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Jiahui Zhang,1,* Jingyi Fan,1,* Mariusz Skwarczynski,1 Rachel J Stephenson,1 Istvan Toth,1– 3 Waleed M Hussein1 1School of Chemistry and Molecular Biosciences, The University of Queensland, St Lucia, QLD, Australia; 2School of Pharmacy, The University of Queensland, Woolloongabba, QLD, Australia; 3Institute for Molecular Biosciences, The University of Queensland, St Lucia, QLD, Australia*These authors contributed equally to this workCorrespondence: Waleed M Hussein, School of Chemistry and Molecular Biosciences, The University of Queensland, St Lucia, QLD, 4072, Australia, Tel +61 7 3365 2782, Email w.hussein@uq.edu.auAbstract: Persistent infection with high-risk human papillomaviruses (HPVs), such as HPV-16 and HPV-18, can induce cervical cancer in humans. The disease carries high morbidity and mortality among females worldwide. Inoculation with prophylactic HPV vaccines, such as Gardasil® or Cervarix®, is the predominant method of preventing cervical cancer in females 6 to 26 years of age. However, despite the availability of commercial prophylactic HPV vaccines, no therapeutic HPV vaccines to eliminate existing HPV infections have been approved. Peptide-based vaccines, which form one of the most potent vaccine platforms, have been broadly investigated to overcome this shortcoming. Peptide-based vaccines are especially effective in inducing cellular immune responses and eradicating tumor cells when combined with nanoscale adjuvant particles and delivery systems. This review summarizes progress in the development of peptide-based nanovaccines against HPV infection.Keywords: human papillomavirus, cervical cancer, peptide-based vaccines, nanovaccine

OBJECTIVE: To systematically investigate the extent to which patients comply with triage advice from telenurses and to identify factors that potentially influence compliance. METHODS: Findings from 13 studies identified through interdisciplinary research databases (1990-2010) were meta-analyzed. Separate pooled analyses compared patients' compliance rates for emergency services and office care (13 outcomes), emergency services and self care (13 outcomes), and self care and office care (12 outcomes). RESULTS: Overall patient compliance was 62%, but varied by intensity of care recommended with low compliance rates for advice to see a general practitioner. Reasons for noncompliance include patients reporting to have heard a different disposition, patients' intentions and health beliefs. CONCLUSION: Patient compliance to triage recommendations was influenced by the interactive role of patient perceptions and the quality of provider communication, both of which were mediated by access to health services. Further research is needed to clarify whether noncompliance is attributable to poor communication by the nurse or patient misinterpretation. PRACTICE IMPLICATIONS: We highlight the need for communication-skills training in a telephone-consultation context that is patient centered, and specifically addresses building active listening and active advising skills and advantages to structuring the call. [ABSTRACT FROM AUTHOR]

Aims. This study is a meta-ethnography of nurses' experiences with telephone triage and advice and factors that facilitate or impede their decision-making process. Background. Telephone triage and advice services are a rapidly expanding development in health care. Unlike traditional forms of nursing practice, telenurses offer triage recommendations and advice to the general public without visual cues. Data sources. Published qualitative research on telephone triage and advice were sought from interdisciplinary research databases (1980-2008) and bibliographical reviews of retrieved studies. Review methods. Our systematic search identified 16 relevant studies. Two researchers independently reviewed, critically appraised, and extracted key themes and concepts from each study. We followed techniques of meta-ethnography to synthesize the findings, using both reciprocal and refutational translation to compare similar or contradictory findings, and a line-of-arguments synthesis. Results. We identified five major themes that highlight common issues and concerns experienced by telenurses: gaining and maintaining skills, autonomy, new work environment, holistic assessment, and stress and pressure. A line-of-arguments synthesis produced a three-stage model that describes the decision-making process used by telenurses and highlights how assessments largely depend on the ability to 'build a picture' of the patient and the presenting health issue. Conclusion. Telenurses experience a range of common concerns and issues which either impede or facilitate the decision-making process. Although 'building a picture' of the patient is key to making assessments over the telephone, final triage decisions are influenced by balancing the conflicting demands of being both carer and gatekeeper to limited healthcare services. [ABSTRACT FROM AUTHOR]

Objective: The objective of this study was to identify the facilitators and barriers associated with integrating nurse practitioners (NPs) into Canadian emergency departments (EDs) from the perspectives of NPs and ED staff.Methods: We conducted 24 semi-structured interviews with key multidisciplinary stakeholders in 6 Ontario EDs to gain a broad range of perspectives on implementation issues. Data were analyzed using a grounded-theory approach.Results: Qualitative analysis of the interview data revealed 3 major issues associated with NP implementation: organizational context, role clarity and NP recruitment. Organizational context refers to the environment an NP enters and involves issues related to the ED culture, physician reimbursement system and patient volume. Role clarity refers to understanding the NP's function in the ED. Recruitment issues are associated with attracting and retaining NPs to work in EDs. Examples of each issue using respondent's own words are provided.Conclusion: Our study identified 3 issues that illustrate the complex issues involved when implementing NPs in EDs. The findings may inform policy makers and health care professionals in the future development of the role of NPs in Canadian EDs. [ABSTRACT FROM AUTHOR]

