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Background In the absence of field efficacy studies, estimating the real-world effectiveness of vaccines may consider immunogenicity from randomized controlled clinical trials and real-world adherence. Combining seroprotection rates (SPRs) with regimen completion rates gives an estimate of an effective vaccine protection rate (eVPR), which can be leveraged to evaluate real-world cost-effectiveness by linking it with vaccine costs to estimate the cost-per-protected patient (CPP). Methods This study evaluated eVPR and CPP as estimates of vaccine clinical- and cost-effectiveness of two-dose (HepB-CpG) and three-dose (HepB-Alum) hepatitis B virus (HBV) vaccines in the general adult population and a subpopulation with diabetes mellitus. eVPR was calculated from head-to-head SPR data from phase 3 clinical trials directly comparing HepB-CpG and HepB-Alum vaccine regimens and real-world head-to-head adherence data. CPP was calculated as the average cost of each regimen divided by eVPR. Results Higher eVPR in the adult population was achieved with HepB-CpG (68.0%) versus HepB-Alum (41.6%), reflecting the combination of higher SPR and vaccine regimen completion. The CPP for HepB-CpG ($331.31) was $45.67 (95% CI: $36.66, $55.19) less than HepB-Alum ($377.09). Greater savings were observed among persons with diabetes, with CPP $149.60 (95% CI: $80.29, $195.63) lower with HepB-CpG ($367.57) than HepB-Alum ($517.37). Conclusions Metrics estimating vaccine real-world effectiveness and value may guide informed decisions in vaccine selection. For example, using eVPR and CPP, HepB-CpG represents a more effective, value-advantaged approach than HepB-Alum toward reducing HBV infection.

ZusammenfassungWir präsentieren den Fall einer 83-jährigen Patientin mit einem bullösen Pemphigoid (BP) unter Aussparung des linken Armes bei Zustand nach axillärer Lymphadenektomie nach Mammakarzinom. Lokalisierte Formen des bullösen Pemphigoids treten v. a. bei Lymphödemen oder nach Radiatio auf. Das Fehlen des Blasenbefalls nach einer Lymphadenektomie stellt eine seltene und interessante Manifestation dar. Pathophysiologisch könnte durch den Rückgang der T‑Zell-Aktivierung bei fehlenden peripheren Lymphknoten und somit vermindertem entzündlichem Infiltrat die Blasenbildung abgeschwächt sein bzw. vollkommen ausbleiben.

This article presents an evaluation of 4255 autopsy cases recorded at the Dusseldorf Pathology Institute in the years 1914 to 1918. Diagnoses were coded according to the International Classification of Diseases, 10th edition (ICD-10), and the contemporaneous history of the Pathology Institute was reviewed. We found a proportion of 54.1% adults and 45.5% children in our cohort, with a male predominance of 63.9%. Infectious diseases account for the majority of all cases (35.5%), among which tuberculosis is the most frequent, reported in 22.7% of all cases. The second largest diagnosis group is the one of respiratory diseases (16.9%), including pneumonia and influenza. Cases of perinatal conditions account for 10.5% of the collective, followed by neoplasms, injuries, intoxications, or external causes, each representing 6.6%. Cardiovascular diseases account for 5.3% of the cases. In 4.4% of the pediatric and 0.8% of adult cases, a diagnosis of the ICD-10 group “nutritional and endocrine diseases” was made. No diagnosis of hunger edema is reported. Parts of the cohort are 272 war pathology cases (6.4%), made up by soldiers who mainly had died of shotgun injuries. The whole cohort represents the disease spectrum of a German big city population at times of World War I. The data exemplify the epidemiological shift that has occurred in industrialized countries over the last 100 years, from infectious to neoplastic and cardiovascular diseases.

The hepatitis B virus is highly infectious and can cause incurable liver disease, leading to high morbidity rates, increased healthcare utilization, and high mortality. Multiple preventative hepatitis B vaccine options have been available for decades, but adherence to the traditional 6-month vaccine schedule for the approved 3-dose series remains low in adult populations at risk of hepatitis B exposure. A 2-dose hepatitis B vaccine (HEPLISAV-B) approved by the US Food and Drug Administration in 2017 induces rapid seroprotection within 1 month and has a safety profile comparable to a commonly used 3-dose vaccine. In a previous cost-effectiveness study, HEPLISAV-B had a favorable cost-effectiveness profile for multiple at-risk populations. The goal of the current analysis was to update and extend previous findings by evaluating cost-effectiveness of HEPLISAV-B compared with a 3-dose vaccine (Engerix-B) in selected adult populations, including patients with diabetes, chronic liver or kidney disease, end-stage renal disease, healthcare personnel, travelers to countries with endemic hepatitis B, and a public health population. Cost-effectiveness was measured as incremental cost-effectiveness ratios using a health economics Markov model that accounts for adherence rates, seroprotection rates, healthcare costs, and current pricing considerations. Patients progressed between a series of health states, and the difference in lifetime spending and survival for individuals receiving either HEPLISAV-B or Engerix-B was estimated from the perspective of a US managed care payer, HEPLISAV-B had favorable cost-effectiveness profiles for patients with diabetes, healthcare personnel, travelers, and patients with chronic liver disease and dominant incremental cost-effectiveness ratios for patients with chronic kidney disease and end-stage renal disease. A probabilistic sensitivity analysis supported the robustness of the cost-effectiveness profiles, and an additional analysis indicated that HEPLISAV-B was cost-effective in the general adult population. Overall, HEPLISAV-B was cost-effective in multiple adult populations recommended for HBV vaccination in the United States.

Background Hepatitis B virus infection remains an important public health problem in the United States. Currently approved alum-adjuvanted vaccines require three doses and have reduced immunogenicity in adults, particularly in those who have diabetes mellitus, or are older, male, obese, or who smoke. Methods Phase 3 observer–blinded, randomized (2:1 HBsAg-1018 [HEPLISAV-B™]:HBsAg-Eng [Engerix-B®]), active–controlled trial in adults 18–70 years of age. HBsAg-1018 was administered intramuscularly at weeks 0 and 4 and placebo at week 24 and HBsAg-Eng at weeks 0, 4, and 24. The primary immunogenicity endpoint assessed the noninferiority of the seroprotection rate at week 28 in participants with type 2 diabetes mellitus. Secondary endpoints included seroprotection rates in the total trial population and by age, sex, body mass index, and smoking status. Results Among 8374 participants randomized, 961 participants in the per-protocol population had type 2 diabetes mellitus. In diabetes participants, the seroprotection rate in the HBsAg-1018 group at week 28 was 90.0%, compared with 65.1% in the HBsAg-Eng group, with a difference of 24.9% (95% CI: 19.3%, 30.7%), which met the prospectively-defined criteria for noninferiority and statistical significance. In the total study per-protocol population (N = 6826) and each pre-specified subpopulation, the seroprotection rate in the HBsAg-1018 group was statistically significantly higher than in the HBsAg-Eng group. Conclusion Two doses of HBsAg-1018, administered over 4 weeks, induced significantly higher seroprotection rates than three doses of HBsAg-Eng, given over 24 weeks, in adults with factors known to reduce the immune response to hepatitis B vaccines as well as in those without those factors. With fewer doses in a shorter time, and greater immunogenicity, HBsAg-1018 has the potential to significantly improve protection against hepatitis B in adults at risk for hepatitis B infection. Trial Registration clinicaltrials.gov Identifier: NCT02117934.

