Prakash Gorroochurn

Differential Metabolic Impact of Gastric Bypass Surgery Versus Dietary Intervention in Obese Diabetic Subjects Despite Identical Weight Loss

The enhanced decrease in circulating branched-chain amino acids and their metabolites after gastric bypass occurs by mechanisms other than weight loss. Dissecting the Quick Fix In the Wizard of Oz, when Dorothy encounters a split in the yellow brick road, the Scarecrow assures her that all paths lead to the land of Oz. We’ve witnessed the perils Dorothy met along the path she chose; however, we don’t know what she would have encountered had she followed another route to Oz. Similarly, obese patients with type 2 diabetes can take one of two paths to weight loss—dietary intervention or gastric bypass surgery (GBP). Although the end result—weight loss—is the same, the metabolic shifts that occur en route appear to differ. Now, Laferrère et al. show that in patients with equivalent weight loss, those who underwent GBP displayed a larger decrease in certain circulating amino acids than did subjects who pursued the dietary intervention path. This difference may help to explain why patients who opted for the surgical intervention boasted better improvement in glucose homeostasis—including enhanced insulin sensitivity—than did those who lost weight by controlling their dietary intake. Obese patients with type 2 diabetes strive to lose weight for reasons more momentous than an approaching swimsuit season. Weight loss can improve the body’s ability to metabolize glucose and thus stems the serious complications of diabetes. Patients often can reduce or forgo their diabetes medications. However, in such patients, glycemic control is improved to a greater extent within days after GBP—before weight loss occurs—than after diet-induced shedding of pounds and inches. Precisely why remains a mystery, but research in animal models has revealed that higher-than-normal blood concentrations of branched-chain amino acids (BCAAs) and their metabolites play a role in the loss of insulin sensitivity. Furthermore, recent studies in human patients show a robust positive correlation between insulin resistance and blood levels of BCAAs and their by-products. Finally, obese people have higher circulating concentrations of these amino acids compared to their lean counterparts; the same goes for individuals with versus without diabetes. These observations imply that the rapid reversal of diabetes symptoms in GBP patients may have something to do with BCAA metabolism. Here, the authors measured circulating amounts of a variety of amino acids and acylcarnitines—some of which are produced primarily from BCAA metabolism—to characterize the differential metabolic responses to weight loss induced by GBP versus dietary intervention in obese type 2 diabetes patients. Circulating concentrations of total amino acids, BCAAs, and BCAA metabolites all decreased significantly after GBP but not after dietary intervention, despite equivalent weight loss. These findings were consistent in two patient cohorts, one from the New York Obesity Nutrition Research Center and one from Duke University; in the latter group, the effects were shown to persist for months. These data support the notion that the surgical intervention promoted enhanced BCAA metabolism by mechanisms separate from weight loss and suggest that changes in circulating amino acids pave the road to the correction of glycemic control observed after GBP. Glycemic control is improved more after gastric bypass surgery (GBP) than after equivalent diet-induced weight loss in patients with morbid obesity and type 2 diabetes mellitus. We applied metabolomic profiling to understand the mechanisms of this better metabolic response after GBP. Circulating amino acids (AAs) and acylcarnitines (ACs) were measured in plasma from fasted subjects by targeted tandem mass spectrometry before and after a matched 10-kilogram weight loss induced by GBP or diet. Total AAs and branched-chain AAs (BCAAs) decreased after GBP, but not after dietary intervention. Metabolites derived from BCAA oxidation also decreased only after GBP. Principal components (PC) analysis identified two major PCs, one composed almost exclusively of ACs (PC1) and another with BCAAs and their metabolites as major contributors (PC2). PC1 and PC2 were inversely correlated with pro-insulin concentrations, the C-peptide response to oral glucose, and the insulin sensitivity index after weight loss, whereas PC2 was uniquely correlated with levels of insulin resistance (HOMA-IR). These data suggest that the enhanced decrease in circulating AAs after GBP occurs by mechanisms other than weight loss and may contribute to the better improvement in glucose homeostasis observed with the surgical intervention.

