Search

C/EBPs are a family of transcription factors that regulate growth control and differentiation of various tissues. We found that C/EBPγ is highly upregulated in a subset of acute myeloid leukemia (AML) samples characterized by C/EBPα hypermethylation/silencing. Similarly, C/EBPγ was upregulated in murine hematopoietic stem/progenitor cells lacking C/EBPα, as C/EBPα mediates C/EBPγ suppression. Studies in myeloid cells demonstrated that CEBPG overexpression blocked neutrophilic differentiation. Further, downregulation of Cebpg in murine Cebpa-deficient stem/progenitor cells or in human CEBPA-silenced AML samples restored granulocytic differentiation. In addition, treatment of these leukemias with demethylating agents restored the C/EBPα-C/EBPγ balance and upregulated the expression of myeloid differentiation markers. Our results indicate that C/EBPγ mediates the myeloid differentiation arrest induced by C/EBPα deficiency and that targeting the C/EBPα-C/EBPγ axis rescues neutrophilic differentiation in this unique subset of AMLs. [ABSTRACT FROM AUTHOR]

Discrimination performance in perceptual choice tasks is known to reflect both sensory discriminability and nonsensory response bias. In the framework of signal detection theory, these aspects of discrimination performance are quantified through separate measures, sensitivity (d') for sensory discriminability and decision criterion (c) for response bias. However, it is unknown how response bias (i.e., criterion) changes at the single-trial level as a consequence of reinforcement history. We subjected rats to a two-stimulus two-response conditional discrimination task with auditory stimuli and induced response bias through unequal reinforcement probabilities for the two responses. We compared three signal-detection-theory-based criterion learning models with respect to their ability to fit experimentally observed fluctuations of response bias on a trial-by-trial level. These models shift the criterion by a fixed step (1) after each reinforced response or (2) after each nonreinforced response or (3) after both. We find that all three models fail to capture essential aspects of the data. Prompted by the observation that steady-state criterion values conformed well to a behavioral model of signal detection based on the generalized matching law, we constructed a trial-based version of this model and find that it provides a superior account of response bias fluctuations under changing reinforcement contingencies., (© 2024 The Authors. Journal of the Experimental Analysis of Behavior published by Wiley Periodicals LLC on behalf of Society for the Experimental Analysis of Behavior.)

Introduction: Patients living with psychiatric illnesses (PIs) have a high prevalence of obesity. In a 2006 survey, 91.2% of professionals in the bariatric field identified "psychiatric issues" as clear contraindications to weight-loss surgery., Methods: This retrospective matched case-control study investigated the impact, safety, and possible relapse after bariatric metabolic surgery (BMS) in patients with PIs. Also, we tested the incidence of patients who developed PI after BMS and compared the post-procedural weight loss with that in a matched control group without PIs. The cases were matched in a ratio of 1:4 to the control patients standardized for age, sex, preoperative BMI, and type of BMS., Results: Of 5987 patients, 2.82% had a preoperative PI; postoperative de novo PI was present in 0.45%. Postoperative BMI was significantly different between the groups when compared to preoperative BMI (p < 0.001). Percentage of total weight loss (%TWL) after six months was not significantly different between the case (24.6% ± 8.9) and control groups (24.0% ± 8.4, p = 1.000). Early and late complications were not significantly different between the groups. The psychiatric drug use and dosage changes did not differ significantly pre- and postoperatively. Of the psychiatric patients, 5.1% were postoperatively admitted to a psychiatric hospital (p = 0.06) unrelated to BMS, and 3.4% had a prolonged absence from work after surgery., Conclusion: BMS is an effective weight loss treatment and a safe procedure for patients with psychiatric disorders. We found no change in the patients' psychiatric status outside the usual disease course. Postoperative de novo PI was rare in the present study. Furthermore, patients with severe psychiatric illness were excluded from undergoing surgery and, therefore, from the study. Careful follow-up is necessary to guide and protect patients with PI., (© 2023. The Author(s).)