Background: Farming is a stressful occupation, and a growing body of research shows that farm stressors are associated with poor mental health. To date, there are few methodologically sound surveys that assess farm stressors, and none have been validated for the Canadian context. Our study aimed to: (a) investigate the types of stressors experienced by farmers, (b) develop a farm stress assessment tool and test its factor structure and internal consistency, and (c) assess its criterion-related validity to self-reported levels of anxiety, depression, burnout, and resilience among farmers., Methods: We developed a 20-item survey based on a review of the literature, examining existing farm stress surveys, and consulting 10 farmers and agricultural industry experts. Then, a convenience sample of farmers living in Alberta, Canada (Sample 1, N = 354) completed a questionnaire containing the 20-item farm stress survey and four validated measures that assessed depression, anxiety, burnout, and resilience. Sample 1 was used to assess the factor structure using exploratory factor analysis (EFA), internal consistency, and criterion-validity of the survey. Next, a convenience sample of farmers living outside of Alberta (Sample 2, N = 138) was used to evaluate the factor structure of the survey using confirmatory factor analysis (CFA)., Results: The results of the EFA revealed five underlying dimensions of farm stressors: Unexpected work disruptions, Agricultural hazards, Farm and financial planning, Isolation, and Regulations and public pressure. The subscales accounted for 61.6% of the variance, and the internal consistency (Cronbach's alpha) ranged from 0.66 to.75. Subscale correlations were below 0.44, indicating evidence of discriminant validity. Correlations between the five subscales and the four mental health outcome variables supported the criterion-related validity of the survey. The results of the CFA indicated that the data fit the model, and fit was further improved by correlating one pair of error terms., Conclusions: Preliminary analysis of our Farmer Stress Assessment Tool (FSAT) suggests it is a reliable and valid instrument for measuring a range of stressors farmers face. Implications for policy and community-based mental health interventions that help farmers manage the enduring stressors of agriculture is discussed., (© 2024. The Author(s).)

Group A Streptococcus (GAS), or Streptococcus pyogenes , is a gram-positive bacterium that extensively colonises within the human host. GAS is responsible for causing a range of human infections, such as pharyngitis, impetigo, scarlet fever, septicemia, and necrotising fasciitis. GAS pathogens have the potential to elicit fatal autoimmune sequelae diseases (including rheumatic fever and rheumatic heart diseases) due to recurrent GAS infections, leading to high morbidity and mortality of young children and the elderly worldwide. Antibiotic drugs are the primary method of controlling and treating the early stages of GAS infection; however, the recent identification of clinical GAS isolates with reduced sensitivity to penicillin-adjunctive antibiotics and increasing macrolide resistance is an increasing threat. Vaccination is credited as the most successful medical intervention against infectious diseases since it was discovered by Edward Jenner in 1796. Immunisation with an inactive/live-attenuated whole pathogen or selective pathogen-derived antigens induces a potent adaptive immunity and protection against infectious diseases. Although no GAS vaccines have been approved for the market following more than 100 years of GAS vaccine development, the understanding of GAS pathogenesis and transmission has significantly increased, providing detailed insight into the primary pathogenic proteins, and enhancing GAS vaccine design. This review highlights recent advances in GAS vaccine development, providing detailed data from preclinical and clinical studies across the globe for potential GAS vaccine candidates. Furthermore, the challenges and future perspectives on the development of GAS vaccines are also described.

Subunit vaccines hold substantial promise in controlling infectious diseases, due to their superior safety profile, specific immunogenicity, simplified manufacturing processes, and well-defined chemical compositions. One of the most important end-targets of vaccines is a subset of lymphocytes originating from the thymus, known as T cells, which possess the ability to mount an antigen-specific immune response. Furthermore, vaccines confer long-term immunity through the generation of memory T cell pools. Dendritic cells are essential for the activation of T cells and the induction of adaptive immunity, making them key for the in vitro evaluation of vaccine efficacy. Upon internalization by dendritic cells, vaccine-bearing antigens are processed, and suitable fragments are presented to T cells by major histocompatibility complex (MHC) molecules. In addition, DCs can secrete various cytokines to crosstalk with T cells to coordinate subsequent immune responses. Here, we generated an in vitro model using the immortalized murine dendritic cell line, DC2.4, to recapitulate the process of antigen uptake and DC maturation, measured as the elevation of CD40, MHC-II, CD80 and CD86 on the cell surface. The levels of key DC cytokines, tumor necrosis alpha (TNF-α) and interleukin-10 (IL-10) were measured to better define DC activation. This information served as a cost-effective and rapid proxy for assessing the antigen presentation efficacy of various vaccine formulations, demonstrating a strong correlation with previously published in vivo study outcomes. Hence, our assay enables the selection of the lead vaccine candidates based on DC activation capacity prior to in vivo animal studies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Lu, Kong, Zhang, Firdaus, Wells, Stephenson, Toth, Skwarczynski and Cruz.)

Immune stimulants (adjuvants) enhance immune system recognition to provide an effective and individualized immune response when delivered with an antigen. Synthetic cyclic deca-peptides, co-administered with a toll-like receptor targeting lipopeptide, have shown self-adjuvant properties, dramatically boosting the immune response in a murine model as a subunit peptide-based vaccine containing group A Streptococcus peptide antigens.Here, we designed a novel peptide and lipid adjuvant system for the delivery of group A Streptococcus peptide antigen and a T helper peptide epitope. Following linear peptide synthesis on 2-chlorotrityl chloride resin, the linear peptide was cleaved and head-to-tail cyclized in solution. The selective arrangement of amino acids in the deca-peptide allowed for selective conjugation of lipids and/or peptide antigens following cyclisation. Using both solution-phase peptide chemistry and copper-catalyzed azide-alkyne cycloaddition reaction were covalently (and selectively) ligated lipid and/or peptide antigens onto the cyclic deca-peptide core. Subcutaneous administration of the vaccine design to mice resulted in the generation of a large number of serum immunoglobulin (Ig) G antibodies., (© 2024. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Cocaine is one of the most widely used and increasingly popular illicit psychoactive drugs. Unlike other commonly used substances of abuse, cocaine has no pharmacological therapies to treat addiction or aid in rehabilitation. Immunopharmacology has long been touted as a possible avenue to develop effective anticocaine therapies; however, lack of efficacy and designs which are not consistent with simple large-scale production have hindered vaccine translation. We have designed and synthesized a peptide-based anti-cocaine immunogen which we have shown is capable of inducing physiologically relevant immune responses in mice as part of a self-adjuvanting delivery system or in combination with the human-approved commercial adjuvant MF59. We have demonstrated that immunization with the reported vaccine elicits high titers of anti-cocaine IgG and prevents cocaine-induced hyperlocomotion in an in vivo murine model. This peptide-hapten immunogen along with self-adjuvanting liposomal-based delivery system provides a platform for the development of effective anti-drug vaccines.

