , respectively; P < 0.05). Among Study group pRTRs with functioning allografts (n = 4), treatment resulted in an increase in eGFR from nadir levels (27.0 ± 19.9 vs 55.6 ± 18.3 mL/min/1.73 m , P < 0.05). In the Study group, complications included neutropenia, BK and EBV viremia, and infusion-related hypotension and hypertension.

Summary: (a) Graft loss in Study group while remaining high (43%) was lower than that reported in the published pediatric literature. (b) Our protocol was associated with improvement in eGFR in all surviving pRTRs within the Study group. (c) No life-threatening complications or malignancy were reported during the observation period.
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http://dx.doi.org/10.1111/petr.13500DOI Listing
September 2019

CD68/CD31 immunohistochemistry double stain demonstrates increased accuracy in diagnosing pathologic antibody-mediated rejection in cardiac transplant patients.

Am J Transplant 2019 11 9;19(11):3149-3154. Epub 2019 Sep 9.

Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas.

Pathologic antibody-mediated rejection (pAMR) occurs in 10% of cardiac transplant patients and is associated with increased mortality. The endomyocardial biopsy remains the primary diagnostic tool to detect and define pAMR. However, certain challenges arise for the pathologist. Accurate identification of >10% of intravascular macrophages along with endothelial swelling, which remains a critical component of diagnosing pAMR, is one such challenge. We used double labeling with an endothelial and histiocytic marker to improve diagnostic accuracy. Twenty-two cardiac transplant endomyocardial biopsies were screened using a CD68/CD31 immunohistochemical (IHC) double stain. To determine whether pAMR diagnosis would change using the double stain, intravascular macrophage staining was compared to using CD68 alone. Twenty-two cardiac pAMR cases from patients were included. Fifty-nine percent of cases previously called >10% intravascular macrophage positive by CD68 alone were called <10% positive using the CD68/CD31 double stain. Not using the double stain was associated with a significant overcall. In C4d-negative cases, using the CD68/CD31 double stain downgraded the diagnosis of pAMR2 to pAMR1 in 32% of cases. It was concluded that more than one third of patients were overdiagnosed with pAMR using CD68 by IHC alone. We demonstrate the value of using a CD68/CD31 double stain to increase accuracy.
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http://dx.doi.org/10.1111/ajt.15540DOI Listing
November 2019

2013 Banff Criteria for Acute Antibody-Mediated Rejection Are Superior to 2007 Banff Criteria in the Diagnosis and Assessment of Renal Allograft Outcomes.

Transplant Proc 2019 Jul - Aug;51(6):1791-1795. Epub 2019 Jul 10.

Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas. Electronic address:

Background: The 2013 Banff meeting updated the requirements for the diagnosis of acute/active antibody-mediated rejection (AAMR) in kidney allografts. There has been speculation that the changes lower the threshold for diagnosing AAMR, and may lead to possible unnecessary and expensive treatment.

Methods: We compared the 2013 Banff classification for AAMR to the previous 2007 Banff to determine if there was an increase in the number of patients receiving a diagnosis of AAMR and if the diagnosis affected allograft survival and post-biopsy 3-month and 6-month creatinine and eGFR values.

Results: A total of 212 renal allograft biopsies were compared to both 2007 and 2013 Banff classification requirements for AAMR. Ten patients (11 biopsies) met the 2007 criteria. An additional 15 patients (20 biopsies) met the 2013 criteria. These 2 groups showed no statistically significant demographic differences. By applying the 2013 Banff classification, we observed a 2.5-fold increase in the number of AAMR cases. One-year post-transplant allograft survival was higher in the 2013 group (.85 vs .55) and the 3-month and 6-month post-biopsy creatinine values were significantly lower for the 2013 group (1.6 ± .6 vs 3.3 ± 2.2, P value .01, and 1.7 ± .6 vs 3.4 ± 2.8, P value .03). The 3-month and 6-month eGFR values were higher in the 2013 group, although not statistically significant.

