Scripps Clinic Research Articles

Is Insomnia Associated with Mortality?

Is Insomnia Associated with Mortality?

Jürg Tschopp—1951–2011—an immortal contribution

Jürg Tschopp—1951–2011—an immortal contribution

Development of cladribine at Scripps for hairy cell leukemia and current results

Hairy cell leukemia (HCL) is an indolent, mature B-cell lymphoproliferative malignancy that clinically manifests as pancytopenia and fibrosis of the bone marrow, ultimately leading to recurrent infections and splenomegaly. This article reviews the extensive experience at Scripps Clinic with cladribine (2-chlorodeoxyadenosine; 2-CdA) in HCL. It is currently recommended as first-line treatment in HCL, because of its proven efficacy with associated low toxicity profile and brevity of treatment duration, with the majority of responses being complete (CRs). This was achieved after only a single 7-day infusion. We also discuss the success of cladribine in patients with relapsed and refractory HCL and potential approaches to eradicating minimal residual disease (MRD). MRD is thought to predict for future relapses. The eradication of MRD warrants continued study in order to further improve disease-free survival, which may translate into ultimately curing patients with HCL.

Papers Presented at the Annual Meetings of the Knee Society: Editorial Comment

Papers Presented at the Annual Meetings of the Knee Society: Editorial Comment

Inadequate Self-Care Practices in Patients with Implantable Devices: Implications for Remote Monitoring

Inadequate Self-Care Practices in Patients with Implantable Devices: Implications for Remote Monitoring Lisa D. Rathman, Roy S. Small, J. Thomas Heywood, John A. Andriulli, W.H. Wilson Tang; Heart Failure Clinic, The Heart Group/Lancaster Heart and Stroke Foundation, Lancaster, PA; Scripps Clinic Torrey Pines, La Jolla, CA; UMDNJ, Voorhees, NJ; Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, OH

Use of intranasal ketorolac and modified oral aspirin challenge for desensitization of aspirin-exacerbated respiratory disease

Intranasal ketorolac challenges can induce respiratory reactions in patients with aspirin-exacerbated respiratory disease (AERD). To determine whether intranasal ketorolac challenges might be used for aspirin desensitization. One hundred patients with suspected AERD who were referred to Scripps Clinic from May 1, 2007 to December 31, 2009 were challenged with 4 increasing doses of ketorolac intranasally at 30-minute intervals. Symptoms, objective changes in the results of their nasal examination, peak nasal inspiratory flow rates, and forced expiratory volume in 1 second (FEV(1)) values were recorded. After nasal ketorolac dosing, patients were given oral aspirin as part of the challenge and desensitization. A control group consisted of 100 patients who had previously undergone our standard oral aspirin challenges and desensitization. Both groups were consecutively enrolled and had similar clinical characteristics. Compared with the standard oral aspirin challenge and desensitization, intranasal ketorolac and modified aspirin challenge significantly attenuated the mean percentage decrease in FEV(1) values (8.5% vs 13.4%; P = .01) and decreased the percentage of extrapulmonary reactions (23% vs 45%; P = .002), particularly laryngospasm (7% vs19%; P = .02) and gastrointestinal reactions (12% vs 33%; P = .001). This new protocol was significantly shorter, lasting an average of 1.9 vs 2.6 days (P = <.001). In fact, 83% of the patients completed the new protocol in less than 48 hours compared with only 20% in the oral challenge control group (P < .001). Intranasal ketorolac challenge and desensitization followed by rapid oral aspirin challenges is effective, safe, and less time-consuming than our standard oral aspirin desensitization protocol.

