Evaluation of statistical approaches for association testing in noisy drug screening data.

BACKGROUND: Identifying associations among biological variables is a major challenge in modern quantitative biological research, particularly given the systemic and statistical noise endemic to biological systems. Drug sensitivity data has proven to be a particularly challenging field for identifying associations to inform patient treatment. RESULTS: To address this, we introduce two semi-parametric variations on the commonly used concordance index: the robust concordance index and the kernelized concordance index (rCI, kCI), which incorporate measurements about the noise distribution from the data. We demonstrate that common statistical tests applied to the concordance index and its variations fail to control for false positives, and introduce efficient implementations to compute p-values using adaptive permutation testing. We then evaluate the statistical power of these coefficients under simulation and compare with Pearson and Spearman correlation coefficients. Finally, we evaluate the various statistics in matching drugs across pharmacogenomic datasets. CONCLUSIONS: We observe that the rCI and kCI are better powered than the concordance index in simulation and show some improvement on real data. Surprisingly, we observe that the Pearson correlation was the most robust to measurement noise among the different metrics.

National Collegiate Athletic Association Division I Certified Athletic Trainers' Perceptions of the Benefits of Sport Psychology Services.

CONTEXT: Certified athletic trainers (ATs) are responsible for integrating relevant professionals into the rehabilitation team to assist with the holistic care of injured athletes. OBJECTIVE: To explore National Collegiate Athletic Association Division I (DI) ATs' experience with sport psychology consultants (SPCs), willingness to encourage athletes to use SPCs for injury rehabilitation, and perceptions of the benefits of sport psychology services. DESIGN: Quantitative study. SETTING: A Web-based survey was administered to a national sample of DI ATs. PATIENTS OR OTHER PARTICIPANTS: A total of 659 (341 men, 318 women) ATs completed the survey. MAIN OUTCOME MEASURE(S): Athletic trainers' experience with SPCs, willingness to encourage athletes to seek sport psychology services, and perceptions of the benefits of those services in injury-rehabilitation settings were self-reported using a rating scale that ranged from 1 (never or not at all) to 5 (definitely or extremely). RESULTS: Logistic regression revealed that the availability of SPCs, previous encouragement to athletes to seek sport psychology services, and previous positive interactions with SPCs predicted the ATs' willingness to encourage athletes to use these services (P < .0001). The services ATs rated the highest for injury rehabilitation were managing anxiety and emotion, improving coping techniques, and building confidence (ie, confidence in returning to sport and building confidence). Chi-square analyses indicated that female ATs' ratings of perceived benefits were higher (P ≤ .001) than those of male ATs, and the ratings of ATs who were likely to encourage the use of SPCs were higher (P ≤ .001) than those who were unlikely to encourage SPC service use. CONCLUSIONS: Athletic trainers in our study who had previous positive SPC experiences were most likely to use SPCs and their services during the injury-rehabilitation process. Possible implications are offered for how ATs interested in sport psychology services might call on SPCs to complement their work with injured athletes.

Athletes' use of mental skills during sport injury rehabilitation.

CONTEXT: Existing theoretical frameworks and empirical research support the applicability and usefulness of integrating mental skills throughout sport injury rehabilitation. OBJECTIVE: To determine what, if any, mental skills athletes use during injury rehabilitation, and by who these skills were taught. Cross-cultural differences were also examined. DESIGN: Cross-sectional design. SETTING: College athletes from 5 universities in the United States and a mixture of collegiate, professional, and recreational club athletes from the United Kingdom and Finland were recruited for this study. PARTICIPANTS: A total of 1283 athletes from the United States, United Kingdom, and Finland, who participated in diverse sports at varying competitive levels took part in this study. MAIN OUTCOME MEASURES: As part of a larger study on athletes' expectations of injury rehabilitation, participants were asked a series of open-ended and closed-ended questions concerning their use of mental skills during injury rehabilitation. RESULTS: Over half (64.0%) of the sample reported previous experience with athletic training, while 27.0% indicated that they used mental skills during injury rehabilitation. The top 3 mental skills reported were goal setting, positive self-talk/positive thoughts, and imagery. Of those athletes that used mental skills, 71.6% indicated that they felt mental skills helped them to rehabilitate faster. A greater proportion of athletes from the United States (33.4%) reported that they used mental skills during rehabilitation compared with athletes from the United Kingdom (23.4%) and Finland (20.3%). A small portion (27.6%) of the participants indicated that their sports medicine professional had taught them how to use mental skills; only 3% were taught mental skills by a sport psychologist. CONCLUSIONS: The low number of athletes who reported using mental skills during rehabilitation is discouraging, but not surprising given research findings that mental skills are underutilized by injured athletes in the 3 countries examined. More effort should be focused on educating and training athletes, coaches, and sports medicine professionals on the effectiveness of mental training in the injury rehabilitation context.