Conclusions: These results suggest that use of Banff 2013 criteria in place of Banff 2007 may result in diagnosing milder and earlier cases of AAMR with the possibility of initiating earlier treatment and improving graft outcomes.
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http://dx.doi.org/10.1016/j.transproceed.2019.04.060DOI Listing
November 2019

Telomere length and genetic variant associations with interstitial lung disease progression and survival.

Eur Respir J 2019 04 11;53(4). Epub 2019 Apr 11.

Dept of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA.

Leukocyte telomere length (LTL), rs35705950 and rs5743890 have been associated with idiopathic pulmonary fibrosis (IPF).In this observational cohort study, we assessed the associations between these genomic markers and outcomes of survival and rate of disease progression in patients with interstitial pneumonia with autoimmune features (IPAF, n=250) and connective tissue disease-associated interstitial lung disease (CTD-ILD, n=248). IPF (n=499) was used as a comparator.The LTL of IPAF and CTD-ILD patients (mean age-adjusted log-transformed T/S of -0.05±0.29 and -0.04±0.25, respectively) is longer than that of IPF patients (-0.17±0.32). For IPAF patients, LTL <10th percentile is associated with faster lung function decline compared to LTL ≥10th percentile (-6.43% per year -0.86% per year; p<0.0001) and worse transplant-free survival (hazard ratio 2.97, 95% CI 1.70-5.20; p=0.00014). The rs35705950 minor allele frequency (MAF) is greater for IPAF patients (23.2, 95% CI 18.8-28.2; p<0.0001) than controls and is associated with worse transplant-free IPAF survival (hazard ratio 1.92, 95% CI 1.18-3.13; p=0.0091). Rheumatoid arthritis (RA)-associated ILD (RA-ILD) has a shorter LTL than non-RA CTD-ILD (-0.14±0.27 -0.01±0.23; p=0.00055) and higher MAF (34.6, 95% CI 24.4-46.3 14.1, 95% CI 9.8-20.0; p=0.00025). Neither LTL nor are associated with transplant-free CTD-ILD survival.LTL and MAF have different associations with lung function progression and survival for IPAF and CTD-ILD.
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http://dx.doi.org/10.1183/13993003.01641-2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6612265PMC
April 2019

Hypercoagulability predicts worse outcomes in young patients undergoing lower extremity revascularization.

J Vasc Surg 2019 Jul 21;70(1):175-180. Epub 2018 Dec 21.

Vascular and Endovascular Department, Novant Health Heart and Vascular Institute, Charlotte, NC.

Objective: Although we know that young patients with peripheral artery disease (PAD) have worse outcomes than older patients, there is a scarcity of information about the incidence of hypercoagulability in this population. Our aim was to analyze outcomes of young patients diagnosed with a hypercoagulable state (unusual tendency toward thrombosis) after lower extremity revascularization compared with similar patients without hypercoagulability.

Methods: All patients 50 years of age or younger undergoing an initial procedure for lower extremity PAD from 2000 to 2015 at the Cleveland Clinic were retrospectively analyzed. Patients with a hypercoagulability panel were included and classified into groups as hypercoagulable positive (HP) or hypercoagulable negative (HN). Demographics, preoperative risk factors, form of presentation, level of disease, and type of intervention were analyzed in addition to perioperative complications, early failure, and length of stay. Primary outcomes were limb loss and primary, primary assisted, and secondary patencies. Outcomes were analyzed and Kaplan-Meier curves generated.

Results: Ninety-one patients were included for a total of 118 limbs. Mean follow-up was 32 months; 55% of patients had a hypercoagulable disorder, with 59% having lupus anticoagulant and 32% hyperhomocysteinemia. In the HP group, 71% were men; 49% were men in the HN group. Patients overall had a high prevalence of smoking (86%), hypertension (36%), and hyperlipidemia (33%). Acute limb ischemia was the most common form of presentation for both groups (50% HP, 38% HN). The aortoiliac segment was the most commonly affected (38% HP, 50% HN). The most frequent operation in the HN group was endarterectomy or bypass (32%); in the HP group, it was an endovascular intervention (29%). Perioperative occlusion or failure was 18% in the HN group vs 30% in the HP group (P > .05). Primary patency, primary assisted patency, and secondary patency at 36 months were all better for the HN group (no statistical significance) in all treatment groups. Major amputation at 36 months was significantly worse for the HP group (40% vs 10% in the HN group; P < .005). There was no difference in perioperative complications or length of stay.

