Cost effectiveness of simplified HCV screening-and-treatment interventions for people who inject drugs in Dar-es-Salaam, Tanzania.

BACKGROUND: Compared to other countries in sub-Saharan Africa, Tanzania has a relatively progressive illicit drug harm reduction (HR) policy, through a predominantly opioid substitution therapy-based programme. However, access to hepatitis C virus (HCV) diagnosis and curative direct acting antiviral therapy remains elusive. We developed a cost-effectiveness model to evaluate a simplified HCV screening-and-treatment intervention amongst PWID in Dar-es-Salaam, Tanzania. METHODS: A decision tree and Markov state transition model compared existing practice (no access to HCV viral confirmation and treatment) with the integration of point-of-care HCV screening and treatment within (1) existing HR services and (2) expansion to include PWID not currently engaged in HR. Outcome measures were screening, treatment, HR and disease-related costs per PWID, quality-adjusted life years (QALY) and disability adjusted life years (DALY). Cost-effectiveness was evaluated from a healthcare payer's perspective over a 30-year time horizon over a range of willingness-to-pay thresholds (USD$273 to USD$1,050). Both deterministic and probabilistic sensitivity analyses have been conducted. RESULTS: Assuming a chronic HCV prevalence of 18.8%, screening-and-treatment in existing HR settings resulted in an ICER per QALY-gained and DALY averted of USD$633 and USD$1,161, respectively. Expanding to include an outreach programme for unengaged PWID yielded an ICER per QALY-gained and DALY-averted of USD$4,091 and USD$10,288. Factors affecting the sensitivity of the ICER value included the cost of HR and the health utility of non-cirrhotic disease states. CONCLUSION: Simplified HCV screening and treatment of PWID has the potential to be cost-effective in Dar-es-Salaam, Tanzania. In practice, synergism of human and financial resources with established health programmes may offer a pragmatic solution to minimise operational costs.

Intrauterine Growth Restriction Causes Abnormal Embryonic Dentate Gyrus Neurogenesis in Mouse Offspring That Leads to Adult Learning and Memory Deficits.

Human infants who suffer from intrauterine growth restriction (IUGR), which is a failure to attain their genetically predetermined weight, are at increased risk for postnatal learning and memory deficits. Hippocampal dentate gyrus (DG) granule neurons play an important role in memory formation; however, it is unknown whether IUGR affects embryonic DG neurogenesis, which could provide a potential mechanism underlying abnormal postnatal learning and memory function. Using a mouse model of the most common cause of IUGR, induced by hypertensive disease of pregnancy, we first assessed adult learning and memory function. We quantified the percentages of embryonic hippocampal DG neural stem cells (NSCs) and progenitor cells and developing glutamatergic granule neurons, as well as hippocampal volumes and neuron cell count and morphology 18 and 40 d after delivery. We characterized the differential embryonic hippocampal transcriptomic pathways between appropriately grown and IUGR mouse offspring. We found that IUGR offspring of both sexes had short-term adult learning and memory deficits. Prenatally, we found that IUGR caused accelerated embryonic DG neurogenesis and Sox2+ neural stem cell depletion. IUGR mice were marked by decreased hippocampal volumes and decreased doublecortin+ neuronal progenitors with increased mean dendritic lengths at postnatal day 18. Consistent with its known molecular role in embryonic DG neurogenesis, we also found evidence for decreased Wnt pathway activity during IUGR. In conclusion, we have discovered that postnatal memory deficits are associated with accelerated NSC differentiation and maturation into glutamatergic granule neurons following IUGR, a phenotype that could be explained by decreased embryonic Wnt signaling.

Cost-effectiveness of strategies to improve HCV screening, linkage-to-care and treatment in remand prison settings in England.

