The cellular cytidine deaminase APOBEC3G (A3G) was first described as an anti-HIV-1 restriction factor, acting by directly deaminating reverse transcripts of the viral genome. HIV-1 Vif neutralizes the activity of A3G, primarily by mediating degradation of A3G to establish effective infection in host target cells. Lymphoma cells, which express high amounts of A3G, can restrict Vif-deficient HIV-1. Interestingly, these cells are more stable in the face of treatments that result in double-stranded DNA damage, such as ionizing radiation and chemotherapies. Previously, we showed that the Vif-derived peptide (Vif25-39) efficiently inhibits A3G deamination, and increases the sensitivity of lymphoma cells to ionizing radiation. In the current study, we show that additional peptides derived from Vif, A3G, and APOBEC3F, which contain the LYYF motif, inhibit deamination activity. Each residue in the Vif25-39 sequence moderately contributes to the inhibitory effect, whereas replacing a single residue in the LYYF motif completely abrogates inhibition of deamination. Treatment of A3G-expressing lymphoma cells exposed to ionizing radiation with the new inhibitory peptides reduces double-strand break repair after irradiation. Incubation of cultured irradiated lymphoma cells with peptides that inhibit double-strand break repair halts their propagation. These results suggest that A3G may be a potential therapeutic target that is amenable to peptide and peptidomimetic inhibition.
OBJECTIVES: The aim of this study was to investigate the relationships between 25-hydroxy vitamin D (25[OH]D) and markers of vitamin D status in inflammatory bowel disease (IBD).
METHODS: We conducted a retrospective case-control study of 59 pediatric patients with IBD (age 16.4 ± 2.2 y) and 116 controls (age 14.6 ± 4.4 y), to investigate the association between 25(OH)D and albuminemia for protein-losing enteropathy (PLE) and hepatic dysfunction; alanine transaminase (ALT) for hepatic inflammation; erythrocyte sedimentation rate (ESR) for intestinal inflammation; body mass index (BMI) for adiposity; seasons and skin pigmentation for insolation. Vitamin D deficiency was defined as 25(OH)D < 50 nmol/L; abnormal liver enzyme by ALT >40 U/L; overweight status by BMI of ≥85th but <95th >percentile, and obesity by BMI ≥95th percentile. Seasons were categorized as summer, winter, spring, and fall.
RESULTS: Patients with IBD had a higher prevalence of vitamin D deficiency (42.4% versus 26.7%; P = 0.04), elevated ALT (16.9% versus 2.6%; P < 0.001), and lower albumin (41.1 ± 4.8 versus 45.1 ± 3.8; P < 0.001) than controls. In both the IBD cohort and controls, 25(OH)D was highest in summer and lowest in winter, and significantly higher in white than in non-white patients. ESR varied significantly with 25(OH)D (R(2) = 0.24; β = -0.32; P = 0.010), and only patients with IBD with elevated ESR had lower 25(OH)D than controls (49.5 ± 25.2 versus 65.3 ± 28.0 nmol/L; P = 0.045).
CONCLUSION: Intestinal inflammation, not the loss of albumin-bound vitamin D in the gut, is the primary intestinal determinant of vitamin D status in IBD. The extraintestinal determinants are seasons and skin pigmentation, but not adiposity and hepatic inflammation.
In this brief video, Dr. Jonathan Delman describes Participatory Action Research and its importance.
Integrating Recovery-Oriented Practices for Individuals with Co-Occurring Disorders: With Tobacco & Schizophrenia Case Example
This webinar discusses motivation-based, recovery-oriented treatment plans for co-occurring disorders, including community resources. It describes how to integrate recovery practices such as dual recovery therapy, mindfulness-based interventions, and Open Dialogue into mental health and addiction treatment settings.
Multiple Chronic Conditions and Psychosocial Limitations in Patients Hospitalized with an Acute Coronary Syndrome
BACKGROUND: As adults live longer, multiple chronic conditions have become more prevalent over the past several decades. We describe the prevalence of, and patient characteristics associated with, cardiac and non-cardiac-related multimorbidities in patients discharged from the hospital after an acute coronary syndrome.