Evaluating medical marijuana dispensary policies: spatial methods for the study of environmentally-based interventions.

In 1996, California was the first state to pass a Compassionate Use Act allowing for the legal use of marijuana for medical purposes. Here we review several current policy and land use environmental interventions designed to limit problems related to the influx of medical marijuana dispensaries across California cities. Then we discuss the special challenges, solutions, and techniques used for studying the effects of these place-based policies. Finally, we present some of the advanced spatial analytic techniques that can be used to evaluate the effectiveness of environmental interventions, such as those related to reducing problems associated with the proliferation of medical marijuana dispensaries. Further, using data from a premise survey of all the dispensaries in Sacramento, this study will examine what characteristics and practices of these dispensaries are related to crime within varying distances from the dispensaries (e.g., 100, 250, 500, and 1,000 feet). We find that some security measures, such as security cameras and having a door man outside, implemented by medical marijuana dispensary owners might be effective at reducing crime within the immediate vicinity of the dispensaries.

The impact of lifetime alcohol use on hepatitis C treatment outcomes in privately insured members of an integrated health care plan.

UNLABELLED: Treatment of chronic hepatitis C infection (HCV(+) ) has historically been shown to be less effective in patients with a heavy drinking history. The effect of moderate and heavy alcohol use on treatment with pegylated interferon-alpha and ribavirin (P/R) in an insured household population has not been previously reported. We investigated the effect of alcohol on treatment outcome in a cohort of 421 treatment-naïve HCV(+) patients, members of an integrated health care plan treated with P/R between January 2002 and June 2008. A detailed drinking history was obtained for 259 (61.5%) eligible patients. Regular drinking was reported by 93.1% of patients before HCV diagnosis, by 30.9% between HCV diagnosis and treatment, by 1.9% during treatment, and 11.6% after the end of treatment. Heavy drinking patterns were reported by 67.9%, 63.5% of patients drank more than 100 kg of ethanol before initiating HCV treatment, and 29.3% reported abstaining less than the required 6 months before treatment. Despite these reports of heavy drinking, sustained virological responses (SVRs) were obtained in 80.2% of patients with HCV genotypes 2 or 3 and 45.1% of patients with genotypes 1, 4, or 6. Pretreatment drinking patterns and total alcohol intake were both unrelated to SVR rates. Abstaining less than 6 months before treatment was related to lower SVR rates in moderate, but not heavy, drinkers. HCV treatment relapse was unrelated to drinking after treatment ended. CONCLUSION: The amount of alcohol consumed before HCV treatment did not have a negative effect on treatment outcomes in our population. A history of heavy drinking should not be considered a deterrent to HCV treatment in members of an integrated health care plan who are closely monitored.

Survey results of the training, nutrition, and mental preparation of triathletes: practical implications of findings.