Untreated group A Streptococcus (GAS) can lead to a range of life-threatening diseases, including rheumatic heart disease. To date, no therapeutic or prophylactic vaccines are commercially available to treat or prevent GAS infection. Development of a peptide-based subunit vaccine offers a promising solution, negating the safety issues of live-attenuated or inactive vaccines. Subunit vaccines administer small peptide fragments (antigens), which are typically poorly immunogenic. Therefore, these peptide antigens require formulation with an immune stimulant and/or vaccine delivery platform to improve their immunogenicity. We investigated polyelectrolyte complexes (PECs) and polymer-coated liposomes as self-adjuvanting delivery vehicles for a GAS B cell peptide epitope conjugated to a universal T-helper epitope and a synthetic toll-like receptor 2-targeting moiety lipid core peptide-1 (LCP-1). A structure-activity relationship of cationic PEC vaccines containing different external PEI-coatings (poly(ethylenimine); 10 kDa PEI, 25 kDa PEI, and a synthetic mannose-functionalized 25 kDa PEI) formed vaccines PEC-1, PEC-2, and PEC-3, respectively. All three PEC vaccines induced J8-specific systemic immunoglobulin G (IgG) antibodies when administered intranasally to female BALB/c mice without the use of additional adjuvants. Interestingly, PEC-3 induced the highest antibody titers among all tested vaccines, with the ability to effectively opsonize two clinically isolated GAS strains. A comparative study of PEC-2 and PEC-3 with liposome-based delivery systems was performed subcutaneously. LCP-1 was incorporated into a liposome formulation (DPPC, DPPG and cholesterol), and the liposomes were externally coated with PEI (25 kDa; Lip-2) or mannosylated PEI (25 kDa; Lip-3). All liposome vaccines induced stronger humoral immune responses compared to their PEC counterparts. Notably, sera of mice immunized with Lip-2 and Lip-3 produced significantly higher opsonic activity against clinically isolated GAS strains compared to the positive control, P25-J8 emulsified with the commercial adjuvant, complete Freund's adjuvant (CFA). This study highlights the capability of a PEI-liposome system to act as a self-adjuvanting vehicle for the delivery of GAS peptide antigens and protection against GAS infection.

Cocaine is one of the oldest and most widely used illicit drugs in the world and is responsible for major worldwide medical and social problems. Drug addiction is a disease state where the body relies on a substance for normal functioning and develops a physical dependence leading to compulsive and repetitive use despite negative consequences to the user's health, mental state, or social life. The primary driver for the development of anti-cocaine vaccines has been the failure to develop effective pharmacological treatments to combat cocaine dependence. Despite several decades of research, no approved pharmacological treatments for cocaine dependence are available to assist addicts to overcome cocaine withdrawal or to prevent drug relapse. This Perspective highlights the challenges associated with anti-cocaine vaccines, including the current state of anti-cocaine vaccines and catalytic antibody research to aid in the fight against cocaine addiction.

Human papilloma virus (HPV) is responsible for all cases of cervical cancer. While prophylactic vaccines are available, the development of peptide-based vaccines as a therapeutic strategy is still under investigation. In comparison with the traditional and currently used treatment strategies of chemotherapy and surgery, vaccination against HPV is a promising therapeutic option with fewer side effects. A peptide derived from the HPV-16 E7 protein, called 8Qm, in combination with adjuvants showed promise as a therapeutic vaccine. Here, the ability of polymerized natural amino acids to act as a self-adjuvating delivery system as a therapeutic vaccine was investigated for the first time. Thus, 8Qm was conjugated to polyleucine by standard solid-phase peptide synthesis and self-assembled into nanoparticles or incorporated in liposomes. The liposome bearing the 8Qm conjugate significantly increased mice survival and decreased tumor growth after a single immunization. Further, these liposomes eradicated seven-day-old well-established tumors in mice. Dendritic cell (DC)-targeting moieties were introduced to further enhance vaccine efficacy, and the newly designed liposomal vaccine was tested in mice bearing 11-day-old tumors. Interestingly, these DCs-targeting moieties did not significantly improve vaccine efficacy, whereas the simple liposomal formulation of 8Qm-polyleucine conjugate was still effective in tumor eradication. In summary, a peptide-based anticancer vaccine was developed that stimulated strong cellular immune responses without the help of a classical adjuvant.

The sporting season across post-secondary institutions was canceled in March 2020 due to COVID-19, and student-athletes had to maintain their training at home. It is unclear what personal and contextual factors facilitated student-athletes' ability to maintain their training routines at home when social distancing and lockdown (SD/L) policies were put in place. Our cross-sectional study of 433 student-athletes examined (a) how athletes adapted their training, (b) what training barriers they experienced, (c) whether motivational profiles were associated with differences in training behaviors and mental health, and (d) what variables predicted athletes' motivation to train during this prolonged offseason. Student-athletes across Canada were recruited to complete an online survey between August and September 2020. Results showed that athletes significantly reduced their training load and intensity, with approximately 25% exercising two or fewer days a week. Barriers to training included limited access to fitness resources and equipment, having inconsistent training schedules, and experiencing emotional distractions, with some of these barriers more common among female athletes than male athletes. For motivation profiles, athletes with higher levels of intrinsic motivation tended to maintain the intensity of their workouts and experienced lower mood disturbance. A hierarchical multiple regression revealed that being male, being younger, having higher levels of intrinsic and introjected motivation, having access to fitness resources, maintaining a steady training schedule, having fewer emotional distractions, and lower mood disturbance were significant predictors to being motivated to train during the pandemic. We discuss strategies coaches and trainers can implement to best support their student-athletes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Purc-Stephenson, Zimmerman and Edwards.)

