BACKGROUND: The incremental prognostic value of rest-redistribution (201)Tl compared with stress and rest perfusion abnormalities has not been defined. METHODS AND RESULTS: We identified 458 patients ...who underwent rest (201)Tl /stress (exercise or adenosine) (99m)Tc sestamibi single-photon emission computed tomography (SPECT) and had late (18 to 24 hours) (201)Tl imaging, were not revascularized within 60 days of SPECT, and were followed up at >1 year. SPECT images were visually analyzed with the use of a 20-segment model on a scale of 0 to 4. Thirty-seven cardiac deaths (CDs) and 17 nonfatal myocardial infarctions occurred. Univariate Cox proportional hazards analysis showed that the presence of a large amount of rest (201)Tl reversibility (rest-late summed difference score SDS of >8) was a significant predictor of CD (chi(2) = 5.77, P = 0.02) and CD or myocardial infarction (chi(2) = 5.3, P = 0.02). The CD rate was 9.3% y(-1) in patients with rest-late SDS of >8 compared with 3.6% y(-1) in patients with a mild/moderate amount of rest reversibility (rest-late SDS 3 to 8) and 3.4% y(-1) in patients with no rest reversibility (rest-late SDS <3) (P = 0.029). Kaplan-Meier survival analysis demonstrated significantly lower cumulative survival rates in patients with rest-late SDS of >8 (P = 0.01). Multivariate Cox proportional hazards analysis demonstrated that the presence of a large amount of resting reversibility was an independent and incremental predictor of CD after adjustment for stress and rest perfusion information. Multivariate logistic regression analysis demonstrated that resting reversibility was not an independent predictor of referral to coronary angiography and revascularization. CONCLUSIONS: The identification of a large amount of resting (201)Tl reversibility is an independent predictor of CD over stress and rest perfusion abnormalities.
Aberrant growth of blood vessels in the choroid layer of the eye, termed choroidal neovascularization (CNV), is the pathological hallmark of exudative age-related macular degeneration (AMD), causing ...irreversible blindness among the elderly. Co-localization of proangiogenic factors and hypoxia inducible factors (HIF) in neovascular membranes from AMD eyes suggests the role of hypoxia in pathogenesis of CNV. In order to utilize hypoxic conditions in RPE for therapeutic purposes, we developed an optimized hypoxia regulated, RPE cell-specific gene therapy to inhibit choroidal neovascularization. An adeno-associated virus (AAV2) vector comprising a RPE-specific promoter and HIF-1 response elements (HRE) was designed to regulate production of human endostatin (a powerful angiostatic protein) in RPE. The vector was tested in a mouse model of laser-induced CNV using subretinal delivery. Spectral domain optical coherence tomography (SD-OCT) images from live mice and confocal images from lectin stained RPE flat mount sections demonstrated reduction in CNV areas by 80% compared to untreated eyes. Quantitative real-time polymerase chain reaction (qPCR) confirmed exogenous endostatin mRNA expression from the regulated vector that was significantly elevated 3, 7, and 14 days following laser treatment, but its expression was completely shut off after 45 days. Thus, RPE-specific, hypoxia-regulated delivery of anti-angiogenic proteins could be a valuable therapeutic approach to treat neovascular AMD at the time and in the ocular space where it arises.
Key points
An optimized gene therapy vector targeting hypoxia and tissue-specific expression has been designed.
The inhibitory role of gene therapy vector was tested in a mouse model of laser-induced CNV.
An 80% reduction in choroidal neovascularization was achieved by the optimized vector.
