Pharmacogenomic prescribing opportunities in percutaneous coronary intervention and bone marrow transplant patients.

Aim: To evaluate the potential impact of preemptive multigene pharmacogenomic (PGx) testing on medication prescribing in real-world clinical settings. Patients & methods: Prescription frequencies for 65 medications with actionable PGx recommendations were collected in 215 percutaneous coronary intervention (PCI) and 131 allogeneic hematopoietic cell transplant (allo-HCT) patients. A simulation projected the number of PGx-guided prescribing opportunities. Results: In PCI and allo-HCT patients, respectively, 66.5 and 90.1% were prescribed at least one medication with actionable PGx prescribing recommendations. Simulations projected 26.5 and 41.2 total PGx-guided prescribing opportunities per 100 PCI and allo-HCT patients, respectively, if multigene PGx results were available. Conclusion: A multigene PGx testing strategy offers potential to optimize medication prescribing beyond clopidogrel and tacrolimus in PCI and allo-HCT patients.

Evaluation of the performance of a prior tacrolimus population pharmacokinetic kidney transplant model among adult allogeneic hematopoietic stem cell transplant patients.

Tacrolimus is a calcineurin inhibitor used to prevent acute graft versus host disease in adult patients receiving allogeneic hematopoietic stem cell transplantation (HCT). Previous population pharmacokinetic (PK) models have been developed in solid organ transplant, yet none exists for patients receiving HCT. The primary objectives of this study were to (1) use a previously published population PK model in adult patients who underwent kidney transplant and apply it to allogeneic HCT; (2) evaluate model-predicted tacrolimus steady-state trough concentrations and simulations in patients receiving HCT; and (3) evaluate covariates that affect tacrolimus PK in allogeneic HCT. A total of 252 adult patients receiving allogeneic HCT were included in the study. They received oral tacrolimus twice daily (0.03 mg/kg) starting 3 days prior to transplant. Data for these analyses included baseline clinical and demographic data, genotype data for single nucleotide polymorphisms in CYP3A4/5 and ABCB1, and the first tacrolimus steady-state trough concentration. A dosing simulation strategy based on observed trough concentrations (rather than model-based predictions) resulted in 12% more patients successfully achieving tacrolimus trough concentrations within the institutional target range (5-10 ng/ml). Stepwise covariate analyses identified HLA match and conditioning regimen (myeloablative vs. reduced intensity) as significant covariates. Ultimately, a previously published tacrolimus population PK model in kidney transplant provided a platform to help establish a model-based dose adjustment strategy in patients receiving allogenic HCT, and identified HCT-specific covariates to be considered for future prospective studies. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? Tacrolimus is a cornerstone immunosuppressant used in patients who undergo organ transplantations. However, because of its narrow therapeutic index and wide interpatient pharmacokinetic (PK) variability, optimizing its dose is crucial to maximize efficacy and minimize tacrolimus-induced toxicities. Prior to this study, no tacrolimus population PK models have been developed for adult patients receiving allogeneic hematopoietic stem cell transplantation (HCT). Therefore, research effort was warranted to develop a population PK model that begins to propose more precision tacrolimus dosing and begins to address both a clinical and scientific gap in this patient population. WHAT QUESTION DID THIS STUDY ADDRESS? The study addressed whether there is value in utilizing the observed tacrolimus steady-state trough concentrations from patients receiving allogeneic HCT within the context of a pre-existing population PK model developed for kidney transplant. The study also addressed whether there are clinically relevant covariates specific to adult patients receiving allogeneic HCT. WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE? Inclusion of a single steady-state tacrolimus trough concentration is beneficial to model predictions. The dosing simulation strategy based on observed tacrolimus concentration, rather than the model-predicted concentration, resulted in more patients achieving the target range at first steady-state collection. Future studies should evaluate HLA matching and myeloablative conditioning versus reduced intensity conditioning regimens as covariates. These data and model-informed dose adjustments should be included in future prospective studies. This research could also serve as a template as to how to assess the utility of prior information for other disease settings. HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE? The M2 model fitting method and D2 dosing simulation method can be applied to other clinical pharmacology studies where only a single steady-state trough concentration is available per patient in the presence of a previously published population PK model.

Influence of Germline Genetics on Tacrolimus Pharmacokinetics and Pharmacodynamics in Allogeneic Hematopoietic Stem Cell Transplant Patients.

