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A half century of scalloping in the work habits of the United States Congress.

It has been suggested that the work environment of the United States Congress bears similarity to a fixed-interval reinforcement schedule. Consistent with this notion, Weisberg and Waldrop (1972) described a positively accelerating pattern in annual congressional bill production (selected years from 1947 to 1968) that is reminiscent of the scalloped response pattern often attributed to fixed-interval schedules, but their analysis is now dated and does not bear on the functional relations that might yield scalloping. The present study described annual congressional bill production over a period of 52 years and empirically evaluated predictions derived from four hypotheses about the mechanisms that underlie scalloping. Scalloping occurred reliably in every year. The data supported several predictions about congressional productivity based on fixed-interval schedule performance, but did not consistently support any of three alternative accounts. These findings argue for the external validity of schedule-controlled operant behavior as measured in the laboratory. The present analysis also illustrates a largely overlooked role for applied behavior analysis: that of shedding light on the functional properties of behavior in uncontrolled settings of considerable interest to the public.

Efficiency↗

The generalized matching law in elite sport competition: football play calling as operant choice.

A mathematical model of operant choice, the generalized matching law was used to analyze play-calling data from the 2004 National Football League season. In all analyses, the relative ratio of passing to rushing plays was examined as a function of the relative ratio of reinforcement, defined as yards gained, from passing versus rushing. Different analyses focused on season-aggregate data for the league as a whole, game-by-game data for the league as a whole, and game-by-game data for individual teams. In all analyses except those for a few individual teams, the generalized matching law accounted for a majority of variance in play calling. The typical play-calling pattern reflected undermatching (suggesting imperfect sensitivity of play calling to yardage-gained reinforcers) and a bias for calling rushing plays. Bias was found to be a function of both the relative risk of turnovers and the relative variability in yards gained associated with passing versus rushing plays. The external validity of the matching analyses was supported by significant correlations between parameters of the generalized matching law and team success on offense and season winning percentage. These results illustrate the broad applicability of the generalized matching law to problems outside of the laboratory.

Choice Behavior↗

Genetic insights into lung squamous cell carcinoma: how TP53 and CSMD3 co-mutations shape prognosis and immune response.

BACKGROUND: Lung squamous cell carcinoma (LUSC) accounts for a significant proportion of lung cancer cases and is often associated with smoking and various environmental factors. The prognostic and immunologic implications of TP53 and CSMD3 co-mutations in LUSC remain poorly understood. This study aimed to investigate the role of TP53/CSMD3 co-mutations in LUSC using comprehensive bioinformatics analyses. METHODS: Data from 487 LUSC patients were obtained from The Cancer Genome Atlas (TCGA) database, with external validation performed using the combined cohort. Patients were stratified into TP53/CSMD3 co-mutation, single-mutation, and wild-type (WT) groups. Prognostic analysis was conducted using Kaplan-Meier survival curves. Tumor mutational burden (TMB) was calculated, and immune cell infiltration was assessed using multiple algorithms. Differentially expressed genes (DEGs) between co-mutated and WT groups were identified, followed by Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. A nomogram incorporating mutation status, gender, age, and tumor stage (T stage) was developed for individualized prognostic prediction. RESULTS: The TP53/CSMD3 co-mutated group exhibited significantly better overall survival (OS) compared to single-mutation and WT groups. TMB scores were markedly higher in co-mutated patients, suggesting potential sensitivity to immune checkpoint inhibitors. Immune infiltration analysis revealed distinct profiles, including elevated CD8 T cells and reduced immunosuppressive components, in the co-mutation group. A total of 403 DEGs were identified between co-mutated and WT groups, with significant enrichment in immune-related pathways. Mechanistically, the co-mutation was associated with distinct downregulation of complement negative regulators (CFH/CFI), indicating complement hyperactivation independent of TMB. The constructed nomogram provided accurate individualized prognostic assessments. CONCLUSIONS: The co-mutation of TP53 and CSMD3 identifies a distinct LUSC subtype with favorable survival, marked by high TMB and an immune-activated microenvironment. Beyond TMB-driven neoantigen generation, the significant downregulation of complement negative regulators (CFH/CFI) reveals an independent complement hyperactivation pathway associated with CSMD3 loss. The constructed nomogram provides accurate individualized survival prediction. These findings establish TP53/CSMD3 co-mutation as a promising prognostic biomarker and offer mechanistic insights for personalized immunotherapy strategies. Future prospective cohorts are warranted to validate its predictive value.

