Hospitalists in Teaching Hospitals: Opportunities but Not Without Danger

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/73210/1/j.1525-1497.2004.42002.x.pd

Towards the clinical implementation of pharmacogenetics in bipolar disorder.

BackgroundBipolar disorder (BD) is a psychiatric illness defined by pathological alterations between the mood states of mania and depression, causing disability, imposing healthcare costs and elevating the risk of suicide. Although effective treatments for BD exist, variability in outcomes leads to a large number of treatment failures, typically followed by a trial and error process of medication switches that can take years. Pharmacogenetic testing (PGT), by tailoring drug choice to an individual, may personalize and expedite treatment so as to identify more rapidly medications well suited to individual BD patients.DiscussionA number of associations have been made in BD between medication response phenotypes and specific genetic markers. However, to date clinical adoption of PGT has been limited, often citing questions that must be answered before it can be widely utilized. These include: What are the requirements of supporting evidence? How large is a clinically relevant effect? What degree of specificity and sensitivity are required? Does a given marker influence decision making and have clinical utility? In many cases, the answers to these questions remain unknown, and ultimately, the question of whether PGT is valid and useful must be determined empirically. Towards this aim, we have reviewed the literature and selected drug-genotype associations with the strongest evidence for utility in BD.SummaryBased upon these findings, we propose a preliminary panel for use in PGT, and a method by which the results of a PGT panel can be integrated for clinical interpretation. Finally, we argue that based on the sufficiency of accumulated evidence, PGT implementation studies are now warranted. We propose and discuss the design for a randomized clinical trial to test the use of PGT in the treatment of BD

The Impact of Duty Hours on Resident Self Reports of Errors

BACKGROUND: Resident duty hour limitations aim, in part, to reduce medical errors. Residents’ perceptions of the impact of duty hours on errors are unknown. OBJECTIVE: To determine residents’ self-reported contributing factors, frequency, and impact of hours worked on suboptimal care practices and medical errors. DESIGN: Cross-sectional survey. SUBJECTS: 164 Internal Medicine Residents at the University of California, San Francisco. MEASUREMENTS AND RESULTS: Residents were asked to report the frequency and contributing factors of suboptimal care practices and medical errors, and how duty hours impacted these practices and aspects of resident work-life. One hundred twenty-five residents (76%) responded. The most common suboptimal care practices were working while impaired by fatigue and forgetting to transmit information during sign-out. In multivariable models, residents who felt overwhelmed with work (p = 0.02) and who reported spending >50% of their time in nonphysician tasks (p = 0.002) were more likely to report suboptimal care practices. Residents reported work-stress (a composite of fatigue, excessive workload, distractions, stress, and inadequate time) as the most frequent contributing factor to medical errors. In multivariable models, only engaging in suboptimal practices was associated with self-report of higher risk for medical errors (p < 0.001); working more than 80 hours per week was not associated with suboptimal care or errors. CONCLUSION: Our findings suggest that administrative load and work stressors are more closely associated with resident reports of medical errors than the number of hours work. Efforts to reduce resident duty hours may also need to address the nature of residents’ work to reduce errors

Heterozygous missense mutations in steroidogenic factor 1 (SF1/Ad4BP, NR5A1) are associated with 46,XY disorders of sex development with normal adrenal function

Context: Steroidogenic factor 1 ( SF1/AdBP4/FTZF1, NR5A1) is a nuclear receptor transcription factor that plays a key role in regulating adrenal and gonadal development, steroidogenesis, and reproduction. Targeted deletion of Nr5a1 ( Sf1) in the mouse results in adrenal and gonadal agenesis, XY sex-reversal, and persistent Mullerian structures in males. Consistent with the murine phenotype, human mutations in SF1 were described initially in two 46, XY individuals with female external genitalia, Mullerian structures ( uterus), and primary adrenal failure.Objective: Given recent case reports of haploinsufficiency of SF1 affecting testicular function in humans, we aimed to identify SF1 mutations in a cohort of individuals with a phenotypic spectrum of 46, XY gonadal dysgenesis/impaired androgenization ( now termed 46, XY disorders of sex development) with normal adrenal function.Methods and Patients: The study included mutational analysis of NR5A1 in 30 individuals with 46, XY disorders of sex development, followed by functional studies of SF1 activity.Results: Heterozygous missense mutations in NR5A1 were found in four individuals ( four of 30, 13%) with this phenotype. These mutations ( V15M, M78I, G91S, L437Q) were shown to impair transcriptional activation through abnormal DNA binding ( V15M, M78I, G91S), altered subnuclear localization ( V15M, M78I), or disruption of the putative ligand-binding pocket ( L437Q). Two mutations appeared to be de novo or germline changes. The other two mutations appeared to be inherited in a sex-limited dominant manner because the mother is heterozygous for the change.Conclusions: These studies demonstrate that SF1 mutations are more frequent than previously suspected causes of impaired fetal and postnatal testicular function in 46, XY individuals

