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DNA polymerases beta and lambda do not directly affect Ig variable region somatic hypermutation although their absence reduces the frequency of mutations

Mon, 08/24/2015 - 3:25pm

During somatic hypermutation (SHM) of antibody variable (V) region genes, activation-induced cytidine deaminase (AID) converts dC to dU, and dUs can either be excised by uracil DNA glycosylase (UNG), by mismatch repair, or replicated over. If UNG excises the dU, the abasic site could be cleaved by AP-endonuclease (APE), introducing the single-strand DNA breaks (SSBs) required for generating mutations at A:T bp, which are known to depend upon mismatch repair and DNA Pol eta. DNA Pol beta or lambda could instead repair the lesion correctly. To assess the involvement of Pols beta and lambda in SHM of antibody genes, we analyzed mutations in the VDJh4 3' flanking region in Peyer's patch germinal center (GC) B cells from polbeta(-/-)pollambda(-/-), pollambda(-/-), and polbeta(-/-) mice. We find that deficiency of either or both polymerases results in a modest but significant decrease in V region SHM, with Pol beta having a greater effect, but there is no effect on mutation specificity, suggesting they have no direct role in SHM. Instead, the effect on SHM appears to be due to a role for these enzymes in GC B cell proliferation or viability. The results suggest that the BER pathway is not important during V region SHM for generating mutations at A:T bp. Furthermore, this implies that most of the SSBs required for Pol eta to enter and create A:T mutations are likely generated during replication instead. These results contrast with the inhibitory effect of Pol beta on mutations at the Ig Smu locus, Smu DSBs and class switch recombination (CSR) reported previously. We show here that B cells deficient in Pol lambda or both Pol beta and lambda proliferate normally in culture and undergo slightly elevated CSR, as shown previously for Pol beta-deficient B cells.

Skin color, sex, and educational attainment in the post-civil rights era

Mon, 08/24/2015 - 3:25pm

We assess the relationship between skin color and educational attainment for native-born non-Hispanic Black and White men and women, using data from the Coronary Artery Risk Development in Young Adults (CARDIA) Study. CARDIA is a medical cohort study with twenty years of social background data and a continuous measure of skin color, recorded as the percent of light reflected off skin. For Black men and women, we find a one-standard-deviation increase in skin lightness to be associated with a quarter-year increase in educational attainment. For White women, we find an association approximately equal in magnitude to that found for Black respondents, and the pattern of significance across educational transitions suggests that skin color for White women is not simply a proxy for family background. For White men, any relationship between skin color and attainment is not robust and, analyses suggest, might primarily reflect differences in family background. Findings suggest that discrimination on the basis of skin color may be less specific to race than previously thought.

A DNA break- and phosphorylation-dependent positive feedback loop promotes immunoglobulin class-switch recombination

Mon, 08/24/2015 - 3:25pm

The ability of activation-induced cytidine deaminase (AID) to efficiently mediate class-switch recombination (CSR) is dependent on its phosphorylation at Ser38; however, the trigger that induces AID phosphorylation and the mechanism by which phosphorylated AID drives CSR have not been elucidated. Here we found that phosphorylation of AID at Ser38 was induced by DNA breaks. Conversely, in the absence of AID phosphorylation, DNA breaks were not efficiently generated at switch (S) regions in the immunoglobulin heavy-chain locus (Igh), consistent with a failure of AID to interact with the endonuclease APE1. Additionally, deficiency in the DNA-damage sensor ATM impaired the phosphorylation of AID at Ser38 and the interaction of AID with APE1. Our results identify a positive feedback loop for the amplification of DNA breaks at S regions through the phosphorylation- and ATM-dependent interaction of AID with APE1.

Relapse among cigarette smokers: the CARDIA longitudinal study - 1985-2011

Mon, 08/24/2015 - 3:25pm

RATIONALE: There is little information about long-term relapse patterns for cigarette smokers.

OBJECTIVE: To describe long-term prevalence of relapse and related smoking patterns by sex, race, age, and education level among a community-based cohort of young adults followed for 25 years.

