Leaning in and moving forward: a call to action and review of diversity initiatives in SAGES.

BACKGROUND: Diversity, equity, and inclusion have been an intentional focus for SAGES well before the COVID-19 pandemic and the coincident societal recognition of social injustices and racism. Longstanding inequities within our society, healthcare, and the surgery profession have come to light in the aftermath of events that rose to attention around the time of Covid. In so doing, they have brought into focus disparities, injustices, and inequalities that have long been present in the field of surgery, selectively affecting the most vulnerable. METHODS: This White paper examines the current state of diversity within the field of surgery and SAGES (Society of American Gastrointestinal and Endoscopic Surgeons) approach and effort to pave the way forward to meaningful change. We delineate the imperative for diversity, equity, and inclusion for all. By all, we mean to be inclusive of the diversity of gender and sexual orientation, race, ethnicity, geography, sex, and disability in the field of surgery. RESULTS: SAGES is an organization that lives at the intersection of education and innovation. It has a vital role in assisting the surgical profession in addressing these issues and needs and being a force alongside others for sustained and necessary change. SAGES can only realize these goals through a commitment across all aspects of the organization to embed diversity, equity, and inclusion into our very fabric. CONCLUSION: True diversity, equity, and inclusion within a surgical organization is vital for its longevity, growth, relevance, and impact. Unfortunately, the absence of DEI limits opportunity, robs the organization of collective intelligence in an environment in which its presence is critical, contributes to health inequities, and impoverishes all within the society and its value to all with whom it interfaces. SAGES is an organization that lives at the intersection of education and innovation. It has a vital role in assisting the surgical profession in addressing these issues and needs and being a force alongside others for sustained and necessary change. SAGES can only realize these goals through a commitment across all aspects of the organization to embed diversity, equity, and inclusion into our very fabric. Strategies like those highlighted in this White Paper, may be within our grasp and we can learn yet more if we remain in a place of humility and teachability in the future.

Chimeric antigen receptor signaling: Functional consequences and design implications.

Chimeric antigen receptor (CAR) T cell therapy has transformed the care of refractory B cell malignancies and holds tremendous promise for many aggressive tumors. Despite overwhelming scientific, clinical, and public interest in this rapidly expanding field, fundamental inquiries into CAR T cell mechanistic functioning are still in their infancy. Because CAR T cells are manufactured from donor T lymphocytes, and because CARs incorporate well-characterized T cell signaling components, it has largely been assumed that CARs signal analogously to canonical T cell receptors (TCRs). However, recent studies demonstrate that many aspects of CAR signaling are unique, distinct from endogenous TCR signaling, and potentially even distinct among various CAR constructs. Thus, rigorous and comprehensive proteomic investigations are required for rational engineering of improved CARs. Here, we review what is known about proximal CAR signaling in T cells, compare it to conventional TCR signaling, and outline unmet challenges to improving CAR T cell therapy.

A technique for re-utilizing catheter insertion sites in children with difficult central venous access.

Maintenance of central venous access in patients with chronic medical conditions such as short bowel syndrome demands forethought and ingenuity. We describe an innovative technique for re-utilizing central venous access sites in patients who have chronic central venous access needs. Records of patients undergoing this technique were reviewed between August 2012 and December 2015. The technique involves "cutting-down" to the sterile fibrous tunnel that naturally forms around tunneled catheters. The fibrous sheath is then isolated and controlled much as would be done for a venous "cut-down." A separate exit site is then created for the new catheter and it is tunneled to the "cut-down" site per routine. The non-functioning catheter is then removed from the surgical field. The proximal fibrous sheath is finally cannulated either directly with the new catheter or with a wire/dilator system. This technique effectively re-uses the same venous access point while allowing for a complete change of the physical line and external site. Twenty attempts at this technique were made in twelve patients; six patients underwent the site re-utilization procedure multiple times. Re-using the fibrous tunnel to re-cycle the internal catheter site was successful in seventeen of twenty attempts. All patients had chronic conditions leading to difficult long-term central venous access [short bowel syndrome (6), hemophilia (2), cystic fibrosis (1), chronic need for central IV access (3)]. Indications for catheter replacement included catheter occlusion/mechanical failure/breakage (9), dislodgement (6), infection (1), and inadequate catheter length due to patient growth (4). Broviac/Hickman catheter sites were most commonly re-used (13; one failure); re-using a portcath site was successful in 5 of 7 attempts. There were no short term infections or mechanical complications. We describe a novel technique for salvaging tunneled central venous catheter access sites. This technique is well suited for patients with difficult and long-term central venous access needs, particularly those with chronic conditions such as intestinal failure. It is specifically useful when tunneled lines are broken, precipitated or clotted and unamenable to wiring.

