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BACKGROUND Moderate-to-severe hemophilia B is treated with lifelong, continuous coagulation factor IX replacement to prevent bleeding. Gene therapy for hemophilia B aims to establish sustained factor IX activity, thereby protecting against bleeding without burdensome factor IX replacement. METHODS In this open-label, phase 3 study, after a lead-in period (≥6 months) of factor IX prophylaxis, we administered one infusion of adeno-associated virus 5 (AAV5) vector expressing the Padua factor IX variant (etranacogene dezaparvovec; 2×1013 genome copies per kilogram of body weight) to 54 men with hemophilia B (factor IX activity ≤2% of the normal value) regardless of preexisting AAV5 neutralizing antibodies. The primary end point was the annualized bleeding rate, evaluated in a noninferiority analysis comparing the rate during months 7 through 18 after etranacogene dezaparvovec treatment with the rate during the lead-in period. Noninferiority of etranacogene dezaparvovec was defined as an upper limit of the two-sided 95% Wald confidence interval of the annualized bleeding rate ratio that was less than the noninferiority margin of 1.8. Superiority, additional efficacy measures, and safety were also assessed. RESULTS The annualized bleeding rate decreased from 4.19 (95% confidence interval [CI], 3.22 to 5.45) during the lead-in period to 1.51 (95% CI, 0.81 to 2.82) during months 7 through 18 after treatment, for a rate ratio of 0.36 (95% Wald CI, 0.20 to 0.64; P<0.001), demonstrating noninferiority and superiority of etranacogene dezaparvovec as compared with factor IX prophylaxis. Factor IX activity had increased from baseline by a least-squares mean of 36.2 percentage points (95% CI, 31.4 to 41.0) at 6 months and 34.3 percentage points (95% CI, 29.5 to 39.1) at 18 months after treatment, and usage of factor IX concentrate decreased by a mean of 248,825 IU per year per participant in the post-treatment period (P<0.001 for all three comparisons). Benefits and safety were observed in participants with predose AAV5 neutralizing antibody titers of less than 700. No treatment-related serious adverse events occurred. CONCLUSIONS Etranacogene dezaparvovec gene therapy was superior to prophylactic factor IX with respect to the annualized bleeding rate, and it had a favorable safety profile. [ABSTRACT FROM AUTHOR]

Background: To investigate the impact of intrapatient variability (IPV) in the levels of immunosuppressant drugs on health outcomes after liver transplantation., Methods: A comprehensive systematic review and meta-analysis were conducted, examining literature from MEDLINE/PubMed, Embase, Web of Science, Cochrane Reviews, and Cochrane CENTRAL., Results: The analysis focused on acute rejection, graft survival, acute kidney injury, and cancer risk as health outcomes. Of 2901 articles screened, 10 met the inclusion criteria. The results indicate a 19% reduction in the risk of acute rejection in patients with lower IPV (RR = 0.81; 95% confidence interval, 0.66-0.99), although 6 studies found no significant association between high IPV and acute rejection. Contrasting results were observed for graft survival, with 1 study indicating worse outcomes for high IPV, whereas another reported no significant difference. High IPV was consistently associated with acute kidney injury across 3 studies. One study suggested a link between high IPV and hepatocellular carcinoma, although a meta-analysis for these outcomes was not feasible., Conclusions: These findings point to a marginal but statistically significant association between high IPV and an increased risk of acute rejection, highlighting the importance of precise management of immunosuppressive drugs in liver transplant recipients to enhance patient outcomes., (Copyright © 2024 The Author(s). Transplantation Direct. Published by Wolters Kluwer Health, Inc.)

Background: The National Hemophilia Foundation (NHF) conducted extensive all-stakeholder inherited bleeding disorder (BD) community consultations to inform a blueprint for future research. Sustaining and expanding the specialized and comprehensive Hemophilia Treatment Center care model, to better serve all people with inherited BDs (PWIBD), and increasing equitable access to optimal health emerged as top priorities., Research Design and Methods: NHF, with the American Thrombosis and Hemostasis Network (ATHN), convened multidisciplinary expert working groups (WG) to distill priority research initiatives from consultation findings. WG5 was charged with prioritizing health services research (HSR); diversity, equity, and inclusion (DEI); and implementation science (IS) research initiatives to advance community-identified priorities., Results: WG5 identified multiple priority research themes and initiatives essential to capitalizing on this potential. Formative studies using qualitative and mixed methods approaches should be conducted to characterize issues and meaningfully investigate interventions. Investment in HSR, DEI and IS education, training, and workforce development are vital., Conclusions: An enormous amount of work is required in the areas of HSR, DEI, and IS, which have received inadequate attention in inherited BDs. This research has great potential to evolve the experiences of PWIBD, deliver transformational community-based care, and advance health equity.

