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Astudy of Pasteurella multocida cells reveals that conditions of iron restriction may lead to a reduction is capsular material thickness. The cells grown in iron-restricted culture media also express iron-regulated proteins. Polymyxin B-gold labelling reveals that cells grown under iron-restricted conditions are heavily labelled unlike cells grown in iron-sufficient conditions.

The paper presents results of the comparative analysis of business process modelling tools for supporting automated compliance management in organisations. By compliance in the paper we mean compliance to legislation, regulations of municipalities, external regulatory requirements and also internal organisational policies. The goal of the research is (1) to identify main attributes of business process modelling tools relevant in compliance management, and (2) to use the identified attributes for analysis of the tools to better understand the scope of their capability to support compliance management. The attributes of the tools have been derived from the related research. The analysis of the tools has been performed by installing each tool and evaluating it against a set of the identified attributes. The obtained results are useful in choosing the tools for compliance management in general and for open source solutions to develop new compliance management tools in particular.

Background and Objectives: A plasma transfusion dose should be weight-based (10-20 mL/kg), which equates to three to four units in an average-sized adult; therefore, the transfusion of single units under most circumstances is sub-therapeutic., Materials and Methods: This retrospective observational study examined the prevalence of single-unit plasma transfusion in adults within a 12-hospital system from 1 January 2018, to 31 December 2019., Results: During the study period, 5791 patients received plasma transfusions. The overall prevalence of single-unit plasma was 17.1% for 988 patients. The majority, 3047 (52.6%), occurred at one hospital, 2132 (36.9%) among five hospitals and 612 (10.7%) at the remaining six hospitals. Cardiac and gastrointestinal (GI)/transplant transfused 2707 (46.8%), combined respiratory, neurological, orthopaedic and congenital/dermatology/other comprised 2133 (36.9%) of the six hospitals that transfused less than 200 patients, four (66.7%) transfused single units above the overall prevalence., Conclusion: In this hospital system, more than one in six patients received a transfusion of a single plasma unit. Six of the 12 hospitals had 89.5% of the patients who were transfused plasma. Six service lines transfused 83.7% of all patients receiving plasma. Hospitals that infrequently transfused plasma were more likely to under-dose., (© 2024 International Society of Blood Transfusion.)

Importance: Anxiety disorders are prevalent and undertreated among young adults. Digital mental health interventions for anxiety are promising but limited by a narrow range of therapeutic components and low user engagement., Objective: To investigate the efficacy of and engagement with Maya, a scalable, self-guided, comprehensive mobile cognitive behavioral therapy (CBT) intervention with embedded engagement features, comparing the effects of 3 incentive conditions., Design, Setting, and Participants: This randomized clinical trial recruited young adults aged 18 to 25 years with anxiety disorders through online advertisements and outpatient psychiatry clinics at Weill Cornell Medicine. Enrollment was between June 16, 2021, and November 11, 2022. Data analysis was performed from December 21, 2022, to June 14, 2024., Intervention: Participants received a 6-week program of the intervention and were randomized to 1 of 3 different text message-based incentive conditions (gain-framed, loss-framed, or gain-social support)., Main Outcomes and Measures: The primary outcome was change in anxious symptoms from baseline to end of treatment, as measured by the Hamilton Anxiety Rating Scale (HAM-A). The Anxiety Sensitivity Index and the Leibowitz Social Anxiety Scale scores were secondary measures., Results: The sample consisted of 59 participants (mean [SD] age, 23.1 [1.9] years; 46 [78%] female; 22 [37%] Asian, 3 [5%] Black, 5 [8%] Hispanic or Latino, 1 [2%] American Indian or Alaska Native, 25 [42%] White, and 6 [10%] >1 race; 32 [54%] college-educated and 12 [20%] graduate or professional school-educated; mean [SD] baseline HAM-A score, 15.0 [6.5]). Anxiety, measured by HAM-A, decreased across conditions from baseline to end of the intervention (mean difference, -5.64; 95% CI, -7.23 to -4.05), and symptomatic improvement was maintained at the week 12 follow-up (baseline to follow-up mean difference, -5.67; 95% CI, -7.29 to -4.04). However, there was no evidence that change in anxiety differed by incentive condition (loss-framed vs gain-social support mean difference, -1.40; 95% CI, -4.72 to 1.93; gain-framed vs gain-social support mean difference, 1.38; 95% CI, -1.19 to 3.96). Secondary anxiety measures (Anxiety Sensitivity Index and Liebowitz Social Anxiety Scale scores) showed a similar pattern of improvement, with no evidence of differences between incentive conditions. Participants completed most of the 12 sessions (mean [SD], 10.8 [2.1]; 95% CI, 10.3-11.4), and User Mobile Application Rating Scale app quality ratings exceeded the published threshold for acceptability at all study visits. There was no evidence that either session completion or app quality ratings differed by incentive condition., Conclusions and Relevance: In this randomized clinical trial of an app-based intervention for anxiety, the primary hypothesis that improvement in anxiety would be greatest in the condition using gain of points plus social incentives was not supported; however, the results suggest that a CBT application incorporating a full suite of CBT skills and embedded user engagement features was efficacious in improving symptoms in young adults with anxiety disorders. Given these findings, digital interventions represent a promising step toward wider dissemination of high-quality, evidence-based interventions., Trial Registration: ClinicalTrials.gov Identifier: NCT05130281.