Rearrangments in Histone-lysine-N-methyltransferase 2A (KMT2Ar) are associated with pediatric, adult and therapy-induced acute leukemias. Infants with KMT2Ar acute lymphoblastic leukemia (ALL) have a poor prognosis with an event-free-survival of 38%. Herein we evaluate 1116 FDA approved compounds in primary KMT2Ar infant ALL specimens and identify a sensitivity to proteasome inhibition. Upon exposure to this class of agents, cells demonstrate a depletion of histone H2B monoubiquitination (H2Bub1) and histone H3 lysine 79 dimethylation (H3K79me2) at KMT2A target genes in addition to a downregulation of the KMT2A gene expression signature, providing evidence that it targets the KMT2A transcriptional complex and alters the epigenome. A cohort of relapsed/refractory KMT2Ar patients treated with this approach on a compassionate basis had an overall response rate of 90%. In conclusion, we report on a high throughput drug screen in primary pediatric leukemia specimens whose results translate into clinically meaningful responses. This innovative treatment approach is now being evaluated in a multi-institutional upfront trial for infants with newly diagnosed ALL., (© 2023. The Author(s).)

Background: Social network analysis can elucidate tuberculosis transmission dynamics outside the home and may inform novel network-based case-finding strategies., Methods: We assessed the association between social network characteristics and prevalent tuberculosis infection among residents (aged ≥15 years) of 9 rural communities in Eastern Uganda. Social contacts named during a census were used to create community-specific nonhousehold social networks. We evaluated whether social network structure and characteristics of first-degree contacts (sex, human immunodeficiency virus [HIV] status, tuberculosis infection) were associated with revalent tuberculosis infection (positive tuberculin skin test [TST] result) after adjusting for individual-level risk factors (age, sex, HIV status, tuberculosis contact, wealth, occupation, and Bacillus Calmette-Guérin [BCG] vaccination) with targeted maximum likelihood estimation., Results: Among 3 335 residents sampled for TST, 32% had a positive TST results and 4% reported a tuberculosis contact. The social network contained 15 328 first-degree contacts. Persons with the most network centrality (top 10%) (adjusted risk ratio, 1.3 [95% confidence interval, 1.1-1.1]) and the most (top 10%) male contacts (1.5 [1.3-1.9]) had a higher risk of prevalent tuberculosis, than those in the remaining 90%. People with ≥1 contact with HIV (adjusted risk ratio, 1.3 [95% confidence interval, 1.1-1.6]) and ≥2 contacts with tuberculosis infection were more likely to have tuberculosis themselves (2.6 [ 95% confidence interval: 2.2-2.9])., Conclusions: Social networks with higher centrality, more men, contacts with HIV, and tuberculosis infection were positively associated with tuberculosis infection. Tuberculosis transmission within measurable social networks may explain prevalent tuberculosis not associated with a household contact. Further study on network-informed tuberculosis case finding interventions is warranted., Competing Interests: Potential conflicts of interest. G. C. reports participation on a data safety monitoring board or advisory board as a member of a data monitoring committee for an National Institutes of Health (NIH)–funded clinical trial (TB Screening Improves Preventive Therapy Uptake [TB SCRIPT] trial). E. D. C. reports support from the NIH (grant 1R01AI151209-01 [paid to institution]) and consulting fees from the Infectious Diseases Research Collaboration, Kampala, Uganda (paid to the author for Integrated HIV & Hypertension Study consulting). D. V. H. reports nonfinancial support from Gilead (drug donation for an NIH study) and Abbott (diagnostic test donation). All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Is the pursuit of interdisciplinary or innovative research beneficial or detrimental for the impact of early career researchers? We focus on young scholars as they represent an understudied population who have yet to secure a place within academia. Which effects promise higher scientific recognition (i.e., citations) is therefore crucial for the high-stakes decisions young researchers face. To capture these effects, we introduce measurements for interdisciplinarity and novelty that can be applied to a researcher's career. In contrast to previous studies investigating research impact on the paper level, hence, our paper focuses on a career perspective (i.e., the level of authors). To consider different disciplinary cultures, we utilize a comprehensive dataset on U.S. physicists (n = 4003) and psychologists (n = 4097), who graduated between 2008 and 2012, and traced their publication records. Our results indicate that conducting interdisciplinary research as an early career researcher in physics is beneficial, while it is negatively associated with research impact in psychology. In both fields, physics and psychology, early career researchers focusing on novel combinations of existing knowledge are associated with higher future impact. Taking some risks by deviating to a certain degree from mainstream paradigms seems therefore like a rewarding strategy for young scholars., Competing Interests: The authors have declared that no competing interests exist.

