Hemorrhoids: what are the options in 2018?

PURPOSE OF REVIEW: Efforts continue to improve the treatment of patients with symptomatic hemorrhoidal disease by interventions designed to improve efficiency and effectiveness, including by reducing intraoperative and postoperative pain, decreasing operating times, minimizing blood loss and controlling symptoms and recurrence rates. Simultaneously, there are also renewed efforts to minimize the number of patients who will require procedural intervention by focusing on conservative measures that encourage better bowel regulation and habits. The purpose of this brief report is to review the current status of the diagnosis and treatment of patients with hemorrhoidal disease. Overall, new procedures or procedural refinements to existing techniques continue to be introduced with promising short-term outcomes - at least in some instances. In most instances, long-term follow-up or equivalency data are still being accumulated such that a definitive, unequivocal answer to what is truly the best alternative to traditional hemorrhoidectomy remains controversial. One of the challenges is heterogeneity as regards diagnosis, intervention and, especially, outcomes measures such that comparing therapies is too difficult. A recent initiative to standardize metrics has promise. RECENT FINDINGS: Recent studies largely appear to suggest that conservative treatment approaches and managing patient expectations are critically important in which a primary objective should be to minimize the progression to symptomatic disease and complications in patients who are diagnosed with hemorrhoids. The pace of change as regards the development of new or improved surgical techniques appears may be accelerating. SUMMARY: Progress is being made and the knowledge base is being expanded as regards the treatment options for patients with hemorrhoids and expected outcomes. A key initiative to standardize the approaches to diagnosis and treatment about staging, procedural interventions and outcomes will facilitate comparative analytics, if successful.

Structural correlates of the creatine transporter function regulation: the undiscovered country.

Creatine (Cr) and phosphocreatine constitute an energy shuttle that links ATP production in mitochondria to subcellular locations of ATP consumption. Cells in tissues that are reliant on this energy shuttle, such as myocytes and neurons, appear to have very limited ability to synthesize creatine. Therefore, these cells depend on Cr uptake across the cell membrane by a specialized creatine transporter (CrT solute carrier SLC6A8) in order to maintain intracellular creatine levels. Cr supplementation has been shown to have a beneficial effect in numerous in vitro and in vivo models, particularly in cases of oxidative stress, and is also widely used by athletes as a performance enhancement nutraceutical. Intracellular creatine content is maintained within narrow limits. However, the physiological and cellular mechanisms that mediate Cr transport during health and disease (such as cardiac failure) are not understood. In this narrative mini-review, we summarize the last three decades of research on CrT structure, function and regulation.

Removal of Potential Phosphorylation Sites does not Alter Creatine Transporter Response to PKC or Substrate Availability.

BACKGROUND: Creatine, Phosphocreatine, and creatine kinases, constitute an energy shuttle that links ATP production in mitochondria with cellular consumption sites. Myocytes and neurons cannot synthesize creatine and depend on uptake across the cell membrane by a specialized transporter to maintain intracellular creatine levels. Although recent studies have improved our understanding of creatine transport in cardiomyocytes, the structural elements underlying the creatine transporter protein regulation and the relevant intracellular signaling processes are unknown. METHODS: The effects of pharmacological activation of kinases or phosphatases on creatine transport in cardiomyocytes in culture were evaluated. Putative phosphorylation sites in the creatine transporter protein were identified by bioinformatics analyses, and ablated using site-directed mutagenesis. Mutant transporter function and their responses to pharmacological PKC activation or changes in creatine availability in the extracellular environment, were evaluated. RESULTS: PKC activation decreases creatine transport in cardiomyocytes in culture. Elimination of high probability potential phosphorylation sites did not abrogate responses to PKC activation or substrate availability. CONCLUSION: Modulation of creatine transport in cardiomyocytes is a complex process where phosphorylation at predicted sites in the creatine transporter protein does not significantly alter activity. Instead, non-classical structural elements in the creatine transporter and/or interactions with regulatory subunits may modulate its activity.

Normal cardiac function in mice with supraphysiological cardiac creatine levels.