BACKGROUND: A simplified cascade-of-care may improve screening and treatment uptake among incarcerated individuals. We assessed the cost-effectiveness of traditional and simplified screening and treatment in a London remand prison. METHODS: Using empirical data from Her Majesty's Prison (HMP) Wormwood Scrubs, London, we designed a decision tree and Markov transition state model using national average data for HCV screening and treatment for the base-case scenario. This compared two alternative strategies; (a) general prison population screening and treatment and (b) prioritising screening and treatment among people who inject drugs (PWID) combined with general prison population screening and treatment. Strategies varied the rates of screening (47%-90%), linkage-to-care (60%-86%) and treatment (21%-85%). Cost, utility and disease transition rates were obtained from existing literature. Outcome measures were as follows: screening, treatment and disease-related costs per admitted individual, quality-adjusted life years (QALYs). Incremental cost-effectiveness ratios (ICERs) were calculated for each intervention. All costs and utilities were discounted at a rate of 3.5% per annum. Both univariate and probabilistic sensitivity analyses have been conducted. RESULTS: In our cohort of 5239 incarcerated individuals with an estimated chronic HCV prevalence of 2.6%, all strategy ICER values (£3565-10 300) fell below the national willingness to pay threshold (£30 000). Increased successful treatment (7%-54%) was observed by an optimising cascade-of-care. A robust sensitivity analysis identified treatment cost of, QALY for mild liver disease and probability of completing treatment as important factors that impact the ICER value. CONCLUSION: In our remand setting, optimising adherence to the cascade-of-care is cost-effective. Where universal screening is not practical, a stratified approach focused on intensive screening and treatment of PWID also results in increased treatment uptake and is highly cost-effective.

Consistent high prevalence of undiagnosed blood-borne virus infection in patients attending large urban emergency departments in England.

Understanding local viral hepatitis and HIV epidemiology is essential if WHO elimination targets are to be achieved. We demonstrate a consistently high prevalence of undiagnosed active infection in urban emergency department attendees in England, with variations in local risk groups crucial to informing targeted testing initiatives.

In-field evaluation of Xpert® HCV viral load Fingerstick assay in people who inject drugs in Tanzania.

BACKGROUND: Although novel hepatitis C virus (HCV) RNA point-of-care technology has the potential to enhance the diagnosis in resource-limited settings, very little real-world validation of their utility exists. We evaluate the performance of HCV RNA quantification using the Xpert® HCV viral load Fingerstick assay (Xpert® HCV VL Fingerstick assay) as compared to the World Health Organisation pre-qualified plasma Xpert® HCV VL assay among people who inject drugs (PWID) attending an opioid agonist therapy (OAT) clinic in Dar-es-Salaam, Tanzania. METHODS: Between December 2018 and February 2019, consecutive HCV seropositive PWID attending the OAT clinic provided paired venous and Fingerstick samples for HCV RNA quantification. These were processed onsite using the GeneXpert® platform located at the Central tuberculosis reference laboratory. RESULTS: A total of 208 out of 220 anti-HCV-positive participants recruited (94.5%) had a valid Xpert® HCV VL result available; 126 (61%; 95% CI 53.8-67.0) had detectable and quantifiable HCV RNA. About 188 (85%) participants had paired plasma and Fingerstick whole blood samples; the sensitivity and specificity for the quantification of HCV RNA levels were 99.1% and 98.7% respectively. There was an excellent correlation (R2  = .95) and concordance (mean difference 0.13 IU/mL, (95% CI -0.9 to 0.16 IU/mL) in HCV RNA levels between plasma samples and Fingerstick samples. CONCLUSION: This study found excellent performance of the Xpert® HCV VL Fingerstick assay for HCV RNA detection and quantification in an African-field setting. Its clinical utility represents an important watershed in overcoming existing challenges to HCV diagnosis, which should play a crucial role in HCV elimination in Africa.

Time matters: Point of care screening and streamlined linkage to care dramatically improves hepatitis C treatment uptake in prisoners in England.

BACKGROUND: In England, opt-out dry blood spot prison screening for HIV, hepatitis B and hepatitis C (HCV) has been introduced to scale-up access to care. Recent advances in point-of-care HCV diagnostics provide an opportunity to improve diagnosis and treatment uptake. We compared the retention along and time intervals between each aspect of the HCV care continuum for an alternative rapid point-of-care-testing and simplified treatment strategy with existing national opt-out HCV dry blood spot testing and treatment at a large remand prison in West London. METHODS: Between September 2017 and December 2018 universal opt-out dry blood spot HCV testing, clinical assessment and treatment uptake were recorded at Her Majesty's Prison Wormwood Scrubs. Outcomes were compared to a point-of-care-based (salivary Oraquick® anti-HCV screening and Xpert® HCV fingerstick viral load) screening and streamlined treatment pathway offered to all new arrivals to the HMP Wormwood Scrubs substance misuse unit, which ran in parallel to dry blood spot testing between September and December 2018. RESULTS: During the study period 2442 out of 5239 inmates (46.6%) underwent dry blood spot screening, resulting in 62 (2.6%) HCV RNA positive cases. Thirteen (21.3%) individuals commenced therapy and no viral relapse cases were observed to date. In comparison, 162 out of 181 (89.5%) inmates admitted to the substance misuse unit agreed to rapid point-of-care testing; 20 (12.3%) HCV RNA positive cases. Seventeen (85.0%) of eligible inmates commenced treatment. The median length of stay (90 vs 30 days), time to screening (6 vs 2 days), assessment (14 vs 3 days) and treatment (36 vs 1 day) were shorter for the rapid point-of-care screen-and-treat group. CONCLUSION: Current scaling-up of prison dry blood spot HCV screening and treatment in England is sub-optimal. In our setting, the cascade of care is time and resource sensitive and is greatly improved by the introduction of a simplified screen-and-treat strategy.