Background: Clinical application of population pharmacokinetics (popPK) is of increasing interest to patients with hemophilia, providers, and payers. Routine use of popPK profiles in factor replacement prophylaxis decision making has the potential to maintain or improve efficacy and reduce product consumption., Aim: To investigate the feasibility of implementation and longitudinal assessment of pharmacokinetic (PK)-tailored prophylaxis in routine clinical practice for hemophilia A and to describe factors that influence decision making for prescribed hemophilia prophylaxis., Methods: This longitudinal, multicenter, prospective feasibility study of children and adults with hemophilia A without inhibitors used the Web Accessible Population Pharmacokinetic Service-Hemophilia (WAPPS-Hemo) to generate PK profiles. Assessments over 12 weeks captured data on prescribed prophylaxis, popPK tool use, provider decision making, and patient-reported outcomes., Results: Eighteen participants aged 6 to 39 years enrolled; half used extended half-life concentrates. Patient interest in their PK centered on general curiosity followed by a desire for participation in physical activity and decrease in infusion frequency. Providers used the WAPPS clinical calculator feature to simulate prophylaxis regimens under different dose, infusion, and trough conditions. Most targeted troughs were 1 to 3 IU/dL. The feasibility assessment demonstrated challenges with patient recruitment; however, the majority of participants successfully completed study assessments meeting feasibility targets., Conclusion: A larger-scale study powered to evaluate the impact of PK-tailored prophylaxis on clinical and patient-reported outcomes is feasible with study design modifications to support increased recruitment rate. Shared decision making incorporating patient and provider goals is important and facilitated by regimen simulations with the clinical calculator., (© 2020 The Authors. Research and Practice in Thrombosis and Haemostasis published by Wiley Periodicals, Inc on behalf of International Society on Thrombosis and Haemostasis.)

Etranacogene dezaparvovec (AMT-061) is a recombinant AAV5 vector including a gene cassette containing the factor IX (FIX) Padua variant under the control of a liver-specific promoter. A phase 2b study was conducted to confirm that a single dose of 2 × 1013 genome copies per kilogram of etranacogene dezaparvovec will result in FIX activity ≥5% 6 weeks after dosing. Secondary end points included FIX activity at other time points, bleed frequency, FIX replacement, and safety. Etranacogene dezaparvovec was administered as a single IV infusion to 3 adults with severe to moderately severe hemophilia B. Before treatment, participants had low levels of preexisting neutralizing antibodies to AAV5. This article reports a planned 26-week interim assessment. At week 6, mean FIX activity was 31% (23.9%-37.8%), increasing to 47% (33.2%-57.0%) at 26 weeks, with 2 subjects exhibiting sustained activity >40%. Consistent with the FIX activity, etranacogene dezaparvovec was associated with a complete bleed cessation with no need for FIX replacement therapy up to 26 weeks. Etranacogene dezaparvovec was generally well tolerated. No clinically significant elevations in levels of liver enzymes or inflammatory markers were observed, and no use of corticosteroids related to treatment was required. In individuals with severe to moderately severe hemophilia B, etranacogene dezaparvovec resulted in clinically relevant increases in FIX activity, cessation of bleeds, and abrogation of the need for FIX replacement, despite the presence of preexisting anti-AAV5 neutralizing antibodies detected by using a highly sensitive luciferase assay. Consistency of results in the 3 participants supported an expanded evaluation of the safety/efficacy of etranacogene dezaparvovec in the HOPE-B (Health Outcomes With Padua Gene; Evaluation in Hemophilia-B) phase 3 trial. The current trial was registered at www.clinicaltrials.gov as #NCT03489291., (© 2019 by The American Society of Hematology.)