Background: Norovirus (NoV) is the most common cause of diarrheal episodes globally. Issues with in vitro cultivation systems, genetic variation, and animal models have hindered vaccine development. Plant-derived virus-like particles (VLPs) may address some of these concerns because they are highly immunogenic, can be administered by different routes, and can be rapidly produced to accommodate emerging viral strains., Methods: NoV VLPs (NoVLP) composed of the surface viral protein (VP) 1 of the GI and GII genogroups were produced in Nicotiana benthamiana using an Agrobacterium tumefaciens-based recombinant transient expression system. Leaves from infiltrated plants were harvested and NoVLPs were extracted and purified. The safety and immunogenicity of the GII.4 NoVLP, the genotype currently causing most human disease, were subsequently examined in rabbits and mice., Results: Fifteen GI and GII NoVLPs were successfully expressed in N. benthamiana and were structurally similar to NoV virions, as determined by cryogenic transmission electron microscopy. The NoVLP was well-tolerated, with no local or systemic signs of toxicity in rabbits. Three intramuscular doses of the GII.4 NoVLP adjuvanted with aluminum hydroxide induced robust IgG titers, IgG-secreting cells, histo-blood group antigen blocking titers, and IFNγ-secreting T cells in mice. In addition to circulating antibodies, oral administration of the NoVLP in mice induced significant IgA levels in feces, indicative of a mucosal response., Conclusions: The plant-made NoVLP vaccine was safe and immunogenic in mice and rabbits. Multi-modal vaccination, combining oral and intramuscular administration could be considered for future clinical development to maximize systemic and mucosal immune responses., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: GA, DB, MAD, BJW, MMC, MD, POL, SP, and ST are employees of Medicago Inc. JS is employee of the Center for Vaccine Preventable Diseases, Dalla Lana School of Public Health, University of Toronto, ON, Canada, where she is supported by a postdoctoral fellowship from the Canadian Immunization Research Network. HH is employee of Research Institute of the McGill University Health Centre (under MITACS Elevate post-doctorate fellowship), Montreal, QC, Canada. MB and CD are employees of Providence Therapeutics. NL is employee of PharmaJet, CO, USA., (Copyright © 2023. Published by Elsevier Ltd.)

Psychopathic traits have been routinely associated with poor treatment outcomes in correctional settings. Less is known about how psychopathic traits relate to treatment processes (e.g., perceptions of treatment; adjustment to treatment), particularly in nonforensic settings. The current study tested for relationships between psychopathic traits, as operationalized by the Triarchic Psychopathy Measure (TriPM) and treatment processes and outcomes in a sample of 200 U.S. military veterans enrolled in a residential substance use disorder treatment program at a Veteran's Affairs (VA) medical center. Participants were interviewed using several measurement instruments at 4 time points: treatment entry, 1 month into treatment, treatment discharge, and 12 months post discharge. The TriPM was administered at baseline, and measures of treatment processes/outcomes were measured during treatment and at postdischarge. The TriPM scales exhibited differential associations with treatment processes and outcomes in multivariate analyses. Specifically, higher Boldness was associated with fewer psychiatric symptoms at baseline, but more rule-breaking behaviors and more peer-reported conflicts with other residents in treatment; higher Meanness predicted more negative perceptions of the treatment milieu; and higher Disinhibition predicted poorer substance use outcomes posttreatment. Together, these findings demonstrate associations between psychopathy and therapy processes/outcomes and highlight the potentially unique contribution of psychopathic traits to substance use disorder treatment programming. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

