Trial Design and Statistical Considerations on the Assessment of Pharmacodynamic Similarity.

Pharmacodynamics (PD) similarity is an important component to support the claim of similarity between two drugs or devices. This article investigates the trial design and statistical considerations in the equivalence test of PD endpoints. Using bone resorption marker CTX as a case study, the relationship between the PD readouts and drug potency was explored to evaluate the sensitivity of the PD endpoint and guide equivalence margin selection. For PD data that have high baseline variability, one conventional similarity assessment method was to apply baseline-normalization followed by the standard bioequivalence (BE) test (Lancet Haematol. 4:e350-61, 2017, Ann Rheum Dis. 2017). This study showcased the drawbacks of the conventional method for PD data that were close to inhibition saturation, as the baseline-normalization significantly skewed the distribution of the PD data toward non-log-normal. In such cases, the standard BE test can produce an inflated type I error. Alternatively, ANCOVA, when applied to the un-normalized PD data with the baseline as a covariate, produced a satisfactory type I error with sufficient power. Therefore, ANCOVA was recommended for equivalence test of PD markers that has a saturated inhibition profile and high variability at baseline. Moreover, the relationship between PD readouts and drug potency was used to explore the sensitivity of the PD endpoint and it could help justify the equivalence margins, since the standard 80% to 125% BE margin often does not apply to PD. Finally, a decision tree was proposed to help guide the design of the PD equivalence study in the choice of PD endpoints and statistical methods.

Ecological momentary assessment of smoking behaviors in native and converted intermittent smokers.

BACKGROUND AND OBJECTIVES: About 22% of adult smokers in the U.S. are intermittent cigarette smokers (ITS). ITS can be further classified as native ITS who never smoked daily and converted ITS who formerly smoked daily but reduced to intermittent smoking. Ecological momentary assessment (EMA) was conducted to determine the behaviors and experiences that are associated with the decision to smoke. METHODS: The study included 24 native ITS and 36 converted ITS (N = 60) from the Pennsylvania Adult Smoking Study. A baseline questionnaire, daily log, and an EMA smoking log that assessed emotions, activities, and smoking urges was filled out with each cigarette for 1 week to capture 574 smoking sessions. RESULTS: Both groups had very low levels of cigarette dependence. Both groups were more tempted to smoke in positive or negative situations than situations associated with habituation. EMA showed that the most common emotional state during smoking sessions was positive (47%), followed by negative (32%), neutral (16%), and mixed (5%) emotions. Smokers were more likely to smoke during activities of leisure (48%) than during performative duties (29%), social (16%) or interactive occasions (7%). Converted ITS were more likely to smoke alone compared to native ITS (p < .001). DISCUSSION AND CONCLUSIONS: ITS report minimal levels of dependence when captured on traditional scales of nicotine dependence, yet experience loss of autonomy and difficulty quitting. The majority of the ITS reported positive emotions and leisure activities while smoking, and smoked during the evening. SCIENTIFIC SIGNIFICANCE: The current paper identifies environmental and behavioral factors that are associated with smoking among ITS in real time. (Am J Addict 2018;27:131-138).

Reduced nicotine content cigarettes in smokers of low socioeconomic status: study protocol for a randomized control trial.

BACKGROUND: The Family Smoking Prevention and Tobacco Control Act gave the Food and Drug Administration jurisdiction over the regulation of all tobacco products, including their nicotine content. Under this act, a major strategy to reduce harm from cigarette tobacco is lowering the nicotine content without causing unintended adverse consequences. Initial research on reduced nicotine content (RNC) cigarettes has shown that smokers of these cigarettes gradually decrease their smoking frequency and biomarkers of exposure. The effectiveness of this strategy needs to be demonstrated in different populations whose response to RNC cigarettes might be substantially mediated by personal or environmental factors, such as low socioeconomic status (SES) populations. This study aims to evaluate the response to a reduced nicotine intervention in low SES smokers, as defined here as those with less than 16 years of education, by switching smokers from high nicotine commercial cigarettes to RNC cigarettes. METHODS/DESIGN: Adults (N = 280) who have smoked five cigarettes or more per day for the past year, have not made a quit attempt in the prior month, are not planning to quit, and have less than 16 years of education are recruited into a two-arm, double-blinded randomized controlled trial. First, participants smoke their usual brand of cigarettes for 1 week and SPECTRUM research cigarettes containing a usual amount of nicotine for 2 weeks. During the experimental phase, participants are randomized to continue smoking SPECTRUM research cigarettes that contain either (1) usual nicotine content (UNC) (11.6 mg/cigarette) or (2) RNC (11.6 to 0.2 mg/cigarette) over 18 weeks. During the final phase of the study, all participants are offered the choice to quit smoking with nicotine replacement therapy, continue smoking the research cigarettes, or return to their usual brand of cigarettes. The primary outcomes of the study include retention rates and compliance with using only research cigarettes and no use of other nicotine-containing products. Secondary outcomes are tobacco smoke biomarkers, nicotine dependence measures, smoking topography, stress levels, and adverse health consequences. DISCUSSION: Results from this study will provide information on whether low SES smokers can maintain a course of progressive nicotine reduction without increases in incidence of adverse effects. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01928719 . Registered on 21 August 2013.