Rabbit antithymocyte globulin (rATG) use for immunosuppression induction is widespread but is contraindicated by the presence of anti-rATG antibodies. This study reports the incidence of positive anti-rATG antibody titers in patients before and after renal transplant and evaluates associated outcomes and costs. In addition, it will correlate CD40L and interleukin (IL)-21 with anti-rATG antibody titers., Methods: Clinical and billing records from the Indiana University Transplant Laboratory were reviewed for positive versus negative anti-rATG antibody titers, graft survival, and 7-day readmission costs between 2004 and 2018. Serum from patients with positive and negative rATG antibody titers were quantitated for CD40L and IL-21 by enzyme-linked immunosorbent assay., Results: On average, between 2004 and May 2018, 163 kidney transplants per year were performed. Anti-rATG antibody titers were ordered for 17 patients/year, of which 18.2% were positive at 1:100 titer either pre- or post-transplant. Time to graft loss correlated with a positive rATG titer at time of readmission. Moreover, second kidney transplant increased the anti-rATG positive rate. A weak correlation was observed between anti-rATG titer and recipient age. Seven-day readmission treatment costs were significantly lower in patients with positive anti-rATG titer. IL-21 and CD40L were significantly greater in patients with positive anti-rATG titers after transplant when compared with negative anti rATG patients., Conclusions: Positive anti-rATG antibody titer is associated with a significant negative impact on outcomes. Monitoring of anti-rATG antibody titer is recommended to optimize treatment options in patients, especially in the setting of second transplants. Elucidation of the mechanisms associated with positive anti-rATG antibody is required. IL-21 and CD40L are potential targets for future study., (Copyright © 2019 The Author(s). Transplantation Direct. Published by Wolters Kluwer Health, Inc.)

BackgroundApproximately 40% of adolescent women experience heavy menstrual bleeding (HMB), and 10-62% of them have an underlying bleeding disorder (BD). Diagnosing a BD remains challenging because of limitations of available clinical platelet function assays. The aim of this study was to characterize platelet function in a population of adolescent women with HMB using small-volume whole-blood assays.MethodsAnticoagulated whole blood was used to assess platelet GPIIbIIIa activation, α-granule secretion, and aggregation in response to multiple agonists. Platelet adhesion on collagen or von Willebrand Factor (VWF) under static and shear flow was also assessed.ResultsFifteen participants with HMB were included in the study, of which eight were diagnosed with a clinically identifiable BD. Platelet activation was blunted in response to calcium ionophore in participants without a BD diagnosis compared with that in all other participants. Impaired GPIIbIIIa activation was observed in response to all GPCR agonists, except adenosine diphosphate (ADP), in participants with qualitative platelet disorders. Our assays detected platelet aggregation in the majority of participants with a BD in response to ADP, collagen-related peptide (CRP), thrombin receptor activator 6 (TRAP-6), or U46619. Platelet adhesion and aggregation on collagen and VWF was decreased for participants with VWD.ConclusionParticipants with and without BD exhibited aberrant platelet function in several assays in response to select agonists.

Background: Hepatitis E virus (HEV) Genotype 3 (G3) in England comprises two principal phylogenetic groups (Group 1 and Group 2) and can be transmitted by transfusion. Unselected screening identified 79 viremic donors; 76 participated in a follow-up study., Study Design and Methods: Viral RNA dynamics, phylogenetics, and seroconversion were characterized in the donors. Detailed demographic, travel, clinical, and lifestyle questionnaires were undertaken., Results: The majority of viremic individuals (57/79) were seronegative at time of donation but all seroconverted. Viremia was short-lived, with a median of 6.5 weeks to confirmed viral clearance. All infections were acquired in the United Kingdom and were G3, with Group 2 viruses predominating (43/54; 80%). Infection was associated with some clinical symptoms both at and after donation (8/77; 10%). Viral loads and symptoms were more pronounced in Group 1 infections. There was no serologic evidence of reinfection. Donors were more commonly male (p = 0.002); both male and female donors were older than comparator donors. Animal contact was unlikely to be the source of infection. Consumption of chicken and pig meat was common to all infected donors; processed pig meat was most commonly purchased from one particular retail chain., Conclusion: Viremic donors represent primary infection in older members of the community and reflect a widespread zoonotic in the United Kingdom. The two phylogenetic groups of HEV G3 display different pathogenicity and the more common Group 2 appears less adapted to humans. There are no objective demographic criteria that can identify donors at enhanced HEV risk., (© 2016 AABB.)