Drug-Eluting Stent Restenosis

In 1977, using a wire-tipped balloon, Dr Andreas Gruentzig performed the first percutaneous coronary intervention on a blockage in Mr Adolph Bachmann’s left anterior descending coronary artery.1a The continued success of this pioneering event has been documented by follow-up angiography at 10 years and again at 23 years postprocedure. Mr Bachmann’s follow-up angiograms may be the most viewed on the planet, because they were obtained during dramatic, live demonstration conferences in front of thousands of physicians and were published in the New England Journal of Medicine .1b In fact, Mr Bachmann was recently honored at an event attended by over 10 000 people at a large medical meeting. It is indeed very fortunate for the field of interventional cardiology that Mr Bachmann’s left anterior descending artery blockage did not recur. Article see p 42 In 2010, despite all the promising technology and all the research, creativity, effort, and dollars poured into the field, the problem of restenosis, although vastly reduced, has not been eliminated. It is not an exaggeration to state that at my institution, Scripps Clinic, nearly every working day we see at least 1 patient with restenosis of a drug-eluting stent (DES). One report estimated 200 000 repeat revascularizations are performed every year in the United States for DES failure.2 Despite tremendous progress in lowering the incidence of restenosis with DES, given the large number of percutaneous coronary intervention procedures performed worldwide every year, even a low restenosis rate translates into a significant absolute number of patients experiencing this problem. The problem of DES restenosis is pervasive enough that all physicians caring for patients with coronary disease should be well versed in its treatment. Early data from the bare-metal stent era informed us that if restenosis were to occur, we could expect it within 6 …

Wrist actigraphic scoring for sleep laboratory patients: algorithm development

Wrist actigraphy is employed increasingly in sleep research and clinical sleep medicine. Critical evaluation of the performance of new actigraphs and software is needed. Actigraphic sleep-wake estimation was compared with polysomnographic (PSG) scoring as the standard in a clinical sleep laboratory. A convenience sample of 116 patients undergoing clinical sleep recordings volunteered to participate. Actiwatch-L recordings were obtained from 98 participants, along with 18 recordings using the newer Spectrum model (Philips Electronics), but some of the actigraphic recordings could not be adequately aligned with the simultaneous PSGs. Of satisfactory alignments, 40 Actiwatch recordings were used as a training set to empirically develop a new Scripps Clinic algorithm for sleep-wake scoring. The Scripps Clinic algorithm was then prospectively evaluated in 39 Actiwatch recordings and 16 Spectrum recordings, producing epoch-by-epoch sleep-wake agreements of 85-87% and kappa statistics averaging 0.52 (indicating moderate agreement). Wake was underestimated by the scoring algorithm. The correlations of PSG versus actigraphic wake percentage estimates were r = 0.6690 for the Actiwatch and r = 0.2197 for the Spectrum. In general, using a different weighting of activity counts from previous and subsequent epochs, the Scripps Clinic algorithm discriminated sleep-wake more successfully than the manufacturer's Actiware algorithms. Neither algorithm had fully satisfactory agreement with PSG. Further evaluations of algorithms for these actigraphs are needed, along with controlled comparisons of different actigraphic designs and software.

Vascular complications of exposure for anterior lumbar interbody fusion

The purpose of this study is to document the incidence of vascular complications during anterior lumbar interbody fusion (ALIF) in 212 consecutive patients treated at the Scripps Clinic and determine what factors adversely affected outcome. We reviewed the prospectively maintained database of all ALIF procedures performed at Scripps Clinic between August 2004 and June 2009. All procedures were performed by a spine surgeon in conjunction with a vascular surgeon who performed the exposure portion of the operation, and protected the vessels from injury during the instrumentation phase of the operation. Two hundred twelve ALIF operations were identified. The mean age of the patients was 53.8 years, and 120 (56.6%) were female. The mean body mass index (BMI) was 29.6 (range, 18.1 to 47.8). Twenty-two (10.4%) operations were performed at the L4-5 disc space, 149 (70.3%) at L5-S1, and 41 (19.3%) involved L4-L5 with L5-S1. The mean estimated blood loss (EBL) was 143 milliliters. There was a significant direct correlation between increasing BMI and EBL (P = .018). Thirteen (6.1%) vascular injuries occurred of which five were major (38.5%). One major arterial injury (0.5%) occurred and required arterial thrombectomy and stent placement. Four of the major vascular injuries were venous in nature and required a multi-suture repair. The remaining eight injuries (61.5%) were venous, the majority of which required a suture repair. There were no mortalities. There was an increase risk of vascular injury when both L4-L5 and L5-S1 were exposed (P = .003) and with the male gender (P = .013). Calcification of the aorto-iliac system did not exert an effect on EBL or vascular injury. In four cases, the surgeon was unable to expose the appropriate disc levels. Anterior exposure of the spine for ALIF can be performed safely with a team approach that includes a vascular surgeon. Preoperative evaluation by a vascular surgeon is advisable. Patients with increased BMI and bi-level exposures should be approached with caution.

