Developing power plant materials using the life cycle lens.

The Spherical Tokamak for Energy Production (STEP) environment will include magnetic, thermal, mechanical and environmental loads far greater than those seen in the Joint European Torus campaigns of the past decade or currently contemplated for ITER. Greater still are the neutron peak dose rates of 10-6 displacements per atom, per second, which in-vessel materials in STEP are anticipated to be exposed to. Reduced activation and high-fluence resilience therefore dominate the materials strategy to support the STEP Programme. The latter covers the full life cycle from downselected compositions and new microstructural developments to irradiation-informed modelling and end-of-life strategies. This article discusses how the materials downselection is oriented in plant power trade-off space, outlines the development of an advanced ferritic-martensitic structural steel, describes the 'Design by Fundamentals' mesoscale modelling approach and reports some of the waste mitigation routes intended to make STEP operations as sustainable as possible.This article is part of the theme issue 'Delivering Fusion Energy - The Spherical Tokamak for Energy Production (STEP)'.

Magnetic Resonance Liver Iron Concentration Can Guide Venesection Decision-Making in Hyperferritinemia.

BACKGROUND: The clinical benefit of venesection in suspected iron overload can be unclear and serum ferritin may overestimate the degree of iron overload. AIMS: To help inform practice, we examined magnetic resonance liver iron concentration (MRLIC) in a cohort investigated for haemochromatosis. METHODS: One hundred and six subjects with suspected haemochromatosis underwent HFE genotyping and MRLIC with time-matched serum ferritin and transferrin saturation values. For those treated with venesection, volume of blood removed was calculated as a measure of iron overload. RESULTS: Forty-seven C282Y homozygotes had median ferritin 937 µg/l and MRLIC 4.83 mg/g; MRLIC was significantly higher vs non-homozygotes for any given ferritin concentration. No significant difference in MRLIC was observed between homozygotes with and without additional risk factors for hyperferritinemia. Thirty-three compound heterozygotes (C282Y/H63D) had median ferritin 767 µg/l and MRLIC 2.58 mg/g; ferritin < 750 µg/l showed 100% specificity for lack of significant iron overload (< 3.2 mg/g). 79% of C282Y/H63D had additional risk factors-mean MRLIC was significantly lower in this sub-group (2.4 mg/g vs 3.23 mg/g). 26 C282Y heterozygous or wild-type had median ferritin 1226 µg/l and MRLIC 2.13 mg/g; 69% with additional risk factors had significantly higher ferritin concentrations (with comparable MRLIC) and ferritin < 1000 µg/l showed 100% specificity for lack of significant iron overload. In 31 patients (26 homozygotes, 5 C282Y/H63D) venesected to ferritin < 100 µg/l, MRLIC and total venesection volume correlated strongly (r = 0.749), unlike MRLIC and serum ferritin. CONCLUSION: MRLIC is an accurate marker of iron overload in haemochromatosis. We propose serum ferritin thresholds in non-homozygotes which, if validated, could tailor cost-effective use of MRLIC in venesection decision-making.

Quantitative BOLD imaging at 3T: Temporal changes in hepatocellular carcinoma and fibrosis following oxygen challenge.

PURPOSE: To evaluate the utility of oxygen challenge and report on temporal changes in blood oxygenation level-dependent (BOLD) contrast in normal liver, hepatocellular carcinoma (HCC) and background fibrosis. MATERIALS AND METHODS: Eleven volunteers (nine male and two female, mean age 33.5, range 27-41 years) and 10 patients (nine male and one female, mean age 68.9, range 56-87 years) with hepatocellular carcinoma on a background of diffuse liver disease were recruited. Imaging was performed on a 3T system using a multiphase, multiecho, fast gradient echo sequence. Oxygen was administered via a Hudson mask after 2 minutes of free-breathing. Paired t-tests were performed to determine if the mean pre- and post-O2 differences were statistically significant. RESULTS: In patients with liver fibrosis (n = 8) the change in T2* following O2 administration was elevated (0.88 ± 0.582 msec, range 0.03-1.69 msec) and the difference was significant (P = 0.004). The magnitude of the BOLD response in patients with HCC (n = 10) was larger, however the response was more variable (1.07 ± 1.458 msec, range -0.93-3.26 msec), and the difference was borderline significant (P = 0.046). The BOLD response in the volunteer cohort was not significant (P = 0.121, 0.59 ± 1.162 msec, range -0.81-2.44 msec). CONCLUSION: This work demonstrates that the BOLD response following oxygen challenge within cirrhotic liver is consistent with a breakdown in vascular autoregulatory mechanisms. Similarly, the elevated BOLD response within HCC is consistent with the abnormal capillary vasculature within tumors and the arterialization of the blood supply. Our results suggest that oxygen challenge may prove a viable BOLD contrast mechanism in the liver. J. Magn. Reson. Imaging 2016;44:739-744.

