Citations

SummaryClinical trials often include binary end points. In some cases, no successes are observed and the usual large sample estimates of relative risk are undefined. The paper proposes an estimator for relative risk based on the median unbiased estimator. The relative risk estimator proposed is well defined and performs satisfactorily for a wide range of data configurations. To facilitate the use of the estimator, a deterministic bootstrap confidence interval is also proposed, and an SAS macro is available to perform the necessary calculations. An on-going randomized clinical trial motivated the development of the estimator and is used to illustrate the approach.

This manuscript explores specific examples and criteria in which an alternative regulatory process to the existing combination rule would be appropriate and feasible and thus could be adopted by developers.

We executed a genome-wide association scan for age-related macular degeneration (AMD) in 2,157 cases and 1,150 controls. Our results validate AMD susceptibility loci near CFH ( P < 10 −75 ), ARMS2 ( P < 10 −59 ), C2/CFB ( P < 10 −20 ), C3 ( P < 10 −9 ), and CFI ( P < 10 −6 ). We compared our top findings with the Tufts/Massachusetts General Hospital genome-wide association study of advanced AMD (821 cases, 1,709 controls) and genotyped 30 promising markers in additional individuals (up to 7,749 cases and 4,625 controls). With these data, we identified a susceptibility locus near TIMP3 (overall P = 1.1 × 10 −11 ), a metalloproteinase involved in degradation of the extracellular matrix and previously implicated in early-onset maculopathy. In addition, our data revealed strong association signals with alleles at two loci ( LIPC , P = 1.3 × 10 −7 ; CETP , P = 7.4 × 10 −7 ) that were previously associated with high-density lipoprotein cholesterol (HDL-c) levels in blood. Consistent with the hypothesis that HDL metabolism is associated with AMD pathogenesis, we also observed association with AMD of HDL-c—associated alleles near LPL ( P = 3.0 × 10 −3 ) and ABCA1 ( P = 5.6 × 10 −4 ). Multilocus analysis including all susceptibility loci showed that 329 of 331 individuals (99%) with the highest-risk genotypes were cases, and 85% of these had advanced AMD. Our studies extend the catalog of AMD associated loci, help identify individuals at high risk of disease, and provide clues about underlying cellular pathways that should eventually lead to new therapies.

Background There are sparse data available regarding outcome of meniscal repair performed at the time of ACL reconstruction in the pediatric and adolescent population. Purpose To review the results of meniscal repair performed at the time of ACL reconstruction in pediatric and adolescent patients. Study Design Case series; Level of evidence, 4. Methods The records of all patients age 18 years or younger who underwent meniscal repair at the time of ACL reconstruction between 1990 and 2005 were reviewed. Ninety-nine patients (56 female, 43 male) with an average age of 16 years (range, 13-18) were included. Average injury to surgery interval was 107 days (range, 2-1109). Clinical outcomes were assessed at a mean of 8 years postoperatively (range, 2-19). A multivariate model was used to compare this cohort with a previously published cohort of patients with isolated meniscal tears. Results The clinical success rate of meniscal repair was 84% for simple tears, 59% for displaced bucket-handle tears, and 57% for complex tears (74% overall). Twenty-six menisci (26% overall) failed repair and 25 patients underwent repeat arthroscopic surgery (19 partial meniscectomies, 6 re-repairs). The average Tegner and International Knee Documentation Committee scores were 6.2 (range, 2-10) and 90.3 (range, 52-100), respectively. Risk factors for failure included complex and bucket-handle tear (P = .01), medial meniscal tears (P = .03), and skeletal immaturity (P = .01). Compared with isolated meniscal repairs in a similar pediatric and adolescent population, complex tears repaired in combination with ACL reconstruction did significantly better (57% vs 13%; P = .004). Conclusion Clinically successful repair of meniscal tears treated at the time of ACL reconstruction in patients 18 years or younger depends on tear type, with complex and bucket-handle tears being negative prognostic factors. Complex tears have a higher rate of clinical success when repaired at the time of ACL reconstruction versus when repaired in isolation.