Lung squamous cell carcinoma (LUSC)↗

Evidence-based public health: moving beyond randomized trials.

Randomized controlled trials (RCTs) are essential for evaluating the efficacy of clinical interventions, where the causal chain between the agent and the outcome is relatively short and simple and where results may be safely extrapolated to other settings. However, causal chains in public health interventions are complex, making RCT results subject to effect modification in different populations. Both the internal and external validity of RCT findings can be greatly enhanced by observational studies using adequacy or plausibility designs. For evaluating large-scale interventions, studies with plausibility designs are often the only feasible option and may provide valid evidence of impact. There is an urgent need to develop evaluation standards and protocols for use in circumstances where RCTs are not appropriate.

Causality↗

Early rheumatoid arthritis: pitfalls in diagnosis and review of recent clinical trials.

The treatment of rheumatoid arthritis (RA) has changed dramatically in the past decade as advancements in the understanding of the pathobiology of the disease have led to novel therapeutic agents. The recognition that early diagnosis and treatment leads to improvements in morbidity and mortality has altered the therapeutic strategy such that early therapy is now considered the standard of care. This review focuses on the challenges in making the diagnosis of early RA, including a broad differential diagnosis for inflammatory polyarthritis, poor performance of the standard classification criteria, difficulty in clinical assessment of synovitis, absence of absolute laboratory tests, inability of conventional radiography to detect bony changes early, and barriers to rheumatology care. Additionally, the pathogenesis of RA is highlighted, with particular emphasis on cytokine biology as it relates to therapeutic regimens. Relevant clinical trials in early RA are reviewed and discussed, including trials of combination disease-modifying antirheumatic drugs and biological therapy. The role of induction therapy as a novel therapeutic approach is highlighted. The search for predictors of response is reviewed and the external validity of the trials is analysed. Finally, the trials in early RA therapy suggest that swift intervention with combinations of medications is required for patients with severe RA. However, further research is needed to determine which regimen is appropriate for the individual patient with RA.

Arthritis, Rheumatoid↗

Injuries in cross-country skiing: a critical appraisal of the literature.

This study comprehensively reviews and critically appraises recent literature on cross-country skiing injuries. Particular attention was paid to the study design when reviewing the literature, thereby producing a measure of internal and external validity. From these data, the factors associated with the aetiology, frequency, site distribution and types of cross-country skiing injuries are examined. The incidence of injury in cross-country skiing is estimated to be between 0.49 and 5.63 per 1000 skier days. The most common injuries are medial collateral ligament sprains of the knee, and ulnar collateral ligament sprains of the thumb. Overuse and cold injuries (e.g. hypothermia and frostbite) appear to be common as well, although the data do not provide an estimate of incidence. Comments in the literature on prevention of these injuries are mainly empirical: they recommend safer equipment, wise choice of terrain and a general increase in skier awareness of ways to prevent injury. However, rigorous studies that adequately evaluate preventive intervention strategies have yet to be conducted. Cross-country skiing is relatively safe and a suitable activity for physical fitness and rehabilitation. In the future, studies employing an analytical design will be required to evaluate the effectiveness of injury prevention intervention strategies.

Arm Injuries↗

Bridging decision analytic modelling with a cross-sectional study. Application to Parkinson's disease.

The ideal study design for demonstrating the possible health outcomes and costs associated with a new drug would be a naturalistic prospective study. However, it is not often feasible to derive the required information from scientifically sound prospective studies. In these cases, decision analytic models may provide some of the missing information. However, the use of a Delphi panel to gather data for these models is a major concern because of potential bias and data accuracy. Because reimbursement of pharmaceuticals is often based on economic data derived from modelling studies, it is obvious that potential bias due to the use of Delphi panels should be minimised. In this manuscript we present an alternative data source for modelling studies: the cross-sectional study. Data from such studies can be used to yield costs and utilities for Markov health states. The overall combined design may be considered a hybrid between a naturalistic prospective study and a modelling study by maximising the pros and minimising the cons of both types of design, including an increase of external validity. This hybrid design is based on bridging the probabilities derived from the literature and clinical trials with information on costs and utilities from a cross-sectional study. This design also has logistical advantages, namely a shorter required study duration compared with prospective naturalistic studies for chronic diseases. This combined design was illustrated using a Markov model for Parkinson's disease.