Background: Adult patients with diabetes mellitus (DM) have a greater risk of contracting hepatitis B virus (HBV) than the general population, including those ≥ 60 years of age. When infected, patients with DM have more severe HBV-related morbidity and accelerated progression. The CDC recommends HBV vaccination of all adults with DM who are ≥ 60 years of age at the discretion of the treating physician. Due to persistent challenges, including hyporesponsiveness with current 3-dose vaccines, 87% of individuals with DM who are ≥ 60 years of age remain unvaccinated. HBsAg-1018 (Heplisav-BTM) is a 2-dose HBV vaccine with demonstrated higher protection rates than a 3-dose vaccine, particularly in populations known to be hyporesponsive. In this post-hoc analysis of a phase 3 trial, we assessed the safety and efficacy of HBsAg-1018 in patients with type 2 DM (T2DM) who were ≥ 60 years of age. Methods: Patients with T2DM and who were 60-70 years old received either 2-dose HBsAg-1018 at 0 and 4 weeks and placebo at 24 weeks or 3-dose HBsAg-Eng (Engerix-B®) at 0, 4, and 24 weeks. Peak (week 24, HBsAg-1018 vs. week 28, HBsAg-Eng) seroprotection rates (SPRs) and safety were assessed by subgroups (sex, body mass index [BMI], and smoking status). Results: A total of 480 patients (HBsAg-1018, n=327; HBsAg-Eng, n=153) were included in this analysis. Among patients who received all study injections, the peak SPR was significantly higher with HBsAg-1018 at week 24 (88.2% [231/262]) than with HBsAg-Eng at week 28, giving an overall difference of 29.7% (95% CI: 20.5, 39.1; P Conclusion: Two-dose HBsAg-1018 provides better protection against HBV than a 3-dose vaccine (HBsAg-Eng) with a similar safety profile in patients ≥ 60 years of age with T2DM regardless of subgroup. Disclosure R.N. Hyer: Employee; Self; Dynavax Technologies. R.S. Janssen: Employee; Self; Dynavax Technologies.

Background Immunologic response to a complete vaccine regimen of currently licensed alum-adjuvanted hepatitis B vaccines is reduced in several subpopulations, including older adults, men, obese persons, and smokers. Two phase 3 trials in healthy adults demonstrated that 2 doses over 1 month of an investigational hepatitis B vaccine (HBsAg-1018) induced superior seroprotection rates (SPRs) to 3 doses over 6 months of the licensed vaccine Engerix-B ® (HBsAg-Eng). Methods An exploratory analysis of immunogenicity was conducted in subpopulations from pooled data for the 2 phase 3 trials. Results In each subpopulation, the peak SPR in the HBsAg-1018 group was statistically significantly higher than the peak SPR in the HBsAg-Eng group. Peak HBsAg-1018 SPRs ranged from 91.6% to 99.7%, while peak HBsAg-Eng SPRs ranged from 67.7% to 92.9%. Conclusion In these exploratory analyses, 2 doses of HBsAg-1018 induced statistically significantly higher rates of seroprotection than 3 doses of HBsAg-Eng across all subpopulations.

study question: Is first trimester phthalate exposure associated with anogenital distance (AGD), a biomarker of prenatal androgen exposure, in newborns? summaryanswer: Concentrations of diethylhexyl phthalate (DEHP) metabolites in first trimester maternal urine samples are inversely associated with AGD in male, but not female, newborns. what is known already: AGD is a sexually dimorphic measure reflecting prenatal androgen exposure. Prenatal phthalate exposure has been associated with shorter male AGD in multiple animal studies. Prior human studies, which have been limited by small sample size and imprecise timing of exposure and/or outcome, have reported conflicting results. study design, size, duration: The Infant Development and the Environment Study (TIDES) is a prospective cohort study of pregnant women recruited in prenatal clinics in San Francisco, CA, Minneapolis, MN, Rochester, NY and Seattle, WA in 2010– 2012. Participants delivered 787 infants; 753 with complete data are included in this analysis. participants/materials, setting, methods: Any woman over 18 years old who was able to read and write English (or Spanish in CA), who was ,13 weeks pregnant, whose pregnancy was not medically threatened and who planned to deliver in a study hospital was eligible to participate. Analyses include all infants whose mothers provided a first trimester urine sample and who were examined at or shortly after birth. Specific gravity (SpG) adjusted concentrations of phthalate metabolites in first trimester urine samples were examined in relation to genital measurements. In boys (N ¼ 366), we obtained two measures of anogenital distance (AGD) (anoscrotal distance, or AGDAS and anopenile distance, AGDAP) as well as penile width (PW). In girls (N ¼ 373), we measured anofourchette distance (AGDAF) and anoclitoral distance (AGDAC). We used multivariable regression models that adjusted for the infant’s age at exam, gestational age, weight-for-length Z-score, time of day of urine collection, maternal age and study center. main results and the role of chance: Three metabolites of DEHP were significantly and inversely associated with both measures of boys’ AGD. Associations (b, 95% confidence interval (CI)) between AGDAS and (log10) SpG-adjusted phthalate concentrations were: 21.12 (22.16, 20.07) for mono-2-ethylhexyl phthalate (MEHP), 21.43, (22.49, 20.38) for mono-2-ethyl-5-oxohexyl phthalate (MEOHP), and 21.28 (22.29, 20.27) for mono-2-ethyl-5-hydroxyhexyl (MEHHP). Associations were of similar magnitude for AGDAP. Associations were weaker and not statistically significant for PW. No other phthalate metabolites were associated with any genital measurement in boys. No phthalate metabolites were associated with either AGD measure in girls. limitations, reasons for caution: Exposure assessment was based on a single first trimester urine sample, which may have introduced exposure misclassification. In addition, significant between-center differences suggest that this measurement is difficult to standardize. wider implications of the findings: Our findings are consistent with multiple rodent studies and most human studies which were far smaller. The data we report here suggest that even at current low levels, environmental exposure to DEHP can adversely affect male genital development resulting in reproductive tract changes that may impact reproductive health later in life. These findings have important implications for public policy since most pregnant women are exposed to this ubiquitous chemical.

Many patients with chronic kidney disease (CKD) are hyporesponsive to currently licensed alum-adjuvanted hepatitis B vaccines, including Engerix-B(®) (HBsAg-Eng). Seroprotection rates (SPRs) are further reduced in CKD patients with diabetes mellitus. Three doses of an investigational hepatitis B vaccine (HBsAg-1018) that uses a Toll-like receptor 9 agonist demonstrated superior SPRs to 4 double doses of HBsAg-Eng in a large phase 3 trial of CKD patients.A prespecified subgroup analysis of immunogenicity was conducted in CKD participants with type 2 diabetes in the phase 3 trial.In 328 participants, the peak SPR in the HBsAg-1018 group met criteria for noninferiority and superiority to the peak SPR in the HBsAg-Eng group. The peak geometric mean concentration of antibody against hepatitis B surface antigen in the HBsAg-1018 group was statistically significantly higher than in the HBsAg-Eng group.HBsAg-1018 induced significantly higher seroprotection than HBsAg-Eng in CKD patients with diabetes.

Background Less than 1 in 3 US adults who initiated the 3-dose (0, 1, 6 months) hepatitis B vaccine series have completed it. HepB-CpG (Heplisav-B; Dynavax) is a new licensed adjuvanted vaccine that requires only 2 doses (0, 1 month). As part of a cluster study performed at Kaiser Permanente Southern California, we compared compliance with second dose and series completion for HepB-CpG vs. comparator vaccine (Engerix-B; GlaxoSmithKline) recipients. Methods The cohort included adults not on dialysis who received their first dose of hepatitis B vaccine in family or internal medicine departments from 8/7/2018 to 2/1/2019. Second dose compliance was assessed for the full cohort, but series completion was assessed for a subset vaccinated from August 7, 2018 to September 30, 2018 to allow at least 6 months’ follow-up. Compliance rates were estimated using the Kaplan Meier method. Adjusted hazard ratios (aHR) were estimated using Cox proportional hazard regression with robust variance to account for within medical center correlation, adjusting for age, race/ethnicity, census block income and education, prior healthcare utilization, and factors that trigger alerts for hepatitis B vaccination (diabetes and testing for sexually transmitted infections). Results There were 6500 HepB-CpG and 7733 comparator vaccine recipients (1,442 and 2,604 prior to September 30, 2018). Rates of second dose compliance at 60 days were 32.9% for HepB-CpG and 29.1% for comparator vaccine, and rates of series completion at 210 days were 56.9% and 20.6%. There was no significant difference in second dose compliance (aHR 1.14, 95% CI: 0.91, 1.47), but HepB-CpG recipients were 5 times more likely to complete the series (aHR 5.17; 95% CI: 3.84, 6.98). Second dose compliance and series completion were significantly less likely among Blacks compared with Whites and significantly more likely among Asians, adults ≥60 years compared with those < 30 years, and adults living in census blocks with a median annual income of $40,000–69,000 compared with < $40,000. Conclusion Overall, second dose compliance was similar, but series completion was better for HepB-CpG recipients than comparator vaccine recipients, suggesting that the 2-dose vaccine could lead to improvements in coverage and protection against hepatitis B virus. Disclosures All authors: No reported disclosures.

