Multiple independent origins of a protease inhibitor resistance mutation in salvage therapy patients

<p>Abstract</p> <p>Background</p> <p>Combination anti-viral therapies have reduced treatment failure rates by requiring multiple specific mutations to be selected on the same viral genome to impart high-level drug resistance. To determine if the common protease inhibitor resistance mutation L90M is only selected once or repeatedly on different HIV genetic backbones during the course of failed anti-viral therapies we analyzed a linked region of the viral genome during the evolution of multi-drug resistance.</p> <p>Results</p> <p>Using L90M allele specific PCR we amplified and sequenced gag-pro regions linked to very early L90M containing HIV variants prior to their emergence and detection as dominant viruses in 15 failed salvage therapy patients. The early minority L90M linked sequences were then compared to those of the later L90M viruses that came to dominate the plasma quasispecies. Using Bayesian evolutionary analysis sampling trees the emergence of L90M containing viruses was seen to take place on multiple occasion in 5 patients, only once for 2 patients and an undetermined number of time for the remaining 8 patients.</p> <p>Conclusion</p> <p>These results indicate that early L90M mutants can frequently be displaced by viruses carrying independently selected L90M mutations rather than by descendents of the earlier mutants.</p

Hormone Therapy and the Risk of Breast Cancer in BRCA1 Mutation Carriers

Background: Hormone therapy (HT) is commonly given to women to alleviate the climacteric symptoms associated with menopause. There is concern that this treatment may increase the risk of breast cancer. The potential association of HT and breast cancer risk is of particular interest to women who carry a mutation in BRCA1 because they face a high lifetime risk of breast cancer and because many of these women take HT after undergoing prophylactic surgical oophorectomy at a young age. Methods: We conducted a matched case-control study of 472 postmenopausal women with a BRCA1 mutation to examine whether or not the use of HT is associated with subsequent risk of breast cancer. Breast cancer case patients and control subjects were matched with respect to age, age at menopause, and type of menopause (surgical or natural). Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated with conditional logistic regression. Statistical tests were two-sided. Results: In this group of BRCA1 mutation carriers, the adjusted OR for breast cancer associated with ever use of HT compared with never use was 0.58 (95% CI = 0.35 to 0.96; P =. 03). In analyses by type of HT, an inverse association with breast cancer risk was observed with use of estrogen only (OR = 0.51, 95% CI = 0.27 to 0.98; P =. 04); the association with use of estrogen plus progesterone was not statistically significant (OR = 0.66, 95% CI = 0.34 to 1.27; P =. 21). Conclusion: Among postmenopausal women with a BRCA1 mutation, HT use was not associated with increased risk of breast cancer; indeed, in this population, it was associated with a decreased risk

Conflict or cooperation? The successful resolution of U.S. trade disputes.

Since the end of WWII, the liberal trade regime has seen an unprecedented rate of expansion and growth. Trade between the U.S.A. and its largest trading partners has been at the forefront of this expansion. With this growth in trade has come changes in the nature of trade disputes. This growth and change, though, has resulted in a system of dispute resolution that varies among the U.S.A.'s trade partners through governmental behavior in the resolution of these disputes. The evolution of trade dispute behavior is evident in the U.S.A.'s use of both domestic and international trade dispute mechanisms, specifically anti-dumping, countervailing duty, Section 301, GATT, and the U.S.-Canada Free Trade Agreement mechanisms. This study examines variance in the U.S.A.'s use of these trade dispute mechanisms with Canada, the European Union, and Japan from 1979--1994 using cross-sectional data and statistical analysis. This study finds that the target country argument, developed herein, explains U.S. trade dispute behavior. The target country argument posits that the use of specific trade dispute mechanisms and the degree of conflict escalation is dependent upon the past relationship with that specific trade partner. Put most simply, the U.S.A.'s use of trade dispute mechanisms varies with the trade dispute partner and the information gathered in each dispute is context specific. Contrary to conventional wisdom, it is found that variance in trade dispute resolution is not explained solely by either interdependence or to domestic interest groups.Ph.D.Political scienceSocial SciencesUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/123474/2/3079528.pd

Population-Based Outreach Versus Usual Care to Prevent Suicide Attempt: Study Protocol for a Randomized Clinical Trial

Background: Suicide is the 10th leading cause of death. PHQ-9 item #9 (which asks about suicidal thoughts) identifies those at risk of suicide attempt/death. Patients with scores of 2 or 3 on item 9 show a sustained increase in risk, with a cumulative hazard near 4% over 12 months. Methods: Outpatients who score a 2 or 3 on item #9 of the PHQ-9 are identified using electronic health record (EHR) data at three Mental Health Research Network sites: Group Health Cooperative, HealthPartners and Kaiser Permanente Colorado. Using a modified Zelen design, patients are automatically assigned 1:1:1 to continue in usual care (ie, no contact) or to be offered one of two population-based prevention programs meant to supplement usual care: 1) Care Management (systematic outreach to assess risk, EHR-based tools for risk-based pathways, and care management to facilitate and monitor recommended follow-up care); or 2) Skills Training (interactive online training in dialectical behavioral therapy skills supported by reminder and reinforcement messages). Randomization automatically occurs within each site’s sampling computer program, stratified by item #9 score. A computer-generated concealed allocation table provides randomly generated assignments in block sizes of either 6 or 9. The multisite interventions are embedded in the EHR. Online patient-provider secure messaging via the EHR patient portal is used for patient invitation and outreach as well as administration of suicide risk questionnaires. Secure provider-to-provider messaging is used to communicate with primary care and mental health providers. Population management and reporting tools are used to apply follow-up algorithms and deliver recommendations to care managers regarding outreach and follow-up. Nonfatal and fatal suicide attempts are identified using state vital statistics data and diagnoses of self-inflicted injury from EHR and claim records. Primary evaluation will compare risk of first suicide attempt over the 18 months following randomization. Groups will be compared according to initial treatment assignment, regardless of level of participation in either intervention. Results: To date, 4,869 outpatients out of a planned 18,000 have been randomized across the three sites. Conclusion: Our experience thus far illustrates the promise and challenges of implementing multisite clinical trial recruitment and intervention delivery in EHR systems