In 2008, the NIH launched an undiagnosed diseases program to investigate difficult to diagnose, and typically, multi-system diseases. The objective of this study was to evaluate the presence of psychiatric symptoms or psychiatric diagnoses in a cohort of patients seeking care at the Emory Special Diagnostic Service clinic. We hypothesized that psychiatric symptoms would be prevalent and associated with trauma exposure, and a decreased quality of life and functioning. This is a cross-sectional, retrospective analysis of 247 patients seen between February 7, 2014 and May 31, 2017. The sources for data included the Emory Health History Questionnaire (HHQ) that had the work and social adjustment and quality of life enjoyment and satisfaction questionnaire–short form (QLSQ) embedded in it; medical records, and the comprehensive standardized special diagnostic clinic forms. Primary outcomes were presence of any psychiatric symptom, based on report of the symptom on the HHQ or medical record, or presence of a confirmed preexisting psychiatric disorder. Seventy-two percent of patients had at least one psychiatric symptom while 24.3% of patients had a pre-existing psychiatric diagnosis. Patients with any psychiatric symptom had significantly diminished Q-LES-Q scores (45.27 ± 18.63) versus patients with no psychiatric symptoms (62.01 ± 21.57, t = 5.60, df = 225, p<0.0001) and they had significantly greater functional disability. Patients with a psychiatric disorder also had significantly diminished Q-LES-Q scores (45.16 ± 17.28) versus those without a psychiatric diagnosis (51.85 ± 21.54, t = 2.11, df = 225, p = 0.036) but did not have significantly increased functional impairment. Both patients with psychiatric symptoms and ones with psychiatric disorders had an increased prevalence of trauma. Psychiatric symptoms are prevalent in patients evaluated for undiagnosed disorders. The presence of any psychiatric symptom, with or without a formal psychiatric diagnosis, significantly decreases quality of life and functioning. This suggests that assessment for psychiatric symptoms should be part of the evaluation of individuals with undiagnosed disorders and may have important diagnostic and treatment implications.
Background Incidence of community acquired pneumonia is high globally. In Bangladesh, more male children than female children are brought to hospitals for pneumonia. We examined if there was disparities in the severity of illness and outcome by sex among children who were admitted with pneumonia to hospitals in Bangladesh. Methods Hospitalized children, aged 2 to 59 months, meeting a case definition of pneumonia were recruited in seven hospitals following parental consent. At baseline, study doctors obtained socio-demographic characteristics and care seeking behaviors for pneumonia, and then clinical data were collected throughout the hospital stay. Multivariate analysis was performed to determine if the sex of the child had a relationship with either illness severity on admission or outcome in the hospital. Results Between May 2004 and December 2008, 6,856 children, including 35% females, were recruited. A total of 1,371 (19.9%) children had non-severe pneumonia, 4,118 (60.0%) had severe pneumonia, and 1,367 (19.9%) had very severe pneumonia. A higher proportion of hospitalized females had very severe pneumonia as compared to males (21.5% versus 19.1%; P = 0.01), but there was no difference by sex in the proportion of children with severe or non-severe pneumonia. There was no difference by sex observed in the clinical management provided in the hospital, but a greater proportion of females (4.7%) as compared to males (3.6%) died in hospitals (P = 0.04). In multivariate analyses, female sex was associated with very severe pneumonia on admission (OR: 1.26, 95% CI: 1.09–1.47) and fatal outcome in the hospitals (OR: 1.31, 95% CI: 1.01–1.71). Death in female children admitted with very severe pneumonia was 4 times higher than that reported in males (OR: 4.37, 95% CI: 3.24–5.89). Conclusion Our data demonstrates a sex-based disparity in the severity of pneumonia and deaths among children admitted to hospitals in Bangladesh, despite no existing disparity by sex in hospital treatment. These findings call for further investigations to explore the determinants of health seeking behavior by parents with children with pneumonia in a community that favors males to females, and to understand the role of differences by sex in childhood pneumonia outcomes in Bangladesh.
