Perioperative and swallowing outcomes in patients undergoing 4- and 5-level anterior cervical discectomy and fusion.

OBJECTIVE: Anterior cervical discectomy and fusion (ACDF) is a common and robust procedure performed on the cervical spine. Literature on ACDF for 4 or more segments is sparse. Increasing the number of operative levels increases surgical complexity, tissue retraction, and risks of complications, particularly dysphagia. The overall risks of these complications and rates of dysphagia are not well studied for surgery on 4 or more segments. In this study, the authors evaluated their institution's perioperative experience with 4- and 5-level ACDFs. METHODS: The authors retrospectively reviewed patients who underwent 4- or 5-level ACDF at their institution over a 6-year period (May 2013-May 2019). Patient demographics, perioperative complications, readmission rates, and swallowing outcomes were recorded. Outcomes were analyzed with a multivariate linear regression. RESULTS: A total of 174 patients were included (167 had 4-level and 7 had 5-level ACDFs). The average age was 60.6 years, and 54.0% of patients (n = 94) were men. A corpectomy was performed in 12.6% of patients (n = 22). After surgery, 56.9% of patients (n = 99) experienced dysphagia. The percentage of patients with dysphagia decreased to 22.8% (37/162) at 30 days, 12.9% (17/132) at 90 days, and 6.3% (5/79) and 2.8% (1/36) at 1 and 2 years, respectively. Dysphagia was more likely at 90 days postoperatively in patients with gastroesophageal reflux (OR 4.4 [95% CI 1.5-12.8], p = 0.008), and the mean (± SD) lordosis change was greater in patients with dysphagia than those without at 90 days (19.8° ± 13.3° vs 9.1° ± 10.2°, p = 0.003). Dysphagia occurrence did not differ with operative implants, including graft and interbody type. The mean length of time to solid food intake was 2.4 ± 2.1 days. Patients treated with dexamethasone were more likely to achieve solid food intake prior to discharge (OR 4.0 [95% CI 1.5-10.6], p = 0.004). Postsurgery, 5.2% of patients (n = 9) required a feeding tube due to severe approach-related dysphagia. Other perioperative complication rates were uniformly low. Overall, 8.6% of patients (n = 15) returned to the emergency department within 30 days and 2.9% (n = 5) required readmission, whereas 1.1% (n = 2) required unplanned return to surgery within 30 days. CONCLUSIONS: This is the largest series of patients undergoing 4- and 5-level ACDFs reported to date. This procedure was performed safely with minimal intraoperative complications. More than half of the patients experienced in-hospital dysphagia, which increased their overall length of stay, but dysphagia decreased over time.

The potent AMPK inhibitor BAY-3827 shows strong efficacy in androgen-dependent prostate cancer models.

PURPOSE: 5' adenosine monophosphate-activated kinase (AMPK) is an essential regulator of cellular energy homeostasis and has been associated with different pathologies, including cancer. Precisely defining the biological role of AMPK necessitates the availability of a potent and selective inhibitor. METHODS: High-throughput screening and chemical optimization were performed to identify a novel AMPK inhibitor. Cell proliferation and mechanistic assays, as well as gene expression analysis and chromatin immunoprecipitation were used to investigate the cellular impact as well as the crosstalk between lipid metabolism and androgen signaling in prostate cancer models. Also, fatty acid turnover was determined by examining lipid droplet formation. RESULTS: We identified BAY-3827 as a novel and potent AMPK inhibitor with additional activity against ribosomal 6 kinase (RSK) family members. It displays strong anti-proliferative effects in androgen-dependent prostate cancer cell lines. Analysis of genes involved in AMPK signaling revealed that the expression of those encoding 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR), fatty acid synthase (FASN) and 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 2 (PFKFB2), all of which are involved in lipid metabolism, was strongly upregulated by androgen in responsive models. Chromatin immunoprecipitation DNA-sequencing (ChIP-seq) analysis identified several androgen receptor (AR) binding peaks in the HMGCR and PFKFB2 genes. BAY-3827 strongly down-regulated the expression of lipase E (LIPE), cAMP-dependent protein kinase type II-beta regulatory subunit (PRKAR2B) and serine-threonine kinase AKT3 in responsive prostate cancer cell lines. Also, the expression of members of the carnitine palmitoyl-transferase 1 (CPT1) family was inhibited by BAY-3827, and this was paralleled by impaired lipid flux. CONCLUSIONS: The availability of the potent inhibitor BAY-3827 will contribute to a better understanding of the role of AMPK signaling in cancer, especially in prostate cancer.

