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Attribute hierarchy is a common assumption in the educational context, where the mastery of one attribute is assumed to be a prerequisite to the mastery of another one. The attribute hierarchy can be incorporated through a restricted Q matrix that implies the specified structure. The latent class-based cognitive diagnostic models (CDMs) usually do not assume a hierarchical structure among attributes, which means all profiles of attributes are possible in a population of interest. This study investigates different estimation methods to the classification accuracy for a family of CDMs when they are combined with a restricted Q-matrix design. A simulation study is used to explain the misclassification caused by an unrestricted estimation procedure. The advantages of the restricted estimation procedure utilizing attribute hierarchies for increased classification accuracy are also further illustrated through a real data analysis on a syllogistic reasoning diagnostic assessment. This research can provide guidelines for educational and psychological researchers and practitioners when they use CDMs to analyze the data with a restricted Q-matrix design and make them be aware of the potentially contaminated classification results if ignoring attribute hierarchies., Competing Interests: Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

In order to look more closely at the many particular skills examinees utilize to answer items, cognitive diagnosis models have received much attention, and perhaps are preferable to item response models that ordinarily involve just one or a few broadly defined skills, when the objective is to hasten learning. If these fine-grained skills can be identified, a sharpened focus on learning and remediation can be achieved. The focus here is on how to detect when learning has taken place for a particular attribute and efficiently guide a student through a sequence of items to ultimately attain mastery of all attributes while administering as few items as possible. This can be seen as a problem in sequential change-point detection for which there is a long history and a well-developed literature. Though some ad hoc rules for determining learning may be used, such as stopping after M consecutive items have been successfully answered, more efficient methods that are optimal under various conditions are available. The CUSUM, Shiryaev-Roberts and Shiryaev procedures can dramatically reduce the time required to detect learning while maintaining rigorous Type I error control, and they are studied in this context through simulation. Future directions for modelling and detection of learning are discussed., (© 2016 The British Psychological Society.)

Latent class models for cognitive diagnosis have been developed to classify examinees into one of the 2 (K) attribute profiles arising from a K-dimensional vector of binary skill indicators. These models recognize that response patterns tend to deviate from the ideal responses that would arise if skills and items generated item responses through a purely deterministic conjunctive process. An alternative to employing these latent class models is to minimize the distance between observed item response patterns and ideal response patterns, in a nonparametric fashion that utilizes no stochastic terms for these deviations. Theorems are presented that show the consistency of this approach, when the true model is one of several common latent class models for cognitive diagnosis. Consistency of classification is independent of sample size, because no model parameters need to be estimated. Simultaneous consistency for a large group of subjects can also be shown given some conditions on how sample size and test length grow with one another.

The issue of latent trait granularity in diagnostic models is considered, comparing and contrasting latent trait and latent class models used for diagnosis. Relationships between conjunctive cognitive diagnosis models (CDMs) with binary attributes and noncompensatory multidimensional item response models are explored, leading to a continuous generalization of the Noisy Input, Deterministic "And" Gate (NIDA) model. A model that combines continuous and discrete latent variables is proposed that includes a noncompensatory item response theory (IRT) term and a term following the discrete attribute Deterministic Input, Noisy "And" Gate (DINA) model in cognitive diagnosis. The Tatsuoka fraction subtraction data are analyzed with the proposed models as well as with the DINA model, and classification results are compared. The applicability of the continuous latent trait model and the combined IRT and CDM is discussed, and arguments are given for development of simple models for complex cognitive structures., Competing Interests: Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Preclinical studies have shown that the inhibition of ornithine decarboxylase (ODC) by alpha-difluoromethylornithine (DFMO) and resultant decreases in tissue concentrations of polyamines (putrescine and spermidine) prevents neoplastic developments in many tissue types. Clinical studies of oral DFMO at 500 mg/m(2)/day revealed it to be safe and tolerable and resulted in significant inhibition of phorbol ester-induced skin ODC activity. Two hundred and ninety-one participants (mean age, 61 years; 60% male) with a history of prior nonmelanoma skin cancer (NMSC; mean, 4.5 skin cancers) were randomized to oral DFMO (500 mg/m(2)/day) or placebo for 4 to 5 years. There was a trend toward a history of more prior skin cancers in subjects randomized to placebo, but all other characteristics including sunscreen and nonsteroidal anti-inflammatory drug use were evenly distributed. Evaluation of 1,200 person-years of follow-up revealed a new NMSC rate of 0.5 events/person/year. The primary end point, new NMSCs, was not significantly different between subjects taking DFMO and placebo (260 versus 363 cancers, P = 0.069, two-sample t test). Evaluation of basal cell (BCC) and squamous cell cancers separately revealed very little difference in squamous cell cancer between treatment groups but a significant difference in new BCC (DFMO, 163 cancers; placebo, 243 cancers; expressed as event rate of 0.28 BCC/person/year versus 0.40 BCC/person/year, P = 0.03). Compliance with DFMO was >90% and it seemed to be well tolerated with evidence of mild ototoxicity as measured by serial audiometric examination when compared with placebo subjects. The analysis of normal skin biopsies revealed a significant (P < 0.05) decrease in 12-0-tetradecanoylphorbol-13-acetate-induced ODC activity (month 24, 36, and 48) and putrescine concentration (month 24 and 36 only) in DFMO subjects. Subjects with a history of skin cancer taking daily DFMO had an insignificant reduction (P = 0.069) in new NMSC that was predominantly due to a marked reduction in new BCC. Based on these data, the potential of DFMO, alone or in combination, to prevent skin cancers should be explored further.