The combined glucose-lowering effect of exenatide and dapagliflozin has not yet been studied. We investigated this combination (single-dose or 4-week dosing) in diabetic ob/ob mice. Vehicle-corrected basal glucose showed greater reduction 1 h following exenatide + dapagliflozin than with exenatide or dapagliflozin alone, and stayed significantly lower for all groups versus vehicle over 3 h. During an oral glucose tolerance test, glucose excursion (30 min post-dose) was significantly lower for exenatide + dapagliflozin versus exenatide or dapagliflozin, or vehicle. Exenatide + dapagliflozin and exenatide, but not dapagliflozin alone, reduced glucose excretion over 24 h versus vehicle. After dosing for 4 weeks, exenatide, dapagliflozin and exenatide + dapagliflozin similarly decreased haemoglobin A1c (HbA1c). Body weight was reduced only with exenatide or exenatide + dapagliflozin. The glomerular filtration rate was similar with exenatide, dapagliflozin and vehicle, and increased with exenatide + dapagliflozin. Optimized combinatorial dosing of these antidiabetic agents may provide additive glucose lowering in type 2 diabetes mellitus.

Background Hemodialysis patients are at increased risk of hepatitis B virus (HBV) infection and patients with chronic kidney disease (CKD) are commonly hyporesponsive to HBV vaccines. Current recommendations for CKD patients are to utilize 4 double-doses (2 × 20 mcg HBsAg) of a licensed hepatitis B vaccine (HBsAg-Eng). Methods An observer-blind, randomized, active-controlled, parallel group, multicenter trial was conducted among 521 patients 18–75 years of age with CKD, comparing 3 single doses of an investigational hepatitis B vaccine (20 mcg rHBsAg + 3000 mcg 1018, a toll-like receptor 9 agonist) given at 0, 4, and 24 weeks to 4 double-doses of HBsAg-Eng (2 × 20 mcg rHBsAg + 500 mcg alum) given at 0, 4, 8, and 24 weeks (total of 8 injections). Participants were followed for 1 year. Results Among 467 participants in the modified intent-to-treat population, at the primary endpoint at week 28, the seroprotection rate (SPR: % with anti-HBs ≥ 10 mIU/mL) in the HBsAg-1018 group (89.9%) met criteria for noninferiority and superiority to the SPR in the HBsAg-Eng group (81.8%). At week 28, the percentage of participants with anti-HBs ≥ 100 mIU/mL in theHBsAg-1018 group (73.6%) was significantly higher than in the HBsAg-Eng group (63.2%). In addition, the geometric mean concentration of anti-HBs in the HBsAg-1018 group (587.1 mIU/mL) was significantly higher than in the HBsAg-Eng group (156.5 mIU/mL). At weeks 8 and 12 after the first study injection, SPRs in the HBsAg-1018 group were significantly higher than in the HBsAg-Eng group. At 52 weeks, the immune response toHBsAg-1018 remained higher than to HBsAg-Eng. HBsAg-1018 was generally well tolerated and had a similar safety profile to HBsAg-Eng. Conclusion In CKD patients, 3 doses of HBsAg-1018 induced significantly higher seroprotection, earlier seroprotection, and more durable seroprotection than 4 double doses of HBsAg-Eng.

Vinculin (Vcl) plays a key structural role in ventricular myocytes that, when disrupted, can lead to contractile dysfunction and dilated cardiomyopathy. To investigate the role of Vcl in myocyte and myocardial function, cardiomyocyte-specific Vcl knockout mice (cVclKO) and littermate control wild-type mice were studied with transmission electron microscopy (TEM) and in vivo magnetic resonance imaging (MRI) tagging before the onset of global ventricular dysfunction. MRI revealed significantly decreased systolic strains transverse to the myofiber axis in vivo, but no changes along the muscle fibers or in fiber tension in papillary muscles from heterozygous global Vcl null mice. Myofilament lattice spacing from TEM was significantly greater in cVclKO versus wild-type hearts fixed in the unloaded state. AFM in Vcl heterozygous null mouse myocytes showed a significant decrease in membrane cortical stiffness. A multiscale computational model of ventricular mechanics incorporating cross-bridge geometry and lattice mechanics showed that increased transverse systolic stiffness due to increased lattice spacing may explain the systolic wall strains associated with Vcl deficiency, before the onset of ventricular dysfunction. Loss of cardiac myocyte Vcl may decrease systolic transverse strains in vivo by decreasing membrane cortical tension, which decreases transverse compression of the lattice thereby increasing interfilament spacing and stress transverse to the myofibers.

Plasmodium knowlesi is an intracellular malaria parasite whose natural vertebrate host is Macaca fascicularis (the ‘kra’ monkey); however, it is now increasingly recognized as a significant cause of human malaria, particularly in southeast Asia1,2. Plasmodium knowlesi was the first malaria parasite species in which antigenic variation was demonstrated3, and it has a close phylogenetic relationship to Plasmodium vivax4, the second most important species of human malaria parasite (reviewed in ref. 4). Despite their relatedness, there are important phenotypic differences between them, such as host blood cell preference, absence of a dormant liver stage or ‘hypnozoite’ in P. knowlesi, and length of the asexual cycle (reviewed in ref. 4). Here we present an analysis of the P. knowlesi (H strain, Pk1(A+) clone5) nuclear genome sequence. This is the first monkey malaria parasite genome to be described, and it provides an opportunity for comparison with the recently completed P. vivax genome4 and other sequenced Plasmodium genomes6,7,8. In contrast to other Plasmodium genomes, putative variant antigen families are dispersed throughout the genome and are associated with intrachromosomal telomere repeats. One of these families, the KIRs9, contains sequences that collectively match over one-half of the host CD99 extracellular domain, which may represent an unusual form of molecular mimicry., Nature, 455, ISSN:0028-0836, ISSN:1476-4687

Rationale: Long-term survivors of cystic fibrosis (CF) (age > 40 yr) are a growing population comprising both patients diagnosed with classic manifestations in childhood, and nonclassic phenotypes typically diagnosed as adults. Little is known concerning disease progression and outcomes in these cohorts. Objectives: Examine effects of age at diagnosis and gender on disease progression, setting of care, response to treatment, and mortality in long-term survivors of CF. Methods: Retrospective analysis of the Colorado CF Database (1992–2008), CF Foundation Registry (1992–2007), and Multiple Cause of Death Index (1992–2005). Measurements and Main Results: Patients with CF diagnosed in childhood and who survive to age 40 years have more severe CFTR genotypes and phenotypes compared with adult-diagnosed patients. However, past the age of 40 years the rate of FEV1 decline and death from respiratory complications were not different between these cohorts. Compared with males, childhood-diagnosed females were less likely to reach age 40 years, experienced faster FEV1 declines, and no survival advantage. Females comprised the majority of adult-diagnosed patients, and demonstrated equal FEV1 decline and longer survival than males, despite a later age at diagnosis. Most adult-diagnosed patients were not followed at CF centers, and with increasing age a smaller percentage of CF deaths appeared in the Cystic Fibrosis Foundation Registry. However, newly diagnosed adults demonstrated sustained FEV1 improvement in response to CF center care. Conclusions: For patients with CF older than 40 years, the adult diagnosis correlates with delayed but equally severe pulmonary disease. A gender-associated disadvantage remains for females diagnosed in childhood, but is not present for adult-diagnosed females.

To determine the status of the HIV epidemic in the United States and Canada.We used data on AIDS and HIV diagnoses for 1996-2005 reported to the United States and Canadian national surveillance systems to determine trends in AIDS and HIV (33 US states only) diagnoses and to identify population groups most affected by HIV. HIV incidence for Canada was determined using back-calculation methods. We also determined the proportion of persons diagnosed late (HIV diagnosis within 12 months before AIDS diagnosis).AIDS diagnosis rates were higher in 2005 among blacks (54.1 per 100,000) and Hispanics (18.0) compared with whites (5.9) in the United States and among blacks (4.7) and aboriginal peoples (4.9) compared with whites (0.7) in Canada. Since 2001, HIV diagnoses increased among men who have sex with men in both countries and in Canada, increased among persons from HIV-endemic countries and where heterosexual contact was the only identified risk of transmission. Overall, HIV incidence remained relatively stable in Canada during that period. A large proportion of persons were diagnosed late in the disease process (United States, 54.3%; Canada, 64.2%).Rates of HIV transmission remain a challenge in both the United States and Canada as overall diagnosis rates have not decreased in recent years. Renewed prevention efforts are needed to further reduce the high HIV diagnosis rates among racial/ethnic minorities and to decrease HIV transmission among men who have sex with men.