Cross-Sectional Studies↗

Encouraging smokers to quit: the cost effectiveness of reimbursing the costs of smoking cessation treatment.

BACKGROUND: Smoking cessation should be encouraged in order to increase life expectancy and reduce smoking-related healthcare costs. Results of a randomised trial suggested that reimbursing the costs of smoking cessation treatment (SCT) may lead to an increased use of SCT and an increased number of quitters versus no reimbursement. OBJECTIVE: To assess whether reimbursement for SCT is a cost-effective intervention (from the Dutch societal perspective), we calculated the incremental costs per quitter and extrapolated this outcome to incremental costs per QALY saved versus no reimbursement. METHODS: In the reimbursement trial, 1266 Dutch smokers were randomly assigned to the intervention or control group using a randomised double consent design. Reimbursement for SCT was offered to the intervention group for a period of 6 months. No reimbursement was offered to the control group. Prolonged abstinence from smoking was determined 6 months after the end of the reimbursement period. The QALYs gained from quitting were calculated until 80 years of age using data from the US. Costs (year 2002 values) were determined from the societal perspective during the reimbursement period (May-November 2002). Benefits were discounted at 4% per annum. The uncertainty of the incremental cost-effectiveness ratios was estimated using non-parametric bootstrapping. RESULTS: Eighteen participants in the control group (2.8%) and 35 participants in the intervention group (5.5%) successfully quit smoking. The costs per participant were 291 euro and 322 euro, respectively. If society is willing to pay 1000 euro or 10,000 euro for an additional 12-month quitter, the probability that reimbursement for SCT would be cost effective was 50% or 95%, respectively. If society is willing to pay 18,000 euro for a QALY, the probability that reimbursement for SCT would be cost effective was 95%. However, the external validity of the extrapolation from quitters to QALYs is uncertain and several assumptions had to be made. CONCLUSION: Reimbursement for SCT may be cost effective if Dutch society is willing to pay 10,000 euro for an additional quitter or 18,000 euro for a QALY.

Adolescent↗

Comparison of predictive ability of water solubility QSPR models generated by MLR, PLS and ANN methods.

ADME/Tox computational screening is one of the most hot topics of modern drug research. About one half of the potential drug candidates fail because of poor ADME/Tox properties. Since the experimental determination of water solubility is time-consuming also, reliable computational predictions are needed for the pre-selection of acceptable "drug-like" compounds from diverse combinatorial libraries. Recently many successful attempts were made for predicting water solubility of compounds. A comprehensive review of previously developed water solubility calculation methods is presented here, followed by the description of the solubility prediction method designed and used in our laboratory. We have selected carefully 1381 compounds from scientific publications in a unified database and used this dataset in the calculations. The externally validated models were based on calculated descriptors only. The aim of model optimization was to improve repeated evaluations statistics of the predictions and effective descriptor scoring functions were used to facilitate quick generation of multiple linear regression analysis (MLR), partial least squares method (PLS) and artificial neural network (ANN) models with optimal predicting ability. Standard error of prediction of the best model generated with ANN (with 39-7-1 network structure) was 0.72 in logS units while the cross validated squared correlation coefficient (Q(2)) was better than 0.85. These values give a good chance for successful pre-selection of screening compounds from virtual libraries, based on the predicted water solubility.

Chemical Phenomena↗

QSAR modeling of carcinogenic risk using discriminant analysis and topological molecular descriptors.

A discriminant analysis model is presented for carcinogenic risk. The data set is obtained from the two-year rodent study FDA/CDER database and was divided into a training set of 1022 organic compounds and an external validation test set of 50 compounds. The model is designed to use as a decision support tool for a defined decision threshold, and is thus a binary discrimination into "high risk" and "low risk" categories. The carcinogenic risk classification is based on the method for estimating human risk from two-year rodent studies developed at the FDA/CDER/ICSAS. The paradigm chosen for this model allows a straightforward risk analysis based on historic information, as well as the computation of coverage, probability and confidence metrics that can further qualify the computed result. The molecular structures were represented as MDL mol files. The molecular structure information was obtained as topological structure descriptors, including atom-type and group-type E-State and hydrogen E-State indices, molecular connectivity chi indices, topological polarity, and counts of molecular features. The MDL QSAR software computed all these descriptors. Furthermore, the discriminant analyses were all performed with the MDL QSAR software. The reported model is based on fifty-three descriptors, using the nonparametric normal kernel method and the Mahalanobis distance to determine proximity. The model performed very well on the fifty compounds of the test set, yielding the following statistics: 76% correctly classified "high risk" (carcinogenic) and 84% correctly classified as "low risk" (non-carcinogenic).