Background.  Engagement of individuals infected with hepatitis C virus (HCV) with care pathways remains a major barrier to realizing the benefits of new and more effective antiviral therapies. After an exploratory study, we have undertaken an evidence-based redesign of care pathways for HCV, including the following: (1) reflex testing of anti-HCV-positive samples for HCV RNA; (2) annotation of laboratory results to recommend referral of actively infected patients to specialist clinics; (3) educational programs for primary care physicians and nurses; and (4) the establishment of needs-driven community clinics in substance misuse services. Methods.  In this study, we conducted a retrospective cohort study of progression through care pathways of individuals with a new diagnosis of HCV infection made between January 2010 and January 2012. We also analyzed patient flow through new care pathways and compared this with our baseline study of identical design. Results.  A total of 28 980 samples were tested for anti-HCV antibody during the study period and yielded 273 unique patients with a new diagnosis of HCV infection. Of these, 38% were tested in general practice, 21% were tested in substance misuse services, 23% were tested in secondary care, and 18% were tested in local prisons. Overall, 80% of patients were referred to specialist clinics, 70% attended for assessment, and 38% commenced treatment, in comparison to 49%, 27%, and 10%, respectively, in the baseline study. Referral rates from all testing sources improved. Conclusions.  This study provides timely evidence that progression through care pathways can be enhanced, and it demonstrates reduction of key barriers to eradication of HCV.

Background: Recent studies have identified HIV infection as a potential risk factor for invasive meningococcal disease (IMD), suggesting that HIV-infected individuals could benefit from meningococcal vaccination to reduce their risk of this rare, but severe and potentially fatal infection. In the United Kingdom, as in most industrialised countries, HIV is not considered a risk factor for IMD., Methods: IMD incidence and relative risk by age group and meningococcal capsular group in HIV-positive compared with HIV-uninfected individuals was estimated through data linkage of national datasets in England between 2011 and 2013., Results: IMD incidence among persons diagnosed with HIV was 6.6 per 100,000 compared to 1.5 per 100,000 among HIV-negative individuals, with a relative risk of 4.5 (95 % CI, 2.7-7.5). All but one case occurred in adults aged 16-64 years, who had a 22.7-fold (95 % CI, 12.4-41.6; P <0.001) increased risk compared with the HIV-negative adults. IMD risk by capsular group varied with age. HIV-positive children and adolescents had a higher risk of meningococcal group B disease, while adults were at increased risk of groups C, W and Y disease. Most HIV-positive individuals had been born in Africa, had acquired HIV through heterosexual contact, and were known to be HIV-positive and receiving antiretroviral treatment at IMD diagnosis. The most common clinical presentation was septicemia and, although intensive care admission was common, none died of IMD., Conclusions: HIV-positive children and adults are at significantly increased risk of IMD, providing an evidence base for policy makers to consider HIV as a risk factor for meningococcal vaccination.

Introduction: The effect of HCV infection on HIV disease progression remains unclear; the effect of HCV infection duration on HIV disease progression is unknown., Methods: We used data from a cohort of HIV seroconverters to investigate the effect of HCV infection duration on time from HIV seroconversion to CD4 <350 cells/mm3, AIDS or death, censoring at the earlier of cART initiation or last clinic visit, adjusting for confounders and splitting data into follow up periods from HIV seroconversion (<2, 2-4 and >4 years). We additionally compared CD4 cell decline following HCV infection to that of mono-infected individuals with similar HIV infection duration by fitting a random effects model. In a separate analysis, we used linear mixed models to we examine the effect of HCV infection and its duration on CD4 increase over 48 weeks following cART., Results: Of 1655 individuals, 97 (5.9%) were HCV co-infected. HCV<1 year was associated with a higher risk of endpoint in each follow-up period from HIV seroconversion (HR [95% CI] 2.58 [1.51, 4.41], p = 0.001; 3.80 [1.20, 12.03], p = 0.023; 2.03 [0.88, 4.71], p = 0.098 for <2, 2-4 and >4 years respectively), compared to mono-infected individuals. However, we found no evidence of an association for those with HCV>2 years (all p>0.89). Individuals experienced a somewhat greater decrease in CD4 count following HCV infection lasting 13 months, relative to individuals with HIV alone, (estimate = -3.33, 95% CI [-7.29, 0.63] cells/mm3 per month, p = 0.099). Of 1502 initiating cART, 106 (7.1%) were HCV co-infected, with no evidence of HCV duration at cART being associated with immunological response (p = 0.45)., Conclusions: The impact of HCV co-infection on HIV disease progression appears to be restricted to the first year after HCV infection.

