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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.

A 56-year-old, otherwise healthy, man was referred to the Academic Tattoo Clinic Amsterdam because of pain and itch in a multicoloured tattoo on his right arm since one month. Two weeks before the start of the complaints the patient had gotten the tattoo in Bali, Indonesia. The patient had no fever or other physical complaints. Physical examination revealed multiple erythematosquamous papules and pustules, especially in the black and white coloured parts of the tattoo (Fig. 1a).

Background: This was a phase 1, dose-escalation open-label trial to evaluate the safety and immunogenicity of MVC-COV1901, a SARS-CoV-2 S-2P protein vaccine adjuvanted with aluminum hydroxide and CpG 1018. Methods: 45 healthy adults from 20 to 49 years of age were to be administered two vaccinations of MVC-COV1901 in doses of 5 μg, 15 μg, or 25 μg of spike protein at 28 days apart. There were 15 participants in each dose group; all were followed for 28 days after the second vaccination at the time of the interim analysis. Adverse events (AEs) and laboratory data were recorded for the safety evaluation. Blood samples were collected for wild-type SARS-CoV-2 and pseudovirus neutralization assays, SARS-CoV-2 spike-specific immunoglobulin G (IgG), and cellular immune response at various time points. Findings: Solicited adverse events were mostly mild and similar in all three dose groups. No subject experienced fever. After the second vaccination, serum neutralizing activity for wild-type virus was detected in all participants of the 15 μg and 25 μg dose groups with geometric mean values (76•3 [95% CI: 53•75 ~108•33], and 167•4 [95% CI: 122.05 ~229.61]) 1•8 to 3•9 times those of a panel of control convalescent serum specimens (42•7, [95%CI: 26•38~69•04]). The cellular immune response induced by MVC-COV1901 demonstrated substantially higher numbers of IFN-γ- than IL-4- producing cells in human peripheral blood mononuclear cells, suggesting a Th1-skewed immune response. Interpretation: The MVC-COV1901 vaccine was well tolerated and elicited robust immune responses especially in the 15 μg and 25 μg dose groups and is suitable for further development. Trial Registration: ClinicalTrials.gov NCT 04487210 Funding: Medigen Vaccine Biologics Corporation. Conflict of Interest: Szu-Min Hsieh, Shan-Chwen Chang, Wang-Da Liu, Yu-Shan Huang declared that they have no knowncompeting financial interests or personal relationships that could have appeared to influence the work reported in this paper; Yi-Jiun Lin, Erh-Fang Hsieh, Wei-Cheng Lian, Charles Chen, I-Chen Tai are employee ofMedigen Vaccine Biologics Corporation and reported grants from Taiwan Centers for Disease Control, Ministry of Health and Welfare, during the conduct of the study. In addition, Yi-Jiun. Lin and Charles Chen have a patent US63/040,696 pending. Robert Janssen is an employee of Dynavax Technologies Corporation. Ethical Approval: The trial protocol and informed consent form were approved by the Taiwan Food and Drug Administration and the ethics committee at the site. The trial was conducted in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice. An independent data and safety monitoring board (DSMB) was established to monitor safety data and the trial conduct.

Background Hemodialysis patients are at increased risk of hepatitis B virus (HBV) infection and are poorly responsive to HBV vaccines. Current vaccine recommendations for hemodialysis patients utilize more than twice the amount of hepatitis B surface antigen (HBsAg) used for healthy adults and achieve lower immune responses. Methods An open-label, single-arm, multicenter trial was conducted among adults 18 years of age and older who were initiating or undergoing hemodialysis who had not previously received hepatitis B vaccine. Participants received four doses of HepB-CpG (HEPLISAV-B®) (20 mcg rHBsAg + 3000 mcg CpG 1018, a Toll-like receptor 9 agonist) administered at 0, 4, 8, and 16 weeks. Participants are being followed for 68 weeks. This paper reports the final immunogenicity analysis of the primary endpoint at study week 20 and an interim safety analysis. Results We enrolled 119 participants receiving hemodialysis who were followed for a median of 47.4 weeks. Of the 119 participants, 75 were in the per-protocol population. At week 20, the seroprotection rate (% with antibodies to hepatitis B surface antigen [anti-HBs] ≥ 10 mIU/mL) was 89.3% and the percentage of participants with anti-HBs ≥ 100 mIU/mL was 81.3%. The anti-HBs geometric mean concentration was 1061.8 mIU/mL. HepB-CpG was well tolerated with no observed safety concerns. Conclusion In patients receiving hemodialysis, HepB-CpG given as four doses was well tolerated and induced very high anti-HBs concentrations and seroprotection in a very high proportion of recipients.

