Patient- and system-related barriers for the earlier diagnosis of colorectal cancer

<p>Abstract</p> <p>Background</p> <p>A cohort of colorectal cancer (CRC) patients represents an opportunity to study missed opportunities for earlier diagnosis. Primary objective: To study the epidemiology of diagnostic delays and failures to offer/complete CRC screening. Secondary objective: To identify system- and patient-related factors that may contribute to diagnostic delays or failures to offer/complete CRC screening.</p> <p>Methods</p> <p>Setting: Rural Veterans Administration (VA) Healthcare system. Participants: CRC cases diagnosed within the VA between 1/1/2000 and 3/1/2007. Data sources: progress notes, orders, and pathology, laboratory, and imaging results obtained between 1/1/1995 and 12/31/2007. Completed CRC screening was defined as a fecal occult blood test or flexible sigmoidoscopy (both within five years), or colonoscopy (within 10 years); delayed diagnosis was defined as a gap of more than six months between an abnormal test result and evidence of clinician response. A summary abstract of the antecedent clinical care for each patient was created by a certified gastroenterologist (GI), who jointly reviewed and coded the abstracts with a general internist (TW).</p> <p>Results</p> <p>The study population consisted of 150 CRC cases that met the inclusion criteria. The mean age was 69.04 (range 35-91); 99 (66%) were diagnosed due to symptoms; 61 cases (46%) had delays associated with system factors; of them, 57 (38% of the total) had delayed responses to abnormal findings. Fifteen of the cases (10%) had prompt symptom evaluations but received no CRC screening; no patient factors were identified as potentially contributing to the failure to screen/offer to screen. In total, 97 (65%) of the cases had missed opportunities for early diagnosis and 57 (38%) had patient factors that likely contributed to the diagnostic delay or apparent failure to screen/offer to screen.</p> <p>Conclusion</p> <p>Missed opportunities for earlier CRC diagnosis were frequent. Additional studies of clinical data management, focusing on following up abnormal findings, and offering/completing CRC screening, are needed.</p

General practitioner advice on physical activity: Analyses in a cohort of older primary health care patients (getABI)

<p>Abstract</p> <p>Background</p> <p>Although the benefits of physical activity for health and functioning are recognized to extend throughout life, the physical activity level of most older people is insufficient with respect to current guidelines. The primary health care setting may offer an opportunity to influence and to support older people to become physically active on a regular basis. Currently, there is a lack of data concerning general practitioner (GP) advice on physical activity in Germany. Therefore, the aim of this study was to evaluate the rate and characteristics of older patients receiving advice on physical activity from their GP.</p> <p>Methods</p> <p>This is a cross-sectional study using data collected at 7 years of follow-up of a prospective cohort study (German epidemiological trial on ankle brachial index, getABI). 6,880 unselected patients aged 65 years and above in the primary health care setting in Germany were followed up since October 2001. During the 7-year follow-up telephone interview, 1,937 patients were asked whether their GP had advised them to get regular physical activity within the preceding 12 months. The interview also included questions on socio-demographic and lifestyle variables, medical conditions, and physical activity. Logistic regression analysis (unadjusted and adjusted for all covariables) was used to examine factors associated with receiving advice. Analyses comprised only complete cases with regard to the analysed variables. Results are expressed as odds ratios (ORs) with 95% confidence intervals (95% CI).</p> <p>Results</p> <p>Of the 1,627 analysed patients (median age 77; range 72-93 years; 52.5% women), 534 (32.8%) stated that they had been advised to get regular physical activity. In the adjusted model, those more likely to receive GP advice on physical activity were men (OR [95% CI] 1.34 [1.06-1.70]), patients suffering from pain (1.43 [1.13-1.81]), coronary heart disease and/or myocardial infarction (1.56 [1.21-2.01]), diabetes mellitus (1.79 [1.39-2.30]) or arthritis (1.37 [1.08-1.73]), and patients taking a high (> 5) number of medications (1.41 [1.11-1.80]).</p> <p>Conclusions</p> <p>The study revealed a relatively low rate of older primary health care patients receiving GP advice on physical activity. GPs appeared to focus their advice on patients with chronic medical conditions. However, there are likely to be many more patients who would benefit from advice.</p

How useful are systematic reviews for informing palliative care practice? Survey of 25 Cochrane systematic reviews