Very long-term eradication of minimal residual disease in patients with hairy cell leukemia after a single course of cladribine

AbstractCladribine induces protracted remissions in patients with hairy cell leukemia (HCL). However, many long-term responders ultimately relapse. We sought to determine whether long-term complete responders subsequent to a single 7-day course of cladribine were without minimal residual disease (MRD) and potentially cured of HCL. From the 358-person Scripps Clinic cladribine database, we identified 19 patients in continuous and complete hematologic response (median age, 75 years; median time from diagnosis, 18 years; and median time from cladribine, 16 years). Nine of 19 (47%) patient samples had no evidence of residual disease; 7 of 19 (37%) samples had MRD; and 3 of 19 (16%) had morphologic evidence of HCL in hematoxylin and eosin–stained bone marrow sections. These results indicate that HCL is potentially curable after cladribine treatment. In addition, patients with MRD and even gross morphologic disease can live many years without manifesting hematologic relapses.

Schwannoma of the femoral nerve

aDepartment of Orthopaedic Surgery, University of California San Diego Medical Center, San Diego, California bDivision of Orthopaedic Surgery, Scripps Clinic, San Diego, California cDepartment of Orthopaedic Surgery, Veterans Affairs Medical Center, La Jolla, California Correspondence to William J. Peace, MD, UCSD Medical Center, 200 W. Arbor Dr. MC8894, San Diego, CA 92103-8894 Tel: +619 543 7247; fax: +619 543 2540; e-mail: [email protected]

Blood flow dynamics after laser therapy of port wine stain birthmarks

During laser therapy of port wine stain (PWS) birthmarks, regions of perfusion may persist. We hypothesize that such regions are not readily observable even when laser surgery is performed by highly experienced clinicians. The objective of this study was to use objective feedback to assess the acute vascular response to laser therapy. A clinic-friendly laser speckle imaging (LSI) instrument was developed to provide the clinician with real-time images of blood flow during laser therapy. Images were acquired from patients undergoing laser therapy of PWS birthmarks at Scripps Clinic and the Beckman Laser Institute and Medical Clinic. Blood flow maps were extracted from the acquired imaging data. Histogram-based analysis was applied in grading the degree of heterogeneity present in the blood flow maps after laser therapy. Collectively, two types of patient responses were observed in response to laser exposure: (1) an immediate increase in perfusion within minutes after laser therapy; and (2) an overall decrease in blood perfusion approximately 1 hour after laser therapy, with distinct regions of persistent perfusion apparent in the majority of post-treatment blood-flow images. A comparison of blood flow in PWS and adjacent normal skin demonstrated that PWS blood flow can be greater than, or sometimes equivalent to, that of normal skin. In general, a decrease in skin perfusion is observed during pulsed laser therapy of PWS birthmarks. However, a heterogeneous perfusion map was frequently observed. These regions of persistent perfusion may be due to incomplete photocoagulation of the targeted vessels. We hypothesize that immediate retreatment of these regions identified with LSI, will result in enhanced removal of the PWS vasculature. Lasers Surg. Med. 41:563-571, 2009. (c) 2009 Wiley-Liss, Inc.

Total Plasma Homocysteine: The Mediator/Marker Controversy Continues

Featured Article: Jacobsen DW, Gatautis VJ, Green R, Robinson K, Savon SR, Secic M, et al. Rapid HPLC determination of total homocysteine and other thiols in serum and plasma: sex differences and correlation with cobalamin and folate concentrations in healthy subjects. Clin Chem 1994;40:873–81.1 My interest in homocysteine metabolism began in the late 1960s when I was a postdoctoral fellow in the Department of Biochemistry at Scripps Clinic and Research Foundation (now the Scripps Research Institute) working on B12-dependent enzymes. In 1969 Kilmer McCully reported an association between increased homocysteine and premature cardiovascular disease in 2 patients with homocystinuria (1). Although assays for total plasma homocysteine (tHcy), the sum of reduced and oxidized homocysteine species, were yet to be developed, homocystinuria was generally assumed to be a condition in which blood concentrations of homocysteine were highly increased. In 1985 Refsum et al. described a radioenzymatic assay for tHcy (2) that made it possible to assess the association of …