Purpose: Testosterone administration can lead to increased antipyrine clearance in humans. Medical or surgical castration is a standard treatment of progressive prostate carcinoma, but the effect of the subsequent fall of testosterone concentrations upon drug metabolism has not been reported., Methods: Eleven men with a biopsy-proven diagnosis of progressive prostate cancer were enrolled after providing informed consent. CYP3A4 activity was determined using the erythromycin breath test (EBT) in each patient prior to their beginning with an LHRH-agonist (leuprolide or goserelin). No patients had elected to undergo orchiectomy during the period of subject accrual. Each subject underwent a second EBT 2 months after beginning LHRH suppression. Blood samples were collected at these time points to determine changes in testosterone and leutinizing hormone., Results: All subjects had a predictable drop in serum testosterone concentrations over the 8-week course of the study, but concentrations in three did not fall below castrate levels (<50 ng/dl). There was no statistically significant change in CYP3A4 activity using the EBT method (p = 0.88). The extent and direction of changes in CYP3A4 activity was highly variable, with three subjects experiencing an increase in activity, and five demonstrating a decrease in activity., Conclusion: There is no clinically significant change in CYP3A4 activity after medical castration. No changes in the clearance of docetaxel or other CYP3A4 substrates are likely during and after medical castration. Although similar findings are expected after orchiectomy, we were not able to test this presumption because of patient preference for medical castration.

Objective: To assess the efficacy and toxicity of the combination of interferon-alpha and doxycycline in patients with metastatic renal cell carcinoma and to assess the effect of this treatment on serum vascular endothelial growth factor (VEGF) levels., Patients and Methods: Seventeen patients with Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 and life expectancy greater than 4 months with radiologically evident advanced renal cell carcinoma were enrolled. Eight patients had prior nephrectomy and 10 patients were treated within 4 months of their diagnosis. Treatment consisted of interferon-alpha up to 9 million units subcutaneously three times per week and doxycycline 300 mg orally twice per day for weeks one and three of each four-week cycle. Toxicity was evaluated on a biweekly basis and response on a bimonthly basis. VEGF plasma levels were assessed monthly as a measure of potential antiangiogenic effect., Results: No objective responses were seen. The mean duration of study was 2.6 cycles (range: 0.8-6.0 cycles). Three patients (17%) tolerated therapy and displayed stable disease for greater than four months. Five patients withdrew from study before the first response evaluation. Ten patients experienced grade 2 gastrointestinal toxicity requiring dose reduction of doxycycline. Eight patients experienced grade 2 fatigue requiring dose reduction of interferon. VEGF plasma levels were initially suppressed in patients who demonstrated progressive disease but not in patients with stable disease., Conclusion: This regimen of doxycycline and interferon-alpha was not efficacious as treatment for renal cell carcinoma. Plasma VEGF levels were significantly decreased during the first two cycles of treatment, but this does not correlate with clinical outcome.

Objective: To evaluate whether early diagnosis of cystic fibrosis (CF) through newborn screening (NBS) and early vitamin E status are associated with cognitive function., Study Design: We assessed cognitive function for 71 children without meconium ileus (ages 7.3-16.9 years) enrolled in the screened (S) or control (C) group of the Wisconsin CF Neonatal Screening Project. The Test of Cognitive Skills, 2nd edition generated the cognitive skills index (CSI; mean = 100, SD = 16). Vitamin E deficiency at diagnosis was defined as plasma alpha-tocopherol (alpha-T) below 300 microg/dL (<300E). Primary analyses evaluated CSI scores across the 4 levels of group (S or C) by using alpha-T status (<300E or >300E) with analysis of covariance., Results: After adjusting for covariates, CSI in the C<300E group was significantly lower than each of the other groups (C>300E, S<300E, and S>300E; P < .05). The highest proportion of CSI scores >84 occurred in the C<300E group (41%). Patients in this group also had the lowest mean head circumference z-scores at diagnosis., Conclusions: Our results show that prolonged alpha-T deficiency in infancy is associated with lower subsequent cognitive performance. Thus, diagnosis via NBS may benefit the cognitive development of children with CF, particularly in those prone to vitamin E deficiency during infancy.