Background: Analysis of laboratory testing data collected through the Sentinel Surveillance programme has provided a method for identifying individuals who have recently acquired their hepatitis C virus (HCV) infection. Access to samples from these individuals provided a rare opportunity to undertake molecular characterization studies., Objectives: To describe the epidemiology and genetic diversity of hepatitis C in recent seroconverter infections and to predict how this will impact on HCV treatment and control., Study Design: One hundred and forty seven samples were available from individuals, identified to have recently acquired their HCV infection. Genotype determination with additional phylogenetic analysis was carried out on NS5B sequences. Analysis across the NS3 region investigated the presence of antiviral resistance mutations. Where possible, molecular data was linked to demographic and risk/behavioural factor information., Results: The majority of new infections occurred in males with a mean age of 37 years. The most commonly observed genotypes were 1a (49%) and 3a (42%) and injecting drug use (58%) was the most common risk factor. Genotype distribution differed between persons who inject drugs and those with other risk factors suggesting two possible epidemics. Phylogenetic analysis indicated possible transmission networks within specific risk groups. Amino acid changes associated with antiviral resistance were noted in the NS3 region in some samples., Conclusions: Continued surveillance of linked molecular, virological, demographic and epidemiological information on recently acquired infections will contribute to understanding the on-going HCV epidemic in England., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Background: As populations in the developed world shift toward an older and more ethnically diverse population, the challenges of recruiting and retaining sufficient donors to secure an adequate, safe supply of blood in the future will increase., Study Design and Methods: The study population included all first-time (n = 348,740) and repeat (n = 1,805,255) blood donors and their donations (n = 3,854,460) received by NHS Blood and Transplant during 2010 and 2011. Rates of new and repeat donors per 1000 population were estimated using Office for National Statistics 2011 population estimates. Factors associated with new blood donors returning within 6 months were analyzed using multivariate logistic regression., Results: The majority (87.9%) of donors were white British; 5.5% were unknown; 3.4% white Irish or white other; and 3.2% composed of all other ethnic groups. The median ages of new and repeat donors in 2010 were 28.0 and 45.0 years, respectively, compared to 29.0 and 47.0 years in 2011. Rates of donation varied by ethnicity, ranging from 1.59 per 1000 among Asian Bangladeshi origin, compared to 22.1 per 1000 among white British origin. Approximately two in five (38.4%) new blood donors returned within 6 months and were more likely to be male and of white ethnicity., Conclusions: Blood supply is impacted by numerous factors, including an aging population and an increasing population of migrant communities with lower donation rates. It is therefore critical that changes within the blood donor and wider population are monitored to inform donor recruitment and retention strategies., (© 2014 AABB.)

Background: Hepatitis B virus (HBV) remains the infection most frequently recognized by donation testing in blood donors. It is usually a persistent infection and mostly reflects the country of origin of the donor or the donor's family. There are, however, a minority of acute infections and this study undertook their phylogenetic analysis to determine the likely source of infection., Study Design and Methods: Plasma samples from 11 donors donating between July 2005 and June 2010, whose test results revealed recent infection with hepatitis B, were available for further analysis. Plasma DNA was extracted, amplified, sequenced, and analyzed phylogenetically. Donor and virus characteristics were compared with the overall demography of all hepatitis B-infected donors attending over the same period., Results: Three of the 11 individuals were first-time donors. Nine were male, of whom eight were white British. All had serum markers of very recent infection. Only two indicated known HBV exclusion risk factors at postdonation discussion not declared previously. Genotype A was present in seven, Genotype B in two, and Genotype C in two, contrasting with the pattern in persistently infected persons in the United Kingdom. A single A2 strain was identified in six of the white British male donors, suggesting epidemiologic linkage., Conclusion: Phylogenetic analysis of HBV-infected donors performed in real time can potentially lead to identification of undeclared risk factors that donor health questionnaires may fail to identify., (© 2013 AABB.)