The development of interval breast malignancies in patients with BRCA mutations

At present, there is no consensus regarding how frequently BRCA mutation carriers should be screened for malignancies using breast imaging techniques. An interval malignancy is defined as a malignancy that becomes evident during the period between annual screening mammography scans; the finding of such a malignancy indicates that the malignancy either went undetected by the last breast imaging scan or developed during the interval since that last scan.

Comparing genetic ancestry and self-described race in African Americans born in the United States and in Africa

Genetic association studies can be used to identify factors that may contribute to disparities in disease evident across different racial and ethnic populations. However, such studies may not account for potential confounding if study populations are genetically heterogeneous. Racial and ethnic classifications have been used as proxies for genetic relatedness. We investigated genetic admixture and developed a questionnaire to explore variables used in constructing racial identity in two cohorts: 50 African Americans and 40 Nigerians. Genetic ancestry was determined by genotyping 107 ancestry informative markers. Ancestry estimates calculated with maximum likelihood estimation were compared with population stratification detected with principal components analysis. Ancestry was approximately 95% west African, 4% European, and 1% Native American in the Nigerian cohort and 83% west African, 15% European, and 2% Native American in the African American cohort. Therefore, self-identification as African American agreed well with inferred west African ancestry. However, the cohorts differed significantly in mean percentage west African and European ancestries (P < 0.0001) and in the variance for individual ancestry (P ≤ 0.01). Among African Americans, no set of questionnaire items effectively estimated degree of west African ancestry, and self-report of a high degree of African ancestry in a three-generation family tree did not accurately predict degree of African ancestry. Our findings suggest that self-reported race and ancestry can predict ancestral clusters but do not reveal the extent of admixture. Genetic classifications of ancestry may provide a more objective and accurate method of defining homogenous populations for the investigation of specific population-disease associations. (Cancer Epidemiol Biomarkers Prev 2008;17(6):1329–38)

Non-replication of association studies: “pseudo-failures” to replicate?

Recently, serious doubts have been cast on the usefulness of association studies as a means to genetically dissect complex diseases because most initial findings fail to replicate in subsequent studies. The reasons usually invoked are population stratification, genetic heterogeneity, and inflated Type I errors. In this article, we argue that, even when these problems are addressed, the scientific community usually has unreasonably high expectations on replication success, based on initial low P values, a phenomenon known as the replication fallacy. We present a modified formula that gives the replication power of a second association study based on the P value of an initial study. When both studies have similar sample sizes, this formula shows that: (1) a P value only slightly lower than the nominal α results in only approximately 50% replication power; (2) very low P values are required to achieve a replication power of at least 80% (e.g., at α = 0.05, a P value of <0.005 is required). Because many initially significant findings result in low replication power, replication failure should not be surprising or be interpreted as necessarily refuting the initial findings. We refer to replication failures for which the replication power is low as “pseudo-failures.”

Randomized trial of critical time intervention to prevent homelessness after hospital discharge.

OBJECTIVE This study assessed the effectiveness of a previously tested model, critical time intervention (CTI), in producing an enduring reduction in the risk of homelessness for persons with severe mental illness who were discharged from inpatient psychiatric treatment facilities. METHODS A total of 150 previously homeless men and women with severe mental illness and who were discharged from inpatient psychiatric hospitalization to transitional residences on the hospital grounds were randomly assigned to receive usual care or usual care plus CTI at the point of discharge to the community. The nine-month intervention aims to gradually pass responsibility to community sources for providing ongoing support after the intervention ends, thereby leading to a durable reduction in risk of future homelessness. After participants were discharged from the transitional residence (length of stay six to 937 days), their housing status was assessed every six weeks for 18 months via participant self-report collected by interviewers blind to study condition. RESULTS In an intent-to-treat analysis, participants assigned to the CTI group had significantly less homelessness at the end of the follow-up period (the final three six-week intervals) than those assigned to the control group (odds ratio=.22, 95% confidence interval=.06-.88). CONCLUSIONS A relatively brief, focused intervention for persons with severe mental illness led to a reduction in the risk of homelessness that was evident nine months after the intervention ended. This work suggests that targeted, relatively short interventions applied at critical transition points may enhance the efficacy of long-term supports for persons with severe mental illness who are living in the community.