An extensive antigenic footprint underpins immunodominant TCR adaptability against a hypervariable viral determinant.

Mutations in T cell epitopes are implicated in hepatitis C virus (HCV) persistence and can impinge on vaccine development. We recently demonstrated a narrow bias in the human TCR repertoire targeted at an immunodominant, but highly mutable, HLA-B*0801-restricted epitope ((1395)HSKKKCDEL(1403) [HSK]). To investigate if the narrow TCR repertoire facilitates CTL escape, structural and biophysical studies were undertaken, alongside comprehensive functional analysis of T cells targeted at the natural variants of HLA-B*0801-HSK in different HCV genotypes and quasispecies. Interestingly, within the TCR-HLA-B*0801-HSK complex, the TCR contacts all available surface-exposed residues of the HSK determinant. This broad epitope coverage facilitates cross-genotypic reactivity and recognition of common mutations reported in HCV quasispecies, albeit to a varying degree. Certain mutations did abrogate T cell reactivity; however, natural variants comprising these mutations are reportedly rare and transient in nature, presumably due to fitness costs. Overall, despite a narrow bias, the TCR accommodated frequent mutations by acting like a blanket over the hypervariable epitope, thereby providing effective viral immunity. Our findings simultaneously advance the understanding of anti-HCV immunity and indicate the potential for cross-genotype HCV vaccines.

Myoferlin: A Potential Marker of Response to Radiation Therapy and Survival in Locally Advanced Rectal Cancer.

PURPOSE: Patients with locally advanced rectal cancer often require neoadjuvant chemoradiation therapy to downstage the disease, but the response is variable with no predictive biomarkers. We have previously revealed through proteomic profiling that myoferlin is associated with response to radiation therapy. The aims of this study were to further validate this finding and explore the potential for myoferlin to act as a prognostic and/or therapeutic target. METHODS AND MATERIALS: Immunohistochemical analysis of a tissue microarray (TMA) for 111 patients was used to validate the initial proteomic findings. Manipulation of myoferlin was achieved using small interfering RNA, a small molecular inhibitor (wj460), and a CRISPR-Cas9 knockout cell line. Radiosensitization after treatment was assessed using 2-dimensional clonogenic assays, 3-dimensional spheroid models, and patient-derived organoids. Underlying mechanisms were investigated using electrophoresis, immunofluorescence, and immunoblotting. RESULTS: Analysis of both the diagnostic biopsy and tumor resection samples confirmed that low myoferlin expression correlated with a good response to neoadjuvant long-course chemoradiation therapy. High myoferlin expression was associated with spread to local lymph nodes and worse 5-year survival (P = .01; hazard ratio, 3.5; 95% CI, 1.27-10.04). This was externally validated using the Stratification in Colorectal Cancer database. Quantification of myoferlin using immunoblotting in immortalized colorectal cancer cell lines and organoids demonstrated that high myoferlin expression was associated with increased radioresistance. Biological and pharmacologic manipulation of myoferlin resulted in significantly increased radiosensitivity across all cell lines in 2-dimensional and 3-dimensional models. After irradiation, myoferlin knockdown cells had a significantly impaired ability to repair DNA double-strand breaks. This appeared to be mediated via nonhomologous end-joining. CONCLUSIONS: We have confirmed that high expression of myoferlin in rectal cancer is associated with poor response to neoadjuvant therapy and worse long-term survival. Furthermore, the manipulation of myoferlin led to increased radiosensitivity in vitro. This suggests that myoferlin could be targeted to enhance the sensitivity of patients with rectal cancer to radiation therapy, and further work is required.