[Complex cutaneous Leishmaniasis from the "Old World" : Therapeutic challenges in two complicated disease courses]. / Komplexe kutane Leishmaniasis der Alten Welt : Therapeutische Herausforderungen bei 2 komplizierten Verläufen.

Here we describe two complicated cases of complex Old World cutaneous Leishmaniasis due to L. infantum and L. aethiopica. Both of our patients infected with the Leishmania parasite presented with a completely different clinical picture, course of disease, and treatment response. Clinical healing was achieved after multiple courses of treatment with a variety of different antileishmanial drugs. Nephrotoxity was a limiting side effect.

[A chronic wound from Vietnam]. / Eine chronische Wunde aus Vietnam.

Chronic skin lesions that occur in patients who have previously stayed in tropical countries pose a diagnostic challenge for physicians. In particular, if there is a granulomatous inflammatory reaction histologically, infectious diseases should also be included in the differential diagnosis. Particularly in persons returning from high-risk regions such as Vietnam, this includes cutaneous tuberculosis, which entails a thorough examination of the patient and comprehensive therapy. This case study shows which steps should be considered if cutaneous tuberculosis is suspected.

Treating Cancer by Spindle Assembly Checkpoint Abrogation: Discovery of Two Clinical Candidates, BAY 1161909 and BAY 1217389, Targeting MPS1 Kinase.

Inhibition of monopolar spindle 1 (MPS1) kinase represents a novel approach to cancer treatment: instead of arresting the cell cycle in tumor cells, cells are driven into mitosis irrespective of DNA damage and unattached/misattached chromosomes, resulting in aneuploidy and cell death. Starting points for our optimization efforts with the goal to identify MPS1 inhibitors were two HTS hits from the distinct chemical series "triazolopyridines" and "imidazopyrazines". The major initial issue of the triazolopyridine series was the moderate potency of the HTS hits. The imidazopyrazine series displayed more than 10-fold higher potencies; however, in the early project phase, this series suffered from poor metabolic stability. Here, we outline the evolution of the two hit series to clinical candidates BAY 1161909 and BAY 1217389 and reveal how both clinical candidates bind to the ATP site of MPS1 kinase, while addressing different pockets utilizing different binding interactions, along with their synthesis and preclinical characterization in selected in vivo efficacy models.

[Leprosy in Amazonas-impressions of the National Leprosy Program]. / Lepra in Amazonien ­ Eindrücke aus einem Kontrollprogramm.

Due to the often late detection and the neurological disability as a consequence of the disease, leprosy plays an important role in the public health system of emerging countries with the highest prevalence such as India and Brazil. The National Leprosy Control Program of the Ministry of Health and the Health Institutions of the Federal States in Brazil has implemented a strategy to ensure successful treatment of people in rural areas both at the preventive and curative level. A successful screening program, timely treatment of patients according to the stage of disease, and the introduction of preventive measures have significantly reduced the prevalence of leprosy in Brazil over the last 20 years. Due to limited medical care and socioeconomic weakness in the Amazon region in Brazil, the early eradication of leprosy does not seem to be currently realistic.

Neurosurgery Resident Wellness and Recovery from Burnout: A 39-Year Single-Institution Experience.

OBJECTIVE: Physician burnout in neurosurgery is highly prevalent and occurs most severely during residency. Although earlier assessments have identified stressors contributing to neurosurgery resident burnout, recovery interventions have not been studied extensively. We aimed to characterize burnout patterns and factors contributing to recovery through a single-institution assessment of neurosurgery residents across 4 decades. METHODS: We administered a 59-item questionnaire to all living current and former residents of a large neurosurgical training institution (n = 96). Respondents indicated the timeline of burnout or hardship during residency and evaluated burnout stressors and recovery factors through a 5-point Likert scale and free-text response. RESULTS: The survey response rate was 67% (64 of 96). The overall self-reported burnout rate was 30% (19 of 64). Recent trainees were significantly more likely to report burnout (P < 0.05). Postgraduate year 2 was cited by 66% of respondents as the onset of burnout or hardship. The most common stressors included work-life imbalance (55%) and imbalance of resident duties (33%). The highest-impact recovery factors were end of a rotation or postgraduate year (80%), increased sleep (48%), and meaningful relationships with colleagues (42%). Institution-specific factors, such as outdoor activities (52%) and intraprogram social events (34%), were also influential in recovery. In free-text responses, respondents identified a strong sense of mission in neurosurgical training as a central driver of recovery to wellness. CONCLUSIONS: Institutional support structures promoting mentorship and camaraderie are actionable methods to encourage resident burnout recovery. This study serves as a model for other programs to identify their "critical periods" of burnout and effective wellness interventions.