The expression of endostatin was limited to retinal pigment epithelium and regulated by hypoxia.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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Background: Testicular seminoma is highly curable; however, treatments can cause long-term morbidity in survivors. Following chemotherapy for advanced seminoma, positron emission ...tomography with 2-18Ffluoro-2-deoxy-D-glucose together with computerised tomography (PET-CT) can identify patients with residual masses who do not need additional treatment. Its role in detecting recurrence during active surveillance, particularly in patients with small indeterminate masses, is unknown. We assessed the clinical utility of PET-CT in testicular seminoma undergoing active surveillance for stage 1 disease and following curative-intent treatment for advanced disease. Methods: An institutional database was interrogated to identify patients with testicular seminoma who underwent PET-CT between 2000-2020. Demographic, clinicopathological, PET-CT findings and outcome data were retrieved. The positive predictive value (PPV) of PET-CT for correctly identifying disease recurrence was calculated, with disease recurrence (true positive) defined as progressive radiological change, response to treatment or histological confirmation. Negative predictive value (NPV) was calculated for correctly identifying non-recurrence (true negative) at 24-months post PET-CT. Results: We identified 193 PET-CT in 181 stage 1 patients. Of these, 18 (10%) PET-CT were positive, with all correctly diagnosing recurrence, PPV 100%. Of the 138 negative PET-CT with at least 24 months follow up, 5 recurrences developed, NPV 96%. In the subset of PET-CT conducted for suspicion of recurrence in stage 1 patients (n = 71: abnormal imaging n = 65, elevated markers n = 4, other clinical suspicion n = 2), 16 (23%) PET-CT were positive, with all correctly diagnosing recurrence, PPV 100%. In this subset, the NPV is 93% at 24 months (3 recurrences in 44 negative PET-CT). We also identified 154 PET-CT in 77 post-treatment, advanced stage patients. Of these, 69 (45%) PET-CT were positive, with 51 correctly diagnosing recurrence, PPV 74%. Of the 66 negative PET-CT with at least 24 months follow up, 5 recurrences developed, NPV 92%. In the subset of PET-CT performed for suspicion of recurrence following treatment for advanced disease (n = 61: abnormal imaging n = 49, elevated markers n = 5, other clinical suspicion n = 7), 41 (67%) PET-CT were positive, with 36 correctly diagnosing recurrence, PPV 88%. In this subset, the NPV is 94% at 24 months (1 recurrence in 17 negative PET-CT). Conclusions: At our centre, PET-CT has a very high PPV for recurrence, particularly in stage 1 disease, and a very high NPV for non-recurrence in all disease settings. In the subset of PET-CT performed for suspicion of recurrence, PPV is > 88% and NPV is > 93%. The role of PET-CT should be considered in patients with suspicion of recurrence where it may prevent over-treatment in up to 70% patients in stage 1 or 30% in advanced disease.
Ionic liquids have been considered for their potential applications within the nuclear fuel cycle. If ionic liquids are to be successful in their application as solvents for highly radioactive ...materials in any future process, there will be a requirement for them to be robust to high radiation doses. A preliminary assessment of the radiation stability of 1,3-dialkylimidazolium cation based ionic liquids containing nitrate and chloride anions has been performed. The results of radiolysis studies are reported, in which the samples were exposed to alpha radiation from a tandem Van der Graaff generator, beta radiation from a linear accelerator and gamma radiation from cobalt 60 sources. These results suggest that their stability is similar to that of benzene and that they are much more stable than mixtures of tributylphosphate and odourless kerosene under similar irradiation conditions. The radiolysis of 1,3-dialkylimidazolium cation based ionic liquids reflects their combination of the properties of a salt, an alkane and an aromatic. They appear to be relatively radiation resistant and there is certainly no major decomposition of the organic component.
