Pilot study indicates that a gluten-free diet lowers oxidative stress for gluten-sensitive persons with schizophrenia.

One-third of people with schizophrenia have elevated levels of anti-gliadin antibodies (AGA IgG). A 5-week randomized double-blind pilot study was performed in 2014-2017 in an inpatient setting to test the effect of a gluten-free diet (GFD) on participants with schizophrenia or schizoaffective disorder who also had elevated AGA IgG (≥ 20 U) but were negative for celiac disease. This earlier pilot study reported that the GFD-group showed improved gastrointestinal and psychiatric symptoms, and also improvements in TNF-α and the inflammatory cytokine IL-23. Here, we performed measurements of these banked plasma samples to detect levels of oxidative stress (OxSt) using a recently developed iridium (Ir)-reducing capacity assay. Triplicate measurements of these samples showed an Intraclass Correlation Coefficient of 0.84 which indicates good reproducibility. Further, a comparison of the OxSt measurements at the baseline and 5-week end-point for this small sample size shows that the GFD-group (N = 7) had lowered OxSt levels compared to the gluten-containing diet group (GCD; N = 9; p = 0.05). Finally, we showed that improvements in OxSt over these 5 weeks were correlated to improvements in gastrointestinal (r = +0.64, p = 0.0073) and psychiatric (r = +0.52, p = 0.039) symptoms. Also, we showed a possible association between the decrease in OxSt and the lowered levels of IL-23 (r = +0.44, p = 0.087), although without statistical significance. Thus, the Ir-reducing capacity assay provides a simple, objective measure of OxSt with the results providing further evidence that inflammation, redox dysregulation and OxSt may mediate interactions between the gut and brain.

Functional and multi-omics signatures of mitapivat efficacy upon activation of pyruvate kinase in red blood cells from patients with sickle cell disease.

Mitapivat, a pyruvate kinase (PK) activator, shows great potential as a sickle cell disease (SCD)- modifying therapy. Safety and efficacy of mitapivat as a long-term maintenance therapy is currently being evaluated in two open-label studies. Here we apply a comprehensive multi-omics approach to investigate the impact of activating PK on red blood cells (RBCs) from 15 SCD patients. HbSS patients were enrolled in one of the open label, extended studies (NCT04610866). Leuko-depleted RBCs obtained from fresh whole blood at baseline (visit 1, V1), prior to drug initiation and longitudinal time points over the course of the study were processed for multiomics through a stepwise extraction of metabolites, lipids and proteins. Mitapivat therapy had significant effects on the metabolome, lipidome and proteome of SCD RBCs. Mitapivat decreased 2,3-diphosphoglycerate (DPG) levels, increased adenosine triphosphate (ATP) levels, and improved hematologic and sickling parameters in patients with SCD. Agreement between omics measurements and clinical measurements confirmed the specificity of mitapivat on targeting late glycolysis, with glycolytic metabolites ranking as the top correlates to parameters of hemoglobin S (HbS) oxygen affinity (p50) and sickling kinetics (t50) during treatment. Mitapivat markedly reduced levels of proteins of mitochondrial origin within 2 weeks of initiation of drug treatment, with minimal changes in the reticulocyte counts. The first six months of treatment also witnessed transient elevation of lysophosphatidylcholines and oxylipins with depletion in free fatty acids, suggestive of an effect on membrane lipid remodeling. Multi-omics analysis of RBCs identified benefits for glycolysis, as well as activation of the Lands cycle.

In vivo measurement of RBC survival in patients with sickle cell disease before or after hematopoietic stem cell transplantation.

ABSTRACT: Stable, mixed-donor-recipient chimerism after allogeneic hematopoietic stem cell transplantation (HSCT) for patients with sickle cell disease (SCD) is sufficient for phenotypic disease reversal, and results from differences in donor/recipient-red blood cell (RBC) survival. Understanding variability and predictors of RBC survival among patients with SCD before and after HSCT is critical for gene therapy research which seeks to generate sufficient corrected hemoglobin to reduce polymerization thereby overcoming the red cell pathology of SCD. This study used biotin labeling of RBCs to determine the lifespan of RBCs in patients with SCD compared with patients who have successfully undergone curative HSCT, participants with sickle cell trait (HbAS), and healthy (HbAA) donors. Twenty participants were included in the analysis (SCD pre-HSCT: N = 6, SCD post-HSCT: N = 5, HbAS: N = 6, and HbAA: N = 3). The average RBC lifespan was significantly shorter for participants with SCD pre-HSCT (64.1 days; range, 35-91) compared with those with SCD post-HSCT (113.4 days; range, 105-119), HbAS (126.0 days; range, 119-147), and HbAA (123.7 days; range, 91-147) (P<.001). RBC lifespan correlated with various hematologic parameters and strongly correlated with the average final fraction of sickled RBCs after deoxygenation (P<.001). No adverse events were attributable to the use of biotin and related procedures. Biotin labeling of RBCs is a safe and feasible methodology to evaluate RBC survival in patients with SCD before and after HSCT. Understanding differences in RBC survival may ultimately guide gene therapy protocols to determine hemoglobin composition required to reverse the SCD phenotype as it relates directly to RBC survival. This trial was registered at www.clinicaltrials.gov as #NCT04476277.