Patient Understanding of Uterine Fibroids and the Different Surgical Approaches to Hysterectomy.

Objective: The purpose of this study was to assess understanding of the hysterectomy procedure and uterine fibroids among women in a general gynecology clinic. Materials and Methods: This was an anonymous cross-sectional survey. We adapted and pilot tested a survey instrument designed to assess understanding of the hysterectomy procedure and of uterine fibroids. The final version of the survey consisted of basic demographic questions, followed by 28 knowledge questions (Canadian Task Force Classification II-2). The survey was disseminated to women in the waiting room of one of our gynecology clinics. The patient population included women 18 years and older. Results: The mean age of respondents was 33.5 years old. In total, 69.5% of the respondents had at least some college education. In the group of questions related to different types of hysterectomies, the most poorly answered question was "Which type of hysterectomy has the highest risk of damage to the bladder?" Less than 40% of the respondents were able to identify a laparoscopic and robotic hysterectomy based on a written description. Of questions about uterine fibroids, the most poorly answered question was whether cancer that looks like fibroids is common, with >90% of the respondents incorrectly thinking that cancer that resembled fibroids is common. More than half of respondents did not know what a fibroid is. Conclusions: In this analysis of the understanding of the hysterectomy procedure and fibroids among an educated population, overall understanding was poor. Specific areas where knowledge was particularly poor were the different ways of doing a hysterectomy and uterine fibroids.

History and advances in spinal neurosurgery.

Insight into the historic contributions made to modern-day spine surgery provides context for understanding the monumental accomplishments comprising current techniques, technology, and clinical success. Only during the last century did surgical growth occur in the treatment of spinal disorders. With that growth came a renaissance of innovation, particularly with the evolution of spinal instrumentation and fixation techniques. In this article, the authors capture some of the key milestones that have led to the field of spine surgery today, with an emphasis on the historical advances related to instrumentation, navigation, minimally invasive surgery, robotics, and neurosurgical training.

Work safety in plastination.

In this article, information is given on potential physical and health hazards in the steps of the silicone cold temperature method, often referred to as "S 10 Standard Method." The main potential hazards related to plastination, as well as recommended measures to effectively avoid explosion and health hazards are discussed. Some specialty chemicals pose chronic health hazards. Exposure to these chemicals can be avoided by standard laboratory hygiene, that is wearing personal protective equipment like safety goggles and protective gloves. Inhalation hazard, for example when working at open dehydration containers or when opening a gas curing box, is preferentially avoided by the action of an appropriate ventilation system. Acetone is the standard solvent used for dehydration and defatting of the specimens to be plastinated. Like for other flammable liquids, explosion protection must be considered when handling acetone. The concentration of acetone vapour in the air must be kept below the lower explosion limit through appropriate room or workplace ventilation. Furthermore, all potential sources of ignition should be removed from the explosion hazard zone. If electrical devices need to be operated inside the explosion hazard zone, they need a special design and approval. The conditions covered by this approval can be found on the identification plate of the individual device.

Comparative Thermal Effects of J-Plasma®, Monopolar, Argon, and Laser Electrosurgery in a Porcine Tissue Model.