Radiology of eating disorders: a pictorial review.

Eating disorders are a major challenge for health professionals, with many patients receiving ineffective care due to underdiagnosis or poor compliance with treatment. The incidence of eating disorders is increasing worldwide, producing an increasing burden on healthcare systems, and they most often affect young patients, with significant long-term complications. The effects of long-term malnutrition manifest in almost every organ system, and many can be detected radiologically, even without overt clinical findings. Musculoskeletal complications including osteoporosis result in a high incidence of insufficiency fractures, with long-term implications for bone health and growth, while respiratory complications are often recognized late due to disordered physiologic responses to infection. Gastrointestinal complications are numerous and in extreme cases may result in fatal outcomes after acute gastric dilatation and rupture subsequent to binge eating. In patients with severely disordered eating, in particular anorexia nervosa, marked derangement of electrolyte levels may result in refeeding syndrome, which requires emergent management. Recognition of such complications is critical to effective patient care and requires radiologists to be aware of the spectrum of imaging abnormalities that may be seen. Since many patients are reluctant to disclose their underlying condition, radiologists also play a critical role in identifying previously undiagnosed eating disorders.

Antigen-driven patterns of TCR bias are shared across diverse outcomes of human hepatitis C virus infection.

Hepatitis C virus (HCV) infection causes significant morbidity and mortality worldwide. T cells play a central role in HCV clearance; however, there is currently little understanding of whether the disease outcome in HCV infection is influenced by the choice of TCR repertoire. TCR repertoires used against two immunodominant HCV determinants--the highly polymorphic, HLA-B*0801 restricted (1395)HSKKKCDEL(1403) (HSK) and the comparatively conserved, HLA-A*0101-restricted, (1435)ATDALMTGY(1443) (ATD)--were analyzed in clearly defined cohorts of HLA-matched, HCV-infected individuals with persistent infection and HCV clearance. In comparison with ATD, TCR repertoire selected against HSK was more narrowly focused, supporting reports of mutational escape in this epitope, in persistent HCV infection. Notwithstanding the Ag-driven divergence, T cell repertoire selection against either Ag was comparable in subjects with diverse disease outcomes. Biased T cell repertoires were observed early in infection and were evident not only in persistently infected individuals but also in subjects with HCV clearance, suggesting that these are not exclusively characteristic of viral persistence. Comprehensive clonal analysis of Ag-specific T cells revealed widespread use of public TCRs displaying a high degree of predictability in TRBV/TRBJ gene usage, CDR3 length, and amino acid composition. These public TCRs were observed against both ATD and HSK and were shared across diverse disease outcomes. Collectively, these observations indicate that repertoire diversity rather than particular Vß segments are better associated with HCV persistence/clearance in humans. Notably, many of the anti-HCV TCRs switched TRBV and TRBJ genes around a conserved, N nucleotide-encoded CDR3 core, revealing TCR sequence mosaicism as a potential host mechanism to combat this highly variant virus.

Molecular epidemiology of hepatitis B in the Indigenous people of northern Australia.

BACKGROUND AND AIM: The hepatitis B surface antigen was first described in the blood of an Indigenous Australian man, yet little is known about its molecular epidemiology in this population, in which it is endemic. The study aimed to determine the clinical and molecular epidemiology of hepatitis B virus (HBV) in Indigenous people from northern Australia. METHODS: Following ethics approval and informed consent, blood specimens and clinical details from Indigenous adults known to be infected with HBV and who were born and raised in Indigenous communities in northern Australia were obtained. HBV genotypes were determined in isolates with sufficient HBV DNA by polymerase chain reaction by sequencing of the polymerase/surface gene. RESULTS: Between June 2010 and June 2012, 65 patients were recruited from six different regions of northern Australia. Thirty-two patients (49%) were hepatitis B e-antigen-positive, and 48% were hepatitis B e-antibody-positive. No patients were found to be coinfected with hepatitis C virus or human immunodeficiency virus. Of the 49 samples with sufficient viral load for genotyping, 100% were infected with genotype C4, previously only reported from two Indigenous Australians. All isolates had wild-type polymerase gene sequences despite 14 currently or previously receiving antiviral treatment. The canonical sG145R vaccine-escape variant was detected in the surface antigen of virus from two patients. CONCLUSIONS: The exclusive HBV genotype in this ancient population is genotype C4. Whole genome sequencing and clinical follow-up of this cohort are in progress, with the aim of exploring the clinical significance of these findings.