In the midst of the Spring 2020 initial surge of the COVID-19 pandemic in New York, members of the Psychiatry Department of Weill Cornell Medicine/NewYork-Presbyterian Hospital rapidly created and implemented a brief, behavioral skills-based intervention program, "CopeNYP", to address the immediate mental health needs of the employees of the hospital and medical school. We describe the development, implementation and evolution of this telehealth-delivered program staffed primarily by in-house clinical psychologists, postdoctoral fellows, pre-doctoral interns and counselors who were redeployed or volunteered their time to provide urgent support for employees. We discuss the challenges and lessons learned in providing brief, skills-based psychological interventions for employees subjected to chronic stress. As the impact of the pandemic became prolonged, employees faced compounding stressors including social isolation, fear of infection, grief and loss, and sequelae of COVID-19-related illness combined with work-related demands. Our goal is to present our program design, implementation, and utilization as a blueprint for other institutions that would like to develop an evidence-based clinician-staffed psychological intervention program to support ongoing employee mental health needs., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Of the 2.5 million people who are incarcerated in the United States, over half are parents. While it is well-established that incarceration has a detrimental impact on the children of incarcerated parents, less is known regarding the psychological impact of incarceration on parents themselves. The present review summarizes existing literature on the impact of incarceration on parents retrieved via online databases. Published articles were classified according to their overall themes and summarized. Pertinent studies include the psychological and emotional consequences of incarceration on parents, the experience of parenting while incarcerated, including barriers to parenting, the utility of parenting program interventions during periods of incarceration, and how these results differ for mothers and fathers. While the existing evidence introduces these issues, there is a need for additional research on the impact of incarceration on parents. These areas for future research as well as clinical implications are discussed.