Performance, Return to Competition, and Reinjury After Tommy John Surgery in Major League Baseball Pitchers A Review of 147 Cases

Background: Pitching performance metrics, durability, and reinjury after Tommy John surgery in professional baseball players have not been well described. Purpose: The purpose of this study was to determine the likelihood of return to professional competition, reinjury rate, and change in performance after Tommy John surgery in Major League Baseball pitchers. The hypothesis was that performance metrics and durability will decline after surgery. Study Design: Cohort study; Level of evidence, 3. Methods: Publicly available records were accessed to generate a list of all Major League Baseball pitchers from 1999 to 2011 who had undergone ulnar collateral ligament reconstruction at any point in their careers; those with multiple reconstructive procedures were excluded. Return to active (≥1 game) or established (≥10 games) competition and/or placement on the disabled list was documented for each player. Among established players, pitching performance was compared pre- and postoperatively, as well as with age-matched control pitchers. Results: Of 147 pitchers included, 80% returned to pitch in at least 1 Major League Baseball game. Only 67% of established pitchers returned to the same level of competition postoperatively, and 57% of established players returned to the disabled list because of injuries to the throwing arm. Finally, performance declined across several metrics after surgery compared with preinjury levels, such as earned run average, batting average against, walks plus hits per inning pitched, percentage of pitches thrown in the strike zone, innings pitched, percentage fastballs thrown, and average fastball velocity (P < .05 for all). However, these declines were not statistically different from similar declines found in age-matched controls who did not undergo Tommy John surgery. Conclusion: Return to the disabled list after Tommy John surgery is common among professional pitchers (>50%), and performance declines across several major metrics after surgery. Patients undergoing Tommy John surgery should be counseled appropriately regarding the likelihood of return to preinjury levels of competition and performance.

Effect of Population Stratification on Case-Control Association Studies

There has been considerable debate in the literature concerning bias in case-control association mapping studies due to population stratification. In this paper, we perform a theoretical analysis of the effects of population stratification by measuring the inflation in the test’s type I error (or false-positive rate). Using a model of stratified sampling, we derive an exact expression for the type I error as a function of population parameters and sample size. We give necessary and sufficient conditions for the bias to vanish when there is no statistical association between disease and marker genotype in each of the subpopulations making up the total population. We also investigate the variation of bias with increasing subpopulations and show, both theoretically and by using simulations, that the bias can sometimes be quite substantial even with a very large number of subpopulations. In a companion simulation-based paper (Heiman et al., Part I, this issue), we have focused on the CRR (confounding risk ratio) and its relationship to the type I error in the case of two subpopulations, and have also quantified the magnitude of the type I error that can occur with relatively low CRR values.

Effect of Population Stratification on Case-Control Association Studies I. Elevation in False Positive Rates and Comparison to Confounding Risk Ratios (a Simulation Study)