METHODS: We examined 25 years of data from Coronary Artery Risk Development in Young Adults (CARDIA), an ongoing study of a community-based cohort of 5115 men and women aged 18 to 30 years at baseline with periodic re-examinations. At each examination smoking, quitting, and relapse were queried. We examined prevalence of smoking relapse among 3603 participants who attended at least 6 of the 8 examinations.

RESULTS: About 53% of 3603 participants never reported smoking on a regular basis. Among the remaining 1682 ever smokers, 52.8% of those who reported current smoking at baseline were still smoking by the end of the study, compared to 10.7% of those who initiated smoking by year 5. Among those classified as former smokers at baseline, 39% relapsed at least once; of these, 69.5% had quit again by the end of the study. Maximum education level attained, age at study baseline, and race were associated with failure to quit smoking by the end of the study and relapse among those who did quit. Maximum education level attained and age at study baseline were also associated with ability to successfully quit after a relapse.

CONCLUSIONS: Smoking relapse after quitting is common, especially in those with lower education level. Education was the strongest predictor of all three outcomes. Improvements in access to treatment and treatment options, especially for underserved populations, are needed to prevent relapse when smokers quit.

Patient navigation to promote smoking cessation among low-income primary care patients: a pilot randomized controlled trial

Mon, 08/24/2015 - 3:25pm

We conducted a pilot randomized controlled trial to determine the feasibility and acceptability of a patient navigation intervention. Forty-seven smokers from one safety-net hospital were randomized to either a control group, in which they received a smoking cessation brochure and a list of smoking cessation resources, or a navigation group, in which they received the smoking cessation brochure, a list of smoking cessation resources, and patient navigation. Follow-up data were obtained for 33 participants. Nine (47.4%) of 19 of navigation group participants had engaged in smoking cessation treatment by 3 months versus 6 (42.9%) of 14 control group participants (chi-square p = ns). Patient navigation to promote engagement in smoking cessation treatment was feasible and acceptable to participants.

Robot-assisted home hazard assessment for fall prevention: a feasibility study

Mon, 08/24/2015 - 3:25pm

We examined the feasibility of using a remotely manoeuverable robot to make home hazard assessments for fall prevention. We employed use-case simulations to compare robot assessments with in-person assessments. We screened the homes of nine elderly patients (aged 65 years or more) for fall risks using the HEROS screening assessment. We also assessed the participants' perspectives of the remotely-operated robot in a survey. The nine patients had a median Short Blessed Test score of 8 (interquartile range, IQR 2-20) and a median Life-Space Assessment score of 46 (IQR 27-75). Compared to the in-person assessment (mean = 4.2 hazards identified per participant), significantly more home hazards were perceived in the robot video assessment (mean = 7.0). Only two checklist items (adequate bedroom lighting and a clear path from bed to bathroom) had more than 60% agreement between in-person and robot video assessment. Participants were enthusiastic about the robot and did not think it violated their privacy. The study found little agreement between the in-person and robot video hazard assessments. However, it identified several research questions about how to best use remotely-operated robots.

Sociodemographic differences in fast food price sensitivity

Mon, 08/24/2015 - 3:25pm

IMPORTANCE: Fiscal food policies (eg, taxation) are increasingly proposed to improve population-level health, but their impact on health disparities is unknown.

OBJECTIVE: To estimate subgroup-specific effects of fast food price changes on fast food consumption and cardiometabolic outcomes.

DESIGN, SETTING, AND PARTICIPANTS: Twenty-year follow-up (5 examinations) in a biracial US prospective cohort: Coronary Artery Risk Development in Young Adults (CARDIA) (1985/1986-2005/2006, baseline N = 5115). Participants were aged 18 to 30 years at baseline; design indicated equal recruitment by race (black vs white), educational attainment, age, and sex. Community-level price data from the Council for Community and Economic Research were temporally and geographically linked to study participants' home address at each examination.