METHODS: We studied 2,174 patients discharged from the hospital after an acute coronary syndrome at 6 medical centers in Massachusetts and Georgia between April, 2011 and May, 2013. Hospital medical records yielded clinical information including presence of 8 cardiac-related and 8 non-cardiac-related morbidities on admission. We assessed multiple psychosocial characteristics during the index hospitalization using standardized in-person instruments.
RESULTS: The mean age of the study sample was 61 years, 67% were men, and 81% were non-Hispanic whites. The most common cardiac-related morbidities were hypertension, hyperlipidemia, and diabetes (76%, 69%, and 31%, respectively). Arthritis, chronic pulmonary disease, and depression (20%, 18%, and 13%, respectively) were the most common non-cardiac morbidities. Patients with ≥4 morbidities (37% of the population) were slightly older and more frequently female than those with 0-1 morbidity; they were also heavier and more likely to be cognitively impaired (26% vs. 12%), have symptoms of moderate/severe depression (31% vs. 15%), high perceived stress (48% vs. 32%), a limited social network (22% vs. 15%), low health literacy (42% vs. 31%), and low health numeracy (54% vs. 42%).
CONCLUSIONS: Multimorbidity, highly prevalent in patients hospitalized with an acute coronary syndrome, is strongly associated with indices of psychosocial deprivation. This emphasizes the challenge of caring for these patients, which extends well beyond acute coronary syndrome management.
Book Review: Data Management for Researchers: Organize, Maintain and Share Your Data for Research Success
Book review of Data Management for Researchers: Organize, Maintain and Share your Data for Research Success by Kristin Briney, Exeter, UK: Pelagic Publishing, 2015. ISBN 978-1-78427-011-7
Longitudinal Cognitive Trajectories of Women Veterans from the Women's Health Initiative Memory Study
PURPOSE OF THE STUDY: A comparison of longitudinal global cognitive functioning in women Veteran and non-Veteran participants in the Women's Health Initiative (WHI).
DESIGN AND METHODS: We studied 7,330 women aged 65-79 at baseline who participated in the WHI Hormone Therapy Trial and its ancillary Memory Study (WHIMS). Global cognitive functioning (Modified Mini-Mental State Examination [3MSE]) in Veterans (n = 279) and non-Veterans (n = 7,051) was compared at baseline and annually for 8 years using generalized linear modeling methods.
RESULTS: Compared with non-Veterans, Veteran women were older, more likely to be Caucasian, unmarried, and had higher rates of educational and occupational attainment. Results of unadjusted baseline analyses suggest 3MSE scores were similar between groups. Longitudinal analyses, adjusted for age, education, ethnicity, and WHI trial assignment revealed differences in the rate of cognitive decline between groups over time, such that scores decreased more in Veterans relative to non-Veterans. This relative difference was more pronounced among Veterans who were older, had higher educational/occupational attainment and greater baseline prevalence of cardiovascular risk factors (e.g., smoking) and cardiovascular disease (e.g., angina, stroke).
IMPLICATIONS: Veteran status was associated with higher prevalence of protective factors that may have helped initially preserve cognitive functioning. However, findings ultimately revealed more pronounced cognitive decline among Veteran relative to non-Veteran participants, likely suggesting the presence of risks that may impact neuropathology and the effects of which were initially masked by Veterans' greater cognitive reserve.
Influenza A virus (IAV) lacks the enzyme for adding 5' caps to its RNAs and snatches the 5' ends of host capped RNAs to prime transcription. Neither the preference of the host RNA sequences snatched nor the effect of cap-snatching on host processes is completely defined. Previous studies of influenza cap-snatching used poly(A)-selected RNAs from infected cells or relied on annotated host genes to define the snatched host RNAs, and thus lack details on many noncoding host RNAs including snRNAs, snoRNAs, and promoter-associated capped small (cs)RNAs, which are made by "paused" Pol II during transcription initiation. In this study, we used a nonbiased technique, CapSeq, to identify host and viral-capped RNAs including nonpolyadenylated RNAs in the same samples, and investigated the substrate-product correlation between the host RNAs and the viral RNAs. We demonstrated that noncoding host RNAs, particularly U1 and U2, are the preferred cap-snatching source over mRNAs or pre-mRNAs. We also found that csRNAs are highly snatched by IAV. Because the functions of csRNAs remain mostly unknown, especially in somatic cells, our finding reveals that csRNAs at least play roles in the process of IAV infection. Our findings support a model where nascent RNAs including csRNAs are the preferred targets for cap-snatching by IAV and raise questions about how IAV might use snatching preferences to modulate host-mRNA splicing and transcription.