Tacrolimus exhibits high inter-patient pharmacokinetics (PK) variability, as well as a narrow therapeutic index, and therefore requires therapeutic drug monitoring. Germline mutations in cytochrome P450 isoforms 4 and 5 genes (CYP3A4/5) and the ATP-binding cassette B1 gene (ABCB1) may contribute to interindividual tacrolimus PK variability, which may impact clinical outcomes among allogeneic hematopoietic stem cell transplantation (HSCT) patients. In this study, 252 adult patients who received tacrolimus for acute graft versus host disease (aGVHD) prophylaxis after allogeneic HSCT were genotyped to evaluate if germline genetic variants associated with tacrolimus PK and pharmacodynamic (PD) variability. Significant associations were detected between germline variants in CYP3A4/5 and ABCB1 and PK endpoints (e.g., median steady-state tacrolimus concentrations and time to goal tacrolimus concentration). However, significant associations were not observed between CYP3A4/5 or ABCB1 germline variants and PD endpoints (e.g., aGVHD and treatment-emergent nephrotoxicity). Decreased age and CYP3A5*1/*1 genotype were independently associated with subtherapeutic tacrolimus trough concentrations while CYP3A5*1*3 or CYP3A5*3/*3 genotypes, myeloablative allogeneic HSCT conditioning regimen (MAC) and increased weight were independently associated with supratherapeutic tacrolimus trough concentrations. Future lines of prospective research inquiry are warranted to use both germline genetic and clinical data to develop precision dosing tools that will optimize both tacrolimus dosing and clinical outcomes among adult HSCT patients.

Limited evidence for third-party affiliation during development in wild chimpanzees (Pan troglodytes schweinfurthii).

Examining the ontogeny of conflict-mitigating behaviours in our closest living relatives is an important component of understanding the evolutionary origins of cooperation in our species. In this study, we used 26 years of data to investigate the emergence of third-party affiliation (TPA), defined as affiliative contact given to recipients of aggression by uninvolved bystanders (regardless of initiation), in wild immature eastern chimpanzees (Pan troglodytes schweinfurthii) of Gombe National Park, Tanzania. We also characterized TPA by mothers in the same dataset as an adult benchmark for interpreting immature TPA patterns. In summary, we found that immatures did not express TPA as measured by grooming between the ages of 1.5 and 12.0 years, and that there was limited evidence that immatures expressed TPA via play. We also found that mothers did express TPA to offspring, although mothers did not show TPA towards non-offspring. Cases of TPA by mothers to other adults were too few to analyse separately. These results contrast with findings from captive studies which found that chimpanzees as young as 6 years of age demonstrated TPA. We argue that within-species variation in the expression of TPA, both in immatures and adulthood, provides evidence that the conflict management behaviours of young chimpanzees may be heavily influenced by social, ecological and demographic factors.

Assessing sources of error in comparative analyses of primate behavior: Intraspecific variation in group size and the social brain hypothesis.

Phylogenetic comparative methods have become standard for investigating evolutionary hypotheses, including in studies of human evolution. While these methods account for the non-independence of trait data due to phylogeny, they often fail to consider intraspecific variation, which may lead to biased or erroneous results. We assessed the degree to which intraspecific variation impacts the results of comparative analyses by investigating the "social brain" hypothesis, which has provided a framework for explaining complex cognition and large brains in humans. This hypothesis suggests that group life imposes a cognitive challenge, with species living in larger social groups having comparably larger neocortex ratios than those living in smaller groups. Primates, however, vary considerably in group size within species, a fact that has been ignored in previous analyses. When within-species variation in group size is high, the common practice of using a mean value to represent the species may be inappropriate. We conducted regression and resampling analyses to ascertain whether the relationship between neocortex ratio and group size across primate species persists after controlling for within-species variation in group size. We found that in a sample of 23 primates, 70% of the variation in group size was due to between-species variation. Controlling for within-species variation in group size did not affect the results of phylogenetic analyses, which continued to show a positive relationship between neocortex ratio and group size. Analyses restricted to non-monogamous primates revealed considerable intraspecific variation in group size, but the positive association between neocortex ratio and group size remained even after controlling for within-species variation in group size. Our findings suggest that the relationship between neocortex size and group size in primates is robust. In addition, our methods and associated computer code provide a way to assess and account for intraspecific variation in other comparative analyses of primate evolution.

Early social exposure in wild chimpanzees: mothers with sons are more gregarious than mothers with daughters.

In many mammals, early social experience is critical to developing species-appropriate adult behaviors. Although mother-infant interactions play an undeniably significant role in social development, other individuals in the social milieu may also influence infant outcomes. Additionally, the social skills necessary for adult success may differ between the sexes. In chimpanzees (Pan troglodytes), adult males are more gregarious than females and rely on a suite of competitive and cooperative relationships to obtain access to females. In fission-fusion species, including humans and chimpanzees, subgroup composition is labile and individuals can vary the number of individuals with whom they associate. Thus, mothers in these species have a variety of social options. In this study, we investigated whether wild chimpanzee maternal subgrouping patterns differed based on infant sex. Our results show that mothers of sons were more gregarious than mothers of daughters; differences were especially pronounced during the first 6 mo of life, when infant behavior is unlikely to influence maternal subgrouping. Furthermore, mothers with sons spent significantly more time in parties containing males during the first 6 mo. These early differences foreshadow the well-documented sex differences in adult social behavior, and maternal gregariousness may provide sons with important observational learning experiences and social exposure early in life. The presence of these patterns in chimpanzees raises questions concerning the evolutionary history of differential social exposure and its role in shaping sex-typical behavior in humans.