Intrauterine Growth Restriction and Hyperoxia as a Cause of White Matter Injury.

Intrauterine growth restriction (IUGR) is estimated to occur in 5% of pregnancies, with placental insufficiency being the most common cause in developed countries. While it is known that white matter injury occurs in premature infants, the extent of IUGR on white matter injury is less defined in term infants. We used a novel murine model that utilizes a thromboxane A2 (TXA2) analog (U46619), a potent vasoconstrictor, to induce maternal hypertension and mimic human placental insufficiency-induced IUGR to study the white matter. We also investigated the role of hyperoxia as an additional risk factor for white matter injury, as IUGR infants are at increased risk of respiratory comorbidities leading to increased oxygen exposure. We found that TXA2 analog-induced IUGR results in white matter injury as demonstrated by altered myelin structure and changes in the oligodendroglial cell/oligodendrocyte population. In addition, our study demonstrates that hyperoxia exposure independently results in white matter perturbation. To our knowledge, this is the first study to report single and combined effects of IUGR with hyperoxia impacting the white matter and motor function. These results draw attention to the need for close monitoring of motor development in IUGR babies following hospital discharge as well as highlighting the importance of limiting, as clinically feasible, the degree of oxygen overexposure to potentially improve motor outcomes in this population of infants.

Elbasvir/grazoprevir and sofosbuvir for hepatitis C virus genotype 3 infection with compensated cirrhosis: A randomized trial.

Many direct-acting antiviral regimens have reduced activity in people with hepatitis C virus (HCV) genotype (GT) 3 infection and cirrhosis. The C-ISLE study assessed the efficacy and safety of elbasvir/grazoprevir (EBR/GZR) plus sofosbuvir (SOF) with and without ribavirin (RBV) in compensated cirrhotic participants with GT3 infection. This was a phase 2, randomized, open-label study. Treatment-naive participants received EBR/GZR + SOF + RBV for 8 weeks or EBR/GZR + SOF for 12 weeks, and peginterferon/RBV treatment-experienced participants received EBR/GZR + SOF ± RBV for 12 weeks or EBR/GZR + SOF for 16 weeks. The primary endpoint was HCV RNA <15 IU/mL 12 weeks after the end of treatment (sustained virologic response at 12 weeks [SVR12]). Among treatment-naive participants, SVR12 was 91% (21/23) in those treated with RBV for 8 weeks and 96% (23/24) in those treated for 12 weeks. Among treatment-experienced participants, SVR12 was 94% (17/18) and 100% (17/17) in the 12-week arm, with and without RBV, respectively, and 94% (17/18) in the 16-week arm. Five participants failed to achieve SVR: 2 relapsed (both in the 8-week arm), 1 discontinued due to vomiting/cellulitis (16-week arm), and 2 discontinued (consent withdrawn/lost to follow-up). SVR12 was not affected by the presence of resistance-associated substitutions (RASs). There was no consistent change in insulin resistance, and 5 participants reported serious adverse events (pneumonia, chest pain, opiate overdose, cellulitis, decreased creatinine). High efficacy was demonstrated in participants with HCV GT3 infection and cirrhosis. Treatment beyond 12 weeks was not required, and efficacy was maintained regardless of baseline RASs. CONCLUSION: Data from this study support the use of EBR/GZR plus SOF for 12 weeks without RBV for treatment-naive and peginterferon/RBV-experienced people with GT3 infection and cirrhosis (ClinicalTrials.gov NCT02601573). (Hepatology 2018;67:2113-2126).