Vaccines are one of the most significant medical interventions in the fight against infectious diseases. Since their discovery by Edward Jenner in 1796, vaccines have reduced the worldwide transmission to eradication levels of infectious diseases, including smallpox, diphtheria, hepatitis, malaria, and influenza. However, the complexity of developing safe and effective vaccines remains a barrier for combating many more infectious diseases. Immune stimulants (or adjuvants) are an indispensable factor in vaccine development, especially for inactivated and subunit-based vaccines due to their decreased immunogenicity compared to whole pathogen vaccines. Adjuvants are widely diverse in structure; however, their overall function in vaccine constructs is the same: to enhance and/or prolong an immunological response. The potential for adverse effects as a result of adjuvant use, though, must be acknowledged and carefully managed. Understanding the specific mechanisms of adjuvant efficacy and safety is a key prerequisite for adjuvant use in vaccination. Therefore, rigorous pre-clinical and clinical research into adjuvant development is essential. Overall, the incorporation of adjuvants allows for greater opportunities in advancing vaccine development and the importance of immune stimulants drives the emergence of novel and more effective adjuvants. This article highlights recent advances in vaccine adjuvant development and provides detailed data from pre-clinical and clinical studies specific to infectious diseases. Future perspectives into vaccine adjuvant development are also highlighted.

Currently there is no approved vaccine to prevent and/or treat group A Streptococcus (GAS) infection. With increasing reports of GAS antibiotic resistance, vaccine adjuvants and targeted delivery systems which induce a strong immune response are a widely acknowledged unmet need. Through extensive structure-activity studies, we investigated a cyclic decapeptide physically mixed with a GAS B cell peptide epitope (J8), a universal T helper epitope (PADRE), and different synthetic lipidic moieties as a conceivable self-adjuvanting GAS vaccine. We explored the structure (orientation)-relationship of the chemically-conjugated B cell epitope and T helper epitope peptide as part of this physically-mixed vaccine. Following in vivo assessment in mice, these cyclic lipopeptide vaccines showed successful induction of J8-specific systemic IgG antibodies when administered subcutaneously without additional adjuvant. Interestingly, an exposed C-terminus of the GAS B cell epitope and a 16-carbon alpha-amino fatty acid lipid was required for strong immunoreactivity, capable of effectively opsonising multiple strains of clinically-isolated GAS bacteria. Physicochemical assessment proved the alpha helix structure of the GAS B cell epitope was retained, impacting particle self-assembly and vaccine immunoreactivity. This study showed the capability for a self-adjuvanting cyclic delivery system to act as a vehicle for the delivery of GAS peptide antigens to treat GAS infection., (Crown Copyright © 2022. Published by Elsevier B.V. All rights reserved.)

Dendrimers are well-defined, highly branched, multivalent and monodisperse molecules which host a range of attractive, yet functional, chemical and biological characteristics. A dendrimers accessible surface groups enable coupling to different functional moieties (e.g., antibodies, peptides, proteins, etc), which is further assisted by the dendrimers tailored size and surface charge. This adaptability allows for the preparation of molecularly precise vaccines with highly specific and predictable properties, and in conjunction with a dendrimers immune stimulating (adjuvanting) property, makes dendrimers attractive substrates for biomedical applications, including vaccines. This review highlights the structural and synthetic evolution of dendrimers throughout history, detailing the dendrimers role as both an adjuvant and carrier system for vaccine antigens, in addition to reviewing the development of commercially available vaccines for use in humans., (Crown Copyright © 2021. Published by Elsevier Ltd. All rights reserved.)

Untreated or reoccurring group A Streptococcus (GAS) infection can lead to a number of post-infection complications, including rheumatic heart disease. There is no licenced vaccine for the treatment or prevention of GAS infection. We identified that a cyclic decapeptide plays a significant positive influence on the adjuvant activity of several lipid-antigen mixtures. Here, three synthetic vaccine components were synthesised: (1) J8-PADRE represents the GAS B cell antigen (J8) conjugated to the universal T helper epitope (PADRE); (2) a synthetic toll like receptor 2 (TLR2) ligand based on a C16 alkyl chain lipid moiety; and (3) a cyclic carrier deca-peptide. Previously, through structure-immune activity investigations, it was observed that a physical mixture of these three components had significantly higher IgG immune responses when compared to a fully conjugated vaccine construct. Expanding the scope of this structure-activity investigation, we show that the presence of the cyclic peptide is required for the induction of a strong, balanced Th1/Th2 immune response when compared with lipid and antigen only, and cyclic lipopeptide plus B/T cell antigen physical mixtures.

We recently reported that polyethylenimine (PEI; molecular weight of 600 Da) acted as a vaccine adjuvant for liposomal group A Streptococcus (GAS) vaccines, eliciting immune responses in vivo with IgG antibodies giving opsonic activity against five Australian GAS clinical isolates. However, to date, no investigation comparing the structure-activity relationship between the molecular weight of PEI and its adjuvanting activity in vaccine development has been performed. We hypothesized that the molecular weight and quantity of PEI in a liposomal vaccine will impact its adjuvanting properties. In this study, we successfully formulated liposomes containing different molecular weights of PEI (600, 1800, 10k and 25k Da) and equivalents of PEI (0.5, 1 and 2) of branched PEI. Outbred mice were administrated the vaccine formulations intranasally, and the mice that received a high ratio of PEI 600 reported a stronger immune response than the mice that received a lower ratio of PEI 600. Interestingly, mice that received the same quantity of PEI 600, PEI 10k and PEI 25k showed similar immune responses in vivo and in vitro. This comparative study highlights the ratio of PEI present in the liposome vaccines impacts adjuvanting activity, however, PEI molecular weight did not significantly enhance its adjuvanting properties. We also report that the stability of PEI liposomes is critical for vaccines to elicit the desired immune response., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Identifying the immunogenic moieties and their precise structure of carbohydrates plays an important role for developing effective carbohydrate-based subunit vaccines. This study assessed the structure-immunogenicity relationship of carbohydrate moieties of a single repeating unit of group A carbohydrate (GAC) present on the cell wall of group A Streptococcus (GAS) using a rationally designed self-adjuvanted lipid-core peptide, instead of a carrier protein. Immunological evaluation of fully synthetic glyco-lipopeptides (particle size: 300-500 nm) revealed that construct consisting of higher rhamnose moieties (trirhamnosyl-lipopeptide) was able to induce enhanced immunogenic activity in mice, and GlcNAc moiety was not found to be an essential component of immunogenic GAC mimicked epitope. Trirhamnosyl-lipopeptide also showed 75-97% opsonic activity against four different clinical isolates of GAS and was comparable to a subunit peptide vaccine (J8-lipopeptide) which illustrated 65-96% opsonic activity.