Association between aneurysm shoulder stress and abdominal aortic aneurysm expansion: a longitudinal follow-up study.

BACKGROUND: Aneurysm expansion rate is an important indicator of the potential risk of abdominal aortic aneurysm (AAA) rupture. Stress within the AAA wall is also thought to be a trigger for its rupture. However, the association between aneurysm wall stresses and expansion of AAA is unclear. METHODS AND RESULTS: Forty-four patients with AAAs were included in this longitudinal follow-up study. They were assessed by serial abdominal ultrasonography and computed tomography scans if a critical size was reached or a rapid expansion occurred. Patient-specific 3-dimensional AAA geometries were reconstructed from the follow-up computed tomography images. Structural analysis was performed to calculate the wall stresses of the AAA models at both baseline and final visit. A nonlinear large-strain finite element method was used to compute the wall-stress distribution. The relationship between wall stresses and expansion rate was investigated. Slowly and rapidly expanding aneurysms had comparable baseline maximum diameters (median, 4.35 cm [interquartile range, 4.12 to 5.0 cm] versus 4.6 cm [interquartile range, 4.2 to 5.0 cm]; P=0.32). Rapidly expanding AAAs had significantly higher shoulder stresses than slowly expanding AAAs (median, 300 kPa [interquartile range, 280 to 320 kPa] versus 225 kPa [interquartile range, 211 to 249 kPa]; P=0.0001). A good correlation between shoulder stress at baseline and expansion rate was found (r=0.71; P=0.0001). CONCLUSION: A higher shoulder stress was found to have an association with a rapidly expanding AAA. Therefore, it may be useful for estimating the expansion of AAAs and improve risk stratification of patients with AAAs.

Juvenile haemochromatosis.

Juvenile haemochromatosis is a severe inherited iron-loading disorder that can present in children and adolescents. Typical manifestations include heart failure, endocrine failure (including diabetes and hypogonadism), cirrhosis, and arthropathy. Compared with HFE haemochromatosis, juvenile haemochromatosis affects female and male individuals similarly, presents at a younger age, and causes multiple organ dysfunction; the principle of iron loading into tissues from the gut is shared by both forms, but the process is far more rapid in juvenile haemochromatosis. Juvenile haemochromatosis is initially recognised by extreme increases of serum ferritin and transferrin saturation, which is supported by an MRI showing iron deposition in the heart and liver. MRI software techniques allow quantification of iron in these organs, and can therefore be used to monitor progress. Juvenile haemochromatosis is autosomal recessive and is generally associated with mutations in HJV (type 2A) or HAMP (type 2B). Mutations in TFR2 cause an intermediate severity phenotype (type 3), but this phenotype can cross over into the juvenile haemochromatosis spectrum so it might need to be additionally considered during diagnosis. Treatment needs to be administered without delay, in the form of aggressive iron chelation, and a multidisciplinary approach is essential. Because iron is removed, organ function is restored, which could obviate the need for cardiac or liver transplantation. Substantial restoration of health can ensue, but patients require life-long monitoring. Family screening is an important component of the management of juvenile haemochromatosis. Genetic advances which underpin the haemochromatosis types also clarify the role of iron metabolism in health and disease, particularly the role of hepcidin in regulating iron homoeostasis. Therefore, juvenile haemochromatosis is an important condition to understand; it can present insidiously in children and adolescents, and awareness of the diagnosis is needed to inform early recognition and treatment.

Submarine canyons: hotspots of benthic biomass and productivity in the deep sea.