New approaches are needed to fight the human immunodeficiency virus (HIV) epidemic, now in its third decade in the United States. The epidemiology of HIV in the past decades illustrates these new challenges. Annual incident cases of acquired immunodeficiency syndrome (AIDS) declined 38% and deaths from AIDs declined 63% between 1995 and 1998, due primarily to the introduction of combination antiretroviral therapy (ART).1,2 However, the annual number of incident AIDS cases and deaths remained stable from 1999 through 2006, and the estimated number of new HIV infections occurring annually in the U.S. has remained stable since 2000.1,3 This article seeks to put the current emphasis of the Centers for Disease Control and Prevention (CDC) on HIV testing programs in the context of the epidemiology of the U.S. HIV epidemic; to describe major CDC prevention initiatives that involve HIV testing, focusing on the Advancing HIV Prevention (AHP) initiative;4 and to describe what has been learned in the first five years since new strategies for preventing HIV infection were outlined in the AHP initiative.

Purpose: Anaplastic thyroid carcinoma is rare, yet lethal despite aggressive therapy. Molecular targeting may be beneficial using the rexinoid LGD1069, a retinoid X receptor–selective agonist, as a novel treatment. In this report, we describe the efficacy of LGD1069 in anaplastic thyroid carcinoma in vitro and assess the in vivo treatment effects on a responsive cancer. Additionally, we explore potential mediators of the rexinoid effect on a responsive anaplastic thyroid cancer using comparative microarray analysis. Experimental Design: Anaplastic thyroid cancer cell lines DRO, ARO, and FRO were treated with LGD1069 in vitro. Responsive DRO xenograft tumors were treated with control chow or chow containing a low dose (30 mg/kg/d) or a high dose (100 mg/kg/d) of LGD1069. Comparative microarray analysis of DRO cells treated with LGD1069 compared with volume-equivalent control was assessed after 24 h of treatment to evaluate early gene expression changes. Results: DRO xenograft tumor growth was inhibited by LGD1069 treatment in a dose-dependent manner. Comparative microarray analysis showed that 80 genes had a significant increase in expression and 29 genes had a decrease in expression after 24 h of treatment with LGD1069. Expression of angiopoietin-like 4 (ANGPTL4) mRNA was increased 6.5-fold. A trend towards an increase in ANGPTL4 mRNA (not statistically significant) was seen in treated tumors in vivo and this correlated with decreased tumor vascularity and increased necrosis. Conclusions: LGD1069 therapy decreases proliferation in an anaplastic thyroid cancer cell line that expresses retinoid X receptor-γ, and this effect is confirmed with decreased tumor size in vivo in a nude mouse model. ANGPTL4 is increased in DRO in response to LGD1069 and may be a potential mediator of the effects of rexinoid treatment.

The recommendations for human immunodeficiency virus (HIV) testing in the United States were recently revised. An important goal of these revisions is to reduce the proportion of individuals infected with HIV who are unaware of their infection. In the new guidelines, screening is recommended for all individuals aged 13-64 years in any health care setting, provided that they are notified that testing will be performed and do not decline testing. It was further recommended that individuals at high risk for HIV infection be screened annually. Through wider screening, the identification of persons with unrecognized HIV is expected to facilitate treatment and allow better targeting of HIV prevention strategies.

Background: New HIV infections stem from people who are aware they are HIV positive (approximately 75% of infected persons in the USA) and those who are unaware of their HIV-positive status (approximately 25%). Objective: We estimated the relative contribution of these two groups in sexually transmitting new HIV infections to at-risk (HIV-negative or unknown serostatus) partners in the USA. Methods: The parameters in the estimation included: number of people aware and unaware they are infected with HIV; 33% of the aware group are at low risk of transmitting HIV because of low/undetectable viral load; 57% relative reduction in the prevalence of unprotected anal and vaginal intercourse (UAV) with at-risk partners in persons aware (compared to unaware) they have HIV; and assumed differences in the average number of at-risk UAV partners in each awareness group (ranging from equal to twice as many in the unaware group). Results: The proportion of sexually transmitted HIV from the HIV-positive unaware group was estimated to range from 0.54 (assuming no difference in average number of at-risk UAV partners between groups) to 0.70 (assuming twice as many at-risk UAV partners in the unaware group). Using the lower bounds, the transmission rate from the unaware group was 3.5 times that of the aware group after adjusting for population size differences between groups. Conclusion: The results indicate that the HIV/AIDS epidemic can be lessened substantially by increasing the number of HIV-positive persons who are aware of their status.

Recent outbreaks of syphilis among men who have sex with men (MSM) in major cities in the United States and reported increases in sexual risk behavior have raised concerns about potential increases in human immunodeficiency virus (HIV) transmission. The majority of MSM who have early syphilis are HIV infected; in preliminary studies, rates of recent HIV infection among them are also high. Data from San Francisco, Los Angeles, and Seattle-King County, however, suggest no temporal increases in HIV incidence among MSM seeking HIV testing at select large public sites during the syphilis outbreaks. Because most HIV incidence and behavioral data are from large metropolitan areas with large gay populations and well-established HIV epidemics, we do not know whether, nationally, incidence of HIV infection among MSM has been increasing, decreasing, or stable during syphilis outbreaks. Further studies of HIV incidence in larger and smaller cities with different maturities of HIV epidemic are warranted. Comprehensive and integrated HIV/STD prevention and control efforts are also needed to halt the spread of syphilis and reduce HIV transmission among gay and bisexual men.

This study evaluated the magnitude and distribution of unrecognized HIV infection among young men who have sex with men (MSM) and of those with unrecognized infection, the prevalence and correlates of unprotected anal intercourse (UAI), perceived low risk for infection, and delayed HIV testing. MSM aged 15-29 years were approached, interviewed, counseled, and tested for HIV at 263 randomly sampled venues in 6 US cities from 1994-2000. Of 5649 MSM participants, 573 (10%) tested positive for HIV. Of these, 91% of black, 69% of Hispanic, and 60% of white MSM (77% overall) were unaware of their infection. The 439 MSM with unrecognized infection reported a total of 2253 male sex partners in the previous 6 months; 51% had UAI; 59% perceived that they were at low risk for being infected; and 55% had not tested in the previous year. The HIV epidemic among MSM in the United States continues unabated, in part, because many young HIV-infected MSM are unaware of their infection and unknowingly expose their partners to HIV. To advance HIV prevention in the third decade of HIV/AIDS, prevention programs must reduce unrecognized infection among young MSM by increasing the demand for and availability of HIV testing services.

Less sensitive (LS) HIV-1 enzyme immunoassays (EIAs) have significantly improved the quantity and quality of HIV surveillance data. The first LS-HIV-1 EIA, the Abbott 3A11-LS, provided reliable incidence data, but the assay required specialized equipment, and the lack of available reagents made testing difficult. This study evaluated the use of an alternate assay, a modified version of the Vironostika HIV-1 EIA (Vironostika-LS), to be used for LS testing. The Vironostika-LS has similar performance characteristics to the Abbott 3A11-LS with additional advantages. This 96-well formatted assay is commonly found in public health laboratories for routine HIV-1 testing and can be used with both serum and dried blood spot specimens. The estimated mean time from seroconversion (defined using a standardized optical density cutoff of 1.0) with the Vironostika-LS was 170 days (95% CI, 145-200 days). When the Vironostika-LS was applied to a matched serum set previously tested with the Abbott 3A11-LS, the Vironostika-LS accurately identified 97% of specimens with recent or long-standing HIV infection. The paper also reports Vironostika-LS quality control guidelines and the results from 3 rounds of proficiency testing.