Infringement of product-by-process claims in US clarified

US patent law has long allowed a patentee to claim an invention in which a product is made by a particular process in the format of a so-called ‘product-by-process’ claim: see eg, Ex parte Painter, 1891 C.D. 200, 200–201 (Comm’r Pat. 1891). Precedent from the US Court of Appeals for the Federal Circuit was arguably in conflict as to whether an accused product must be made by the claimed process in order to be found to literally infringe the claim. In Scripps Clinic & Research Foundation v Genentech, Inc., 927 F.2d 1565, 1583 (Fed. Cir. 1991), the panel found that ‘the correct reading of productby-process claims is that they are not limited to product prepared by the process set forth in the claims’. However, in the following year, a different panel in Atlantic Thermoplastics Co. v Faytex Corp., 970 F.2d 834, 846-47 (Fed. Cir. 1992), found that ‘process terms in product-by-process claims serve as limitations in determining infringement’. The full Court sua sponte took the issue as to whether process limitations incorporated into product-by-process claims serve as limitations in determining infringement in the pair of appeals brought involving Abbott Labs. US Patent No. 4,935,507 (‘the ‘507 patent’): see Abbott Labs. v Sandoz, Inc., No. 2007-1400 & Lupin Ltd v Abbott Labs., No. 2007-1446, 566 F.3d 1282 (Fed. Cir. 18 May 2009) (en banc). It is only this issue that the present summary addresses.

Percutaneous Revascularization Is the Preferred Strategy for Patients With Significant Left Main Coronary Stenosis

In the early 1970s, coronary artery bypass graft (CABG) was found to improve late survival in comparison to medical therapy in patients with significant left main stenosis.1–3 Once CABG became the standard of care for left main disease, a distinction between “protected”—by at least 1 patent bypass graft to the left coronary artery—and “unprotected left main (UPLM)”— no patent bypass graft to the left coronary artery—was made. In the 1980s, early attempts at balloon angioplasty of UPLM stenoses were associated with poor early outcomes because of coronary dissection, abrupt closure, and restenosis. Mortality rates as high as 30% at 1 year were reported.4–6 In the 1990s, bare metal stents were introduced and soon used to treat UPLM disease. Several small registries found a low rate of procedural complications, but repeat revascularization rates of 20% to 30% because of restenosis were considered unacceptable.7–12 Early bare metal stent registries for UPLM also found high mortality rates, particularly in high-risk patients, such as patients with acute coronary syndromes and poor left ventricular function. Importantly, high-risk subgroups often presented with late sudden death after stenting.11,13 In the early 2000s, the introduction of drug-eluting stents (DES), with the promise of vastly reduced rates of restenosis,14–17 raised the possibility of improved late outcomes in this challenging patient group. Response by Smith p 1033 Clinical outcomes after treatment of UPLM disease with either the sirolimus-eluting stent or the paclitaxel-eluting stent from >20 small registries have been published. Results reported in these registries vary widely.18–40 As depicted in Table 1, cardiac mortality between 6 and 12 months after the procedure ranges from 0% to 11%. Target lesion revascularization (TLR) or target vessel revascularization (TVR) rates range from 2% to 38%. This wide variation in clinical outcome appears largely because of variation …

