HELPing older people with very severe chronic obstructive pulmonary disease (HELP-COPD):mixed-method feasibility pilot randomised controlled trial of a novel intervention

BACKGROUND: Extending palliative care to those with advanced non-malignant disease is advocated, but the implications in specific conditions are poorly understood. AIMS: We piloted a novel nurse-led intervention, HELPing older people with very severe chronic obstructive pulmonary disease (HELP-COPD), undertaken 4 weeks after discharge from hospital, which sought to identify and address the holistic care needs of people with severe COPD. METHODS: This 6-month mixed-method feasibility pilot trial randomised (ratio 3:1) patients to HELP-COPD or usual care. We assessed the feasibility of using validated questionnaires as outcome measures and analysed the needs/actions recorded in the HELP-COPD records. Semi-structured interviews with a purposive sample of patients, carers and professionals explored the perceptions of HELP-COPD. Verbatim transcriptions and field notes were analysed using Normalisation Process Theory as a framework. RESULTS: We randomised 32 patients (24 to HELP-COPD); 19 completed the study (death=3, ill-health=4, declined=6). The HELP-COPD record noted a mean of 1.6 actions/assessment, mostly provision of information or self-help actions: only five referrals were made. Most patients were positive about HELP-COPD, discussing their concerns and coping strategies in all domains, but the questionnaires were burdensome for some patients. Adaptation to their slowly progressive disability and a strong preference to rely on family support was reflected in limited acceptance of formal services. Professionals perceived HELP-COPD as addressing an important aspect of care, although timing overlapped with discharge planning. CONCLUSIONS: The HELP-COPD intervention was well received by patients and the concept resonated with professionals, although delivery post discharge overlapped with existing services. Integration of brief holistic care assessments in the routine primary care management of COPD may be more appropriate

Family physicians' perceptions of academic detailing: a quantitative and qualitative study

<p>Abstract</p> <p>Background</p> <p>The efficacy of academic detailing in changing physicians' knowledge and practice has been the subject of many primary research publications and systematic reviews. However, there is little written about the features of academic detailing that physicians find valuable or that affect their use of it. The goal of our project was to explore family physicians' (FPs) perceptions of academic detailing and the factors that affect their use of it.</p> <p>Methods</p> <p>We used 2 methods to collect data, a questionnaire and semi-structured telephone interviews. We mailed questionnaires to all FPs in the Dalhousie Office of Continuing Medical Education database and analyzed responses of non-users and users of academic detailing. After a preliminary analysis of questionnaire data, we conducted semi-structured interviews with 7 FPs who did not use academic detailing and 17 who did use it.</p> <p>Results</p> <p>Overall response rate to the questionnaire was 33% (289/869). Response rate of non-users of academic detailing was 15% (60/393), of users was 48% (229/476). The 3 factors that most encouraged use of academic detailing were the topics selected, the evidence-based approach adopted, and the handout material. The 3 factors that most discouraged the use of academic detailing were spending office time doing CME, scheduling time to see the academic detailer, and having CME provided by a non-physician. Users of academic detailing rated it as being more valuable than other forms of CME. Generally, interview data confirmed questionnaire data with the exception that interview informants did not view having CME provided by a non-physician as a barrier. Interview informants mentioned that the evidence-based approach adopted by academic detailing had led them to more critically evaluate information from other CME programs, pharmaceutical representatives, and journal articles, but not advice from specialists.</p> <p>Conclusion</p> <p>Users of academic detailing highly value its educational value and tend to view information from other sources more critically because of its evidence-based approach. Non-users are unlikely to adopt academic detailing despite its high educational value because they find using office time for CME too much of a barrier. To reach these physicians with academic detailing messages, we will have to find other CME formats.</p

Health status in the TORCH study of COPD: treatment efficacy and other determinants of change