Unlabelled: The aim of this work was to develop and validate an algorithm to monitor rates of, and response to, treatment of patients infected with hepatitis C virus (HCV) across England using routine laboratory HCV RNA testing data. HCV testing activity between January 2002 and December 2011 was extracted from the local laboratory information systems of a sentinel network of 23 laboratories across England. An algorithm based on frequency of HCV RNA testing within a defined time period was designed to identify treated patients. Validation of the algorithm was undertaken for one center by comparison with treatment data recorded in a clinical database managed by the Trent HCV Study Group. In total, 267,887 HCV RNA test results from 100,640 individuals were extracted. Of these, 78.9% (79,360) tested positive for viral RNA, indicating an active infection, 20.8% (16,538) of whom had a repeat pattern of HCV RNA testing suggestive of treatment monitoring. Annual numbers of individuals treated increased rapidly from 468 in 2002 to 3,295 in 2009, but decreased to 3,110 in 2010. Approximately two thirds (63.3%; 10,468) of those treated had results consistent with a sustained virological response, including 55.3% and 67.1% of those with a genotype 1 and non-1 virus, respectively. Validation against the Trent clinical database demonstrated that the algorithm was 95% sensitive and 93% specific in detecting treatment and 100% sensitive and 93% specific for detecting treatment outcome., Conclusions: Laboratory testing activity, collected through a sentinel surveillance program, has enabled the first country-wide analysis of treatment and response among HCV-infected individuals. Our approach provides a sensitive, robust, and sustainable method for monitoring service provision across England., (Copyright © 2013 The Authors. Hepatology published by Wiley on behalf of the American Association for the Study of Liver Diseases.)

Background: In 2010 hepatitis B virus (HBV) was the most frequently detected infection in UK blood donation screening, typically found in first-time, male, chronically infected donors born abroad. To date there has been no comprehensive characterization of the virologic profile of these infections., Study Design and Methods: Epidemiologic and serologic data were collected retrospectively for 344 chronically HBV-infected blood donors identified from July 2005 to June 2010. Additional laboratory testing was carried out to determine the HBV genotype, viral load, and prevalence of clinically significant mutations and to detect hepatitis delta virus (HDV) coinfection., Results: Five HBV genotypes (A-E) were found, Genotypes D (45%), A (20%), and E (20%) were the most prevalent. A strong association was seen between genotype and donor ethnicity (p < 0.001) and between genotype and place of residence (p = 0.006). Clinically significant mutations were observed across hepatitis B surface antigen (17%), basal core promoter (25%) and precore (78%) regions. An antiviral resistance profile was identified in one donor. Evidence of HDV coinfection was found in 2% of donors., Conclusion: The data show the diversity of HBV in asymptomatic chronic infections detected in blood donors in England and North Wales and demonstrates the presence of mutations which may impact on disease. The global nature of these infections and the inability to identify chronically infected donors before donation highlights the importance of using screening assays capable of detecting a broad range of genotypes and mutations. Furthermore, the integration of the virologic and demographic data allows us to more accurately construct a profile of our chronically HBV-infected blood donors., (© 2012 American Association of Blood Banks.)

Background: With less than a 5% survival rate pancreatic adenocarcinoma (PDAC) is almost uniformly lethal. In order to make a significant impact on survival of patients with this malignancy, it is necessary to diagnose the disease early, when curative surgery is still possible. Detailed knowledge of the natural history of the disease and molecular events leading to its progression is therefore critical., Methods and Findings: We have analysed the precursor lesions, PanINs, from prophylactic pancreatectomy specimens of patients from four different kindreds with high risk of familial pancreatic cancer who were treated for histologically proven PanIN-2/3. Thus, the material was procured before pancreatic cancer has developed, rather than from PanINs in a tissue field that already contains cancer. Genome-wide transcriptional profiling using such unique specimens was performed. Bulk frozen sections displaying the most extensive but not microdissected PanIN-2/3 lesions were used in order to obtain the holistic view of both the precursor lesions and their microenvironment. A panel of 76 commonly dysregulated genes that underlie neoplastic progression from normal pancreas to PanINs and PDAC were identified. In addition to shared genes some differences between the PanINs of individual families as well as between the PanINs and PDACs were also seen. This was particularly pronounced in the stromal and immune responses., Conclusions: Our comprehensive analysis of precursor lesions without the invasive component provides the definitive molecular proof that PanIN lesions beget cancer from a molecular standpoint. We demonstrate the need for accumulation of transcriptomic changes during the progression of PanIN to PDAC, both in the epithelium and in the surrounding stroma. An identified 76-gene signature of PDAC progression presents a rich candidate pool for the development of early diagnostic and/or surveillance markers as well as potential novel preventive/therapeutic targets for both familial and sporadic pancreatic adenocarcinoma.