Background— Microbubble safety concerns led to changes in product recommendations for patients with pulmonary hypertension. Noninvasive estimation of right ventricular systolic pressure (RVSP) is equivalent to pulmonary artery systolic pressure in the absence of pulmonary outflow obstruction. We analyzed the short- and long-term outcomes of patients who received microbubble contrast and those who did not during stress echocardiography (SE) according to resting RVSP. Methods and Results— From November 2003 to December 2007, 26 774 patients underwent SE. RVSP (mean, 32.6�9.6 mm Hg) was measured in 16 434 patients. Of these, 6164 (37.5%) received contrast for left ventricular opacification and 10 270 (62.5%) did not. Short-term (≤72 hours and ≤30 days) and long-term (4.3 years) end points were death and myocardial infarction. Analysis was done for rest RVSP cut-points ≥35, ≥50, and ≥60 mm Hg and tricuspid regurgitant velocities ≥2.7 ms −1 and ≥3.5 ms −1 . Adjusted Cox regression models were used. The contrast cohort comprised older patients (age, 67�12 versus 64�14 years; P <0.001), who were more likely to have positive SE results (35% versus 30%, P <0.001) compared with the noncontrast cohort. Using RVSP ≥50 mm Hg, there was no significant difference in short-term events between the contrast and noncontrast cohorts. For long-term events, there was no significant difference between both cohorts (adjusted hazard ratios [95% confidence intervals] for death, 1.10 [0.80 to 1.50], P =0.56; and myocardial infarction, 0.34 [0.11 to 1.03], P =0.06). Similar results were obtained at different RVSP and tricuspid regurgitant cut-points. Contrast agent–related adverse effects occurred in <1% of patients. Conclusion— RVSP had no impact on predisposition to adverse outcomes in patients undergoing contrast SE in the population studied.

Following the death of a youth hockey coach in a fight with a parent in 2000, the Mayo Clinic Sports Medicine Center and Minnesota Hockey collaborated to implement a three-component Hockey Education Program (HEP). HEP was initiated in 2003 to ensure youth players develop sportsmanship, skills, and a Fair Play approach to the game. Another goal was to decrease attrition of players, coaches, and officials. Coaching Excellence, a component of HEP, is based on 25 years of youth sport research. The HEP manuals Coaches Who Never Lose and Sports and Your Child contain the philosophy, objectives, and guidelines to ensure implementation of HEP components across players, coaches, and parents. The Skill Development component emphasizes learning age-appropriate hockey skills though skill progression. Increasing the practice-to-game ratio to 3–4 practices per game greatly increases the maximum time players skate with the puck during developmental years. Pre- and post-season Skills Challenges allow coaches, players, and parents to gauge improvement, and structure practices to address identified skill deficits. The Fair Play (FP) component emphasizes sportsmanship. Teams earn a FP point each game if they incur less than a preset number of penalty minutes. A coach receiving a game misconduct or a parent∕spectator asked to leave the game will cause the team to forfeit their FP point. FP points are factored into league standings across the state. This past season, 17 678 records of game data were obtained and 25 % (4420) were randomly selected for analysis. The data analysis permits comparison across seasons and changes are made accordingly. Based on four years of data, most Minnesota youth hockey games are played in a sportsmanlike manner. Checking from behind and head contact penalties have decreased since the penalty minutes for these dangerous infractions were increased.

Ice hockey is a fast-paced, aggressive sport whose participants are subject to relatively high rates of injury. Although there is a growing emphasis on the epidemiology of ice hockey research and its application towards reducing injuries, the literature has never been organized into an accessible database. Ice hockey is played in North America, Europe, Scandinavia, the U.K., and several other non-English speaking countries, yet injury reports not written in English are often ignored in review articles. The purpose of this project was to synthesize the existing world literature on ice hockey injuries into a framework of epidemiologic criteria, accessible in an organized, retrievable library. An extensive search of the following databases was done: MEDLINE, BIOSIS, EMBASE, NTIS, CURRENT CONTENTS, DISSERTATION ABSTRACTS, SPORT DISCUS, CINAHL, and WEB OF SCIENCE. Key words used were “ice hockey” and “injuries,” and the search range was 1966 to July 2007. Endnote X (Thompson Corp., Stamford, CT) was used for reference compilation. Eight hundred sixty seven documents were catalogued, from 27 countries in 8 languages. Documents were first categorized by type, including injury (226), equipment (45), case reports (94), review articles (294), editorials (39), or as focusing on the physiological, psychological, or medical aspects of ice hockey (169). Documents were then subdivided by study type and whether they were prospective (117) or retrospective (109). Further subdivisions beyond these levels were based on the inclusion of certain critical epidemiological criteria, including exposure time, a clear definition of “injury,” and the level of play, among others. This comprehensive database should make future ice hockey research more efficient, as well as promote sound epidemiology and a more global perspective.

