Methemoglobinemia in the Era of COVID-19: A Potential Confounder of Glycemic Control.

Glycated hemoglobin A1c (HbA1c) is frequently used as a measure of glycemic control but can be inaccurate in certain clinical scenarios leading to poor estimates of insulin requirements. We present the case of a 76-year-old man with diabetes and COVID infection. HbA1c was measured at 5.7%, though the patient reported home glucose readings of 200 to 300 mg/dL (11.1-16.65 mmol/L). Pulse oximetry on presentation was 50% to 60%, which initially improved to 93% with supplemental oxygen of 15 L via nonrebreather face mask. Treatment with remdesivir and dexamethasone was initiated, but the patient was again found to have low oxygen saturations requiring bilevel positive airway pressure and transfer to the intensive care unit. The patient was started on 1.1 U/kg of insulin daily in a basal-bolus regimen. The patient developed severe hyperglycemia requiring 2.4 U/kg to achieve glycemic control. Co-oximeter analysis of an arterial blood gas sample revealed methemoglobinemia. Exchange transfusion was performed with clinical improvement. Subsequent measurement of fructosamine was 360 umol/L (360 000 µmol/L), correlating with reported home glucose measurements. Methemoglobinemia may impair glycation of hemoglobin or interfere with measurement of HbA1c, thereby compromising the use of this molecule as a marker for glycemic control in patients with this condition.

Diabetes-Related Quality of Life: Learning From Individuals Making Lifestyle Changes to Improve Type 2 Diabetes Control.

PURPOSE: The purpose of this study was to explore how treatment adherence and lifestyle changes required for glycemic control in type 2 diabetes (T2D) are related to quality of life (QoL) among predominantly ethnic minority and socioeconomically disadvantaged adults engaged in making changes to improve T2D self-management. METHODS: Adults with T2D in New York City were recruited for the parent study based on recent A1C (≥7.5%) and randomly assigned to 1 of 2 arms, receiving educational materials and additional self-management support calls, respectively. Substudy participants were recruited from both arms after study completion. Participants (N = 50; 62% Spanish speaking) were interviewed by phone using a semistructured guide and were asked to define QoL and share ways that T2D, treatment, self-management, and study participation influenced their QoL. Interviews were analyzed using thematic analysis. RESULTS: QoL was described as a multidimensional health-related construct with detracting and enhancing factors related to T2D. Detracting factors included financial strain, symptom progression and burden, perceived necessity to change cultural and lifestyle traditions, and dietary and medical limitations. Enhancing factors included social support, diabetes education, health behavior change, sociocultural connection. CONCLUSION: QoL for diverse and socioeconomically disadvantaged adults with T2D is multifaceted and includes aspects of health, independence, social support, culture, and lifestyle, which may not be captured by existing QoL measures. Findings may inform the development of a novel QoL measure for T2D.

Design and methods of NYC care calls: An effectiveness trial of telephone-delivered type 2 diabetes self-management support.

Although problems with type 2 diabetes (T2D) self-management and treatment adherence often co-occur with emotional distress, few translatable intervention approaches are available that can target these related problems in primary care practice settings. The New York City (NYC) Care Calls study is a randomized controlled trial that tests the effectiveness of structured support for diabetes self-management and distress management, delivered via telephone by health educators, in improving glycemic control, self-management and emotional well-being among predominantly ethnic minority and socioeconomically disadvantaged adults with suboptimally controlled T2D. English- and Spanish-speaking adults treated for T2D in NYC primary care practices were recruited based on having an A1C ≥ 7.5% despite being prescribed medications for diabetes. Participants (N = 812) were randomly assigned to a telephonic intervention condition with a stepped protocol of 6-12 phone calls over 1 year, delivered by a health educator, or to a comparison condition of enhanced usual care. The primary outcome is change in A1C over one year, measured at baseline and again approximately 6- and 12-months later. Secondary outcomes measured on the same schedule include blood pressure, patient-reported emotional distress, treatment adherence and self-management behaviors. A comprehensive effectiveness evaluation is guided by the RE-AIM framework (Reach, Effectiveness, Adoption, Implementation, Maintenance) to gather data that can inform dissemination and implementation of the intervention, if successful. This paper describes the study rationale, trial design, and methodology.

