Research Spotlight

Barker, C.M., Cork, D.P., McCullough, P.A., Mehta, H.S., Van Houten, J., Gunnarsson, C., Ryan, M., Irish, W., Mollenkopf, S. and Verta, P. (2020). “Comparison of Survival in Patients with Clinically Significant Tricuspid Regurgitation with and without Heart Failure (From the Optum Integrated File).” Am J Cardiol Dec 29;S0002-9149(20)31422-3. [Epub ahead of print].

Full text of this article.

This study aimed to quantify survival rates for patients with Tricuspid Regurgitation (TR) using real-world data. Several clinical conditions are associated with tricuspid regurgitation (TR), including heart failure (HF), other valve disease (OVD), right-sided heart disease (RSHD), and others that impact mortality. Optum data from January 1, 2007, through December 31, 2018 included patients age ≥18 years with TR and 12 months of continuous health plan enrollment before TR. Exclusion criteria were end-stage renal disease or known/primary organ pathology. Cohorts were created hierarchically: (1) TR with HF; (2) TR with OVD (no HF); (3) TR with RSHD only (no OVD or HF); (4) TR only. Survival was estimated using a Cox hazard model with an interaction term for TR severity and adjusted for patient demographics and Elixhauser comorbidities. A total of 33,686 met study inclusion (1) TR with HF (26.6%); (2) TR with OVD (36.7%); (3) TR with RSHD only (17.1%); (4) TR only (19.6%). TR Patients (regardless of severity) with HF, OVD or RSHD had an increased risk of mortality compared to patients with TR alone. TR severity was also significantly associated (hazard ratio= 1.33; P=0.0002) with an increased risk of all-cause mortality. In conclusion, TR severity is significantly associated with an increased risk of all-cause mortality, independent of associated conditions including HF, OVD, or RSHD. In patients with severe TR, the mortality risk is most pronounced for patients who had RSHD without HF or OVD prior to their TR diagnosis.

Aulivola, B., Mitchell, E.L., Rowe, V.L., Smeds, M.R., Abramowitz, S., Amankwah, K.S., Chen, H.T., Dittman, J.M., Erben, Y., Humphries, M.D., Lahiri, J.A., Pascarella, L., Quiroga, E., Singh, T.M., Wang, L.J. and Eidt, J.F. (2020). “Ensuring Equity, Diversity and Inclusion in the Society for Vascular Surgery A Report of the Society for Vascular Surgery Task Force on Equity, Diversity and Inclusion.” J Vasc Surg Dec 14;S0741-5214(20)32602-1. [Epub ahead of print].

Full text of this article.

Diversity, equity, and inclusion represent interconnected goals meant to ensure that all individuals, regardless of their innate identity characteristics, feel welcomed and valued amongst their peers. Equity is achieved when all individuals have equal access to leadership and career advancement opportunities as well as fair compensation for their work. It is well known that the unique backgrounds and perspectives contributed by a diverse workforce strengthen and improve medical organizations overall. The Society for Vascular Surgery (SVS) is committed to supporting the highest quality leadership, patient care, surgical education, and societal recommendations through promoting diversity, equity, and inclusion within the SVS. The overarching goal of this document is to provide specific context and guidance for enhancing diversity, equity, and inclusion within the SVS as well as setting the tone for conduct and processes beyond the SVS, within other national and regional vascular surgery organizations and practice settings.

Abdallah, M.A., Kuo, Y.F., Asrani, S., Wong, R.J., Ahmed, A., Kwo, P., Terrault, N., Kamath, P.S., Jalan, R. and Singal, A.K. (2020). “Validating a novel score based on interaction between ACLF grade and MELD score to predict waitlist mortality.” J Hepatol Dec 13;S0168-8278(20)33840-X. [Epub ahead of print].

Full text of this article.

BACKGROUND AND AIM: Among candidates listed for liver transplant (LT), MELD score may not capture acute on chronic liver failure (ACLF) severity. Data on interaction between ACLF and MELD score in predicting waitlist (WL) mortality are scanty. METHODS: UNOS database (01/2002 to 06/2018) on LT listings for adults with cirrhosis and ACLF (without HCC) was analyzed. ACLF grades 1, 2, 3a, and 3b- were defined using modified EASL-CLIF criteria. RESULTS: Of 18,416 candidates with ACLF at listing (mean age 54 years, 69% males, 63% Caucasians), 90-d WL mortality (patient death or being too sick for LT) was 21.6% (18%, 20%, 25%, and 39% for ACLF grades 1, 2, 3a, and 3b respectively). Fine and Gray regression model identified interaction between MELD and ACLF grade, with higher impact of ACLF at lower MELD score. Other variables included candidate’s age, gender, liver disease etiology, listing MELD, ACLF grade, obesity, and performance status. A score developed using parameter estimates from the interaction model on the derivation cohort (N=9181) stratified the validation cohort (N=9235) to four quartiles Q1 (score <10.42), Q2 (10.42-12.81), Q3 (12.82-15.50), and Q4 (>15.50). WL mortality increased with each quartile from 13%, 18%, 23%, and 36% respectively. Observed versus expected deciles on WL mortality in validation cohort showed good calibration (goodness of fit P=0.98) and correlation (R=0.99). CONCLUSION: Among selected candidates who are in ACLF at listing, MELD score and ACLF interact in predicting cumulative risk of 90-d WL mortality, with higher impact of ACLF grade at lower listing MELD score. Validating these findings in large prospective studies will support to factor in both MELD and ACLF in prioritizing transplant candidates and allocation of liver grafts.E