Group A Streptococcus (GAS) and GAS-related infections are a worldwide challenge, with no commercial GAS vaccine available. Polyethylenimine (PEI) attaches to the cells' surface and delivers cargo into endosomal and cytosolic compartments. We hypothesized that this will confer mucosal adjuvant properties for peptide antigens against group A Streptococcus (GAS). In this study, we successfully demonstrated the development of PEI incorporated liposomes for the delivery of a lipopeptide-based vaccine (LCP-1) against GAS. Outbred mice were administrated with the vaccine formulations intranasally, and immunological investigation showed that the PEI liposomes elicited significant mucosal and systemic immunity with the production of IgA and IgG antibodies. Antibodies were shown to effectively opsonize multiple isolates of clinically isolated GAS. This proof-of-concept study showed the capability for PEI liposomes to act as a safe vehicle for the delivery of GAS peptide antigens to elicit immune responses against GAS infection, making PEI a promising addition to liposomal mucosal vaccines.

Group A Streptococcus (GAS) infection causes a range of life-threatening diseases, including rheumatic heart disease. Cyclic peptides offer an attractive solution for presentation of short peptide antigens due to their stability and structurally constrained conformation. We investigated a cyclic carrier decapeptide incorporating a B cell GAS peptide epitope, a universal T helper epitope, and a synthetic toll-like receptor 2-targeting moiety as a possible self-adjuvanting GAS vaccine. A structure-activity relationship of the cyclic lipopeptide vaccine showed successful induction of J8-specific systemic immunoglobulin G (IgG) antibodies when administered subcutaneously without an additional adjuvant. Interestingly, the physical mixture control induced the highest titers of all vaccine compounds, with antibodies from mice immunized with this physical mixture control shown to effectively opsonize multiple strains of clinically isolated GAS bacteria. This study showed the capability for a self-adjuvanting cyclic delivery system to act as a vehicle for the delivery of GAS peptide antigens to treat GAS infections.

Group A Streptococcus (GAS) and GAS-associated infections are a global challenge, with no licensed GAS vaccine on the market. The GAS M protein is a critical virulence factor in the fight against GAS infection, and it has been a primary target for GAS vaccine development. Measuring functional opsonic antibodies against GAS is an important component in the clinical development path for effective vaccines. In this study, we compared the opsonic activity of two synthetic, self-adjuvanting subunit vaccines containing either the J8- or 88/30-epitope in Swiss outbred mice using intranasal administration. Following primary immunization and three boosts, sera were assessed for IgG activity using ELISA, and opsonization activity against seven randomly selected clinical isolates of GAS was measured. Vaccine constructs containing the conservative J8-epitope showed significant opsonic activity against six out of the seven GAS clinical isolates, while the vaccine containing the variable 88/30-epitope did not show any significant opsonic activity.

Carbohydrates are considered as promising targets for vaccine development against infectious diseases where cell surface glycan's on many infectious agents are attributed to playing an important role in pathogenesis. Understanding the relationship between carbohydrates and immune components at a molecular level is crucial for the development of well-defined vaccines. Recently, carbohydrate immunology research has been accelerated by the development of new technologies that contribute to the design of optimum antigens, synthesis of antigens and the studies of antigen-antibody interactions, and as a result, several promising carbohydrate-based vaccine candidates have been prepared in recent years. This article briefly presents the mechanistic pathways of polysaccharide, glycoconjugate, glycolipid and zwitterionic vaccines and the interplay between carbohydrate antigen and immune response., (Copyright © 2020. Published by Elsevier B.V.)

Fmoc solid-phase peptide synthesis (SPPS) is the most common approach used to synthesize natural and unnatural peptides. However, the synthesis of sequences longer than 30-60 amino acids is associated with a drastic reduction in peptide quality. Thus, large and complex peptides are normally synthesized as fragments, which are then conjugated together. Here, we describe the synthesis of a large, branched peptide, a multi-epitope vaccine candidate against Group A Streptococcus, with the help of microwave-assisted Fmoc-SPPS, thiol-maleimide conjugation, and copper(I)-catalyzed alkyne-azide cycloaddition (CuAAC) "click" reaction.

Background: Despite a diverse range of curricular advancements to address the difficult transition from classroom learning to clinical training during medical education, hurdles persist. A 4-week course was designed at the Philadelphia College of Osteopathic Medicine (PCOM) to make this transition easier., Objectives: To determine whether PCOM students' comfort and preparedness increased after taking a 4-week clinical transition course before third-year clinical clerkships, and to determine whether faculty perceptions of student preparedness and comfort were improved after participation in the course compared with previous third-year students., Methods: Second-year osteopathic medical students at PCOM participated in a 4-week course, Introduction to Clinical Clerkship (I2C). The course included 16 small-group exercises, which all took place before students began their third-year clerkship rotations. The exercises in the course extended beyond the skills learned during their classroom years. Students were given a pre- and postcourse survey to evaluate their comfort level with 58 different aspects of clinical practice. Participating faculty were surveyed to evaluate their perception of student preparedness and comfort compared with previous third-year students who had not undergone the exercise., Results: After completing the I2C course, third-year osteopathic medical students (n=232) reported increased comfort with 57 of the 58 learning objectives and each of the 5 coded clinical competency areas (patient assessment, effective communication, hospital logistics, procedural skills, and core knowledge) (P<.01). Preceptors reported that students who completed the I2C course were more prepared (54.5%) and more comfortable (63.4%) with clinical duties, as compared with their recollections of previous third-year osteopathic medical students., Conclusion: Within the 5 competencies, students on average felt more comfortable and were perceived by faculty as better prepared than previous students who had not taken the I2C course. The establishment of a preclinical transition exercise appears to help bridge the gap between the preclinical and clinical years. This learning model allows medical students to feel both more comfortable and better prepared throughout the transition from classroom learning to clinical rotations.