Introduction: Premonitory urges in Tourette disorder are often linked to altered somatosensory processing, which might include deficits in metacognition. We explored tactile and visual metacognitive ability in people with Tourette disorder and healthy control participants., Methods: Patients with Tourrete disorder and healthy control participants completed a tactile and a visual metacognitive task. On each trial, participants did a forced choice discrimination and then rated their confidence in their decision. To quantify metacognitive ability, we used m-ratio - a bias-free measure that allows for comparisons across modalities. Correlations between severity of tics and premonitory urges with tactile metacognitive sensitivity were also performed., Results: Metacognitive ability in both tactile and visual domains was comparable between adults with Tourette disorder and healthy controls. We also found no evidence for correlations between tactile metacognitive ability and severity of premonitory urges or tic severity., Conclusions: Tactile and visual metacognition is not impaired in adults with Tourette disorder. These results question the role of altered tactile metacognition in pathophysiology of tic disorders., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

We can make exquisitely precise movements without the apparent need for conscious monitoring. But can we monitor the low-level movement parameters when prompted? And what are the mechanisms that allow us to monitor our movements? To answer these questions, we designed a semivirtual ball throwing task. On each trial, participants first threw a virtual ball by moving their arm (with or without visual feedback, or replayed from a previous trial) and then made a two-alternative forced choice on the resulting ball trajectory. They then rated their confidence in their decision. We measured metacognitive efficiency using meta-d'/d' and compared it between different informational domains of the first-order task (motor, visuomotor or visual information alone), as well as between two different versions of the task based on different parameters of the movement: proximal (position of the arm) or distal (resulting trajectory of the ball thrown). We found that participants were able to monitor their performance based on distal motor information as well as when proximal information was available. Their metacognitive efficiency was also equally high in conditions with different sources of information available. The analysis of correlations across participants revealed an unexpected result: While metacognitive efficiency correlated between informational domains (which would indicate domain-generality of metacognition), it did not correlate across the different parameters of movement. We discuss possible sources of this discrepancy and argue that specific first-order task demands may play a crucial role in our metacognitive ability and should be considered when making inferences about domain-generality based on correlations. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Confidence judgments are a central tool in metacognition research. In a typical task, participants first perform perceptual (first-order) decisions and then rate their confidence in these decisions. The relationship between confidence and first-order accuracy is taken as a measure of metacognitive performance. Confidence is often assumed to stem from decision-monitoring processes alone, but processes that co-occur with the first-order decision may also play a role in confidence formation. In fact, some recent studies have revealed that directly manipulating motor regions in the brain, or the time of first-order decisions relative to second-order decisions, affects confidence judgments. This finding suggests that confidence could be informed by a readout of reaction times in addition to decision-monitoring processes. To test this possibility, we assessed the contribution of response-related signals to confidence and, in particular, to metacognitive performance (i.e., a measure of the adequacy of these confidence judgments). In human volunteers, we measured the effect of making an overt (vs covert) decision, as well as the effect of pairing an action to the stimulus about which the first-order decision is made. Against our expectations, we found no differences in overall confidence or metacognitive performance when first-order responses were covert as opposed to overt. Further, actions paired to visual stimuli presented led to higher confidence ratings, but did not affect metacognitive performance. These results suggest that confidence ratings do not always incorporate motor information., (Copyright © 2020 Filevich et al.)