P24 Background: There is evidence that estrogen affects the vascular wall, independent of modifications to plasma lipoproteins, by accelerating reendothelialization of damaged blood vessels and by ...inhibiting smooth muscle cell proliferation. Therefore, we intended to investigate the relationship between hormone replacement therapy (HRT) use and prevalence of coronary calcium (CC) in postmenopausal women. Methods: Cardiac electron beam computed tomography (EBCT) was performed on 793 postmenopausal women participating in the Cedars-Sinai Cardiovascular Observational Study. At the time of their EBCT, 509 women were receiving HRT and 284 were not receiving HRT. The total coronary calcium score was determined using the Agatston method. A self-report of HRT use was assessed in all participants, as well as measurements of other known cardiovascular risk factors. Results: Independent sample t-tests identified the means of the following variables as significantly different between the two groups of women: age, LDL, HDL, and BMI. Self reports of hypertension, smoking, exercise and diet were similar between the two groups. Analysis of variance, controlling for confounders, showed a significant difference (p<.001) between the marginal means (MM) of the two HRT groups for total coronary calcium score, total number of calcified lesions, and total volume of calcium. The MM total CC score was 96.40 (±256.39) for HRT users and 150.97 (±362.54) for non-users. The MM number of lesions for users was 2.16 (±3.37) and 3.36 (±4.75) for non-users. The MM volume of calcium for users was 0.078 (±0.20) and 0.122 (±0.29) for non-users. Conclusions: Total coronary calcium score, total lesions, and total volume were found to be significantly lower in postmenopausal women receiving HRT than for those not receiving HRT. These findings support the hypothesis that hormone replacement therapy is associated with a lower prevalence of coronary calcium in postmenopausal women, which may be due to the independent effects of estrogen on coronary vessel walls.
OBJECTIVES
The study compared the prognostic significance of myocardial perfusion single-photon emission computed tomography (SPECT) (MPS) in patients early and late after coronary artery bypass ...graft surgery (CABG).
BACKGROUND
The long-term effectiveness of CABG is limited by graft stenosis. The greatest incidence of graft occlusion occurs between five and eight years after surgery. However, little is known regarding the appropriate time to stress patients post-CABG with respect to risk stratification.
METHODS
We identified 1,765 patients, who underwent MPS 7.1 ± 5.0 years post-CABG. All patients underwent rest Tl-201/stress Tc-99m sestamibi MPS and were followed up ≥1 year after testing. Patients with early CABG or PTCA (<60 days after MPS) were censored. The prognostic population consisted of 1,544 patients. A semiquantitative visual analysis employing a 20-segment model was used to define summed stress score (SSS), summed rest score (SRS), summed difference score (SDS), and the number of nonreversible segments (NRS).
RESULTS
During follow-up, 53 cardiac deaths (CD) occurred. There was a significant increase in annual CD rates as a function of SSS. A multivariate analysis identified age, ischemia (SDS), and infarct size (NRS) as independent predictors of CD. Nuclear variables added incremental value to prescan information. The annual CD rate was relatively low (1.3%) in patients ≤5 years post-CABG. In this subgroup only age and infarct size (NRS) were predictive of CD.
CONCLUSION
MPS is strongly predictive of subsequent CD in post-CABG patients and adds incremental value over clinical and treadmill test information. Our data suggest that symptomatic patients ≤5 years and all patients >5 years post-CABG may benefit from testing.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Background —The incremental prognostic value of rest-redistribution 201 Tl compared with stress and rest perfusion abnormalities has not been defined. Methods and Results —We identified 458 patients ...who underwent rest 201 Tl /stress (exercise or adenosine) 99m Tc sestamibi single-photon emission computed tomography (SPECT) and had late (18 to 24 hours) 201 Tl imaging, were not revascularized within 60 days of SPECT, and were followed up at >1 year. SPECT images were visually analyzed with the use of a 20-segment model on a scale of 0 to 4. Thirty-seven cardiac deaths (CDs) and 17 nonfatal myocardial infarctions occurred. Univariate Cox proportional hazards analysis showed that the presence of a large amount of rest 201 Tl reversibility (rest-late summed difference score SDS of >8) was a significant predictor of CD (χ 2 =5.77, P =0.02) and CD or myocardial infarction (χ 2 =5.3, P =0.02). The CD rate was 9.3% y −1 in patients with rest-late SDS of >8 compared with 3.6% y −1 in patients with a mild/moderate amount of rest reversibility (rest-late SDS 3 to 8) and 3.4% y −1 in patients with no rest reversibility (rest-late SDS <3) ( P =0.029). Kaplan-Meier survival analysis demonstrated significantly lower cumulative survival rates in patients with rest-late SDS of >8 ( P =0.01). Multivariate Cox proportional hazards analysis demonstrated that the presence of a large amount of resting reversibility was an independent and incremental predictor of CD after adjustment for stress and rest perfusion information. Multivariate logistic regression analysis demonstrated that resting reversibility was not an independent predictor of referral to coronary angiography and revascularization. Conclusions —The identification of a large amount of resting 201 Tl reversibility is an independent predictor of CD over stress and rest perfusion abnormalities.
