David Carrell

Effectiveness of Home Blood Pressure Monitoring, Web Communication, and Pharmacist Care on Hypertension Control: A Randomized Controlled Trial

CONTEXT Treating hypertension decreases mortality and disability from cardiovascular disease, but most hypertension remains inadequately controlled. OBJECTIVE To determine if a new model of care that uses patient Web services, home blood pressure (BP) monitoring, and pharmacist-assisted care improves BP control. DESIGN, SETTING, AND PARTICIPANTS A 3-group randomized controlled trial, the Electronic Communications and Home Blood Pressure Monitoring study was based on the Chronic Care Model. The trial was conducted at an integrated group practice in Washington state, enrolling 778 participants aged 25 to 75 years with uncontrolled essential hypertension and Internet access. Care was delivered over a secure patient Web site from June 2005 to December 2007. INTERVENTIONS Participants were randomly assigned to usual care, home BP monitoring and secure patient Web site training only, or home BP monitoring and secure patient Web site training plus pharmacist care management delivered through Web communications. MAIN OUTCOME MEASURES Percentage of patients with controlled BP (<140/90 mm Hg) and changes in systolic and diastolic BP at 12 months. RESULTS Of 778 patients, 730 (94%) completed the 1-year follow-up visit. Patients assigned to the home BP monitoring and Web training only group had a nonsignificant increase in the percentage of patients with controlled BP (<140/90 mm Hg) compared with usual care (36% [95% confidence interval {CI}, 30%-42%] vs 31% [95% CI, 25%-37%]; P = .21). Adding Web-based pharmacist care to home BP monitoring and Web training significantly increased the percentage of patients with controlled BP (56%; 95% CI, 49%-62%) compared with usual care (P < .001) and home BP monitoring and Web training only (P < .001). Systolic BP was decreased stepwise from usual care to home BP monitoring and Web training only to home BP monitoring and Web training plus pharmacist care. Diastolic BP was decreased only in the pharmacist care group compared with both the usual care and home BP monitoring and Web training only groups. Compared with usual care, the patients who had baseline systolic BP of 160 mm Hg or higher and received home BP monitoring and Web training plus pharmacist care had a greater net reduction in systolic BP (-13.2 mm Hg [95% CI, -19.2 to -7.1]; P < .001) and diastolic BP (-4.6 mm Hg [95% CI, -8.0 to -1.2]; P < .001), and improved BP control (relative risk, 3.32 [95% CI, 1.86 to 5.94]; P<.001). CONCLUSION Pharmacist care management delivered through secure patient Web communications improved BP control in patients with hypertension. Trial Registration clinicaltrials.gov Identifier: NCT00158639.

Systematic comparison of phenome-wide association study of electronic medical record data and genome-wide association study data

Candidate gene and genome-wide association studies (GWAS) have identified genetic variants that modulate risk for human disease; many of these associations require further study to replicate the results. Here we report the first large-scale application of the phenome-wide association study (PheWAS) paradigm within electronic medical records (EMRs), an unbiased approach to replication and discovery that interrogates relationships between targeted genotypes and multiple phenotypes. We scanned for associations between 3,144 single-nucleotide polymorphisms (previously implicated by GWAS as mediators of human traits) and 1,358 EMR-derived phenotypes in 13,835 individuals of European ancestry. This PheWAS replicated 66% (51/77) of sufficiently powered prior GWAS associations and revealed 63 potentially pleiotropic associations with P < 4.6 × 10−6 (false discovery rate < 0.1); the strongest of these novel associations were replicated in an independent cohort (n = 7,406). These findings validate PheWAS as a tool to allow unbiased interrogation across multiple phenotypes in EMR-based cohorts and to enhance analysis of the genomic basis of human disease.

Rare coding variants in the phospholipase D3 gene confer risk for Alzheimer's disease

Genome-wide association studies (GWAS) have identified several risk variants for late-onset Alzheimers disease (LOAD). These common variants have replicable but small effects on LOAD risk and generally do not have obvious functional effects. Low-frequency coding variants, not detected by GWAS, are predicted to include functional variants with larger effects on risk. To identify low-frequency coding variants with large effects on LOAD risk, we carried out whole-exome sequencing (WES) in 14 large LOAD families and follow-up analyses of the candidate variants in several large LOAD case–control data sets. A rare variant in PLD3 (phospholipase D3; Val232Met) segregated with disease status in two independent families and doubled risk for Alzheimer’s disease in seven independent case–control series with a total of more than 11,000 cases and controls of European descent. Gene-based burden analyses in 4,387 cases and controls of European descent and 302 African American cases and controls, with complete sequence data for PLD3, reveal that several variants in this gene increase risk for Alzheimer’s disease in both populations. PLD3 is highly expressed in brain regions that are vulnerable to Alzheimer’s disease pathology, including hippocampus and cortex, and is expressed at significantly lower levels in neurons from Alzheimer’s disease brains compared to control brains. Overexpression of PLD3 leads to a significant decrease in intracellular amyloid-β precursor protein (APP) and extracellular Aβ42 and Aβ40 (the 42- and 40-residue isoforms of the amyloid-β peptide), and knockdown of PLD3 leads to a significant increase in extracellular Aβ42 and Aβ40. Together, our genetic and functional data indicate that carriers of PLD3 coding variants have a twofold increased risk for LOAD and that PLD3 influences APP processing. This study provides an example of how densely affected families may help to identify rare variants with large effects on risk for disease or other complex traits.

