...consideration of the value-laden nature of policy interventions and the creation of forums to debate the moral and ethical dimensions of different approaches to urban health and city environments ...are essential. ...attention to health inequalities within urban areas should be a key focus of planning the urban environment.
Background Critical limb ischemia (CLI) is a life- and limb-threatening condition affecting 1% to 10% of the population with peripheral arterial disease. Traditional revascularization options are not ...possible for up to 50% of CLI patients, in which case, the use of cellular therapies, such as bone marrow-derived mesenchymal stem cells (MSCs), hold great promise as an alternative revascularization therapy. However, no randomized, controlled phase 3 trials to date have demonstrated an improvement in limb salvage with cellular therapies. This may be due to poor cell quality (ie, inability to generate a sufficient number of angiogenic MSCs) or to the inadequate retention and viability of MSCs after delivery, or both. Because concerns remain about the expansion and angiogenic potential of autologous MSCs in the CLI population, the objective of this study was to examine the effect of our novel culture media supplement, pooled human platelet lysate (PL), in lieu of the standard fetal bovine serum (FBS), to improve the expansion potential of MSCs from CLI patients. We also characterized the in vitro angiogenic activity of MSCs from the tibia of amputated CLI limbs compared with MSCs from healthy donors. Methods MSCs were obtained from the tibia of four CLI patients (ISC) and four ISC patients with diabetes mellitus (ISC+DM) undergoing major amputation. Healthy MSCs were aspirated from the iliac crest of four young and healthy donors. MSCs were isolated and expanded in culture with PL or FBS. MSCs from passage 3 to 6 were used for phenotypic marker expression and for adipogenic and osteogenic differentiation and were tested for their in vitro angiogenic activity on human microdermal endothelial cells. In parallel MSCs were cultured to passage 11 for population-doubling calculations. Results MSCs from ISC and ISC+DM patients and from healthy patients exhibited appropriate expression of cell surface markers and differentiation capacity. Population doublings were significantly greater for PL-stimulated compared with FBS-stimulated MSCs in all groups. Biologically active amounts of angiogens were identified in the secretome of all MSCs without consistent trends among groups. PL expansion did not adversely affect the angiogenic activity of MSCs compared with FBS. The ISC and ISC+DM MSCs demonstrated angiogenic effects on endothelial cells similar to those of healthy and ISC MSCs. Conclusion PL promotes the rapid expansion of MSCs from CLI and healthy persons. Importantly, MSCs expanded from CLI patients demonstrate the desired angiogenic activity compared with their healthy counterparts. We conclude that autologous MSCs from CLI patients can be sufficiently expanded with PL and be expected to deliver requisite angiogenic effects in vivo. We expect the improved expansion of ISC and ISC+DM with PL to be helpful in improving the successful delivery of autologous MSCs to patients with CLI.
To quantify optical and biomechanical properties of the feline cornea before and after photorefractive keratectomy (PRK) and assess the relative contribution of different biological factors to ...refractive outcome.
Department of Ophthalmology, University of Rochester, Rochester, New York, USA.
Adult cats had 6.0 diopter (D) myopic or 4.0 D hyperopic PRK over 6.0 or 8.0 mm optical zones (OZ). Preoperative and postoperative wavefront aberrations were measured, as were intraocular pressure (IOP), corneal hysteresis, the corneal resistance factor, axial length, corneal thickness, and radii of curvature. Finally, postmortem immunohistochemistry for vimentin and alpha-smooth muscle actin was performed.
Photorefractive keratectomy changed ocular defocus, increased higher-order aberrations, and induced myofibroblast differentiation in cats. However, the intended defocus corrections were only achieved with 8.0 mm OZs. Long-term flattening of the epithelial and stromal surfaces was noted after myopic, but not after hyperopic, PRK. The IOP was unaltered by PRK; however, corneal hysteresis and the corneal resistance factor decreased. Over the ensuing 6 months, ocular aberrations and the IOP remained stable, while central corneal thickness, corneal hysteresis, and the corneal resistance factor increased toward normal levels.
