Proof Relevant Corecursive Resolution

Resolution lies at the foundation of both logic programming and type class context reduction in functional languages. Terminating derivations by resolution have well-defined inductive meaning, whereas some non-terminating derivations can be understood coinductively. Cycle detection is a popular method to capture a small subset of such derivations. We show that in fact cycle detection is a restricted form of coinductive proof, in which the atomic formula forming the cycle plays the role of coinductive hypothesis. This paper introduces a heuristic method for obtaining richer coinductive hypotheses in the form of Horn formulas. Our approach subsumes cycle detection and gives coinductive meaning to a larger class of derivations. For this purpose we extend resolution with Horn formula resolvents and corecursive evidence generation. We illustrate our method on non-terminating type class resolution problems.Comment: 23 pages, with appendices in FLOPS 201

Low pH immobilizes and kills human leukocytes and prevents transmission of cell-associated HIV in a mouse model

BACKGROUND: Both cell-associated and cell-free HIV virions are present in semen and cervical secretions of HIV-infected individuals. Thus, topical microbicides may need to inactivate both cell-associated and cell-free HIV to prevent sexual transmission of HIV/AIDS. To determine if the mild acidity of the healthy vagina and acid buffering microbicides would prevent transmission by HIV-infected leukocytes, we measured the effect of pH on leukocyte motility, viability and intracellular pH and tested the ability of an acidic buffering microbicide (BufferGel(®)) to prevent the transmission of cell-associated HIV in a HuPBL-SCID mouse model. METHODS: Human lymphocyte, monocyte, and macrophage motilities were measured as a function of time and pH using various acidifying agents. Lymphocyte and macrophage motilities were measured using video microscopy. Monocyte motility was measured using video microscopy and chemotactic chambers. Peripheral blood mononuclear cell (PBMC) viability and intracellular pH were determined as a function of time and pH using fluorescent dyes. HuPBL-SCID mice were pretreated with BufferGel, saline, or a control gel and challenged with HIV-1-infected human PBMCs. RESULTS: Progressive motility was completely abolished in all cell types between pH 5.5 and 6.0. Concomitantly, at and below pH 5.5, the intracellular pH of PBMCs dropped precipitously to match the extracellular medium and did not recover. After acidification with hydrochloric acid to pH 4.5 for 60 min, although completely immotile, 58% of PBMCs excluded ethidium homodimer-1 (dead-cell dye). In contrast, when acidified to this pH with BufferGel, a microbicide designed to maintain vaginal acidity in the presence of semen, only 4% excluded dye at 10 min and none excluded dye after 30 min. BufferGel significantly reduced transmission of HIV-1 in HuPBL-SCID mice (1 of 12 infected) compared to saline (12 of 12 infected) and a control gel (5 of 7 infected). CONCLUSION: These results suggest that physiologic or microbicide-induced acid immobilization and killing of infected white blood cells may be effective in preventing sexual transmission of cell-associated HIV

Evaluation of two formulations of adjuvanted RTS, S malaria vaccine in children aged 3 to 5 years living in a malaria-endemic region of Mozambique: a Phase I/IIb randomized double-blind bridging trial

BACKGROUND: Previous trials of the RTS, S malaria candidate vaccine have shown that this vaccine is safe, tolerated and immunogenic. The development plan for this vaccine aims at administering it in the first year of life through the Expanded Program on Immunization (EPI). The objective was to evaluate the safety and reactogenicity of RTS, S/AS02D (0.5 ml dose), a pediatric formulation of GlaxoSmithKline Biologicals' current malaria candidate vaccine RTS, S/AS02A (0.25 ml dose). A 0.5 ml dose of AS02D is composed of the same active ingredients in the same quantities as in a 0.25 ml dose of AS02A and has been developed to be easily introduced into routine EPI practices. METHODS: We performed a phase I/IIb randomized double-blind bridging study in a malaria-endemic region of Mozambique, to compare the safety and immunogenicity of both candidate vaccines with the aim of replacing RTS, S/AS02A with RTS, S/AS02D as the candidate pediatric vaccine. 200 Mozambican children aged 3 to 5 years were randomized 1:1 to receive one of the 2 vaccines according to a 0, 1, 2 month schedule. RESULTS: Both vaccines were safe and had similar reactogenicity profiles. All subjects with paired pre and post-vaccination samples showed a vaccine response with respect to anti-circumsporozoite (CS) antibodies irrespective of initial anti-CS serostatus. Geometric mean titers (GMTs) were 191 EU/ml (95% CI 150–242) in recipients of RTS, S/AS02D compared to 180 EU/ml (95% CI 146–221) in recipients of RTS, S/AS02A. For the anti-hepatitis B surface antigen (HBsAg), all subjects were seroprotected at day 90, and the GMTs were 23978 mIU/ml (95% CI 17896–32127) in RTS, S/AS02D recipients and 17410 mIU/ml (95% CI 13322–22752) in RTS, S/AS02A recipients. There was a decrease in anti-CS GMTs between months 3 and 14 in both groups (191 vs 22 EU/mL in RTS, S/AS02D group and 180 vs 29 EU/mL in RTS, S/AS02A group). CONCLUSION: Our data show that the RTS, S/AS02D is safe, well tolerated, and demonstrates non-inferiority (defined as upper limit of the 95% confidence interval of the anti-CS GMT ratio of RTS, S/AS02A to RTS, S/AS02D below 3.0) of the antibody responses to circumsporozoite and HBsAg induced by the RTS, S/AS02D as compared to the RTS, S/AS02A