Objective: To describe the experiences and strategies of employees with arthritis to maintain employment, and to use this information to build a conceptual model., Methods: We conducted a systematic review of qualitative studies that examined the work experiences of employees with arthritis. Published studies on arthritis and employment were searched from electronic databases (1980-2017) and bibliographic reviews of relevant studies. We used meta-ethnography to synthesize the findings., Results: We reviewed 17 studies that reported on the experiences of 873 employees. We identified 11 main themes that highlight common issues experienced by employees with arthritis and grouped these into 4 higher-order categories: changing nature of the disease (emotional issues, cognitive struggles, unpredictable physical symptoms), intrapersonal issues (personal meaning of work, preserving a work identity), interpersonal issues (managing disclosure, gaining coworker support, organizational culture issues), and work-sustainability strategies (making personal adjustments, using social support, using workplace accommodations). Using these themes, we developed the Job Sustainability Model to illustrate how disease, personal, and work-related factors interact to influence what type of coping behaviors are used and when. Initially, employees with arthritis rely on making personal adjustments, using social support, and medical intervention. However, when these coping behaviors fail to be effective, they draw upon workplace accommodations and resources., Conclusion: Arthritis disrupts an employee's work life by impairing his or her capacity to be a productive worker. Our results highlight how employees with arthritis make strategic adaptations to maintain a productive work life for as long as possible. The findings of this study have implications for work-related interventions aimed at preserving employment., (© 2018, American College of Rheumatology.)

Adjuvant development and understanding the physicochemical properties of particles and interpreting the subsequent immunological responses is a challenge faced by many researchers in the vaccine field. We synthesized and investigated the physicochemical properties and immunogenicity of a library of multiple epitope self-adjuvant lipopeptides in a novel asymmetric arrangement. Vaccine candidates were synthesized using a combination of solid-phase peptide synthesis and copper-mediated click chemistry. In vivo studies showed that vaccine constructs containing a single OVA CD8 + T-cell epitope and two N-terminally located C16 lipid moieties were more effective at generating robust cellular immune responses compared to the same molecule containing multiple copies of the OVA CD8 + T-cell epitope with or without the C16 moieties. Furthermore, attachment of the two C16 lipids to the N-terminus provoked formation of long β-sheet fibrils and was shown to induce a higher CD8 + donor T-cell frequency and IFN-γ secretion, compared to vaccine constructs with an internal lipid placement. A regression analysis indicated that particle secondary structure had a significant impact on CD8 + donor T-cell frequency and cytolytic activity. In addition, IFN-γ production was influenced significantly by particle shape. The findings of this research will impact the future design of a vaccine intended to elicit cellular immune responses., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Bacterial cell-surface-derived or mimicked carbohydrate moieties that act as protective antigens are used in the development of antibacterial glycoconjugate vaccines. The carbohydrate antigen must have a minimum length or size to maintain the conformational structure of the antigenic epitope(s). The presence or absence of O-acetate, phosphate, glycerol phosphate and pyruvate ketal plays a vital role in defining the immunogenicity of the carbohydrate antigen. The nature of the carrier protein, spacer and conjugation pattern used to develop the glycoconjugate vaccine also defines its overall spatial orientation which in turn affects its avidity and selectivity of interaction with the desired target(s). In addition, the ratio of carbohydrate to protein in glycoconjugate vaccines also makes an important contribution in determining the optimum immunological response. This Review article presents the importance of these variables in the development of antibacterial glycoconjugate vaccines and their effects on immune efficacy., (© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Self-assembled peptides have shown outstanding characteristics for vaccine delivery and drug targeting. Peptide molecules can be rationally designed to self-assemble into specific nanoarchitectures in response to changes in their assembly environment including: pH, temperature, ionic strength, and interactions between host (drug) and guest molecules. The resulting supramolecular nanostructures include nanovesicles, nanofibers, nanotubes, nanoribbons, and hydrogels and have a diverse range of mechanical and physicochemical properties. These molecules can be designed for cell-specific targeting by including adhesion ligands, receptor recognition ligands, or peptide-based antigens in their design, often in a multivalent display. Depending on their design, self-assembled peptide nanostructures have advantages in biocompatibility, stability against enzymatic degradation, encapsulation of hydrophobic drugs, sustained drug release, shear-thinning viscoelastic properties, and/or adjuvanting properties. These molecules can also act as intracellular transporters and respond to changes in the physiological environment. Furthermore, this class of materials has shown sequence- and structure-dependent impacts on the immune system that can be tailored to non-immunogenic for drug targeting, and immunogenic for vaccine delivery. This review explores self-assembled peptide nanostructures (beta sheets, alpha helices, peptide amphiphiles, amino acid pairing, elastin like polypeptides, cyclic peptides, short peptides, Fmoc peptides, and peptide hydrogels) and their application in vaccine delivery and drug targeting., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Schistosoma japonicum insulin receptors (SjIRs) have been identified as encouraging vaccine candidates. Interrupting or blocking the binding between host insulin and the schistosome insulin receptors (IRs) may result in reduced glucose uptake leading to starvation and stunting of worms with a reduction in egg output. To further understand how schistosomes are able to exploit host insulin for development and growth, and whether these parasites and their mammalian hosts compete for the same insulin source, we identified insulin binding sites on the SjIRs. Based on sequence analysis and the predicted antigenic structure of the primary sequences of the SjIRs, we designed nine and eleven peptide analogues from SjIR-1 and SjIR-2, respectively. Using the Octet RED system, we identified analogues derived from SjIR-1 (10) and SjIR-2 (20, 21 and 22) with insulin-binding sequences specific for S. japonicum. Nevertheless, the human insulin receptor (HIR) may compete with the SjIRs in binding human insulin in other positions which are important for HIR binding to insulin. However, no binding occurred between insulin and parasite analogues derived from SjIR-1 (2, 7 and 8) and SjIR-2 (14, 16 and 18) at the same locations as HIR sequences which have been shown to have strong insulin binding affinities. Importantly, we found two analogues (1 and 3), derived from SjIR-1, and two analogues (13 and 15) derived from SjIR-2, were responsible for the major insulin binding affinity in S. japonicum. These peptide analogues were shown to have more than 10 times (in KD value) stronger binding capacity for human insulin compared with peptides derived from the HIR in the same sequence positions. Paradoxically, analogues 1, 3, 13 and 15 do not appear to contain major antigenic determinants which resulted in poor antibody responses to native S. japonicum protein. This argues against their future development as peptide-vaccine candidates.