A Simple Formula to Identify Patients with Advanced Stage Gastric Adenocarcinoma

Purpose: Definitive staging of gastric adenocarcinoma (GAC) involves surgical resection and extensive lymph node dissection. A patient's comorbidities may often preclude a surgical procedure or render the decision to proceed to surgery a difficult one. However, without staging, it is difficult to provide an accurate prognosis. The average 5-year survival of patients with Stage I GAC is 60–86%, however, patients with stage II, III and IV GAC have 5-year survival rates of 34, 20 and 7%, respectively. In addition, observational studies have demonstrated that the natural history of GAC differs between ethnicities. We hypothesize that assessing for the age, serum total protein (TP), albumin (Alb) and hemoglobin (Hgb) at the time of diagnosis can accurately assess for advanced stage GAC in a non-Asian cohort of patients. Methods: A review of the electronic medical records of the Scripps Clinic and Green Hospital from 1997–2008 was performed to identify patients with a de novo diagnosis of GAC with subsequent surgical staging. Adenocarcinomas involving the gastroesophageal junction were excluded. Data regarding cancer stage, ethnicity, age, TP, Alb and Hgb at the time of diagnosis were collected. A “staging score” was also developed to simultaneously assess for all four factors: Staging score = (Hgb × TP × Alb)/age. Patients of Asian descent were not evaluated in this investigation. Results: There were 70 de novo diagnoses of GAC in the study period with 56 cases staged by surgical resection. Forty-six of the GAC cases were of a non-Asian ethnicity and comprised the study cases. Although a trend towards significance was observed, no single factor of age, TP, Alb or Hgb demonstrated a significant difference between early and advanced stage GAC (Table 1). However, the staging score demonstrated a statistically significant difference between stage I and stage II-IV GAC (P= 0.04). Using a staging score cut-off of 255, the positive and negative predictive values of this test for Stage I GAC were 44.0 and 95.7%, respectively.Table 1: Patient Characteristics: Early versus Late Stage Gastric AdenocarcinomaConclusion: We conclude that patients with a staging score of less than 255 are highly likely to have an advanced stage of GAC. This formula provides a simple and inexpensive method of identifying a cohort of patients, who are likely to have a poorer prognosis. The ability to recognize patients with an unfavorable prognosis before surgical staging provides clinicians and patients useful prognostic information and may potentially assist in their decision to pursue aggressive therapy. A prospective study to validate this scoring system is warranted.

Potential curability of cladribine in selected patients with hairy cell leukemia

18010 Background: Hairy cell leukemia (HCL) is an uncommon, chronic B-cell lymphoproliferative disorder associated with pancytopenia, splenomegaly, and recurrent infections. Cladribine as a single seven-day continuous intravenous infusion achieves an overall response rate of 98%, and complete response rate of 91%. Follow-up studies have documented minimal residual disease (MRD) in at least 50% of complete responders and continued clinical relapses, with 108 months median follow-up (range, 86–172). This suggests that all complete responders are at continuous risk for relapse. With twenty-year follow-up now available in some patients, we sought to determine if any patients were without MRD and potentially cured of HCL after a single seven-day course of cladribine. Methods: The Scripps Clinic cladribine phase II database of 379 patients was screened for patients who are alive, in a continuous hematologic remission, and received only a single seven-day course of cladribine. Patients agreed to undergo complete blood counts (CBC) and bone marrow aspiration and biopsy (BM). BM samples were analyzed for morphologic evidence of HCL and for MRD by flow cytometry to detect monoclonal B-cells with HCL phenotypic characteristics. Immunoglobulin heavy chain gene rearrangement studies were performed in some patients. Results: Of the 379 patients screened, we had accurate contact information on 75 patients; 20 patients met inclusion criteria and agreed to undergo CBC and BM. Patient characteristics: 17 males and 3 females; median age, 53 years (range, 39 to 75); median pretreatment duration, 2 years (range, 0.1 to 12.3); median duration following cladribine treatment, 17 years (range, 11 to 20). Prior to cladribine, 13 patients were untreated; 10 had undergone splenectomy, interferon, or chlorambucil. All patients had a normal CBC. Of these 20 patients, 9 patients had no evidence of MRD on BM; 7 patients had MRD; 4 patients had morphological evidence of HCL. Conclusions: Cladribine can potentially cure HCL in a subset of patients. Patients with MRD or even morphologically demonstrable disease can remain asymptomatic with normal blood counts up to twenty years after a single course of cladribine. No significant financial relationships to disclose.

Treatment of Dermatofibroma Sarcoma Protuberans Using Modified Mohs Micrographic Surgery: No Recurrences and Smaller Defects

The purpose of this study was to evaluate the use of modified Mohs micrographic surgery (MMS) for dermatofibroma sarcoma protuberans (DFSP) in a single institution by a single surgeon. The authors conducted a retrospective analysis of 25 patients with DFSP who were treated with modified MMS over the past 19 years at Scripps Clinic. Of the 25 patients treated with modified MMS for DFSP, there were no identifiable recurrences. The mean follow-up time was 101 months. The defect sizes of DFSP lesions treated by modified MMS are smaller than if the lesions had been treated with the standard wide local excision (WLE) margins of 3 cm. This is a retrospective analysis using the data of one surgeon. Five of the 25 patients were not examined in our office. Not all patients had 5-year follow-up. There were no cases of the fibrosarcomatous variant. Our data support the growing literature that modified MMS achieves excellent local control for DFSP with a possible benefit of smaller defects when compared with treatment with WLE. The authors have indicated no significant interest with commercial supporters.