Cat corneas exhibited optical, histological, and biomechanical reactions to PRK that resembled those previously described in humans, especially when the OZ size was normalized to the total corneal area. However, cats exhibited significant stromal regeneration, causing a return to preoperative corneal thickness, corneal hysteresis and the corneal resistance factor without significant regression of optical changes induced by the surgery. Thus, the principal effects of laser refractive surgery on ocular wavefront aberrations can be achieved despite clear interspecies differences in corneal biology.
Abstract Background The decrement in utility attributable to side effects from combination antiretroviral therapy (CART) is unknown and likely to influence clinical decisions regarding CART ...initiation and cost-effectiveness. Objective To quantify the decrement in utility attributable to side effects from CART. Methods We estimated SF-6D utilities (quality-of-life weights on a scale from 0.29 worst possible health to 1.00 perfect health) from SF-12 scores among patients with HIV in the Veterans Aging Cohort Study by using a published and validated conversion algorithm. We then compared utilities among patients who: 1) did not have bothersome symptoms while taking CART; 2) had bothersome symptoms that they thought might be due to CART; and 3) had bothersome symptoms that they were confident were due to CART; we controlled for other characteristics known to influence quality of life and stratified analyses by CD4 count. Results Among 1864 patients with available data, symptoms perceived to be attributable to CART were associated with a mean (95% confidence interval) decrement in utility of 0.06 (0.05, 0.08) points in univariate analyses and 0.08 (0.06, 0.10) in multivariable analyses, clinically significant differences that are comparable to utility decrements reported for partial impotence or mild angina. Other significant predictors of changes in SF-6D utilities were hazardous alcohol consumption, recent drug use, cigarette smoking, homelessness, and African American race ( R2 = 0.12). Stratifying by CD4 count, symptoms attributable to CART side effects decreased utility by 0.03 to 0.08 points. Conclusions Symptoms perceived to be related to CART are associated with a substantial decrement in utility.
Abstract Purpose The Palisades of Vogt (POV) constitute the corneal epithelial stem cell niche, but identification of this region in ex-vivo tissue is difficult. Here we introduce a simple, direct ...method of identifying the POV in unsectioned, ex-vivo human tissue. Methods Twenty-two eyes were studied, four whole and eighteen rims. Orientation of whole eyes was determined and the eyes were marked to maintain their cardinal orientation prior to dissection. Samples were imaged with brightfield, linearly polarized light and transmitted circularly polarized light (CPL) and optical coherence tomography (OCT) volumes were acquired in all twelve clock hours around the limbus. Five samples were also fluorescently labeled to identify the epithelial basement membrane, and whole mounts were imaged with laser scanning confocal microscopy. Images were compared to confirm that the structures visible with polarized light were POV. Results Under CPL the POV presented as amber radial ridges visible in the superior and inferior regions of the tissue. Identification of POV was confirmed by correlating the structures seen under CPL, OCT and laser-scanning confocal microscopy. Conclusions CPL can be used to quickly identify POV regions in donor tissue. This technique can assist in targeted harvesting of stem cell regions for research and tissue for limbal transplant.
The purpose of this study was to compare the accuracy of (11)Ccholine positron emission tomography (CHOL-PET) with that of the combination of T2-weighted and diffusion-weighted (T2W/DW) magnetic ...resonance imaging (MRI) for delineating malignant intraprostatic lesions (IPLs) for guiding focal therapies and to investigate factors predicting the accuracy of CHOL-PET.
This study included 21 patients who underwent CHOL-PET and T2W/DW MRI prior to radical prostatectomy. Two observers manually delineated IPL contours for each scan, and automatic IPL contours were generated on CHOL-PET based on varying proportions of the maximum standardized uptake value (SUV). IPLs identified on prostatectomy specimens defined reference standard contours. The imaging-based contours were compared with the reference standard contours using Dice similarity coefficient (DSC), and sensitivity and specificity values. Factors that could potentially predict the DSC of the best contouring method were analyzed using linear models.