Factors Associated With Suicide Outcomes 12 Months After Screening Positive for Suicide Risk in the Emergency Department
OBJECTIVE: The main objective was to identify which patient characteristics have the strongest association with suicide outcomes in the 12 months after an index emergency department (ED) visit.
METHODS: Data were analyzed from the first two phases of the Emergency Department Safety Assessment and Follow-up Evaluation (ED-SAFE). The ED-SAFE study, a quasi-experimental, interrupted time-series design, involved participation from eight general medical EDs across the United States. Participants included adults presenting to the ED with active suicidal ideation or an attempt in the past week. Data collection included baseline interview; six- and 12-month chart reviews; and six-, 12-, 24-, 36-, and 52-week telephone follow-up assessments. Regression analyses were conducted.
RESULTS: Among 874 participants, the median age was 37 years (interquartile range 27-47), with 56% of the sample being female (N=488), 74% white (N=649), and 13% Hispanic (N=113). At baseline, 577 (66%) participants had suicidal ideation only, whereas 297 (34%) had a suicide attempt in the past week. Data sufficient to determine outcomes were available for 782 (90%). In the 12 months after the index ED visit, 195 (25%) had documentation of at least one suicide attempt or suicide. High school education or less, an ED visit in the preceding six months, prior nonsuicidal self-injury, current alcohol misuse, and suicidal intent or plan were predictive of future suicidal behavior.
CONCLUSIONS: Continuing to build an understanding of the factors associated with future suicidal behaviors for this population will help guide design and implementation of improved suicide screening and interventions in the ED and better allocation of scarce resources.
Biosimilars, based on biopharmaceuticals approved by regulatory agencies that are no longer under patent protection, have efficacy and safety comparable to their reference products, and are a new therapeutic option to treat inflammatory diseases. Biosimilars must be distinguished from 'biomimics' or 'biocopies', which are marketed in some countries but have not been evaluated according to the stringent regulatory pathway used for biosimilars. CT-P13, based on infliximab, was the first biosimilar approved for the treatment of inflammatory diseases; however, some countries did not allow extrapolation of indications to all eight diseases for which the reference drug infliximab is approved. Antidrug antibodies can reduce drug levels and affect clinical efficacy, but although available data suggest that biosimilars and their reference products have comparable immunogenicity, this important property might differ between individual biopharmaceuticals. This Review discusses biosimilars already approved within the past 3 years to treat rheumatic diseases, as well as others that are currently under development. The main challenges posed by biosimilars are also addressed, such as the extrapolation of indications to diseases only studied for the reference drug, and the definition of strategies for adequate pharmacovigilance to monitor biosimilars after marketing approval.
Cardiovascular disease-a leading cause of morbidity and mortality among adults-is strongly influenced by platelet function through acute thrombotic and atherogenic mechanisms. Pathways that regulate platelet activity and lead to coronary occlusion are central to the pathogenesis of acute coronary syndromes. Platelet activation contributes to other thrombotic disorders and cardiovascular diseases, including stroke. Anucleate platelets are now understood to contain transcripts that might relate to other physiological or pathophysiological conditions, be released into the circulation, participate in protein formation, and engage in horizontal RNA transfer to other vascular cells. These platelet transcripts include microRNAs (miRNAs), which are small noncoding RNAs involved in many molecular processes, most notably regulation of gene expression. In platelets, these noncoding RNAs seem to participate in vascular homeostasis, inflammation, and platelet function. In addition, levels of platelet miRNAs in the circulation are associated with the presence or extent of cardiovascular diseases, such as atrial fibrillation and peripheral vascular disease. Accumulating data suggest mechanistic roles for platelet-derived miRNAs in haemostasis, thrombosis, and unstable coronary syndromes. In addition, evidence suggests that platelet-derived miRNAs might have important roles as biomarkers of cardiovascular disease susceptibility, prognosis, or treatment.
Editorial recommending that the significant sexual orientation health disparities among gay and bisexual men in regard to skin cancer and use of indoor tanning must be studied.