MAIN OUTCOMES AND MEASURES: Participant-reported number of fast food eating occasions per week, body mass index (BMI), and homeostasis model assessment insulin resistance (HOMA-IR) from fasting glucose and insulin concentrations. Covariates included individual-level and community-level social and demographic factors.

RESULTS: In repeated measures regression analysis, multivariable-adjusted associations between fast food price and consumption were nonlinear (quadratic, P < .001), with significant inverse estimated effects on consumption at higher prices; estimates varied according to race (interaction P = .04), income (P = .07), and education (P = .03). At the 10th percentile of price ($1.25/serving), blacks and whites had mean fast food consumption frequency of 2.20 (95% CI, 2.07-2.33) and 1.55 (1.45-1.65) times/wk, respectively, whereas at the 90th percentile of price ($1.53/serving), respective mean consumption estimates were 1.86 (1.75-1.97) and 1.50 (1.41-1.59) times/wk. We observed differential price effects on HOMA-IR (inverse for lower educational status only [interaction P = .005] and at middle income only [interaction P = .02]) and BMI (inverse for blacks, less education, and middle income; positive for whites, more education, and high income [all interaction P < .001]).

CONCLUSIONS AND RELEVANCE: We found greater fast food price sensitivity on fast food consumption and insulin resistance among sociodemographic groups that have a disproportionate burden of chronic disease. Our findings have implications for fiscal policy, particularly with respect to possible effects of fast food taxes among populations with diet-related health disparities.

Recommendations for a culturally relevant Internet-based tool to promote physical activity among overweight young African American women, Alabama, 2010-2011

Mon, 08/24/2015 - 3:25pm

INTRODUCTION: Innovative approaches are needed to promote physical activity among young adult overweight and obese African American women. We sought to describe key elements that African American women desire in a culturally relevant Internet-based tool to promote physical activity among overweight and obese young adult African American women.

METHODS: A mixed-method approach combining nominal group technique and traditional focus groups was used to elicit recommendations for the development of an Internet-based physical activity promotion tool. Participants, ages 19 to 30 years, were enrolled in a major university. Nominal group technique sessions were conducted to identify themes viewed as key features for inclusion in a culturally relevant Internet-based tool. Confirmatory focus groups were conducted to verify and elicit more in-depth information on the themes.

RESULTS: Twenty-nine women participated in nominal group (n = 13) and traditional focus group sessions (n = 16). Features that emerged to be included in a culturally relevant Internet-based physical activity promotion tool were personalized website pages, diverse body images on websites and in videos, motivational stories about physical activity and women similar to themselves in size and body shape, tips on hair care maintenance during physical activity, and online social support through social media (eg, Facebook, Twitter).

CONCLUSION: Incorporating existing social media tools and motivational stories from young adult African American women in Internet-based tools may increase the feasibility, acceptability, and success of Internet-based physical activity programs in this high-risk, understudied population.

Smoking-cessation e-referrals: a national dental practice-based research network randomized controlled trial

Mon, 08/24/2015 - 3:25pm

BACKGROUND: Tobacco use is still the leading preventable cause of death and morbidity in the U.S. Web-assisted tobacco interventions are an effective but underutilized tool in assisting smokers with quitting. The dental visit is an excellent opportunity to assist smokers in quitting by referring them to these tobacco-cessation online programs.

PURPOSE: The study purpose was to test two patient referral methods-paper referrals (information prescriptions) versus paper plus e-referrals-to a web-assisted smoking-cessation induction system.

DESIGN: RCT that used implementation research methods.

PARTICIPANTS/SETTING: A total of 100 community-based dental practices were enrolled and 1814 smokers were referred to the web-assisted tobacco induction system.

INTERVENTION: The study intervention was a proactive e-referral of smokers to a web-assisted tobacco induction system called Decide2Quit.org, and the control group used paper referrals (information prescriptions) to refer smokers to the Decide2Quit.org.