Objective: Patients who have cystic fibrosis (CF) and experience delayed diagnosis by traditional methods have greater nutritional insult compared with peers diagnosed via neonatal screening. The objective of this study was to evaluate cognitive function in children with CF and the influence of both early diagnosis through neonatal screening and the potential effect of early malnutrition., Methods: Cognitive assessment data were obtained for 89 CF patients (aged 7.3-17 years) during routine clinic visits. Patients had been enrolled in either the screened (N = 42) or traditional diagnosis (control) group (N = 47) of the Wisconsin CF Neonatal Screening Project. The Test of Cognitive Skills, Second Edition was administered to generate the Cognitive Skills Index (CSI) and cognitive factor scores (Verbal, Nonverbal, and Memory)., Results: Cognitive scores in the overall study population were similar to normative data (CSI mean [standard deviation]: 102.5 [16.6]; 95% confidence interval: 99.1-105.9). The mean (standard deviation) CSI scores for the screened and control groups were 104.4 (14.4) and 99.8 (18.5), respectively. Significantly lower cognitive scores correlated with indicators of malnutrition and unfavorable family factors such as single parents, lower socioeconomic status, and less parental education. Our analyses revealed lower cognitive scores in patients with low plasma alpha-tocopherol (alpha-T) levels at diagnosis. In addition, patients in the control group who also had vitamin E deficiency at diagnosis (alpha-T < 300 microg/dl) showed significantly lower CSI scores in comparison with alpha-T-sufficient control subjects and both deficient and sufficient alpha-T subsets of screened patients., Conclusion: Results suggest that prevention of prolonged malnutrition by early diagnosis and nutritional therapy, particularly minimizing the duration of vitamin E deficiency, is associated with better cognitive functioning in children with CF.

Objectives: We studied how physicians' relative satisfaction and/or dissatisfaction with 10 distinct aspects of their work protected against or promoted their plans for leaving their jobs., Study Design: Cross-sectional mail survey., Population: A total of 1939 practicing generalists and specialists across the United States., Outcome Measured: We used logistic regression analysis to assess whether physicians in the top and bottom quartiles of satisfaction for each of 10 aspects of their work and communities were more or less likely to anticipate leaving their jobs within 2 years, compared with physicians in mid-satisfaction quartiles. Separate analyses were compiled for generalists vs specialists, and physicians by age groups (27-44 years, 45-54 years, and 55 years and older)., Results: Generalists and specialists had generally comparable levels of satisfaction, whereas physicians in the oldest age group indicated greater satisfaction than younger physicians in 8 of the 10 work areas. One quarter (27%) of physicians anticipated a moderate- to-definite likelihood of leaving their practices within 2 years. The percentage that anticipated leaving varied with physicians' age, starting at 29% of those 34 years or younger, steadily decreasing with age until reaching a nadir of 22% of those from 45 to 49 years, then reversing direction to steadily increase thereafter. Relative dissatisfaction with pay and with relationships with communities was associated with plans for leaving in nearly all physician groups. For specific specialty and age groups, anticipated departure also correlated with relative dissatisfaction with other selected areas of work., Conclusions: To promote retention, these data suggest that physicians and their employers should avoid physician dissatisfaction in particular. Building particularly high levels of satisfaction generally is not helpful for this end. Avoiding relative dissatisfaction with pay and with community relationships appears broadly important.

Objective: To study the impact that physician, practice, and patient characteristics have on physician stress, satisfaction, mental, and physical health., Data Sources: Based on a survey of over 5,000 physicians nationwide. Four waves of surveys resulted in 2,325 complete responses. Elimination of ineligibles yielded a 52 percent response rate; 1,411 responses from primary care physicians were used., Study Design: A conceptual model was tested by structural equation modeling. Physician job satisfaction and stress mediated the relationship between physician, practice, and patient characteristics as independent variables and physician physical and mental health as dependent variables., Principle Findings: The conceptual model was generally supported. Practice and, to a lesser extent, physician characteristics influenced job satisfaction, whereas only practice characteristics influenced job stress. Patient characteristics exerted little influence. Job stress powerfully influenced job satisfaction and physical and mental health among physicians., Conclusions: These findings support the notion that workplace conditions are a major determinant of physician well-being. Poor practice conditions can result in poor outcomes, which can erode quality of care and prove costly to the physician and health care organization. Fortunately, these conditions are manageable. Organizational settings that are both "physician friendly" and "family friendly" seem to result in greater well-being. These findings are particularly important as physicians are more tightly integrated into the health care system that may be less clearly under their exclusive control.