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 global public health problem. Approved alum-adjuvanted vaccines are well tolerated but require three doses and have reduced immunogenicity in adults. A two-dose vaccine containing hepatitis B surface antigen combined with a novel, Toll-like receptor 9 agonist adjuvant (HBsAg-1018 [HEPLISAV–B®]) has demonstrated significantly higher seroprotection rates than a three dose vaccine. Methods A post hoc analysis compared the safety of HBsAg-1018 with HBsAg-Eng (Engerix-B®), in three randomized, observer-blinded, active-controlled, multi-center phase 3 trials in adults. HBsAg-1018 was administered intramuscularly at weeks 0 and 4 and placebo at week 24 and HBsAg-Eng at weeks 0, 4, and 24. Results Post-injection reactions, adverse events, medically attended adverse events, and new-onset immune-mediated adverse events were balanced between vaccine groups. Anti-nuclear antibodies, anti-double stranded DNA antibodies, anti-neutrophil cytoplasmic antibodies, and antiphospholipid antibodies were balanced between groups. A transient increase in anti-beta2 glycoprotein 1 IgM was observed in the HBsAg-1018 group but was not associated with a thrombotic event. Serious adverse events and deaths were generally balanced between groups. Conclusion HBsAg-1018 had a similar safety profile to HBsAg-Eng. With improved immunogenicity and fewer doses over a shorter time, HBsAg-1018 has the potential to provide improved seroprotection and a significant public health benefit to adults 18 years of age or older.

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.

The start of complementary feeding in infancy plays an essential role in promoting healthy eating habits. Evidence shows that it is important what infants are offered during this first introduction of solid foods: e.g. starting exclusively with vegetables is more successful for vegetable acceptance than starting with fruits. How infants are introduced to solid foods also matters: if parents are sensitive and responsive to infant cues during feeding, this may promote self-regulation of energy intake and a healthy weight. However, the effectiveness of the what and the how of complementary feeding has never been experimentally tested in the same study. In the current project the what and how (and their combination) are tested in one study to determine their relative importance for fostering vegetable acceptance and self-regulation of energy intake in infants. A four-arm randomized controlled trial (Baby’s First Bites (BFB)) was designed for 240 first-time Dutch mothers and their infants, 60 per arm. In this trial, we compare the effectiveness of (a) a vegetable-exposure intervention focusing on the what in complementary feeding; (b) a sensitive feeding intervention focusing on the how in complementary feeding, (c) a combined intervention focusing on the what and how in complementary feeding; (d) an attention-control group. All mothers participate in five sessions spread over the first year of eating solid foods (child age 4–16 months). Primary outcomes are vegetable consumption, vegetable liking and self-regulation of energy intake. Secondary outcomes are child eating behaviors, child anthropometrics and maternal feeding behavior. Outcomes are assessed before, during and directly after the interventions (child age 18 months), and when children are 24 and 36 months old. The outcomes are expected to assess the impact of the interventions and provide new insights into the mechanisms underlying the development of vegetable acceptance, self-regulation and healthy eating patterns in infants and toddlers, as well as the prevention of overweight. The results may be used to improve current dietary advice given to parents of their young children on complementary feeding. The trial was retrospectively registered during inclusion of participants at the Netherlands National Trial Register (identifier NTR6572 ) and at ClinicalTrials.gov ( NCT03348176 ). Protocol issue date: 1 April 2018; version number 1.

