Aaron D. Blackwell

Addressing Tri-Morbidity (Hepatitis C, Psychiatric Disorders, and Substance Use): The Importance of Routine Mental Health Screening as a Component of a Comanagement Model of Care

BACKGROUND Recent studies suggest that most patients with hepatitis C virus (HCV) infection commonly present to medical clinics with active psychiatric and substance use disorders. However, routine screening for these disorders is generally not done. OBJECTIVES The purpose of our study was to assess prospectively the frequency of psychiatric and substance use disorders in patients presenting for initial assessment of a positive HCV antibody test result. METHODS A sample of 293 patients represented the majority of patients scheduled for their initial hepatology clinic visit at the Portland Veterans Affairs Medical Center between September 2002 and September 2003. The patient screening questionnaire, Alcohol Use Disorders Identification Test-Consumption (AUDIT-C), and the Beck Depression Inventory (BDI-II) were administered to all patients. RESULTS At screening, 93% of the patients had a current or past history of at least 1 psychiatric disorder, and 73% had >or=2 disorders. The most common disorders included depression (81%), posttraumatic stress disorder (62%), any substance use disorder (58%), bipolar disorder (20%), and other psychotic disorders (17%). One hundred two patients (35%) had baseline BDI-II scores in the moderate-to-severe range of depression (>19), and 61 (21%) had AUDIT-C scores indicating current heavy alcohol use (>or=4). CONCLUSIONS Psychiatric and substance use disorders are highly prevalent among veterans with chronic hepatitis C. Thirty-five percent have significant symptoms of depression before the initiation of treatment with interferon (IFN). Routine screening for underlying psychiatric and substance use disorders and early treatment intervention before initiating antiviral therapy is essential to prevent worsening of depression and to optimize the outcome of treatment with IFN. Comanagement treatment models involving mental health care may expand the pool of patients eligible to receive treatment with IFN, as well as enhance treatment outcomes.

Does Blood Pressure Inevitably Rise With Age?: Longitudinal Evidence Among Forager-Horticulturalists

The rise in blood pressure with age is a major risk factor for cardiovascular and renal disease, stroke, and type 2 diabetes mellitus. Age-related increases in blood pressure have been observed in almost every population, except among hunter-gatherers, farmers, and pastoralists. Here we tested for age-related increases in blood pressure among Tsimane forager-farmers. We also test whether lifestyle changes associated with modernization lead to higher blood pressure and a greater rate of age-related increase in blood pressure. We measured blood pressure longitudinally on 2248 adults age ≥20 years (n=6468 observations over 8 years). Prevalence of hypertension was 3.9% for women and 5.2% for men, although diagnosis of persistent hypertension based on multiple observations reduced prevalence to 2.9% for both sexes. Mixed-effects models revealed systolic, diastolic, and pulse blood pressure increases of 2.86 (P<0.001), 0.95 (P<0.001), and 1.95 mmHg (P<0.001) per decade for women and 0.91 (P<0.001), 0.93 (P<0.001), and −0.02 mmHg (P=0.93) for men, substantially lower than rates found elsewhere. Lifestyle factors, such as smoking and Spanish fluency, had minimal effect on mean blood pressure and no effect on age-related increases in blood pressure. Greater town proximity was associated with a lower age-related increase in pulse pressure. Effects of modernization were, therefore, deemed minimal among Tsimane, in light of their lean physique, active lifestyle, and protective diet.The rise in blood pressure with age is a major risk factor for cardiovascular and renal disease, stroke, and type 2 diabetes mellitus. Age-related increases in blood pressure have been observed in almost every population, except among hunter-gatherers, farmers, and pastoralists. Here we tested for age-related increases in blood pressure among Tsimane forager-farmers. We also test whether lifestyle changes associated with modernization lead to higher blood pressure and a greater rate of age-related increase in blood pressure. We measured blood pressure longitudinally on 2248 adults age ≥20 years (n=6468 observations over 8 years). Prevalence of hypertension was 3.9% for women and 5.2% for men, although diagnosis of persistent hypertension based on multiple observations reduced prevalence to 2.9% for both sexes. Mixed-effects models revealed systolic, diastolic, and pulse blood pressure increases of 2.86 ( P <0.001), 0.95 ( P <0.001), and 1.95 mmHg ( P <0.001) per decade for women and 0.91 ( P <0.001), 0.93 ( P <0.001), and −0.02 mmHg ( P =0.93) for men, substantially lower than rates found elsewhere. Lifestyle factors, such as smoking and Spanish fluency, had minimal effect on mean blood pressure and no effect on age-related increases in blood pressure. Greater town proximity was associated with a lower age-related increase in pulse pressure. Effects of modernization were, therefore, deemed minimal among Tsimane, in light of their lean physique, active lifestyle, and protective diet. # Novelty and Significance {#article-title-30}