There has been considerable debate in the literature concerning bias in case-control association mapping studies due to population stratification. In this paper, we perform a theoretical analysis of the effects of population stratification by measuring the inflation in the tests type I error (or false-positive rate). Using a model of stratified sampling, we derive an exact expression for the type I error as a function of population parameters and sample size. We give necessary and sufficient conditions for the bias to vanish when there is no statistical association between disease and marker genotype in each of the subpopulations making up the total population. We also investigate the variation of bias with increasing subpopulations and show, both theoretically and by using simulations, that the bias can sometimes be quite substantial even with a very large number of subpopulations. In a companion simulation-based paper (Heiman et al., Part I, this issue), we have focused on the CRR (confounding risk ratio) and its relationship to the type I error in the case of two subpopulations, and have also quantified the magnitude of the type I error that can occur with relatively low CRR values.Objectives: This is the first of two articles discussing the effect of population stratification on the type I error rate (i.e., false positive rate). This paper focuses on the confounding risk ratio (CRR). It is accepted that population stratification (PS) can produce false positive results in case-control genetic association. However, which values of population parameters lead to an increase in type I error rate is unknown. Some believe PS does not represent a serious concern [1, 2], whereas others believe that PS may contribute to contradictory findings in genetic association [3]. We used computer simulations to estimate the effect of PS on type I error rate over a wide range of disease frequencies and marker allele frequencies, and we compared the observed type I error rate to the magnitude of the confounding risk ratio. Methods: We simulated two populations and mixed them to produce a combined population, specifying 160 different combinations of input parameters (disease prevalences and marker allele frequencies in the two populations). From the combined populations, we selected 5000 casecontrol datasets, each with either 50, 100, or 300 cases and controls, and determined the type I error rate. In all simulations, the marker allele and disease were independent (i.e., no association). Results: The type I error rate is not substantially affected by changes in the disease prevalence per se. We found that the CRR provides a relatively poor indicator of the magnitude of the increase in type I error rate. We also derived a simple mathematical quantity, ¢, that is highly correlated with the type I error rate. In the companion article (part II, in this issue) [4], we extend this work to multiple subpopulations and unequal sampling proportions. Conclusion: Based on these results, realistic combinations of disease prevalences and marker allele frequencies can substantially increase the probability of finding false evidence of marker disease associations. Furthermore, the CRR does not indicate when this will occur.

Gastric bypass surgery, but not caloric restriction, decreases dipeptidyl peptidase 4 activity in obese patients with type 2 diabetes.

The mechanism by which incretins and their effect on insulin secretion increase markedly following gastric bypass (GBP) surgery is not fully elucidated. We hypothesized that a decrease in the activity of dipeptidyl peptidase‐4 (DPP‐4), the enzyme which inactivates incretins, may explain the rise in incretin levels post‐GBP. Fasting plasma DPP‐4 activity was measured after 10‐kg equivalent weight loss by GBP (n = 16) or by caloric restriction (CR,n = 14) in obese patients with type 2 diabetes. DPP‐4 activity decreased after GBP by 11.6% (p = 0.01), but not after CR. The increased peak glucagon‐like peptide‐1 (GLP‐1) and glucose‐dependent insulinotropic polypeptide (GIP) response to oral glucose after GBP did not correlate with DPP‐4 activity. The decrease in fasting plasma DPP‐4 activity after GBP occurred by a mechanism independent of weight loss and did not relate to change in incretin concentrations. Whether the change in DPP‐4 activity contributes to improved diabetes control after GBP remains therefore to be determined.

Redefining the Acetabular Component Safe Zone for Posterior Approach Total Hip Arthroplasty

BACKGROUND Acetabular component orientation influences joint stability in total hip arthroplasty (THA). The purpose of this study was to evaluate the effect of cup orientation and other variables on hip dislocation risk and to define a posterior approach specific safe zone. METHODS A cohort of 1289 posterior approach primary THA cases was prospectively followed and component position measured radiographically. RESULTS Cup malposition, with respect to the Lewinnek safe zone, was an independent risk factor for dislocation (OR1.88). Modifying the anteversion safe zone limits to 10-25° strongly predicted increased dislocation risk (OR2.69). No dislocations occurred within a zone defined by a circle centered at 41.4° abduction and 17.1° anteversion, radius 4.3°. CONCLUSION Utilizing a posterior approach specific safe zone of 10-25° anteversion and 30-50° abduction may minimize THA dislocations. LEVEL OF EVIDENCE Level III.