Phase 1 Study of a Combination AMA1 Blood Stage Malaria Vaccine in Malian Children

Apical Membrane Antigen-1 (AMA1) is one of the leading blood stage malaria vaccine candidates. AMA1-C1/Alhydrogel consists of an equal mixture of recombinant AMA1 from FVO and 3D7 clones of P. falciparum, adsorbed onto Alhydrogel. A Phase 1 study in semi-immune adults in Mali showed that the vaccine was safe and immunogenic, with higher antibody responses in those who received the 80 microg dose. The aim of this study was to assess the safety and immunogenicity of this vaccine in young children in a malaria endemic area.This was a Phase 1 dose escalating study in 36 healthy children aged 2-3 years started in March 2006 in Donéguébougou, Mali. Eighteen children in the first cohort were randomized 2 ratio 1 to receive either 20 microg AMA1-C1/Alhydrogel or Haemophilus influenzae type b Hiberix vaccine. Two weeks later 18 children in the second cohort were randomized 2 ratio 1 to receive either 80 microg AMA1-C1/Alhydrogel or Haemophilus influenzae type b Hiberix vaccine. Vaccinations were administered on Days 0 and 28 and participants were examined on Days 1, 2, 3, 7, and 14 after vaccination and then about every two months. Results to Day 154 are reported in this manuscript.Of 36 volunteers enrolled, 33 received both vaccinations. There were 9 adverse events related to the vaccination in subjects who received AMA1-C1 vaccine and 7 in those who received Hiberix. All were mild to moderate. No vaccine-related serious or grade 3 adverse events were observed. There was no increase in adverse events with increasing dose of vaccine or number of immunizations. In subjects who received the test vaccine, antibodies to AMA1 increased on Day 14 and peaked at Day 42, with changes from baseline significantly different from subjects who received control vaccine.AMA-C1 vaccine is well tolerated and immunogenic in children in this endemic area although the antibody response was short lived.Clinicaltrials.gov NCT00341250

Knowledge, Attitudes and Practices (KAP) related to the Pandemic (H1N1) 2009 among Chinese General Population: a Telephone Survey

<p>Abstract</p> <p>Background</p> <p>China is at greatest risk of the Pandemic (H1N1) 2009 due to its huge population and high residential density. The unclear comprehension and negative attitudes towards the emerging infectious disease among general population may lead to unnecessary worry and even panic. The objective of this study was to investigate the Chinese public response to H1N1 pandemic and provide baseline data to develop public education campaigns in response to future outbreaks.</p> <p>Methods</p> <p>A close-ended questionnaire developed by the Chinese Center for Disease Control and Prevention was applied to assess the knowledge, attitudes and practices (KAP) of pandemic (H1N1) 2009 among 10,669 responders recruited from seven urban and two rural areas of China sampled by using the probability proportional to size (PPS) method.</p> <p>Results</p> <p>30.0% respondents were not clear whether food spread H1N1 virusand. 65.7% reported that the pandemic had no impact on their life. The immunization rates of the seasonal flu and H1N1vaccine were 7.5% and 10.8%, respectively. Farmers and those with lower education level were less likely to know the main transmission route (cough or talk face to face). Female and those with college and above education had higher perception of risk and more compliance with preventive behaviors. Relationships between knowledge and risk perception (OR = 1.69; 95%CI 1.54-1.86), and knowledge and practices (OR = 1.57; 95%CI 1.42-1.73) were found among the study subjects. With regard to the behavior of taking up A/H1N1 vaccination, there are several related factors found in the current study population, including the perception of life disturbed (OR = 1.29; 95%CI 1.11-1.50), the safety of A/H1N1 vaccine (OR = 0.07; 95%CI 0.04-0.11), the knowledge of free vaccination policy (OR = 7.20; 95%CI 5.91-8.78), the state's priority vaccination strategy(OR = 1.33; 95%CI 1.08-1.64), and taking up seasonal influenza vaccine behavior (OR = 4.69; 95%CI 3.53-6.23).</p> <p>Conclusions</p> <p>This A/H1N1 epidemic has not caused public panic yet, but the knowledge of A/H1N1 in residents is not optimistic. Public education campaign may take the side effects of vaccine and the knowledge about the state's vaccination strategy into account.</p