MAIN OUTCOME MEASUREMENTS: The outcome measurements were the referral numbers, Decide2Quit registration numbers, and the smokers' quit rate. Data were collected in 2010-2011 and analyses were completed in 2012. RESULTS: Although total referrals from intervention practices was lower than control, subsequent proportions of registrations among smokers referred to Decide2Quit.org were nearly fourfold higher (adjusted mean percentages: 29.5% vs 7.6%, p < 0.01) in intervention compared with control practices. Subsequent rates of cessation among referred smokers were threefold higher (adjusted mean percentages: 3.0% vs 0.8%, p=0.03) in intervention practices as compared with control.

CONCLUSIONS: Intervention practices using the e-referral system had higher smoker registration numbers and higher quit smoking rates than the control practices. This study finds that e-referrals are effective in getting smokers to the web-assisted smoking-cessation induction system and in assisting with quitting that more than compensates for any additional effort that e-referrals require on the part of the practitioner.

CLINICAL TRIAL REGISTRATION: DPBRN Hygienists Internet Quality Improvement in Tobacco Cessation (HiQuit); NCT01108432. Preventive Medicine All rights reserved.

Outcomes of anticoagulation therapy in patients with mental health conditions

Mon, 08/24/2015 - 3:25pm

BACKGROUND: Patients with mental health conditions (MHCs) experience poor anticoagulation control when using warfarin, but we have limited knowledge of the association between specific mental illness and warfarin treatment outcomes.

OBJECTIVE: To examine the relationship between the severity of MHCs and outcomes of anticoagulation therapy.

DESIGN: Retrospective cohort analysis.

PARTICIPANTS: We studied 103,897 patients on warfarin for 6 or more months cared for by the Veterans Health Administration during fiscal years 2007-2008. We identified 28,216 patients with MHCs using ICD-9 codes: anxiety disorders, bipolar disorder, depression, post-traumatic stress disorder, schizophrenia, and other psychotic disorders.

MAIN MEASURES: Outcomes included anticoagulation control, as measured by percent time in the therapeutic range (TTR), as well as major hemorrhage. Predictors included different categories of MHC, Global Assessment of Functioning (GAF) scores, and psychiatric hospitalizations.

KEY RESULTS: Patients with bipolar disorder, depression, and other psychotic disorders experienced TTR decreases of 2.63 %, 2.26 %, and 2.92 %, respectively (p < 0.001), after controlling for covariates. Patients with psychotic disorders other than schizophrenia experienced increased hemorrhage after controlling for covariates [hazard ratio (HR) 1.24, p = 0.03]. Having any MHC was associated with a slightly increased hazard for hemorrhage (HR 1.19, p < 0.001) after controlling for covariates.

CONCLUSION: Patients with specific MHCs (bipolar disorder, depression, and other psychotic disorders) experienced slightly worse anticoagulation control. Patients with any MHC had a slightly increased hazard for major hemorrhage, but the magnitude of this difference is unlikely to be clinically significant. Overall, our results suggest that appropriately selected patients with MHCs can safely receive therapy with warfarin.

Towards collaborative filtering recommender systems for tailored health communications

Mon, 08/24/2015 - 3:25pm

The goal of computer tailored health communications (CTHC) is to promote healthy behaviors by sending messages tailored to individual patients. Current CTHC systems collect baseline patient "profiles" and then use expert-written, rule-based systems to target messages to subsets of patients. Our main interest in this work is the study of collaborative filtering-based CTHC systems that can learn to tailor future message selections to individual patients based explicit feedback about past message selections. This paper reports the results of a study designed to collect explicit feedback (ratings) regarding four aspects of messages from 100 subjects in the smoking cessation support domain. Our results show that most users have positive opinions of most messages and that the ratings for all four aspects of the messages are highly correlated with each other. Finally, we conduct a range of rating prediction experiments comparing several different model variations. Our results show that predicting future ratings based on each user's past ratings contributes the most to predictive accuracy.

Hospitalist involvement in family medicine residency training: A CERA study

Mon, 08/24/2015 - 3:25pm

BACKGROUND AND OBJECTIVES: Little is known about the impact of hospitalists on family medicine residencies. We surveyed family medicine residency directors to assess attitudes about hospitalists and their involvement in residency teaching.