Objectives: To explore attitudes toward circumcision among men who have sex with men (MSM) in London and the feasibility of conducting research into circumcision and HIV prevention in this population., Methods: A convenience sample of MSM visiting central London gyms completed a confidential, self-administered questionnaire between May and June 2008. Information was collected on participants' demographic characteristics, self-reported HIV status, sexual behavior, circumcision status, attitudes toward circumcision, and willingness to participate in research on circumcision and HIV prevention., Results: Of 653 MSM, 29.0% reported that they were circumcised. Overall, HIV prevalence was 23.3%; this did not differ significantly between circumcised and uncircumcised men (18.6% vs. 25.2%, respectively; adjusted odds ratio 0.79, 95% confidence interval: 0.50-1.26). A similar proportion of circumcised and uncircumcised men reported unprotected anal intercourse in the previous 3 months (38.8% vs. 36.7%, adjusted odds ratio 1.06, 95% confidence interval: 0.72-1.55). Uncircumcised men were less likely to think that there were benefits of circumcision than circumcised men (31.2% vs. 65.4, P < 0.001). Only 10.3% of uncircumcised men said that they would be willing to participate in research on circumcision as an HIV prevention strategy., Conclusions: Most uncircumcised MSM in this London survey were unwilling to participate in research on circumcision and HIV prevention. Only a minority of uncircumcised men thought that there were benefits of circumcision. It is unlikely that circumcision would be a feasible strategy for HIV prevention among MSM in London.

Objectives: To examine changes in the sexual behavior of London gay men between 1998 and 2008., Methods: Gay men using London gyms were surveyed annually between 1998 and 2005, and again in 2008 (n=6064; range, 482-834 per year). Information was collected on human immunodeficiency virus (HIV) status of the respondent, unprotected anal intercourse (UAI) in the previous 3 months, type (main or casual) and HIV status of partner for UAI. Nonconcordant UAI (ncUAI) was defined as UAI with a partner of unknown or discordant HIV status. Concordant UAI (cUAI) was defined as UAI with a partner of the same HIV status ("serosorting")., Results: Between 1998 and 2008, the percentage of men reporting UAI increased from 24.3% to 36.6% (P=0.07). This overall increase concealed important differences between nonconcordant and concordant UAI. While the percentage of men engaging in cUAI increased steadily between 1998 and 2008 (9.8%, 20.8%; P=0.01), the percentage reporting ncUAI increased between 1998 and 2001 (14.5%, 23.7%; P<0.001), decreased between 2001 and 2005 (23.7%, 15.6%; P<0.001), and then leveled off between 2005 and 2008 (15.6%, 15.7%; P=0.2). However, the percentage of men reporting ncUAI with a main partner increased between 2005 and 2008 for HIV-positive men (2.5%, 8.1%; P<0.05) and HIV negative men (2.1%, 5.5%; P=0.06). While the percentage of HIV negative men who reported cUAI with a main partner (i.e., serosorting) increased between 1998 and 2008 (12.4%, 21.1%; P<0.05), less than half established seroconcordance by testing together., Conclusions: The patterns of sexual behavior among London's gay men between 1998 and 2008 were dynamic and complex. Our data suggest that HIV risk with a main partner and HIV testing among couples should be given greater priority by health promotion programmes.