Recent developments in the use of pyruvate kinase activators as a new approach for treating sickle cell disease.

ABSTRACT: Pyruvate kinase (PK) is a key enzyme in glycolysis, the sole source of adenosine triphosphate, which is essential for all energy-dependent activities of red blood cells. Activating PK shows great potential for treating a broad range of hemolytic anemias beyond PK deficiency, because they also enhance activity of wild-type PK. Motivated by observations of sickle-cell complications in sickle-trait individuals with concomitant PK deficiency, activating endogenous PK offers a novel and promising approach for treating patients with sickle-cell disease.

Association of common infections with cognitive performance in the Baltimore Epidemiologic Catchment Area study follow-up.

INTRODUCTION: Growing evidence suggests that some common infections are causally associated with cognitive impairment; however, less is known about the burden of multiple infections. METHODS: We investigated the cross-sectional association of positive antibody tests for herpes simplex virus, cytomegalovirus (CMV), Epstein-Barr virus (EBV), varicella zoster virus (VZV), and Toxoplasma gondii (TOX) with Mini-Mental State Examination (MMSE) and delayed verbal recall performance in 575 adults aged 41-97 from the Baltimore Epidemiologic Catchment Area Study. RESULTS: In multivariable-adjusted zero-inflated Poisson (ZIP) regression models, positive antibody tests for CMV (p = .011) and herpes simplex virus (p = .018) were individually associated with poorer MMSE performance (p = .011). A greater number of positive antibody tests among the five tested was associated with worse MMSE performance (p = .001). DISCUSSION: CMV, herpes simplex virus, and the global burden of multiple common infections were independently associated with poorer cognitive performance. Additional research that investigates whether the global burden of infection predicts cognitive decline and Alzheimer's disease biomarker changes is needed to confirm these findings.

Association of Psychotic Experiences and Incident Depression in a Longitudinal Population-Based Community Survey.

Objective: The present study aims to determine if psychotic experiences in a general population sample are a risk factor for depressive disorders at a 15-year follow-up visit. Method: A longitudinal population cohort of adults over age 18 from East Baltimore were followed from 1981 to 1996 with 1409 participants included in analyses. Delusions and hallucinations and depressive disorders were assessed using DSM-III criteria. Odds ratios were obtained using logistic regression with psychotic experiences modeled both dichotomously and as count variables as predictors of major and minor depressive disorders at wave three. Age, race, and sex were included as covariates in the model. Results: Both delusions and hallucinations were associated with an increased odds of incident depressive disorders. Delusions, but not hallucinations, were associated with increased odds of major depressive disorder (adjusted odds ratio, 3.04 [95% CI = 1.29-7.13]) and both delusions and hallucinations were associated with increased odds of minor depressive disorder (adjusted odds ratios, 4.6 [95% CI = 2.11-10.04] and 3.93 [95% CI = 2.11-7.32]). There was a dose-response relationship in number of psychotic experiences reported and odds of depressive disorders. Conclusions: Lifetime psychotic experiences, particularly delusions, in the absence of mental disorders, are associated with later depressive disorders. Results persist in a dose-response manner. Future research should determine whether transitory versus persistent psychotic experiences have a differential effect on later depression.

Psychiatric comorbidity in the Baltimore ECA follow-up study: the matrix approach.