Conclusions: Young patients undergoing lower extremity revascularization for PAD have worse outcomes when associated with hypercoagulability. There are trends to decreased patency of revascularization in these patients, with significantly more major amputations. No clear differences between modalities of treatment were demonstrated.
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http://dx.doi.org/10.1016/j.jvs.2018.09.062DOI Listing
July 2019

A Cellular Anatomy of the Normal Adult Human Prostate and Prostatic Urethra.

Cell Rep 2018 12;25(12):3530-3542.e5

Department of Urology, UT Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address:

A comprehensive cellular anatomy of normal human prostate is essential for solving the cellular origins of benign prostatic hyperplasia and prostate cancer. The tools used to analyze the contribution of individual cell types are not robust. We provide a cellular atlas of the young adult human prostate and prostatic urethra using an iterative process of single-cell RNA sequencing (scRNA-seq) and flow cytometry on ∼98,000 cells taken from different anatomical regions. Immunohistochemistry with newly derived cell type-specific markers revealed the distribution of each epithelial and stromal cell type on whole mounts, revising our understanding of zonal anatomy. Based on discovered cell surface markers, flow cytometry antibody panels were designed to improve the purification of each cell type, with each gate confirmed by scRNA-seq. The molecular classification, anatomical distribution, and purification tools for each cell type in the human prostate create a powerful resource for experimental design in human prostate disease.
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http://dx.doi.org/10.1016/j.celrep.2018.11.086DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6411034PMC
December 2018

Bile Cast Nephropathy: A Pathologic Finding with Manifold Causes Displayed in an Adult with Alcoholic Steatohepatitis and in a Child with Wilson's Disease.

Case Rep Nephrol Dial 2018 Sep-Dec;8(3):207-215. Epub 2018 Sep 27.

Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.

Bile cast nephropathy (BCN) is seen in patients who have acute kidney injury and severe hyperbilirubinemia due to a wide range of hepatobiliary system diseases. Findings seen by renal biopsy include acute tubular injury with necrotic and sloughed epithelial cells, yellow-green pigment within tubular epithelial cells, and pigmented granular casts. Hall's special stain for bile turns these casts green. In recent years, BCN has been described in a small number of case reports and clinical studies primarily in the setting of severe liver dysfunction. We present 2 diverse cases of BCN. The first involves an adult with hepatorenal syndrome secondary to alcoholic steatohepatitis and early cirrhosis. Second, we describe the first reported case of BCN in a child with fulminant hepatic failure due to Wilson's disease. Our cases expand the spectrum of causative diseases, and they provide further evidence that BCN is a distinct pathologic entity which may be found in both adult and pediatric patients with a variety of severe liver diseases.
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http://dx.doi.org/10.1159/000493231DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6206956PMC
September 2018

Utility of Bronchoalveolar Lavage and Transbronchial Biopsy in Patients with Hypersensitivity Pneumonitis.

Lung 2018 10 29;196(5):617-622. Epub 2018 Jun 29.

Division of Pulmonary and Critical Care Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX, 75219, USA.

Introduction: Making the diagnosis of HP is challenging due to a lack of consensus criteria and variability of both pathologic and radiographic findings. The purpose of this retrospective study was to determine the diagnostic utility of the combination of BAL lymphocyte count and TBBX in patients with HP.

Methods: We conducted a retrospective cohort study of all patients with a MDD diagnosis of HP at a single center.

Results: 155 patients were included in the study. 49% of patients who underwent BAL had a lymphocyte count > 20, 42% had a lymphocyte count > 30, and 34% had lymphocyte count > 40%. The median BAL lymphocyte count was higher in inflammatory HP compared to fibrotic HP. The addition of TBBX to BAL significantly increased the diagnostic yield regardless of the BAL lymphocyte cutoff used. The yield of bronchoscopy with TBBX and BAL when a lymphocyte count > 40% was used as a cutoff was 52%.

