The need for guidance in antidepressant drug development: Revisiting the role of the forced swim test and tail suspension test.

Depressive disorders are one of the most common mental disorders globally and progress in treating these disorders has been hampered, in part, by a lack of suitable nonclinical efficacy tests. Two common tests used in nonclinical efficacy studies of antidepressants-the forced swim test (FST) and tail suspension test (TST)-have come under criticism in recent years for their inconsistency and lack of validity, yet they continue to be used in the pharmaceutical industry. In this review, we provide a rationale for why international pharmaceutical regulatory and guidance agencies should begin issuing direction on methods for non-clinical efficacy testing that traditionally use the FST and TST, particularly considering that some regulators, such as those in the U.S. and E.U., allow the authorization of clinical trials to proceed without requiring tests in animals. The area of antidepressant drug discovery represents an important opportunity for reducing the attrition of psychiatric drugs, harmonizing regulatory requirements, and reducing animal use. Specific recommendations for the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) have been provided.

Diagnostic journey and life impact of cholangiocarcinoma: results from surveys of patient and caregiver experiences.

Aim: To understand cholangiocarcinoma symptoms, diagnosis and treatment experience from the patient and caregiver perspective, including cholangiocarcinoma's impact on daily life, quality of life (QoL) and mental health. Methods: Patients and caregivers participated in two online surveys (in partnership with the Cholangiocarcinoma Foundation). Results: The patient survey data (n = 707) show a substantial impact of cholangiocarcinoma on QoL and mental health, with 34% of patients reporting symptoms consistent with moderately severe/severe depression. The caregiver survey data (n = 60) show that although caregivers experience satisfaction in their role of caring for a loved one, managing the demands of caregiving exacts a physical, mental and emotional toll. Conclusion: These surveys highlight the need for better palliative and supportive care interventions.

What is this article about? It shows results from two surveys, one for people with cholangiocarcinoma (CCA, pronounced ko·lan·jee·o·car·sin·no·muh), and one for caregivers (people who take care of family or friends with CCA without payment). CCA is a rare and aggressive cancer. The caregivers we surveyed were not necessarily taking care of the people with CCA who we surveyed. We did the surveys to find out how CCA changed the lives of people in these two groups. What were the results? We surveyed 707 people with CCA. Patients reported in the survey that having CCA impacted their daily lives in lots of ways. Most needed help with daily chores like housekeeping and shopping. Both tiredness and anxiety were reported by about two in three people with CCA. More than one in three had said they had symptoms indicating potential depression, which means patients should have their mental health evaluated. CCA also reduced their sexual desire and intimacy with their partner. We surveyed 60 caregivers who reported both good and bad experiences taking care of a person with CCA. The good experiences included knowing that their loved one was well cared for and learning to deal with difficult situations. Many caregivers also felt closer to their loved one with CCA. The bad experiences included exhaustion and emotional and mental stress. Caregivers felt challenged by trying to understand CCA and the treatment options available. What do the results of the study mean? Patients with CCA and their caregivers need more help and support.

A qualitative content analysis of an online forum for people with kidney disease: Exploring the role of companion and non-companion animals.

BACKGROUND: Companion and other animals have been known to promote wellbeing of people living with chronic disease by assisting in emotional regulation, social interaction and enhancing self-identity. However, little is known about the impact of animals on people with kidney disease, who often live with treatment burden, as well as compromised immune systems making them vulnerable to zoonotic diseases. OBJECTIVES: To explore the impact companion and non-companion animals have on the lives of people living with kidney disease. DESIGN: Qualitative Content Analysis of 518 posts from an online forum. PARTICIPANTS: One hundred seventy-two people (109 female, 41 male and 22 unknown) posting to an online forum for people undergoing kidney dialysis. RESULTS: Benefits of bonds with animals included reciprocal love and affection, emotional support, stress reduction, aiding relaxation, assisting social interaction, animals' intuitive comfort when unwell, feelings of loyalty, and motivation to live, concerns relating to zoonotic disease risk, and patients' impressions of health professionals' opinions on animals. CONCLUSIONS: This study reinforces the existence of strong bonds between humans and animals, as well as demonstrating the importance of and concerns regarding interacting with non-companion animals for people with chronic kidney disease (CKD). There is a mismatch between patients' perception of infection risk and the advice and opinions of some healthcare professionals. Recognition and support for the role of animals as social supports are warranted in history taking, patient education of risk, and the biopsychosocial benefits of animals.