Glycosylated hemoglobin, but not advanced glycation end products, predicts severity of coronary artery disease in patients with or without diabetes.

BACKGROUND: The association between coronary artery disease (CAD) and diabetes mellitus (DM) is strong but the physiologic mechanisms responsible for this association remain unclear. Patients with DM exhibit high circulating levels of glycated proteins and lipoproteins called advanced glycation end products (AGEs) which have been implicated in the development of oxidative damage to vascular endothelium. We examined the relationships between the presence and extent of CAD and AGEs in patients undergoing elective coronary artery catheterization in an urban teaching hospital. METHODS: Patients with possible CAD (n = 364) were recruited prior to elective cardiac catheterization (52% male, 48% diabetic). Regression and correlation analyses were used to examine the relationship between serum AGE concentrations, soluble AGE receptor (sRAGE) concentration, HbA1c, LDL and the presence of obstructive CAD along with the burden of CAD measured by SYNTAX and SYNTAX II scores. RESULTS: AGE and sRAGE levels did not significantly correlate with any of the studied coronary artery disease parameters. HbA1c showed positive correlation with both SYNTAX and SYNTAX II scores in patients with and without diabetes. CONCLUSION: In this cross-sectional study of patients with possible CAD, serum AGEs and sRAGE concentrations did not correlate with SYNTAX or SYNTAX II scores regardless of diabetic status. HbA1C correlated positively with the SYNTAX and SYNTAX II scores in both diabetic and non-diabetic populations.

Randomized trial of a hospice video educational tool for patients with advanced cancer and their caregivers.

BACKGROUND: Patients with advanced cancer and their caregivers have substantial misperceptions regarding hospice, which contributes to its underuse. METHODS: The authors conducted a single-site randomized trial of a video educational tool versus a verbal description of hospice in 150 hospitalized patients with advanced cancer and their caregivers. Patients without a caregiver were eligible. Intervention participants (75 patients and 18 caregivers) viewed a 6-minute video depicting hospice. Control participants (75 patients and 26 caregivers) received a verbal description identical to the video narrative. The primary outcome was patient preference for hospice. Secondary outcomes included patient and/or caregiver knowledge and perceptions of hospice, and hospice use. RESULTS: Between February 2017 and January 2019, approximately 55.7% of eligible patients (150 of 269 eligible patients) and 44 caregivers were enrolled. After the intervention, there was no difference noted with regard to patients' preferences for hospice (86.7% vs 82.7%; P = .651). Patients in the video group reported greater knowledge regarding hospice (9.0 vs 8.4; P = .049) and were less likely to endorse that hospice is only about death (6.7% vs 21.6%; P = .010). Among deceased patients, those assigned to the intervention were more likely to have used hospice (85.2% vs 63.6%; P = .01) and to have had a longer hospice length of stay (median, 12 days vs 3 days; P < .001). After the intervention, caregivers assigned to view the video were more likely to prefer hospice for their loved ones (94.4% vs 65.4%; P = .031), reported greater knowledge concerning hospice (9.7% vs 8.0%; P = .001), and were less likely to endorse that hospice is only about death (0.0% vs 23.1%; P = .066). CONCLUSIONS: A hospice video did not significantly impact patients' preferences for hospice care. Patients with advanced cancer and their caregivers who were assigned to view the video were more informed regarding hospice and reported more favorable perceptions of hospice. Patients were more likely to use hospice and to have a longer hospice length of stay.

Coping and Modifiable Psychosocial Factors are Associated with Mood and Quality of Life in Patients with Chronic Graft-versus-Host Disease.