Animals↗

Looking for signs of Alzheimer's disease.

This study examined the correlates of symptom-seeking behavior for Alzheimer's disease (AD) among middle-aged persons. Symptom seeking, the tendency to search for signs of disease, is one manifestation of an individual's concern about developing AD. The data were obtained from a survey of two subsamples of 40-60 year old adults: 1) 108 adult children with a living parent with a diagnosis of probable AD; and 2) 150 adults in a matched group with no parental history of AD. Bivariate and multivariate analyses were used to identify significant predictors of symptom seeking, which was measured by a composite index comprised of responses from three questions about checking for signs of AD, interpreting signs as symptoms of AD, and soliciting external validation for concerns. Four clusters of predictors were examined: memory assessment, AD experience, sociodemographics, and well-being. Within these clusters, the constellations of significant predictors varied by subsample, but the most robust predictors were aspects of subjective assessments of memory functioning and AD experience. An understanding of the correlates of symptom seeking for AD has implications for early detection of the disease as well as identifying populations under stress from excessive worry about their own future health.

Adult↗

The relevance of occupational epidemiology to radiation protection standards.

Large-scale epidemiological studies of U.S. Department of Energy workers have been underway since the 1960s. Despite the increasing availability of information about long-term follow-up of badge-monitored nuclear workers, standard-setting bodies continue to rely on the Life Span Study (LSS) of A-bomb survivors as the primary epidemiological basis for making judgments about hazards of low-level radiation. Additionally, faith in the internal and external validity of studies of A-bomb survivors has influenced decisions about the design, analysis, and interpretation of many worker studies. A systematic comparison of the LSS and worker studies in terms of population characteristics, types of radiation exposures, selection factors, and dosimetry errors suggests that the priority given to dose response findings from the LSS is no longer warranted. Evidence from worker studies suggests that excess radiation-related cancer deaths occur at doses below the current occupational limits; low-dose effects have also been seen in studies of childhood cancers in relation to fetal irradiation. These findings should be considered in revising current radiation protection standards.

Journal Article↗

An empirical delineation of the heterogeneity of chronic unexplained fatigue in women.

OBJECTIVES: To test the hypothesis that medically unexplained chronic fatigue and chronic fatigue syndrome (CFS) are heterogeneous conditions, and to define the different conditions using both symptom and laboratory data. METHODS: We studied 159 women from KS, USA. A total of 51 of these suffered from fatigue consistent with established criteria for CFS, 55 had chronic fatigue of insufficient symptoms/severity for a CFS diagnosis and 53 were healthy controls matched by age and body mass index (BMI) against those with CFS. We used principal components analyses to define factors that best described the variable space and to reduce the number of variables. The 38 most explanatory variables were then used in latent class analyses to define discrete subject groups. RESULTS: Principal components analyses defined six discrete factors that explained 40% of the variance. Latent class analyses provided several interpretable solutions with four, five and six classes. The four-class solution was statistically most convincing, but the six-class solution was more interpretable. Class 1 defined 41 (26%) subjects with obesity and relative sleep hypnoea. Class 2 were 38 (24%) healthy subjects. Class 3 captured 24 (15%) obese relatively hypnoeic subjects, but with low heart rate variability and cortisol. Class 4 were 23 (14%) sleep-disturbed and myalgic subjects without obesity or significant depression. The two remaining classes with 22 (14%) and 11 (7%) subjects consisted of the most symptomatic and depressed, but without obesity or hypnoea. Class 5 had normal sleep indices. Class 6 was characterized by disturbed sleep, with low sleep heart rate variability, cortisol, and sex hormones. CONCLUSION: Chronic medically unexplained fatigue is heterogeneous. The putative syndromes were differentiated by obesity, sleep hypnoea, depression, physiological stress response, sleep disturbance, interoception and menopausal status. If these syndromes are externally validated and replicated, they may prove useful in determining the causes, pathophysiology and treatments of CFS.