The sensitive/less-sensitive (S/LS) enzyme immunoassay (EIA) testing strategy for discriminating "early" from "longstanding" HIV infection has been widely applied for detecting recent seroconverters and estimating HIV incidence rates. The originally developed assay (3A11-LS EIA; Abbott Laboratories, Abbott Park, IL) involved performance of LS EIAs using a bead-based assay that required specialized equipment and reagents of limited availability. In contrast, 96-microwell-based EIAs are more universally applied for HIV serodiagnosis throughout the world. The authors report development and preliminary validation of an LS protocol using an EIA in a 96-well format: the Vironostika HIV-1 MicroElisa System (Vironostika-LS EIA; Bio Merieux, Raleigh, NC). The results with samples from recent HIV-1 seroconverters, persons with longstanding HIV-1 asymptomatic infection, patients on highly active antiretroviral therapy, and AIDS patients show a high degree of correlation between the Vironostika-LS EIA and 3A11-LS EIA. The authors also demonstrate that the Abbott 3A11-LS EIA and Vironostika-LS EIA performed comparably on HIV-1-positive samples from persons infected with non-B HIV-1 subtypes. These results support the potential use of the Vironostika-LS EIA for detection of recent HIV-1 infections for incidence projections and for other epidemiologic, clinical, and molecular surveillance applications.

A major mechanism whereby malaria parasites evade the host immune response to give chronic infections in patients' blood for months, or even years, is antigenic variation. In order to generate variant antigens, parasites require large multigene families. Although several gene families involved in these phenomena have been identified in the human malaria Plasmodium falciparum, to date no variant antigen gene families have been identified in malaria species that will infect widely used rodent laboratory hosts. Here we present, for the first time, to our knowledge, a large multigene family conserved in both rodent and human malarias, which is a strong candidate as a major variant antigen gene family. In each of four species of Plasmodium, three rodent malarias and the human pathogen P. vivax, homologues of the gene family were found to have a conserved three-exon structure. In the rodent malaria P. chabaudi, transcription of members of the gene family was developmentally regulated with maximum expression in late trophozoite stages, which is the developmental stage known to express variant antigen proteins.

OBJECTIVES We compared recent risk behaviors and HIV seroconversion among young men who have sex with men (MSM) who were first-time, infrequent, and repeat HIV testers. METHODS Male adolescents and young men aged 15 to 22 years were randomly sampled, interviewed, counseled, and tested for HIV at 194 gay-identified venues in seven U.S. cities from 1994 through 1998. Analyses were restricted to MSM who reported having never tested or last tested HIV-negative. RESULTS Of 3430 participants, 36% tested for the first time, 39% had tested infrequently (one or two times), and 26% had tested repeatedly (> or = three times). Compared with first-time testers, repeat testers were more likely to report recent risk behaviors and to acquire HIV (7% versus 4%). Over 75% of repeat testers who seroconverted acquired HIV within 1 year of their last test. Compared with repeat testers, first-time testers reported similar use of health care but delayed testing for nearly 2 additional years after initiating risk. CONCLUSIONS Many young MSM soon acquire HIV after repeated use of HIV counseling and testing services. Providers must strengthen practices to identify, counsel, and test young MSM and provide enhanced behavioral interventions for those with persistent risks.

Summary Background During the past decade, developing countries have received limited support for blood safety programmes. The Kenya Ministry of Health did a collaborative multicentre assessment to establish the risk of HIV transmission by transfusion in Kenya, to promote awareness of blood safety issues in this country with a mature HIV epidemic, and to identify methods to reduce the risk of HIV transmission by blood transfusion in Kenya. Methods For 12 weeks, from April to July 1994, we collected information and blood samples from all blood donors, and pretransfusion samples were collected from all recipients in six government hospitals in Kenya. Blood donations were collected and screened for HIV according to standard practice in the hospital laboratories. Test results at a reference laboratory were compared with those of the hospital laboratories and risk of transfusion-associated HIV transmission was calculated. Findings The prevalence of HIV among blood donors was 6·4% (120 of 1877) and varied by hospital (range 2–20%). HIV test results were available for 1290 donor-recipient pairs. Of these, 26 HIV-positive donations were given to HIV-negative patients. We estimate that 2·0% of transfusions transmitted HIV. Problems in the hospitals that contributed to transfusion risk included inconsistent refrigeration, data entry errors, equipment failure, and lack of a quality-assurance programme. Interpretation A high proportion of blood transfusions transmitted HIV in this high-prevalence area of Africa, primarily because of erroneous laboratory practices. On the basis of these results, the Kenya Ministry of Health introduced a number of practical and inexpensive interventions to improve national blood safety.

In the United States, HIV prevention programs have historically tailored activities for specific groups primarily on the basis of behavioral risk factors and demographic characteristics. Through the Serostatus Approach to Fighting the Epidemic (SAFE), the Centers for Disease Control and Prevention is now expanding prevention programs, especially for individuals with HIV, to reduce the risk of transmission as a supplement to current programs that primarily focus on reducing the risk of acquisition of the virus. For individuals with HIV, SAFE comprises action steps that focus on diagnosing all HIV-infected persons, linking them to appropriate high-quality care and prevention services, helping them adhere to treatment regimens, and supporting them in adopting and sustaining HIV risk reduction behavior. SAFE couple a traditional infectious disease control focus on the infected person with behavioral interventions that have been standard for HIV prevention programs.

Characterizing human immunodeficiency virus (HIV) expression in semen during primary infection remains essential to understanding the risk of sexual transmission. This investigation represents the first systematic evaluation of male genital tract shedding to use a nonhuman primate model, including the impact of exposure route and viral virulence. Male macaques were inoculated with either a chronic disease-causing virus (HIV-2(GB122); n=4 intravenous; n=4 intrarectal) or an acutely pathogenic simian/HIV strain (SHIV(89.6P); n=2 intravenous). All macaques were systemically infected, and seminal plasma virion-associated RNA (vRNA) levels were approximately 10-fold lower than those in blood. In HIV-2(GB122) infection, seminal virus was delayed by 1-2 weeks compared with that in blood. Intrarectal inoculation resulted in a shorter duration of seminal vRNA expression and intermittent seminal cell provirus. No delays, higher peaks ( approximately 50-fold), or longer durations in seminal virus expression were noted for SHIV(89.6P) infection. This novel model definitively establishes that virus dissemination results in early peak seminal levels and provides a basis for evaluating interventions targeting male genital tract expression.

The development of a serologic algorithm to determine recent HIV seroconversion, using sensitive/less-sensitive testing strategies, has generated widespread interest in applying this approach to estimate HIV-1 incidence in various populations around the world. To evaluate this approach in non-B subtypes, longitudinal specimens (n = 522) collected from 90 incident infections among injecting drug users in Bangkok (subtype B infection, n = 18; subtype E infection, n = 72) were tested by the 3A11-LS assay. Standardized optical density (SOD) was calculated, using median values, and the window period between seroconversion as determined by sensitive and less sensitive tests was estimated by a maximum-likelihood model described previously. Our results show that the mean window period of the 3A11-LS assay was 155 days (95% CI, 128-189 days) for subtype B but was 270 days (95% CI, 187-349 days) for subtype E specimens from Thailand. About 4% of individuals with incident subtype E infections remained below the threshold (SOD of 0.75), even 2 years after seroconversion. Among the patients with clinical AIDS and declining antibodies, none of the 7 individuals with subtype B, but 10 (8.7%) of 115 with subtype E infections, were misclassified as recent infections. Lowering the cutoff to an SOD of 0.45 for subtype E specimens resulted in a mean window period of 185 days (95% CI, 154-211 days), with all individuals seroconverting, and reduced the number of subtype E-infected patients with AIDS who were misclassified as having recent infection to 2.6%. Our results demonstrate that the 3A11-LS assay has different performance characteristics in detecting recent infections among individuals infected with subtypes B or E. Determining appropriate cutoffs and mean window periods for other HIV-1 subtypes will be necessary before this approach can be reliably implemented in settings where non-B subtypes are common.

The emergence of a new infectious disease, AIDS, in the early 1980s resulted in the development of a national AIDS surveillance system. AIDS surveillance data provided an understanding of transmission risks and characterized communities affected by the epidemic. Later, these data provided the basis for allocating resources for prevention and treatment programs. New treatments have dramatically improved survival. Resulting declines in AIDS incidence and deaths offer hope that HIV disease can be successfully managed. However, to prevent and control HIV/AIDS in the coming decades, the public health community must address new challenges. These include the defining of the role of treatment in reducing infectiousness; the potential for an epidemic of treatment-resistant HIV; side effects of treatment; complacency that leads to relapses to high-risk behaviors; and inadequate surveillance and research capacity at state and local levels to guide the development of health interventions. Meeting these challenges will require reinvesting in the public health capacity of state and local health departments, restructuring HIV/AIDS surveillance programs to collect the data needed to guide the response to the epidemic, and providing timely answers to emerging epidemiologic questions.