Creatine and phosphocreatine levels are decreased in heart failure, and reductions in myocellular phosphocreatine levels predict the severity of the disease and portend adverse outcomes. Previous studies of transgenic mouse models with increased creatine content higher than two times baseline showed the development of heart failure and shortened lifespan. Given phosphocreatine's role in buffering ATP content, we tested the hypothesis whether elevated cardiac creatine content would alter cardiac function under normal physiological conditions. Here, we report the creation of transgenic mice that overexpress the human creatine transporter (CrT) in cardiac muscle under the control of the α-myosin heavy chain promoter. Cardiac transgene expression was quantified by qRT-PCR, and human CrT protein expression was documented on Western blots and immunohistochemistry using a specific anti-CrT antibody. High-energy phosphate metabolites and cardiac function were measured in transgenic animals and compared with age-matched, wild-type controls. Adult transgenic animals showed increases of 5.7- and 4.7-fold in the content of creatine and free ADP, respectively. Phosphocreatine and ATP levels were two times as high in young transgenic animals but declined to control levels by the time the animals reached 8 wk of age. Transgenic mice appeared to be healthy and had normal life spans. Cardiac morphometry, conscious echocardiography, and pressure-volume loop studies demonstrated mild hypertrophy but normal function. Based on our characterization of the human CrT protein expression, creatine and phosphocreatine content, and cardiac morphometry and function, these transgenic mice provide an in vivo model for examining the therapeutic value of elevated creatine content for cardiac pathologies.

Multifactorial analysis of the learning curve for robot-assisted laparoscopic biliopancreatic diversion with duodenal switch.

OBJECTIVE: To assess the impact of surgeon, patient, and case-specific factors on the learning curve of robot-assisted laparoscopic biliopancreatic diversion with duodenal switch (RA-LBPD/DS). BACKGROUND: The BPD/DS has better resolution of diabetes and hypercholesterolemia, and the best long-term weight loss compared to the laparoscopic gastric band or the Roux-en-Y gastric bypass. Despite excellent results, the BPD/DS is least commonly performed because of greater malabsorption, longer operative duration, and higher technical complication rates. A reduction in technical complications and operative duration will enable the BPD/DS to be offered more frequently. METHODS: Consecutive patients (N = 120) undergoing RA-LBPD/DS between October 2000 and August 2008 were analyzed using univariate and multivariate logistic regression to determine the influence of surgeon and patient factors on complications and operative duration. Independent variables were case number, age, gender, body mass index, American Society of Anesthesiologists (ASA) score, difficult anatomy, and need for extensive adhesiolysis. Dependent variables were complications (leaks, bleeding, and conversion) and operative duration. The best-fit model predicted the risk factors for complications, and a risk-adjusted cumulative sum analysis estimated the learning curve. RESULTS: : Operative duration decreased an average of 3 minutes with each successive case (P < 0.001, R² = 0.63) and with patient's female gender. Adhesiolysis, difficult anatomy, liver biopsy, and higher ASA score increased operative duration. The incidence of high blood loss (13.3%), conversion (2.2%), and leaks (5.8%) were experienced by a total of 22 patients (18.3%). There was no mortality. Complications declined after 50 cases and were strongly predicted by increasing surgeon case number. CONCLUSIONS: The learning curve for the RA-LBPD/DS is 50 cases. Risk factors influencing outcomes were identified.

Exposing cardiomyocytes to subclinical concentrations of doxorubicin rapidly reduces their creatine transport.

Doxorubicin is commonly used to treat leukemia, lymphomas, and solid tumors, such as soft tissue sarcomas or breast cancer. A major side effect of doxorubicin therapy is dose-dependent cardiotoxicity. Doxorubicin's effects on cardiac energy metabolism are emerging as key elements mediating its toxicity. We evaluated the effect of doxorubicin on [(14)C]creatine uptake in rat neonatal cardiac myocytes and HL-1 murine cardiac cells expressing the human creatine transporter protein. A significant and irreversible decrease in creatine transport was detected after an incubation with 50-100 nmol/l doxorubicin. These concentrations are well below peak plasma levels (5 µmol/l) and within the ranges (25-250 nmol/l) for steady-state plasma concentrations reported after the administration of 15-90 mg/m(2) doxorubicin for chemotherapy. The decrease in creatine transport was not solely because of increased cell death due to doxorubicin's cytotoxic effects. Kinetic analysis showed that doxorubicin decreased V(max), K(m), and creatine transporter protein content. Cell surface biotinylation experiments confirmed that the amount of creatine transporter protein present at the cell surface was reduced. Cardiomyocytes rely on uptake by a dedicated creatine transporter to meet their intracellular creatine needs. Our findings show that the cardiomyocellular transport capacity for creatine is substantially decreased by doxorubicin administration and suggest that this effect may be an important early event in the pathogenesis of doxorubicin-mediated cardiotoxicity.