The First Step in Health Reform for Those With Serious Mental Illness: Integrating the Dis-Integrated Mental Health System
Increasing attention is being directed toward meeting the psychiatric and medical needs of persons with persistent or recurrent mental illness through the integration of behavioral and medical healthcare. There are many models being considered or tested to achieve this objective. These models, however, generally ignore the challenge of integrating systems that are themselves dis-integrated. Also ignored is the fact that many persons with persistent or recurrent mental illness operate in the context of an array of entitlements; receive "services" from the criminal justice, as well as the health and behavioral health systems; and all these systems are both siloed and fail to meet the needs of this population. This article examines the current state of the cornucopia of services available to individuals with persistent or recurrent mental illness inclusive of federal statutes and policies to impact these services. Recommendations are made to move the dis-integrated system of mental health services toward an internally integrated system that would have the capacity to become integrated with a medical system of care and treatment to achieve a behavioral-medical integrated health delivery system.
Medication adherence monitoring has relied largely on indirect measures of pill ingestion including patient self-report, pharmacy refills, electronically triggered pill bottles, and pill counts. Our objective is to describe an ingestible biosensor system comprising a radio-frequency identification (RFID)-tagged gelatin capsule. Once the capsule dissolves in the stomach, the RFID tag activates to transmit a unique signal to a relay device which transmits a time-stamped message to a cloud-based server that functions as a direct measure of medication adherence. We describe a constellation of mobile technologies that provide real-time direct measures of medication adherence. Optimizing connectivity, relay design, and interactivity with users are important in obtaining maximal acceptability. Potential concerns including gut retention of metallic components of the ingestible biosensor and drug dissolution within a gelatin capsule should be considered. An ingestible biosensor incorporated into a medication management system has the potential to improve medication compliance with real-time monitoring of ingestion and prompt early behavioral intervention. Integration of ingestible biosensors for multiple disease states may provide toxicologists with salient data early in the care of poisoned patients in the future. Further research on device design and interventions to improve adherence is needed and will shape the evolving world of medication adherence.
Depression and quality of life before and after breast cancer diagnosis in older women from the Women's Health Initiative
PURPOSE: Distress and reduced quality of life (QOL) are common among people with cancer. No study has compared these variables after breast cancer diagnosis to pre-cancer diagnosis levels.
METHODS: Data on women with breast cancer 50 years of age or older (n = 6949) were analyzed from the Women's Health Initiative (1993-2013). Health-related QOL (physical function, mental health) was measured using Rand-36. Depressive symptoms were measured with the six-item Center for Epidemiologic Studies Depression scale. Assessments occurred before and after the cancer diagnosis. Hierarchical linear modeling compared pre-cancer QOL and depressive symptoms to levels post-diagnosis and tested whether pre-cancer physical activity, stressful life events, sleep disturbance, and pain predicted post-diagnosis outcomes.
RESULTS: Compared with pre-cancer levels, depressive symptoms increased (20.0 % increase at 0-6 months, 12.9 % increase at 6-12 months), while physical function (-3.882 points at 0-6 months, -3.545 at 6-12 months) and mental health decreased (-2.899 points at 0-6 months, -1.672 at 6-12 months) in the first year after diagnosis (all p < .01). Depressive symptoms returned to pre-cancer levels after 10 years, but QOL remained significantly lower. At more than 10 years post-diagnosis, physical function was 2.379 points lower than pre-cancer levels (p < 0.01) while mental health was 1.922 points lower (p < 0.01). All pre-cancer predictors were associated with all outcomes. Pain predicted uniquely greater decreases in physical function post-diagnosis.
CONCLUSIONS: Depressive symptoms increased and QOL decreased following breast cancer diagnosis compared with pre-cancer levels, particularly in the first year.
IMPLICATIONS FOR CANCER SURVIVORS: QOL may remain lower for years after breast cancer diagnosis, although decreases are small.
The association between latent depression subtypes and remission after treatment with citalopram: A latent class analysis with distal outcome
BACKGROUND: The objectives were to characterize latent depression subtypes by symptoms, evaluate sex differences in and examine correlates of these subtypes, and examine the association between subtype and symptom remission after citalopram treatment.