Life History, Immune Function, and Intestinal Helminths: Trade-Offs Among Immunoglobulin E, C-Reactive Protein, and Growth in an Amazonian Population

Objectives. Infection with helminths is associated with shifts in host immunity, including increased production of immunoglobulin E (IgE) and reduced inflammation. Given limited energy budgets, these shifts may involve changes in energy allocation toward competing demands. Here we test for potential trade‐offs between growth, IgE, and the inflammatory marker C‐reactive protein (CRP).

Association of human transferrin receptor with GABARAP

A yeast two‐hybrid screen identified a specific interaction between the cytoplasmic domain of transferrin receptor (TfR) and GABARAP, a 14 kDa protein that binds to the γ2 subunit of neuronal GABAA receptors. The specificity of the TfR–GABARAP interaction was demonstrated by in vitro binding assays with purified proteins and by co‐immunoprecipitation of GABARAP with endogenous TfR from HeLa cell lysates. Replacement of the YTRF internalization motif with ATRA within the cytoplasmic domain of TfR reduced interaction with GABARAP in the yeast two‐hybrid screen and in vitro binding assays. The intracellular location of GABARAP using chimeric GABARAP–GFP showed that the majority of GABARAP was located in perinuclear vesicles. Our results show that GABARAP plays a more general role outside the confines of neuronal cells and GABAA receptors.

Evidence for a peak shift in a humoral response to helminths: age profiles of IgE in the Shuar of Ecuador, the Tsimane of Bolivia, and the U.S. NHANES.

Background The peak shift model predicts that the age-profile of a pathogens prevalence depends upon its transmission rate, peaking earlier in populations with higher transmission and declining as partial immunity is acquired. Helminth infections are associated with increased immunoglobulin E (IgE), which may convey partial immunity and influence the peak shift. Although studies have noted peak shifts in helminths, corresponding peak shifts in total IgE have not been investigated, nor has the age-patterning been carefully examined across populations. We test for differences in the age-patterning of IgE between two South American forager-horticulturalist populations and the United States: the Tsimane of Bolivia (n = 832), the Shuar of Ecuador (n = 289), and the U.S. NHANES (n = 8,336). We then examine the relationship between total IgE and helminth prevalences in the Tsimane. Methodology/Principal Findings Total IgE levels were assessed in serum and dried blood spots and age-patterns examined with non-linear regression models. Tsimane had the highest IgE (geometric mean  = 8,182 IU/ml), followed by Shuar (1,252 IU/ml), and NHANES (52 IU/ml). Consistent with predictions, higher population IgE was associated with steeper increases at early ages and earlier peaks: Tsimane IgE peaked at 7 years, Shuar at 10 years, and NHANES at 17 years. For Tsimane, the age-pattern was compared with fecal helminth prevalences. Overall, 57% had detectable eggs or larva, with hookworm (45.4%) and Ascaris lumbricoides (19.9%) the most prevalent. The peak in total IgE occurred around the peak in A. lumbricoides, which was associated with higher IgE in children <10, but with lower IgE in adolescents. Conclusions The age-patterning suggests a peak shift in total IgE similar to that seen in helminth infections, particularly A. lumbricoides. This age-patterning may have implications for understanding the effects of helminths on other health outcomes, such as allergy, growth, and response to childhood vaccination.