Chronic graft-versus-host disease (GVHD) is one of most common complications following allogeneic hematopoietic cell transplantation (HCT) and the most significant contributor to morbidity and nonrelapse mortality. The physical burdens and psychosocial difficulties of these patients have not been described systematically. An exploration into the rates and correlates of mood and quality of life (QOL) in patients with chronic GVHD is necessary to develop a clinically relevant, evidence-based intervention to promote well-being. From July 2015 to July 2017, adult allogeneic HCT survivors with established moderate to severe chronic GVHD (N = 52) enrolled in a prospective, longitudinal study at a tertiary academic center. We examined the rates and correlates of depression and anxiety symptoms (Hospital Anxiety and Depression Scale) and explored whether constructs including coping strategies (Coping Inventory for Stressful Situations), symptom burden (Lee Symptom Assessment Scale), physical functioning (Human Activity Profile), and perceived social support (Medical Outcomes Study Social Support Survey) predicted QOL trajectory over time (Functional Assessment of Cancer Therapy-Bone Marrow Transplant) at the baseline, 3-month, and 6-month follow-up. Analyses adjusted for age, sex, chronic GVHD severity, and time since chronic GVHD diagnosis. At the baseline, 3-month, and 6-month follow-up, 32.7%, 31.1%, and 37.8% of patients reported clinically significant depression symptoms, and 30.8%, 20.0%, and 36.4% reported clinically elevated anxiety symptoms, respectively. Adjusting for covariates, greater use of negative emotion-oriented coping (ß = 0.20, P = .002), less use of task-oriented coping (ß = -0.10, P = .021), worse physical functioning (ß = -0.07, P = .004), and higher symptom burden (ß = 0.07, P = .002) were independently associated with depression symptoms at baseline. Greater use of negative emotion-oriented coping (ß = 0.28, P < .001) and worse physical functioning (ß = -0.05, P = .034) were independently associated with anxiety at baseline. Patients who used more negative emotion-oriented coping (ß = -0.58, P = .035), had less task-oriented (ß = 0.40, P = .028) and social diversion-oriented coping (ß = 0.35, P = .039), and had higher symptom burden (ß = -0.30, P = .001), worse physical functioning (ß = 0.32, P < .001), and lower perceived social support (ß = 6.47, P = .003) at baseline reported poorer QOL over time. The unmet physical and psychosocial needs of patients with chronic GVHD are substantial and warrant investigation into evidence-based interventions that may improve QOL and mood by targeting modifiable psychosocial constructs identified in this study.

The role of advanced glycation end-products in the development of coronary artery disease in patients with and without diabetes mellitus: a review.

BACKGROUND: Traditional risk factors are insufficient to explain all cases of coronary artery disease (CAD) in patients with diabetes mellitus (DM). Advanced glycation end-products (AGEs) and their receptors may play important roles in the development and progression of CAD. BODY: Hyperglycemia is the hallmark feature of DM. An increase in the incidence of both micro-and macrovascular complications of diabetes has been observed with increased duration of hyperglycemia. This association persists even after glycemic control has been achieved, suggesting an innate mechanism of "metabolic memory." AGEs are glycated proteins that may serve as mediators of metabolic memory due to their increased production in the setting of hyperglycemia and generally slow turnover. Elevated AGE levels can lead to abnormal cross linking of extracellular and intracellular proteins disrupting their normal structure and function. Furthermore, activation of AGE receptors can induce complex signaling pathways leading to increased inflammation, oxidative stress, enhanced calcium deposition, and increased vascular smooth muscle apoptosis, contributing to the development of atherosclerosis. Through these mechanisms, AGEs may be important mediators of the development of CAD. However, clinical studies regarding the role of AGEs and their receptors in advancing CAD are limited, with contradictory results. CONCLUSION: AGEs and their receptors may be useful biomarkers for the presence and severity of CAD. Further studies are needed to evaluate the utility of circulating and tissue AGE levels in identifying asymptomatic patients at risk for CAD or to identify patients who may benefit from invasive intervention.