METHODS: Latent class analysis was applied to baseline data from 2772 participants in the Sequenced Treatment Alternatives to Relieve Depression trial. Indicators were from the Quick Inventory of Depressive Symptomatology. Separate multinomial logistic models identified correlates of subtypes and the association between subtype and the distal outcome of remission.
RESULTS: Four latent subtypes were identified: Mild (men: 37%, women: 27%), Moderate (men: 24%, women: 21%), Severe with Increased Appetite (men: 13%, women: 22%), and Severe with Insomnia (men: 26%, women: 31%). Generalized anxiety disorder, bulimia, and social phobia were correlated with Severe with Increased Appetite and generalized anxiety disorder, post-traumatic stress disorder, and social phobia with Severe with Insomnia. Relative to those with the Mild subtype, those with Severe with Increased Appetite (odds ratiomen (OR): 0.48; 95% confidence interval (CI): 0.25-0.92; OR women: 0.59; 95% CI: 0.41-0.86) and those with Severe Depression with Insomnia (ORmen: 0.65; 95% CI: 0.41-1.02; ORwomen: 0.45; 95% CI: 0.32-0.64) were less likely to achieve remission.
LIMITATIONS: The sample size limited exploration of higher order interactions.
CONCLUSIONS: Insomnia and increased appetite distinguished latent subtypes. Sex and psychiatric comorbidities differed between the subtypes. Remission was less likely for those with the severe depression subtypes. Sleep disturbances, appetite changes, and other mental disorders may play a role in the etiology and treatment of depression.
BACKGROUND: Dietary supplements are taken by about half of Americans. Knowledge of dietary supplement use is important because they may interact with prescription drugs or other supplements, cause adverse reactions including psychiatric symptoms, or contain inherently toxic ingredients or contaminants. This study explores the use of dietary supplements by patients with bipolar disorder in the US.
METHODS: Data were obtained from an ongoing, naturalistic study of patients with bipolar disorder who received pharmacological treatment as usual. The patients self-reported their daily mood, sleep, and medications taken, including all drugs prescribed for bipolar disorder or that the patient felt impacted their mood. These included other prescribed drugs, over-the-counter drugs and dietary supplements. Drugs that received premarketing approval from the FDA were not included as dietary supplements. Patient demographics and daily medication use were characterized.
RESULTS: Data were available from 348 patients in the US who returned a mean 249.5 days of data. In addition to prescribed psychiatric drugs, 101 of the 348 patients (29 %) used a dietary supplement for at least 7 days and 69 (20 %) used a supplement long term (for at least 50 % of days). Of the 101 supplement users, 72 (71.3 %) took one supplement daily. The 101 patients tried over 40 different supplements, and the long-term users took 19 different supplements. The most commonly taken supplements for both groups were fish oil, B vitamins, melatonin, and multivitamins. Patients using supplements were more likely to be white (p < 0.001), older (p = 0.009), and ill for more years (p = 0.025).
CONCLUSIONS: Many patients with bipolar disorder use dietary supplements in addition to prescribed drugs. Physicians should obtain detailed information about all dietary supplements taken by patients with bipolar disorder.
INTRODUCTION: Motivational interviewing (MI) skills are relevant for primary care providers (PCPs) who are responsible for caring for patients with diseases affected by behavior. There are significant challenges associated with developing PCP's MI skills. We report on an effort to document the acquisition of MI skills by PCPs using an objective measure of MI competence, the Motivational Interviewing Treatment Integrity (MITI) coding system.
METHOD: Eleven PCPs volunteered to participate in 6 MI workshops over a period of 6 months and to submit work samples between each of these workshops to be assessed with the MITI coding system.
RESULTS: Thirteen of the expected 55 work samples were submitted before the final workshop. A revised approach was implemented in which each participant completed 2 simulated patient encounters. None of the providers reached the MITI's Beginning Proficiency threshold of MI skill.
DISCUSSION: Six MI workshops were not sufficient to help motivated PCPs achieve Beginning Proficiency as measured by the MITI. Participants failed to submit most of the work samples for feedback on their MI practice, which may have contributed to their limited acquisition of MI skills. Helping PCPs develop MI skills likely requires more than participation in a series of workshops totaling 18 h. Questions remain about the feasibility of training PCPs to be competent in MI. Approaches such as use of simulated patients, peer observation, or specific protected time for obtaining work samples may be required.