Effects of excess thromboxane A2 on placental development and nutrient transporters in a Mus musculus model of fetal growth restriction.

Hypertensive disease of pregnancy (HDP) with placental insufficiency is the most common cause of fetal growth restriction (FGR) in the developed world. Despite the known negative consequences of HDP both to the mother and fetus, little is known about the longitudinal placental changes that occur as HDP progresses in pregnancy. This is because longitudinal sampling of human placentae during each gestation is impossible. Therefore, using a mouse model of thromboxane A2-analog infusion to mimic human HDP in the last trimester, we calculated placental efficiencies based on fetal and placental weights; quantified spongiotrophoblast and labyrinth thicknesses and vascular density within these layers; examined whether hypoxia signaling pathway involving vascular endothelial growth factor A (VEGFA) and its receptors (VEGFR1, VEGFR2) and matrix metalloproteinases (MMPs) contributed to vascular change; and examined nutrient transporter abundance including glucose transporters 1 and 3 (GLUT1, GLUT3), neutral amino acid transporters 1, 2, and 4 (SNAT1, SNAT2, and SNAT4), fatty acid transporters 2 and 4 (FATP2, FATP4), and fatty acid translocase (CD36) from embryonic day 15.5 to 19 in a 20-day C57Bl/6J mouse gestation. We conclude that early-to-mid gestation hypertensive placentae show compensatory mechanisms to preserve fetal growth by increasing placental efficiencies and maintaining abundance of important nutrient transporters. As placental vascular network diminishes over late hypertension, placental efficiency diminishes and fetal growth fails. Neither hypoxia signaling pathway nor MMPs mediated the vascular diminution in this model. Hypertensive placentae surprisingly exhibit a sex-differential expression of nutrient transporters in late gestation despite showing fetal growth failure in both sexes.

Comparative Evaluation of Veriflow® Salmonella Species to USDA and FDA Culture-Based Methods for the Detection of Salmonella spp. in Food and Environmental Samples.

Veriflow® Salmonella species (Veriflow SS) is a molecular-based assay for the presumptive detection of Salmonella spp. from environmental surfaces (stainless steel, sealed concrete, plastic, and ceramic tile), dairy (2% milk), raw meat (20% fat ground beef), chicken carcasses, and ready-to-eat (RTE) food (hot dogs). The assay utilizes a PCR detection method coupled with a rapid, visual, flow-based assay that develops in 3 min post-PCR amplification and requires only an 18 h enrichment for maximum sensitivity. The Veriflow SS system eliminates the need for sample purification, gel electrophoresis, or fluorophore-based detection of target amplification and does not require complex data analysis. This Performance Tested MethodSM validation study demonstrated the ability of the Veriflow SS method to detect low levels of artificially inoculated or naturally occurring Salmonella spp. in eight distinct environmental and food matrixes. In each reference comparison study, probability of detection analysis indicated that there was no significant difference between the Veriflow SS method and the U.S. Department of Agriculture Food Safety and Inspection Service Microbiology Laboratory Guidebook Chapter 4.06 and the U.S. Food and Drug Administration Bacteriological Analytical Manual Chapter 5 reference methods. A total of 104 Salmonella strains were detected in the inclusivity study, and 35 nonspecific organisms went undetected in the exclusivity study. The study results show that the Veriflow SS method is a sensitive, selective, and robust assay for the presumptive detection of Salmonella spp. sampled from environmental surfaces (stainless steel, sealed concrete, plastic, and ceramic tile), dairy (2% milk), raw meat (20% fat ground beef), chicken carcasses, and RTE food (hot dogs).

Comparative Evaluation of Veriflow®Listeria Species to USDA Culture-Based Method for the Detection of Listeria spp. in Food and Environmental Samples.