Pilot study of a multimodal intervention to enhance sexual function in survivors of hematopoietic stem cell transplantation.

BACKGROUND: Although sexual dysfunction is common after hematopoietic stem cell transplantation (HCT), interventions to address sexual function are lacking. METHODS: We conducted a pilot study to assess the feasibility and preliminary efficacy of a multimodal intervention to address sexual dysfunction in allogeneic HCT survivors. Transplant clinicians screened HCT survivors ≥3 months post-HCT for sexual dysfunction causing distress. Those who screened positive attended monthly visits with a trained transplant clinician who: 1) performed an assessment of the causes of sexual dysfunction; 2) educated and empowered the patient to address his or her sexual concerns; and 3) implemented therapeutic interventions targeting the patient's needs. Feasibility was defined as having approximately 75% of patients who screened positive agreeing to participate and 80% attending at least 2 intervention visits. We administered the Patient-Reported Outcomes Measurement Information System (PROMIS) sexual function and satisfaction measure, the Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT), and the Hospital Anxiety and Depression Scale (HADS) to evaluate sexual function, quality of life (QOL), and mood, respectively, at baseline and 6 months postintervention. RESULTS: Approximately 33.1% of patients (50 of 151 patients) screened positive for sexual dysfunction causing distress and 94.0% (47 of 50 patients) agreed to participate, with 100% attending 2 intervention visits. Participants reported improvements in satisfaction (P<.0001) and interest in sex (P<.0001), as well as orgasm (P<.0001), erectile function (P<.0001), vaginal lubrication (P = .0001), and vaginal discomfort (P = .0005). At baseline, approximately 32.6% of participants were not sexually active, compared with 6.5% after the intervention (P = .0005). Participants reported improvement in their QOL (P<.0001), depression (P = .0002), and anxiety (P = .0019). CONCLUSIONS: A multimodal intervention to address sexual dysfunction integrated within the transplant clinic is feasible with encouraging preliminary efficacy for improving sexual function, QOL, and mood in HCT survivors. Cancer 2018;124:2438-46. © 2018 American Cancer Society.

Effect of Inpatient Palliative Care During Hematopoietic Stem-Cell Transplant on Psychological Distress 6 Months After Transplant: Results of a Randomized Clinical Trial.

Purpose Inpatient palliative care integrated with transplant care improves patients' quality of life (QOL) and symptom burden during hematopoietic stem-cell transplant (HCT). We assessed patients' mood, post-traumatic stress disorder (PTSD) symptoms, and QOL 6 months post-transplant. Methods We randomly assigned 160 patients with hematologic malignancies who underwent autologous or allogeneic HCT to inpatient palliative care integrated with transplant care (n = 81) or transplant care alone (n = 79). At baseline and 6 months post-transplant, we assessed mood, PTSD symptoms, and QOL with the Hospital Anxiety and Depression Scale and Patient Health Questionnaire, PTSD checklist, and Functional Assessment of Cancer Therapy-Bone Marrow Transplant. To assess symptom burden during HCT, we used the Edmonton Symptom Assessment Scale. We used analysis of covariance while controlling for baseline values to examine intervention effects and conducted causal mediation analyses to examine whether symptom burden or mood during HCT mediated the effect of the intervention on 6-month outcomes. Results We enrolled 160 (86%) of 186 potentially eligible patients between August 2014 and January 2016. At 6 months post-transplant, intervention participants reported lower depression symptoms on the Hospital Anxiety and Depression Scale and Patient Health Questionnaire (adjusted mean difference, -1.21 [95% CI, -2.26 to -0.16; P = .024] and -1.63 [95% CI, -3.08 to -0.19; P = .027], respectively) and lower PTSD symptoms (adjusted mean difference, -4.02; 95% CI, -7.18 to -0.86; P = .013), but no difference in QOL or anxiety. Symptom burden and anxiety during HCT hospitalization partially mediated the effect of the intervention on depression and PTSD at 6 months post-transplant. Conclusion Inpatient palliative care integrated with transplant care leads to improvements in depression and PTSD symptoms at 6 months post-transplant. Reduction in symptom burden and anxiety during HCT partially accounts for the effect of the intervention on these outcomes.