BACKGROUND: Psychiatric comorbidity is defined as the joint occurrence of two or more mental or substance use disorders. Widespread psychiatric comorbidity has been reported in treatment and population-based studies. The aim of this study was to measure the extent and impact of psychiatric comorbidity in a cohort of the Baltimore Epidemiologic Catchment Area study. METHODS: We examined the comorbidity burden of 16 mental disorders in a cohort of 847 participants using both established and novel analytical approaches The Comorbidity to Diagnosis Inflation Ratio (CDIR), is a statistical instrument that quantifies impact of pairwise comorbid associations, both on the whole sample, as well as on each specific disorder. RESULTS: Most anxiety disorders had substantial co-occurrence with each other, as well as with Major Depressive Disorder (MDD). In addition, mood disorders had a high degree of comorbidity with Alcohol Dependence (AD). The CDIR for the whole sample was 1.32, indicating a ratio of 132 comorbidities per 100 diagnoses. The conditions with high sample prevalence were relatively less comorbid than the low prevalence conditions. Obsessive Compulsive Disorder had a comorbidity burden that was 89% greater than the overall sample. CONCLUSION: Anxiety disorders are highly interrelated, as well as highly comorbid with depression. The comorbidity phenomenon is linked to the differential prevalence of the analyzed conditions. Comorbidity frequency (most prevalent comorbid condition) appears mutually exclusive to comorbidity burden (most widely interrelated condition). While AD and MDD were the most frequently diagnosed disorders; low prevalence conditions as OCD and GAD were the most widely interrelated.

A retrospective on statistical mechanical models for hemoglobin allostery.

Understanding allosteric interactions in proteins has become one of the major research areas in protein science. The original aim of the famous theoretical model of Monod, Wyman, and Changeux (MWC) was to explain the regulation of enzymatic activity in biochemical pathways. However, its first successful quantitative application was to explain cooperative oxygen binding by hemoglobin, often called the "hydrogen molecule of biology." The combination of its original application and the enormous amount of research on hemoglobin has made it the paradigm for studies of allostery, especially for multi-subunit proteins, and for the development of statistical mechanical models to describe how structure determines function. This article is a historical account of the development of statistical mechanical models for hemoglobin to explain both the cooperative binding of oxygen (called homotropic effects by MWC) and how oxygen binding is affected by ligands that bind distant from the heme oxygen binding site (called heterotropic allosteric effects by MWC). This account makes clear the many remaining challenges for describing the relationship of structure to function for hemoglobin in terms of a satisfactory statistical mechanical model.

Drug discovery by a basic research scientist.

I was fortunate to do my military service during the Vietnam era as a medical officer at the National Institutes of Health (NIH) in Bethesda, Maryland. My first research at NIH was concerned with making a variety of optical measurements on nucleic acid bases and proteins, including single crystal spectra in linearly polarized light and near infrared circular dichroism, interpreting the spectra using molecular orbital and crystal field theories. What I do now is drug discovery, a field at the opposite end of the scientific spectrum. This article gives a brief account of my transition from spectroscopy to sickle cell hemoglobin polymerization to protein folding to drug discovery for treating sickle cell disease. My lab recently developed a high throughput assay to screen the 12,657 compounds of the California Institute of Biomedical Research ReFrame drug repurposing library. This is a precious library because the compounds have either been FDA approved or have been tested in clinical trials. Since the 1970s numerous agents have been reported in the literature to inhibit HbS polymerization and/or sickling with only one successful drug, hydroxyurea, and another of dubious value, voxelotor, even though it has been approved by the FDA. Our screen has discovered 106 anti-sickling agents in the ReFrame compound library. We estimate that as many as 21 of these compounds could become oral drugs for treating sickle cell disease because they inhibit at concentrations typical of the free concentrations of oral drugs in human serum.

Phenotypic screening of the ReFRAME drug repurposing library to discover new drugs for treating sickle cell disease.

Stem cell transplantation and genetic therapies offer potential cures for patients with sickle cell disease (SCD), but these options require advanced medical facilities and are expensive. Consequently, these treatments will not be available for many years to the majority of patients suffering from this disease. What is urgently needed now is an inexpensive oral drug in addition to hydroxyurea, the only drug approved by the FDA that inhibits sickle-hemoglobin polymerization. Here, we report the results of the first phase of our phenotypic screen of the 12,657 compounds of the Scripps ReFRAME drug repurposing library using a recently developed high-throughput assay to measure sickling times following deoxygenation to 0% oxygen of red cells from sickle trait individuals. The ReFRAME library is a very important collection because the compounds are either FDA-approved drugs or have been tested in clinical trials. From dose-response measurements, 106 of the 12,657 compounds exhibit statistically significant antisickling at concentrations ranging from 31 nM to 10 µM. Compounds that inhibit sickling of trait cells are also effective with SCD cells. As many as 21 of the 106 antisickling compounds emerge as potential drugs. This estimate is based on a comparison of inhibitory concentrations with free concentrations of oral drugs in human serum. Moreover, the expected therapeutic potential for each level of inhibition can be predicted from measurements of sickling times for cells from individuals with sickle syndromes of varying severity. Our results should motivate others to develop one or more of these 106 compounds into drugs for treating SCD.