Frequency and Risk Indicators of Tooth Decay among Pregnant Women in France: A Cross-Sectional Analysis

INTRODUCTION: Little is known on the prevalence of tooth decay among pregnant women. Better knowledge of tooth decay risk indicators during pregnancy could help to develop follow-up protocols for women at risk, along with better prevention strategies. The aim of this study was to assess the frequency of tooth decay and the number of decayed teeth per woman in a large sample of pregnant women in France, and to study associated risk indicators. METHODS: A secondary cross-sectional analysis of data from a French multicentre case-control study was performed. The sample was composed of 1094 at-term women of six maternity units. A dental examination was carried out within 2 to 4 days post-partum. Socio-demographic and behavioural characteristics were obtained through a standardised interview with the women. Medical characteristics were obtained from the women's medical records. Risk indicators associated with tooth decay were identified using a negative binomial hurdle model. RESULTS: 51.6% of the women had tooth decay. The mean number of decayed teeth among women having at least one was 3.1 (s.d. = 2.8). Having tooth decay was statistically associated with lower age (aOR = 1.58, 95%CI [1.03,2.45]), lower educational level (aOR = 1.53, 95%CI [1.06,2.23]) and dental plaque (aOR = 1.75, 95%CI [1.27,2.41]). The number of decayed teeth was associated with the same risk indicators and with non-French nationality and inadequate prenatal care. DISCUSSION: The frequency of tooth decay and the number of decayed teeth among pregnant women were high. Oral health promotion programmes must continue to inform women and care providers about the importance of dental care before, during and after pregnancy. Future research should also assess the effectiveness of public policies related to oral health in target populations of pregnant women facing challenging social or economic situations

Mutation Analysis of NR5A1 Encoding Steroidogenic Factor 1 in 77 Patients with 46, XY Disorders of Sex Development (DSD) Including Hypospadias

BACKGROUND: Mutations of the NR5A1 gene encoding steroidogenic factor-1 have been reported in association with a wide spectrum of 46,XY DSD (Disorder of Sex Development) phenotypes including severe forms of hypospadias. METHODOLOGY/PRINCIPAL FINDINGS: We evaluated the frequency of NR5A1 gene mutations in a large series of patients presenting with 46,XY DSD and hypospadias. Based on their clinical presentation 77 patients were classified either as complete or partial gonadal dysgenesis (uterus seen at genitography and/or surgery, n = 11), ambiguous external genitalia without uterus (n = 33) or hypospadias (n = 33). We identified heterozygous NR5A1 mutations in 4 cases of ambiguous external genitalia without uterus (12.1%; p.Trp279Arg, pArg39Pro, c.390delG, c140_141insCACG) and a de novo missense mutation in one case with distal hypospadias (3%; p.Arg313Cys). Mutant proteins showed reduced transactivation activity and mutants p.Arg39Pro and p.Arg313Cys did not synergize with the GATA4 cofactor to stimulate reporter gene activity, although they retained their ability to physically interact with the GATA4 protein. CONCLUSIONS/SIGNIFICANCE: Mutations in NR5A1 were observed in 5/77 (6.5%) cases of 46,XY DSD including hypospadias. Excluding the cases of 46,XY gonadal dysgenesis the incidence of NR5A1 mutations was 5/66 (7.6%). An individual with isolated distal hypopadias carried a de novo heterozygous missense mutation, thus extending the range of phenotypes associated with NR5A1 mutations and suggesting that this group of patients should be screened for NR5A1 mutations

Immunophenotypic features of tumor infiltrating lymphocytes from mammary carcinomas in female dogs associated with prognostic factors and survival rates