Understanding how people rate their confidence is critical for the characterization of a wide range of perceptual, memory, motor and cognitive processes. To enable the continued exploration of these processes, we created a large database of confidence studies spanning a broad set of paradigms, participant populations and fields of study. The data from each study are structured in a common, easy-to-use format that can be easily imported and analysed using multiple software packages. Each dataset is accompanied by an explanation regarding the nature of the collected data. At the time of publication, the Confidence Database (which is available at https://osf.io/s46pr/) contained 145 datasets with data from more than 8,700 participants and almost 4 million trials. The database will remain open for new submissions indefinitely and is expected to continue to grow. Here we show the usefulness of this large collection of datasets in four different analyses that provide precise estimations of several foundational confidence-related effects.

Background: Universal antiretroviral therapy (ART) with annual population testing and a multidisease, patient-centered strategy could reduce new human immunodeficiency virus (HIV) infections and improve community health., Methods: We randomly assigned 32 rural communities in Uganda and Kenya to baseline HIV and multidisease testing and national guideline-restricted ART (control group) or to baseline testing plus annual testing, eligibility for universal ART, and patient-centered care (intervention group). The primary end point was the cumulative incidence of HIV infection at 3 years. Secondary end points included viral suppression, death, tuberculosis, hypertension control, and the change in the annual incidence of HIV infection (which was evaluated in the intervention group only)., Results: A total of 150,395 persons were included in the analyses. Population-level viral suppression among 15,399 HIV-infected persons was 42% at baseline and was higher in the intervention group than in the control group at 3 years (79% vs. 68%; relative prevalence, 1.15; 95% confidence interval [CI], 1.11 to 1.20). The annual incidence of HIV infection in the intervention group decreased by 32% over 3 years (from 0.43 to 0.31 cases per 100 person-years; relative rate, 0.68; 95% CI, 0.56 to 0.84). However, the 3-year cumulative incidence (704 incident HIV infections) did not differ significantly between the intervention group and the control group (0.77% and 0.81%, respectively; relative risk, 0.95; 95% CI, 0.77 to 1.17). Among HIV-infected persons, the risk of death by year 3 was 3% in the intervention group and 4% in the control group (0.99 vs. 1.29 deaths per 100 person-years; relative risk, 0.77; 95% CI, 0.64 to 0.93). The risk of HIV-associated tuberculosis or death by year 3 among HIV-infected persons was 4% in the intervention group and 5% in the control group (1.19 vs. 1.50 events per 100 person-years; relative risk, 0.79; 95% CI, 0.67 to 0.94). At 3 years, 47% of adults with hypertension in the intervention group and 37% in the control group had hypertension control (relative prevalence, 1.26; 95% CI, 1.15 to 1.39)., Conclusions: Universal HIV treatment did not result in a significantly lower incidence of HIV infection than standard care, probably owing to the availability of comprehensive baseline HIV testing and the rapid expansion of ART eligibility in the control group. (Funded by the National Institutes of Health and others; SEARCH ClinicalTrials.gov number, NCT01864603.)., (Copyright © 2019 Massachusetts Medical Society.)

The paper addresses the problem of cultural proximity in qualitative cross-cultural research on aging, presenting insights into a methodology of systematic 'estrangement'. Based on interdisciplinary research on the social time orientations of elderly people in Germany, Hong Kong, and the US, we discuss the question of how shared identities and taken-for-granted assumptions may bias the findings in comparative aging studies. With Alfred Schütz's phenomenological concept of 'lifeworld' as a methodological device, we focus on the issue of the diverging 'systems of relevance' that each of the national project teams obviously referred to when gathering and interpreting the data. The paper suggests that, by way of organizing an interactive research setting that is open for the reciprocity of perspectives, one of the major problems for cross-cultural research on aging may be overcome or at least mitigated., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: The Patient Self-Determination Act (PSDA) requires hospitals, home health agencies, nursing homes, and hospice providers to offer new patients information about advance directives. There is little evidence regarding whether encounters with these health-care providers prompt advance directive completion by patients., Objective: To examine whether encounters with various types of health-care providers were associated with higher odds of completing advance directives by older patients., Method: Logistic regression using longitudinal data from the 2012 and 2014 waves of the Health and Retirement Study. Participants were 3752 US adults aged 65 and older who reported not possessing advance directives in 2012. Advance directive was defined as a living will and/or durable power of attorney for health care. Four binary variables measured whether participants had spent at least 1 night in a hospital, underwent outpatient surgery, received home health or hospice care, or spent at least one night in a nursing home between 2012 and 2014., Results: Older adults who received hospital, nursing home, or home health/hospice care were more likely to complete advance directives. Outpatient surgery was not associated with advance directive completion., Conclusions: Older adults with no advance directive in 2012 who encountered health-care providers covered by the PSDA were more likely to have advance directives by 2014. The exception was outpatient surgery which is frequently provided in freestanding surgery centers not subject to PSDA mandates. It may be time to consider amending the PSDA to cover freestanding surgery centers.