Veriflow® Listeria species (Veriflow LS) is a molecular-based assay for the presumptive detection of Listeria spp. from environmental surfaces (stainless steel, sealed concrete, plastic, and ceramic tile) and ready-to-eat (RTE) food matrixes (hot dogs and deli meat). The assay utilizes a PCR detection method coupled with a rapid, visual, flow-based assay that develops in 3 min post-PCR amplification and requires only a 24 h enrichment for maximum sensitivity. The Veriflow LS system eliminates the need for sample purification, gel electrophoresis, or fluorophore-based detection of target amplification and does not require complex data analysis. This Performance Tested MethodSM validation study demonstrated the ability of the Veriflow LS assay to detect low levels of artificially inoculated Listeria spp. in six distinct environmental and food matrixes. In each unpaired reference comparison study, probability of detection analysis indicated that there was no significant difference between the Veriflow LS method and the U.S. Department of Agriculture Food Safety and Inspection Service Microbiology Laboratory Guide Chapter 8.08 reference method. Fifty-one strains of various Listeria spp. were detected in the inclusivity study, and 35 nonspecific organisms went undetected in the exclusivity study. The study results show that the Veriflow LS is a sensitive, selective, and robust assay for the presumptive detection of Listeria spp. sampled from environmental surfaces (stainless steel, sealed concrete, plastic, and ceramic tile) and RTE food matrixes (hot dogs and deli meat).

Intrauterine Growth Restriction Alters Mouse Intestinal Architecture during Development.

Infants with intrauterine growth restriction (IUGR) are at increased risk for neonatal and lifelong morbidities affecting multiple organ systems including the intestinal tract. The underlying mechanisms for the risk to the intestine remain poorly understood. In this study, we tested the hypothesis that IUGR affects the development of goblet and Paneth cell lineages, thus compromising the innate immunity and barrier functions of the epithelium. Using a mouse model of maternal thromboxane A2-analog infusion to elicit maternal hypertension and resultant IUGR, we tested whether IUGR alters ileal maturation and specifically disrupts mucus-producing goblet and antimicrobial-secreting Paneth cell development. We measured body weights, ileal weights and ileal lengths from birth to postnatal day (P) 56. We also determined the abundance of goblet and Paneth cells and their mRNA products, localization of cellular tight junctions, cell proliferation, and apoptosis to interrogate cellular homeostasis. Comparison of the murine findings with human IUGR ileum allowed us to verify observed changes in the mouse were relevant to clinical IUGR. At P14 IUGR mice had decreased ileal lengths, fewer goblet and Paneth cells, reductions in Paneth cell specific mRNAs, and decreased cell proliferation. These findings positively correlated with severity of IUGR. Furthermore, the decrease in murine Paneth cells was also seen in human IUGR ileum. IUGR disrupts the normal trajectory of ileal development, particularly affecting the composition and secretory products of the epithelial surface of the intestine. We speculate that this abnormal intestinal development may constitute an inherent "first hit", rendering IUGR intestine susceptible to further injury, infection, or inflammation.

Comparative Evaluation of Veriflow® Listeria monocytogenes to USDA and AOAC Culture Based Methods for the Detection of Listeria monocytogenes in Food.

Veriflow® Listeria monocytogenes (LM) is a molecular based assay for the presumptive detection of Listeria monocytogenes from environmental surfaces, dairy, and ready-to-eat (RTE) food matrixes (hot dogs and deli meat). The assay utilizes a PCR detection method coupled with a rapid, visual, flow-based assay that develops in 3 min post PCR amplification and requires only 24 h of enrichment for maximum sensitivity. The Veriflow LM system eliminates the need for sample purification, gel electrophoresis, or fluorophore-based detection of target amplification, and does not require complex data analysis. This Performance Tested Method(SM) validation study demonstrated the ability of the Veriflow LM method to detect low levels of artificially inoculated L. monocytogenes in seven distinct environmental and food matrixes. In each unpaired reference comparison study, probability of detection analysis indicated no significant difference between the Veriflow LM method and the U.S. Department of Agriculture, Food Safety and Inspection Service Microbiology Laboratory Guidebook 8.08 or AOAC 993.12 reference method. Fifty strains of L. monocytogenes were detected in the inclusivity study, while 39 nonspecific organisms were undetected in the exclusivity study. The study results show that Veriflow LM is a sensitive, selective, and robust assay for the presumptive detection of L. monocytogenes sampled from environmental, dairy, or RTE (hot dogs and deli meat) food matrixes.

Intrauterine growth restriction perturbs nucleosome depletion at a growth hormone-responsive element in the mouse IGF-1 gene.