Adjuvant radiotherapy in the treatment of invasive intraductal papillary mucinous neoplasm of the pancreas: an analysis of the surveillance, epidemiology, and end results registry.

BACKGROUND: Management and outcomes of patients with invasive intraductal papillary mucinous neoplasm (IPMN) of the pancreas are not well established. We investigated whether adjuvant radiotherapy (RT) improved cancer-specific survival (CSS) and overall survival (OS) among patients undergoing surgical resection for invasive IPMN. METHODS: The Surveillance, Epidemiology, and End Results (SEER) registry was used in this retrospective cohort study. All adult patients with resection of invasive IPMN from 1988 to 2007 were included. CSS and OS were analyzed using Kaplan-Meier curves. Unadjusted and propensity-score-adjusted Cox proportional-hazards modeling were used for subgroup analyses. RESULTS: 972 patients were included. Adjuvant RT was administered to 31.8% (n=309) of patients. There was no difference in overall median CSS or OS in patients who received adjuvant RT (5-year CSS: 26.5 months; 5-year OS: 23.5 months) versus those who did not (CSS: 28.5 months, P=0.17; OS: 23.5 months, P=0.23). Univariate predictors of survival were lymph node (LN) involvement, T4-classified tumors, and poorly differentiated tumor grade (all P<0.05). In the propensity-score-adjusted analysis, adjuvant RT was associated with improved 5-year CSS [hazard ratio (HR): 0.67, P=0.004] and 5-year OS (HR: 0.73, P=0.014) among all patients with LN involvement, though further analysis by T-classification demonstrated no survival differences among patients with T1/T2 disease; patients with T3/T4-classified tumors had improved CSS (HR: 0.71, P=0.022) but no difference in OS (HR: 0.76, P=0.06). CONCLUSION: On propensity-score-adjusted analysis, adjuvant RT was associated with improved survival in selected subsets of patients with invasive IPMN, particularly those with T3/T4 tumors and LN involvement.

Laparoscopic appendectomy outcomes on the weekend and during the week are no different: a national study of 151,774 patients.

BACKGROUND: The "weekend effect" is defined as increased morbidity and mortality for patients admitted on weekends compared with weekdays. It has been observed for several diseases, including myocardial infarction and renal insufficiency; however, it has not yet been investigated for laparoscopic appendectomy in acute appendicitis-one of the most prevalent surgical diagnoses. METHODS: The present study is based on the Nationwide Inpatient Sample (NIS) from 1999 to 2008. The following outcomes were compared between patients undergoing laparoscopic appendectomy for acute appendicitis admitted on weekdays versus weekends: severity of appendicitis, intraoperative and postoperative complications, conversion rate, in-hospital mortality, and length of hospital stay. Unadjusted and risk-adjusted generalized linear regression analyses were performed. RESULTS: Overall, 151,774 patients were included, mean age was 39.6 years, 52.6% (n = 79,801) were male, and 25.3% (n = 38,317) were admitted on weekends. After risk adjustment, the conversion rate was lower [odds ratio (OR): 0.94, p = 0.004, number needed to harm (NNH): 244], whereas pulmonary complications (OR: 1.12, p = 0.028, NNH: 649) and reoperations (OR: 1.21, p = 0.013, NNH: 1,028) were slightly higher on weekends than on weekdays. Overall postoperative complications (OR: 1.03, p = 0.24), mortality (OR: 1.37, p = 0.075) and length of hospital stay (mean on weekday: 2.00 days, weekends: 2.01 days, p = 0.29) were not statistically different. CONCLUSIONS: The present investigation provides evidence that no clinically significant "weekend effect" for patients undergoing laparoscopic appendectomy exists. Therefore, hospital or staffing policy changes are not justified based on the findings from this large national study.

AMPK and substrate availability regulate creatine transport in cultured cardiomyocytes.

