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An autogenous arteriovenous fistula is the optimal vascular access for hemodialysis. In the case of brachiocephalic fistula, cephalic arch stenosis commonly develops leading to access failure. We have hypothesized that a contribution to fistula failure is low wall shear stress resulting from post-fistula creation hemodynamic changes that occur in the cephalic arch. Twenty-two subjects with advanced renal failure had brachiocephalic fistulae placed. The following procedures were performed at mapping (pre-operative) and at fistula maturation (8-32 weeks post-operative): venogram, Doppler to measure venous blood flow velocity, and whole blood viscosity. Geometric and computational modeling was performed to determine wall shear stress and other geometric parameters. The relationship between hemodynamic parameters and clinical findings was examined using univariate analysis and linear regression. The percent low wall shear stress was linearly related to the increase in blood flow velocity (p < 0.01). This relationship was more significant in non-diabetic patients (p < 0.01) than diabetic patients. The change in global measures of arch curvature and asymmetry also evolve with time to maturation (p < 0.05). The curvature and hemodynamic changes during fistula maturation increase the percentage of low wall shear stress regions within the cephalic arch. Low wall shear stress may contribute to subsequent neointimal hyperplasia and resultant cephalic arch stenosis. If this hypothesis remains tenable with further studies, ways of protecting the arch through control of blood flow velocity may need to be developed.

In the present study, we analyzed the functional profile of CD8+ T-cell responses directed against autologous transmitted/founder HIV-1 isolates during acute and early infection, and examined whether multifunctionality is required for selection of virus escape mutations. Seven anti-retroviral therapy-naïve subjects were studied in detail between 1 and 87 weeks following onset of symptoms of acute HIV-1 infection. Synthetic peptides representing the autologous transmitted/founder HIV-1 sequences were used in multiparameter flow cytometry assays to determine the functionality of HIV-1-specific CD8+ T memory cells. In all seven patients, the earliest T cell responses were predominantly oligofunctional, although the relative contribution of multifunctional cell responses increased significantly with time from infection. Interestingly, only the magnitude of the total and not of the poly-functional T-cell responses was significantly associated with the selection of escape mutants. However, the high contribution of MIP-1β-producing CD8+ T-cells to the total response suggests that mechanisms not limited to cytotoxicity could be exerting immune pressure during acute infection. Lastly, we show that epitope entropy, reflecting the capacity of the epitope to tolerate mutational change and defined as the diversity of epitope sequences at the population level, was also correlated with rate of emergence of escape mutants.

Background: We sought to measure resident physician knowledge of HIV epidemiology and screening guidelines, attitudes toward testing, testing practices, and barriers and facilitators to routine testing. Methods: Resident physicians in internal medicine, pediatrics, obstetrics and gynecology, and emergency medicine were surveyed. Results: Overall response rate was 63% (162 of 259). Half knew details of the HIV screening guidelines, but few follow these recommendations. Less than one-third reported always or usually performing routine testing. A significant proportion reported only sometimes or never screening patients with risk factors. This was despite a strong belief that HIV screening improves patient care and public health. The most common barriers to testing were competing priorities and forgetting to order the test. Elimination of written consent and electronic reminders was identified as facilitators to routine testing. Although an institutional policy assigns responsibility for test notification and linkage of HIV-positive patients to care to the HIV care program, only 29% were aware of this. Conclusions: Few resident physicians routinely screen for HIV infection and some don’t test patients with risk factors. While competing priorities remain a significant barrier, elimination of written consent form and electronic reminders has facilitated testing. Increasing the awareness of policies regarding test notification and linkage to care may improve screening.