This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Recent evidence suggests that grammatical aspect can bias how individuals perceive criminal intentionality during discourse comprehension. Given that criminal intentionality is a common criterion for legal definitions (e.g., first-degree murder), the present study explored whether grammatical aspect may also impact legal judgments. In a series of four experiments participants were provided with a legal definition and a description of a crime in which the grammatical aspect of provocation and murder events were manipulated. Participants were asked to make a decision (first- vs. second-degree murder) and then indicate factors that impacted their decision. Findings suggest that legal judgments can be affected by grammatical aspect but the most robust effects were limited to temporal dynamics (i.e., imperfective aspect results in more murder actions than perfective aspect), which may in turn influence other representational systems (i.e., number of murder actions positively predicts perceived intentionality). In addition, findings demonstrate that the influence of grammatical aspect on situation model construction and evaluation is dependent upon the larger linguistic and semantic context. Together, the results suggest grammatical aspect has indirect influences on legal judgments to the extent that variability in aspect changes the features of the situation model that align with criteria for making legal judgments.
The prairie vole (Microtus ochrogaster) is an important model organism for the study of social behavior, yet our ability to correlate genes and behavior in this species has been limited due to a lack of genetic and genomic resources. Here we report the BAC-based targeted sequencing of behaviorally-relevant genes and flanking regions in the prairie vole. A total of 6.4 Mb of non-redundant or haplotype-specific sequence assemblies were generated that span the partial or complete sequence of 21 behaviorally-relevant genes as well as an additional 55 flanking genes. Estimates of nucleotide diversity from 13 loci based on alignments of 1.7 Mb of haplotype-specific assemblies revealed an average pair-wise heterozygosity (8.4×10 -3 ). Comparative analyses of the prairie vole proteins encoded by the behaviorally-relevant genes identified > 100 substitutions specific to the prairie vole lineage. Finally, our sequencing data indicate that a duplication of the prairie vole AVPR1A locus likely originated from a recent segmental duplication spanning a minimum of 105 kb. In summary, the results of our study provide the genomic resources necessary for the molecular and genetic characterization of a high-priority set of candidate genes for regulating social behavior in the prairie vole.
Social relationships have important effects on alcohol drinking. There are conflicting reports, however, about whether early-life family structure plays an important role in moderating alcohol use in humans. We have previously modeled social facilitation of alcohol drinking in peers in socially monogamous prairie voles. We have also modeled the effects of family structure on the development of adult social and emotional behaviors. Here we assessed whether alcohol intake would differ in prairie voles reared by both parents compared to those reared by a single mother. We also assessed whether meadow voles, a closely related species that do not form lasting reproductive partnerships, would differ in alcohol drinking or in the effect of social influence on drinking. Prairie voles were reared either bi-parentally (BP) or by a single mother (SM). BP- and SM-reared adult prairie voles and BP-reared adult meadow voles were given limited access to a choice between alcohol (10%) and water over four days and assessed for drinking behavior in social and non-social drinking environments. While alcohol preference was not different between species, meadow voles drank significantly lower doses than prairie voles. Meadow voles also had significantly higher blood ethanol concentrations than prairie voles after receiving the same dose, suggesting differences in ethanol metabolism. Both species, regardless of rearing condition, consumed more alcohol in the social drinking condition than the non-social condition. Early life family structure did not significantly affect any measure. Greater drinking in the social condition indicates that alcohol intake is influenced similarly in both species by the presence of a peer. While the ability of prairie voles to model humans may be limited, the lack of differences in alcohol drinking in BP- and SM-reared prairie voles lends biological support to human studies demonstrating no effect of single-parenting on alcohol abuse.