Effects of Early Integrated Palliative Care on Caregivers of Patients with Lung and Gastrointestinal Cancer: A Randomized Clinical Trial.

BACKGROUND: The family and friends (caregivers) of patients with advanced cancer often experience tremendous distress. Although early integrated palliative care (PC) has been shown to improve patient-reported quality of life (QOL) and mood, its effects on caregivers' outcomes is currently unknown. MATERIALS AND METHODS: We conducted a randomized trial of early PC integrated with oncology care versus oncology care alone for patients who were newly diagnosed with incurable lung and noncolorectal gastrointestinal cancers and their caregivers. The early PC intervention focused on addressing the needs of both patients and their caregivers. Eligible caregivers were family or friends who would likely accompany patients to clinic visits. The intervention entailed at least monthly patient visits with PC from the time of diagnosis. Caregivers were encouraged, but not required, to attend the palliative care visits. We used the Hospital Anxiety and Depression Scale (HADS) and Medical Health Outcomes Survey Short-Form to assess caregiver mood and QOL. RESULTS: Two hundred seventy-five caregivers (intervention n = 137; control n = 138) of the 350 patients participated. The intervention led to improvement in caregivers' total distress (HADS-total adjusted mean difference = -1.45, 95% confidence interval [CI] -2.76 to -0.15, p = .029), depression subscale (HADS-depression adjusted mean difference = -0.71, 95% CI -1.38 to -0.05, p = .036), but not anxiety subscale or QOL at week 12. There were no differences in caregivers' outcomes at week 24. A terminal decline analysis showed significant intervention effects on caregivers' total distress (HADS-total), with effects on both the anxiety and depression subscales at 3 and 6 months before patient death. CONCLUSION: Early involvement of PC for patients with newly diagnosed lung and gastrointestinal cancers leads to improvement in caregivers' psychological symptoms. This work demonstrates that the benefits of early, integrated PC models in oncology care extend beyond patient outcomes and positively impact the experience of caregivers. IMPLICATIONS FOR PRACTICE: Early involvement of palliative care for patients with newly diagnosed lung and gastrointestinal cancers leads to improvement in caregivers' psychological symptoms. The findings of this trial demonstrate that the benefits of the early, integrated palliative care model in oncology care extend beyond patient outcomes and positively impact the experience of caregivers. These findings contribute novel data to the growing evidence base supporting the benefits of integrating palliative care earlier in the course of disease for patients with advanced cancer and their caregivers.

Evaluation of hepatitis C virus as a risk factor for HIV-associated neuroretinal disorder.

BACKGROUND: Both hepatitis C virus (HCV) and human immunodeficiency virus (HIV) penetrate the central nervous system. HIV-associated neuroretinal disorder (HIV-NRD), a visual impairment of reduced contrast sensitivity and reading ability, is associated with cytokine dysregulation and genetic polymorphisms in the anti-inflammatory interleukin 10 (IL-10) signaling pathway. We investigated associations between HCV and HIV-NRD and between HCV and single-nucleotide polymorphisms (SNPs) in the IL-10 receptor 1 (IL10R1) gene. METHODS: Logistic and Cox regression analysis were used to analyze risk factors for HIV-NRD in 1576 HIV-positive patients who did not have an ocular opportunistic infection at enrollment. Median follow-up was 4.9 years (interquartile range, 2.4-8.8 years). Four IL10R1 SNPs were examined in a subset of 902 patients. RESULTS: The group included 290 patients with chronic HCV infection, 74 with prior infection, and 1212 with no HCV markers. There were 244 prevalent cases of HIV-NRD and 263 incident cases (rate = 3.9/100 person-years). In models adjusted for demographics, HIV treatment and status, liver function, and immune status, both the prevalence and incidence of HIV-NRD were significantly higher in patients with chronic HCV infection (odds ratio = 1.54; 95% confidence interval [CI], 1.03-2.31 and hazard ratio = 1.62; 95% CI, 1.13-2.34, respectively), compared to patients with no HCV markers. Chronic HCV was associated with rs2228055 and 2 additional IL-10R1 SNPs expected to reduce IL-10 signaling. HIV-NRD was not significantly associated with these SNPs. CONCLUSIONS: HCV is a possible risk factor for HIV-NRD. Genetic analysis suggests that alterations in the IL-10 signaling pathway may increase susceptibility to HIV-NRD and HCV infection. Inflammation may link HCV and HIV-NRD.