Importance Receipt of hepatitis B virus vaccine is important to prevent infection. However, adherence to the hepatitis B vaccine series among adults at risk of infection has been low. Objective To assess whether recipients of a 2-dose hepatitis B vaccine with cytosine phosphoguanine adjuvant (HepB-CpG vaccine; Heplisav-B) are more likely to complete their series compared with recipients of a 3-dose vaccine with alum adjuvant (comparator vaccine; Engerix-B [HepB-alum]). Design, Setting, and Participants This nested cohort study was conducted from August 7 to December 31, 2018, at Kaiser Permanente Southern California, an integrated health care system with a diverse population of approximately 4.6 million members. Adults not receiving dialysis who received a first dose of a hepatitis B vaccine series in family practice or internal medicine departments of 15 Kaiser Permanente Southern California medical centers were followed up through electronic health records for up to 1 year after receipt of the first dose. Data were analyzed from March 16 to September 23, 2020. Exposures Receipt of a first dose of the HepB-CpG vaccine (2-dose vaccine) vs receipt of a first dose of the HepB-alum vaccine (3-dose vaccine). Main Outcomes and Measures Series completion within the recommended vaccine schedule plus 3 months (primary outcome) and series completion within 1 year after receipt of the first dose (secondary outcome). Results Of 4727 individuals who initiated the HepB-CpG vaccine series and 6161 individuals who initiated the HepB-alum vaccine series included in the study, 2876 (60.8%) and 3789 (61.5%), respectively, were ages 40 to 59 years, 2415 (51.1%) and 3113 (50.5%) were male, and 2364 (50.0%) and 2881 (46.8%) were Hispanic. The vaccine series was completed within the recommended schedule plus 3 months for 2111 (44.7%) individuals who initiated the HepB-CpG vaccine series and 1607 (26.1%) individuals who initiated the HepB-alum vaccine series, and within 1 year for 2858 (60.5%) and 1989 (32.3%) individuals, respectively. The individuals who initiated the HepB-CpG vaccine series were significantly more likely to complete the series (adjusted relative risk, 1.77; 95% CI, 1.68-1.87). Results were consistent across clinical and demographic strata. Conclusions and Relevance In this study, use of the HepB-CpG vaccine was associated with hepatitis B vaccine series completion, but tailored strategies to increase completion of hepatitis B vaccine series are warranted.

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 HEPLISAV-B® [hepatitis B vaccine (recombinant), adjuvanted] uses a cytidine phospho-guanosine (CpG) oligonucleotide or “1018,” a Toll-like receptor 9 agonist, as an adjuvant. Engerix-B® [hepatitis B vaccine (recombinant)], as well as other hepatitis B vaccines, use alum. HEPLISAV-B, a 2-dose vaccine given at Weeks 0 and 4, was recently approved for use in adults ≥18 years for the prevention of hepatitis B. Approval of HEPLISAV-B was based on three pivotal phase 3 noninferiority trials, comparing it with Engerix-B, a 3-dose vaccine given at Day 0, Day 30, and 6 months. Immunogenicity and safety results for these trials, HBV-10, HBV-16 and HBV-23, have been published previously; the safety of HEPLISAV-B was generally similar to Engerix-B. Methods The 3 randomized trials were observer-blinded and collectively included subjects aged 18–70 years. Immunogenicity analysis based on antibody against hepatitis B surface antigen (anti-HBs) levels were based on the per-protocol analysis. Presented here are reverse cumulative frequency plots of anti-HBs serum concentrations for the 3 trials. Results Across the trials, reverse cumulative frequency plots of anti-HBs concentrations showed a higher proportion (>90%) of HEPLISAV-B subjects developed a seroprotective antibody level (anti-HBs levels ≥10 mIU/mL) compared with Engerix-B subjects (80% to ~90%). A higher proportion of HEPLISAV-B subjects had anti-HBs levels between 10 mIU/mL and 1,000 mIU/mL. While a higher proportion of Engerix-B subjects had anti-HBs levels >1,000 mIU/mL, a significantly higher proportion of Engerix-B subjects did not develop seroprotective antibody levels. The response curves indicate a more consistent immune response with a higher percentage of subjects achieving seroprotection with less variability for HEPLISAV-B compared with Engerix-B, which showed a more variable response and fewer subjects achieving seroprotection. Conclusion HEPLISAV-B, using a CpG adjuvant, results in a higher percentage of persons achieving seroprotection and produces a more uniform and consistent induction of protective antibody levels than Engerix-B, an alum-adjuvanted vaccine. Disclosures R. N. Hyer, Dynavax Technologies Corporation: Employee and Shareholder, Salary and Stock options. R. Janssen, Dynavax Technologies Corporation: Employee and Shareholder, Salary and Stock options.

