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Mismatch repair proteins and AID activity are required for the dominant negative function of C-terminally deleted AID in class switching

Mon, 08/10/2015 - 8:35am

Activation-induced cytidine deaminase (AID) is essential for class-switch recombination (CSR) and somatic hypermutation (SHM) of Ig genes. The AID C terminus is required for CSR, but not for S-region DNA double-strand breaks (DSBs) during CSR, and it is not required for SHM. AID lacking the C terminus (DeltaAID) is a dominant negative (DN) mutant, because human patients heterozygous for this mutant fail to undergo CSR. In agreement, we show that DeltaAID is a DN mutant when expressed in AID-sufficient mouse splenic B cells. To have DN function, DeltaAID must have deaminase activity, suggesting that its ability to induce DSBs is important for the DN function. Supporting this hypothesis, Msh2-Msh6 have been shown to contribute to DSB formation in S regions, and we find in this study that Msh2 is required for the DN activity, because DeltaAID is not a DN mutant in msh2(-/-) cells. Our results suggest that the DNA DSBs induced by DeltaAID are unable to participate in CSR and might interfere with the ability of full-length AID to participate in CSR. We propose that DeltaAID is impaired in its ability to recruit nonhomologous end joining repair factors, resulting in accumulation of DSBs that undergo aberrant resection. Supporting this hypothesis, we find that the S-S junctions induced by DeltaAID have longer microhomologies than do those induced by full-length AID. In addition, our data suggest that AID binds Smu regions in vivo as a monomer.

Effect of self-referral on bone mineral density testing and osteoporosis treatment

Mon, 08/10/2015 - 8:35am

BACKGROUND: Despite national guidelines recommending bone mineral density screening with dual-energy x-ray absorptiometry (DXA) in women aged 65 years and older, many women do not receive initial screening.

OBJECTIVE: To determine the effectiveness of health system and patient-level interventions designed to increase appropriate DXA testing and osteoporosis treatment through (1) an invitation to self-refer for DXA (self-referral); (2) self-referral plus patient educational materials; and (3) usual care (UC, physician referral).

RESEARCH DESIGN: Parallel, group-randomized, controlled trials performed at Kaiser Permanente Northwest (KPNW) and Kaiser Permanente Georgia (KPG). SUBJECTS: Women aged 65 years and older without a DXA in past 5 years.

MEASURES: DXA completion rates 90 days after intervention mailing and osteoporosis medication receipt 180 days after initial intervention mailing.

RESULTS: From > 12,000 eligible women, those randomized to self-referral were significantly more likely to receive a DXA than UC (13.0%-24.1% self-referral vs. 4.9%-5.9% UC, P < 0.05). DXA rates did not significantly increase with patient educational materials. Osteoporosis was detected in a greater proportion of self-referral women compared with UC (P < 0.001). The number needed to receive an invitation to result in a DXA in KPNW and KPG regions was approximately 5 and 12, respectively. New osteoporosis prescription rates were low (0.8%-3.4%) but significantly greater among self-referral versus UC in KPNW.

CONCLUSIONS: DXA rates significantly improved with a mailed invitation to schedule a scan without physician referral. Providing women the opportunity to self-refer may be an effective, low-cost strategy to increase access for recommended osteoporosis screening.

Composite model for profiling physicians across domains of care

Mon, 08/10/2015 - 8:35am

Physician profiling methods are envisioned as a means of promoting healthcare quality by recognizing the contributions of individual physicians. Developing methods that can reliably distinguish among physicians' performance is challenging because of small sample sizes, incomplete data, and physician panel differences. In this study, we developed a hierarchical, weighted composite model to reliably compare primary care physicians across domains of care, and we demonstrated its use within a clinical system. We evaluated 199 primary care physicians from a large integrated healthcare delivery system using 19 quality and two efficiency measures taken from the Healthcare Effectiveness Data and Information Set and existing pay-for-performance programs. Individual measures were calculated, compared to benchmarks, and grouped into two composites: one focused on quality and one on efficiency. Each composite was fitted to the model, assessed for reliability (signal-to-noise ratio), and weighted to create a single summary score for each primary care physician. The quality-of-care composite had a median reliability of .98, with 99.5% of all physician reliability estimates exceeding threshold. The efficiency composite had a median reliability of .97, with 94.9% of all physician reliability estimates exceeding threshold. Our results demonstrate that reliable physician profiling is possible across care domains using a hierarchical composite model based on multiple data. The model was used to distribute incentive payouts among primary care physicians but is adaptable to many settings.