Conclusions: Our study suggests that the combination of TBBX with BAL significantly increases the likelihood that the procedure will provide adequate additional information to allow a confident MDD diagnosis of HP and may reduce the need for SLB in the diagnostic workup of HP.
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http://dx.doi.org/10.1007/s00408-018-0139-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6576254PMC
October 2018

Meningothelial-like Nodules of the Lung Show SSTR2a Immunohistochemical Staining.

Arch Pathol Lab Med 2018 07;142(7):781-782

Department of Pathology, University of Texas Southwestern Medical Center, Dallas.

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http://dx.doi.org/10.5858/arpa.2018-0079-LEDOI Listing
July 2018

An Empirical Approach Leveraging Tumorgrafts to Dissect the Tumor Microenvironment in Renal Cell Carcinoma Identifies Missing Link to Prognostic Inflammatory Factors.

Cancer Discov 2018 09 8;8(9):1142-1155. Epub 2018 Jun 8.

Kidney Cancer Program, Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, Texas.

By leveraging tumorgraft (patient-derived xenograft) RNA-sequencing data, we developed an empirical approach, DisHet, to dissect the tumor microenvironment (eTME). We found that 65% of previously defined immune signature genes are not abundantly expressed in renal cell carcinoma (RCC) and identified 610 novel immune/stromal transcripts. Using eTME, genomics, pathology, and medical record data involving >1,000 patients, we established an inflamed pan-RCC subtype (IS) enriched for regulatory T cells, natural killer cells, T1 cells, neutrophils, macrophages, B cells, and CD8 T cells. IS is enriched for aggressive RCCs, including -deficient clear-cell and type 2 papillary tumors. The IS subtype correlated with systemic manifestations of inflammation such as thrombocytosis and anemia, which are enigmatic predictors of poor prognosis. Furthermore, IS was a strong predictor of poor survival. Our analyses suggest that tumor cells drive the stromal immune response. These data provide a missing link between tumor cells, the TME, and systemic factors. We undertook a novel empirical approach to dissect the renal cell carcinoma TME by leveraging tumorgrafts. The dissection and downstream analyses uncovered missing links between tumor cells, the TME, systemic manifestations of inflammation, and poor prognosis. .
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http://dx.doi.org/10.1158/2159-8290.CD-17-1246DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6125163PMC
September 2018

Leukocyte-Associated Ig-like Receptor 1 Inhibits T1 Responses but Is Required for Natural and Induced Monocyte-Dependent T17 Responses.

J Immunol 2018 07 8;201(2):772-781. Epub 2018 Jun 8.

Division of Transplantation, Department of Surgery, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53792;

Leukocyte-associated Ig-like receptor 1 (LAIR1) is an ITIM-bearing collagen receptor expressed by leukocytes and is implicated in immune suppression. However, using a divalent soluble LAIR1/Fc recombinant protein to block interaction of cell surface LAIR1 with matrix collagen, we found that whereas T1 responses were enhanced as predicted, T17 responses were strongly inhibited. Indeed, LAIR1 on both T cells and monocytes was required for optimal T17 responses to collagen type (Col)V. For pre-existing "natural" T17 response to ColV, the LAIR1 requirement was absolute, whereas adaptive T17 and T1/17 immune responses in both mice and humans were profoundly reduced in the absence of LAIR1. Furthermore, the addition of C1q, a natural LAIR1 ligand, decreased T1 responses in a dose-dependent manner, but it had no effect on T17 responses. In IL-17-dependent murine organ transplant models of chronic rejection, LAIR1 but not LAIR1 littermates mounted strong fibroproliferative responses. Surface LAIR1 expression was higher on human T17 cells as compared with T1 cells, ruling out a receptor deficiency that could account for the differences. We conclude that LAIR1 ligation by its natural ligands favors T17 cell development, allowing for preferential activity of these cells in collagen-rich environments. The emergence of cryptic self-antigens such as the LAIR1 ligand ColV during ischemia/reperfusion injury and early acute rejection, as well as the tendency of macrophages/monocytes to accumulate in the allograft during chronic rejection, favors T17 over T1 development, posing a risk to long-term graft survival.
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http://dx.doi.org/10.4049/jimmunol.1701753DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7039397PMC
July 2018

Proliferative Glomerulonephritis with Monoclonal Immunoglobulin G Lambda Deposits: Report of the First Pediatric Case.