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Millions of children throughout Africa undertake many forms of farm and domestic work. Some of this work is for wages, some is on their ...family's own small plots and some is forced and/or harmful.
This book examines children's involvement in such work. It argues that framing all children's engagement in economic activity as 'child labour', with all the associated negative connotations, is problematic. This is particularly the case in Africa where many rural children must work to survive and where, the contributors argue, much of the work undertaken is not harmful.
The conceptual and case-based chapters reframe the debate about children's work and harm in rural Africa with the aim of shifting research, public discourse and policy so that they better serve the interest of rural children and their families.
Abstract
Astronomers do not have a complete picture of the effects of wide-binary companions (semimajor axes greater than 100 au) on the formation and evolution of exoplanets. We investigate these ...effects using new data from Gaia Early Data Release 3 and the Transiting Exoplanet Survey Satellite mission to characterize wide-binary systems with transiting exoplanets. We identify a sample of 67 systems of transiting exoplanet candidates (with well-determined, edge-on orbital inclinations) that reside in wide visual binary systems. We derive limits on orbital parameters for the wide-binary systems and measure the minimum difference in orbital inclination between the binary and planet orbits. We determine that there is statistically significant difference in the inclination distribution of wide-binary systems with transiting planets compared to a control sample, with the probability that the two distributions are the same being 0.0037. This implies that there is an overabundance of planets in binary systems whose orbits are aligned with those of the binary. The overabundance of aligned systems appears to primarily have semimajor axes less than 700 au. We investigate some effects that could cause the alignment and conclude that a torque caused by a misaligned binary companion on the protoplanetary disk is the most promising explanation.
The kākāpō is a flightless parrot endemic to New Zealand. Once common in the archipelago, only 201 individuals remain today, most of them descending from an isolated island population. We report the ...first genome-wide analyses of the species, including a high-quality genome assembly for kākāpō, one of the first chromosome-level reference genomes sequenced by the Vertebrate Genomes Project (VGP). We also sequenced and analyzed 35 modern genomes from the sole surviving island population and 14 genomes from the extinct mainland population. While theory suggests that such a small population is likely to have accumulated deleterious mutations through genetic drift, our analyses on the impact of the long-term small population size in kākāpō indicate that present-day island kākāpō have a reduced number of harmful mutations compared to mainland individuals. We hypothesize that this reduced mutational load is due to the island population having been subjected to a combination of genetic drift and purging of deleterious mutations, through increased inbreeding and purifying selection, since its isolation from the mainland ∼10,000 years ago. Our results provide evidence that small populations can survive even when isolated for hundreds of generations. This work provides key insights into kākāpō breeding and recovery and more generally into the application of genetic tools in conservation efforts for endangered species.
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First genome sequencing and population genomic analyses of the critically endangered kākāpōGeneration of a high-quality annotated reference genome assembly for kākāpōSequencing of 49 kākāpō genomes from surviving island and extinct mainland populationsGenomic analyses of long-term isolated populations inform conservation strategies
Dussex et al. sequence modern and historical genomes from the critically endangered kākāpō to investigate the genetic consequences of long-term small population size. They find that the remaining kākāpō from a small island population are inbred but have fewer deleterious mutations compared to the now-extinct mainland population, providing insights into conservation strategies.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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