Submarine canyons are dramatic and widespread topographic features crossing continental and island margins in all oceans. Canyons can be sites of enhanced organic-matter flux and deposition through entrainment of coastal detrital export, dense shelf-water cascade, channelling of resuspended particulate material and focusing of sediment deposition. Despite their unusual ecological characteristics and global distribution along oceanic continental margins, only scattered information is available about the influence of submarine canyons on deep-sea ecosystem structure and productivity. Here, we show that deep-sea canyons such as the Kaikoura Canyon on the eastern New Zealand margin (42 degrees 01' S, 173 degrees 03' E) can sustain enormous biomasses of infaunal megabenthic invertebrates over large areas. Our reported biomass values are 100-fold higher than those previously reported for deep-sea (non-chemosynthetic) habitats below 500 m in the ocean. We also present evidence from deep-sea-towed camera images that areas in the canyon that have the extraordinary benthic biomass also harbour high abundances of macrourid (rattail) fishes likely to be feeding on the macro- and megabenthos. Bottom-trawl catch data also indicate that the Kaikoura Canyon has dramatically higher abundances of benthic-feeding fishes than adjacent slopes. Our results demonstrate that the Kaikoura Canyon is one of the most productive habitats described so far in the deep sea. A new global inventory suggests there are at least 660 submarine canyons worldwide, approximately 100 of which could be biomass hotspots similar to the Kaikoura Canyon. The importance of such deep-sea canyons as potential hotspots of production and commercial fisheries yields merits substantial further study.

Cost-effectiveness analysis of endovascular versus open surgical repair of acute abdominal aortic aneurysms based on worldwide experience.

PURPOSE: To present an economic evaluation of endovascular versus open surgical repair of ruptured abdominal aortic aneurysms (AAA). METHODS: Endovascular aneurysm repair (EVAR) is currently being appraised by the National Institute for Clinical Excellence. To aid in this appraisal, a health economic model developed to demonstrate the cost-effectiveness of EVAR for elective treatment of non-ruptured AAAs versus OSR was used for an analysis in the emergency setting. The base case data on 730 patients undergoing EVAR was extracted from our recently published 22-study meta-analysis of 7040 patients presenting with acute AAA (ruptured or symptomatic) treated with either emergency EVAR or OSR. These data reflected a patient population with an average age of 70 years. The base case model, which assumed a time horizon of 30 years and applied all-cause mortality rates, was subjected to a number of 1-way sensitivity analyses. A multivariate analysis was undertaken using 10,000 Monte-Carlo simulations. RESULTS: EVAR dominated OSR in the base case analysis, with a mean cumulative cost/patient of pound17,422 ($26,133) for EVAR and pound18,930 ($28,395) for OSR [- pound1508 ($2262) difference]. The mean quality-adjusted life years (QALYs)/patient was 3.09 for EVAR versus 2.49 for OSR (0.64 difference). EVAR was cost-effective compared with OSR at a threshold value of pound20,000 to pound30,000 ($30,000-$45,000)/QALY. In no single combination tested did open surgical repair provide the patient with more QALYs than EVAR. Sensitivity analyses demonstrated that the results were most sensitive to length of hospital and intensive care stays, use of blood products, and the cost of the evar device, which were the main cost drivers. CONCLUSION: While the UK's National Institute for Clinical Excellence does not set an absolute limit at which treatments would not be funded, pound30,000 ($45,000) is generally regarded as the upper limit of acceptability. At this level, there is almost a 100% probability that EVAR is a cost-effective treatment for ruptured AAA.

Diffusion-weighted magnetic resonance imaging for the detection of lipid-rich necrotic core in carotid atheroma in vivo.

INTRODUCTION: Research has shown that knowing the morphology of carotid atheroma improves current risk stratification for predicting subsequent thrombo-embolic events. Previous magnetic resonance (MR) ex vivo studies have shown that diffusion-weighted imaging (DWI) can detect lipid-rich necrotic core (LR/NC) and fibrous cap. This study aims to establish if this is achievable in vivo. METHODS: Twenty-six patients (mean age 73 years, range 54-87 years) with moderate to severe carotid stenosis confirmed on ultrasound were imaged. An echo-planar DWI sequence was performed along with standard high-resolution MR imaging. Apparent diffusion coefficient (ADC) maps were evaluated. Two independent readers reported the mean ADC values from regions of interest defining LR/NCs and fibrous caps. For subjects undergoing carotid endarterectomy (n = 19), carotid specimens were obtained and stained using Nile red. RESULTS: The mean ADC values were 1.0 × 10(-3) mm(2)/s (±SD 0.3 × 10(-3) mm(2)/s) and 0.7 × 10(-3) mm(2)/s (±SD 0.2 × 10(-3) mm(2)/s) for fibrous cap and LR/NC, respectively; the difference was significant (p < 0.0001). The intra-class correlation coefficients summarising the agreement between the two independent readers were 0.84 and 0.60 for fibrous cap and LR/NC, respectively. Comparison of quantitative ADC values and histology (by subjective grading of lipid content) showed a significant correlation: heavier lipid staining matched lower ADC values (r = -0.435, p = 0.005). CONCLUSIONS: This study indicates that DWI can be used to distinguish LR/NC and the fibrous cap. The study also suggests that the mean ADC value may be linearly related to subjective graded LR/NC content determined by histology.