INTRODUCTION: The objective of this study was to understand how J-Plasma® (Bovie Medical Corporation, Clearwater, Florida) surgical energy compares to monopolar, argon beam, and CO2 laser devices in terms of depth of penetration and lateral thermal spread in a porcine tissue model. MATERIALS AND METHODS: Using a porcine animal model, we applied the thermal energy of the J-Plasma® laser, Bovie Monopolar Pencil™ (Bovie Medical Corporation, Clearwater, Florida), argon beam coagulator, and CO2 laser to porcine small bowel, bladder, and peritoneal tissues at equivalent settings. Tissue was excised and sent to pathology for histologic evaluation. Primary outcome was depth of penetration and lateral thermal spread. RESULTS: When applied to peritoneum tissue, CO2 laser had the greatest lateral thermal spread at 2.99mm, while the argon beam had the lowest at just under 1.5mm. With regard to depth of penetration, the monopolar pencil had the highest while J-Plasma® had the lowest. When applied to bladder tissue, the argon beam was associated with the greatest lateral thermal spread (3.1mm) as compared to the other three devices (all less than 1mm). In terms of depth of penetration of bladder tissue, J-Plasma® again had the lowest value, while the monopolar pencil had the highest. When applied to small intestine tissue, the argon beam had the greatest lateral spread (3.51mm), while J-Plasma® had the lowest (less than 1mm). Regarding depth of penetration of small intestine tissue, argon beam had the highest value at 1.8mm compared to the other three devices (all below 0.6mm). CONCLUSION: Consistent with our previous study, J-Plasma® had minimal lateral and depth spread when applied to various tissue types. J-Plasma® performed better or similar when compared to monopolar, argon beam, and laser electrosurgical devices. Further studies in-vivo are needed to evaluate safety and surgical application of the J-Plasma® device.

Odontoid Fusion.

Anterior odontoid screw fixation allows for the internal fixation of unstable odontoid fractures with low morbidity, good fusion rates, and preservation of the atlanto-axial range of motion when applied in appropriate clinical cases. Advances in surgical techniques have allowed for safer, more minimally invasive approaches that reduce the risk of injury to vital prevertebral structures and minimize soft tissue retraction. Moreover, improvements in surgical image guidance technology for spinal surgery that have been applied to odontoid screw placement have helped improve surgeon confidence about exact screw trajectories. In this chapter, we review traditional screw placement techniques and highlight the trends in technical improvements that improve the safety and efficacy of these procedures.

Temporal Trends in the Uptake and Continuation of the Etonogestrel Implant in a Large Private Practice Setting.

OBJECTIVE: To assess temporal trends in the uptake and continuation of the etonogestrel subdermal implant in a large private practice setting. METHODS: This was a retrospective cohort study based on billing records from a large multispecialty private practice in Las Vegas, Nevada. We looked at women of all ages seeking long-acting reversible contraception (LARC) between January 1, 2013, and December 31, 2016. The main outcome measure was uptake of the etonogestrel subdermal implant, expressed as a fraction of all insertions of LARC across four calendar years (2013-2016). The Kaplan-Meier method was used to estimate 12-month continuation stratified by year of insertion. RESULTS: There were 3477 total LARC insertions across the 4-year study period. In unadjusted analyses, the uptake of the etonogestrel implant increased from 3.0% of LARC insertions in 2013 to 9% in 2016 among women aged 30 years and older. For women younger than 30 years, the uptake of the implant stayed stable from 2013 to 2015 (22.8%, 21.7%, and 22.4%, respectively), but increased to 30.9% in 2016. We modeled the uptake of the implant as a function of year of insertion adjusted for age (continuous) and insurance status (private vs. Medicaid), and we stratified the models by age (younger than 30 years, 30 years, and older than 30 years). The positive association between year of insertion and uptake of the implant was significantly stronger for women aged 30 years and older, compared to women younger than 30 years. There was a progressive decrease in the 12-month continuation of implant from 2013 (95.7%) to 2015 (57.7%). CONCLUSIONS: In this large private practice setting, among women aged 30 years and older, we observed a threefold increase in the uptake of the subdermal implant from 2013 to 2016. We also observed a significant decrease in the 12-month continuation of the implant over time. Further studies of implant uptake and continuation in the private practice setting are needed.

Thermal Effect of J-Plasma® Energy in a Porcine Tissue Model: Implications for Minimally Invasive Surgery.