Profound alterations in myocellular creatine and phosphocreatine levels are observed during human heart failure. To maintain its intracellular creatine stores, cardiomyocytes depend upon a cell membrane creatine transporter whose regulation is not clearly understood. Creatine transport capacity in the intact heart is modulated by substrate availability, and it is reduced in the failing myocardium, likely adding to the energy imbalance that characterizes heart failure. AMPK, a key regulator of cellular energy homeostasis, acts by switching off energy-consuming pathways in favor of processes that generate energy. Our objective was to determine the effects of substrate availability and AMPK activation on creatine transport in cardiomyocytes. We studied creatine transport in rat neonatal cardiomyocytes and HL-1 cardiac cells expressing the human creatine transporter cultured in the presence of varying creatine concentrations and the AMPK activator 5-aminoimidazole-4-carboxamide-1-ß-d-ribonucleoside (AICAR). Transport was enhanced in cardiomyocytes following incubation in creatine-depleted medium or AICAR. The changes in transport were due to alterations in V(max) that correlated with changes in total and cell surface creatine transporter protein content. Our results suggest a positive role for AMPK in creatine transport modulation for cardiomyocytes in culture.

Complex abdominal wall hernias: a new classification system and approach to management based on review of 133 consecutive patients.

BACKGROUND: Plastic surgeons are increasingly involved in the repair of complex ventral hernias. Although this typically involves recurrent incisional hernias, operative strategies can be applied to most abdominal wall defects, including chronic wounds with or without exposed mesh, enterocutaneous fistulas, or hernias associated with significant pannus formation. METHODS: This is a retrospective review of a single institution/single surgeon experience of complex ventral hernia repair performed over a 5-year period. Patients were classified into different hernia types based on their characteristics and underwent hernia repair according to the presented algorithm. RESULTS: A total of 133 patients underwent a complex ventral hernia repair between January 2005 and September 2009. The separation of components technique was used in the majority of cases. Permanent or biologic mesh was added in select patients. Adjunctive procedures were performed as indicated. The majority of short-term (less than 1 year) recurrences occurred in patients expected to have impaired wound healing due to comorbid conditions. In these patients, the recurrence rate was reduced when autologous repair was reinforced with mesh. CONCLUSION: Autologous tissue is the preferred method for reconstruction of complex ventral hernias. In certain instances, such as contamination, use of an acellular dermal matrix mesh is added as a temporizing measure. A subset of patients who will be prone to recurrence remains. Long-term follow-up is needed to confirm reliable and reproducible results.

Will the clinicians support the researchers and teachers? Results of a salary satisfaction survey of 947 academic surgeons.

OBJECTIVE: To determine whether academic surgeons are satisfied with their salaries, and if they are willing to forego some compensation to support departmental academic endeavors. BACKGROUND: Increasing financial constraints have led many academic surgery departments to rely on increasingly on clinical revenue generation for the cross-subsidization of research and teach missions. METHODS: Members of 3 academic surgical societies (n = 3059) were surveyed on practice characteristics and attitudes about financial compensation. Univariate and multivariate logistic regression analyses were performed to identify determinants of salary satisfaction and willingness to forego compensation to support academic missions. RESULTS: One thousand thirty-eight (33.9%) surgeons responded to our survey, 947 of whom maintain an academic practice. Of these academic surgeons, 49.7% expressed satisfaction with their compensation. Length of career, administrative responsibility for compensation and membership in the American Surgical Association or the Society of University Surgeons were predictive of salary satisfaction on univariate analysis. Frequent emergency call duty, increased clinical activity, and greater perceived difference between academic and private practice compensation were predictive of salary dissatisfaction. On multivariate analysis, increased clinical activity was inversely associated with both salary satisfaction (adjusted odds ratio [AOR], 0.77; [95% CI: 0.64, 0.94]; P = 0.009) and amount of compensation willingly killed for an academic practice (AOR, 0.71; [0.61, 0.83]; P < 0.0005). CONCLUSIONS: Increasing reliance on clinical revenue to subsidize nonclinical academic missions is disaffecting many academic surgeons. Redefined mission priorities, enhanced nonfinancial rewards, utilization of nonclinical revenue sources (eg, philanthropy, grants), increased efficiency of business practices and/or redesign of fund flows may be necessary to sustain recruitment and retention of young academic surgeons.

The association of departmental leadership gender with that of faculty and residents in radiology.