Individual, Area, and Provider Characteristics Associated With Care Received for Stages I to III Breast Cancer in a Multistate Region of Appalachia.

PURPOSE: We describe individual, area, and provider characteristics associated with care patterns for early-stage breast cancer in Appalachian counties of Kentucky, North Carolina, Ohio, and Pennsylvania. METHODS: Cases of stages I to III breast cancer from 2006 to 2008 were linked to Medicare claims occurring within 1 year of diagnosis. Rates of guideline-concordant endocrine therapy (n = 1,429), chemotherapy (n = 1,480), and radiation therapy (RT) after breast-conserving surgery were studied; RT was studied in women age ≥ 70 years with stage I estrogen receptor (ER) -positive/progesterone receptor (PR) -positive cancer, for whom RT was optional (n = 1,108), and in all others, for whom RT was guideline concordant (n = 1,422). Univariable and multivariable analyses were performed. Independent variables included age, race, county-level economic status, state, surgeon graduation year and volume, comorbidity, diagnosis year, Medicaid/Medicare dual status, histology, tumor size, tumor sequence, positive lymph nodes, ER/PR status, stage, trastuzumab use, and surgery type. RESULTS: Population mean age was 74 years; 97% were white. For endocrine therapy, chemotherapy, and RT, guideline concordance was 76%, 48%, and 83%, respectively. Where it was optional, 77% received RT. Guideline-concordant endocrine therapy was lower in North Carolina versus Pennsylvania (odds ratio [OR], 0.60; 95% CI, 0.41 to 0.88) and higher if surgeon graduated between 1984 and 1988 versus ≥ 1989 (OR, 1.58; 95% CI, 1.06 to 2.34). Guideline-concordant chemotherapy varied significantly by state, county-level economic status, and surgeon volume. In guideline-concordant RT, lower surgeon volume (v highest) predicted RT use (OR, 1.63; 95% CI, 1.61 to 2.36). In optional RT, North Carolina residence (v Pennsylvania; OR, 0.29; 95% CI, 0.17 to 0.48) and counties with higher economic status (OR, 0.61; 95% CI, 0.40 to 0.94) predicated RT omission. CONCLUSION: Notable variation in care by geographic and surgical provider characteristics provides targets for further research in underserved areas.

Clinical, sociodemographic, and service provider determinants of guideline concordant colorectal cancer care for Appalachian residents.

BACKGROUND: Colorectal cancer represents a significant cause of morbidity and mortality, particularly in Appalachia where high mortality from colorectal cancer is more prevalent. Adherence to treatment guidelines leads to improved survival. This paper examines determinants of guideline concordance for colorectal cancer. METHODS: Colorectal cancer patients diagnosed in 2006-2008 from 4 cancer registries (Kentucky, Ohio, Pennsylvania, and North Carolina) were linked to Medicare claims (2005-2009). Final sample size after exclusions was 2,932 stage I-III colon, and 184 stage III rectal cancer patients. The 3 measures of guideline concordance include adjuvant chemotherapy (stage III colon cancer, <80 years), ≥12 lymph nodes assessed (resected stage I-III colon cancer), and radiation therapy (stage III rectal cancer, <80 years). Bivariate and multivariate analyses with clinical, sociodemographic, and service provider covariates were estimated for each of the measures. RESULTS: Rates of chemotherapy, lymph node assessment, and radiation were 62.9%, 66.3%, and 56.0%, respectively. Older patients had lower rates of chemotherapy and radiation. Five comorbidities were significantly associated with lower concordance in the bivariate analyses: myocardial infarction, congestive heart failure, respiratory diseases, dementia with chemotherapy, and diabetes with adequate lymph node assessment. Patients treated by hospitals with no Commission on Cancer (COC) designation or lower surgical volumes had lower odds of adequate lymph node assessment. CONCLUSIONS: Clinical, sociodemographic, and service provider characteristics are significant determinants of the variation in guideline concordance rates of 3 colorectal cancer measures.

