How important are concurrent vehicle control groups in (sub)chronic non-human primate toxicity studies conducted in pharmaceutical development? An opportunity to reduce animal numbers.

Safety assessment of human pharmaceuticals demands extensive animal experiments before a compound can be tested in patients or released on the market. Such experiments typically include concurrent vehicle control groups. Reconsidering the need for concurrent controls could support the strive to reduce the use of animals for scientific purposes. We reviewed reports from 20 (sub)chronic toxicity studies that were conducted in non-human primates (NHP) to characterize hazards of novel human pharmaceuticals. Firstly, we determined the toxicological endpoints that were identified to characterize the hazard. Secondly, we evaluated if the hazard could have been identified without reference to the concurrent controls. Thirdly, we employed an alternative statistical method to test for any significant change related to dose level or time. We found that toxicologically relevant hazards were identifiable without reference to concurrent controls, because individual measurements could be compared with pre-dosing values or because individual measurements could be compared to historical reference data. Effects that could not be evaluated without reference to concurrent controls were clinical observations and organ weights for which appropriate historical reference data was not available, or immune responses that could not be compared to pre-dosing measurements because their magnitude would change over time. Our investigation indicates that concurrent control groups in (sub)chronic NHP toxicity studies are of limited relevance for reaching the study objective. Under certain conditions, regulatory (sub)chronic NHP toxicity studies represent a good starting point to implement virtual control groups rather than concurrent control groups in nonclinical safety testing.

Trends and Factors Associated With Physician Burnout at a Multispecialty Academic Faculty Practice Organization.

Importance: Physician burnout is common, and prevalence may differ throughout a clinician's career. Burnout has negative consequences for physician wellness, patient care, and the health care system. Identifying factors associated with burnout is critical in designing and implementing initiatives to reduce burnout. Objective: To measure trends and identify factors associated with physician burnout. Design, Setting, and Participants: Survey study conducted from May 16 to June 15, 2014, and again from May 16 to June 15, 2017, measuring rates of physician burnout in a large academic medical practice. Factors associated with burnout out were evaluated. In 2014, 1774 of 1850 eligible physicians (95.9%) completed the survey. In 2017, 1882 of 2031 (92.7%) completed the survey. Exposures: Medical specialty, demographic characteristics, years in practice, and reported rates of burnout. Main Outcomes and Measures: Burnout rates measured at 2 points and risk factors associated with burnout. Results: Respondents included 1027 men (57.9%) and 747 women (42.1%) in 2014 and 962 men (51.1%) and 759 women (40.3%) in 2017. The mean (SD) number of years since training completion was 15.3 (11.3) in the 2014 survey data and 15.1 (11.3) in the 2017 data. Burnout increased from 40.6% to 45.6% between the 2 points. The increased rate was associated with an increase in exhaustion (from 52.9% in 2014 to 57.7% in 2017; difference, 4.8%; 95% CI, 1.6%-8.0%; P = .004) and cynicism (from 44.8% in 2014 to 51.1% in 2017; difference, 6.3%; 95% CI, 3.1%-9.6%; P < .001). Compared with midcareer physicians (11-20 years since training), early-career physicians (≤10 years since training) were more susceptible to burnout (odds ratio, 1.36; 95% CI, 1.05-1.77), while physicians in their late career (>30 years since training) were less vulnerable (odds ratio, 0.59; 95% CI, 0.40-0.88). Conclusions and Relevance: Efforts to alleviate physician burnout and administrative burden require a combination of a shared commitment from physicians and organizations and central and locally implemented programs. Continued research is necessary to establish the most effective initiatives to decrease physician burnout at the individual and organizational level.

Nonsyndromic oligodontia : Does the Tooth Agenesis Code (TAC) enable prediction of the causative mutation?

OBJECTIVES: The literature suggests an association between phenotype and causative mutation in nonsyndromic oligodontia. Thus, the present study was designed to verify this hypothesis in a consecutive cohort of patients. METHODS: All patients with nonsyndromic oligodontia who had been treated at the study center (Department of Orthodontics, University of Giessen, Germany) over the period 1986-2013 were contacted. Candidates were included only if at least one more family member had hypo- or oligodontia (i.e., without regard to the number of congenitally missing teeth). A total of 20 patients were included. After evaluating the dental status of each participant, the Tooth Agenesis Code (TAC) was applied. On this basis, a tentative diagnosis was made to predict which gene (MSX1, AXIN2, EDA, or PAX9) was likely to show mutation. Afterwards this hypothesis was confirmed or rejected by analyzing a saliva sample for mutation of the predicted gene. If confirmed, any available family members were also genetically analyzed. RESULTS: Based on their TAC scores and sums, gene mutations were predicted for MXS1 in 11, AXIN2 in 3, EDA in 6, and PAX9 in none of the patients. The evaluation of MSX1 yielded variants in 4 of 11 cases, all of which were classified as nonpathogenic since they were not considered as functional mutations. The evaluation of EDA yielded a pathogenic exon-7 mutation in 2 of 6 patients, both being brothers with different TAC scores; the same mutation, which represents a novel missense mutation, was also found in other members of the same family. The evaluation of AXIN2 yielded variants in 3 of 3 cases, all of which were classified as nonpathogenic. CONCLUSIONS: Our findings obtained in consecutive patients with nonsyndromic oligodontia did not reveal any clinically relevant associations between oligodontia phenotype (based on TAC) and causative mutations for nonsyndromic oligodontia.