INTRODUCTION: Cryptococcal meningitis is one of the leading causes of death among people with HIV in Africa, primarily due to delayed presentation, poor availability and high cost of treatment. Routine cryptococcal antigen (CrAg) screening of patients with a CD4 count less than 100 cells/mm3, followed by pre-emptive therapy if positive, might reduce mortality in high prevalence settings. Using the cryptococcal antigen (CrAg) lateral flow assay (LFA), screening is possible at the point of care (POC). However, critical shortages of health staff may limit adoption. This study investigates the feasibility of lay counsellors conducting CrAg LFA screening in rural primary care clinics in Lesotho. METHODS: From May 2014 to June 2015, individuals who tested positive for HIV were tested for CD4 count and those with CD4 <100 cells/mm3 were screened with CrAg LFA. All tests were performed by lay counsellors. CrAg-positive asymptomatic patients received fluconazole, while symptomatic patients were referred to hospital. Lay counsellors were trained and supervised by a laboratory technician and counsellor activity supervisor. Additionally, nurses and doctors were trained on CrAg screening and appropriate treatment. RESULTS: During the study period, 1,388 people were newly diagnosed with HIV, of whom 129 (9%) presented with a CD4 count <100 cells/mm3. Of these, 128 (99%) were screened with CrAg LFA and 14/128 (11%) tested positive. Twelve of the 14 (86%) were asymptomatic, and received outpatient fluconazole. All commenced ART with a median time to initiation of 15.5 days [IQR: 14-22]. Of the asymptomatic patients, nine (75%) remained asymptomatic after a median time of 5 months [IQR; 3-6] of follow up. One (8%) became co-infected with tuberculosis and died and two were transferred out. The two patients with symptomatic cryptococcal meningitis (CM) were referred to hospital, where they later died. CONCLUSIONS: CrAg LFA screening by lay counsellors followed by pre-emptive fluconazole treatment for asymptomatic cases, or referral to hospital for symptomatic cases, proved feasible. However, regular follow-up to ensure proper management of cryptococcal disease was needed. These early results support the wider use of CrAg LFA screening in remote primary care settings where upper cadres of healthcare staff may be in short supply.
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David H. Chae;
Sean Clouston;
Mark L. Hatzenbuehler;
Michael Kramer;
Hannah Cooper;
Sacoby M. Wilson;
Seth I. Stephens-Davidowitz;
Robert S. Gold;
Bruce G. Link
Racial disparities in health are well-documented and represent a significant public health concern in the US. Racism-related factors contribute to poorer health and higher mortality rates among Blacks compared to other racial groups. However, methods to measure racism and monitor its associations with health at the population-level have remained elusive. In this study, we investigated the utility of a previously developed Internet search-based proxy of area racism as a predictor of Black mortality rates. Area racism was the proportion of Google searches containing the "N-word" in 196 designated market areas (DMAs). Negative binomial regression models were specified taking into account individual age, sex, year of death, and Census region and adjusted to the 2000 US standard population to examine the association between area racism and Black mortality rates, which were derived from death certificates and mid-year population counts collated by the National Center for Health Statistics (2004-2009). DMAs characterized by a one standard deviation greater level of area racism were associated with an 8.2% increase in the all-cause Black mortality rate, equivalent to over 30,000 deaths annually. The magnitude of this effect was attenuated to 5.7% after adjustment for DMA-level demographic and Black socioeconomic covariates. A model controlling for the White mortality rate was used to further adjust for unmeasured confounders that influence mortality overall in a geographic area, and to examine Black-White disparities in the mortality rate. Area racism remained significantly associated with the allcause Black mortality rate (mortality rate ratio = 1.036; 95% confidence interval = 1.015, 1.057; p = 0.001). Models further examining cause-specific Black mortality rates revealed significant associations with heart disease, cancer, and stroke. These findings are congruent with studies documenting the deleterious impact of racism on health among Blacks. Our study contributes to evidence that racism shapes patterns in mortality and generates racial disparities in health.
Single nucleotide polymorphisms (SNPs) in the FK506 binding protein 5 (FKBP5) gene combine with traumatic events to increase risk for post-traumatic stress and major depressive disorders (PTSD and MDD). These SNPs increase FKBP51 protein expression through a mechanism involving demethylation of the gene and altered glucocorticoid signaling. Aged animals also display elevated FKBP51 levels, which contribute to impaired resiliency to depressive-like behaviors through impaired glucocorticoid signaling, a phenotype that is abrogated in FKBP5-/-mice. But the age of onset and progressive stability of these phenotypes remain unknown. Moreover, it is unclear how FKBP5 deletion affects other glucocorticoid-dependent processes or if age-associated increases in FKBP51 expression are mediated through a similar epigenetic process caused by SNPs in the FKBP5 gene. Here, we show that FKBP51-mediated impairment in stress resiliency and glucocorticoid signaling occurs by 10 months of age and this increased over their lifespan. Surprisingly, despite these progressive changes in glucocorticoid responsiveness, FKBP5-/-mice displayed normal longevity, glucose tolerance, blood composition and cytokine profiles across lifespan, phenotypes normally associated with glucocorticoid signaling. We also found that methylation of Fkbp5 decreased with age in mice, a process that likely explains the age-associated increases in FKBP51 levels. Thus, epigenetic upregulation of FKBP51 with age can selectively impair psychological stress-resiliency, but does not affect other glucocorticoid-mediated physiological processes. This makes FKBP51 a unique and attractive therapeutic target to treat PTSD and MDD. In addition, aged wild-type mice may be a useful model for investigating the mechanisms of FKBP5 SNPs associated with these disorders.