<p>Abstract</p> <p>Background</p> <p>In contemporary medical research, randomised controlled trials are seen as the gold standard for establishing treatment effects where it is ethical and practical to conduct them. In palliative care such trials are often impractical, unethical, or extremely difficult, with multiple methodological problems. We review the utility of Cochrane reviews in informing palliative care practice.</p> <p>Methods</p> <p>Published reviews in palliative care registered with the Cochrane Pain, Palliative and Supportive Care Group as of December 2007 were obtained from the Cochrane Database of Systematic Reviews, issue 1, 2008. We reviewed the quality and quantity of primary studies available for each review, assessed the quality of the review process, and judged the strength of the evidence presented. There was no prior intention to perform any statistical analyses.</p> <p>Results</p> <p>25 published systematic reviews were identified. Numbers of included trials ranged from none to 54. Within each review, included trials were heterogeneous with respect to patients, interventions, and outcomes, and the number of patients contributing to any single analysis was generally much lower than the total included in the review. A variety of tools were used to assess trial quality; seven reviews did not use this information to exclude low quality studies, weight analyses, or perform sensitivity analysis for effect of low quality. Authors indicated that there were frequently major problems with the primary studies, individually or in aggregate. Our judgment was that the reviewing process was generally good in these reviews, and that conclusions were limited by the number, size, quality and validity of the primary studies.</p> <p>We judged the evidence about 23 of the 25 interventions to be weak. Two reviews had stronger evidence, but with limitations due to methodological heterogeneity or definition of outcomes. No review provided strong evidence of no effect.</p> <p>Conclusion</p> <p>Cochrane reviews in palliative care are well performed, but fail to provide good evidence for clinical practice because the primary studies are few in number, small, clinically heterogeneous, and of poor quality and external validity. They are useful in highlighting the weakness of the evidence base and problems in performing trials in palliative care.</p

Subcortical volumes across the lifespan: Data from 18,605 healthy individuals aged 3-90 years

Age has a major effect on brain volume. However, the normative studies available are constrained by small sample sizes, restricted age coverage and significant methodological variability. These limitations introduce inconsistencies and may obscure or distort the lifespan trajectories of brain morphometry. In response, we capitalized on the resources of the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) Consortium to examine age-related trajectories inferred from cross-sectional measures of the ventricles, the basal ganglia (caudate, putamen, pallidum, and nucleus accumbens), the thalamus, hippocampus and amygdala using magnetic resonance imaging data obtained from 18,605 individuals aged 3-90 years. All subcortical structure volumes were at their maximum value early in life. The volume of the basal ganglia showed a monotonic negative association with age thereafter; there was no significant association between age and the volumes of the thalamus, amygdala and the hippocampus (with some degree of decline in thalamus) until the sixth decade of life after which they also showed a steep negative association with age. The lateral ventricles showed continuous enlargement throughout the lifespan. Age was positively associated with inter-individual variability in the hippocampus and amygdala and the lateral ventricles. These results were robust to potential confounders and could be used to examine the functional significance of deviations from typical age-related morphometric patterns

The Cockayne Syndrome Natural History (CoSyNH) study:clinical findings in 102 individuals and recommendations for care

Purpose: Cockayne syndrome (CS) is a rare, autosomal-recessive disorder characterized by microcephaly, impaired postnatal growth, and premature pathological aging. It has historically been considered a DNA repair disorder; fibroblasts from classic patients often exhibit impaired transcription-coupled nucleotide excision repair. Previous studies have largely been restricted to case reports and small series, and no guidelines for care have been established. Methods: One hundred two study participants were identified through a network of collaborating clinicians and the Amy and Friends CS support groups. Families with a diagnosis of CS could also self-recruit. Comprehensive clinical information for analysis was obtained directly from families and their clinicians. Results and Conclusion: We present the most complete evaluation of Cockayne syndrome to date, including detailed information on the prevalence and onset of clinical features, achievement of neurodevelopmental milestones, and patient management. We confirm that the most valuable prognostic factor in CS is the presence of early cataracts. Using this evidence, we have created simple guidelines for the care of individuals with CS. We aim to assist clinicians in the recognition, diagnosis, and management of this condition and to enable families to understand what problems they may encounter as CS progresses

A DNA/MVA-based candidate human immunodeficiency virus vaccine for Kenya induces multi-specific T cell responses in rhesus macaques.

The minimum requirement for candidate human immunodeficiency virus (HIV) vaccines to enter clinical evaluation in humans should be their demonstrable immunogenicity in non-human primates: induction of antibodies neutralizing primary HIV isolates or elicitation of broad T cell-mediated immune responses. Here, we showed in rhesus macaques that the very same vaccines that had entered clinical trials in Oxford and Nairobi, plasmid pTHr.HIVA DNA and recombinant modified vaccinia virus Ankara MVA.HIVA in a prime-boost protocol (Hanke and McMichael, Nature Medicine 6, 951-955, 2000), induced cellular immune responses specific for multiple HIV-derived epitopes. This was demonstrated by using the intracellular cytokine staining and ELISPOT assays detecting interferon-gamma and pools of peptides employed in the clinical studies. These results have both boosted our expectations for the performance of these vaccines in humans and increased our confidence about the choice of these assays as the primary readouts in the on-going human trials

Cardiac positioning using an apical suction device maintains beating heart hemodynamics