We developed a scheme using routinely available data to estimate the risk of human immunodeficiency virus (HIV) dementia in HIV-infected persons over time. We performed a longitudinal review of medical records from more than 100 medical facilities in 11 U.S. cities. A total of 19,462 HIV-infected persons without history of dementia enrolled in a multi-institution survey. The main outcome measure was the development of HIV dementia (1987 case definition) during the median follow-up period of 17 months (range, 1 to 72 months). Of 19,462 HIV-infected persons, HIV dementia developed in 880 persons (4.5%; 2.6% per person-year). The strongest predictors of HIV dementia were CD4+ T-lymphocyte count, anemia, and AIDS-defining infections or cancer. The 2-year probability of HIV dementia was highest for persons who had a CD4+ T-lymphocyte count of fewer than 100 cells/microL and an AIDS-defining illness or anemia or both (18.6 to 24.9%). Intermediate risk was observed in persons with CD4+ T-lymphocyte count of 100 to 199 cells/microL and an AIDS-defining illness or anemia or both or in persons with a CD4+ T-lymphocyte count of fewer than 100 cells/microL but without another risk factor (2-year probability, 10.4 to 15.2%). The 2-year probability that HIV dementia would develop was lowest (1.0%) for persons with CD4+ T-lymphocyte count of more than 200 cells/microL and no other risk factors. Risk stratification using routine clinical information provides information that may prove useful in patient care decisions.

Central Africa is a region highly affected by the tuberculosis (TB) pandemic; however, data on local epidemiology are scarce. In the quest for gearing up towards tailored interventions, assessment of local baseline situations is mandatory. We conducted a retrospective study of 62 children registered in the TB register of a hospital in Lambarene, Gabon. The evaluation revealed a discrepancy between the TB burden and the commitment to control TB. Extrapolation of the incidence suggests an unexpectedly high childhood TB burden, assuming that the official overall TB incidence is an underestimate of the true TB burden in Gabon.

To determine whether US residents are infected with subtypes of human immunodeficiency virus (HIV) type 1 other than subtype B (Western), the predominant North American subtype with a unique GPGR genetic sequence in the V3 loop, viruses from 22 HIV-infected adults were serotyped and subtyped. Twenty patients had subtype B (Western), of whom 15 had serotype B (Western), 3 had serotype A/C, 1 had serotype B (Thai), and 1 had a nontypeable serotype. Two had subtype A, both serotype A/C. Both subtype A-infected patients, only 1 of whom had been outside the United States, reported sex with persons traveling abroad, suggesting possible acquisition in the United States. Because US residents are infected with non-subtype B (Western) strains, US surveillance for HIV-1 diversity is needed to elucidate subtype-specific transmission patterns and pathogenesis and to guide evaluation and development of HIV diagnostic tests and vaccines.

To determine the association between human immunodeficiency virus (HIV) infection and stroke among young persons.Retrospective case-control study.Large, inner-city public hospital.All patients aged 19 to 44 years with a diagnosis of stroke, whose HIV status was determined, admitted from January 1990 through June 1994. Controls matched for age and sex were selected from patients who were admitted during the same period for status asthmaticus whose HIV status was known.The associations of HIV infection with all strokes and with cerebral infarction, after adjustment for other cerebrovascular risk factors, were evaluated by Mantel-Haenszel stratified analyses. The subtypes and causes of stroke in HIV-infected patients were compared with HIV-seronegative patients.The HIV infection was associated with stroke (odds ratio [OR], 2.3; 95% confidence interval [CI], 1.0-5.3) and cerebral infarction (OR, 3.4; 95% CI, 1.1-8.9), after adjustment for other cerebrovascular risk factors. Among patients with stroke, cerebral infarction was more frequent in HIV-infected patients than in HIV-seronegative patients (20 [80%] of 25 vs 48 [56%] of 88, P = .04). The frequency of cerebral infarctions associated with meningitis (P.001) and protein S deficiency (P = .06) was higher in HIV-infected patients than in seronegative patients.Our study suggests that HIV infection is associated with an increased risk of stroke, particularly cerebral infarction in young patients. This risk is probably mediated by increased susceptibility of HIV-infected patients to meningitis and protein S deficiency.

BACKGROUND: This study evaluated the usefulness of the serologic test for syphilis (STS) in preventing the transmission of human immunodeficiency virus (HIV), hepatitis B and C viruses, and human T- lymphotropic virus via the transfusion of seronegative, infectious window-period blood. STUDY DESIGN AND METHODS: Demographic and laboratory information on blood donations made between January 1992 and June 1994 in 18 American Red Cross regions was analyzed. It was assumed that the same proportion of HIV-positive and HIV-infectious window- period donations reacted on STS and were negative on other screening tests (hepatitis B and C viruses and human T-lymphotropic virus). This proportion multiplied by the estimated number of HIV-infectious window- period donations is the number of post-screening HIV-infectious donations removed by STS. RESULTS: Of 4,468,570 donations, 12,145 (0.27%) were STS positive and 377 (0.008%) were HIV positive. Among donations that were negative on other screening tests, STS-reactive donations were 12 times more likely to be HIV positive (odds ratio=11.9; 95% CI=5,26). However, of an estimated 13 infectious window- period donations, 0.2 would have been removed because of a reactive STS, at a cost of over $16 million. CONCLUSION: STS is a poor marker and a costly strategy for preventing post-screening HIV infections and other blood-borne diseases.

Article abstract-Background and purpose: Numerous case series have proposed a relationship between "crack" cocaine use and stroke. We performed a retrospective case control study at a large inner-city public hospital to determine the relationship between crack use and stroke among young persons. Methods: We reviewed records of all patients aged 20 to 39 years with a diagnosis of stroke, and of controls selected from patients with noncocaine-related diagnoses, admitted from January 1990 through June 1994. We collected information regarding cocaine use, time of last use, route of use, and the results of urine toxicologic studies. We performed backward stepwise logistic regression analyses to determine the association of crack use at any time and acute crack use (defined as use within 48 hours prior to presentation) with stroke and stroke subtypes. Results: Among patients with information regarding presence or absence of crack use (66 of 144 stroke patients and 99 of 147 controls), crack use at any time was not associated with stroke (odds ratio [OR] = 0.7, 95% CI 0.4-1.8) or cerebral infarction (OR = 0.5, 95% CI 0.2-1.2). Among patients providing temporal information regarding crack use, acute crack use was not associated with stroke (OR = 1.9, 95% CI 0.7-5.1) or cerebral infarction (OR = 1.2, 95% CI 0.4-3.8). Conclusions: Crack use at any time or acute crack use was not significantly associated with stroke or cerebral infarction in our patient population. NEUROLOGY 1997;48: 341-345

Aim Glucose-dependent insulinotropic peptide (GIP) is an incretin hormone that is released from intestinal K cells in response to nutrient ingestion. We aimed to investigate the therapeutic potential of the novel N- and C-terminally modified GIP analogue AC163794. Methods AC163794 was synthesized by solid-phase peptide synthesis. Design involved the substitution of the C-terminus tail region of the dipeptidyl peptidase IV (DPP-IV)-resistant GIP analogue [d-Ala2]GIP(1–42) with the unique nine amino acid tail region of exenatide. The functional activity and binding of AC163794 to the GIP receptor were evaluated in RIN-m5F β-cells. In vitro metabolic stability was tested in human plasma and kidney membrane preparations. Acute insulinotropic effects were investigated in isolated mouse islets and during an intravenous glucose tolerance test in normal and diabetic Zucker fatty diabetic (ZDF) rats. The biological actions of AC163794 were comprehensively assessed in normal, ob/ob and high-fat-fed streptozotocin (STZ)-induced diabetic mice. Acute glucoregulatory effects of AC163794 were tested in diet-induced obese mice treated subchronically with AC3174, the exendatide analogue [Leu14] exenatide. Human GIP or [d-Ala2]GIP(1–42) were used for comparison. Results AC163794 exhibited nanomolar functional GIP receptor potency in vitro similar to GIP and [d-Ala2]GIP(1–42). AC163794 was metabolically more stable in vitro and displayed longer duration of insulinotropic action in vivo versus GIP and [d-Ala2]GIP(1–42). In diabetic mice, AC163794 improved HbA1c through enhanced insulinotropic action, partial restoration of pancreatic insulin content and improved insulin sensitivity with no adverse effects on fat storage and metabolism. AC163794 provided additional baseline glucose-lowering when injected to mice treated with AC3174. Conclusions These studies support the potential use of a novel GIP analogue AC163794 for the treatment of type 2 diabetes.