Immunologic profiling in schizophrenia and rheumatoid arthritis.

The negative relationship between schizophrenia (SCZ) and rheumatoid arthritis (RA) has been observed for 85 years, but the mechanisms driving this association are unknown. This study analyzed differences in profiles of cytokines (IL-1ß, IL-Ra, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IFNγ, TNFα), selected genes (HLA-DRB1, IL1RN, HP2), and antibodies related to gluten sensitivity (AGA-IgG, AGA-IgA), celiac disease (tTG), and systemic autoimmunity (ANA, anti-CCP, RF) in 40 subjects with SCZ, 40 with RA, and 40 healthy controls (HC). HLA-DRB1*04:01 alleles were enriched in persons with SCZ and RA compared with HC, and the HP2/HP2 genotype was 2-fold more prevalent in AGA/tTG-positive versus negative SCZ patients. Patients with SCZ demonstrated 52.5% positivity for any of the antibodies tested, compared to 90% of RA patients and 30% of HC. Cluster analysis of the cytokines revealed three clusters: one associated with SCZ marked by high levels of IL-1Ra, one associated with HC, and one associated with both SCZ and RA marked by elevated levels of IFNγ, TNFα, and IL-6. These analyses suggest that stratification of SCZ patients by cytokine profile may identify unique SCZ subgroups and enable the use of currently available cytokine-targeted treatment strategies.

The Relationship Between Latinxs' Acculturative Experiences and Mental and Behavioral Disorder in the National Latino and Asian American Study.

Mental and behavioral disorders are among the leading contributors to disability among US-residing Latinxs. When treated as a homogeneous group, important disparities in the prevalence of such disorders among Latinx subgroups (e.g., by ethnic heritage) are obscured. However, Latinxs may also be characterized by their acculturative experiences while living in the USA, such as discrimination, neighborhood context and family conflict. Latent Profile Analysis with distal outcomes was used to estimate differences in psychiatric disorder prevalence across acculturative subgroups. Data from 2,541 Latinx participants (age 18 +) in the National Latino and Asian American Study (NLAAS) were used to estimate differences in the proportion of three categories of DSM-IV disorder: depressive, anxiety and substance use by four latent subgroups of Latinxs based on their acculturative experiences. Latinxs reporting more positive acculturative experiences had the lowest prevalence of all three disorders (14.8%, 13.6% and 7.1%, respectively). Those whose lives were characterized by high levels of family conflict and discrimination combined with low levels of social cohesion and neighborhood safety had the highest disorder prevalence (34.0%, 26.6% and 22.5%; all p < 0.01 compared to positive experiences subgroup). Latinxs with moderate levels of discrimination and conflict, along with those with high conflict and cohesion, were better off as compared to those with high negative experiences and low cohesion. These latent subgroups of Latinxs according to their acculturative experiences hold important implications for identifying high-risk groups for developing a psychiatric disorder. Findings also point to the protective role of family and neighborhood cohesion when facing high levels of adversity, which may inform prevention and intervention efforts.

A phase 1 dose escalation study of the pyruvate kinase activator mitapivat (AG-348) in sickle cell disease.

Polymerization of deoxygenated hemoglobin S underlies the pathophysiology of sickle cell disease (SCD). In activating red blood cell pyruvate kinase and glycolysis, mitapivat (AG-348) increases adenosine triphosphate (ATP) levels and decreases the 2,3-diphosphoglycerate (2,3-DPG) concentration, an upstream precursor in glycolysis. Both changes have therapeutic potential for patients with SCD. Here, we evaluated the safety and tolerability of multiple ascending doses of mitapivat in adults with SCD with no recent blood transfusions or changes in hydroxyurea or l-glutamine therapy. Seventeen subjects were enrolled; 1 subject was withdrawn shortly after starting the study. Sixteen subjects completed 3 ascending dose levels of mitapivat (5, 20, and 50 mg, twice daily [BID]) for 2 weeks each; following a protocol amendment, the dose was escalated to 100 mg BID in 9 subjects. Mitapivat was well tolerated at all dose levels, with the most common treatment-emergent adverse events (AEs) being insomnia, headache, and hypertension. Six serious AEs (SAEs) included 4 vaso-occlusive crises (VOCs), non-VOC-related shoulder pain, and a preexisting pulmonary embolism. Two VOCs occurred during drug taper and were possibly drug related; no other SAEs were drug related. Mean hemoglobin increase at the 50 mg BID dose level was 1.2 g/dL, with 9 of 16 (56.3%) patients achieving a hemoglobin response of a ≥1 g/dL increase compared with baseline. Mean reductions in hemolytic markers and dose-dependent decreases in 2,3-DPG and increases in ATP were also observed. This study provides proof of concept that mitapivat has disease-modifying potential in patients with SCD. This trial was registered at www.clinicaltrials.gov as #NCT04000165.