Background: Cardiac positioning during off-pump coronary artery bypass (OPCAB) using deep pericardial sutures (DPS) typically results in some degree of hemodynamic compromise. We sought to determine whether cardiac positioning using an apical suction device was hemodynamically superior to DPS. Methods: Five healthy pigs underwent sternotomy and instrumentation to measure right atrial (RA) pressure, left ventricular (LV) pressure and volume, and aortic pressure and flow. These variables were recorded at baseline, with simple attachment of the apical suction device (Xpose™ Access Device, Guidant, Inc.), and during exposure of the posterior descending artery (PDA) and obtuse marginal (OM) branches of the left circumflex artery using DPS and the apical suction device. Results: Application of the apical suction device to the beating heart in neutral anatomic position did not result in any statistically significant change in hemodynamics compared to baseline except for a small decrease in RA pressure. DPS positioning resulted in statistically significant compromise in nearly all measured hemodynamic parameters, including cardiac output (-21% PDA, -30% OM), mean arterial pressure (-8% PDA, -26% OM), and stroke work (-31% PDA, -38% OM). In addition, LV end-diastolic pressure decreased (-59% PDA, -51% OM) while RA pressure increased (+17% PDA, +16% OM). Similar target exposure using the apical suction device resulted in near-baseline hemodynamics. The only statistically significant changes were a modest decrease in cardiac output (-18% OM) and RA pressure (-11% PDA). Conclusion: DPS positioning significantly compromises hemodynamics due to reduced LVfilling. The apical suction device provides good exposure with less hemodynamic compromise.link_to_subscribed_fulltex

Long-term follow up of human T-cell responses to conserved HIV-1 regions elicited by DNA/simian adenovirus/MVA vaccine regimens

BACKGROUND:Durability of vaccine-elicited immune responses is one of the key determinants for vaccine success. Our aim is to develop a vaccination strategy against the human immunodeficiency virus type 1 (HIV-1), which induces protective and durable CD8+ T-cell responses. The central theorem of our approach is to focus T cells on highly conserved regions of the HIV-1 proteome and this is achieved through the use of the first-generation conserved vaccine immunogen HIVconsv. This immunogen vectored by plasmid DNA, simian adenovirus and poxvirus MVA was tested in healthy, HIV-1-negative adults in UK and induced high magnitudes of HIVconsv-specific plurifunctional CD8+ T cells capable of in vitro HIV-1 inhibition. Here, we assessed the durability of these responses. METHODS:Vaccine recipients in trial HIV-CORE 002 were invited to provide a blood sample at 1 and 2 years after vaccination. Their PBMCs were tested in IFN-γ ELISPOT, 25-analyte Luminex, CFSE proliferation and intracellular cytokine staining assays, the last enhanced by HLA-peptide dextramer analysis. RESULTS:12/12 (1 year) and 8/8 (2 years) returning subjects had median (range) of 990 (150-2495) and 763 (70-1745) IFN-γ SFU/106 PBMC specific for HIVconsv, respectively, and recognized 5 (1-6) out of 6 peptide pools at 2 years. Over one-half of the HIVconsv-specific cells expressed at least 3 functions IFN-γ, TNF-α and CD107a, and were capable of proliferation. Among dextramer-reactive cells, naïve, transitional, effector and terminally differentiated memory subsets were similarly represented. CONCLUSIONS:First generation HIVconsv vaccine induced human T cells, which were plurifunctional and persisted for at least 2 years. TRIAL REGISTRATION:ClinicalTrials.gov NCT01151319

Efficient induction of T cells against conserved HIV-1 regions by mosaic vaccines delivered as self-amplifying mRNA

Focusing T cell responses on the most vulnerable parts of HIV-1, the functionally conserved regions of HIV-1 proteins, is likely a key prerequisite for vaccine success. For a T cell vaccine to efficiently control HIV-1 replication, the vaccine-elicited individual CD8+ T cells and as a population have to display a number of critical traits. If any one of these traits is suboptimal, the vaccine is likely to fail. Fine-tuning of individual protective characteristics of T cells will require iterative stepwise improvements in clinical trials. Although the second-generation tHIVconsvX immunogens direct CD8+ T cells to predominantly protective and conserved epitopes, in the present work, we have used formulated self-amplifying mRNA (saRNA) to deliver tHIVconsvX to the immune system. We demonstrated in BALB/c and outbred mice that regimens employing saRNA vaccines induced broadly specific, plurifunctional CD8+ and CD4+ T cells, which displayed structured memory subpopulations and were maintained at relatively high frequencies over at least 22 weeks post-administration. This is one of the first thorough analyses of mRNA vaccine-elicited T cell responses. The combination of tHIVconsvX immunogens and the highly versatile and easily manufacturable saRNA platform may provide a long-awaited opportunity to define and optimize induction of truly protective CD8+ T cell parameters in human volunteers