Background: This study is the first clinical trial for a parenteral non-replicating rotavirus vaccine developed using virus-like particle (VLP) technology., Methods: This open-labeled, randomized, placebo-controlled trial was conducted in two parts: Part A (a first-in-human study in Australian adults) and Part B (ascending dose and descending age in South African adults, toddlers and infants). In Part A, two cohorts of 10 adults were assigned to receive a single intramuscular injection of 1 of 2 escalating dose levels of the rotavirus VLP (Ro-VLP) vaccine (7 μg or 21 μg) or placebo. In Part B, one cohort of 10 adults was assigned to receive a single injection of the Ro-VLP vaccine (21 μg) or placebo, two cohorts of 10 toddlers were assigned to receive 2 injections of 1 of 2 escalating dose levels of the Ro-VLP vaccine (7 μg or 21 μg) or placebo 28 days apart, and three cohorts of 20 infants were assigned to receive 3 injections of 1 of 3 escalating dose levels of the Ro-VLP vaccine (2.5 μg, 7 μg or 21 μg) or placebo or 2 doses of oral Rotarix 28 days apart. Safety, reactogenicity and immunogenicity were assessed., Results: There were no safety or tolerability concerns after administration of the Ro-VLP vaccine. The Ro-VLP vaccine induced an anti-G1P[8] IgG response in infants 4 weeks after the second and third doses. Neutralizing antibody responses against homologous G1P[8] rotavirus were higher in all Ro-VLP infant groups than in the placebo group 4 weeks after the third dose. No heterotypic immunity was elicited by the Ro-VLP vaccine., Conclusions: The Ro-VLP vaccine was well tolerated and induced a homotypic immune response in infants, suggesting that this technology platform is a favorable approach for a parenteral non-replicating rotavirus vaccine., Clinical Trial Registration: NCT03507738., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: MM (Monica McNeal) has laboratory service agreements with Merck &Co., Inc, outside of the submitted work. No other authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Virus-like particles (VLPs) are unable to replicate in the recipient but stimulate the immune system through recognition of repetitive subunits. Parenterally delivered rotavirus-VLP (Ro-VLP) vaccine could have the potential to overcome the weaknesses of licensed oral live-attenuated rotavirus vaccines, namely, low efficacy in low-income and high mortality settings and a potential risk of intussusception., Methods: A monovalent Ro-VLP composed of viral protein (VP) 7, VP6 and VP2 of G1 genotype specificity was produced in Nicotiana benthamiana using Agrobacterium tumefaciens infiltration-based transient recombinant expression system. Plants expressing recombinant G1 Ro-VLP were harvested, then the resultant biomass was processed through a series of clarification and purification steps including standard extraction, filtration, ultrafiltration and chromatography. The purified G1 Ro-VLP was subsequently examined for its immunogenicity and toxicological profile using animal models., Results: G1 Ro-VLP had a purity of ≥90% and was structurally similar to triple-layered rotavirus particles as determined by cryogenic transmission electron microscopy. Two doses of aluminum hydroxide-adjuvanted G1 Ro-VLP (1 μg, 5 μg or 30 μg), administered intramuscularly, elicited a robust homotypic neutralizing antibody response in rats. Also, rabbits administered G1 Ro-VLP (10 μg or 30 μg) four times intramuscularly with aluminum hydroxide adjuvant did not show any significant toxicity., Conclusions: Plant-derived Ro-VLP composed of VP7, VP6 and VP2 structural proteins would be a plausible alternative to live-attenuated oral rotavirus vaccines currently distributed worldwide., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Psychopathic individuals are notorious for their callous disregard for others' emotions. Prior research has linked psychopathy to deficits in affective mechanisms underlying empathy (e.g., affective sharing), yet research relating psychopathy to cognitive mechanisms underlying empathy (e.g., affective perspective-taking and Theory of Mind) requires further clarification. To elucidate the neurobiology of cognitive mechanisms of empathy in psychopathy, we administered an fMRI task and tested for global as well as emotion-specific deficits in affective perspective-taking. Adult male incarcerated offenders (N = 94) viewed images of two people interacting, with one individual's face obscured by a shape. Participants were cued to either identify the emotion of the obscured individual or identify the shape from one of two emotion or shape choices presented on each trial. Target emotions included anger, fear, happiness, sadness, and neutral. Contrary to predictions, psychopathy was unrelated to neural activity in the Affective Perspective-taking > Shape contrast. In line with predictions, psychopathy was negatively related to task accuracy during affective perspective-taking for fear, happiness, and sadness. Psychopathy was related to reduced hemodynamic activity exclusively during fear perspective-taking in several areas: left anterior insula extending into posterior orbitofrontal cortex, right precuneus, left superior parietal lobule, and left superior occipital cortex. Although much prior research has emphasized psychopathy-related abnormalities in affective mechanisms mediating empathy, current results add to growing evidence of psychopathy-related abnormalities in a cognitive mechanism related to empathy. These findings highlight brain regions that are hypoactive in psychopathy when explicitly processing another's fear., (Copyright © 2020. Published by Elsevier Inc.)

The worldwide COVID-19 pandemic has required healthcare systems to implement strategies for effective healthcare delivery while managing blood supply chain disruptions and shortages created by infection-limiting practices that have reduced blood donations. At Cleveland Clinic, we have made multiple synchronous efforts: a call for increased blood collection, alignment of efforts among transfusion medicine departments (blood banks), enhanced monitoring and triage of blood product use, and increased education on patient blood management practices regarding blood utilization and anemia management. In addition, we created an algorithm to assess anemia risks in patients whose elective surgery was cancelled to optimize preoperative hemoglobin levels., (Copyright © 2020 The Cleveland Clinic Foundation. All Rights Reserved.)