Present on the surface of antigen presenting cells (APCs), the mannose receptor (MR) has long been recognized as a front-line receptor in pathogen recognition. During the past decade many attempts have been made to target this receptor for applications including vaccine and drug development. In the present study, a library of vaccine constructs comprising fluorescently labeled mannosylated lipid-dendrimers that contained the ovalbumin CD4(+) epitope, OVA(323-339), as the model peptide antigen were synthesized using fluorenylmethyloxycarbonyl (Fmoc) solid phase peptide synthesis (SPPS). The vaccine constructs were designed with an alanine spacer between the O-linked mannose moieties to investigate the impact of distance between the mannose units on receptor-mediated uptake and/or binding in APCs. Uptake studies performed on F4/80(+) and CD11c(+) cells showed significant uptake and/or binding for lipopeptides containing mannose, and also the lipopeptide without mannose when compared to the control peptides (peptide with no lipid and peptide with no mannose and no lipid). Furthermore, mannan inhibition assays demonstrated that uptake of the mannosylated and lipidated peptides was receptor mediated. To address the specificity of receptor uptake, surface plasmon resonance studies were performed using biacore technology and confirmed high affinity of the mannosylated and lipidated vaccine constructs toward the MR. These studies confirm that both mannose and lipid moieties play significant roles in receptor-mediated uptake on APCs, potentially facilitating vaccine development.

Aim: Systematically evaluate lipid core peptide vaccine delivery platforms to identify core features promoting strong CD8(+) T-cell responses., Materials & Methods: Three different self-adjuvanting lipid core peptide nanovaccines each comprising four copies of the dominant ovalbumin CD8(+) T-cell epitope and varying in the utilization of a polylysine or glucose core with 2-amino-hexadecanoic acid (C16) or 2-amino-dodecanoic acid (C12) lipids were synthesized. Vaccines were tested for ability to induce CD8(+) T-cell responses and inhibit tumor growth in vivo., Results: The construct utilizing C12 lipids and polylysine core induced very robust effector T cells shown to have in vivo effector capability as demonstrated by in vivo cytotoxicity and ability to inhibit tumor growth as well as modulation of dendritic cell activation., Conclusion: The C12 polylysine platform was an effective configuration for induction of potent CD8(+) T-cell responses.

Designing a lipopeptide (LP) vaccine with a specific asymmetric arrangement of epitopes may result in an improved display of antigens, increasing host-cell recognition and immunogenicity. This study aimed to synthesise and characterise the physicochemical properties of a library of asymmetric LP-based vaccine candidates that contained multiple CD4(+) and CD8(+) T-cell epitopes from the model protein antigen, ovalbumin. These fully synthetic vaccine candidates were prepared by microwave-assisted solid phase peptide synthesis. The C12 or C16 lipoamino acids were coupled to the N or C terminus of the OVA CD4 peptide epitope. The OVA CD4 LPs and OVA CD8 peptide constructs were then conjugated using azide-alkyne Huisgen cycloaddition to give multivalent synthetic vaccines. Physiochemical characterisation of these vaccines showed a tendency to self-assemble in aqueous media. Changes in lipid length and position induced self-assembly with significant changes to their morphology and secondary structure as shown by transmission electron microscopy and circular dichroism., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Multiplex serology was performed for the detection of total immunoglobulin (Ig) and IgM antibodies against porcine circovirus type 2 (PCV2), porcine reproductive and respiratory syndrome virus (PRRSV), and swine influenza virus (SIV) antigens in feral swine (Sus scrofa). Serum samples were collected from the islands of Oahu (292 pigs) and Hawaii (52 pigs) between 2007 and 2010. The highest antibody prevalence was to PCV2 (63%), followed by SIV (7.8%) and PRRSV (5.8%). Antigen-specific IgM was detected at a much lower prevalence. PCR amplification and sequence analysis of PCV2 in three IgM-positive samples identified PCV2b as the only genotype. While the prevalence of PCV2 and PRRSV remained similar between 2007 and 2010, the percentage of SIV-positive samples on Oahu increased from 2% to 19%. Our results demonstrate the utility of multiplex serology for pathogen surveillance in feral pig populations.

A better understanding of the molecular mechanisms required for schistosomes to take up glucose, the major nutritional source exploited by these blood flukes from their mammalian hosts and the subsequent metabolism required to fuel growth and fecundity, can provide new avenues for developing novel interventions for the control of schistosomiasis. This aspect of parasitism is particularly important to paired adult schistosomes, due to their considerable requirements for the energy needed to produce the extensive numbers of eggs laid daily by the female worm. This review describes recent advances in characterizing glucose metabolism in adult schistosomes. Potential intervention targets are discussed within the insulin signaling and glycolysis pathways, both of which play critical roles in the carbohydrate and energy requirements of schistosomes.

Objective: The Posttraumatic Growth Inventory (PTGI) assesses positive changes after a traumatic or serious life crisis. However, there are differing views regarding its factor structure and little understanding if it captures the positive changes experienced among individuals diagnosed with a chronic disease. Using confirmatory factor analysis (CFA), the proposed five-factor structure and measurement invariance of the PTGI was examined using two chronic illness samples: arthritis and inflammatory bowel disease (IBD)., Method: Individuals diagnosed with arthritis (n = 301) or IBD (n = 544) recruited from the community and the Internet completed the PTGI. Using a pooled sample, CFA tested five hypothesized models of the underlying factors structure of the PTGI. A stepwise procedure for testing the measurement invariance across the two groups evaluated the factor structure, factorial invariance, and latent mean invariance., Results: Using the pooled sample, the CFA supported the hypothesized five-factor model, revealing the PTGI is multidimensional. Multigroup CFA supported invariance of the PTGI across the two groups although there were significant differences in latent means., Conclusions: The findings support that the PTGI assesses five related dimensions of PTG and that different chronic disease groups experience different types of positive changes. PTG may therefore be relevant as a meaningful treatment goal for people with chronic diseases as it is for people affected by other traumatic events., (PsycINFO Database Record (c) 2014 APA, all rights reserved.)