Impaired retrograde transport by the Dynein/Dynactin complex contributes to Tau-induced toxicity.

The gene mapt codes for the microtubule-associated protein Tau. The R406W amino acid substitution in Tau is associated with frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) characterized by Tau-positive filamentous inclusions. These filamentous Tau inclusions are present in a group of neurodegenerative diseases known as tauopathies, including Alzheimer's disease (AD). To gain more insights into the pathomechanism of tauopathies, we performed an RNAi-based large-scale screen in Drosophila melanogaster to identify genetic modifiers of Tau[R406W]-induced toxicity. A collection of RNAi lines, putatively silencing more than 7000 genes, was screened for the ability to modify Tau[R406W]-induced toxicity in vivo. This collection covered more than 50% of all protein coding fly genes and more than 90% of all fly genes known to have a human ortholog. Hereby, we identified 62 genes that, when silenced by RNAi, modified Tau-induced toxicity specifically. Among these 62 modifiers were three subunits of the Dynein/Dynactin complex. Analysis on segmental nerves of fly larvae showed that pan neural Tau[R406W] expression and concomitant silencing of Dynein/Dynactin complex members synergistically caused strong pathological changes within the axonal compartment, but only minor changes at synapses. At the larval stage, these alterations did not cause locomotion deficits, but became evident in adult flies. Our data suggest that Tau-induced detrimental effects most likely originate from axonal rather than synaptic dysfunction and that impaired retrograde transport intensifies detrimental effects of Tau in axons. In conclusion, our findings contribute to the elucidation of disease mechanisms in tauopathies like FTDP-17 or AD.

Massachusetts General Physicians Organization's quality incentive program produces encouraging results.

Physicians are increasingly becoming salaried employees of hospitals or large physician groups. Yet few published reports have evaluated provider-driven quality incentive programs for salaried physicians. In 2006 the Massachusetts General Physicians Organization began a quality incentive program for its salaried physicians. Eligible physicians were given performance targets for three quality measures every six months. The incentive payments could be as much as 2 percent of a physician's annual income. Over thirteen six-month terms, the program used 130 different quality measures. Although quality-of-care improvements and cost reductions were difficult to calculate, anecdotal evidence points to multiple successes. For example, the program helped physicians meet many federal health information technology meaningful-use criteria and produced $15.5 million in incentive payments. The program also facilitated the adoption of an electronic health record, improved hand hygiene compliance, increased efficiency in radiology and the cancer center, and decreased emergency department use. The program demonstrated that even small incentives tied to carefully structured metrics, priority setting, and clear communication can help change salaried physicians' behavior in ways that improve the quality and safety of health care and ease the physicians' sense of administrative burden.

Drosophila as a screening tool to study human neurodegenerative diseases.

In an aging society, research involving neurodegenerative disorders is of paramount importance. Over the past few years, research on Alzheimer's and Parkinson's diseases has made tremendous progress. Experimental studies, however, rely mostly on transgenic animal models, preferentially using mice. Although experiments on mice have enormous advantages, they also have some inherent limitations, some of which can be overcome by the use of Drosophila melanogaster as an experimental animal. Among the major advantages of using the fly is its small genome, which can also be modified very easily. The fact that its genome lends itself to diverse alterations (e. g. mutagenesis, transposons) has made the fly a useful organism to perform large-scale and genome-wide screening approaches. This has opened up an entirely new field of experimental research aiming to elucidate genetic interactions and screen for modifiers of disease processes in vivo. Here, we provide a brief overview of how flies can be used to analyze molecular mechanisms underlying human neurodegenerative diseases.

Electrophysiological signature of working and long-term memory interaction in the human hippocampus.

