Impact of dairy manure addition on soil nutrients in northeast and south central Kansas

Sixty four percent of the fields (14 of 22) in northeast and south central Kansas would be able to apply dairy manure on a nitrogen basis if the current swine manure application regulations were adopted. Due to high phosphorus levels in some fields, two of the 11 fields in northeast Kansas could not have any manure applied to them. Two other fields in northeast and four fields in south central Kansas would have to limit manure application rates to annual phosphorus required by the crops. Our results indicate minimal accumulation of nitrogen and potassium in the soil profile.; Dairy Day, 2001, Kansas State University, Manhattan, KS, 2001

A Comparative Phase I Study of Combination, Homologous Subtype-C DNA, and Env gp 140 Protein/Adjuvant HIV Vaccines in Two Immunization Regimes

There remains an urgent need for a prophylactic HIV vaccine. We compared combined MVA and adjuvanted gp140 to sequential MVA/gp140 after DNA priming. We expected Env-specific CD4+ T-cells after DNA and MVA priming, and Env-binding antibodies in 100% individuals after boosting with gp140 and that combined vaccines would not compromise safety and might augment immunogenicity. Forty volunteers were primed three times with DNA plasmids encoding (CN54) env and (ZM96) gag-pol-nef at 0, 4 and 8 weeks then boosted with MVA-C (CN54 env and gag-pol-nef) and glucopyranosyl lipid adjuvant—aqueous formulation (GLA-AF) adjuvanted CN54gp140. They were randomised to receive them in combination at the same visit at 16 and 20 weeks (accelerated) or sequentially with MVA-C at 16, 20, and GLA-AF/gp140 at 24 and 28 weeks (standard). All vaccinations were intramuscular. Primary outcomes included ≥grade 3 safety events and the titer of CN54gp140-specific binding IgG. Other outcomes included neutralization, binding antibody specificity and T-cell responses. Two participants experienced asymptomatic ≥grade 3 transaminitis leading to discontinuation of vaccinations, and three had grade 3 solicited local or systemic reactions. A total of 100% made anti-CN54gp140 IgG and combining vaccines did not significantly alter the response; geometric mean titer 6424 (accelerated) and 6578 (standard); neutralization of MW965.2 Tier 1 pseudovirus was superior in the standard group (82 versus 45% responders, p =  0.04). T-cell ELISpot responses were CD4+ and Env-dominant; 85 and 82% responding in the accelerated and standard groups, respectively. Vaccineinduced IgG responses targeted multiple regions within gp120 with the V3 region most immunodominant and no differences between groups detected. Combining MVA and gp140 vaccines did not result in increased adverse events and did not significantly impact upon the titer of Env-specific binding antibodies, which were seen in 100% individuals. The approach did however affect other immune responses; neutralizing antibody responses, seen only to Tier 1 pseudoviruses, were poorer when the vaccines were combined and while T-cell responses were seen in >80% individuals in both groups and similarly CD4 and Env dominant, their breadth/polyfunctionality tended to be lower when the vaccines were combined, suggesting attenuation of immunogenicity and cautioning against this accelerated regimen

the CUTHIVAC-001 randomized trial

Targeting of different tissues via transcutaneous (TC), intradermal (ID) and intramuscular (IM) injection has the potential to tailor the immune response to DNA vaccination. In this Phase I randomised controlled clinical trial in HIV-1 negative volunteers we investigate whether the site and mode of DNA vaccination influences the quality of the cellular immune responses. We adopted a strategy of concurrent immunization combining IM injection with either ID or TC administration. As a third arm we assessed the response to IM injection administered with electroporation (EP). The DNA plasmid encoded a MultiHIV B clade fusion protein designed to induce cellular immunity. The vaccine and regimens were well tolerated. We observed differential shaping of vaccine induced virus-specific CD4 + and CD8 + cell-mediated immune responses. DNA given by IM + EP promoted strong IFN-γ responses and potent viral inhibition. ID + IM without EP resulted in a similar pattern of response but of lower magnitude. By contrast TC + IM (without EP) shifted responses towards a more Th-17 dominated phenotype, associated with mucosal and epidermal protection. Whilst preliminary, these results offer new perspectives for differential shaping of desired cellular immunity required to fight the wide range of complex and diverse infectious diseases and cancers

Community-Acquired Klebsiella pneumoniae Bacteremia: Global Differences in Clinical Patterns

We initiated a worldwide collaborative study, including 455 episodes of bacteremia, to elucidate the clinical patterns of Klebsiella pneumoniae. Historically, community-acquired pneumonia has been consistently associated with K. pneumoniae. Only four cases of community-acquired bacteremic K. pneumoniae pneumonia were seen in the 2-year study period in the United States, Argentina, Europe, or Australia; none were in alcoholics. In contrast, 53 cases of bacteremic K. pneumoniae pneumonia were observed in South Africa and Taiwan, where an association with alcoholism persisted (p=0.007). Twenty-five cases of a distinctive syndrome consisting of K. pneumoniae bacteremia in conjunction with community-acquired liver abscess, meningitis, or endophthalmitis were observed. A distinctive form of K. pneumoniae infection, often causing liver abscess, was identified, almost exclusively in Taiwan