Mitapivat increases ATP and decreases oxidative stress and erythrocyte mitochondria retention in a SCD mouse model.

Polymerization of deoxygenated sickle hemoglobin (HbS) leads to erythrocyte sickling. Enhancing activity of the erythrocyte glycolytic pathway has anti-sickling potential as this reduces 2,3-diphosphoglycerate (2,3-DPG) and increases ATP, factors that decrease HbS polymerization and improve erythrocyte membrane integrity. These factors can be modulated by mitapivat, which activates erythrocyte pyruvate kinase (PKR) and improves sickling kinetics in SCD patients. We investigated mechanisms by which mitapivat may impact SCD by examining its effects in the Townes SCD mouse model. Control (HbAA) and sickle (HbSS) mice were treated with mitapivat or vehicle. Surprisingly, HbSS had higher PKR protein, higher ATP, and lower 2,3-DPG levels, compared to HbAA mice, in contrast with humans with SCD, in whom 2,3-DPG is elevated compared to healthy subjects. Despite our inability to investigate 2,3-DPG-mediated sickling and hemoglobin effects, mitapivat yielded potential benefits in HbSS mice. Mitapivat further increased ATP without significantly changing 2,3-DPG or hemoglobin levels, and decreased levels of leukocytosis, erythrocyte oxidative stress, and the percentage of erythrocytes that retained mitochondria in HbSS mice. These data suggest that, even though Townes HbSS mice have increased PKR activity, further activation of PKR with mitapivat yields potentially beneficial effects that are independent of changes in sickling or hemoglobin levels.

The association between traumatic life events and insomnia symptoms among men and women: Results from the Baltimore Epidemiologic Catchment Area follow-up study.

STUDY OBJECTIVES: Trauma exposure likely contributes to poor sleep, but relatively few studies have empirically tested this, instead focusing on posttraumatic stress disorder. Moreover, little is known about sex differences in sleep after trauma. The current study used a cross-sectional and retrospective design to test hypotheses that trauma exposure would be associated with subsequent insomnia symptoms, particularly among women, even after accounting for important covariates. METHOD: Data from Wave 3 (1993-1996) of the Baltimore Epidemiologic Catchment Area Study (N = 1920) were used to examine associations between remote (prior to past year) and recent (past year) trauma and current sleep disturbance (insomnia, hypersomnia symptoms) in the total sample (Mage= 55, 63.2% women, 57.7% white), and separately in men and women. Sensitivity analyses were conducted among individuals with no pretrauma sleep disturbance to examine incident sleep disturbance. RESULTS: Among all participants, both remote (odds ratio [OR] = 1.95, 95% confidence interval [CI] [1.34, 2.85]) and recent (OR = 1.94, 95% CI [1.31, 2.87]) trauma exposure were associated with increased odds of insomnia (OR = 2.41, 95% CI [1.54, 3.76]) but not hypersomnia. Associations between trauma and insomnia were particularly strong among women, but null among men. The relationship between trauma exposure and insomnia symptoms persisted among individuals with no pretrauma history of insomnia. CONCLUSION: Results suggest women may be vulnerable to insomnia symptoms as sequelae of trauma. Future research should examine prospective associations between trauma and sleep in larger samples and how assessment and treatment of insomnia among women trauma survivors reduces the public health impact of trauma and poor sleep.

The relationship between social and environmental factors and symptom severity in the seriously mentally ill population.