Abstract Introduction Treatment of ulcerative colitis (UC) now includes mucosal healing. Adoption of histologic end points is hindered by a lack of evidence guiding optimal sampling, interpretation, and reproducibility of results. Methods We analyzed biopsy fragments from colonoscopies in 92 patients with UC. Fragments were scored using 6-point histologic inflammatory activity (HIA) scale. Variability was determined using ordinal representations of HIA scores. The most frequently observed score and percentage of biopsy fragments with that score were determined for each biopsy, each segment, and across all 3 segments for each colonoscopy. Mean percentages and 95% confidence intervals (CIs) were calculated. Results We reviewed 1802 biopsy fragments. The mean percentages of intrasegment biopsy fragments with the same HIA score were 85.5% (95% CI, 80.9% to 92.9%), 79.6% (95% CI, 76.0% to 87.3%), and 82.7% (95% CI, 79.1% to 90.0%) for the rectum, left colon, and right colon, respectively. The mean percentage of intersegment biopsy fragments with the same HIA score was 70.2% (95% CI, 65.7% to 82.5%). The mean percentages of intrabiopsy fragments with the same HIA score were 83.3% (95% CI, 77.6% to 93.5%), 83.6% (95% CI, 80.1% to 89.7%), and 90.2% (95% CI, 87.6% to 94.7%) for the rectum, left colon, and right colon, respectively. All 3 analyses revealed increased variation when a greater degree of histologic inflammation was present in the biopsies (mean HIA score ≥2). Conclusions We found minimal variability between degree of inflammation among biopsy fragments within and among different colorectal segments in UC, suggesting that even a single biopsy would adequately reflect the inflammation of the entire colorectum. These findings have significant implications for the use of histology as a clinical target and trial end point in UC.

Vaccine design is challenging when the infectious agent is genetically diverse. Polyvalent 'mosaic' antigens might be used to address this challenge, and these two studies show promising results in monkeys infected with HIV-1 ( pages 268–270 and pages 319–323 ). An effective HIV vaccine must elicit immune responses that recognize genetically diverse viruses 1 , 2 . It must generate CD8 + T lymphocytes that control HIV replication and CD4 + T lymphocytes that provide help for the generation and maintenance of both cellular and humoral immune responses against the virus 3 , 4 , 5 . Creating immunogens that can elicit cellular immune responses against the genetically varied circulating isolates of HIV presents a key challenge for creating an HIV vaccine 6 , 7 . Polyvalent mosaic immunogens derived by in silico recombination of natural strains of HIV are designed to induce cellular immune responses that recognize genetically diverse circulating virus isolates 8 . Here we immunized rhesus monkeys by plasmid DNA prime and recombinant vaccinia virus boost with vaccine constructs expressing either consensus or polyvalent mosaic proteins. As compared to consensus immunogens, the mosaic immunogens elicited CD8 + T lymphocyte responses to more epitopes of each viral protein than did the consensus immunogens and to more variant sequences of CD8 + T lymphocyte epitopes. This increased breadth and depth of epitope recognition may contribute both to protection against infection by genetically diverse viruses and to the control of variant viruses that emerge as they mutate away from recognition by cytotoxic T lymphocytes.

The variation of luminal pH and transit time in an individual is unknown, yet is necessary to interpret single measurements. This study aimed to assess the intrasubject variability of gut pH and transit time in healthy volunteers using SmartPill devices (Covidien, Minneapolis, MN). Each subject (n=10) ingested two SmartPill devices separated by 24 h. Mean pH values were calculated for 30 min after gastric emptying (AGE), before the ileocecal (BIC) valve, after the ileocecal (AIC) valve, and before body exit (BBE). Intrasubject variability was determined by comparing mean values from both ingestions for an individual subject using standard deviations, 95% limits of agreement, and Bland-Altman plots. Tandem device ingestion occurred without complication. The median (full range) intrasubject standard deviations for pH were 0.02 (0.0002-0.2048) for AGE, 0.06 (0.0002-0.3445) for BIC, 0.14 (0.0018-0.3042) for AIC, and 0.08 (0.0098-0.5202) for BBE. There was a significant change in pH for AIC (mean difference: -0.45±0.31, P=0.0015) observed across all subjects. The mean coefficients of variation for transit time were 12.0±7.4% and 25.8±15.8% for small and large bowels, respectively (P=0.01). This study demonstrates the safety and feasibility of tandem gut transit and pH assessments using the SmartPill device. In healthy individuals and over 24 h, the gut pH profile does not markedly fluctuate in a given region with more variation seen in the colon compared with the small bowel, which has important implications for future physiology and drug delivery studies.