Purpose of the Study: Where to grow older occupies the minds of many aging adults. This study examines how anticipation of the fourth age influences third-age residential reasoning. It also investigates the role of social relationships in choosing housing for later life., Design and Methods: Analyses were based on semi-structured interviews with 30 community-dwelling retirees aged 67-97 who were asked about preparations for the future, including housing., Results: Replies about future housing fell into two categories: preemptive and contingent. In preemptive reasoning, participants anticipated that their current homes would be suitable over the long term and explained why, while those engaged in contingent reasoning could imagine a possible future move to more supportive housing and even had destination places in mind. Both types of responses reflect residential reasoning that is ongoing and driven in large part by anticipation of fourth-age vulnerabilities. Peers influenced participants' thinking about whether, when, and where to move. Relationships with spouses and offspring were also factors commonly mentioned in residential reasoning, both in terms of sources of support and perceived obligations., Implications: The fourth age is generally conceived as an experience of loss, but it also functions as a social imaginary. Our study suggests that the fourth age, both as a potential personal destiny and a social construct, influences housing decisions among those firmly in the third age. More attention in housing research to prudential anticipation of the fourth age as well as the relational aspects of residential reasoning would enhance understanding of late-life housing choices., (© The Author 2016. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Dihydroartemisinin (DHA)-piperaquine is promising for malaria chemoprevention in pregnancy. We assessed the impacts of pregnancy and efavirenz-based antiretroviral therapy on exposure to DHA and piperaquine in pregnant Ugandan women. Intensive sampling was performed at 28 weeks gestation in 31 HIV-uninfected pregnant women, in 27 HIV-infected pregnant women receiving efavirenz, and in 30 HIV-uninfected nonpregnant women. DHA peak concentration and area under the concentration time curve (AUC 0-8hr ) were 50% and 47% lower, respectively, and piperaquine AUC 0-21d was 40% lower in pregnant women compared to nonpregnant women. DHA AUC 0-8hr and piperaquine AUC 0-21d were 27% and 38% lower, respectively, in pregnant women receiving efavirenz compared to HIV-uninfected pregnant women. Exposure to DHA and piperaquine were lower among pregnant women and particularly in women on efavirenz, suggesting a need for dose modifications. The study of modified dosing strategies for these populations is urgently needed., (© 2017 American Society for Clinical Pharmacology and Therapeutics.)

Acute megakaryoblastic leukemia (AMKL) is a subtype of acute myeloid leukemia (AML) in which cells morphologically resemble abnormal megakaryoblasts. While rare in adults, AMKL accounts for 4-15% of newly diagnosed childhood AML cases. AMKL in individuals without Down syndrome (non-DS-AMKL) is frequently associated with poor clinical outcomes. Previous efforts have identified chimeric oncogenes in a substantial number of non-DS-AMKL cases, including RBM15-MKL1, CBFA2T3-GLIS2, KMT2A gene rearrangements, and NUP98-KDM5A. However, the etiology of 30-40% of cases remains unknown. To better understand the genomic landscape of non-DS-AMKL, we performed RNA and exome sequencing on specimens from 99 patients (75 pediatric and 24 adult). We demonstrate that pediatric non-DS-AMKL is a heterogeneous malignancy that can be divided into seven subgroups with varying outcomes. These subgroups are characterized by chimeric oncogenes with cooperating mutations in epigenetic and kinase signaling genes. Overall, these data shed light on the etiology of AMKL and provide useful information for the tailoring of treatment.