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.

Gallstone disease has a high incidence, and most common presentations are well known and recognized. Particulalry in the elderly population though, uncommon presentations of gallstone disease are more frequent, and can easily be missed or misinterpreted. In this article we present 5 such patients with an atypical presentation of gallstone disease. We will then discuss atypical gallstone disease in more detail.

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.

(CHEST 2008; 134:1074–1079) A 33-year-old man was brought to the emergency department with dyspnea, chest pain, and confusion. His symptoms began 2 weeks prior, with intermittent mild anterior chest pain, palpitations, exertional breathlessness, and diaphoresis. The symptoms gradually worsened, and on the morning of presentation he complained of severe chest pain and dyspnea at rest. Several hours later, he was found by his wife on the floor, confused and tremulous. His wife called emergency services and he was transported to the emergency department. In the emergency department, the patient was unresponsive to verbal and tactile stimuli. He was orotracheally intubated for airway protection. The patient’s wife said that he was healthy before his recent symptoms began. Although he was not taking any medications, she thought he was told in the past that he should take a thyroid medication. He had no allergies, no family history of heritable disease, and never used tobacco, alcohol, or recreational drugs. He had emigrated from Mexico at age 23 years and worked as a carpenter. He lived at home with his wife and two children.

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.

b d Public health departments collect a vast array of identifiable information in the course of mandatory reporting efforts and other surveillance activities. These undertakings span a range of conditions from infectious threats and chronic diseases including cancer, to immunization status and birth defects. Advocates for expanded surveillance extended the practice to occupational diseases and, most ambitiously, to profiles of childhood health status. Syndromic surveillance is also increasingly undertaken in the new post-September 11 security environ - ment. In the one Supreme Court case addressing public health surveillance, a unanimous tribunal upheld the right of the state to conduct surveillance. 1

A small-angle detector will complete the performance of the cold time-of-flight spectrometer FOCUS at the Swiss Spallation Source SINQ of the Paul Scherrer Institute, Villigen, Switzerland. It is constructed from position-sensitive 3He tubes located 2.5 m away from the sample, and covers an area of about 95 × 70 cm2 with a spatial resolution of approximately 1.5 cm. The 2D detector is located within a vacuum chamber, next to the argon chamber of the existing large angle detectors, and covers an angular range from 2 to 22°. Commissioning of the 2D small angle detector will start in spring 2006.

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.

FOCUS is a cold neutron time-of-flight spectrometer at the swiss spallation neutron source SINQ (Paul Scherrer Institute). Various quasielastic and inelastic neutron scattering experiments have been performed so far using a pyrolithic graphite monochromator with incident wavelengths between 2 and 6 A. Recently, the instrument has been complementarily equipped with a new mica monochromator. This device is mechanically identical to the graphite monochromator but it covers the wavelength range from 6 to 15 A. With that new monochromator an energy resolution below 10 μeV (FWHM) is feasible on FOCUS which is a factor of 5 below the former value accessible with the graphite monochromator. The design as well as first experiences with the new monochromator will be discussed. One of the first measurements using the mica monochromator, which investigated the dynamics of Na 4 B(OH) 4 3+ clusters confined in pores of a zeolite is presented.

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.

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.

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.

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.

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.

In spring 99 the SINQ time-of-flight (TOF) spectrometer FOCUS became operational. The instrument can be used either in time focusing or monochromatic focusing conditions. In this contribution we want to report on recent measurements exploring the elastic and inelastic energy resolution of the instrument for the various settings. It was found that especially the usage of higher-order reflections of the double focusing pyrolitic graphite monochromator allows for energy resolutions in the order of 0.3 meV at a neutron energy loss in the order of 8–14 meV.

Disease incidence (new cases of disease per person per year) is usually measured by using longitudinal data. However, several recent proposals for measuring the incidence of human immunodeficiency virus (HIV) rely on cross-sectional data only. These methods assume each person is only sampled once; however, in some instances, it is necessary to consider these cross-sectional methods when individuals are represented more than once in the survey sample. We derive an extension of the cross-sectional incidence estimator that is valid for data from repeatedly screened populations and show under what conditions our new estimator reduces to the old estimator. An example involving estimation of HIV incidence among repeat blood donors is presented.

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.

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.