RATIONALE AND OBJECTIVES: Although the number of women graduating from medical school continues to increase, their representation in radiology residency programs has not increased over the past 10 years. We examined whether the gender of radiology faculty and residents differed according to the gender of the departmental leadership. MATERIALS AND METHODS: We issued an anonymous Web-based survey via e-mail to all 188 radiology residency program directors listed in the Fellowship and Residency Electronic Interactive Database (FREIDA Online). Data regarding the gender of the department chairperson, residency program director, faculty, and residents were collected. The institutional review board granted a waiver for this study, and all subjects provided informed consent. RESULTS: Of the 84 program directors who responded, 9 (10.7%) were chaired by females and 75 (89.3%) by males; residency program director positions were held by 36 (42.9%) females and 48 (57.1%) males. More programs were located in the northeastern United States (n = 31, 36.9%) than in any other region, and more were self-described as academic (n = 36, 42.9%) than any other practice type. Programs that were led by a male chairperson had a similar proportion of female faculty (25.2% versus 27.3%; P = .322) and residents (26.2% versus 27.4%; P = .065) compared with those led by a female. Similarly, radiology departments with a male residency program director had a similar proportion of female residents (24.8% versus 28.7%; P = .055) compared with programs with a female residency program director. CONCLUSION: The gender composition of radiology faculty and residents does not differ significantly according to the gender of the departmental chairperson or residency program director. Nevertheless, there continues to be a disparity in the representation of women among radiology faculty and residents.

Geographic variation in lumbar fusion for degenerative disorders: 1990 to 2000.

BACKGROUND CONTEXT: Past studies have shown that proportion of lumbar fusion surgery to all forms of lumbar surgery is variable among geographic regions. At present, no studies have investigated whether fusion outcome is associated with geographic region. PURPOSE: The purpose of this study was to examine the postoperative complication rate, postoperative mortality rate, hospital length of stay (LOS), hospital routine discharge rate, and total charges associated with surgical care across the geographic regions. STUDY DESIGN/SETTING: Retrospective cohort study using national sample administrative data. PATIENT SAMPLE: The study included 23,143 patients who underwent lumbar spine fusion surgery with a principal diagnosis of lumbar spine disease related to degeneration. OUTCOME MEASURES: Functional measures included complication rate, mortality rate, and hospital LOS; routine discharge; and total charges for care. METHODS: Selected variables from the Nationwide Inpatient Sample database were used for comparison across the geographic regions of the South, Midwest, Northeast, and West. Bivariate statistical analyses compared postoperative complication rates, mortality rates, hospital LOS, routine discharge rate, and total charges associated with surgical care across the geographic regions. RESULTS: Significant differences in routine discharge (p<.001), cauda equina complications (p=.001), LOS (p<.001), and inflation-adjusted charges (p<.001) were found for the South and the West (demonstrated lower routine discharges and higher rates of complications involving cauda equina syndromes) and the Northeast and the Midwest (involved higher LOS than the South and the West but lower reported charges after adjustments for inflation). CONCLUSIONS: The findings suggest that surgical fusion outcome is associated with regional variations. It is likely that patient selection and physician preferences are associated with these findings. Similar to variations in proportion of lumbar fusion surgery among geographic regions, outcomes for surgical fusions also vary across regions.

Hypoxia decreases creatine uptake in cardiomyocytes, while creatine supplementation enhances HIF activation.

Creatine (Cr), phosphocreatine (PCr), and creatine kinases (CK) comprise an energy shuttle linking ATP production in mitochondria with cellular consumption sites. Myocytes cannot synthesize Cr: these cells depend on uptake across the cell membrane by a specialized creatine transporter (CrT) to maintain intracellular Cr levels. Hypoxia interferes with energy metabolism, including the activity of the creatine energy shuttle, and therefore affects intracellular ATP and PCr levels. Here, we report that exposing cultured cardiomyocytes to low oxygen levels rapidly diminishes Cr transport by decreasing Vmax and Km Pharmacological activation of AMP-activated kinase (AMPK) abrogated the reduction in Cr transport caused by hypoxia. Cr supplementation increases ATP and PCr content in cardiomyocytes subjected to hypoxia, while also significantly augmenting the cellular adaptive response to hypoxia mediated by HIF-1 activation. Our results indicate that: (1) hypoxia reduces Cr transport in cardiomyocytes in culture, (2) the cytoprotective effects of Cr supplementation are related to enhanced adaptive physiological responses to hypoxia mediated by HIF-1, and (3) Cr supplementation increases the cellular ATP and PCr content in RNCMs exposed to hypoxia.