BACKGROUND: Little is known about factors that determine health status decline in clinical trials of COPD. OBJECTIVES: To examine health status changes over 3 years in the TORCH study of salmeterol+fluticasone propionate (SFC) vs. salmeterol alone, fluticasone propionate alone or placebo. METHODS: St George's Respiratory Questionnaire (SGRQ) was administered at baseline then every 6 months. MEASUREMENTS AND MAIN RESULTS: Data from 4951 patients in 28 countries were available. SFC produced significant improvements over placebo in all three SGRQ domains during the study: (Symptoms -3.6 [95% CI -4.8, -2.4], Activity -2.8 [95% CI -3.9, -1.6], Impacts -3.2 [95% CI -4.3, -2.1]) but the pattern of change over time differed between domains. SGRQ deteriorated faster in patients with Global Initiative for Chronic Obstructive Lung Disease (GOLD) stages III & IV relative to GOLD stage II (p < 0.001). There was no difference in the relationship between deterioration in SGRQ Total score and forced expiratory volume in one second (FEV1) decline (as % predicted) in men and women. Significantly faster deterioration in Total score relative to FEV1 % predicted was seen in older patients (≥ 65 years) and there was an age-related change in Total score that was independent of change in FEV1. The relationship between deterioration in FEV1 and SGRQ did not differ in different world regions, but patients in Asia-Pacific showed a large improvement in score that was unrelated to FEV1 change. CONCLUSIONS: In addition to treatment effects, health status changes in clinical trials may be influenced by demographic and disease-related factors. Deterioration in health status appears to be fastest in older persons and those with severe airflow limitation

Phosphorylation of p65(RelA) on Ser547 by ATM Represses NF-κB-Dependent Transcription of Specific Genes after Genotoxic Stress

The NF-κB pathway is involved in immune and inflammation responses, proliferation, differentiation and cell death or survival. It is activated by many external stimuli including genotoxic stress. DNA double-strand breaks activate NF-κB in an ATM-dependent manner. In this manuscript, a direct interaction between p65(RelA) and the N-terminal extremity of ATM is reported. We also report that only one of the five potential ATM-(S/T)Q target sites present in p65, namely Ser547, is specifically phosphorylated by ATM in vitro. A comparative transcriptomic analysis performed in HEK-293 cells expressing either wild-type HA-p65 or a non-phosphorylatable mutant HA-p65S547A identified several differentially transcribed genes after an etoposide treatment (e.g. IL8, A20, SELE). The transcription of these genes is increased in cells expressing the mutant. Substitution of Ser547 to alanine does not affect p65 binding abilities on the κB site of the IL8 promoter but reduces p65 interaction with HDAC1. Cells expressing p65S547A have a higher level of histone H3 acetylated on Lys9 at the IL8 promoter, which is in agreement with the higher gene induction observed. These results indicate that ATM regulates a sub-set of NF-κB dependent genes after a genotoxic stress by direct phosphorylation of p65

The C-Terminal Domain of the MutL Homolog from Neisseria gonorrhoeae Forms an Inverted Homodimer

The mismatch repair (MMR) pathway serves to maintain the integrity of the genome by removing mispaired bases from the newly synthesized strand. In E. coli, MutS, MutL and MutH coordinate to discriminate the daughter strand through a mechanism involving lack of methylation on the new strand. This facilitates the creation of a nick by MutH in the daughter strand to initiate mismatch repair. Many bacteria and eukaryotes, including humans, do not possess a homolog of MutH. Although the exact strategy for strand discrimination in these organisms is yet to be ascertained, the required nicking endonuclease activity is resident in the C-terminal domain of MutL. This activity is dependent on the integrity of a conserved metal binding motif. Unlike their eukaryotic counterparts, MutL in bacteria like Neisseria exist in the form of a homodimer. Even though this homodimer would possess two active sites, it still acts a nicking endonuclease. Here, we present the crystal structure of the C-terminal domain (CTD) of the MutL homolog of Neisseria gonorrhoeae (NgoL) determined to a resolution of 2.4 Å. The structure shows that the metal binding motif exists in a helical configuration and that four of the six conserved motifs in the MutL family, including the metal binding site, localize together to form a composite active site. NgoL-CTD exists in the form of an elongated inverted homodimer stabilized by a hydrophobic interface rich in leucines. The inverted arrangement places the two composite active sites in each subunit on opposite lateral sides of the homodimer. Such an arrangement raises the possibility that one of the active sites is occluded due to interaction of NgoL with other protein factors involved in MMR. The presentation of only one active site to substrate DNA will ensure that nicking of only one strand occurs to prevent inadvertent and deleterious double stranded cleavage