The best automatic contouring method, 60% of the maximum SUV (SUV60) , had similar correlations (DSC: 0.59) with the manual PET contours (DSC: 0.52, P=.127) and significantly better correlations than the manual MRI contours (DSC: 0.37, P<.001). The sensitivity and specificity values were 72% and 71% for SUV60; 53% and 86% for PET manual contouring; and 28% and 92% for MRI manual contouring. The tumor volume and transition zone pattern could independently predict the accuracy of CHOL-PET.
CHOL-PET is superior to the combination of T2W/DW MRI for delineating IPLs. The accuracy of CHOL-PET is insufficient for gland-sparing focal therapies but may be accurate enough for focal boost therapies. The transition zone pattern is a new classification that may predict how well CHOL-PET delineates IPLs.
Daily oral emtricitabine (FTC, F)/tenofovir disoproxil fumarate (TDF) combination is approved for HIV pre-exposure prophylaxis (PrEP) in men and women. Tenofovir alafenamide fumarate (TAF) is a ...newer, more potent prodrug of tenofovir (TFV), and in combination with FTC, has recently been approved for prevention of HIV through rectal transmission.
This Phase I, prospective, interventional, randomized study was conducted in three clinical sites: PROFAMILIA, Santo Domingo, Dominican Republic; University of Pittsburgh and Eastern Virginia Medical School. We assessed the multi-compartmental pharmacokinetics (primary outcome) and safety (secondary outcome) among HIV uninfected women randomized to F/TDF (200mg/300mg) or F/TAF (200mg/25mg; F/TAF25) (n=24) in a single dose phase (SDP) and F/TDF, F/TAF (200mg/10mg; F/TAF10), or F/TAF25 (n=75) in a multiple dose (14 daily doses) phase (MDP). We described PK parameters in plasma, peripheral blood mononuclear cells (PBMCs), and cervicovaginal (CV) and rectal fluids and tissues. ClinicalTrials.gov #NCT02904369, completed.
Recruitment for the study began on 5 October 2016. The first participant was enrolled on 6 October 2016 and the last participant completed the study 21 November 2017.
TFV concentrations area under curve (AUC) were ~20 fold lower following F/TAF versus F/TDF. TFV-diphosphate (TFV-DP) AUC concentrations in PBMCs were 7-fold higher with F/TAF25 versus F/TDF. Median TFV-DP concentrations in vaginal tissue (4hours post last dose) were approximately 6-fold higher with F/TAF25 versus F/TDF. TFV and TFV-DP were lower with F/TAF versus F/TDF in rectal tissue. Concentrations of FTC and FTC-triphosphate (FTC-TP) were similar across matrices and treatment arms. Gastrointestinal adverse events (AEs) occurred more frequently in F/TDF users (44.0%) than in either F/TAF group (11.5 and 12.0%).
F/TAF was safe and well-tolerated. TFV-DP concentrations were higher in PBMCs and similar or higher (4h post dose) in female genital tract tissues for F/TAF versus F/TDF. High FTC and FTC-TP concentrations in all compartments support the potential of F/TAF as a new PrEP combination for women.
United States Agency for International Development (USAID)/the President's Emergency Plan for AIDS Relief (PEPFAR) through Cooperative Agreement AID-OAA-A-14-00011 with CONRAD/Eastern Virginia Medical School. This publication resulted in part from research supported by the University of North Carolina at Chapel Hill Center for AIDS Research (CFAR).
Abstract Objective The assessment of health-related quality-of-life (HRQoL) in rheumatoid arthritis (RA) is becoming increasingly common in both research and clinical practice. One of the most widely ...used tools for measuring HRQoL is the Medical Outcomes Study 36-item Short-Form Health Survey (SF-36). We conducted a systematic review examining the impact of RA on HRQoL, measured through the SF-36. Methods MEDLINE and Embase were searched for observational studies reporting mean and standard deviation scores for each domain of the SF-36 in adult RA patients. Studies were reviewed in accordance with PRISMA guidelines, and a random-effects meta-analysis was performed. Results In total, 31 studies were eligible for inclusion in the meta-analysis, including 22,335 patients. Meta-analyses found that pooled mean HRQoL score for the SF-36 physical component summary was 34.1 (95% CI: 22.0–46.1) and mental component summary was 45.6 (95% CI: 30.3–60.8). Increased age was associated with reduced physical function and physical component summary (PCS) scores but improved mental health and mental component summary (MCS) scores. Female gender was associated with improved scores on role physical, bodily pain and PCS but reduced mental health and MCS scores. Longer disease duration was associated with improved MCS. Patients with RA have a substantially reduced HRQoL in comparison to both other physical illnesses and in comparison to normative datasets from UK and USA populations. Conclusions RA has a substantial impact on HRQoL. This supports recent NICE guidelines stipulating that RA patients should be regularly assessed for the impact their disease has on HRQoL and appropriate management provided.