Intrauterine growth restriction (IUGR) is a common human pregnancy complication. IUGR offspring carry significant postnatal risk for early-onset metabolic syndrome, which is associated with persistent reduction in IGF-1 protein expression. We have previously shown that preadolescent IUGR male mice have decreased hepatic IGF-1 mRNA and circulating IGF-1 protein at postnatal day 21, the age when growth hormone (GH) normally upregulates hepatic IGF-1 expression. Here we studied nucleosome occupancy and CpG methylation at a putative growth hormone-responsive element in intron 2 (in2GHRE) of the hepatic IGF-1 gene in normal, sham-operated, and IUGR mice. Nucleosome occupancy and CpG methylation were determined in embryonic stem cells (ESCs) and in liver at postnatal days 14, 21, and 42. For CpG methylation, additional time points out to 2 yr were analyzed. We confirmed the putative mouse in2GHRE was GH-responsive, and in normal mice, a single nucleosome was displaced from the hepatic in2GHRE by postnatal day 21, which exposed two STAT5b DNA binding sites. Nucleosome displacement correlated with developmentally programmed CpG demethylation. Finally, IUGR significantly altered the nucleosome-depleted region (NDR) at the in2GHRE of IGF-1 on postnatal day 21, with either complete absence of the NDR or with a shifted NDR exposing only one of two STAT5b DNA binding sites. An NDR shift was also seen in offspring of sham-operated mothers. We conclude that prenatal insult such as IUGR or anesthesia/surgery could perturb the proper formation of a well-positioned NDR at the mouse hepatic IGF-1 in2GHRE necessary for transitioning to an open chromatin state.

IUGR prevents IGF-1 upregulation in juvenile male mice by perturbing postnatal IGF-1 chromatin remodeling.

BACKGROUND: Intrauterine growth restriction (IUGR) offspring with rapid catch-up growth are at increased risk for early obesity especially in males. Persistent insulin-like growth factor-1 (IGF-1) reduction is an important risk factor. Using a mouse model of maternal hypertension-induced IUGR, we examined IGF-1 levels, promoter DNA methylation, and histone H3 covalent modifications at birth (D1). We additionally investigated whether prenatal perturbations could reset at preadolescence (D21). METHODS: IUGR was induced via maternal thromboxane A2-analog infusion in mice. RESULTS: IUGR uniformly decreased D1 IGF-1 mRNA and protein levels with reduced promoter 1 (P1) transcription and increased P1 DNA methylation. IUGR males also had increased H3K4ac at exon 5 and 3' distal UTR. At D21, IUGR males continued to have decreased IGF-1 levels, originating from both P1 and P2 with reduced 1A variant. IUGR males also had decreased activation mark of H3K4me3 at P1 compared with sham males. In contrast, D21 IUGR females normalized their IGF-1 levels, in association with an increased activation mark of H3K4me3 at P1 compared with sham females. CONCLUSION: IUGR uniformly affected D1 hepatic IGF-1 epigenetic modifications in both sexes. However, at preadolescence, IUGR males are unable to correct for the prenatal reduction possibly due to a more perturbed IGF-1 chromatin structure.

Veriflow Campylobacter. Performance tested method 101201.

Veriflow Campylobacter is a molecular based assay for the presumptive and qualitative detection of the most common occurring foodborne Campylobacter species: C. jejuni and C. coli. The assay utilizes a PCR detection method coupled with a rapid, visual, flow-based assay that develops in 3 min post PCR amplification and requires only 24 h of non-specialized enrichment for maximum sensitivity. The Veriflow Campylobacter system eliminates the need for microaerobic chambers, gel electrophoresis or fluorophore based detection of target amplification, and does not require complex data analysis. This Performance Tested Method validation study demonstrated the ability of the Veriflow method to detect naturally occurring Campylobacterfrom chicken carcass rinsates. In the reference comparison study, Chi-square and probability of detection analyses of two unpaired studies indicated that there was no significant difference between the Veriflow Campylobacter method and the U.S. Department of Agriculture (USDA)/Food Safety and Inspection Service (FSIS) reference method. There was no indication of false positive or false negative detection in the reference comparison study, and all 50 C. jejuni and C. coli strains were detected, while 35 nonspecific organisms were undetected in the exclusivity/ inclusivity study. The study results show that Veriflow Campylobacter is a sensitive, selective and robust assay for the detection of C. jejuni and C. coli in chicken carcass rinsates.

Lipid profiling of pre-treatment liver biopsy tissue predicts sustained virological response in patients with chronic hepatitis C.