BACKGROUND: Readmission rates are a measure of surgical quality and an object of clinical and regulatory scrutiny. Despite increasing efforts to improve quality and contain cost, 6% to 25% of patients are readmitted after colorectal surgery.
OBJECTIVE: The aim of this study is to define the predictors and costs of readmission following colorectal surgery.
DESIGN: This is a retrospective cohort study of patients undergoing elective and nonelective colectomy and/or proctectomy in the Healthcare Cost and Utilization Project Florida State Inpatient Database 2007 to 2011. Readmission is defined as inpatient admission within 30 days of discharge. Univariate analyses were performed of sex, age, Elixhauser score, race, insurance type, procedure, indication, readmission diagnosis, cost, and length of stay. Multivariate analysis was performed by logistic regression. Sensitivity analysis of nonemergent admissions was conducted.
SETTINGS: This study was conducted in Florida acute-care hospitals.
PATIENTS: Patients undergoing colectomy and proctectomy from 2007 to 2011 were included.
INTERVENTION(S): There were no interventions.
MAIN OUTCOME MEASURE(S): The primary outcomes measured were readmission and the cost of readmission.
RESULTS: A total of 93,913 patients underwent colectomy; 14.7% were readmitted within 30 days. From 2007 to 2011, readmission rates remained stable (14.6%-14.2%, trend p = 0.1585). After multivariate adjustment, patient factors associated with readmission included nonwhite race, age < 65, and a diagnosis code other than neoplasm or diverticular disease (p < 0.0001). Patients with Medicare or Medicaid were more likely to be readmitted than those with private insurance (p < 0.0001). Patients with longer index admissions, those with stomas, and those undergoing all procedures other than sigmoid or transverse colectomy were more likely to be readmitted (p < 0.0001). High-volume hospitals had higher rates of readmission (p < 0.0001). The most common reason for readmission was infection (32.9%). Median cost of readmission care was $7030 (intraquartile range, $4220-$13,247). Fistulas caused the most costly readmissions ($15,174; intraquartile range, $6725-$26,660).
LIMITATIONS: Administrative data and retrospective design were limitations of this study.
CONCLUSIONS: Readmissions rates after colorectal surgery remain common and costly. Nonprivate insurance, IBD, and high hospital volume are significantly associated with readmission.
Racial Differences in the Performance of Existing Risk Prediction Models for Incident Type 2 Diabetes: The CARDIA Study
OBJECTIVE: In 2010, the American Diabetes Association (ADA) added hemoglobin A1c (A1C) to the guidelines for diagnosing type 2 diabetes. However, existing models for predicting diabetes risk were developed prior to the widespread adoption of A1C. Thus, it remains unknown how well existing diabetes risk prediction models predict incident diabetes defined according to the ADA 2010 guidelines. Accordingly, we examined the performance of an existing diabetes prediction model applied to a cohort of African American (AA) and white adults from the Coronary Artery Risk Development Study in Young Adults (CARDIA).
RESEARCH DESIGN AND METHODS: We evaluated the performance of the Atherosclerosis Risk in Communities (ARIC) diabetes risk prediction model among 2,456 participants in CARDIA free of diabetes at the 2005-2006 exam and followed for 5 years. We evaluated model discrimination, calibration, and integrated discrimination improvement with incident diabetes defined by ADA 2010 guidelines before and after adding baseline A1C to the prediction model.
RESULTS: In the overall cohort, re-estimating the ARIC model in the CARDIA cohort resulted in good discrimination for the prediction of 5-year diabetes risk (area under the curve [AUC] 0.841). Adding baseline A1C as a predictor improved discrimination (AUC 0.841 vs. 0.863, P = 0.03). In race-stratified analyses, model discrimination was significantly higher in whites than AA (AUC AA 0.816 vs. whites 0.902; P = 0.008).
CONCLUSIONS: Addition of A1C to the ARIC diabetes risk prediction model improved performance overall and in racial subgroups. However, for all models examined, discrimination was better in whites than AA. Additional studies are needed to further improve diabetes risk prediction among AA. long as the work is properly cited, the use is educational and not for profit, and the work is not altered.