Background Treatment of the multiligament-injured knee remains controversial. Purpose To compare clinical and functional outcomes of a consecutive series of multiligament-injured knees that underwent repair of the fibular collateral ligament (FCL) and posterolateral corner (PLC), followed by delayed cruciate ligament reconstructions, with those that had single-stage multiligament reconstruction. Study Design Cohort study; Level of evidence, 3. Methods Patients with multiligament knee injury treated by a single surgeon were identified in our prospective database. Between February 2004 and May 2005, patients underwent repair of medial- and lateral-sided injuries, followed by delayed cruciate ligament reconstructions. Between May 2005 and February 2007, patients underwent single-stage multiligament knee reconstruction. All patients followed a standard rehabilitation protocol. Inclusion criteria were minimum 2-year follow-up and multiligament knee injury including the FCL/PLC. International Knee Documentation Committee subjective and Lysholm scores and objective clinical data were documented. Results We identified 45 knees (42 patients); 17 knees (14 patients) were excluded, leaving 28 knees (28 patients) in the study. The repair/staged group (10 knees in 10 patients) had a mean follow-up of 34 months (range, 24-49 months). The reconstruction group (18 knees in 18 patients) had a mean follow-up of 28 months (range, 24-41 months). Four of the 10 FCL/PLC repairs (40%) and 1 of the 18 FCL/PLC reconstructions (6%) failed (P = .04). After revision reconstructions, there were no statistically significant differences between mean International Knee Documentation Committee subjective scores (79 vs. 77, P = .92) and mean Lysholm scores (85 vs 88, P = .92). Regression analysis showed no effect on failure based on age, sex, injury mechanism, time to surgery, interval between stages, total number of ligaments injured, or location of tear. Conclusion Our series demonstrated a statistically significant higher rate of failure for repair compared with reconstruction of the FCL/PLC. Reconstruction of the FCL/PLC structures is a more reliable option than repair alone in the setting of a multiligament knee injury.

Abstract We have a long-term interest in the connectivity between autoimmunity and tumor rejection. However, outside of the melanocyte/melanoma paradigm, little is known about whether autoimmune responses to normal tissue can induce rejection of tumors of the same histologic type. Here, we induced direct, pathogen-like cytotoxicity to the normal pancreas in association with the immune adjuvant heat shock protein 70. In sharp contrast to our studies with a similar approach for the treatment of prostate cancer, inflammatory killing of the normal pancreas induced a Th1-like, anti-self-response to pancreatic antigens, which was rapidly suppressed by a concomitant suppressive regulatory T cell (Treg) response. Interestingly, even when Treg cells were depleted, the Th1-like response was insufficient to induce significant ongoing autoimmunity. However, the Th1-like response to antigens expressed in the pancreas at the time of damage was sufficient to induce rejection of tumors expressing either a foreign (ova) antigen or fully syngeneic tumor antigens (on Panc02 tumor cells), provided that Treg were depleted before inflammatory killing of the normal pancreas. Taken together, these data indicate that profound differences exist between the immunoprotective mechanisms in place between different tissues (pancreas and prostate) in their response to pathogen-like damage. Moreover, they also show that, although multiple layers of immunologic safeguards are in place to prevent the development of severe autoimmune consequences in the pancreas (in contrast to the prostate), tumor rejection responses can still be decoupled from pathologic autoimmune responses in vivo, which may provide novel insights into the immunotherapeutic treatment of pancreatic cancer. [Cancer Res 2009;69(19):7767–74]