Physician religiosity can influence their ethical attitude toward medical procedures and can thereby impact healthcare delivery. Using a national survey of American Muslim physicians, we explored the association between physician recommendation of three controversial medical procedures—tubal ligation, abortion, and porcine-based vaccine—and their (1) religiosity, (2) utilization of bioethics resources, and (3) perception of whether the procedure was a medical necessity and if the scenario represented a life threat. Generally, multivariate models found that physicians who read the Qur'an more often as well as those who perceived medical necessity and/or life threat had a higher odds recommending the procedures, whereas those who sought Islamic bioethical guidance from Islamic jurists (or juridical councils) more often had a lower odds. These associations suggest that the bioethical framework of Muslim physicians is influenced by their reading of scripture, and the opinions of Islamic jurists and that these influences may, paradoxically, be interpreted to be in opposition over some medical procedures.

Background Complete macroscopic resection surgery, pleurectomy and decortication (PD) improve survival in selected patients with malignant pleural mesothelioma (MPM). Yet its value has been questioned because of concern that this extensive surgical procedure may disrupt health-related quality of life (HRQoL). Methods HRQoL was studied in patients undergoing PD surgery for MPM using EORTC QLQ-C30 instrument at baseline (prior to surgery), 1, 4–5, 7–8, and 10–11 months following surgery. Global health and variables in function and symptom domains were investigated. Sub-groups analyses were performed for ECOG performance status (PS), histological sub-types and pathological tumor volume (pTV). Within-patient comparisons to baseline scores were made using Wilcoxon signed-rank test. Trends over time were evaluated using Cuzick’s nonparametric test. Results There were 114 patients with median age of 70 years (range: 50–88) and PS 0: 35 (30.7%), epithelioid histology: 61 (53.5%) and volume <600 ml: 58 (50.9%). Patients with good PS (PS 0), epithelioid histology and small pTV had greater level of functioning and were less symptomatic at baseline. Overall global health worsened at the first postoperative month ( p  = 0.0005) with subsequent improvement. Non-epithelioid histology and patients with large pTV demonstrated greater improvement in global health, function and symptoms domains following a PD. Conclusions At baseline, the overall health-related quality of life, function and symptom domains were adversely affected in non-epithelioid histology and patients with large pTV. However, greatest improvement in global health, symptom and function domains were observed first month after PD and during the follow-up in these sub-groups.

An effective HIV vaccine must elicit immune responses that recognize genetically diverse viruses. It must generate CD8 super(+) T lymphocytes that control HIV replication and CD4 super(+) T lymphocytes that provide help for the generation and maintenance of both cellular and humoral immune responses against the virus. Creating immunogens that can elicit cellular immune responses against the genetically varied circulating isolates of HIV presents a key challenge for creating an HIV vaccine. Polyvalent mosaic immunogens derived by in silico recombination of natural strains of HIV are designed to induce cellular immune responses that recognize genetically diverse circulating virus isolates. Here we immunized rhesus monkeys by plasmid DNA prime and recombinant vaccinia virus boost with vaccine constructs expressing either consensus or polyvalent mosaic proteins. As compared to consensus immunogens, the mosaic immunogens elicited CD8 super(+) T lymphocyte responses to more epitopes of each viral protein than did the consensus immunogens and to more variant sequences of CD8 super(+) T lymphocyte epitopes. This increased breadth and depth of epitope recognition may contribute both to protection against infection by genetically diverse viruses and to the control of variant viruses that emerge as they mutate away from recognition by cytotoxic T lymphocytes.