Arm versus forearm tourniquet for carpal tunnel decompression - Which is better? A randomized controlled trial.

UNLABELLED: Tourniquet pain is a common source of complaint for patients undergoing carpal tunnel decompression and practice varies as to the tourniquet position used. There is little evidence to suggest benefit of one position over another. Our aim was to compare patient and surgeon experience of forearm and arm tourniquets. Following a power calculation, 100 patients undergoing open carpal tunnel decompression under local anaesthetic were randomized to either an arm or a forearm tourniquet. Measurements of blood pressure, heart rate and pain were taken at 2.5 min intervals. The operating surgeon also provided a visual analogue scale rating for the extent of bloodless field achieved and for any obstruction caused by the tourniquet. There was no statistically significant inter-group difference in patient pain or physiological response, tourniquet time, bloodless field or length of procedure. The degree of obstruction caused by the tourniquet was significantly higher in the forearm group. LEVEL OF EVIDENCE: I. Prospective Randomized Controlled Trial.

A reliable surgical treatment for digital mucous cysts.

There is no clear consensus about the best operative technique for the treatment of digital mucous cysts. We carried out a retrospective review of all patients who underwent excision of a digital mucous cyst using a local advancement skin flap over a 10-year period. A total of 69 patients were included and were reviewed at an average of 38 months (minimum 6 months) post-operatively. No patients were lost to follow-up. There was only one case of cyst recurrence. Of these 67 patients were happy with the scar and 63 patients said they would have the procedure again; 36 patients had a pre-operative nail deformity and 21 reported that the deformity grew out after the procedure.

Single incision Nuss procedure for pectus excavatum.

PURPOSE: To describe a unique single incision modification of the Nuss procedure and compare results to a historical cohort of standard Nuss patients. METHODS: A retrospective review of 32 patients who underwent the Nuss procedure at a tertiary academic medical center over a 4-year period (2007-2010). Fourteen consecutive patients who underwent the modified technique (MN) were compared to the previous 18 patients who underwent the standard procedure (SN). We evaluated for differences between group demographics, operative variables, and postoperative course. The major technical modification was performing the entire procedure through a single right lateral thoracic incision. The dissection for bar placement on the left side of the chest was performed in a subcutaneous, pre-sternal and pre-muscular plane from the right-sided incision. The bar was placed from the right side and positioned in the standard fashion. Thoracoscopy was preformed via the same incision using a 45-degree thoracoscope and multiple trocar positions. The bar was anchored to the chest wall with a unilateral bar stabilizer. RESULTS: There were no statistically significant differences between the study groups in any of the patient, operative or postoperative care parameters. CONCLUSION: The single incision modified Nuss procedure is as safe and efficacious as the standard technique.

Somatic p16(INK4a) loss accelerates melanomagenesis.

Loss of p16(INK4a)-RB and ARF-p53 tumor suppressor pathways, as well as activation of RAS-RAF signaling, is seen in a majority of human melanomas. Although heterozygous germline mutations of p16(INK4a) are associated with familial melanoma, most melanomas result from somatic genetic events: often p16(INK4a) loss and N-RAS or B-RAF mutational activation, with a minority possessing alternative genetic alterations such as activating mutations in K-RAS and/or p53 inactivation. To generate a murine model of melanoma featuring some of these somatic genetic events, we engineered a novel conditional p16(INK4a)-null allele and combined this allele with a melanocyte-specific, inducible CRE recombinase strain, a conditional p53-null allele and a loxP-stop-loxP activatable oncogenic K-Ras allele. We found potent synergy between melanocyte-specific activation of K-Ras and loss of p16(INK4a) and/or p53 in melanomagenesis. Mice harboring melanocyte-specific activated K-Ras and loss of p16(INK4a) and/or p53 developed invasive, unpigmented and nonmetastatic melanomas with short latency and high penetrance. In addition, the capacity of these somatic genetic events to rapidly induce melanomas in adult mice suggests that melanocytes remain susceptible to transformation throughout adulthood.