The National Practitioner Data Bank: what CRNAs need to know.

As a nationwide flagging system, the National Practitioner Data Bank (NPDB) allows state licensing boards, hospitals, and other registered healthcare entities the ability to monitor practitioners through reporting and inquiry about the qualifications and competency of healthcare practitioners seeking clinical privileges where incompetence or unprofessional conduct could adversely affect a patient's welfare. Certified Registered Nurse Anesthetists are not exempt from being reported on or queried by registered reporting and querying entities. The NPDB warehouses data pertaining to adverse actions or medical malpractice payments taken against a practitioner. Based on the updated federal ruling published in the Federal Register regarding the NPDB and Section 1921 of the Social Security Act, the NPDB has expanded the definition of healthcare practitioners to include all healthcare practitioners as a means of protecting beneficiaries of the Social Security Act's healthcare programs. As such, nurse anesthetists should be aware of the additional reportable information that may be collected or disseminated based on the updated ruling pertaining to the NPDB.

The national practitioner data bank and CRNA anesthesia-related malpractice payments.

A retrospective analysis of the National Practitioner Data Bank (NPDB) Public Use Data File was performed on anesthesia-related malpractice payments from 2004 to 2010. Anesthesia-related allegations, malpractice act or omission codes, severity of injury, and cost were assessed. The NPDB captured 369 anesthesia-related malpractice payments associated with Certified Registered Nurse Anesthetists (CRNAs), of which the 3 most frequently coded injury classifications for severity were death, minor permanent injury, and grave permanent injury. In general, the most costly payments based on median cost were major permanent injury, followed by grave permanent injury and death. When reviewing specific allegations of malpractice act or omission among the total number of CRNA malpractice payments, the most common allegations were improper performance,, failure to monitor, and problem with intubation. Patients between the ages of 40 and 59 years, inpatients, and female gender were independently more prevalent among CRNA malpractice claims leading to payment than other patient demographics.

Evaluation of race and insurance status as predictors of undergoing laparoscopic appendectomy in children.

OBJECTIVE: The objective of this study was to determine the relationship of race and socioeconomic factors and the method used for appendectomies in children (open vs. laparoscopic). SUMMARY BACKGROUND DATA: Previous studies have shown racial and insurance-related differences associated with the management of appendicitis in adults. It is not known whether these differences are observed in children. METHODS: Children (<15 years) undergoing appendectomy from 1996 to 2002 were identified in the Nationwide Inpatient Sample. Severity of appendicitis and underlying chronic illnesses were determined by ICD-9 codes. Hospital characteristics evaluated included teaching status and location, children's hospital status, and volume of appendectomies. Hierarchical unadjusted and risk-adjusted logistic regression analyses were performed. RESULTS: Among 72,189 children undergoing an appendectomy for appendicitis, 11,714 (16%) underwent a laparoscopic appendectomy. Multivariate analysis showed that whites were more likely to undergo a laparoscopic appendectomy than blacks (odds ratio, 1.14; 95% CI, 1.03-1.25, P = 0.01) but not other races. A significant interaction between payer source and children's hospital designation was observed, with the odds of children with private insurance undergoing laparoscopic appendectomy being significantly higher than those without private insurance at nonchildren's hospitals but not at children's hospitals. CONCLUSIONS: There are significant racial and insurance-related differences in use of laparoscopic appendectomy in children that are most evident at nonchildren's hospitals. These findings provide evidence that factors at hospitals dedicated to children may lead to better access to new technologies.

Transporting efficacious treatments to field settings: the link between supervisory practices and therapist fidelity in MST programs.

Validated a measure of clinical supervision practices, further validated a measure of therapist adherence, and examined the association between supervisory practices and therapist adherence to an evidence-based treatment model (i.e., multisystemic therapy [MST]) in real-world clinical settings. Evidence of linkages between supervisor adherence to the MST supervisory protocol, as assessed through therapist reports, and therapist adherence to MST principles, as assessed through caregiver reports, was obtained from 285 families of youths presenting serious clinical problems, and 74 therapists and 12 supervisors of 16 teams in 9 organizations providing MST across 3 states. The findings provide a valuable step in examining the determinants of therapist fidelity to complex treatments in real-world clinical settings.