<p>Abstract</p> <p>Background</p> <p>The immune system plays an important role in the multifactorial biologic system during the development of neoplasias. However, the involvement of the inflammatory response in the promotion/control of malignant cells is still controversial, and the cell subsets and the mechanisms involved are poorly investigated. The goal of this study was to characterize the clinical-pathological status and the immunophenotyping profile of tumor infiltrating lymphocytes and their association with the animal survival rates in canine mammary carcinomas.</p> <p>Methods</p> <p>Fifty-one animals with mammary carcinomas, classified as carcinomas in mixed tumors-MC-BMT = 31 and carcinomas-MC = 20 were submitted to systematic clinical-pathological analysis (tumor size; presence of lymph node and pulmonary metastasis; clinical stage; histological grade; inflammatory distribution and intensity as well as the lymphocytic infiltrate intensity) and survival rates. Twenty-four animals (MC-BMT = 16 and MC = 8) were elected to the immunophenotypic study performed by flow cytometry.</p> <p>Results</p> <p>Data analysis demonstrated that clinical stage II-IV and histological grade was I more frequent in MC-BMT as compared to MC. Univariate analysis demonstrated that the intensity of inflammation (moderate/intense) and the proportion of CD4⁺(≥ 66.7%) or CD8⁺T-cells (<33.3%) were not associated with worse survival rate. Multivariate analysis demonstrated that only lymphocytic infiltrate intensity ≥ 600 (<it>P </it>= 0.02) remained as independent prognostic factor. Despite the clinical manifestation, the lymphocytes represented the predominant cell type in the tumor infiltrate. The percentage of T-cells was higher in animals with MC-BMT without metastasis, while the percentage of B-lymphocytes was greater in animals with metastasized MC-BMT (<it>P </it>< 0.05). The relative percentage of CD4⁺T-cells was significantly greater in metastasized tumors (both MC-BMT and MC), (<it>P </it>< 0.05) while the proportion of CD8⁺T-cells was higher in MC-BMT without metastasis. Consequently, the CD4⁺/CD8⁺ratio was significantly increased in both groups with metastasis. Regardless of the tumor type, the animals with high proportions of CD4⁺and low CD8⁺T-cells had decreased survival rates.</p> <p>Conclusion</p> <p>The intensity of lymphocytic infiltrate and probably the relative abundance of the CD4⁺and CD8⁺T-lymphocytes may represent important survival prognostic biomarkers for canine mammary carcinomas.</p

Convergent functional genomics of anxiety disorders: translational identification of genes, biomarkers, pathways and mechanisms

Anxiety disorders are prevalent and disabling yet understudied from a genetic standpoint, compared with other major psychiatric disorders such as bipolar disorder and schizophrenia. The fact that they are more common, diverse and perceived as embedded in normal life may explain this relative oversight. In addition, as for other psychiatric disorders, there are technical challenges related to the identification and validation of candidate genes and peripheral biomarkers. Human studies, particularly genetic ones, are susceptible to the issue of being underpowered, because of genetic heterogeneity, the effect of variable environmental exposure on gene expression, and difficulty of accrual of large, well phenotyped cohorts. Animal model gene expression studies, in a genetically homogeneous and experimentally tractable setting, can avoid artifacts and provide sensitivity of detection. Subsequent translational integration of the animal model datasets with human genetic and gene expression datasets can ensure cross-validatory power and specificity for illness. We have used a pharmacogenomic mouse model (involving treatments with an anxiogenic drug—yohimbine, and an anti-anxiety drug—diazepam) as a discovery engine for identification of anxiety candidate genes as well as potential blood biomarkers. Gene expression changes in key brain regions for anxiety (prefrontal cortex, amygdala and hippocampus) and blood were analyzed using a convergent functional genomics (CFG) approach, which integrates our new data with published human and animal model data, as a translational strategy of cross-matching and prioritizing findings. Our work identifies top candidate genes (such as FOS, GABBR1, NR4A2, DRD1, ADORA2A, QKI, RGS2, PTGDS, HSPA1B, DYNLL2, CCKBR and DBP), brain–blood biomarkers (such as FOS, QKI and HSPA1B), pathways (such as cAMP signaling) and mechanisms for anxiety disorders—notably signal transduction and reactivity to environment, with a prominent role for the hippocampus. Overall, this work complements our previous similar work (on bipolar mood disorders and schizophrenia) conducted over the last decade. It concludes our programmatic first pass mapping of the genomic landscape of the triad of major psychiatric disorder domains using CFG, and permitted us to uncover the significant genetic overlap between anxiety and these other major psychiatric disorders, notably the under-appreciated overlap with schizophrenia. PDE10A, TAC1 and other genes uncovered by our work provide a molecular basis for the frequently observed clinical co-morbidity and interdependence between anxiety and other major psychiatric disorders, and suggest schizo-anxiety as a possible new nosological domain