Background: The peripheral cannabinoid receptor (CB2) is mainly detected on B cells in the germinal centers (GCs) of the immune system, using an antibody directed against the extra cellular N-terminal domain of the receptor. We retrospectively investigated the CB2 receptor expression in diffuse large B-cell lymphomas (DLBCL) and its clinical relevance for treatment outcome., Patients and Methods: We have constructed a tissue micro-array (TMA) using lymphoma tissue of a large cohort of patients with DLBCL (N = 104) who were treated with CHOP., Results:   Forty-five out of 79 evaluable cases (57%) were CB2 positive. The expression of CB2 receptors was variably present in both the germinal center B cell (GCB) (n = 31) and the non-GCB/activated B-cell (ABC) (n = 43) DLBCL subtypes. CB2 positivity was not associated with a different outcome in this patient cohort (CR; P = 0.87, EFS; P = 0.32, DFS; P = 0.06 and OS; P = 0.18). Implementation of CB2 expression in the Hans algorithm using the markers CD10, BCL6, and MUM1 did not result in added prognostic value (all P-values >0.1)., Conclusions: We hypothesize that although CB2 is normally expressed in GCs, the expression in one of the malignant counterparts such as DLBCL is aberrant. This may be an explanation for the absence of prognostic relevance for the expression of this protein., (© 2011 John Wiley & Sons A/S.)

Purpose: Until now molecular biologic techniques have not been easily used in daily clinical practice to stratify patients for therapeutic purposes. Therefore, we have investigated the prognostic relevance of the immunohistochemical (IHC) germinal center B-cell (GCB) versus non-GCB diffuse large B-cell lymphoma (DLBCL) subtypes., Patients and Methods: We have analyzed tumor samples from patients treated in 2 prospective multicenter phase III trials, ie HOVON 25 (patients≥65 years, n=153) and HOVON 26 (patients<65 years, n=144) using whole sections (WS) or tissue microarray (TMA). CD10, BCL6, and MUM1 were applied in a specific IHC algorithm. The effect on clinical outcome using WS or TMA and variations in cut-off levels of these markers was also investigated., Results: The GCB subtype was not associated with a better OS in either trial. Small differences were observed in the HOVON 25 trial between techniques, with TMA showing a better outcome for GCB than did WS. Variation of cut-off levels in the specific algorithm did not improve the prediction of clinical outcome., Conclusion: We did not observe a consistent predictive power of the GCB and non-GCB classification by IHC in this large series of DLBCL patients treated with CHOP. This underscores the need to determine the biologic variation and the standardization of the protein expression levels and to further study the relevance of prognostic IHC classifications, preferably in phase III clinical trials.

Purpose: The aim of this investigation was to compare gender differences in physiologic and perceptual responses during a 1-h run at recent marathon pace and running economy at three speeds in recreational marathon runners., Methods: In a counterbalanced design, 10 men and 10 women completed a 1-h treadmill run and a running economy test. Treadmill speed for the 1-h run ranged from 141 to 241 mmin(-1) and 134, 168, and 188 m x min(-1) for running economy. Physiologic parameters (oxygen uptake, carbon dioxide production, pulmonary ventilation, and heart rate) and perceived exertion were measured. Repeated-measures ANOVA was used to compare any gender differences (P < .05) during the 1-h run and a two-way ANOVA was used to compare running economy. With this sample, estimated marathon energy expenditure, body composition, and maximal physiologic function was reported., Results: With the exception of an allometric expression of VO2 (mL x min(-1) kg BW(-0.75)), similar gender physiologic and perceptual responses were found during the 1-h run. Although not significant, the females exercised at a higher percent VO2(max) (8% to 9%) during the run. Similar gender differences were also noted during the running economy tests., Conclusions: Although the male runners completed a recent marathon significantly faster than the females, similar gender physiologic and perceptual responses were generally found during the 1-h treadmill run and the running economy tests.