OBJECTIVE: To evaluate tissue effect of J-Plasma® (Bovie Medical Corporation, Clearwater, Florida) in porcine liver, kidney, muscle, ovarian, and uterine tissue blocks. DESIGN: Prospective study utilizing porcine tissue blocks to evaluate the thermal spread of J-Plasma® device on liver, kidney, muscle, ovarian, and uterine tissue at various power settings, gas flow, and exposure times. MATERIALS AND METHODS: J-Plasma® helium was used in porcine liver, kidney, and muscle tissue at 20%, 50%, and 100% power, and 1 L/min, 3 L/min, and 5 L/min gas flow at one, five, and 10-second intervals. J-Plasma® was then used in ovarian and uterine tissue at maximum power and gas flow settings in intervals of one, five, 10, and 30 seconds. Histologic evaluation of each tissue was then performed to measure thermal spread. RESULTS: Regardless of tissue type, increased power setting, gas flow rate, and exposure time correlated with greater depth of thermal spread in liver, kidney, and muscle tissue. J-Plasma® did not exceed 2 mm thermal spread on liver, kidney, muscle, ovarian, and uterine tissue, even at a maximum setting of 100% power and 5 L/min gas flow after five seconds. Prolonged exposure to J-Plasma® of up to 30 seconds resulted in increased length and width of thermal spread of up to 12 mm, but did not result in significantly increased depth at 2.84 mm. CONCLUSIONS: The J-Plasma® helium device has minimal lateral and depth of thermal spread in a variety of tissue types and can likely be used for a multitude of gynecologic surgical procedures. However, further studies are needed to demonstrate device safety in a clinical setting.

The McCarus-Volker ForniSee®: A Novel Trans-illuminating Colpotomy Device and Uterine Manipulator for Use in Conventional and Robotic-Assisted Laparoscopic Hysterectomy.

PURPOSE: The purpose of this paper is to introduce a novel trans-illuminating culdotomy and uterine manipulator device. MATERIALS AND METHODS: The study was a prospective, non-randomized, non-blinded observational clinical study involving 50 female patients undergoing total laparoscopic hysterectomy (TLH) or laparoscopic supracervical hysterectomy (LSH) for benign indications. The surgeries were performed from March through May 2012 at two institutions. The primary study objectives were to demonstrate the safety and adequate clinical performance of the uterine manipulator device and to illustrate its potential widespread future use in minimally invasive gynecologic procedures. RESULTS: Average patient age was 45.1 years and, of the 50 patients, 33 had undergone previous intra-abdominal surgery. There were no reports of adverse events, difficulty with placement of the instrument, multiple attempts at placement, or difficulty with uterine manipulation. There was only one device-related uterine perforation, and pneumoperitoneum was maintained in all cases during culdotomy. Vaginal tissue left on subjects was less than 5mm. Overall, there were no ureteral injuries, there were two reported incidental cystotomies, and average blood loss was 99.0cc. Postoperative courses were normal for all patients, with only two reported postoperative complications: a possible vaginal cuff abscess and a 2cm vaginal mucosal cuff separation. CONCLUSIONS: The McCarus-Volker ForniSee® (LSI Solutions, Inc., Victor, New York) is a novel trans-illuminating culdotomy device and uterine manipulator that is safe, efficient, functional, and easy to use. Trans-illumination additionally delineates and enhances identification of critical anatomic planes, such as the vesicovaginal junction and cervicovaginal junction.

Contribution of Neural Elements to Thoracic Stability.

AIM: Studies of spinal biomechanics typically do not focus on the contributions to range of motion (ROM) of the primary components of the spinal canal, dura, arachnoid, pia, spinal cord, nerve roots, ligaments, and vessels. We sought to determine the stability offered by these soft tissues in vitro. MATERIAL AND METHODS: Human cadaveric segments were tested intact, after osteoligamentous destabilization, and after transection of T8-9 spinal canal components. Specimens were induced into flexion, extension, axial rotation, and lateral bending using non-constraining, non-destructive pure moment while tracking motion response stereophotogrammetrically. The range of motion (ROM) was compared in each condition after adjusting for soft tissue creep. RESULTS: After spinal canal element transection, ROM increased in all directions (mean 4.7%). This increase was most pronounced during lateral bending (p=0.055). The cumulative ROM from all directions of loading showed a statistically significant mean increase of 3.3% (p=0.040). CONCLUSION: Sectioning of canal elements was found to cause a measurable increase in ROM. Although nonviable tissues were tested, living tissues are also likely to contribute to spinal stability.

Biomechanics of Cervical "Skip" Corpectomy Versus Standard Multilevel Corpectomy.