Bicarbonate-regulated soluble adenylyl cyclase (sAC) mRNA expression and activity in peripheral chemoreceptors.

UNLABELLED: Peripheral arterial chemoreceptors in the carotid body (CB) are modulated by pH/CO(2). Soluble adenylyl cyclase (sAC) is directly stimulated by bicarbonate ions (HCO(3)). Because CO(2)/HCO(3) mediates depolarization in chemoreceptors, we hypothesized that sAC mRNA would be expressed in the CB, and its expression and function would be regulated by CO(2)/HCO(3).Sprague-Dawley rats at postnatal days 16-17 were used to compare sAC mRNA gene expression between CB and non-chemosensitive tissues: superior cervical (SCG), petrosal (PG) and nodose ganglia (NG) by quantitative real time-PCR. Rat sAC gene expression was standardized to the expression of GAPDH (housekeeping gene) and the data were analyzed with the Pfaffl method. Gene and protein expression, and sAC regulation in the testis was used as a positive control. To determine the regulation of sAC mRNA expression and activity, all tissues were exposed to increasing concentrations of bicarbonate (0, 24, 44 mM, titrated with CO(2) and maintained a constant pH of 7.40). RESULTS: sAC mRNA expression was between 2-11% of CB expression in the SCG, PG and NG. Furthermore, only in the CB did HCO(3) upregulate sAC gene expression and increase cAMP levels. CONCLUSION: sAC mRNA and protein expression is present in peripheral arterial chemoreceptors and non-chemoreceptors. In the CB, CO(2)/HCO(3) not only activated sAC but also regulated its expression, suggesting that sAC may be involved in the regulation of cAMP levels in response to hyper/hypocapnia.

Influence of oestradiol and tamoxifen on oestrogen receptors-alpha and -beta protein degradation and non-genomic signalling pathways in uterine and breast carcinoma cells.

Tamoxifen acts as an oestrogen antagonist in the breast reducing cell proliferation, but in the uterus as an oestrogen agonist resulting in increased cell proliferation. Tamoxifen exerts its tissue-specific effects through the oestrogen receptors (ERalpha or ERbeta). The levels and functions of the two ERs affect the response of the target tissue to oestrogen and tamoxifen. We examined the control of ER stability in breast and uterine cell lines using western blotting and RT-PCR. In MCF-7 breast-derived cells, ERalpha and ERbeta proteins were rapidly degraded via the proteasome pathway in response to oestradiol; conversely tamoxifen stabilised both receptors. In Ishikawa uterine-derived cells, oestradiol and tamoxifen stabilised ERalpha but led to degradation of ERbeta by the proteasome pathway. Further investigations showed that oestradiol induced activation of the non-genomic ERalpha/Akt signalling pathway in MCF-7 cells. We have demonstrated that the alternative Erk signalling pathway is activated in Ishikawa cells following oestradiol treatment in the absence of an active proteasome pathway and therefore increased levels of ERbeta. In conclusion, our data have demonstrated tamoxifen or oestradiol control of ER subtype stability and that non-genomic activation of transcription pathways is cell specific.

Inherited thrombophilia: a possible cause of in utero vascular thrombosis in children with intestinal atresia.

BACKGROUND: Congenital atresia of the small and large intestine is thought to evolve from in utero mesenteric vascular occlusion of the corresponding intestinal segment. Because spontaneous thrombosis recently has been described in association with inherited thrombophilia, the authors wondered if inherited thrombophilia also might be found in babies with intestinal atresia. METHODS: Genetic analysis was done on 28 children treated for congenital intestinal atresia. DNA was analyzed for point mutations to detect the 2 most common types of inherited thrombophilia, the G1691A mutation in the factor V gene (factor V Leiden) and the G20210A mutation in the prothrombin gene. In addition, other genetic risk factors for thrombosis were analyzed including the C677T mutation in the methylenetetrahydrofolate reductase gene (MTHFR) and 2 polymorphisms of the factor VII gene (the R353Q and the hypervariable region 4 polymorphisms). RESULTS: The factor V Leiden mutation was present in 5 of 28 (18%) children treated for congenital intestinal atresia. This is increased significantly when compared with the reported carrier frequency of 3% to 7% in the general population and a reported carrier rate of 4.2% in the local population (P <.005). The R353Q polymorphism of the factor VII gene, specifically the RR genotype, was noted in 85% of patients with atresia with an expected frequency of 64% (P <.008). There were no significant associations noted between mutations in the prothrombin gene, the MTHFR gene, or the hypervariable region of the factor VII gene. CONCLUSIONS: The factor V Leiden mutation and the RR subtype of the R353Q polymorphism of the factor VII gene are seen at an increased frequency in children with congenital intestinal atresia. This suggests that inherited thrombophilia may play a role in the etiology of these in utero mesenteric thrombotic events.