Short communication: Inadequate vitamin D exacerbates parathyroid hormone elevations in tenofovir users.

Parathyroid hormone (PTH) elevations are associated with reduced bone mineral density and adverse health outcomes and have been reported in patients with HIV infection. We aimed to examine the impact of vitamin D status and tenofovir (TDF) use on PTH levels among HIV-infected patients receiving combination antiretroviral therapy (cART). Demographics, medication and supplement use, and clinical data, including 25-hydroxyvitamin D [25(OH)D] and PTH, were collected on 45 HIV-infected men on ART. Suboptimal vitamin D status was defined as 25(OH)D < 30 ng/ml. The relationship between antiretroviral agents, suboptimal 25(OH)D, and PTH levels was examined. Among subjects with suboptimal vitamin D status, PTH values greater than or equal to the ULN (87 pg/ml) were more common among TDF users than nonusers: 41% versus 0% (p = 0.018); and median PTH was higher in TDF users: 80 pg/ml versus 55 pg/ml (p = 0.02). Among TDF users, PTH was higher in the group with suboptimal 25(OH)D (p = 0.045). Multivariable linear regression showed that PTH was independently and directly related to TDF use (p = 0.017) and inversely related to 25(OH)D (p = 0.017). PTH was not related to the estimated glomerular filtration rate (p = 0.9). In this cross-sectional study of HIV-infected men on ART, the use of TDF and the level of 25(OH)D were independently associated with PTH levels. Because TDF is a potent and widely used antiretroviral drug, information about cofactors that may exacerbate its side effects is of significant clinical value.

The quasispecies nature and biological implications of the hepatitis C virus.

Many RNA viruses exist as a cloud of closely related sequence variants called a quasispecies, rather than as a population of identical clones. In this article, we explain the quasispecies nature of RNA viral genomes, and briefly review the principles of quasispecies dynamics and the differences with classical population genetics. We then discuss the current methods for quasispecies analysis and conclude with the biological implications of this phenomenon, focusing on the hepatitis C virus.

Mutations in the hepatitis C virus core gene are associated with advanced liver disease and hepatocellular carcinoma.

PURPOSE: Hepatitis C virus (HCV) infection can promote the development of hepatocellular carcinoma (HCC). Published data implicate the HCV core gene in oncogenesis. We tested the hypothesis that core gene sequences from HCC patients differ from those of patients without cirrhosis/HCC. EXPERIMENTAL DESIGN: Full-length HCV sequences from HCC patients and controls were obtained from the investigators and GenBank and compared with each other. A logistic regression model was developed to predict the HCC risk of individual point mutations and other sequence features. Mutations in partial sequences (bases 36-288) from HCC patients and controls were also analyzed. The first base of the AUG start codon was designated position 1. RESULTS: A logistic regression model developed through analysis of full-length core gene sequences identified seven polymorphisms significantly associated with increased HCC risk (36G/C, 209A, 271U/C, 309A/C, 435A/C, 481A, and 546A/C) and an interaction term (for 209A-271U/C) that had an odds ratio <1.0. Three of these polymorphisms could be analyzed in the partial sequences. Two of them, 36G/C and 209A, were again associated with increased HCC risk, but 271U/C was not. The odds ratio of 209A-271U/C was not significant. CONCLUSIONS: HCV core genes from patients with and without HCC differ at several positions. Of interest, 209A has been associated with IFN resistance and HCC in previous studies. Our findings suggest that HCV core gene sequence data might provide useful information about HCC risk. Prospective investigation is needed to establish the temporal relationship between appearance of the viral mutations and development of HCC.