Objective: Exposure to childhood trauma is particularly prevalent among incarcerated juveniles. Although there is a growing understanding of the detrimental impact trauma exposure can have on child and adolescent development, childhood maltreatment can be very difficult to accurately measure. Integration of self-report trauma histories as well as supplemental file reports of trauma exposure may provide the most accurate estimate of experienced trauma among youth in correctional settings., Method: The current study developed an expert-rated assessment of trauma that synthesizes self-report, as well as objective file information, using a sample of 114 incarcerated male juveniles., Results: In addition to establishing scale factor structure, reliability, and validity, the current study provides additional evidence of the prevalence of trauma among incarcerated juveniles and reports on external correlates of the scale that are particularly relevant in correctional settings (e.g., psychopathic traits)., Conclusion: These results suggest that the integration of both self-report and file material can be meaningfully used to assess traumatic symptomology. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Objective: Specification of the etiological mechanisms underlying psychopathy is a key step in developing more effective methods for preventing and remediating the callous and impulsive behavior that characterizes the disorder. Theoretical conceptualizations of psychopathic subtypes propose that a primary variant largely stems from impoverished affect, whereas a secondary variant is hypothesized to develop subsequent to adverse environmental experiences (e.g., childhood maltreatment). However, there has been a dearth of research demonstrating that psychopathic subtypes actually differ in terms of experienced childhood maltreatment in an adult offender population., Method: The current study employed model-based cluster analysis (MBCA) in a sample of incarcerated, psychopathic males (n = 110) to identify subtypes of psychopathic offenders based on a broad personality assessment., Results: Two subgroups emerged: 1 with high levels of negative affect (high-NA) and 1 with low levels of negative affect (low-NA). The high-NA subgroup scored significantly higher on measures of childhood maltreatment., Conclusion: These results provide support for theoretical conceptualizations of psychopathic subtypes, suggesting that psychopathic offenders with high levels of negative affect experience a greater degree of childhood maltreatment. (PsycINFO Database Record, ((c) 2018 APA, all rights reserved).)

Psychopathic individuals are notorious for their grandiose sense of self-worth and disregard for the welfare of others. One potential psychological mechanism underlying these traits is the relative consideration of "self" versus "others". Here we used task-based functional magnetic resonance imaging (fMRI) to identify neural responses during personality trait judgments about oneself and a familiar other in a sample of adult male incarcerated offenders ( n  = 57). Neural activity was regressed on two clusters of psychopathic traits: Factor 1 (e.g., egocentricity and lack of empathy) and Factor 2 (e.g., impulsivity and irresponsibility). Contrary to our hypotheses, Factor 1 scores were not significantly related to neural activity during self- or other-judgments. However, Factor 2 traits were associated with diminished activation to self-judgments, in relation to other-judgments, in bilateral posterior cingulate cortex and right temporoparietal junction. These findings highlight cortical regions associated with a dimension of social-affective cognition that may underlie psychopathic individuals' impulsive traits.

Impairments in processing fearful faces have been documented in both children and adults with psychopathic traits, suggesting a potential mechanism by which psychopathic individuals develop callous and manipulative interpersonal and affective traits. Recently, research has demonstrated that psychopathic traits are associated with reduced fixations to the eye regions of faces in samples of children and community-dwelling adults, however this relationship has not yet been established in an offender sample with high levels of psychopathy. In the current study, we employed eye-tracking with paradigms involving the identification and passive viewing of facial expressions of emotion, respectively, in a sample of adult male criminal offenders (n = 108) to elucidate the relationship between visual processing of fearful facial expressions and interpersonal and affective psychopathic traits. We found that the interpersonal-affective traits of psychopathy were significantly related to fewer fixations to the eyes of fear faces during the emotion recognition task. This association was driven particularly by the interpersonal psychopathic traits (e.g., egocentricity, deceitfulness), whereas fear recognition accuracy was inversely related to the affective psychopathic traits (e.g., callousness, lack of empathy). These findings highlight potential mechanisms for the subset of the interpersonal-affective traits exhibited by psychopathic individuals. (PsycINFO Database Record, ((c) 2018 APA, all rights reserved).)