A case of successful surgical management of primary retroperitoneal mucinous cystadenoma.

Primary retroperitoneal mucinous cystadenoma (PRMC) is a rare tumour. It was first reported in 1965, and since then, less than 100 cases have been reported. It is cystic in nature and most commonly affects the female population. It becomes symptomatic in later stages due to its mass effect, making the diagnosis challenging in its early asymptomatic stage. We report a case of a 32-year-old female who presented with abdominal pain and a mass in left iliac fossa. Diagnostic imaging revealed a large cystic lesion in retroperitoneum. A midline laparotomy was performed, and a complete surgical excision was accomplished without any spillage. Surgical histology confirmed the diagnosis of PRMC. The patient was discharged on postoperative day 2. There was no evidence of tumour recurrence on repeat imaging at 90-day follow-up. Surgical approach, with complete resection and without any spillage, remains the most effective and appropriate treatment for this tumour.

Resilience of seamount benthic communities to trawling disturbance.

Despite bottom trawling being the most widespread, severe disturbance affecting deep-sea environments, it remains uncertain whether recovery is possible once trawling has ceased. Here, we review information regarding the resilience of seamount benthic communities to trawling. We focus on seamounts because benthic communities associated with these features are especially vulnerable to trawling as they are often dominated by emergent, sessile epifauna, and trawling on seamounts can be highly concentrated. We perform a meta-analysis to investigate whether any taxa demonstrate potential for recovery once trawling has ceased. Our findings indicate that mean total abundance can gradually increase after protection measures are placed, although taxa exhibit various responses, from no recovery to intermediate/high recovery, resistance, or signs of early colonisation. We use our results to recommend directions for future research to improve our understanding of the resilience of seamount benthic communities, and thereby inform the management of trawling impacts on these ecosystems.

Targeting Acid Ceramidase to Improve the Radiosensitivity of Rectal Cancer.

Previous work utilizing proteomic and immunohistochemical analyses has identified that high levels of acid ceramidase (AC) expression confers a poorer response to neoadjuvant treatment in locally advanced rectal cancer. We aimed to assess the radiosensitising effect of biological and pharmacological manipulation of AC and elucidate the underlying mechanism. AC manipulation in three colorectal cancer cell lines (HT29, HCT116 and LIM1215) was achieved using siRNA and plasmid overexpression. Carmofur and a novel small molecular inhibitor (LCL521) were used as pharmacological AC inhibitors. Using clonogenic assays, we demonstrate that an siRNA knockdown of AC enhanced X-ray radiosensitivity across all colorectal cancer cell lines compared to a non-targeting control siRNA, and conversely, AC protein overexpression increased radioresistance. Using CRISPR gene editing, we also generated AC knockout HCT116 cells that were significantly more radiosensitive compared to AC-expressing cells. Similarly, two patient-derived organoid models containing relatively low AC expression were found to be comparatively more radiosensitive than three other models containing higher levels of AC. Additionally, AC inhibition using carmofur and LCL521 in three colorectal cancer cell lines increased cellular radiosensitivity. Decreased AC protein led to significant poly-ADP ribose polymerase-1 (PARP-1) cleavage and apoptosis post-irradiation, which was shown to be executed through a p53-dependent process. Our study demonstrates that expression of AC within colorectal cancer cell lines modulates the cellular response to radiation, and particularly that AC inhibition leads to significantly enhanced radiosensitivity through an elevation in apoptosis. This work further solidifies AC as a target for improving radiotherapy treatment of locally advanced rectal cancer.