Internal initiation stimulates production of p8 minicore, a member of a newly discovered family of hepatitis C virus core protein isoforms.

The hepatitis C virus (HCV) core gene is more conserved at the nucleic acid level than is necessary to preserve the sequence of the core protein, suggesting that it contains information for additional functions. We used a battery of anticore antibodies to test the hypothesis that the core gene directs the synthesis of core protein isoforms. Infectious viruses, replicons, and RNA transcripts expressed a p8 minicore containing the C-terminal portion of the p21 core protein and lacking the N-terminal portion. An interferon resistance mutation, U271A, which creates an AUG at codon 91, upregulated p8 expression in Con1 replicons, suggesting that p8 is produced by an internal initiation event and that 91-AUG is the preferred, but not the required, initiation codon. Synthesis of p8 was independent of p21, as shown by the abundant production of p8 from transcripts containing an UAG stop codon that blocked p21 production. Three infectious viruses, JFH-1 (2a core), J6/JFH (2a core), and H77/JFH (1a core), and a bicistronic construct, Bi-H77/JFH, all expressed both p8 and larger isoforms. The family of minicores ranges in size from 8 to 14 kDa. All lack the N-terminal portion of the p21 core. In conclusion, the core gene contains an internal signal that stimulates the initiation of protein synthesis at or near codon 91, leading to the production of p8. Infectious viruses of both genotype 1 and 2 HCV express a family of larger isoforms, in addition to p8. Minicores lack significant portions of the RNA binding domain of p21 core. Studies are under way to determine their functions.

Molecular and bioinformatic evidence of hepatitis C virus evolution in brain.

BACKGROUND: Neurocognitive deficits in patients with hepatitis C virus (HCV) infection prompted a search for HCV in brain. RESULTS: HCV was present in the brains of 7 (54%) of 13 patients with viremia, as determined by 5' UTR and E1 (envelope 1) gene analysis. Brain HCV RNA consensus sequences differed from those in plasma and liver in 4 (57%) of 7 patients. The quality of HCV RNA from postmortem brain and liver was assessed and demonstrated to be suitable for sequence analysis. Quasispecies analysis revealed that several mutations present in clones from >1 brain region were absent in clones from liver and plasma. Brain-specific mutations defined several families of related sequences. The patterns of brain-specific mutations in these families were consistent with the evolution of HCV RNA from a common ancestor. Single-nucleotide-polymorphism analysis confirmed that a prominent brain-specific mutation constituted approximately 10% of HCV RNA in cerebellum and medulla but that this mutation was undetectable in the liver and plasma of the same patient. CONCLUSIONS: This study introduces novel methods for assessing RNA from postmortem samples. It increases the reported cases of HCV in the brain, provides the first E1 sequences from the brain, and contributes to the growing evidence that HCV replicates and evolves within the brain.

Clinicopathologic correlates of hepatitis C virus in brain: a pilot study.