Implementing academic detailing for breast cancer screening in underserved communities

<p>Abstract</p> <p>Background</p> <p>African American and Hispanic women, such as those living in the northern Manhattan and the South Bronx neighborhoods of New York City, are generally underserved with regard to breast cancer prevention and screening practices, even though they are more likely to die of breast cancer than are other women. Primary care physicians (PCPs) are critical for the recommendation of breast cancer screening to their patients. Academic detailing is a promising strategy for improving PCP performance in recommending breast cancer screening, yet little is known about the effects of academic detailing on breast cancer screening among physicians who practice in medically underserved areas. We assessed the effectiveness of an enhanced, multi-component academic detailing intervention in increasing recommendations for breast cancer screening within a sample of community-based urban physicians.</p> <p>Methods</p> <p>Two medically underserved communities were matched and randomized to intervention and control arms. Ninety-four primary care community (<it>i.e</it>., not hospital based) physicians in northern Manhattan were compared to 74 physicians in the South Bronx neighborhoods of the New York City metropolitan area. Intervention participants received enhanced physician-directed academic detailing, using the American Cancer Society guidelines for the early detection of breast cancer. Control group physicians received no intervention. We conducted interviews to measure primary care physicians' self-reported recommendation of mammography and Clinical Breast Examination (CBE), and whether PCPs taught women how to perform breast self examination (BSE).</p> <p>Results</p> <p>Using multivariate analyses, we found a statistically significant intervention effect on the recommendation of CBE to women patients age 40 and over; mammography and breast self examination reports increased across both arms from baseline to follow-up, according to physician self-report. At post-test, physician involvement in additional educational programs, enhanced self-efficacy in counseling for prevention, the routine use of chart reminders, computer- rather than paper-based prompting and tracking approaches, printed patient education materials, performance targets for mammography, and increased involvement of nursing and other office staff were associated with increased screening.</p> <p>Conclusion</p> <p>We found some evidence of improvement in breast cancer screening practices due to enhanced academic detailing among primary care physicians practicing in urban underserved communities.</p

Processing of joint molecule intermediates by structure-selective endonucleases during homologous recombination in eukaryotes

Homologous recombination is required for maintaining genomic integrity by functioning in high-fidelity repair of DNA double-strand breaks and other complex lesions, replication fork support, and meiotic chromosome segregation. Joint DNA molecules are key intermediates in recombination and their differential processing determines whether the genetic outcome is a crossover or non-crossover event. The Holliday model of recombination highlights the resolution of four-way DNA joint molecules, termed Holliday junctions, and the bacterial Holliday junction resolvase RuvC set the paradigm for the mechanism of crossover formation. In eukaryotes, much effort has been invested in identifying the eukaryotic equivalent of bacterial RuvC, leading to the discovery of a number of DNA endonucleases, including Mus81–Mms4/EME1, Slx1–Slx4/BTBD12/MUS312, XPF–ERCC1, and Yen1/GEN1. These nucleases exert different selectivity for various DNA joint molecules, including Holliday junctions. Their mutant phenotypes and distinct species-specific characteristics expose a surprisingly complex system of joint molecule processing. In an attempt to reconcile the biochemical and genetic data, we propose that nicked junctions constitute important in vivo recombination intermediates whose processing determines the efficiency and outcome (crossover/non-crossover) of homologous recombination