The Case for Reactive Mass Oral Cholera Vaccinations

Cholera outbreaks have had catastrophic impact on societies for centuries. Despite more than half a century of advocacy for safe water, sanitation and hygiene, approximately 100,000 cholera cases and 5,000 deaths were reported in Zimbabwe between August 2008 and by July 2009. Safe and effective oral cholera vaccines have been licensed and used by affluent tourists for more than a decade to prevent cholera. We asked whether oral cholera vaccines could be used to protect high risk populations at a time of cholera. We calculated how many cholera cases could have been prevented if mass cholera vaccinations would have been implemented in reaction to past cholera outbreaks. We estimate that determined, well organized mass vaccination campaigns could have prevented 34,900 (40%) cholera cases and 1,695 deaths (40%) in Zimbabwe. In the sites with endemic cholera, Kolkata and Zanzibar, a significant number of cases could have been prevented but the impact would have been less dramatic. The barriers which currently prevent the implementation of mass vaccinations, including but not only the cost to purchase the vaccine, seem insurmountable. A concerted effort of donors and key decision makers will be needed to offer better protection to populations at risk

Outcome of primary resurfacing hip replacement: evaluation of risk factors for early revision: 12,093 replacements from the Australian Joint Registry

BACKGROUND AND PURPOSE: The outcome of modern resurfacing remains to be determined. The Australian Orthopaedic Association National Joint Replacement Registry (AOANJRR) started collection of data on hip resurfacing at a time when modern resurfacing was started in Australia. The rate of resurfacing has been higher in Australia than in many other countries. As a result, the AOANJRR has one of the largest series of resurfacing procedures. This study was undertaken to determine the results of this series and the risk factors associated with revision. PATIENTS AND METHODS: Data from the AOANJRR were used to analyze the survivorship of 12,093 primary resurfacing hip replacements reported to the Joint Replacement Registry between September 1999 and December 2008. This was compared to the results of primary conventional total hip replacement reported during the same period. The Kaplan-Meier method and proportional hazards models were used to determine risk factors such as age, sex, femoral component size, primary diagnosis, and implant design. RESULTS: Female patients had a higher revision rate than males; however, after adjusting for head size, the revision rates were similar. Prostheses with head sizes of less than 50 mm had a higher revision rate than those with head sizes of 50 mm or more. At 8 years, the cumulative per cent revision of hip resurfacing was 5.3 (4.6-6.2), as compared to 4.0 (3.8-4.2) for total hip replacement. However, in osteoarthritis patients aged less than 55 years with head sizes of 50 mm or more, the 7-year cumulative per cent revision for hip resurfacing was 3.0 (2.2-4.2). Also, hips with dysplasia and some implant designs had an increased risk of revision. INTERPRETATION: Risk factors for revision of resurfacing were older patients, smaller femoral head size, patients with developmental dysplasia, and certain implant designs. These results highlight the importance of patient and prosthesis selection in optimizing the outcome of hip resurfacing

Circadian Rhythms of Fetal Liver Transcription Persist in the Absence of Canonical Circadian Clock Gene Expression Rhythms In Vivo

The cellular circadian clock and systemic cues drive rhythmicity in the transcriptome of adult peripheral tissues. However, the oscillating status of the circadian clocks in fetal tissues, and their response to maternal cues, are less clear. Most clock genes do not cycle in fetal livers from mice and rats, although tissue level rhythms rapidly emerge when fetal mouse liver explants are cultured in vitro. Thus, in the fetal mouse liver, the circadian clock does not oscillate at the cellular level (but is induced to oscillate in culture). To gain a comprehensive overview of the clock status in the fetal liver during late gestation, we performed microarray analyses on fetal liver tissues. In the fetal liver we did not observe circadian rhythms of clock gene expression or many other transcripts known to be rhythmically expressed in the adult liver. Nevertheless, JTK_CYCLE analysis identified some transcripts in the fetal liver that were rhythmically expressed, albeit at low amplitudes. Upon data filtering by coefficient of variation, the expression levels for transcripts related to pancreatic exocrine enzymes and zymogen secretion were found to undergo synchronized daily fluctuations at high amplitudes. These results suggest that maternal cues influence the fetal liver, despite the fact that we did not detect circadian rhythms of canonical clock gene expression in the fetal liver. These results raise important questions on the role of the circadian clock, or lack thereof, during ontogeny

Design of a Protective Single-Dose Intranasal Nanoparticle-Based Vaccine Platform for Respiratory Infectious Diseases

Despite the successes provided by vaccination, many challenges still exist with respect to controlling new and re-emerging infectious diseases. Innovative vaccine platforms composed of adaptable adjuvants able to appropriately modulate immune responses, induce long-lived immunity in a single dose, and deliver immunogens in a safe and stable manner via multiple routes of administration are needed. This work describes the development of a novel biodegradable polyanhydride nanoparticle-based vaccine platform administered as a single intranasal dose that induced long-lived protective immunity against respiratory disease caused by Yesinia pestis, the causative agent of pneumonic plague. Relative to the responses induced by the recombinant protein F1-V alone and MPLA-adjuvanted F1-V, the nanoparticle-based vaccination regimen induced an immune response that was characterized by high titer and high avidity IgG1 anti-F1-V antibody that persisted for at least 23 weeks post-vaccination. After challenge, no Y. pestis were recovered from the lungs, livers, or spleens of mice vaccinated with the nanoparticle-based formulation and histopathological appearance of lung, liver, and splenic tissues from these mice post-vaccination was remarkably similar to uninfected control mice