Hepatitis C virus (HCV) has been detected in the brain tissues of 10 individuals reported to date; it is unclear what clinical factors are associated with this, and with what frequency it occurs. Accordingly, a pilot analysis utilizing reverse transcriptase-polymerase chain reaction (RT- PCR) to detect and sequence HCV in premortem plasma and postmortem brain and liver from 20 human immunodeficiency virus (HIV)-infected and 10 HIV-naive individuals was undertaken. RNA encoding the first 126 amino acids of the HCV E1 envelope protein and the majority of the E1 signal sequence was analyzed in parallel with an 80-base-long segment of the 5' untranslated region (UTR). Liver HCV was detected only in subjects with premortem HCV viremia (10 HIV-infected and 3 HIV-naive). Brain HCV was detected in 6/10 HCV/HIV-coinfected and 1/3 HCV-monoinfected subjects. In the setting of HIV, the magnitude of plasma HCV load did not correlate with the presence of brain HCV. However, coinfected patients with brain HCV were more often off antiretroviral therapy and tended to have higher plasma HIV loads than those with HCV restricted to liver. Furthermore, premortem cerebrospinal fluid (CSF) analysis revealed that HCV/HIV-coinfected patients with brain HCV had detectable CSF HIV, whereas those without brain HCV had undetectable CSF HIV loads (P = .0205). Neuropsychologic tests showed a trend for hierarchical impairment of abstraction/executive functioning in HIV/HCV coinfection, with mean T scores for HIV monoinfected patients 43.2 (7.3), for liver-only HCV 39.5 (9.0), and for those with HCV in brain and liver 33.2 (5.1) (P = .0927). Predominant brain HCV sequences did not match those of the plasma or liver in 4 of the 6 coinfected patients analyzed. We conclude that in the setting of HIV/HCV coinfection, brain HCV is a common phenomenon unrelated to the magnitude of HCV viremia, but related to active HIV disease and detectable CSF HIV. Furthermore, there is sequence evidence of brain compartmentalization. Differences in abstraction/executive function of HCV/HIV coinfected patients compared to HIV monoinfected warrant further studies to determine if neuropsychiatric effects are predicated upon brain infection.

Psychological responses to continuous terror: a study of two communities in Israel.

OBJECTIVE: The authors evaluated psychological responses to continuous terror. METHOD: Data were collected after 10 months of escalating hostilities against civilians in Israel. The study's participants were randomly selected adults living in two suburbs of Jerusalem, one frequently and directly exposed to acts of terrorism (N=167) and the other indirectly exposed (N=89). Participants provided information about exposure to terror-related incidents, disruption of daily living, symptoms of posttraumatic stress disorder (PTSD), and general distress (assessed with the Brief Symptom Inventory). RESULTS: Residents of the directly exposed community reported more frequent exposure to terror and deeper disruption of daily living. Notwithstanding, the directly and indirectly exposed groups reported comparable rates of PTSD and similar levels of symptoms: 26.95% of the directly exposed group and 21.35% of the indirectly exposed group met DSM-IV PTSD symptom criteria (criteria B through D), and about one-third of those with PTSD symptoms (35.7% in the directly exposed group and 31.5% in the indirectly exposed group) reported significant distress and dysfunction. Subjects who did not meet PTSD symptom criteria had very low levels of PTSD symptoms, and their Brief Symptom Inventory scores were within population norms. Exposure and disruption of daily living contributed to PTSD symptoms in the directly exposed group. Disruption of daily routines contributed to Brief Symptom Inventory scores in both groups. CONCLUSIONS: Continuous terror created similar distress in proximal and remote communities. Exposure to discrete events was not a necessary mediator of terror threat. A subgroup of those exposed developed serious symptoms, whereas others were surprisingly resilient. Disruption of daily routines was a major secondary stressor.

Attention control and ability level in a complex cognitive skill: attention shifting and second-language proficiency.

In this study, we investigated the relationship between attention control and proficiency in a complex cognitive skill. The participants were English-French bilinguals with varying degrees of second-language (French) proficiency. Proficiency was operationalized as efficiency of lexical access in an animacy judgment task, as reflected in the coefficient of variability of response time adjusted for first-language performance on the same task. Attention control was operationalized as the shift cost obtained in a linguistic version of the alternating runs task-switching paradigm. Hierarchical regression revealed that, overall, attention control accounted for 59% of the variance of proficiency and that second-language attention control alone accounted for 32% of the unique variance of proficiency, indicating a high degree of skill domain (second language) specificity in the relationship between attention control and proficiency. The results speak to issues regarding the development of expertise, second-language acquisition, and a cognitive linguistic approach to language and attention.