Growth and Market Integration in Amazonia: A Comparison of Growth Indicators Between Shuar, Shiwiar, and Nonindigenous School Children

We describe and compare the growth of three groups of juveniles, aged 0–18, who experience different degrees of market integration and acculturation in the Ecuadorian Amazon. These include 1,384 indigenous Shuar from the Upano Valley of Ecuador and surrounding areas, 570 nonindigenous colono (or colonist) children from the same area, and 42 Shiwiar from the interior of Ecuador. We use differences between these populations in National Health and Nutrition Examination Survey (NHANES) z‐scores to assess the effects of changing subsistence patterns on Shuar growth and nutrition. Although, for all three groups, mean height‐for‐age z‐scores were negative, Shuar z‐scores were significantly lower than either colono or Shiwiar z‐scores. Mean weight‐for‐age z‐scores were also negative for Shuar and colono juveniles, while mean BMI‐for‐age and weight‐for‐height z‐scores were greater than zero for all three groups. Using NHANES standards, 41% of male and 38% of female Shuar were classified as stunted, versus 16% of male and 20% of female colonos. Compared to Shuar, colonos were three times less likely to be stunted (OR = 0.33, P < 0.01) and Shiwiar were eight times less likely to be stunted (OR = 0.13, P = 0.01). These differences suggest that changes in diet have negatively affected Shuar growth and nutrition. Am. J. Hum. Biol, 2009.

Antagonism between two intestinal parasites in humans: the importance of co-infection for infection risk and recovery dynamics

Co-infection may affect transmission and recovery from infection, but remains an understudied element of disease ecology, particularly with regard to antagonism between parasites sharing a host. Helminth and giardia infections are often endemic in the same populations and both occupy the small intestine; yet few studies have examined interactions between these parasites. We report on helminth–giardia co-infections in a panel study of forager–horticulturalists in the Bolivian lowlands. Parasites were identified in faecal samples from 3275 participants, collected during 5235 medical exams over 6 years. Longitudinal co-infection patterns were examined using logistic mixed and multi-state Markov models. The most prevalent infections were hookworm (56%), Giardia lamblia (30%) and Ascaris lumbricoides (15%). Cross-sectionally, hookworm and A. lumbricoides were negatively associated with G. lamblia (OR = 0.60; OR = 0.65, respectively). Longitudinally, giardia infection was less likely in helminth-infected individuals (HR: 0.46). Infection with helminths was also less likely for individuals infected with giardia (HR: 0.71). Finally, treatment with mebendazole reduced subsequent hookworm infections, but resulted in a marginal increase in the odds of G. lamblia infection. Our results provide evidence for an antagonistic relationship between helminths and giardia, and suggest that co-infection should be considered in disease transmission models and treatment decisions.

Hepatitis C testing and infection rates in bipolar patients with and without comorbid substance use disorders