Preferential Targeting of Conserved Gag Regions after Vaccination with a Heterologous DNA prime - Modified Vaccinia Ankara (MVA) boost HIV-1 vaccine regimen

Prime-boost vaccination strategies against HIV-1 often include multiple variants for a given immunogen for better coverage of the extensive viral diversity. To study the immunologic effects of this approach, we characterized breadth, phenotype, function and specificity of Gag-specific T cells induced by a DNA-prime Modified Vaccinia Ankara (MVA)-boost vaccination strategy, which uses mismatched Gag immunogens in the TamoVac 01 phase IIa trial. Healthy Tanzanian volunteers received three injections of the DNA-SMI vaccine encoding for a subtype B and AB-recombinant Gagp37 and two vaccinations with MVA-CMDR encoding subtype A Gagp55 Gag-specific T-cell responses were studied in 42 vaccinees using fresh peripheral blood mononuclear cells. After the first MVA-CMDR boost, vaccine-induced IFN-γ(+) Gag-specific T cell responses were dominated by CD4(+) T cells (compared to CD8(+) T cells, p<0.001) that co-expressed IL-2 (66.4%) and/or TNFα (63.7%). A median of 3 antigenic regions were targeted with a higher median response magnitude to Gagp24 regions - more conserved between prime and boost - as compared to regions within Gagp15 (not primed) and Gagp17 (less conserved, both p<0.0001). Four regions within Gagp24 were each targeted by 45% to 74% of vaccinees upon restimulation with DNA-SMI-Gag matched peptides. The response rate to individual antigenic regions correlated with the sequence homology between the MVA and DNA Gag encoded immunogens (p=0.04, r(2)=0.47). In summary, after the first MVA-CMDR boost, the sequence-mismatched DNA-prime MVA-boost vaccine strategy induced a Gag-specific T cell response that was dominated by polyfunctional CD4(+) T cells and that targeted multiple antigenic regions within the conserved Gagp24 Protein.IMPORTANCE Genetic diversity is a major challenge for the design of vaccines against variable viruses. While including multiple variants for a given immunogen in prime-boost vaccination strategies is one approach that aims to improve coverage for global virus variants, the immunologic consequences of this strategy have been poorly defined so far. It is unclear whether inclusion of multiple variants in prime-boost vaccination strategies improves recognition of variant viruses by T cells and by which mechanisms this would be achieved; either by improved cross-recogniton of multiple variants for a given antigenic region or rather through preferential targeting of antigenic regions more conserved between prime and boost. Engineering vaccines to induce adaptive immune responses that preferentially target conserved antigenic regions of viral vulnerability might facilitate better immune control after preventive and therapeutic vaccination for HIV and for other variable viruses

Birth weight is associated with postmenopausal breast cancer risk in Swedish women

There is some evidence that birth weight is associated with breast cancer. Whether this association differs between premenopausal and postmenopausal ages is still unclear. The results from this study suggest that higher birth weight is a risk factor for postmenopausal breast cancer (OR 1.06, CI 1.00-1.12, per 100 g), independent of selected early-life and adult factors

PRimary Care Opioid Use Disorders treatment (PROUD) trial protocol: a pragmatic, cluster-randomized implementation trial in primary care for opioid use disorder treatment

BACKGROUND: Most people with opioid use disorder (OUD) never receive treatment. Medication treatment of OUD in primary care is recommended as an approach to increase access to care. The PRimary Care Opioid Use Disorders treatment (PROUD) trial tests whether implementation of a collaborative care model (Massachusetts Model) using a nurse care manager (NCM) to support medication treatment of OUD in primary care increases OUD treatment and improves outcomes. Specifically, it tests whether implementation of collaborative care, compared to usual primary care, increases the number of days of medication for OUD (implementation objective) and reduces acute health care utilization (effectiveness objective). The protocol for the PROUD trial is presented here. METHODS: PROUD is a hybrid type III cluster-randomized implementation trial in six health care systems. The intervention consists of three implementation strategies: salary for a full-time NCM, training and technical assistance for the NCM, and requiring that three primary care providers have DEA waivers to prescribe buprenorphine. Within each health system, two primary care clinics are randomized: one to the intervention and one to Usual Primary Care. The sample includes all patients age 16-90 who visited the randomized primary care clinics from 3 years before to 2 years after randomization (anticipated to be \u3e 170,000). Quantitative data are derived from existing health system administrative data, electronic medical records, and/or health insurance claims ( electronic health records, [EHRs]). Anonymous staff surveys, stakeholder debriefs, and observations from site visits, trainings and technical assistance provide qualitative data to assess barriers and facilitators to implementation. The outcome for the implementation objective (primary outcome) is a clinic-level measure of the number of patient days of medication treatment of OUD over the 2 years post-randomization. The patient-level outcome for the effectiveness objective (secondary outcome) is days of acute care utilization [e.g. urgent care, emergency department (ED) and/or hospitalizations] over 2 years post-randomization among patients with documented OUD prior to randomization. DISCUSSION: The PROUD trial provides information for clinical leaders and policy makers regarding potential benefits for patients and health systems of a collaborative care model for management of OUD in primary care, tested in real-world diverse primary care settings