Adult↗

[High blood pressure in children and adolescents: determinant factors]

OBJECTIVE: To review the state of prevalence of hypertension in childhood and the importance of its possible determinants. METHODS: Analysis of the literature concerned with eleven possible determinant factors - experimental design, internal and external validity. RESULTS AND CONCLUSIONS: Central body fat pattern seems to be a risk factor, while heart rate and tracking would be true markers of future hypertension. Social class, biological maturation, race, sodium intake and genetic factors have not yet been validated through unbiased studies.

Journal Article↗

Proteinuria as a predictor of total plasma homocysteine levels in type 2 diabetic nephropathy.

OBJECTIVE: Patients with diabetes who manifest proteinuria are at increased risk for cardiovascular events. Some studies suggest that proteinuria exerts its cardiovascular effects at least partly through a positive association with total plasma homocysteine (tHcy). Modestly sized but better designed contrary studies find no such link through a limited range of serum creatinine and proteinuria. We tested the hypothesis that proteinuria independently predicts tHcy levels in a larger cohort of type 2 diabetic patients with nephropathy throughout a much broader range of kidney disease and proteinuria. RESEARCH DESIGN AND METHODS: Baseline data for the cross-sectional study were obtained from 717 patients enrolled in the multicenter Irbesartan Diabetic Nephropathy Trial. All subjects had type 2 diabetes, hypertension, and proteinuria and were between 29 and 78 years of age. Data included age, sex, BMI, serum creatinine and albumin, LDL and HDL cholesterol, triglyceride, proteinuria and albuminuria, plasma folate, B12, and pyridoxal 5'-phosphate (PLP) (the active form of B6), HbA(1c), and tHcy levels. Unadjusted and multivariable models were used in the analysis. RESULTS: Crude analyses revealed significant associations between tHcy and age (r = 0.074; P = 0.008), creatinine (r = 0.414; P < 0.001), PLP (r = -0.105; P = 0.021), B12 (r = -0.216; P < 0.001), folate (r = -0.241; P < 0.001), and HbA(1c) (r = -0.119; P = 0.003), with serum albumin approaching significance (r = 0.055; P = 0.072). Only serum creatinine, plasma folate, B12, serum albumin, sex, HbA(1c), and age were independent predictors of tHcy after controlling for all other variables. CONCLUSIONS: By finding no independent correlation between proteinuria (or albuminuria) and tHcy levels, this study improves the external validity of previous negative findings. Therefore, it is unlikely that the observed positive association between proteinuria and cardiovascular disease is directly related to hyperhomocysteinemia.

Cholesterol, HDL↗

the Charlop-Atwell Scale of Motor Coordination: a quick and easy assessment of young children.

The Charlop-Atwell Scale of Motor Coordination was designed to meet the need for a quick and easily used measure of some aspects of gross motor coordination of children between the ages of 4 and 6 years. The scale was provisionally standardized on 201 children who were sampled across age, sex, race and income level. It is short, relatively simple for school teachers and researchers to administer, and does not require special equipment. The scale contains a subjective subtest, based on quality of performance, in addition to an objective subtest based on accuracy of performance. Results show a developmental trend, high test-retest and interobserver reliability, and strong external validity.

Child↗

Relationship of age and sex-role conflict for professional women in human services.

This study provides external validation of the Sex-role Conflict Scale. The relationship between age and sex-role conflict among women with educational interests was investigated. 128 female students in education were assessed on the conflict they experienced in various settings. The mean sex-role conflict scores, although hypothesized to be significantly different, were not among women ages 25 yr. and below, ages 26 to 39 yr., and ages 40 yr. and over. Also investigated was the relationship between age and sex-role conflict in dual-career respondents. Of the 29 respondents who met the criterion for classification, mean sex-role conflict scores were not significantly different for the three age groups. The nonlinear relationship between sex-role conflict and age does not have support for professional women who work in fields other than business.

Adult↗

Depersonalization in kindergarten teachers in relation to rejection of help by fellow teachers and emotional support from family.

The present study investigated the external validity of a model describing the reactions of spurned helpers by examining the relation of spurning with burnout among kindergarten teachers. A second objective was to explore whether emotional support from one's family could reduce the negative effects of feeling spurned on burnout. 48 kindergarten teachers in Macau responded to a questionnaire measuring feeling spurned, emotional support from family, and depersonalization. Analyses indicated the effects of feeling spurned on depersonalization and also the benefit of emotional support; however, no evidence was obtained for he proposed buffering effect of emotional support.

Adult↗