METHODS: Questions were included in the 2012 Council of Academic Family Medicine Educational Research Alliance (CERA) survey of family medicine residency directors. Univariate statistics were used to describe programs, directors, and our questions on the use of hospitalists. Bivariate statistics were used to examine relationships between the use of hospitalists to teach and program characteristics.

RESULTS: Forty-one percent (n=175) of residency directors completed the hospitalist section of the CERA survey. Sixty-six percent of residency programs were community based/university affiliated. The majority of directors who have, or are planning to develop, a hospitalist service currently use an internal medicine service (92.5%), followed by family medicine (39.1%), pediatrics (35.4%), OB/laborists (18.0%), and combined services (8.7%). The majority of programs with a hospitalist training track (or plans to develop one) indicated that this was for a family medicine service. Sixty percent of programs that have a hospitalist service involve hospitalists in teaching. Twenty percent of directors reported that hospitalists serve as family medicine faculty, and 63% viewed them as "good educators." However, 85% reported no reduction in inpatient teaching by family medicine faculty despite using hospitalist teaching services.

CONCLUSIONS: Hospitalists have a significant educational role in family medicine resident training. Further research is needed to explore how hospitalists and family medicine faculty can collaborate to promote enhanced efficiency and effectiveness as residency teachers.

Weight loss motivations: a latent class analysis approach

Mon, 08/24/2015 - 3:25pm

OBJECTIVE: To identify subgroups of adults with respect to weight loss motivations and assess factors associated with subgroup membership.

METHOD: A cross-sectional survey among 414 overweight/ obese employees in 12 Massachusetts high schools was conducted. Latent class analysis (LCA) defined distinct weight loss motivation classes. Multinomial logistic regression assessed participant characteristics with class membership.

RESULTS: Three classes emerged: improving health; improving health and looking/feeling better; and improving health, looking/feeling, better and improving personal/social life. Compared to class 1, class 2 was more likely to be female and younger and class 3 was more likely to be female, younger, have children at home, and perceive themselves as very over-weight.

CONCLUSIONS: Findings can inform targeted weight loss interventions.

Explaining racial disparities in anticoagulation control: results from a study of patients at the Veterans Administration

Mon, 08/24/2015 - 3:25pm

Higher rates of stroke, major hemorrhage, and death among black patients receiving warfarin, compared with white patients, is likely related to poorer anticoagulation control. The research team investigated patient-level and site-level factors that might account for this group difference. A summary measure of anticoagulation control (percent time in therapeutic range [TTR]), patient characteristics, and site-level process of care measures were obtained for 9572 black and 88 481 white patients at the Veterans Health Administration. The research team studied disparity in TTR adjusting for patient and site characteristics. Mean unadjusted TTR for black patients was 6.5% lower than for white patients (P < .001). After accounting for the younger age of blacks, greater degrees of medication use, hospitalization, poverty, living in the South, and 11 other patient characteristics, only 2.0% of this racial disparity persisted. Process of care measures had minimal additional effect. These findings may inform efforts to reduce this racial disparity in achieving good anticoagulation control.

Society of Behavioral Medicine (SBM) position statement: ban indoor tanning for minors

Mon, 08/24/2015 - 3:25pm

The Society of Behavioral Medicine (SBM), an interdisciplinary professional organization focused on the science of health behavior joins the American Academy of Dermatology, the American Academy of Pediatrics, and a host of other national and international organizations in support of a total ban on indoor tanning for minors under the age of 18. According to the International Agency for Research on Cancer, artificial sources of ultraviolet radiation are in the highest category of carcinogens, joining tobacco and asbestos. Strong evidence links indoor tanning to increased risk for melanoma with repeated exposure during childhood being associated with the greatest increase in risk. Several countries and five US states have passed legislation banning indoor tanning in minors. We strongly encourage the remaining US states to do the same in an effort to protect children and prevent new cases of melanoma. SBM also strongly encourages research that explores the use of tanning beds in the home. Home-based indoor tanning has the potential to be especially dangerous given the complete absence of safety regulations. Children are currently protected from exposure to health-harming substances like tobacco and lead; thus, legislation protecting them from artificial sources of ultraviolet radiation is yet another important step forward in improving public health.