Case Rep Nephrol Dial 2018 Jan-Apr;8(1):70-75. Epub 2018 Apr 24.

Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.

Proliferative glomerulonephritis with monoclonal immunoglobulin G deposits (PGNMID) is a recently described, uncommon renal disorder which is considered a monoclonal gammopathy of renal significance. Although some patients will have a detectable monoclonal spike, overt hematologic malignancy is found in only a minority. Most patients with PGNMID are over the age of 50 years, and to our knowledge no cases have been reported in children or adolescents. Renal biopsy shows variable histologic patterns by light microscopy, with membranoproliferative and membranous patterns being most common. Immunofluorescence microscopy demonstrates restriction to a single immunoglobulin G heavy chain isotype and a single light chain subtype. Electron microscopy reveals granular, unorganized deposits. We report a rare pediatric case which occurred in a 17-year-old female. The rarity of this entity in the adult population has not permitted a standard treatment regimen to be established. Our adolescent patient was treated with multiple treatment regimens including prednisone, mycophenolate mofetil, rituximab, bortezomib, and daratumumab. Our case demonstrates that awareness of this disorder by pediatric nephrologists and pathologists is vital to guide accurate disease classification, prognosis, and treatment.
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http://dx.doi.org/10.1159/000488641DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5968240PMC
April 2018

Series of rare lung diseases mimicking imaging patterns of common diffuse parenchymal lung diseases.

Lung India 2018 May-Jun;35(3):231-236

Department of Pulmonology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.

Diffuse parenchymal lung diseases (DPLDs) encompass a variety of restrictive and obstructive lung pathologies. In this article, the authors discuss a series of rare pulmonary entities and their high-resolution computed tomography imaging appearances, which can mimic more commonly encountered patterns of DPLDs. These cases highlight the importance of surgical lung biopsies in patients with imaging findings that do not show typical imaging features of usual interstitial pneumonia.
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http://dx.doi.org/10.4103/lungindia.lungindia_291_17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5946556PMC
April 2018

A novel in vitro metric predicts in vivo efficacy of inhaled silver-based antimicrobials in a murine Pseudomonas aeruginosa pneumonia model.

Sci Rep 2018 04 23;8(1):6376. Epub 2018 Apr 23.

Department of Microbial Pathogenesis and Immunology, Texas A & M Health Science Center, College Station, TX, 77843, United States.

To address the escalating problem of antimicrobial resistance and the dwindling antimicrobial pipeline, we have developed a library of novel aerosolizable silver-based antimicrobials, particularly for the treatment of pulmonary infections. To rapidly screen this library and identify promising candidates, we have devised a novel in vitro metric, named the "drug efficacy metric" (DEM), which integrates both the antibacterial activity and the on-target, host cell cytotoxicity. DEMs calculated using an on-target human bronchial epithelial cell-line correlates well (R > 0.99) with in vivo efficacy, as measured by median survival hours in a Pseudomonas aeruginosa pneumonia mouse model following aerosolized antimicrobial treatment. In contrast, DEMs derived using off-target primary human dermal fibroblasts correlate poorly (R = 0.0595), which confirms our hypothesis. SCC1 and SCC22 have been identified as promising drug candidates through these studies, and SCC22 demonstrates a dose-dependent survival advantage compared to sham treatment. Finally, silver-bearing biodegradable nanoparticles were predicted to exhibit excellent in vivo efficacy based on its in vitro DEM value, which was confirmed in our mouse pneumonia model. Thus, the DEM successfully predicted the efficacy of various silver-based antimicrobials, and may serve as an excellent tool for the rapid screening of potential antimicrobial candidates without the need for extensive animal experimentation.
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http://dx.doi.org/10.1038/s41598-018-24200-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5913254PMC
April 2018

Pathology and radiology correlation of idiopathic interstitial pneumonias.