by
Pavel Krejci;
Lisa Salazar;
Tamara A. Kashiwada;
Katarina Chlebova;
Alena Salasova;
Leslie Michels Thompson;
Vitezslav Bryja;
Alois Kozubik;
William R. Wilcox
Activating mutations in FGFR3 tyrosine kinase cause several forms of human skeletal dysplasia. Although the mechanisms of FGFR3 action in cartilage are not completely understood, it is believed that the STAT1 transcription factor plays a central role in pathogenic FGFR3 signaling. Here, we analyzed STAT1 activation by the N540K, G380R, R248C, Y373C, K650M and K650E-FGFR3 mutants associated with skeletal dysplasias. In a cell-free kinase assay, only K650M and K650E-FGFR3 caused activatory STAT1(Y701) phosphorylation. Similarly, in RCS chondrocytes, HeLa, and 293T cellular environments, only K650M and K650E-FGFR3 caused strong STAT1 activation. Other FGFR3 mutants caused weak (HeLa) or no activation (293T and RCS). This contrasted with ERK MAP kinase activation, which was strongly induced by all six mutants and correlated with the inhibition of proliferation in RCS chondrocytes. Thus the ability to activate STAT1 appears restricted to the K650M and K650E-FGFR3 mutants, which however account for only a small minority of the FGFR3-related skeletal dysplasia cases. Other pathways such as ERK should therefore be considered as central to pathological FGFR3 signaling in cartilage.
Background and Purpose: Diffusion-weighted imaging (DWI) and perfusion MRI were used to examine the spatiotemporal evolution of stroke lesions in adult macaques with ischemic occlusion. Methods: Permanent MCA occlusion was induced with silk sutures through an interventional approach via the femoral artery in adult rhesus monkeys (n = 8, 10-21 years old). The stroke lesions were examined with high-resolution DWI and perfusion MRI, and T2-weighted imaging (T2W) on a clinical 3T scanner at 1-6, 48, and 96 hours post occlusion and validated with H&E staining. Results: The stroke infarct evolved via a natural logarithmic pattern with the mean infarct growth rate = 1.38 ± 1.32 ml per logarithmic time scale (hours) (n = 7) in the hyperacute phase (1-6 hours). The mean infarct volume after 6 hours post occlusion was 3.6±2.8 ml (n = 7, by DWI) and increased to 3.9±2.9 ml (n = 5, by T2W) after 48 hours, and to 4.7±2.2ml (n = 3, by T2W) after 96 hours post occlusion. The infarct volumes predicted by the natural logarithmic function were correlated significantly with the T2W-derived lesion volumes (n = 5, r = 0.92, p = 0.01) at 48 hours post occlusion. The final infarct volumes derived from T2W were correlated significantly with those from H&E staining (r = 0.999, p < 0.0001, n = 4). In addition, the diffusion-perfusion mismatch was visible generally at 6 hours but nearly diminished at 48 hours post occlusion. Conclusion: The infarct evolution follows a natural logarithmic pattern in the hyperacute phase of stroke. The logarithmic pattern of evolution could last up to 48 hours after stroke onset and may be used to predict the infarct volume growth during the acute phase of ischemic stroke. The nonhuman primate model, MRI protocols, and post data processing strategy may provide an excellent platform for characterizing the evolution of acute stroke lesion in mechanistic studies and therapeutic interventions of stroke disease.