Although triathlon is growing in popularity at a remarkable rate, it has not been extensively studied. The aims of this research were to identify preparation strategies used by triathletes and to categorize these strategies according to gender and consultation with triathlon coaches. Survey data collected from 401 triathletes (207 males, 194 females) revealed training, nutritional, and mental preparation habits. Most participants engaged in strength training, consumed food and/or fluids during and after training, set training and competition goals, and applied mental preparation strategies during training and the hour before racing. Water was the most commonly consumed fluid; positive self-talk was the most used mental strategy. Participants were more likely to consult with a triathlon coach than a nutrition or sport psychology professional. Athletes with more years of experience in triathlon and those competing in longer distances were more likely to consult a triathlon coach. Female triathletes were more likely than male triathletes to train with others, use mental preparation strategies, and report feeling anxious before competitions. More male triathletes reported using nutritional supplements during training than their female counterparts. These findings add to the limited research base on triathletes' training habits, and hopefully will help guide practitioners who work with this group. The results provide guidance for collaborative efforts among training, nutrition, and mental health professionals to best support triathletes.

The effectiveness of the controlled release of gentamicin from polyelectrolyte multilayers in the treatment of Staphylococcus aureus infection in a rabbit bone model.

While the infection rate of orthopedic implants is low, the required treatment, which can involve six weeks of antibiotic therapy and two additional surgical operations, is life threatening and expensive, and thus motivates the development of a one-stage re-implantation procedure. Polyelectrolyte multilayers incorporating gentamicin were fabricated using the layer-by-layer deposition process for use as a device coating to address an existing bone infection in a direct implant exchange operation. The films eluted about 70% of their payload in vitro during the first three days and subsequently continued to release drug for more than four additional weeks, reaching a total average release of over 550 microg/cm(2). The coatings were demonstrated to be bactericidal against Staphylococcus aureus, and degradation products were generally nontoxic towards MC3T3-E1 murine preosteoblasts. Film-coated titanium implants were compared to uncoated implants in an in vivo S. aureus bone infection model. After a direct exchange procedure, the antimicrobial-coated devices yielded bone homogenates with a significantly lower degree of infection than uncoated devices at both day four (p < 0.004) and day seven (p < 0.03). This study has demonstrated that a self-assembled ultrathin film coating is capable of effectively treating an experimental bone infection in vivo and lays the foundation for development of a multi-therapeutic film for optimized, synergistic treatment of pain, infection, and osteomyelitis.

Identification of hepatitis C virus NS5A inhibitors.

Using a cell-based replicon screen, we identified a class of compounds with a thiazolidinone core structure as inhibitors of hepatitis C virus (HCV) replication. The concentration of one such compound, BMS-824, that resulted in a 50% inhibition of HCV replicon replication was approximately 5 nM, with a therapeutic index of >10,000. The compound showed good specificity for HCV, as it was not active against several other RNA and DNA viruses. Replicon cells resistant to BMS-824 were isolated, and mutations were identified. A combination of amino acid substitutions of leucine to valine at residue 31 (L31V) and glutamine to leucine at residue 54 (Q54L) in NS5A conferred resistance to this chemotype, as did a single substitution of tyrosine to histidine at amino acid 93 (Y93H) in NS5A. To further explore the region(s) of NS5A involved in inhibitor sensitivity, genotype-specific NS5A inhibitors were used to evaluate a series of genotype 1a/1b hybrid replicons. Our results showed that, consistent with resistance mapping, the inhibitor sensitivity domain also mapped to the N terminus of NS5A, but it could be distinguished from the key resistance sites. In addition, we demonstrated that NS5A inhibitors, as well as an active-site inhibitor that specifically binds NS3 protease, could block the hyperphosphorylation of NS5A, which is believed to play an essential role in the viral life cycle. Clinical proof of concept has recently been achieved with derivatives of these NS5A inhibitors, indicating that small molecules targeting a nontraditional viral protein like NS5A, without any known enzymatic activity, can also have profound antiviral effects on HCV-infected subjects.

Athletic trainers' and physical therapists' perceptions of the effectiveness of psychological skills within sport injury rehabilitation programs.