Who benefits from diabetes self-management interventions? The influence of depression in the Latinos en Control trial

Mon, 08/24/2015 - 3:25pm

BACKGROUND: Depressive symptoms are common among adults with diabetes. Depression and social support may influence diabetes self-management.

PURPOSE: This study aimed to examine change in depressive symptoms and the role of depression and support on clinical and dietary outcomes among Latinos with type 2 diabetes participating in a diabetes self-management intervention.

METHODS: Participants (N = 252) were randomized to the intervention or usual care. Mixed effects models were used to examine interaction effects between intervention status and depressive symptoms (Centers for Epidemiologic Studies Depression (CES-D) score) and support for diabetes self-management behaviors at baseline. Outcomes were measured at baseline and 4 and 12 months and included dietary quality, physical activity, depressive symptoms, and hemoglobin A1c levels.

RESULTS: Intervention participants had lower CES-D scores at follow-up than control participants. An interaction effect between intervention status and CES-D scores predicted diet quality.

CONCLUSION: Latinos with depressive symptoms may derive the greatest benefits from diabetes self-management interventions. Additional research on support during diabetes self-management interventions is warranted.

The PROMIS Physical Function item bank was calibrated to a standardized metric and shown to improve measurement efficiency

Mon, 08/24/2015 - 3:25pm

OBJECTIVE: To document the development and psychometric evaluation of the Patient-Reported Outcomes Measurement Information System (PROMIS) Physical Function (PF) item bank and static instruments.

STUDY DESIGN AND SETTING: The items were evaluated using qualitative and quantitative methods. A total of 16,065 adults answered item subsets (n > 2,200/item) on the Internet, with oversampling of the chronically ill. Classical test and item response theory methods were used to evaluate 149 PROMIS PF items plus 10 Short Form-36 and 20 Health Assessment Questionnaire-Disability Index items. A graded response model was used to estimate item parameters, which were normed to a mean of 50 (standard deviation [SD]=10) in a US general population sample.

RESULTS: The final bank consists of 124 PROMIS items covering upper, central, and lower extremity functions and instrumental activities of daily living. In simulations, a 10-item computerized adaptive test (CAT) eliminated floor and decreased ceiling effects, achieving higher measurement precision than any comparable length static tool across four SDs of the measurement range. Improved psychometric properties were transferred to the CAT's superior ability to identify differences between age and disease groups.

CONCLUSION: The item bank provides a common metric and can improve the measurement of PF by facilitating the standardization of patient-reported outcome measures and implementation of CATs for more efficient PF assessments over a larger range.

Patient-reported functional health and well-being outcomes with drug therapy: a systematic review of randomized trials using the SF-36 health survey

Mon, 08/24/2015 - 3:24pm

OBJECTIVES: To evaluate the responsiveness of the SF-36 Health Survey in drug trials and to determine how often clinically efficacious treatments produce meaningful functional health changes across medical conditions.

RESEARCH DESIGN: We conducted a systematic review of randomized, double-blind, placebo-controlled drug trials published from 1995 to 2011 that documented results for primary clinical endpoints and SF-36 outcomes. PubMed and a database of SF-36 publications were searched. We evaluated responsiveness as concordance (both statistically significant or both nonsignificant) between primary clinical and SF-36 outcomes. To determine how often SF-36 physical and mental component summary (PCS, MCS) score changes were of meaningful magnitude, mean net of placebo changes with treatment were compared against the developer's recommended 3-point threshold for a minimal important difference (MID) across groups of medical conditions.