Polymerase Chain Reaction for Detection of Herpes Simplex Virus (HSV) DNA on Mucosal Surfaces: Comparison with HSV Isolation in Cell Culture

This study compared the rate of isolation of herpes simplex virus (HSV) from >36000 samples of mucosal secretions obtained from 296 HSV-infected persons versus the rate of detection of HSV DNA, by means of a real-time quantitative polymerase chain reaction (PCR) assay. Overall, HSV was isolated in 3.0% of samples, and HSV DNA was detected in 12.1% of samples. The mean number of HSV DNA copies was 10(4.9) in samples obtained on days when HSV lesions were present and 10(4.4) in samples from days when HSV lesions were absent. There was a linear relationship between the ability to isolate virus in culture and the log number of copies of HSV DNA in the sample; this relationship persisted in samples from men or women, in samples from human immunodeficiency virus-negative or -positive participants, and in samples obtained on days when lesions were present or absent. In home-collected specimens, the ratio of PCR positivity to viral-culture positivity rose from 3.8:1 in the winter to 8.8:1 in the summer months, reflecting the lability of viral-culture specimens transported during warm weather.

Medical and Psychosocial Diagnoses in Women With a History of Intimate Partner Violence

BACKGROUND We characterized the relative risk of a wide range of diagnoses in women with a history of intimate partner violence (IPV) compared with never-abused women. METHODS The sample comprised 3568 English-speaking women who were randomly sampled from a large US health plan and who agreed to participate in a telephone survey to assess past-year IPV history using questions from the Behavioral Risk Factor Surveillance System (physical, sexual, and psychological abuse) and the Womens Experience with Battering Scale. Medical and psychosocial diagnoses in the past year were determined using automated data from health plan records. We estimated the relative risk of receiving diagnoses for women with a past-year IPV history compared with women with no IPV history. RESULTS In age-adjusted models, compared with never-abused women, abused women had consistently significantly increased relative risks of these disorders: psychosocial/mental (substance use, 5.89; family and social problems, 4.96; depression, 3.26; anxiety/neuroses, 2.73; tobacco use, 2.31); musculoskeletal (degenerative joint disease, 1.71; low back pain, 1.61; trauma-related joint disorders, 1.59; cervical pain, 1.54; acute sprains and strains, 1.35); and female reproductive (menstrual disorders, 1.84; vaginitis/vulvitis/cervicitis, 1.56). Abused women had a more than 3-fold increased risk of being diagnosed with a sexually transmitted disease (3.15) and a 2-fold increased risk of lacerations (2.17) as well as increased risk of acute respiratory tract infection (1.33), gastroesophageal reflux disease (1.76), chest pain (1.53), abdominal pain (1.48), urinary tract infections (1.79), headaches (1.57), and contusions/abrasions (1.72). CONCLUSION Past-year IPV history was strongly associated with a variety of medical and psychosocial conditions observed in clinical settings.

Patient Web Services Integrated with a Shared Medical Record: Patient Use and Satisfaction

OBJECTIVES This study sought to describe the evolution, use, and user satisfaction of a patient Web site providing a shared medical record between patients and health professionals at Group Health Cooperative, a mixed-model health care financing and delivery organization based in Seattle, Washington. DESIGN This study used a retrospective, serial, cross-sectional study from September 2002 through December 2005 and a mailed satisfaction survey of a random sampling of 2,002 patients. MEASUREMENTS This study measured the adoption and use of a patient Web site (MyGroupHealth) from September 2002 through December 2005. RESULTS As of December 2005, 25% (105,047) of all Group Health members had registered and completed an identification verification process enabling them to use all of the available services on MyGroupHealth. Identification verification was more common among patients receiving care in the Integrated Delivery System (33%) compared with patients receiving care in the network (7%). As of December 2005, unique monthly user rates per 1,000 adult members were the highest for review of medical test results (54 of 1,000), medication refills (44 of 1,000), after-visit-summaries (32 of 1,000), and patient-provider clinical messaging (31 of 1,000). The response rate for the patient satisfaction survey was 46% (n = 921); 94% of survey respondents were satisfied or very satisfied with MyGroupHealth overall. Patients reported highest satisfaction (satisfied or very satisfied) for medication refills (96%), patient-provider messaging (93%), and medical test results (86%). CONCLUSION Use and satisfaction with MyGroupHealth were greatest for accessing services and information involving ongoing, active care and patient-provider communication. Tight integration of Web services with clinical information systems and patient-provider relationships may be important in meeting the needs of patients.