CONTEXT: Psychological skills are alleged to augment sport-injury rehabilitation; however, implementation of mental imagery within rehabilitation programs is limited. OBJECTIVE: To examine attitudes of athletic trainers (ATs) and physical therapists (PTs) on the effectiveness of mental imagery, goal setting, and positive self-talk to improve rehabilitation adherence and recovery speed of injured athletes. DESIGN: The ATs and PTs were contacted via electronic or physical mailings to complete a single administration survey that measured their beliefs about the effectiveness of psychological skills for increasing adherence and recovery speed of injured athletes undergoing rehabilitation. SETTING: Professional member databases of the National Athletic Trainers' Association and the American Physical Therapy Association. PATIENTS OR OTHER PARTICIPANTS: Of the 1000 ATs and 1000 PTs who were selected randomly, 309 ATs (age = 34.18 +/- 8.32 years, years in profession = 10.67 +/- 7.34) and 356 PTs (age = 38.58 +/- 7.51 years, years in profession = 13.18 +/- 6.17) responded. MAIN OUTCOME MEASURE(S): The Attitudes About Imagery (AAI) survey measures attitudes about psychological skills for enhancing adherence and recovery speed of injured athletes. The AAI includes demographic questions and 15 items on a 7-point Likert scale measuring attitudes about the effectiveness of mental imagery, self-talk, goal setting, and pain control on rehabilitation adherence and recovery speed of injured athletes. Test-retest reliability ranged from .60 to .84 and Cronbach alphas ranged from .65 to .90. We calculated 1-way analyses of variance to determine whether differences existed in attitudes as a result of the professionals' education, training experience, and interest. RESULTS: Mean differences were found on attitudes about effectiveness of psychological skills for those who reported formal training and those who reported interest in receiving formal training (P < .05). In addition, ATs held more positive attitudes than PTs on 9 of 15 AAI items (P < .05). CONCLUSIONS: Overall, ATs and PTs held positive attitudes on the effectiveness of psychological skills to augment the rehabilitation process. Clinical implications regarding the use of mental skills are discussed.

Effects of DL-malate on in vitro forage fiber digestion by mixed ruminal microorganisms.

The objective of this study was to evaluate the effects of 0, 4, 8, and 12 mM DL-malate on the in vitro mixed ruminal microorganism fermentation of alfalfa hay and Coastal bermudagrass hay. When alfalfa hay was the substrate, 4 and 8 mM DL-malate numerically increased propionate concentration, and 12 mM DL-malate increased (P < 0.10) propionate. All three concentrations of DL-malate decreased (P < 0.05) the acetate:propionate ratio. In Coastal bermudagrass hay fermentations, all three DL-malate concentrations increased (P < 0.05) propionate and decreased (P < 0.05) the acetate:propionate ratio, while 4 and 12 mM DL-malate numerically increased in vitro dry matter disappearance. When mixed ruminal microorganisms were incubated with 6.25 mM DL-lactic acid and alfalfa hay, 8 and 12 mM DL-malate increased (P < 0.05) final pH, and 12 mM DL-malate increased (P < 0.10) propionate and decreased (P < 0.10) the acetate:propionate ratio. DL-Malate treatment had little effect on in vitro dry matter disappearance. Addition of 8 and 12 mM DL-malate to Coastal bermudagrass hay plus DL-lactic acid fermentations increased (P < 0.05) final pH, and 8 mM DL-malate increased (P < 0.10) in vitro dry matter disappearance. Even though DL-malate treatment consistently increased final pH values in fermentations that included DL-lactic acid, there was not a corresponding increase in in vitro dry matter disappearance of either alfalfa hay or Coastal bermudagrass hay in the 48-h batch culture incubations.

Dihydropyridine neuropeptide Y Y1 receptor antagonists 2. bioisosteric urea replacements.

Structure-activity studies around the urea linkage in BMS-193885 (4a) identified the cyanoguanidine moiety as an effective urea replacement in a series of dihydropyridine NPY Y(1) receptor antagonists. In comparison to urea 4a (K(i)=3.3 nM), cyanoguanidine 20 (BMS-205749) displayed similar binding potency at the Y(1) receptor (K(i)=5.1 nM) and full functional antagonism (K(b)=2.6 nM) in SK-N-MC cells. Cyanoguanidine 20 also demonstrated improved permeability properties in Caco-2 cells in comparison to urea 4a (43 vs 19 nm/s).