During a 2-month period, five patients suffering from invasive infections caused by Aspergillus flavus or Aspergillus fumigatus were identified in the Hematology Department of the University Hospital Dijkzigt (Rotterdam, The Netherlands). To study the epidemiological aspects of invasive aspergillosis, strains from these patients and from the hospital environment, isolated during extensive microbiological screening, were subjected to genotyping. A novel DNA extraction technique, involving freezing, grinding, and direct lysis in guanidium isothiocyanate-containing buffers of mycelial material, was applied. DNA isolation was followed by typing by random amplification of polymorphic DNA (RAPD) analysis. This showed that strains isolated from all patients infected with the same fungal species were genotypically distinct, thus providing evidence against the possibility of an ongoing, single-source nosocomial outbreak. Strains could also be differentiated from strains of geographically diverse origins. However, an A. flavus strain from one of the patients was also frequently encountered in the hospital environment. As all environmental strains were collected after this patient had been diagnosed with invasive disease, the epidemiological value of this observation could not be ascertained. Intensive investigations showed no single source of A. flavus or other aspergilli. RAPD genotyping proved that the outbreak of invasive aspergillosis in the hematology ward consisted of a series of unrelated events and was not due to a common source within the hospital. RAPD fingerprinting of aspergilli may greatly facilitate future investigations of the epidemiology of invasive disease caused by these pathogens.

HEPLISAV™ is an adult hepatitis B vaccine that requires fewer doses over a shorter period of time and elicits higher and earlier seroprotection compared to Engerix-B to reduce the risk of hepatitis B infection. The objective of this analysis was to evaluate the cost-effectiveness of vaccination with HEPLISAV vs. Engerix-B(®) to prevent hepatitis B infection in select populations.Markov models were developed for the following populations: diabetics, patients with chronic or end stage kidney disease, healthcare workers and international travelers to countries with high HBV infection prevalence. Hepatitis B disease progression was modeled using 11 health states: seroprotected, susceptible, acute infection, chronic infection, fulminant hepatic failure, compensated cirrhosis, decompensated cirrhosis, hepatocellular carcinoma, liver transplant, post-transplant care, and death. Seroprotection rates were obtained from two phase 3 clinical trials comparing HEPLISAV with Engerix-B and ranged across various populations from 89-96% for HEPLISAV and 62-81% for Engerix-B. Higher vaccination completion rates were assumed for HEPLISAV compared with Engerix-B given that fewer doses of HEPLISAV are required in a shorter period of time to achieve seroprotection for the evaluated populations. Each cycle length after the first year in the model was 1-year. All future costs and benefits were discounted at 3%. A lifetime analysis and a U.S. payer perspective were used.HEPLISAV has a favorable cost-effectiveness profile with incremental cost effectiveness ratios$25,000 across all populations studied. In the patients with chronic or end stage kidney disease, HEPLISAV was the dominant option and was cost-saving compared with Engerix-B. The cost of vaccine, regimen completion rates, and seroprotection rates were the sensitive variables in the models.HEPLISAV is a cost-effective option to provide high rates of seroprotection and early seroprotection across a range of populations from health care workers to patients with chronic or end stage kidney disease.

In the United States, transmission of the human immunodeficiency virus (HIV) by blood transfusion occurs almost exclusively when a recently infected blood donor is infectious but before antibodies to HIV become detectable (during the "window period"). We estimated the risk of HIV transmission caused by transfusion on the basis of the window period associated with the use of current, sensitive enzyme immunosorbent assays and recent data on HIV incidence among blood donors.We analyzed demographic and laboratory data on more than 4.1 million blood donations obtained in 1992 and 1993 in 19 regions served by the American National Red Cross, as well as the results of HIV-antibody tests of 4.9 million donations obtained in an additional 23 regions.We estimated that, in the 19 study regions, 1 donation in every 360,000 (95 percent confidence interval, 210,000 to 1,140,000) was made during the window period. In addition, it is estimated that 1 in 2,600,000 donations was HIV-seropositive but was not identified as such because of an error in the laboratory. We estimated that 15 to 42 percent of window-period donations were discarded because they were seropositive on laboratory tests other than the HIV-antibody test. When these results were extrapolated to include the additional 23 Red Cross service regions, there was a risk of one case of HIV transmission for every 450,000 to 660,000 donations of screened blood. If the Red Cross centers are assumed to be representative of all U.S. blood centers, among the 12 million donations collected nationally each year an estimated 18 to 27 infectious donations are available for transfusion.The estimated risk of transmitting HIV by the transfusion of screened blood is very small and nearly half that estimated previously, primarily because the sensitivity of enzyme immunosorbent assays has been improved.

Background and Purpose Stroke subtypes and prognosis differ among older black patients compared with whites; however, few data are available regarding stroke among young black patients. Methods To determine the risk factors for stroke, stroke subtype, and prognosis among young black patients, we retrospectively reviewed the medical records of all 15- to 44-year-old patients admitted with stroke to a university-affiliated public hospital from January 1990 through June 1994. Results Of the 248 eligible patients admitted with stroke, 219 were blacks. Hypertension was more frequently associated with stroke in young black than in non-black patients (55% versus 24%, P =.003). Cocaine abuse was frequent among both black and non-black patients (27% versus 38%, P =NS). Hypertensive intracerebral hemorrhage (64%) was the most common subtype of intracerebral hemorrhage (n=67), and lacunar infarction (21%) was the most common subtype of cerebral infarction (n=112) in young black patients. Outcome in black patients with stroke at discharge was 69% independent, 8% dependent, and 23% dead. Conclusions The high frequency of hypertension, hypertensive intracerebral hemorrhage, and lacunar infarction among young black patients with stroke suggests accelerated hypertensive arteriolar damage, possibly due to poor control of hypertension.

Background The currently licensed hepatitis B vaccines have limitations including hyporesponsiveness in older adults, poor compliance, and the extended time for most persons to develop seroprotection (e.g. >6 months). A vaccine containing HBsAg combined with a Toll-like receptor 9 agonist adjuvant (HBsAg-1018) has been developed to overcome these limitations. Methods A Phase 3, multicenter, randomized, subject- and observer-blinded, active-controlled trial was conducted among healthy subjects 40–70 years of age comparing the immunogenicity and safety of two doses of HBsAg-1018 at 0 and 4 weeks to three doses of licensed hepatitis B vaccine, HBsAg-Eng, at 0, 4, and 24 weeks. The primary immunogenicity endpoint was noninferiority of the seroprotection rate (SPR; % with anti-HBs ≥10 mIU/mL) of HBsAg-1018 compared to the SPR of HBsAg-Eng at 8 weeks following the last dose of vaccine. Conditional upon meeting noninferiority, superiority of HBsAg-1018 over HBsAg-Eng was assessed. Safety was compared between the two vaccines. Results At the primary endpoint, the SPR for the HBsAg-1018 group (90.0%) was superior to the SPR for the HBsAg-Eng group (70.5%) with an SPR difference of 19.5% (95% CI, 14.7%, 24.7%). At week 28 when the SPR peaked in the HBsAg-Eng group (72.8%), the SPR in the HBsAg-1018 group (94.8%) was significantly higher than in the HBsAg-Eng group. The SPR in the HBsAg-1018 group was significantly higher than in the HBsAg-Eng group at each study visit from week 4 through week 52. The safety profiles for the two vaccines were similar. Conclusion When compared to the HBsAg-Eng three-dose regimen given at 0, 1, and 6 months, HBsAg-1018 demonstrated superior seroprotection with only two doses at 0 and 1 month. The safety profile of HBsAg-1018 was comparable to that of the licensed vaccine, HBsAg-Eng. HBsAg-1018 would provide a significant public health contribution toward the prevention of hepatitis B infection.