Hum Pathol 2018 02 24;72:1-17. Epub 2017 Nov 24.

University of Texas Southwestern, Department of Pathology, Dallas, Texas, 75235. Electronic address:

By nature, idiopathic interstitial pneumonias have been diagnosed in a multidisciplinary manner. As classifications have been subject to significant refinement over the last decade, the importance of correlating clinical, radiologic, and pathologic information to arrive at a diagnosis, which will predict prognosis in any given patient, has become increasingly recognized. In 2013, the American Thoracic Society and European Respiratory Society updated the idiopathic interstitial pneumonias classification scheme, addressing the most recent updates in the field. The purpose of this review is to highlight the correlations between radiologic and pathologic findings in idiopathic interstitial pneumonias while using updated classification schemes and naming conventions.
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http://dx.doi.org/10.1016/j.humpath.2017.11.009DOI Listing
February 2018

Pathology-radiology correlation of common and uncommon computed tomographic patterns of organizing pneumonia.

Hum Pathol 2018 01 7;71:30-40. Epub 2017 Nov 7.

Department of Radiology, University of Texas Southwestern Medical Center, Dallas, TX, 75235.

Organizing pneumonia (OP) is a common pattern of lung injury that can be associated with a wide range of etiologies. Typical and not-so-typical imaging features of OP occur, as both common and rare lung pathologies can mimic the same imaging pattern as that of OP. This article will attempt to describe the difference between confusing terminologies that have been used in the past for OP and existence of primary versus secondary OP. The role of a multidisciplinary approach as an essential component to correctly diagnose and effectively manage challenging cases of OP will be highlighted. Additionally, we will discuss the limitation of transbronchial and importance of open lung biopsy to make the correct diagnosis. One example of an emerging diagnosis in the spectrum of OP and diffuse alveolar damage is acute fibrinous and organizing pneumonia. Ultimately, the reader should feel comfortable recognizing the many variable presentations of OP and be able to participate knowledgeably in a multidisciplinary team after reading this article. OP is a disease entity with variable radiographic and distinct histological characteristics that requires a multidisciplinary approach to correctly diagnose cryptogenic OP. Classic radiologic findings of OP occur in as low as 60% of cases. Secondary causes include infections, neoplasms, inflammatory disorders, and iatrogenic. Acute fibrinous and organizing pneumonia can appear similarly, but miliary nodules are a clue to diagnosis.
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http://dx.doi.org/10.1016/j.humpath.2017.10.028DOI Listing
January 2018

Lactate Metabolism in Human Lung Tumors.

Cell 2017 Oct;171(2):358-371.e9

Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA; Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX, USA; Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, TX, USA. Electronic address:

Cancer cells consume glucose and secrete lactate in culture. It is unknown whether lactate contributes to energy metabolism in living tumors. We previously reported that human non-small-cell lung cancers (NSCLCs) oxidize glucose in the tricarboxylic acid (TCA) cycle. Here, we show that lactate is also a TCA cycle carbon source for NSCLC. In human NSCLC, evidence of lactate utilization was most apparent in tumors with high fluorodeoxyglucose uptake and aggressive oncological behavior. Infusing human NSCLC patients with C-lactate revealed extensive labeling of TCA cycle metabolites. In mice, deleting monocarboxylate transporter-1 (MCT1) from tumor cells eliminated lactate-dependent metabolite labeling, confirming tumor-cell-autonomous lactate uptake. Strikingly, directly comparing lactate and glucose metabolism in vivo indicated that lactate's contribution to the TCA cycle predominates. The data indicate that tumors, including bona fide human NSCLC, can use lactate as a fuel in vivo.
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http://dx.doi.org/10.1016/j.cell.2017.09.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5684706PMC
October 2017