GWAS of Cerebrospinal Fluid Tau Levels Identifies Risk Variants for Alzheimer’s Disease

Cerebrospinal fluid (CSF) tau, tau phosphorylated at threonine 181 (ptau), and Aβ₄₂ are established biomarkers for Alzheimers disease (AD) and have been used as quantitative traits for genetic analyses. We performed the largest genome-wide association study for cerebrospinal fluid (CSF) tau/ptau levels published to date (n = 1,269), identifying three genome-wide significant loci for CSF tau and ptau: rs9877502 (p = 4.89 × 10⁻⁹ for tau) located at 3q28 between GEMC1 and OSTN, rs514716 (p = 1.07 × 10⁻⁸ and p = 3.22 × 10⁻⁹ for tau and ptau, respectively), located at 9p24.2 within GLIS3 and rs6922617 (p = 3.58 × 10⁻⁸ for CSF ptau) at 6p21.1 within the TREM gene cluster, a region recently reported to harbor rare variants that increase AD risk. In independent data sets, rs9877502 showed a strong association with risk for AD, tangle pathology, and global cognitive decline (p = 2.67 × 10⁻⁴, 0.039, 4.86 × 10⁻⁵, respectively) illustrating how this endophenotype-based approach can be used to identify new AD risk loci.

Design and anticipated outcomes of the eMERGE-PGx project: a multicenter pilot for preemptive pharmacogenomics in electronic health record systems.

We describe here the design and initial implementation of the eMERGE‐PGx project. eMERGE‐PGx, a partnership of the Electronic Medical Records and Genomics Network and the Pharmacogenomics Research Network, has three objectives: (i) to deploy PGRNseq, a next‐generation sequencing platform assessing sequence variation in 84 proposed pharmacogenes, in nearly 9,000 patients likely to be prescribed drugs of interest in a 1‐ to 3‐year time frame across several clinical sites; (ii) to integrate well‐established clinically validated pharmacogenetic genotypes into the electronic health record with associated clinical decision support and to assess process and clinical outcomes of implementation; and (iii) to develop a repository of pharmacogenetic variants of unknown significance linked to a repository of electronic health record–based clinical phenotype data for ongoing pharmacogenomics discovery. We describe site‐specific project implementation and anticipated products, including genetic variant and phenotype data repositories, novel variant association studies, clinical decision support modules, clinical and process outcomes, approaches to managing incidental findings, and patient and clinician education methods.

Natural history of genital herpes simplex virus type 1 infection.

Background Herpes simplex virus type 1 (HSV-1) has been increasingly reported as a cause of genital herpes, yet there have been few studies on the long-term natural history of this infection. Goal The goal was to examine the clinical course of genital HSV-1 infection. Study Design This was a cohort study of patients presenting with culture-proven primary genital HSV-1 infection. Results The median follow-up of the 77 patients was 736 days. The overall rate of recurrences was 1.3/year in the first year of infection, decreasing to 0.7/year in the second year. In the first year of infection, 43% of study patients did not have a recurrence. In the second year of infection, 67% of study patients did not have a recurrence. Conclusion Genital HSV-1 recurs infrequently in most patients, and the rate decreases further in the subsequent years of infection. Because the prognoses of genital HSV-1 and HSV-2 infections differ, determination of the viral type is important for patient counseling.

Two-Day Regimen of Acyclovir for Treatment of Recurrent Genital Herpes Simplex Virus Type 2 Infection

The standard course of antiviral therapy for recurrent genital herpes requires administration of multiple doses of medication for 5 days. To assess the efficacy of a shorter course of antiviral therapy, patients with recurrent genital herpes simplex virus type 2 (HSV-2) infection were enrolled in a randomized, double-blind, placebo-controlled study of acyclovir (800 mg given by mouth 3 times per day [t.i.d.]) for 2 days. Of 131 people enrolled in the study, 84 (51 women and 33 men) were observed for >/=1 recurrence and 65 were observed for 2 recurrences, for which the patient was administered the same study drug (acyclovir or placebo). Acyclovir therapy (800 mg given by mouth t.i.d. for 2 days) significantly reduced the duration of lesions (median for acyclovir versus placebo, 4 days versus 6 days; P=.001), episode (4 days versus 6 days; P<.001), and viral shedding (25 hours versus 58.5 hours; P=.04), and it increased the proportion of aborted episodes (P=.029). A 2-day course of acyclovir is a convenient alternative for treatment of recurrent genital herpes.