Deficits in reinforcement learning are presumed to underlie the impulsive and incorrigible behavior exhibited by psychopathic criminals. However, previous studies documenting reversal learning impairments in psychopathic individuals have not investigated this relationship across a continuous range of psychopathy severity, nor have they examined how reversal learning impairments relate to different psychopathic traits, such as the interpersonal-affective and lifestyle-antisocial dimensions. Furthermore, previous studies have not considered the role that childhood maltreatment and substance use may have in this specific cognitive deficit. Using a standard reversal learning task in a sample of N = 114 incarcerated male offenders, we demonstrate a significant relationship between psychopathy severity and reversal learning errors. Furthermore, we show a significant interaction between psychopathy and childhood maltreatment, but not substance use, such that individuals high in psychopathy with an extensive history of maltreatment committed the greatest number of reversal learning errors. These findings extend the current understanding of reversal learning performance among psychopathic individuals, and highlight the importance of considering childhood maltreatment when studying psychopathy., Competing Interests: Conflict of interest: The authors declare no conflicts of interest.

While there is growing evidence that suffering physical abuse during childhood is subsequently associated with psychopathic traits in both juvenile and adult offenders, there is considerably less research on whether exposure to domestic violence as a witness, rather than as a direct victim, influences the subsequent presentation of psychopathic traits in adulthood. Accordingly, the current study examined the relationship between witnessing domestic violence during childhood (i.e., witnessing, hearing, or intervening in abuse against a parent/sibling) and psychopathic traits in adulthood in a sample of n = 127 incarcerated male offenders. As predicted, witnessing domestic violence was significantly associated with overall level of psychopathy, with a particularly strong relationship to the interpersonal/affective features of psychopathy. Importantly, this relationship held when controlling for the experience of domestic violence as a direct victim. These results add to the growing body of literature linking adverse and traumatic events during childhood with psychopathic traits later in life, and suggest that domestic violence exposure may be one factor contributing to the manipulative, interpersonal style exhibited by individuals high in psychopathy. (PsycINFO Database Record, ((c) 2017 APA, all rights reserved).)

Childhood abuse is a risk factor for the development of externalizing characteristics and disorders, including antisocial personality disorder and psychopathy. However, the precise relationships between particular types of childhood maltreatment and subsequent antisocial and psychopathic traits remain unclear. Using a large sample of incarcerated adult male criminal offenders (n = 183), the current study confirmed that severity of overall childhood maltreatment was linked to severity of both psychopathy and antisocial personality disorder in adulthood. Moreover, this relationship was particularly strong for physical abuse and the antisocial facet of psychopathy. Sexual abuse history was uniquely related to juvenile conduct disorder severity, rather than adult psychopathy or antisocial behaviors. Additionally, there was a significantly stronger relationship between childhood maltreatment and juvenile conduct disorder than between childhood maltreatment and ASPD or psychopathy. These findings bolster and clarify the link between childhood maltreatment and antisocial behavior later in life. (PsycINFO Database Record, ((c) 2016 APA, all rights reserved).)