Gender, racial, and ethnic disclosure in NIH K-Award funded diabetes and obesity clinical trials.

In 1993, the National Institutes of Health (NIH) passed The Revitalization Act (Subtitle B) which mandated that all NIH funded clinical trials have "appropriate representation" of minority and women subjects. Our aim was to evaluate the impact of the mandate by examining the reporting and inclusion of minority and female subjects into NIH K-Award funded clinical trials, addressing the minority predominant diagnoses of diabetes and clinical obesity. Using the CRISP search engine and PUBMED, we selected publications published by the National Institute on Aging (NIA) and National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) K-grant recipients during 1989-2004, associated with all the diabetes and obesity clinical trials. Studies were stratified into three timeline categories (1989-1993, pre-mandate; 1993-1996, post-mandate, and 1997-present, well past mandate) to evaluate trends in the recruiting of minorities and women before, during, and after the passing of the Revitalization Act. Of the 165 papers, only 37% disclosed race, a number that did not improve over time (p=.15), whereas 92% disclosed gender. Clinical trials that focused on females increased across the 3 timeframes (p < .001) for diabetes studies but not obesity studies. Overall, disclosure of race declined over the 3 timeframes whereas individually, the disclosure of African Americans improved.

DADOS-Survey: an open-source application for CHERRIES-compliant Web surveys.

BACKGROUND: The Internet has been increasingly utilized in biomedical research. From online searching for literature to data sharing, the Internet has emerged as a primary means of research for many physicians and scientists. As a result, Web-based surveys have been employed as an alternative to traditional, paper-based surveys. We describe DADOS-Survey, an open-source Web-survey application developed at our institution that, to the best of our knowledge, is the first to be compliant with the Checklist for Reporting Results of Internet E-Surveys (CHERRIES). DADOS-Survey was designed with usability as a priority, allowing investigators to design and execute their own studies with minimal technical difficulties in doing so. RESULTS: To date, DADOS-Survey has been successfully implemented in five Institutional Review Board-approved studies conducted by various departments within our academic center. Each of these studies employed a Web-survey design as their primary methodology. Our initial experience indicates that DADOS-Survey has been used with relative ease by each of the investigators and survey recipients. This has been further demonstrated through formal and field usability testing, during which time suggestions for improvement were incorporated into the software design. CONCLUSION: DADOS-Survey has the potential to have an important role in the future direction of Web-survey administration in biomedical research. This CHERRIES-compliant application is tailored to the emerging requirements of quality data collection in medicine.

Duke Surgery Research Central: an open-source Web application for the improvement of compliance with research regulation.

BACKGROUND: Although regulatory compliance in academic research is enforced by law to ensure high quality and safety to participants, its implementation is frequently hindered by cost and logistical barriers. In order to decrease these barriers, we have developed a Web-based application, Duke Surgery Research Central (DSRC), to monitor and streamline the regulatory research process. RESULTS: The main objective of DSRC is to streamline regulatory research processes. The application was built using a combination of paper prototyping for system requirements and Java as the primary language for the application, in conjunction with the Model-View-Controller design model. The researcher interface was designed for simplicity so that it could be used by individuals with different computer literacy levels. Analogously, the administrator interface was designed with functionality as its primary goal. DSRC facilitates the exchange of regulatory documents between researchers and research administrators, allowing for tasks to be tracked and documents to be stored in a Web environment accessible from an Intranet. Usability was evaluated using formal usability tests and field observations. Formal usability results demonstrated that DSRC presented good speed, was easy to learn and use, had a functionality that was easily understandable, and a navigation that was intuitive. Additional features implemented upon request by initial users included: extensive variable categorization (in contrast with data capture using free text), searching capabilities to improve how research administrators could search an extensive number of researcher names, warning messages before critical tasks were performed (such as deleting a task), and confirmatory e-mails for critical tasks (such as completing a regulatory task). CONCLUSION: The current version of DSRC was shown to have excellent overall usability properties in handling research regulatory issues. It is hoped that its release as an open-source application will promote improved and streamlined regulatory processes for individual academic centers as well as larger research networks.