Competing for space: female chimpanzees are more aggressive inside than outside their core areas.

Female space use can have important fitness consequences, which are likely due to differential access to food resources. Many studies have explored spatial competition in solitary species, but little is known about how individuals in social species compete over shared space. In this study, we investigate spatial patterns of aggression among female East African chimpanzees, Pan troglodytes schweinfurthii. This species provides an excellent opportunity to study spatial competition since (1) female chimpanzees occupy overlapping core areas (small areas of the community range in which individuals concentrate their space use) and (2) female core area quality is correlated with reproductive success, suggesting that females compete over long-term access to core areas. Here, we examine how female aggression towards other females varies inside and outside individual female core areas during a 14-year period at Gombe National Park, Tanzania. Overall, females showed higher rates of aggression inside than outside their own core areas. This pattern was driven by spatial variation in aggression in nonfeeding contexts. While food-related aggression did not vary spatially, females were more aggressive in nonfeeding contexts inside their core areas than they were outside their core areas. These results suggest that female chimpanzees follow a mixed strategy in which they compete for long-term access to resources in their core areas as well as for immediate access to food throughout the community range.

Costs and utilization of intraoperative cholangiography.

BACKGROUND: Routine intraoperative cholangiography (IOC) has been advocated as a viable strategy to reduce common bile duct injury (CDI) during cholecystectomy. This is predicated, in part, on the low cost of IOC, making it a cost-effective preventive strategy. Using billed hospital charges as a proxy for costs, we sought to estimate costs associated with the performance of IOC. METHODS: The 2001 National Inpatient Survey (NIS) database was assessed for IOC utilization and associated charges. Average charges for hospital admission where the primary procedure was laparoscopic cholecystectomy were compared for those associated with and without the performance of IOC. RESULTS: Eighteen percent of cholecystectomies were performed in facilities that never perform IOC. Routine IOC (defined as >75% of cholecystectomies performed in any one hospital having a concomitant IOC) was performed in only 11% of hospitals. In the remaining 71% of hospitals, selective IOC was performed. IOCs were associated with US $706-739 in additional hospital charges when performed in conjunction with laparoscopic cholecystectomy. We project a cost of US $371,356 to prevent a single bile duct injury by using routine cholangiography. CONCLUSION: We conclude that only a minority of hospitals performs cholecystectomies with routine IOC. Because of the significant amount of hospital charges attributable to IOC, routine IOC is not cost-effective as a preventative measure against bile duct injury during cholecystectomy.

Indications for selective intraoperative cholangiography.

The indications for selective intraoperative cholangiography (IOC) include a clinical history of jaundice, pancreatitis, elevated bilirubin level, abnormal liver function test results, increased amylase levels, a high lipase level, or dilated common bile duct on preoperative ultrasonography. Although these clinical features are widely accepted as indications for IOC, they have not been tested for their ability to predict choledocholithiasis. Charts were reviewed for a 6-month time period in 2003 at Parkland Memorial Hospital for all patients undergoing cholecystectomy. Univariate analysis and logistic regression were used to determine which factors predicted choledocholithiasis. Of the 572 patients undergoing cholecystectomies during the study period, 189 underwent IOC and common bile duct stones were found in 57. Only preoperative hyperbilirubinemia or ultrasonograph identification of common bile duct dilation reliably predicted choledocholithiasis. There were 13 cases of choledocholithiasis that would not have been identified by preoperative hyperbilirubinemia or an enlarged common bile duct. However, common bile duct stones were clinically significant in only 2 of the 13 cases. One of these was treated with postoperative endoscopic retrograde cholangiopancreatography, and the other was treated with laparoscopic common bile duct exploration. Preoperative identification of a dilated common bile duct or elevated bilirubin levels can be the sole criteria for performing IOC on a selective basis in patients without malignancy. Reliance on a history of remote jaundice, pancreatitis, elevated liver function test values, or pancreatic enzymes results in unnecessary IOCs.

Health care access and poverty do not explain the higher esophageal cancer mortality in African Americans.

BACKGROUND: Esophageal cancer mortality is increased in African Americans relative to white patients. The reasons for this are unknown but are thought to be related to inadequate access to health care secondary to a higher poverty rate in African American populations. METHODS: The National Health Interview Survey database for years 1986 to 1994 were combined and linked to the National Death Index. Individuals who died from esophageal carcinoma were assessed in the combined database, thus enabling detailed analysis of their socioeconomic status, race, and health care access. RESULTS: Poverty was 4-fold more frequent in African Americans who died from esophageal carcinoma than whites. Despite poverty, African American patients' access to health care was good and was not statistically related to increased mortality. CONCLUSIONS: Although the esophageal carcinoma mortality rate is higher in African Americans than in whites, it is not clearly related to the presence of poverty or to limited health care access. The higher mortality may be related to lifestyle differences, environmental exposure, or difference in disease biology, but it is not related exclusively to socioeconomic factors.