In this concise overview, we discuss recent findings concerning a distinct subgroup of acute myeloid/T-lymphoid leukemia. We describe how we identified these leukemias in multiple cohorts of acute myeloid leukemia (AML) using a combination of gene expression profiling and additional analytic approaches, and how we obtained insight in possible mechanisms leading to their phenotype.

Background: Previous research has shown that a manufacturer's promotional strategy for a brand name drug is typically affected by generic entry. However, little is known about how newer strategies to extend patent life, including product reformulation introduction or obtaining approval to market for additional clinical indications, influence promotion., Objective: To examine the relationships among promotional expenditures, generic entry, reformulation entry and new indication approval., Methods: We used quarterly data on national product-level promotional spending (including expenditures for physician detailing and direct-to-consumer advertising [DTCA], and the retail value of free samples distributed in physician offices) for selective serotonin reuptake inhibitors (SSRIs) over the period 1997-2004. We estimated econometric models of detailing, DTCA and total quarterly promotional expenditures as a function of the timing of generic entry, entry of new product formulations and US FDA approval for new clinical indications for existing medications in the SSRI class. Expenditures by pharmaceutical manufacturers for promotion of antidepressant medications was the main outcome measure., Results: Over the period 1997-2004, there was considerable variation in the composition of promotional expenditures across the SSRIs. Promotional expenditures for the original brand molecule decreased dramatically when a reformulation of the molecule was introduced. Promotional spending (both total and detailing alone) for a specific molecule was generally lower after generic entry than before, although the effect of generic entry on promotional spending appears to be closely linked with the choice of product reformulation strategy pursued by the manufacturer. Detailing expenditures for Paxil were increased after the manufacturer received FDA approval to market the drug for generalized anxiety disorder (GAD), while the likelihood of DTCA outlays for the drug was not changed. In contrast, FDA approval to market Paxil and Zoloft for social anxiety disorder (SAD) did not affect the manufacturers' detailing expenditures but did result in a greater likelihood of DTCA outlays., Conclusion: The introduction of new product formulations appears to be a common strategy for attempting to extend market exclusivity for medications facing impending generic entry. Manufacturers who introduced a reformulation before generic entry shifted most promotion dollars from the original brand to the reformulation long before generic entry, and in some cases manufacturers appeared to target a particular promotion type for a given indication. Given the significant impact that pharmaceutical promotion has on demand for prescription drugs in the US, these findings have important implications for prescription drug spending and public health.

This study examined energy expenditure and physiologic determinants for marathon performance in recreational runners. Twenty recreational marathon runners participated (10 males aged 41 +/- 11.3 years, 10 females aged 42.7 +/- 11.7 years). Each subject completed a V(.-)O2max and a 1-hour treadmill run at recent marathon pace, and body composition was indirectly determined via dual energy X-ray absorptiometry. The male runners exhibited higher V(.-)O2max (ml x kg(-1) x min(-1)) values (52.6 +/- 5.5) than their female counterparts (41.9 +/- 6.6), although ventilatory threshold (T-vent) values were similar between groups (males: 76.2 +/- 6.1 % of V(.-)O2max, females: 75.1 +/- 5.1%). The male runners expended more energy (2,792 +/- 235 kcal) for their most recent marathon as calculated from the 1-hour treadmill run at marathon pace than the female runners (2,436 +/- 297 kcal). Body composition parameters correlated moderately to highly (r ranging from 0.50 to 0.87) with marathon run time. Also, V(.-)O2max (r = -0.73) and ventilatory threshold (r = -0.73) moderately correlated with marathon run time. As a group, the participants ran near their ventilatory threshold for their most recent marathon (r = 0.74). These results indicate the influence of body size on marathon run performance. In general, the larger male and female runners ran slower and expended more kilocalories than smaller runners. Regardless of marathon finishing time, the runners maintained a pace near their T-vent, and as T-vent or V(.-)O2max increased, marathon performance time decreased.