Exposure to Ambient Particulate Matter Is Associated With Accelerated Functional Decline in Idiopathic Pulmonary Fibrosis.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF), a progressive disease with an unknown pathogenesis, may be due in part to an abnormal response to injurious stimuli by alveolar epithelial cells. Air pollution and particulate inhalation of matter evoke a wide variety of pulmonary and systemic inflammatory diseases. We therefore hypothesized that increased average ambient particulate matter (PM) concentrations would be associated with an accelerated rate of decline in FVC in IPF. METHODS: We identified a cohort of subjects seen at a single university referral center from 2007 to 2013. Average concentrations of particulate matter < 10 and < 2.5 µg/m3 (PM10 and PM2.5, respectively) were assigned to each patient based on geocoded residential addresses. A linear multivariable mixed-effects model determined the association between the rate of decline in FVC and average PM concentration, controlling for baseline FVC at first measurement and other covariates. RESULTS: One hundred thirty-five subjects were included in the final analysis after exclusion of subjects missing repeated spirometry measurements and those for whom exposure data were not available. There was a significant association between PM10 levels and the rate of decline in FVC during the study period, with each µg/m3 increase in PM10 corresponding with an additional 46 cc/y decline in FVC (P = .008). CONCLUSIONS: Ambient air pollution, as measured by average PM10 concentration, is associated with an increase in the rate of decline of FVC in IPF, suggesting a potential mechanistic role for air pollution in the progression of disease.

A Neighborhood-Wide Association Study (NWAS): Example of prostate cancer aggressiveness.

PURPOSE: Cancer results from complex interactions of multiple variables at the biologic, individual, and social levels. Compared to other levels, social effects that occur geospatially in neighborhoods are not as well-studied, and empiric methods to assess these effects are limited. We propose a novel Neighborhood-Wide Association Study(NWAS), analogous to genome-wide association studies(GWAS), that utilizes high-dimensional computing approaches from biology to comprehensively and empirically identify neighborhood factors associated with disease. METHODS: Pennsylvania Cancer Registry data were linked to U.S. Census data. In a successively more stringent multiphase approach, we evaluated the association between neighborhood (n = 14,663 census variables) and prostate cancer aggressiveness(PCA) with n = 6,416 aggressive (Stage≥3/Gleason grade≥7 cases) vs. n = 70,670 non-aggressive (Stage<3/Gleason grade<7) cases in White men. Analyses accounted for age, year of diagnosis, spatial correlation, and multiple-testing. We used generalized estimating equations in Phase 1 and Bayesian mixed effects models in Phase 2 to calculate odds ratios(OR) and confidence/credible intervals(CI). In Phase 3, principal components analysis grouped correlated variables. RESULTS: We identified 17 new neighborhood variables associated with PCA. These variables represented income, housing, employment, immigration, access to care, and social support. The top hits or most significant variables related to transportation (OR = 1.05;CI = 1.001-1.09) and poverty (OR = 1.07;CI = 1.01-1.12). CONCLUSIONS: This study introduces the application of high-dimensional, computational methods to large-scale, publically-available geospatial data. Although NWAS requires further testing, it is hypothesis-generating and addresses gaps in geospatial analysis related to empiric assessment. Further, NWAS could have broad implications for many diseases and future precision medicine studies focused on multilevel risk factors of disease.

Analytical and Clinical Validation of Two Commercially Available Immunoassays Used in the Detection of TSHR Antibodies.

BACKGROUND: Graves disease is caused by autoantibodies that target the thyroid-stimulating hormone receptor (TSHR). Anti-TSHR autoantibody measurement is routinely performed to differentiate between Graves disease and other causes of hyperthyroidism. We evaluated the clinical performance of a reference laboratory bioassay [the Thyretain thyroid-stimulating immunoglobulin (TSI) Bioassay by Diagnostic Hybrids] and 2 commercially available immunoassays: the TSI Bridge immunoassay by Siemens and the thyroid-stimulating hormone receptor antibody (TRAb) immunoassay by Roche. We further evaluated the analytical performance of the Siemens TSI and Roche TRAb assays. METHODS: We performed method comparisons using 125 patient specimens submitted for TSI testing for clinical purposes. Concordance of patient results was assessed between the 3 methods, and chart review was performed to further evaluate samples that generated discordant results. All 3 methods were also evaluated for potential interference caused by human chorionic gonadotropin (hCG). RESULTS: The Roche and Siemens assays demonstrated acceptable day-to-day precision, within-run precision, and precision at the clinical decision cutoffs. Despite manufacturer-defined analytical measuring ranges up to 40 IU/L, the Roche and Siemens assays were linear to 20 IU/L and 15 IU/L, respectively. hCG concentrations up to 150000 IU/L did not interfere with any of the methods evaluated. Moderate agreement between methods was observed when testing patient specimens that generated negative (≤1.3) or weakly positive (1.4-3.8) results by the Thyretain assay. One hundred percent agreement was observed when the Thyretain assay was strongly positive (≥3.9). CONCLUSIONS: The 3 commercially available anti-TSHR autoantibody measurement methods demonstrated equivalent performance in patients with untreated Graves disease. Discordant results were observed when testing specimens collected from patients undergoing treatment for Graves disease. In these patients, the Siemens TSI assay more frequently generated results consistent with clinical history, results of other laboratory tests, and imaging studies than the Thyretain Bioassay and Roche TRAb assay.