AIM: Hepatic lipid is important in the pathogenesis and progression of hepatitis C-related liver disease. Polyunsaturated fatty acids have been shown to reduce viral replication in cell culture. Proton magic angle spinning magnetic resonance spectroscopy ((1) H MAS MRS) enables metabolic analysis of intact tissue. The aim was to examine the relationship between hepatic lipid composition by metabolic profiling of liver tissue at baseline and treatment response to pegylated-Interferon alfa2 and Ribavirin. METHODS: Baseline liver biopsy samples from 31 patients with chronic hepatitis C were analyzed histologically and by (1) H MAS MRS. Indices of lipid composition were derived and partial least squares discriminant analysis with cross-validation was used to predict treatment outcome. RESULTS: Of 31 patients, 14 achieved sustained virological response (SVR). Lipid polyunsaturation (median (IQR)) was higher in SVR (3.41% (2.31)) than in treatment failure (TF) (2.15% (1.51)), P = 0.02. Lipid saturation was lower in SVR (85.9% (3.39)) than TF (86.7% (2.17)), P = 0.04. The total lipid content was lower in SVR (1.54% (0.81)) than TF (2.72% (3.47)), P = 0.004. Total choline to lipid ratio was higher in SVR (11.51% (9.99)) than TF (7.5% (6.82)), P = 0.007. Cross-validation correctly predicted the SVR group in 13 of 14 samples with 1 sample misclassified, and the TF group in all 17 samples. CONCLUSIONS: Lipid polyunsaturation was greater and total lipid lower in those with SVR, compared with TF. Metabolic profiling of intact liver biopsy samples predicted SVR with high accuracy. Hepatic lipid composition may impact on treatment success.

Uteroplacental insufficiency alters rat hippocampal cellular phenotype in conjunction with ErbB receptor expression.

INTRODUCTION: Uteroplacental insufficiency (UPI) produces significant neurodevelopmental deficits affecting the hippocampus of intrauterine growth-restricted (IUGR) offspring. IUGR males have worse deficits as compared with IUGR females. The exact mechanisms underlying these deficits are unclear. Alterations in hippocampal cellular composition along with altered expression of neural stem cell (NSC) differentiation molecules may underlie these deficits. We hypothesized that IUGR hippocampi would be endowed with altered neuronal, astrocytic, and immature oligodendrocytic proportions at birth, with males showing greater cellular deficits. We further hypothesized that UPI would perturb rat hippocampal expression of ErbB receptors (ErbB-Rs) and neuregulin 1 (NRG1) at birth and at weaning to account for the short- and long-term IUGR neurological sequelae. METHODS: A well-established rat model of bilateral uterine artery ligation at embryonic day 19.5 was used to induce IUGR. RESULTS: As compared with gender-matched controls, IUGR offspring have altered hippocampal neuronal, astrocytic, and immature oligodendrocytic composition in a subregion- and gender-specific manner at birth. In addition, IUGR hippocampi have altered receptor type- and gender-specific ErbB-R expression at birth and at weaning. DISCUSSION: These cellular and molecular alterations may account for the neurodevelopmental complications of IUGR and for the male susceptibility to worse neurologic outcomes.

Hepatocellular carcinoma in patients with chronic hepatitis C virus infection without cirrhosis.

AIM: To investigate and characterise patients with chronic hepatitis C virus (HCV) infection presenting with hepatocellular carcinoma (HCC) in the absence of cirrhosis. METHODS: Patients with chronic hepatitis C infection without cirrhosis presenting with HCC over a 2-year period were identified. The clinical case notes, blood test results and histological specimens were reviewed to identify whether additional risk factors for the development of HCC were present. RESULTS: Six patients (five male, one female) with chronic hepatitis C infection without cirrhosis presented to a single centre with HCC over a 2-year period. Five patients were treated by surgical resection and one patient underwent liver transplantation. Evaluation of generous histological specimens confirmed the presence of HCC and the absence of cirrhosis in all cases. The degree of fibrosis of the background liver was staged as mild (n = 1), moderate (n = 4) or bridging fibrosis (n = 1). Review of the clinical case notes revealed that all cases had an additional risk factor for the development of HCC (four had evidence of past hepatitis B virus infection; two had a history of excessive alcohol consumption; a further patient had prolonged exposure to immune suppression). CONCLUSION: HCC does occur in patients with non-cirrhotic HCV infection who have other risk factors for hepatocarcinogenesis.