Recent issues regarding efficacy of influenza vaccines have re-emphasized the need of new approaches to face this major public health issue. In a phase 1-2 clinical trial, healthy adults received one intramuscular dose of a seasonal influenza plant-based quadrivalent virus-like particle (QVLP) vaccine or placebo. The hemagglutination inhibition (HI) titers met all the European licensure criteria for the type A influenza strains at the 3μg/strain dose and for all four strains at the higher dosages 21days after immunization. High HI titers were maintained for most of the strains 6months after vaccination. QVLP vaccine induced a substantial and sustained increase of hemagglutinin-specific polyfunctional CD4 T cells, mainly transitional memory and TEMRA effector IFN-γ(+) CD4 T cells. A T cells cross-reactive response was also observed against A/Hong-Kong/1/1968 H3N2 and B/Massachusetts/2/2012. Plant-based QVLP offers an attractive alternative manufacturing method for producing effective and HA-strain matching seasonal influenza vaccines., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Plant-made biotherapeutics are gathering momentum and some plant glycoproteins are allergens. Glycans with core β1-2xylose and α1,3fucose motifs and antennae terminated by mannose residues (e.g.: MMXF) are found on several plant allergens and can cross-react with glyco-epitopes from other sources. To date, reactivity to these cross-reactive determinants has not been associated with clinical symptoms., Objective: We produced VLP vaccines bearing the hemagglutinin(HA) of H5(A/Indonesia/5/05) or H1(A/California/07/09) influenza viruses by transfection of Nicotiana benthamiana. Subjects enrolled in Phase I/II trials were followed for evidence of allergy/hypersensitivity and development of antibodies against plant glyco-epitopes., Methods: A total of 280/349 subjects received either one (H1) or 2 doses (H5) of vaccine (5-45 μg of HA/dose) intramuscularly including 40 with pre-existing plant allergies. Subjects were monitored for 6 months. IgG and IgE to plant glyco-epitopes were measured by ELISA using corn-/egg-derived avidin and bromelain as target antigens., Results: No subject developed allergic/hypersensitivity symptoms. Some (34%) developed transient IgG and, in some cases IgE, to plant glyco-epitopes but no subject mounted an IgE response to the MMXF motif. Antibodies returned to baseline by 6 months in most subjects., Conclusion: VLP vaccines bearing influenza HA glycoproteins can elicit transient IgG and, in some cases, IgE responses that are not associated with either the development or worsening of allergic/hypersensitivity symptoms., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Unlabelled: The recent swine H1N1 influenza outbreak demonstrated that egg-based vaccine manufacturing has an Achille's heel: its inability to provide a large number of doses quickly. Using a novel manufacturing platform based on transient expression of influenza surface glycoproteins in Nicotiana benthamiana, we have recently demonstrated that a candidate Virus-Like Particle (VLP) vaccine can be generated within 3 weeks of release of sequence information. Herein we report that alum-adjuvanted plant-made VLPs containing the hemagglutinin (HA) protein of H5N1 influenza (A/Indonesia/5/05) can induce cross-reactive antibodies in ferrets. Even low doses of this vaccine prevented pathology and reduced viral loads following heterotypic lethal challenge. We further report on safety and immunogenicity from a Phase I clinical study of the plant-made H5 VLP vaccine in healthy adults 18-60 years of age who received 2 doses 21 days apart of 5, 10 or 20 µg of alum-adjuvanted H5 VLP vaccine or placebo (alum). The vaccine was well tolerated at all doses. Adverse events (AE) were mild-to-moderate and self-limited. Pain at the injection site was the most frequent AE, reported in 70% of vaccinated subjects versus 50% of the placebo recipients. No allergic reactions were reported and the plant-made vaccine did not significantly increase the level of naturally occurring serum antibodies to plant-specific sugar moieties. The immunogenicity of the H5 VLP vaccine was evaluated by Hemagglutination-Inhibition (HI), Single Radial Hemolysis (SRH) and MicroNeutralisation (MN). Results from these three assays were highly correlated and showed similar trends across doses. There was a clear dose-response in all measures of immunogenicity and almost 96% of those in the higher dose groups (2 × 10 or 20 µg) mounted detectable MN responses. Evidence of striking cross-protection in ferrets combined with a good safety profile and promising immunogenicity in humans suggest that plant-based VLP vaccines should be further evaluated for use in pre-pandemic or pandemic situations., Trial Registration: ClinicalTrials.gov NCT00984945.

A strain-specific vaccine represents the best possible response to the threat of an influenza pandemic. Rapid delivery of such a vaccine to the world's population before the peak of the first infection wave seems to be an unattainable goal with the current influenza vaccine manufacturing capacity. Plant-based transient expression is one of the few production systems that can meet the anticipated surge requirement. To assess the capability of plant agroinfiltration to produce an influenza vaccine, we expressed haemagglutinin (HA) from strains A/Indonesia/5/05 (H5N1) and A/New Caledonia/20/99 (H1N1) by agroinfiltration of Nicotiana benthamiana plants. Size distribution analysis of protein content in infiltrated leaves revealed that HA was predominantly assembled into high-molecular-weight structures. H5-containing structures were purified and examination by transmission electron microscopy confirmed virus-like particle (VLP) assembly. High-performance thin layer chromatography analysis of VLP lipid composition highlighted polar and neutral lipid contents comparable with those of purified plasma membranes from tobacco plants. Electron microscopy of VLP-producing cells in N. benthamiana leaves confirmed that VLPs accumulated in apoplastic indentations of the plasma membrane. Finally, immunization of mice with two doses of as little as 0.1 microg of purified influenza H5-VLPs triggered a strong immune response against the homologous virus, whereas two doses of 0.5 microg of H5-VLPs conferred complete protection against a lethal challenge with the heterologous A/Vietnam/1194/04 (H5N1) strain. These results show, for the first time, that plants are capable of producing enveloped influenza VLPs budding from the plasma membrane; such VLPs represent very promising candidates for vaccination against influenza pandemic strains.