Intralesional injection of mumps or Candida skin test antigens: a novel immunotherapy for warts.

BACKGROUND: Warts are common and induce physical and emotional discomfort. Numerous therapies exist, yet none is optimal. Despite theoretical advantages, immunotherapeutic modalities are often neglected as first-line wart therapies. OBJECTIVE: To compare treatment with intralesional skin test antigen injection of 1 wart vs cryotherapy of all warts. DESIGN: Pilot study. SETTING: University dermatology outpatient clinic. PATIENTS: A total of 115 consecutive patients with at least 1 nongenital wart. INTERVENTIONS: Patients with warts were tested for immunity to mumps and Candida using commercial antigens. Nonresponders received cryotherapy and immune individuals received cryotherapy or intralesional injection of 1 antiserum. RESULTS: Thirty-four (30%) of the 115 patients did not respond to the test injections and 81 (70%) had detectable immunity. Of the immune group, 26 (32%) received cryotherapy, 45 (56%) received intralesional mumps antiserum, and 10 (12%) received intralesional Candida antiserum. Of the anergic patients, 28 (82%) were treated with cryotherapy; 6 (18%) refused cryotherapy. Of the 39 patients who were treated with immunotherapy and completed the protocol, 29 (74%) had complete clearing of the treated wart. Fourteen (78%) of 18 patients with complete resolution of their immunotherapy-treated wart also had resolution of untreated, distant warts. CONCLUSIONS: Intralesional injection of mumps or Candida antigens into warts of immune individuals represents effective treatment. Observation of clearing of anatomically distinct and distant warts suggests acquisition of human papillomavirus-directed immunity in some patients. We conclude that this novel approach to immunotherapy may serve as first-line treatment in immune individuals with multiple or large warts and as second-line treatment in immune patients for whom cryotherapy fails.

Sources of information on the health effects of environmental tobacco smoke among African-American children and adolescents.

PURPOSE: To determine the common sources of information regarding the effects of smoking on health and their relationship to knowledge, attitudes, and preventative efforts regarding exposure to environmental tobacco smoke (ETS) among urban African-American children and adolescents. METHODS: All students who were enrolled in Grades 5-12 in an urban public school district located in the greater metropolitan area of Detroit, Michigan were surveyed using a structured, written questionnaire that assessed sources of information on the health effects of smoking, as well as knowledge, attitudes, and preventive efforts with respect to exposure to ETS. The primary analytic procedures utilized in the study were correlation analysis and analysis of variance. RESULTS: The African-American students surveyed in this study received information regarding the health effects of smoking from many sources, most notably television, family, and teachers. Second, students who received information on the effects of smoking on health from family and external sources (teacher, parent's friend, and religious leader) had higher overall knowledge, attitude, and preventive efforts scores than students who received information from other sources (friends, electronic media, and printed media). Finally, family influence was greater when parents were not smokers, and influenced elementary students more than middle school or high school students. CONCLUSIONS: The active involvement of teachers, religious leaders, parents, and other influential adults should be elicited in tobacco education and prevention efforts to maximize their effectiveness.

Management of glaucoma in pregnancy and lactation.

A 30-year-old pregnant woman with glaucoma is presented. The management of her case is used as a basis for a discussion of the use of glaucoma medications, including newer formulations, during pregnancy and lactation.

Yellow eyelids heralding lymphoma.

Yellow eyelids are an uncommon finding but can be cosmetically disfiguring to a patient. There are a variety of causes of yellow eyelids. A case study as well as the differential diagnosis of yellow eyelids are presented.

Expression of oestrogen receptor alpha variants in non-malignant breast and early invasive breast carcinomas.