Mapping the urban asthma experience: Using qualitative GIS to understand contextual factors affecting asthma control.

Asthma is complex and connected to a number of factors including access to healthcare, crime and violence, and environmental triggers. A mixed method approach was used to examine the experiences of urban people with asthma in controlling their asthma symptoms. The study started with an initial phase of qualitative interviews in West Philadelphia, a primarily poor African American community. Data from qualitative, semi-structured interviews indicated that stress, environmental irritants, and environmental allergens were the most salient triggers of asthma. Based on the interviews, the team identified six neighborhood factors to map including crime, housing vacancy, illegal dumping, tree canopy and parks. These map layers were combined into a final composite map. These combined methodologies contextualized respondents' perceptions in the framework of the actual community and built environment which tells a more complete story about their experience with asthma.

Geographic distribution of insufficient sleep across the United States: a county-level hotspot analysis.

INTRODUCTION: Insufficient sleep is associated with cardiometabolic risk and neurocognitive impairment. Determinants of insufficient sleep include many social and environmental factors. Assessment of geographic hot/coldspots may uncover novel risk groups and/or targets for public health intervention. The aim of this study was to discern geographic patterns in the first data set to include county-level sleep data. METHODS: The 2009 Behavioral Risk Factor Surveillance System was used. Insufficient sleep was assessed with a survey item and dichotomized. Data from n = 2231 counties were available. Tests for significant spatial concentrations of high/low levels of insufficient sleep (hotspots/coldspots) used the Getis-Ord G* statistic of local spatial concentration, chosen due to the nature of missing data. RESULTS: Eighty-four counties were hotspots, with high levels of insufficient sleep (P < .01), and 45 were coldspots, with low insufficient sleep (P < .01). Hotspots were found in Alabama (1 county), Arkansas (1), Georgia (1), Illinois (1), Kentucky (25), Louisiana (1), Missouri (4), Ohio (7), Tennessee (12), Texas (9), Virginia (6), and West Virginia (16). Coldspots were found in Alabama (1 county), Georgia (2), Illinois (6), Iowa (6), Michigan (2), Minnesota (1), North Carolina (1), Texas (7), Virginia (12), and Wisconsin (6). Several contiguous hotspots and coldspots were evident. Notably, the 17 counties with the highest levels of insufficient sleep were found in a contiguous set at the intersection of Kentucky, Tennessee, Virginia, and West Virginia (all P < .0002). CONCLUSIONS: Geographic distribution of insufficient sleep in the United States is uneven. Some areas (most notably parts of Appalachia) experience disproportionately high amounts of insufficient sleep and may be targets of intervention. Further investigation of determinants of geographic variability needs to be explored, which would enhance the utility of these data for development of public health campaigns.

Environmental variables as potential modifiable risk factors of preterm birth in Philadelphia, PA.

OBJECTIVE: To examine whether variation in neighborhood context is associated with preterm birth (PTB) outcomes and gestational age (GA) at delivery in Philadelphia, and to determine whether these associations might persist when considering relevant individual-level variables. STUDY DESIGN: We analyzed individual-level data collected for a prospective cohort study of singleton pregnancies with preterm labor. We merged block-group level data to each individual's home address. Unadjusted analyses were performed to determine the association between block-group variables and individual-level outcomes. Block-group variables identified as potential risk factors were incorporated into multivariable individual-level models to determine significance. RESULTS: We analyzed data for 817 women. The prevalence of PTB <37 weeks was 41.5%. Although in unadjusted analyses several block-group variables were associated with PTB and GA at delivery, none retained significance in individual-level multivariable models. CONCLUSION: Block-group level data were not associated with PTB outcomes or GA at delivery in Philadelphia.

Vitamin D deficiency and comorbidities in children with sickle cell anemia.

Vitamin D deficiency is known to be common among patients with sickle cell anemia (SCA). Vitamin D levels were measured in 139 children (aged 7.9 to 15.1 years) to study its association with SCA morbidities; severe deficiency <10 ng/mL was present in 64.0% and only 2.2% were sufficient (>30 ng/mL). Vitamin D levels were associated with pulmonary function (forced expiratory volume in 1 second [FEV(1)]), but not associated with either rates of acute pain or acute chest syndrome episodes. Further studies are needed to be able to compare outcomes in those with deficiency to those with sufficiency, as well as to treating patients with SCA with vitamin D to better establish a possible link, if any, between vitamin D and SCA morbidity.

A difference-in-differences analysis of health, safety, and greening vacant urban space.