OBJECTIVES To determine and compare hepatitis C (HCV) screening and testing rates among four groups: those with (i) bipolar disorder [BD group (history of BD but no substance use disorder)]; (ii) substance use disorders [SUD group (history of SUD but no BD)]; (iii) co-occurring disorders [DD group (history of both BD and an SUD)]; and (iv) a control group (no history of either bipolar disorder or substance use disorder). Our hypothesis was that HCV antibody testing rates and HCV prevalence would be higher in the BD, SUD, and DD groups than the control group. METHODS Data were retrospectively collected on 325,410 patients seen between 1998 and 2004 within facilities and clinics of the Veterans Integrated Service Network (VISN) 20 Northwest Veterans Health Care Administration from electronic medical records. HCV screening and prevalence rates were compared between the BD, SUD, DD, and control groups. Odds ratios and relative risks were determined and compared between groups. RESULTS Patients in the BD, SUD, and DD groups had been tested at a higher rate than controls and were at increased risk for HCV infection compared with controls. These high-risk groups had a 1.31-fold, 4.86-fold, and 5.46-fold increase in the relative risk of HCV infection, respectively. Overall, compared to the control group, the relative risk of a patient having HCV if he or she had BD (with or without an SUD) was 3.6. CONCLUSIONS Patients with BD and comorbid SUD had an over fourfold increase in relative risk for HCV than our control group and a similar risk as patients in our SUD group. Furthermore, even if bipolar patients did not have a comorbid SUD (the BD group), their relative risk of HCV was significantly higher than that of the control group. This suggests that patients with BD, particularly those with a comorbid SUD, should be screened and tested for HCV.

Integrated hepatitis C virus treatment : addressing comorbid substance use disorders and HIV infection

Objectives:To examine hepatitis C virus (HCV) and HIV testing patterns within the Northwest Veterans Integrated Service Network (VISN 20). Methods:Using a comprehensive VISN 20 database, we retrospectively reviewed medical records of 293 445 veterans. Results:32.8% of patients were tested for HCV, 5.5% were tested for HIV, and 4.3% were co-tested. Of those tested, 12.3% were HCV positive, 5.4% were HIV positive, and 1.6% were co-infected. 79.1% of HIV-positive patients were tested for HCV, 29.2% of whom tested positive. 34.8% of HCV-positive patients were tested for HIV, 4.9% of whom tested positive. Of those tested, HCV-positive patients were significantly more likely than HCV-negative patients to test positive for HIV; HIV-positive patients were no more likely to test positive for HCV than HIV-negative patients. HIV-positive patients with substance use disorders (SUD) were significantly more likely to test HCV positive than those without. Within the total sample, veterans with SUD were significantly more likely to be tested for both diseases and to test positive for HCV but not HIV. After controlling for other categories of SUD, veterans with a history of cocaine abuse compared with those without were at an increased risk of HIV infection and co-infection. Conclusion:79.1% of HIV-positive but only 34.8% of HCV-positive veterans were co-tested, suggesting barriers to HIV testing may exist in VISN 20. Results also indicate that HCV-positive patients are at increased risk for HIV infection and that HIV-positive patients with SUD are at increased risk of HCV infection; routine co-testing for these patients is therefore warranted. Given significant co-infection rates, HCV and HIV screening and testing should be increasingly integrated. Increased infection rates among patients with SUD also warrant integration of HCV and HIV screening and testing into mental health and addiction programmes.

Implications of market integration for cardiovascular and metabolic health among an indigenous Amazonian Ecuadorian population

Background: Market integration (MI), the suite of social and cultural changes that occur with economic development, has been associated with negative health outcomes such as cardiovascular disease; however, key questions remain about how this transition manifests at the local level. Aim: The present paper investigates the effects of MI on health among Shuar, an indigenous lowland Ecuadorian population, with the goal of better understanding the mechanisms responsible for this health transition. Subjects and methods: This study examines associations between measures of MI and several dimensions of cardiovascular and metabolic health (fasting glucose, lipids [LDL, HDL and total cholesterol; triglycerides] and blood pressure) among 348 adults. Results: Overall, Shuar males and females have relatively favourable cardiovascular and metabolic health. Shuar who live closer to town have higher total (p < 0.001) and HDL cholesterol (p < 0.001), while Shuar in more remote regions have higher diastolic blood pressure (p = 0.007). HDL cholesterol is positively associated with consumption of market foods (r = 0.140; p = 0.045) and ownership of consumer products (r = 0.184; p = 0.029). Conclusions: This study provides evidence that MI among Shuar is not a uniformly negative process but instead produces complex cardiovascular and metabolic health outcomes.