Background: There is an increasing prevalence of non-B subtype HIV type-1 (HIV-1) infections in Europe, reflecting patterns of migration. We examined the characteristics of HIV-1 drug resistance in antiretroviral treatment (ART)-naive individuals migrating to the UK., Methods: Resistance tests reported to the UK HIV Drug Resistance Database between 2001 and 2006 were included. Demographic data were obtained via linkage to national databases. Resistance was defined as ≥ 1 drug resistance mutation. Non-B HIV-1 subtype was used as a surrogate marker of infection acquired outside the UK. Logistic regression was used to examine the association between demographics and the prevalence of resistance., Results: Overall, 196/4,291 (4.6%) samples with non-B subtype showed resistance compared with 745/6,435 (11.6%) samples for subtype B. Among non-B subtypes, the prevalence of resistance decreased over time (6.0% in 2001-2003 to 3.2% in 2006) and was independently associated with later calendar year of sampling (P=0.001). Resistance was confined mainly to one ART class (85%); non-nucleoside reverse transcriptase inhibitor resistance was more common in subtype C (47%) compared with non-B non-C subtypes (29%; P=0.02). M184V was more common in non-B subtypes (non-B 30% versus B 5%; P<0.001) and T215 variants were more common in subtype B (non-B 10% versus B 49%; P<0.001)., Conclusions: In ART-naive individuals living in the UK, but who are likely to have acquired HIV-1 abroad, we observed a downward trend in resistance over time, which is surprising in light of ART roll-out in resource-limited settings. Reassuringly, resistance was mainly confined to one drug class; however, patterns of resistance differed by subtype, with some evidence of possible undisclosed prior therapy in non-B subtypes.

Background & Aims: Markers to differentiate among pancreatic adenocarcinoma, chronic pancreatitis, and normal pancreas would be of significant clinical utility. This study was therefore designed to analyze the proteome of such specimens and identify new candidate proteins for differential diagnosis., Methods: A PowerBlot analysis with more than 900 well-characterized antibodies was performed with tissue specimens from patients with chronic pancreatitis, pancreatic adenocarcinoma, and normal pancreas. Differential expression of selected proteins was confirmed on a larger scale by quantitative reverse transcription-polymerase chain reaction and immunohistochemistry using tissue arrays., Results: A total of 30 and 102 proteins showed significant deregulation between normal pancreas when compared with chronic pancreatitis and pancreatic adenocarcinoma, respectively, and although a substantial proportion were found similarly dysregulated in both chronic pancreatitis and pancreatic adenocarcinoma, several proteins were identified as potential disease-specific markers., Conclusions: A large number of proteins are differentially expressed in chronic pancreatitis and pancreatic adenocarcinoma compared with normal pancreas. Among these, expression analysis of UHRF1, ATP7A, and aldehyde oxidase 1 in combination could potentially provide a useful additional diagnostic tool for fine-needle aspirated or cytological specimens obtained during endoscopic investigations.

Purpose: Although chemotherapy with gemcitabine is a common mode of treatment of pancreatic cancer, 75% of patients do not benefit from this therapy. It is likely that the sensitivity of cancer cells to gemcitabine is determined by a number of different factors., Experimental Design: To identify genes that might contribute to resistance to gemcitabine, 15 pancreatic cancer cell lines were subjected to gemcitabine treatment. Simultaneously, gene expression profiling using a cDNA microarray to identify genes responsible for gemcitabine sensitivity was performed., Results: The pancreatic cancer cell lines could be classified into three groups: a gemcitabine "sensitive," an "intermediate sensitive," and a "resistant" group. Microarray analysis identified 71 genes that show differential expression between gemcitabine-sensitive and -resistant cell lines including 27 genes relatively overexpressed in sensitive cell lines whereas 44 genes are relatively overexpressed in resistant cell lines. Among these genes, 7 genes are potentially involved in the phosphatidylinositol 3-kinase/Akt pathway. In addition to this major signaling pathway, Bcl2/adenovirus E1B 19 kDa protein interacting protein (BNIP3), a Bcl-2 family proapoptotic protein, was identified as being expressed at lower levels in drug-resistant pancreatic cancer cell lines. In an analysis of 21 pancreatic cancer tissue specimens, more than 90% showed down-regulated expression of BNIP3. When expression of BNIP3 was suppressed using small interfering RNA, gemcitabine-induced cytotoxicity in vitro was much reduced., Conclusions: These results suggest that BNIP3 and the phosphatidylinositol 3-kinase/Akt pathway may play an important role in the poor response to gemcitabine treatment in pancreatic cancer patients.