Structural analysis of the N-glycosylation of alfalfa proteins was investigated in order to evaluate the capacity of this plant to perform this biologically important post-translational modification. We show that, in alfalfa, N-linked glycans are processed into a large variety of mature oligosaccharides having core-xylose and core alpha(1,3)-fucose, as well as terminal Lewis(a) epitopes. In contrast, expression of the C5-1 monoclonal antibody in alfalfa plants results in the production of plant-derived IgG1 which is N-glycosylated by a predominant glycan having a alpha(1,3)-fucose and a beta(1,2)-xylose attached to a GlcNAc2Man3GlcNAc2 core. Since this core is common to plant and mammal N-linked glycans, it therefore appears that alfalfa plants have the ability to produce recombinant IgG1 having a N-glycosylation that is suitable for in vitro or in vivo glycan remodelling into a human-compatible plantibody. For instance, as proof of concept, in vitro galactosylation of the alfalfa-derived C5-1 mAb resulted in a homogenous plantibody harbouring terminal beta(1,4)-galactose residues as observed in the mammalian IgG.

Autoantibodies against certain stress or heat shock proteins (Hsps) may play a role in the pathogenesis and/ or prognosis of some diseases. Using immunoblotting with human recombinant Hsps and univariate and multivariate logistic regression models, we have investigated the presence of antibodies against Hsp70, the inducible member of the 70-kDa family of heat shock proteins, and analyzed its possible association with hypertension and working conditions. Plasma and serum were collected from 764 steel mill workers from 6 work sites exposed to (1) severe noise; (2) severe noise and dust; (3) noise, dust, and heat; (4) noise and heat; (5) severe noise and heat; and (6) office conditions (control). Workers with prolonged exposure to stresses such as noise, dust, and high temperature and a combination of these in the workplace had a high incidence (26.6% to 40.2%) of antibodies to Hsp70 compared to the lowest incidence (18.6%) of antibodies to Hsp70 in the control group of office workers. Moreover, there was a statistical association of antibodies against Hsp70 with hypertension. The statistical correlation between the presence of antibodies to Hsp70 and hypertension is higher in the group of workers with blood pressure of 160/95 mmHg than in the 140/90-mmHg group after excluding possible effects of the workplace stresses. These results suggest that harsh workplace conditions can increase the production of antibodies against Hsp70 and that the presence of antibodies to this stress protein may be associated with hypertension. The precise mechanism for the elevation of antibodies against Hsps by environmental and workplace stresses and their relation to hypertension remains to be established.

We examined the penicillin-binding proteins (PBPs) of certain field strains of Streptococcus suis, as well as those from laboratory variants having different degrees of resistance to penicillin. Results indicated that (i) S. suis possesses three distinct groups of PBPs, arbitrarily named here PBP 1, PBP 2, and PBP 3, with approximate molecular weights of 97, 82, and 45 kDa respectively; (ii) PBP profiles of field strains of S. suis having different MICs (< or = 0.03) to 16.0 micrograms/ml) were not uniform (PBP 2 being difficult to detect in strains whose MICs exceeded 0.10 micrograms/ml, and PBP 3 which exhibited shifts in molecular weight of approximately 5 kDa); (iii) laboratory variant PBPs 1 and 2 showed decreased affinity for penicillin as compared to the parent strain in antibiotic competition experiments, even though the PBP profiles of both were similar. We suggest that PBP modifications (altered molecular weight and/or decreased affinity for penicillin) are involved in the mechanism of resistance to penicillin by S. suis.