Zhao, W., Peng, Y., Hu, Y., Guo, X.E., Li, J., Cao, J., Pan, J., Feng, J.Q., Cardozo, C., Jarvis, J., Bauman, W.A. and Qin, W. (2020). “Electrical stimulation of hindlimb skeletal muscle has beneficial effects on sublesional bone in a rat model of spinal cord injury.” Bone 144: 115825.

Full text of this article.

Spinal cord injury (SCI) results in marked atrophy of sublesional skeletal muscle and substantial loss of bone. In this study, the effects of prolonged electrical stimulation (ES) and/or testosterone enanthate (TE) on muscle mass and bone formation in a rat model of SCI were tested. Compared to sham-transected animals, a significant reduction of the mass of soleus, plantaris and extensor digitorum longus (EDL) muscles was observed in animals 6 weeks post-SCI. Notably, ES or ES + TE resulted in the increased mass of the EDL muscles. ES or ES + TE significantly decreased mRNA levels of muscle atrophy markers (e.g., MAFbx and MurF1) in the EDL. Significant decreases in bone mineral density (BMD) (-27%) and trabecular bone volume (-49.3%) at the distal femur were observed in animals 6 weeks post injury. TE, ES and ES + TE treatment significantly increased BMD by +6.4%, +5.4%, +8.5% and bone volume by +22.2%, and +56.2% and+ 60.2%, respectively. Notably, ES alone or ES + TE resulted in almost complete restoration of cortical stiffness estimated by finite element analysis in SCI animals. Osteoblastogenesis was evaluated by colony-forming unit-fibroblastic (CFU-F) staining using bone marrow mesenchymal stem cells obtained from the femur. SCI decreased the CFU-F(+) cells by -56.8% compared to sham animals. TE or ES + TE treatment after SCI increased osteoblastogenesis by +74.6% and +67.2%, respectively. An osteoclastogenesis assay revealed significantly increased TRAP(+) multinucleated cells (+34.8%) in SCI animals compared to sham animals. TE, ES and TE + ES treatment following SCI markedly decreased TRAP(+) cells by -51.3%, -40.3% and -46.9%, respectively. Each intervention greatly reduced the ratio of RANKL to OPG mRNA of sublesional long bone. Collectively, our findings demonstrate that after neurologically complete paralysis, dynamic muscle resistance exercise by ES reduced muscle atrophy, downregulated genes involved in muscle wasting, and restored mechanical loading to sublesional bone to a degree that allowed for the preservation of bone by inhibition of bone resorption and/or by facilitating bone formation.

Wang, L., Moore, D.C., Huang, J., Wang, Y., Zhao, H., J, D.H.Y., Jackson, C.L., Quesenberry, P.J., Cao, W. and Yang, W. (2021). “SHP2 regulates the development of intestinal epithelium by modifying OSTERIX(+) crypt stem cell self-renewal and proliferation.” Faseb j 35(1): e21106.

Full text of this article.

The protein tyrosine phosphatase SHP2, encoded by PTPN11, is ubiquitously expressed and essential for the development and/or maintenance of multiple tissues and organs. SHP2 is involved in gastrointestinal (GI) epithelium development and homeostasis, but the underlying mechanisms remain elusive. While studying SHP2’s role in skeletal development, we made osteoblast-specific SHP2 deficient mice using Osterix (Osx)-Cre as a driver to excise Ptpn11 floxed alleles. Phenotypic characterization of these SHP2 mutants unexpectedly revealed a critical role of SHP2 in GI biology. Mice lacking SHP2 in Osx(+) cells developed a fatal GI pathology with dramatic villus hypoplasia. OSTERIX, an OB-specific zinc finger-containing transcription factor is for the first time found to be expressed in GI crypt cells, and SHP2 expression in the crypt Osx+ cells is critical for self-renewal and proliferation. Further, immunostaining revealed the colocalization of OSTERIX with OLFM4 and LGR5, two bona fide GI stem cell markers, at the crypt cells. Furthermore, OSTERIX expression is found to be associated with GI malignancies. Knockdown of SHP2 expression had no apparent influence on the relative numbers of enterocytes, goblet cells or Paneth cells. Given SHP2’s key regulatory role in OB differentiation, our studies suggest that OSTERIX and SHP2 are indispensable for gut homeostasis, analogous to SOX9’s dual role as a master regulator of cartilage and an important regulator of crypt stem cell biology. Our findings also provide a foundation for new avenues of inquiry into GI stem cell biology and of OSTERIX’s therapeutic and diagnostic potential.