BACKGROUND: The goal of this article is to investigate the relationship of psychiatric symptom severity with internalised stigma, neighbourhood environment, and social support among individuals with serious mental illness. METHOD: Using a longitudinal study design we examined the relationship between psychiatric symptom severity with internalised stigma, neighbourhood environment, and social support among 271 adults with serious mental illness recruited from new admissions to two urban mental health clinics. RESULTS: After controlling for demographics increased stigma levels predicted greater symptom severity, as measured by the Positive and Negative Syndrome Scale (PANSS) Positive, Negative, and General Psychopathology scales over a 4-year period (p < .05). In adjusted models, individuals who reported living in more disadvantaged neighbourhoods also reported higher PANSS Negative and General scores over time (p < .05). Social support from friends and relatives was not significantly related to PANSS Positive, Negative, or General Psychopathology scores among individuals with serious mental illness. CONCLUSIONS: Individuals with serious mental illness who experience internalised stigma and neighbourhood disadvantage experience greater symptom severity over time. Targeting stigma and housing during treatment could potentially impact symptom severity in this population.

Impact of hemoglobin biophysical studies on molecular pathogenesis and drug therapy for sickle cell disease.

Basic research on hemoglobin has been essential for understanding the origin and treatment of many hematological disorders due to abnormal hemoglobins. The most important of the hemoglobinopathies is sickle cell disease - Linus Pauling's "molecular disease" that gave birth to molecular medicine. In this review, I will describe the contributions of basic biophysical research on normal and sickle cell hemoglobin (HbS) to understanding the molecular pathogenesis of the disease and providing the conceptual basis for the various approaches to drug therapy that target HbS polymerization. Most prominent among these are the experimental results on the solubility of HbS as a function of oxygen saturation explained by the allosteric model of Monod, Wyman, and Changeux and the Gill-Wyman thermodynamic linkage relation between solubility and oxygen binding, the solubility of mixtures of HbS with normal or fetal hemoglobin explained by Minton's thermodynamic model, and the highly unusual kinetics of HbS polymerization explained by a novel double nucleation mechanism that also accounts for the aggregation kinetics of the Alzheimer's peptide. The HbS polymerization kinetics are of great importance to understanding the pathophysiology and clinical course, as well as guiding drug development for treating this common and severe disease. The article focuses primarily on experimental and theoretical results from my lab, so it is not a comprehensive review of the subject.

Impact of Conformational Substates and Energy Landscapes on Understanding Hemoglobin Kinetics and Function.

Hans Frauenfelder's discovery of conformational substates in studies of myoglobin carbon monoxide geminate rebinding kinetics at cryogenic temperatures (Austin RH, Beeson KW, Eisenstein L, Frauenfelder H, & Gunsalus IC (1975) Dynamics of Ligand Binding to Myoglobin. Biochemistry 14(24):5355-5373) followed by his introduction of energy landscape theory with Peter Wolynes (Frauenfelder H, Sligar SG, & Wolynes PG (1991) The Energy Landscapes and Motions of Proteins. Science 254(5038):1598-1603) marked the beginning of a new era in the physics and physical chemistry of proteins. Their work played a major role in demonstrating the power and importance of dynamics and of Kramers reaction rate theory for understanding protein function. The biggest impact of energy landscape theory has been in the protein folding field, which is well-known and has been documented in numerous articles and reviews, including a recent one of my own (Eaton WA (2021) Modern Kinetics and Mechanism of Protein Folding: a Retrospective. J. Phys. Chem. B. 125(14):3452-3467). Here I will describe the much less well-known impact of their modern view of proteins on both experimental and theoretical studies of hemoglobin kinetics and function. I will first describe how Frauenfelder's experiments motivated and influenced my own research on myoglobin, which were key ingredients to my work on understanding hemoglobin.

Symptom Severity and Care Delay among Patients with Serious Mental Illness.

PURPOSE: This study investigated associations between psychiatric symptom severity and delay in seeking general medical services among individuals with serious mental illness. METHODS: The association of psychiatric symptom severity, measured by the Positive and Negative Syndrome Scale (PANSS), and general medical care delay was examined among 271 patients at two urban, outpatient psychiatric clinics. RESULTS: Higher scores for PANSS paranoid/belligerence were associated with delays in accessing general medical care (adjusted odds ratio [AOR]=1.46, 95% confidence interval [CI]=1.04-2.01, p=.025). Higher scores on the depression symptom cluster were also associated with care delay (AOR=1.43, 95% CI=1.06-1.93, p=.018). Other symptom types showed no associations with care delay. CONCLUSION: Severity of specific psychiatric symptoms was associated with delays in seeking general medical care among people with serious mental illness. Increased focus on psychiatric symptom management may reduce medical care delay, thereby reducing the elevated morbidity and mortality among this population.