Greening of vacant urban land may affect health and safety. The authors conducted a decade-long difference-in-differences analysis of the impact of a vacant lot greening program in Philadelphia, Pennsylvania, on health and safety outcomes. "Before" and "after" outcome differences among treated vacant lots were compared with matched groups of control vacant lots that were eligible but did not receive treatment. Control lots from 2 eligibility pools were randomly selected and matched to treated lots at a 3:1 ratio by city section. Random-effects regression models were fitted, along with alternative models and robustness checks. Across 4 sections of Philadelphia, 4,436 vacant lots totaling over 7.8 million square feet (about 725,000 m(2)) were greened from 1999 to 2008. Regression-adjusted estimates showed that vacant lot greening was associated with consistent reductions in gun assaults across all 4 sections of the city (P < 0.001) and consistent reductions in vandalism in 1 section of the city (P < 0.001). Regression-adjusted estimates also showed that vacant lot greening was associated with residents' reporting less stress and more exercise in select sections of the city (P < 0.01). Once greened, vacant lots may reduce certain crimes and promote some aspects of health. Limitations of the current study are discussed. Community-based trials are warranted to further test these findings.

Risk of prenatal depression: differences by race.

BACKGROUND: Approximately 20 million adults suffer from depressive illnesses each year and women are at least twice as likely as men to experience depressive disorders and symptoms. Empirical results have been mixed regarding racial differences in depression prevalence. Given that depression has negative effects on maternal outcomes, little has been explored in regard to prenatal depression across racial/ethnic groups. METHODS: This was a cross-sectional study. Data were abstracted from the 2006 National Inpatient Sample. A total of 877,579 women who delivered in a hospital in 2006 were identified. Presentation of depression at admission was the dependent variable. The independent variable was race/ethnicity that was categorized as White, African American, Hispanic, or other race. Patients' demographics, health insurance status, income level, and hospital characteristics were covariates. RESULTS: A little more than one percent (1.15%) of the women in the sample had depression as a comorbidity before the delivery. As compared with White women, African American women were much less likely to have the depression presentation (odds ratio (OR) [95% confidence interval (CI)] 0.43 [0.39, 0.47]), as were Hispanic women (OR [CI] 0.27 [0.25, 0.29]) and women of other races (OR [CI] 0.26 [0.23, 0.30]). Moreover, interactive effects between race/ethnicity and insurance status on the depression risk were also observed. CONCLUSION: Counterintuitive findings that all minority women had lower depression risk as opposed to that of White women may indicate potential under-diagnosed depression and other mental illnesses among minority women. Further research is needed to examine whether the under-reporting or under-identification exists.

Advancing maternal age and infant birth weight among urban African Americans: the effect of neighborhood poverty.

OBJECTIVE: This study sought to determine whether neighborhood poverty modifies the relationship between maternal age and infant birth weight among urban African Americans. DESIGN: Stratified analyses were performed on the vital records of African Americans born in Chicago by means of 1992-1995 computerized birth file with appended 1990 US Census income and 1995 Chicago Department of Public Health data. Four neighborhood-level variables (low median family income, high rates of unemployment, homicide, and lead poisoning) were analyzed. SETTING: This is a population-based study. RESULTS: Twenty-one percent (n=21,811) of women resided in nonimpoverished neighborhoods (zero ecologic risk factors); 23% (n=24,914) of women lived in extremely impoverished neighborhoods (four ecologic risk factors). In nonimpoverished neighborhoods, 30-34 year old women had a moderately low birth weight (1500-2499 g) rate of 13.9% compared to 10.3% for women aged 20-24 years; risk difference (95% confidence interval [CI])=3.5 (2.2-4.6). In contrast, extremely impoverished women aged 30-34 years had a moderately low birth weight rate of 19.8% compared to 11.8% for women aged 20-24 years; risk difference (95% CI)=7.7 (6.1-9.3). This trend persisted among women who received early prenatal care and were primagravids or of low parity. Neighborhood poverty did not modify the association of advancing maternal age and the risk of very low birth weight (<1500 g). CONCLUSIONS: Neighborhood poverty accelerates the rise in moderately low birth weight but not very low birth weight; rates were associated with advancing maternal age among urban African Americans.

Design of novel N-(2,4-dioxo-1,2,3,4-tetrahydro-thieno[3,2-d]pyrimidin-7-yl)-guanidines as thymidine phosphorylase inhibitors, and flexible docking to a homology model.

A novel class of thymidine phosphorylase (TP) inhibitors has been designed based on analogy to the enzyme substrate as well as known inhibitors. Flexible docking studies, using a homology model of human TP, of the designed N-(2,4-dioxo-1,2,3,4-tetrahydro-thieno[3,2-d]pyrimidin-7-yl)-guanidines as well as their synthetic precursors provide insight into the observed experimental trends in binding affinity.