The role of vasoactive intestinal peptide in neuroprotection: interview with Professor Illana Gozes

Professor Illana Gozes was interviewed by Emma Quigley (Senior Editor, Expert Opinion) on 17th April 2007.Professor Illana Gozes BSc, PhD holds the titles of Professor of Clinical Biochemistry; The Lily and Avraham Gildor Chair for the Investigation of Growth Factors; Director of Adams Super Center for Brain Studies and Levi-Edersheim-Gitter fMRI Institute; Head of the Dr Diana and Zelman Elton (Elbaum) Laboratory for Molecular Neuroendocrinology, Tel Aviv University and Chief Scientific Officer, Allon Therapeutics, Inc., Vancouver BC, Canada. Professor Gozes has served as a member (or chair) of several faculty, university or national and international committees and she currently serves on the Board of Directors of Allon Therapeutics, the Scientific Review Board of the ISOA, and is the Editor-in-Chief of the Journal of Molecular Neuroscience. Professor Gozes has received a number of scientific awards for her work including the Landau Award for an excellent PhD dissertation, the Juludan Prize and the Teva Founders Prize for exceptional scientific studies that may lead to biotechnology developments as well as the Bergmann Prize and the Neufeld award for outstanding/leading US-Israel BSF grant proposals, and has published extensively in the fields of molecular neuroscience and neuroprotection (> 200 scientific manuscripts). She is co-inventor of > 15 patents and applications, including the composition of matter patent on AL-108 and AL-208, Allon's lead compounds. Professor Gozes received a BSc from Tel Aviv University, a PhD from The Weizmann Institute of Science and was a Weizmann Postdoctoral Fellow at Massachusetts Institute of Technology, Research Associate/Visiting Scientist at the Salk Institute and the Scripps Clinic and Research Foundation, a Senior Scientist/Associate Professor at the Weizmann Institute and a Fogarty-Scholar-in-Residence at the National Institutes of Health (USA). Professor Gozes directs a very active research laboratory at Tel Aviv University and is mentoring and has mentored directly ∼ 50 graduate students toward their MSc or PhD degrees.

The Severity of Historical ASA/NSAID-Induced Asthma Attacks Does Not Correlate with Severity of Asthma Induced During Oral ASA Challenges

Attacks Does Not Correlate with Severity of Asthma Induced During Oral ASA Challenges A. N. Williams, R. A. Simon, K. M. Woessner, D. D. Stevenson; Scripps Clinic, San Diego, CA. RATIONALE: Historical aspirin (ASA) or nonsteroidal antiinflammatory drug (NSAID)-induced reactions might provide predictive information about the severity of reactions in patients with aspirin exacerbated respiratory disease (AERD) undergoing oral ASA challenges (OAC). METHODS: The provoking doses, treatments, and treatment settings of the historical ASA/NSAID-induced asthma attacks was obtained from 210 consecutive patients with suspected AERD referred for OAC and ASA desensitization. RESULTS: Of 210 subjects, 147 (70%) reported seeking acute medical care for their historical ASA/NSAID-induced asthma attacks. Of these 147, 101 (69%) were treated in ERs and released and 46 (31%) required hospitalization. During OAC in these 147 subjects, 37 (25%) had a >20% decline and 14 (10%) had a >30% decline in FEV1 values. Of the 46 patients previously hospitalized for ASA/NSAID-induced asthma attacks, 15 (33%) had a >20% decline and 6 (13%) had a >30% decline in FEV1 during OAC. By contrast, of the 63 patients who treated their prior ASA/NSAID-induced reactions at home, 10 (16%) had a >20% decline and 5 (8%) had a >30% decline in FEV1 during OAC (p value NS for both). The average provoking doses of ASA were 550 mg for the historical reaction and 62 mg during OAC. CONCLUSIONS: The severity of the historical ASA/NSAID-induced asthma attack was not helpful in predicting asthma severity during OAC. Even though 70% of patients sought acute medical care for asthma attacks provoked by therapeutic doses of ASA/NSAID, a minority had clinically significant asthma during low-dose OAC. These data provide further reassurance regarding the safety of outpatient ASA desensitization. Funding: General Clinical Research Center, Scripps Clinic