High incidence of hepatitis C virus reinfection in a cohort of injecting drug users.

UNLABELLED: An estimated 170 million people worldwide carry the hepatitis C virus (HCV), and in more developed countries the prevalence and incidence of HCV is particularly high among injecting drug users (IDUs). Spontaneous clearance of HCV infection and reinfection is well recognized but the level of protection against further infection conferred by HCV infection and clearance remains uncertain. We conducted a prospective study of HCV infection in IDUs recruited in Melbourne, Australia, using a much shorter median testing interval than in previous studies. Incidences of naive infection and reinfection were calculated by the person-year method and Cox proportional hazards regression used to adjust for covariates. A significantly higher HCV incidence rate was measured in previously infected IDUs (46.8% per year) compared with HCV-naive IDUs (15.5% per year). The hazard ratio for previously infected IDUs compared to HCV-naive IDUs, after adjustment for time-dependent covariates, was 2.54 (95% confidence interval, 1.11-5.78, P > |z| < 0.05). Viral persistence after reinfection appeared similar to that following naive infection. CONCLUSION: Our data suggest that HCV infection in IDUs is more likely following prior infection and clearance than in HCV-naive individuals, implying no increased immunity against further infection. This result has important implications for the future development of an HCV vaccine.

Carotid endarterectomy performed in the morning is associated with increased cerebral microembolization.

OBJECTIVES: Platelet function exhibits circadian variation with highest levels of activity in the morning and plays a central role in arterial thrombotic events, including thrombotic stroke following carotid endarterectomy (CEA). Prior to the platelet-rich thrombus occluding the carotid artery, multiple embolic signals are detected in the middle cerebral artery using transcranial Doppler ultrasound. We hypothesized that patients undergoing CEA early in the day may be at an increased stroke risk and this would manifest as an increased postoperative embolic count. METHODS: Data were collected prospectively on 235 patients undergoing primary CEA. Accurate start and finish times were recorded in addition to the number of postoperative emboli detected in the first three hours after CEA using transcranial Doppler (TCD) monitoring. RESULTS: For operations finishing before midday, there was a 3.6-fold increase in the number of emboli detected relative to afternoon finishes (53.2 vs 14.8, P = .002) with similar results for starts before 10:30 AM (48.1 vs 14.7, P =.002). There was also a significant correlation between start time and emboli count (P = .02). Of the 55 patients with no postoperative emboli, only 19 had a morning start (relative risk 0.63, P = .011). Patients were 6.9 times more likely to require treatment with Dextran-40 to prevent progression onto a thrombotic stroke if their CEA finished before midday (P = .008). CONCLUSION: There is a significantly increased rate of postoperative embolization for operations begun earlier in the day. Carotid endarterectomies performed in the afternoon may be at less risk of developing postoperative thrombotic stroke.

Consecutive infections and clearances of different hepatitis C virus genotypes in an injecting drug user.

BACKGROUND: The hepatitis C virus (HCV) causes significant morbidity and mortality worldwide, and is highly prevalent among injecting drug users (IDUs). Whether initial HCV infection and clearance provides protection from reinfection has not been established, but is an important question for vaccine development. OBJECTIVE: To elucidate an unusual history of HCV infection and clearance in an IDU. STUDY DESIGN: The subject was interviewed and gave blood samples at approximately three-month intervals; all samples were tested for anti-HCV and HCV RNA, genotyped if RNA detected, and checked for mixed genotypes; phylogenetic analysis performed on the subject's and injecting partners' core HCV sequences. RESULTS: We observed consecutive infections with HCV genotypes 3a, 1a and 6l, and intervening clearances, in a young IDU over 449 days. Genotypes 1a and 6l were probably acquired from the subject's injecting partners, who had genetically related infections. CONCLUSION: This case illustrates (1) the ease with which IDUs can acquire HCV, (2) that prior HCV infection does not protect against reinfection with heterologous strains, and (3) that IDUs can clear consecutive HCV infections. Our subject's history of HCV infection and clearance offers hope for vaccine development, yet demonstrates that HCV vaccines must have cross-genotypic effectiveness.