An online social network to increase walking in dog owners: a randomized trial

Mon, 08/10/2015 - 8:35am

PURPOSE: Encouraging dog walking may increase physical activity in dog owners. This cluster-randomized controlled trial investigated whether a social networking Web site (Meetup) could be used to deliver a multicomponent dog walking intervention to increase physical activity.

METHODS: Sedentary dog owners (n = 102) participated. Eight neighborhoods were randomly assigned to the Meetup condition (Meetup) or a condition where participants received monthly e-mails with content from the American Heart Association regarding increasing physical activity. The Meetup intervention was delivered over 6 months and consisted of newsletters, dog walks, community events, and an activity monitor. The primary outcome was steps; secondary outcomes included social support for walking, sense of community, perceived dog walking outcomes, barriers to dog walking, and feasibility of the intervention.

RESULTS: Mixed-model analyses examined change from baseline to postintervention (6 months) and whether change in outcomes differed by condition. Daily steps increased over time (P = 0.04, d = 0.28), with no differences by condition. The time-condition interaction was significant for the perceived outcomes of dog walking (P = 0.04, d = 0.40), such that the Meetup condition reported an increase in the perceived positive outcomes of dog walking, whereas the American Heart Association condition did not. Social support, sense of community, and dog walking barriers did not significantly change. Meetup logins averaged 58.38 per week (SD, 11.62). Within 2 months of the intervention ending, organization of the Meetup groups transitioned from the study staff to Meetup members.

CONCLUSIONS: Results suggest that a Meetup group is feasible for increasing physical activity in dog owners. Further research is needed to understand how to increase participation in the Meetup group and facilitate greater connection among dog owners.

Comparison of trends in US health-related quality of life over the 2000s using the SF-6D, HALex, EQ-5D, and EQ-5D visual analog scale versus a broader set of symptoms and impairments

Mon, 08/10/2015 - 8:35am

BACKGROUND: A number of instruments have been developed to measure health-related quality of life (HRQoL), differing in the health domains covered and their scoring. Although few such measures have been consistently included in US national health surveys over time, the surveys have included data on a broad range of symptoms and impairments, which enables the tracking of population health trends.

OBJECTIVES: To compare trends in HRQoL as measured using existing instruments versus using a broader range of symptoms and impairments collected in multiple years of nationally representative data.

DATA AND MEASURES: Data were from the 2000-2010 Medical Expenditure Panel Survey, which is nationally representative of the noninstitutionalized US population. Level of and trends in HRQoL derived from a broad range of survey symptoms and impairments (SSI) was compared with HRQoL from the SF-6D, the HALex, and, between 2000 and 2003, the EuroQol-5D (EQ-5D) and EQ-5D Visual Analog Scale.

RESULTS: Trends in HRQoL were similar using different measures. The SSI scores correlated 0.66-0.80 with scores from other measures and mean SSI scores were between those of other measures. Scores from all HRQoL measures declined similarly with increasing age and with the presence of comorbid conditions.

CONCLUSIONS: Measuring HRQoL using a broader range of symptoms and impairments than those in a single instrument yields population health trends similar to those from other measures while making maximum use of existing data and providing rich detail on the factors underlying change.

Facilitators and barriers to the active participation of clients with serious mental illnesses in medication decision making: the perceptions of young adult clients

Mon, 08/10/2015 - 8:35am

The active participation of young adults with serious mental illnesses (SMI) in making decisions about their psychotropic medications is beneficial to their care quality and overall health. Many however report not expressing treatment preferences to psychiatrists. Qualitative methods were used to interview 24 young adults with SMI about their experiences making medication decisions with their psychiatrists. An inductive analytic approach was taken to identifying conceptual themes in the transcripts. Respondents reported that the primary facilitators to active participation were the psychiatrist's openness to the client's perspective, the psychiatrist's availability outside of office hours, the support of other mental health providers, and personal growth and self-confidence of the young adults. The primary barriers to active participation reported were the resistance of the psychiatrist, the lack of time for consultations, and limited client self-efficacy. Young adults with SMI can be active participants in making decisions about their psychiatric treatment.