Oestrogen receptor (ER) alpha variants have been described in normal breast and breast carcinomas, but their presence in a range of benign conditions and in small early invasive breast carcinomas has not been considered. Cryostat tissue sections from 19 normal and proliferative breast lesions and 44 carcinomas 15 mm and less in size detected by mammographic screening were screened for ERalpha splice variants using reverse transcriptase-nested PCR. The carcinomas were assessed for mutation by single-stranded conformational polymorphism analysis and variant forms/band shifts were sequenced. ERalpha was detected in all 19 non-malignant cases and exon 7-deleted variants were found in 16 of them. Three cases showed weak expression of exon 5, and two of exon 3 variants. There was no relationship between the presence of variants and the extent of proliferative change, ER status or age. ERalpha mRNA was not detected in two carcinomas; exon 3 deletions were found in four (9. 5%) of the other carcinomas, exon 5 in two (4.8%), and exon 7 in 11 (26.2%), with two variants in four carcinomas and a total of 29.5% of all cases having detectable variants. Two point mutations were found in one, which was a tubular carcinoma. Variant forms were identified in carcinomas of all sizes (bar<10 mm) but were more frequent in those of 15 mm. There was no relationship with type, grade or receptor status. The main difference between non-malignant breast and early invasive cancers related to exons 3 and 5. The findings suggest that ERalpha variants are not involved in breast cancer development but occur with tumour progression and may be a consequence rather than a cause.

Interleukin-1beta deficiency results in reduced NF-kappaB levels in pregnant mice.

Interleukin (IL)-1beta-deficient (IL-1beta(-/-)) mice were assessed for cytokine production during pregnancy. A significant reduction in nuclear factor (NF)-kappaB p65 protein content was observed in the uteri and spleens of pregnant IL-1beta(-/-) mice, as demonstrated by immunohistochemistry and Western immunoblot analysis. In addition, electromobility gel shift assay revealed less DNA binding activity of NF-kappaB p65-containing complex in pregnant IL-1beta(-/-) mice. To investigate differences in cytokine production regulated by NF-kappaB, the levels of tumor necrosis factor-alpha, macrophage inflammatory protein-1alpha, and interferon-gamma were measured in the uterine wall, spleen homogenates, and spleen cell cultures obtained from pregnant mice. Endocervical administration of lipopolysaccharide (LPS) increased cytokine levels in both wild-type (IL-1beta(+/+)) and IL-1beta(-/-) animals, but in IL-1beta(-/-) mice this response was 50-75% lower. Splenocytes from nonpregnant mice exhibited decreased LPS-induced cytokine production when primed in vitro with progesterone. This suppression was 25% greater in IL-1beta(-/-) than in IL-1beta(+/+) mice. These data suggest that constitutive NF-kappaB p65 protein synthesis is regulated by IL-1beta, particularly during pregnancy.

D-dimers in the diagnosis of pulmonary embolism.

The aim of this study was to determine if the absence of circulating D-dimers, as determined by latex agglutination assays, can correctly exclude the presence of pulmonary embolism using pulmonary angiography as the diagnostic endpoint. Blood samples were obtained prospectively at the time of angiography for suspicion of acute pulmonary embolism. Plasma was assayed for D-dimer by five different latex agglutination assays. Angiographic evidence of pulmonary emboli was found in 34% (35/ 103) of patients. The latex agglutination assays had sensitivities of 97 to 100% and specificities of 19 to 29%. The negative predictive value was 94 to 100%. However, a negative D-dimer was rare in patients with recent surgery, malignancy, or total bilirubin > 34 micromol/L (> 2 mg/dl). In 31 patients suspected of pulmonary emboli but without these confounding factors, the five D-dimer assays were negative in 46 to 55% of patients with normal pulmonary angiograms. The negative predictive value in these patients was 100% by all five latex agglutination assays tested. The latex agglutination assays for D-dimer, when the pulmonary angiogram is used as the diagnostic endpoint and in the absence of recent surgery, malignancy, or liver disease, appears to be a clinically useful test in the diagnosis of acute pulmonary embolism.

Renal thrombotic microangiopathy associated with anticardiolipin antibodies in hepatitis C-positive renal allograft recipients.