Summary Background Ovarian cancer has a poor prognosis, with just 40% of patients surviving 5 years. We designed this trial to establish the effect of early detection by screening on ovarian cancer ...mortality. Methods In this randomised controlled trial, we recruited postmenopausal women aged 50–74 years from 13 centres in National Health Service Trusts in England, Wales, and Northern Ireland. Exclusion criteria were previous bilateral oophorectomy or ovarian malignancy, increased risk of familial ovarian cancer, and active non-ovarian malignancy. The trial management system confirmed eligibility and randomly allocated participants in blocks of 32 using computer-generated random numbers to annual multimodal screening (MMS) with serum CA125 interpreted with use of the risk of ovarian cancer algorithm, annual transvaginal ultrasound screening (USS), or no screening, in a 1:1:2 ratio. The primary outcome was death due to ovarian cancer by Dec 31, 2014, comparing MMS and USS separately with no screening, ascertained by an outcomes committee masked to randomisation group. All analyses were by modified intention to screen, excluding the small number of women we discovered after randomisation to have a bilateral oophorectomy, have ovarian cancer, or had exited the registry before recruitment. Investigators and participants were aware of screening type. This trial is registered with ClinicalTrials.gov , number NCT00058032. Findings Between June 1, 2001, and Oct 21, 2005, we randomly allocated 202 638 women: 50 640 (25·0%) to MMS, 50 639 (25·0%) to USS, and 101 359 (50·0%) to no screening. 202 546 (>99·9%) women were eligible for analysis: 50 624 (>99·9%) women in the MMS group, 50 623 (>99·9%) in the USS group, and 101 299 (>99·9%) in the no screening group. Screening ended on Dec 31, 2011, and included 345 570 MMS and 327 775 USS annual screening episodes. At a median follow-up of 11·1 years (IQR 10·0–12·0), we diagnosed ovarian cancer in 1282 (0·6%) women: 338 (0·7%) in the MMS group, 314 (0·6%) in the USS group, and 630 (0·6%) in the no screening group. Of these women, 148 (0·29%) women in the MMS group, 154 (0·30%) in the USS group, and 347 (0·34%) in the no screening group had died of ovarian cancer. The primary analysis using a Cox proportional hazards model gave a mortality reduction over years 0–14 of 15% (95% CI −3 to 30; p=0·10) with MMS and 11% (−7 to 27; p=0·21) with USS. The Royston-Parmar flexible parametric model showed that in the MMS group, this mortality effect was made up of 8% (−20 to 31) in years 0–7 and 23% (1–46) in years 7–14, and in the USS group, of 2% (−27 to 26) in years 0–7 and 21% (−2 to 42) in years 7–14. A prespecified analysis of death from ovarian cancer of MMS versus no screening with exclusion of prevalent cases showed significantly different death rates (p=0·021), with an overall average mortality reduction of 20% (−2 to 40) and a reduction of 8% (−27 to 43) in years 0–7 and 28% (−3 to 49) in years 7–14 in favour of MMS. Interpretation Although the mortality reduction was not significant in the primary analysis, we noted a significant mortality reduction with MMS when prevalent cases were excluded. We noted encouraging evidence of a mortality reduction in years 7–14, but further follow-up is needed before firm conclusions can be reached on the efficacy and cost-effectiveness of ovarian cancer screening. Funding Medical Research Council, Cancer Research UK, Department of Health, The Eve Appeal.
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