RESULTS: Of 805 screened trials, 185 met eligibility criteria. Primary clinical and SF-36 outcomes were concordant in 151 trials (82%). Among clinically efficacious trials, 58% reported net mean SF-36 improvements > /=MID threshold; however, SF-36 changes were often modest (PCS IQR, 1.6-4.1; MCS IQR, 0.8-3.5). Variations in treatment impact were apparent across conditions. Clinically efficacious therapies for rheumatoid arthritis, psoriatic arthritis, and psoriasis consistently achieved the largest SF-36 improvements, with 87% exceeding MID, whereas no efficacious therapies for peripheral arterial disease or chronic obstructive pulmonary disease achieved MID threshold.

CONCLUSIONS: The SF-36 responds to treatment impact, distinguishing drug therapies that, on average, produce meaningful functional health benefits. Overall, just over half of clinically efficacious trials report meaningful functional health improvements, and results vary widely by medical condition.

ATM increases activation-induced cytidine deaminase activity at downstream S regions during class-switch recombination

Mon, 08/24/2015 - 3:24pm

Activation-induced cytidine deaminase (AID) initiates Ab class-switch recombination (CSR) in activated B cells resulting in exchanging the IgH C region and improved Ab effector function. During CSR, AID instigates DNA double-strand break (DSB) formation in switch (S) regions located upstream of C region genes. DSBs are necessary for CSR, but improper regulation of DSBs can lead to chromosomal translocations that can result in B cell lymphoma. The protein kinase ataxia telangiectasia mutated (ATM) is an important proximal regulator of the DNA damage response (DDR), and translocations involving S regions are increased in its absence. ATM phosphorylates H2AX, which recruits other DNA damage response (DDR) proteins, including mediator of DNA damage checkpoint 1 (Mdc1) and p53 binding protein 1 (53BP1), to sites of DNA damage. As these DDR proteins all function to promote repair and recombination of DSBs during CSR, we examined whether mouse splenic B cells deficient in these proteins would show alterations in S region DSBs when undergoing CSR. We find that in atm(-/-) cells Smu DSBs are increased, whereas DSBs in downstream Sgamma regions are decreased. We also find that mutations in the unrearranged Sgamma3 segment are reduced in atm(-/-) cells. Our data suggest that ATM increases AID targeting and activity at downstream acceptor S regions during CSR and that in atm(-/-) cells Smu DSBs accumulate as they lack a recombination partner.

The CAM-S: development and validation of a new scoring system for delirium severity in 2 cohorts

Mon, 08/24/2015 - 3:24pm

BACKGROUND: Quantifying the severity of delirium is essential to advancing clinical care by improved understanding of delirium effect, prognosis, pathophysiology, and response to treatment.

OBJECTIVE: To develop and validate a new delirium severity measure (CAM-S) based on the Confusion Assessment Method.

DESIGN: Validation analysis in 2 independent cohorts.

SETTING: Three academic medical centers.

PATIENTS: The first cohort included 300 patients aged 70 years or older scheduled for major surgery. The second included 919 medical patients aged 70 years or older.

MEASUREMENTS: A 4-item short form and a 10-item long form were developed. Association of the maximum CAM-S score during hospitalization with hospital and posthospital outcomes related to delirium was evaluated.

RESULTS: Representative results included adjusted mean length of stay, which increased across levels of short-form severity from 6.5 days (95% CI, 6.2 to 6.9 days) to 12.7 days (CI, 11.2 to 14.3 days) (P for trend and < 0.001) and across levels of long-form severity from 5.6 days (CI, 5.1 to 6.1 days) to 11.9 days (CI, 10.8 to 12.9 days) (P for trend andlt; 0.001). Representative results for the composite outcome of adjusted relative risk of death or nursing home residence at 90 days increased progressively across levels of short-form severity from 1.0 (referent) to 2.5 (CI, 1.9 to 3.3) (P for trend andlt; 0.001) and across levels of long-form severity from 1.0 (referent) to 2.5 (CI, 1.6 to 3.7) (P for trend and < 0.001).

LIMITATION: Data on clinical outcomes were measured in an older data set limited to patients aged 70 years or older.

CONCLUSION: The CAM-S provides a new delirium severity measure with strong psychometric properties and strong associations with important clinical outcomes.

PRIMARY FUNDING SOURCE: National Institute on Aging.