Hepatitis C virus (HCV) infection has been associated with de novo or recurrent membranoproliferative glomerulonephritis and acute transplant glomerulopathy in transplanted kidneys. Recently, anticardiolipin antibodies (ACA) have been linked with chronic HCV infection. A few reports have suggested an association between ACA and renal allograft thrombosis. This study examines the clinical and pathologic features of HCV-positive renal allograft recipients at our institution. From 1990 to 1996, 379 kidney transplants were performed. We identified 18 recipients (4.8%) with HCV-positive serology pretransplant. Determination of IgG and IgM ACA was performed by enzyme-linked immunosorbent assay, using pretransplant sera. Among the 18 patients, five patients presented with biopsy-proven de novo renal thrombotic microangiopathy (RTMA), occurring 5 to 120 d (median, 14 d) after transplant. No differences in pretransplant characteristics were observed between patients with (n = 5) or without (n = 13) RTMA. All five patients had a positive ACA test (either IgG or IgM titer > 2 SD above normal), compared with only one of 13 patients without RTMA. The mean value for IgG ACA was significantly higher in the RTMA patients than in patients without RTMA (22.9 +/- 14.1 versus 6.9 +/- 4.9 IgG phospholipid units, P = 0.02); however, there were no significant differences in IgM ACA titers. Rheumatoid factor and complement C4 levels were normal in pretransplant sera of patients with RTMA. Patients with RTMA had their cyclosporine withdrawn (four of five) or the dose was decreased (one of five), and one of five underwent plasmapheresis. Four of five patients died within 5 yr after transplant, compared with no deaths in the other 13 patients. Finally, as a control group, seven HCV-negative renal allograft recipients who presented with RTMA/hemolytic uremic syndrome during the same time period were found to have normal ACA values (IgG or IgM). RTMA associated with ACA in HCV-positive renal allograft recipients may represent a new clinical entity. The occurrence of this syndrome may have deleterious consequences for patient and graft survival.

Neurotrophic corneal defects after diode laser cycloablation.

PURPOSE: To report the occurrence of neurotrophic corneal defects after ciliary body ablation with the diode laser. METHODS: Case reports. RESULT: Neurotrophic keratitis, previously associated with cyclocryotherapy, may also be associated with ciliary body ablation with a contact diode laser. CONCLUSION: Practitioners who use the diode laser for ciliary body ablation should be aware of neurotrophic keratitis as a possible complication, especially because the patient population receiving this therapy may have diabetes, chronic eye inflammation, or other conditions predisposing to compromised corneal innervation, which is necessary for epithelial integrity.

Ovarian ablation alone promotes aortic intimal hyperplasia and accumulation of fibroblast growth factor.

BACKGROUND: Estrogen-mediated cardiovascular protection is incompletely explained by its beneficial lipid-modifying effects. Previous studies interrogating direct vascular effects of estrogens have used models of either diet- or injury-induced atherosclerosis. The purpose of this study was to determine the influence of ovarian ablation alone on vascular remodeling. We hypothesized that estrogens are atheroprotective, independent of their influence on lipid metabolism, by directly influencing the production and effects of a prototypical atherogenic mediator, basic fibroblast growth factor (bFGF). METHODS AND RESULTS: Twenty-five female sheep were randomized to sham operation, ovariectomy, or ovariectomy plus 17beta-estradiol replacement. Serum cholesterol and triglyceride levels were serially measured for 1 year and were similar among groups and in the normal range (30 to 60 mg/dL). At 6, 9, and 12 months, ovariectomy resulted in aortoiliac intimal hyperplasia compared with sham (P<0.01) and hormone replacement (P<0.01) groups. The neointima of ovariectomized animals was characterized immunohistochemically by increased vascular smooth muscle cells (VSMCs). Levels of bFGF protein were determined in adjacent aortic segments. Ovariectomized sheep had 2-fold more FGF than sham or ovariectomized sheep that received hormone replacement. In vitro, estradiol inhibited the mitogenic effect of bFGF on human aortic VSMCs. CONCLUSIONS: Without dietary manipulation, ovarian ablation alone induces aortic intimal hyperplasia in the ewe. Estradiol abrogates this response independently of its effects on serum lipids. Hormone replacement decreases the accumulation of the atherogenic peptide bFGF in vivo and inhibits the mitogenic response of VSMCs to bFGF in vitro. These results suggest that estrogens may provide atheroprotection both by modulating local production and by attenuating the influence of bFGF on VSMC growth.