The objective was to evaluate the analgesic efficacy of pre- and postoperative administration of meloxicam on the postsurgical convalescence period of lame dairy cows undergoing resection of the coffin joint. In a blinded, placebo-controlled, explorative clinical trial, 19 lame German Holstein-Friesian cows weighing 536 ± 98 kg (mean ± SD) and aged 5.7 ± 2.8 yr were included. All cows suffered from unilateral lameness due to septic arthritis of the coffin joint. Lame cows were randomly allocated to either the meloxicam group (n=9) or the control group (n=10) and received an intravenous injection of meloxicam (0.5mg/kg of BW) or an equal volume of saline immediately before surgery (d 0) and once daily from d 1 to 4. All cows received a retrograde intravenous local anesthesia (20 mL of procaine 2%) before the surgical intervention. Heart rate, respiratory rate, body temperature, plasma concentrations of cortisol, as well as production parameters (milk yield and feed intake) were evaluated from d 0 to 7. The gait of the animals was assessed daily by lameness scores and by monitoring the cows' activity by means of pedometers attached to both hind legs. Possible adverse effects on abomasal mucosal integrity were monitored by fecal occult blood tests and blood cell counts from d 0 to 7 and on d 14. Under meloxicam treatment plasma cortisol levels, lameness scores, and body temperature were significantly reduced compared with controls. While being treated with meloxicam, the time cows were standing per day was significantly longer compared with controls. In the healthy limb significantly more steps were registered in meloxicam-treated cows than in controls. Feed intake and milk yield were not significantly affected by meloxicam. No group differences were found in number of positive tests for fecal occult blood or blood cell counts. In conclusion, repeated meloxicam application demonstrated effective analgesia in the postsurgical period after resection of septically infected coffin joints in dairy cows without indications of evoking adverse effects on abomasal integrity.

To underline the role of echocardiography in the detection of cardiac involvement in patients with amyloidosis, physical examination, echocardiography and electrocardiography were performed in 30 patients with AA amyloidosis (amyloid protein A, associated with chronic inflammatory disease, usually without cardiomyopathy) and 24 patients with AL amyloidosis (the immunoglobulin light chain derived type, often associated with cardiomyopathy). All patients had histological confirmation of amyloidosis by rectal or subcutaneous abdominal fat biopsy. The combination of increased thickness of the left ventricular posterior wall and interventricular septum with a low voltage electrocardiographic pattern is highly specific for cardiac amyloidosis and was found in 3/30 (10%) of the AA patients and in 13/24 (54%) of the AL patients. The echocardiographic abnormalities were strongly related to the degree of clinical heart disease, showing mildly or moderately increased wall thickness in the early asymptomatic phase or severe thickening and hypokinesia of the left ventricular posterior wall and interventricular septum in clinically apparent cardiac dysfunction. Echocardiography appears to be a sensitive test for the detection of cardiac involvement in amyloidosis, in symptomatic as well as asymptomatic patients.

Progressive multifocal leukoencephalopathy (PML), a rare neurological disease, has been sporadically reported in persons infected with human immunodeficiency virus (HIV), the causative agent of acquired immune deficiency syndrome (AIDS). From January 1981 through February 1989, in San Francisco, we identified 94 HIV-infected persons with PML, of whom 48 (51%) were pathologically confirmed (as required for AIDS case reporting). These 48 patients were significantly older when diagnosed with AIDS (20% older than 50 years) than patients with AIDS without PML. The remaining 46 (49%) patients, diagnosed clinically and by neuroimaging, did not differ significantly from definitive patients in demographic or survival characteristics after PML diagnosis. We detected antibodies to JC virus, the causative agent of PML, in 9 of 14 (64%) AIDS-related patients with PML, and in 9 of 14 (64%) matched control subjects, suggesting that determination of JC virus antibody status before AIDS diagnosis does not reliably indicate which patients will contract PML. Our study shows that the proportion of patients with AIDS who contracted PML remained stable between 1981 and 1988, but increased in the first 2 months of 1989. Our findings further indicate that PML in HIV-infected patients may be underestimated by as much as 50%.

Subjects were 21 men with persistent generalized lymphadenopathy (PGL, n = 13) or AIDS-related complex (ARC, n = 8), who were not receiving anti-retroviral medication, and 21 controls. At baseline, mild cognitive impairment was detected in language, memory, attention, and visual and auditory processing, primarily in patients with ARC. On follow-up, the ARC group showed continued impairment and abnormalities on new measures of distractibility and activities of daily living. Although mild decline in verbal memory was noted for some patients, overall neuropsychological profiles did not show deterioration. Nomenclature for the pattern of mild, stable neuropsychological changes in patients with cognitive symptoms is discussed. Two interdisciplinary panels have recommended the term HIV-1-associated minor cognitive/motor disorder. Unlike the term AIDS dementia, it does not imply progression or a diagnosis of AIDS.

This study evaluates if the Disabilites of the Arm, Shoulder and Hand (DASH) questionnaire is an adequately responsive outcome measure in lateral extensor release for tennis elbow. To measure responsiveness (sensitivity to clinical change), 21 patients with operated tennis elbow completed the DASH questionnaire pre-operatively and again postoperatively. The effect size (2.03) and standardized response (1.54) mean that, as well as the correlation with patient satisfaction and the Roles & Maudsley score (10), the DASH questionnaire is a useful tool to evaluate the outcome of surgical treatment of tennis elbow.

An activating mutation in exon 15 of the BRAF gene is present in a high proportion of cutaneous pigmented lesions. Until recently this mutation had however only been identified in one case of posterior uveal melanoma. Despite this apparent lack of the BRAF mutation, inappropriate downstream activation of the Ras/Raf/MAPK pathway has been described in posterior uveal melanoma. Based on the already recognised morphological and cytogenetic heterogeneity in uveal melanoma, we hypothesised that the BRAF mutation may be present in uveal melanoma but only in some of the tumour cells. In this study, we analysed 20 ciliary body and 30 choroidal melanomas using a nested PCR-based technique resulting in the amplification of a nested product only if the mutation was present. This sensitive technique can identify mutated DNA in the presence of wild-type DNA. The mutation was identified in 4 of 20 (20%) ciliary body and 11 of 30 (40%) choroidal melanomas. Further analysis of separate areas within the same choroidal melanoma demonstrated that the mutation was not present in the entire tumour. In conclusion, the T1799A BRAF mutation is present in a proportion of posterior uveal melanomas but within these tumours the distribution of the mutation is heterogeneous.

Context Incidence of human immunodeficiency virus (HIV) in the United States has not been directly measured. New assays that differentiate recent vs long-standing HIV infections allow improved estimation of HIV incidence. Objective To estimate HIV incidence in the United States. Design, Setting, and Patients Remnant diagnostic serum specimens from patients 13 years or older and newly diagnosed with HIV during 2006 in 22 states were tested with the BED HIV-1 capture enzyme immunoassay to classify infections as recent or long-standing. Information on HIV cases was reported to the Centers for Disease Control and Prevention through June 2007. Incidence of HIV in the 22 states during 2006 was estimated using a statistical approach with adjustment for testing frequency and extrapolated to the United States. Results were corroborated with back-calculation of HIV incidence for 1977-2006 based on HIV diagnoses from 40 states and AIDS incidence from 50 states and the District of Columbia. Main Outcome Measure Estimated HIV incidence. Results An estimated 39 400 persons were diagnosed with HIV in 2006 in the 22 states. Of 6864 diagnostic specimens tested using the BED assay, 2133 (31%) were classified as recent infections. Based on extrapolations from these data, the estimated number of new infections for the United States in 2006 was 56 300 (95% confidence interval [CI], 48 200-64 500); the estimated incidence rate was 22.8 per 100 000 population (95% CI, 19.5-26.1). Forty-five percent of infections were among black individuals and 53% among men who have sex with men. The back-calculation (n = 1.230 million HIV/AIDS cases reported by the end of 2006) yielded an estimate of 55 400 (95% CI, 50 000-60 800) new infections per year for 2003-2006 and indicated that HIV incidence increased in the mid-1990s, then slightly declined after 1999 and has been stable thereafter. Conclusions This study provides the first direct estimates of HIV incidence in the United States using laboratory technologies previously implemented only in clinic-based settings. New HIV infections in the United States remain concentrated among men who have sex with men and among black individuals.