STUDY DESIGN: In vitro biomechanical study of flexibility with finite-element simulation to estimate screw stresses. OBJECTIVE: To compare cervical spinal stability after a standard plated 3-level corpectomy with stability after a plated 3-level "skip" corpectomy where the middle vertebra is left intact (ie, two 1-level corpectomies), and to quantify pullout forces acting on the screws during various loading modes. SUMMARY OF BACKGROUND DATA: Clinically, 3-level cervical plated corpectomy has a high rate of failure, partially because only 4 contact points affix the plate to the upper and lower intact vertebrae. Leaving the intermediate vertebral body intact for additional fixation points may overcome this problem while still allowing dural sac decompression. METHODS: Quasistatic nonconstraining torque (maximum 1 N m) induced flexion, extension, lateral bending, and axial rotation while angular motion was recorded stereophotogrammetrically. Specimens were tested intact and after corpectomy with standard plated and strut-grafted 3-level corpectomy (7 specimens) or "skip" corpectomy (7 specimens). Screw stresses were quantified using a validated finite-element model of C3-C7 mimicking experimentally tested groups. Skip corpectomy with C5 screws omitted was also simulated. RESULTS: Plated skip corpectomy tended to be more stable than plated standard corpectomy, but the difference was not significant. Compared with standard plated corpectomy, plated skip corpectomy reduced peak screw pullout force during axial rotation (mode of loading of highest peak force) by 15% (4-screw attachment) and 19% (6-screw attachment). CONCLUSIONS: Skip corpectomy is a good alternative to standard 3-level corpectomy to improve stability, especially during lateral bending. Under pure moment loading, the screws of a cervical multilevel plate experience the highest pullout forces during axial rotation. Thus, limiting this movement in patients undergoing plated multilevel corpectomy may be reasonable, especially until solid fusion is achieved.

Laminectomy plus Fusion versus Laminectomy Alone for Lumbar Spondylolisthesis.

BACKGROUND: The comparative effectiveness of performing instrumented (rigid pedicle screws affixed to titanium alloy rods) lumbar spinal fusion in addition to decompressive laminectomy in patients with symptomatic lumbar grade I degenerative spondylolisthesis with spinal stenosis is unknown. METHODS: In this randomized, controlled trial, we assigned patients, 50 to 80 years of age, who had stable degenerative spondylolisthesis (degree of spondylolisthesis, 3 to 14 mm) and symptomatic lumbar spinal stenosis to undergo either decompressive laminectomy alone (decompression-alone group) or laminectomy with posterolateral instrumented fusion (fusion group). The primary outcome measure was the change in the physical-component summary score of the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36; range, 0 to 100, with higher scores indicating better quality of life) 2 years after surgery. The secondary outcome measure was the score on the Oswestry Disability Index (range, 0 to 100, with higher scores indicating more disability related to back pain). Patients were followed for 4 years. RESULTS: A total of 66 patients (mean age, 67 years; 80% women) underwent randomization. The rate of follow-up was 89% at 1 year, 86% at 2 years, and 68% at 4 years. The fusion group had a greater increase in SF-36 physical-component summary scores at 2 years after surgery than did the decompression-alone group (15.2 vs. 9.5, for a difference of 5.7; 95% confidence interval, 0.1 to 11.3; P=0.046). The increases in the SF-36 physical-component summary scores in the fusion group remained greater than those in the decompression-alone group at 3 years and at 4 years (P=0.02 for both years). With respect to reductions in disability related to back pain, the changes in the Oswestry Disability Index scores at 2 years after surgery did not differ significantly between the study groups (-17.9 in the decompression-alone group and -26.3 in the fusion group, P=0.06). More blood loss and longer hospital stays occurred in the fusion group than in the decompression-alone group (P<0.001 for both comparisons). The cumulative rate of reoperation was 14% in the fusion group and 34% in the decompression-alone group (P=0.05). CONCLUSIONS: Among patients with degenerative grade I spondylolisthesis, the addition of lumbar spinal fusion to laminectomy was associated with slightly greater but clinically meaningful improvement in overall physical health-related quality of life than laminectomy alone. (Funded by the Jean and David Wallace Foundation and others; SLIP ClinicalTrials.gov number, NCT00109213.).