Recent findings indicate that the hippocampus is not only crucial for long-term memory (LTM) encoding, but plays a role for working memory (WM) as well. In particular, it has been shown that the hippocampus is important for WM maintenance of multiple items or associations between item features. Previous studies using intracranial electroencephalography recordings from the hippocampus of patients with epilepsy revealed slow positive potentials during maintenance of a single item and during LTM encoding, but slow negative potentials during maintenance of multiple items. These findings predict that WM maintenance of multiple items interferes with LTM encoding, because these two processes are associated with slow potentials of opposing polarities in the hippocampus. Here, we tested this idea in a dual-task paradigm involving a LTM encoding task nested into a WM Sternberg task with either a low (one item) or a high (three items) memory load. In the high WM load condition, LTM encoding was significantly impoverished, and slow hippocampal potentials were more negative than in the low WM load condition. Time-frequency analysis revealed that a reduction of slow hippocampal activity in the delta frequency range supported LTM formation in the low load condition, but not during high WM load. Together, these findings indicate that multi-item WM and LTM encoding interfere within the hippocampus.

Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens.

Combinations of estrogen receptor agonists have been shown to exert more potent effects than single compounds in many single-endpoint bioassays. However, to our knowledge, it has never been tested how genome-wide expression programs are shaped by the interplay of multiple estrogenic stimuli. In view of the abundance of dietary phytoestrogens, we selected binary mixtures of these phytochemicals to determine their global impact using high-density DNA microarrays. MCF7 cells, a frequent in vitro model for molecular processes associated with breast cancer, were exposed to a sub-saturating concentration of coumestrol either alone or in combination with analogs that exhibit 1000-fold lower estrogen receptor activity. As expected, in the presence of coumestrol, the induction of many estrogen-sensitive genes was not further increased by the addition of resveratrol or enterolactone. However, it was surprising to find that these weak phytoestrogens, when combined with coumestrol in equal concentrations, were able to more than double the number of significantly regulated transcripts. Thus, phytoestrogens with low receptor affinity interact with other estrogenic agonists to generate more widespread expression fingerprints. This effect involving the number of susceptible transcripts instead of their amplitude of induction remains undetected if mixtures are evaluated with conventional bioassays.

Improving physician note entry rates through an incentive program.

The Massachusetts General Hospital Physicians Organization (MGPO) has implemented physician incentives to drive timely entry of notes into the outpatient electronic health record. Data from the Partners Quality Data Warehouse (QDW) were used to refine and produce a note completion metric and to create reports. This initiative has led to a decrease in the average time to complete a note from 197 to 90 hours, in less than a year.

Global gene expression profiles induced by phytoestrogens in human breast cancer cells.

The nutritional intake of phytoestrogens seems to reduce the risk of breast cancer or other neoplastic diseases. However, these epidemiological findings remain controversial because low doses of phytoestrogens, achievable through soy-rich diets, stimulate the proliferation of estrogen-sensitive tumor cells. The question of whether such phytochemicals prevent cancer or rather pose additional health hazards prompted us to examine global gene expression programs induced by a typical soy product. After extraction from soymilk, phytoestrogens were deconjugated and processed through reverse- and normal-phase cartridges. The resulting mixture was used to treat human target cells that represent a common model system for mammary tumorigenesis. Analysis of mRNA on high-density microarrays revealed that soy phytoestrogens induce a genomic fingerprint that is indistinguishable from the transcriptional effects of the endogenous hormone 17beta-estradiol. Highly congruent responses were also observed by comparing the physiologic estradiol with daidzein, coumestrol, enterolactone, or resveratrol, each representing distinct phytoestrogen structures. More diverging transcriptional profiles were generated when an inducible promoter was used to reconstitute the expression of estrogen receptor beta (ERbeta). Therefore, phytoestrogens appear to mitigate estrogenic signaling in the presence of both ER subtypes but, in late-stage cancer cells lacking ERbeta, these phytochemicals contribute to a tumor-promoting transcriptional signature.

Association between alcohol consumption and postmenopausal breast cancer: results of a case-control study in Montreal, Quebec, Canada.

OBJECTIVES: To determine the association between postmenopausal breast cancer and prior consumption of alcoholic beverages. METHODS: This case-control study, conducted in all Montreal hospitals between 1996 and 1997, included 556 postmenopausal women (age 50-75 years) who had a new histologically confirmed diagnosis of primary, malignant breast cancer. Control subjects (577) were selected from other histologically confirmed sites of cancer. A detailed history of alcohol consumption and other risk factors was obtained by interview. Indices reflecting alcohol consumption were developed and unconditional logistic regression was used to estimate adjusted odds ratios (OR) and 95% confidence intervals (CI). RESULTS: Current regular drinkers of any type of alcohol were at an increased risk of breast cancer (OR = 1.5; 95% CI 1.0-2.2). For all beverages considered, current regular drinkers showed higher risks than ever regular drinkers. The risk of breast cancer was highest among women who reported exclusive drinking of wine on a weekly or daily basis (e.g. current regular drinking: OR = 2.3; 95% CI 1.2-4.3). Women who started to drink wine on or before the age of 40 were at a 2.5 times increased risk (95% CI 1.4-4.4). CONCLUSIONS: Our findings provide further support for a positive association between the risk of postmenopausal breast cancer and alcohol consumption.