Two arginine side-chain protecting groups, N(G)-4-methoxy-2,3,6-trimethylbenzensulfonyl group (Mtr) and N(G)-2,2,5,7,8-pentamethylchroman-6-sulfonyl (Pmc), have been investigated at both the Arg(1) and/or Arg(9) position of the bioactive peptide, Bradykinin using Fluorenylmethyloxycarbonyl (Fmoc) Solid Phase Peptide Synthesis. A more efficient synthesis of the peptide has been found when a combination of Arg(Mtr) is present at position 1 and Arg(Pmc) is present at position 9 giving a cleaved pure yield of 52%.

As the number of vehicles in China rapidly increases and there is no child safety seat law, the issue of road safety for children is a growing concern. The purpose of this study was to examine parents' use and knowledge of car safety seats in Beijing, China. Using a convenience sample of 843 parents, survey results showed that only 64.8% of parents used a safety restraint for their children; the remaining 35.2% of children, of which most were toddlers or school-aged children, travelled unrestrained in vehicles. Among parents who used a safety restraint, only 24.2% were using it correctly based on the child's age (for infants), weight and height. Common reasons for not using a safety seat included difficulty finding safety seats (56.6%), cost (26.1%), and a preference to hold the child (18.1%). Moreover, a large proportion of parents prematurely transitioned their child from a safety seat to seat belt. The results highlight the need to develop injury prevention interventions that communicate the benefits and encourage the use of child safety restraints in China.

Crop residue removal for expanded uses such as feedstocks for cellulosic ethanol production may increase loss of sediment and nutrients in runoff. We assessed on-farm impacts of variable rates of residue removal from no-till winter wheat (Triticum aestivum L.) and plow till grain sorghum [Sorghum bicolor (L.) Moench] on sediment, soil organic carbon (SOC) and nutrient losses in runoff in western Kansas. Five treatments with three replications consisting of removing residues at 0, 25, 50, 75, and 100% after harvest under two tillage levels for wheat (no-till and freshly tilled) and grain sorghum (spring tilled and freshly tilled) were established on 1x2 m plots. Simulated rainfall was applied at 115+/-3 mm h(-1) for 30 min. Compared with plots without residue removal, complete removal increased runoff by 61% in freshly tilled wheat plots, 225% in spring-tilled sorghum plots, and 94% in freshly tilled sorghum plots. Residue removal at rates as low as 50% increased loss of sediment. Complete removal doubled the sediment loss to 14 Mg ha(-1) in tilled wheat, whereas it increased sediment loss from 0.9 to 7.2 Mg ha(-1) in no-till wheat. No-till with 100% residue removal lost as much sediment as freshly tilled wheat plots with 0 or 25% removal. Residue removal at 75 and 100% increased losses of total N, total P, and SOC associated with sediment. Overall, excessive residue removal led to large losses of sediment, sediment-bound SOC, and nutrients in runoff. Furthermore, erosion protection provided by no-till management is lost when residue removal exceeds 25%.

Objectives: As interest in and use of complementary and alternative medicine (CAM) providers continues to grow, it is important to understand which characteristics incline people to experiment with and become frequent consumers of CAM practitioners. The purpose of this study was to examine how personality, as assessed by the five-factor model, was related to the breadth, frequency, and types of provider-based CAM use. Relationships between the personality factors (Openness, Conscientiousness, Extraversion, Agreeableness, and Neuroticism) and motives for consulting CAM providers were also explored., Methods: A convenience sample of 184 current CAM clients recruited through the offices of 12 conventional medicine and 17 CAM practitioners completed a survey package including measures of health status, CAM use, personality, and motivations for using CAM., Results: Only Openness and Agreeableness were consistently linked to different dimensions of CAM use, with each associated with consultations with CAM practitioners, and homeopaths and naturopaths in particular. After controlling for sociodemographic and health status variables in the stepwise multiple regressions, Openness was associated with the variety of CAM providers tried, whereas Agreeableness was linked to both the breadth and frequency of CAM consultations. Holistic and proactive health motivations were associated with both personality factors, and Agreeableness was also associated with motives reflecting a desire for shared decision-making., Conclusions: Findings indicate that individuals who are open and agreeable, as described by the five-factor model of personality, consult CAM practitioners to a greater extent. The motives involved suggest a congruency between CAM and their own perspectives regarding health and patient-provider interactions, which may have implications for understanding treatment adherence and outcomes.

The aim of this study was to examine the attitudes, behaviours, and intentions to consult complementary and alternative medicine (CAM) providers, of health-care consumers living in a region with low physician availability. A survey was completed by a convenience sample of 235 CAM clients and nonconsumers recruited from an underserved urban centre in Canada. Nearly half had experienced difficulties getting an appointment with a physician when needed, and those who had experienced difficulties were more dissatisfied with conventional health care. Most participants (85.1%) indicated that they would consider consulting a CAM provider should they have difficulty getting an appointment with a physician in the future, including nearly 60% of the CAM nonconsumers. Participants who had more experience with CAM, greater perceived control over their symptoms, and were dissatisfied with conventional health care, were more likely to express intentions to use CAM should they experience access difficulties in the future. By situating the motivations for CAM within the context of physician availability our findings highlight the importance of geographical context, or place, for understanding attitudes towards CAM and its utilisation.

Objective: This study investigates the association between ethnic minority status and receiving a screening mammogram within the past 2 years among American women over 50., Method: The findings from 33 studies identified from interdisciplinary research databases (1980 to 2006) were synthesized. Separate pooled analyses compared white non-Hispanics to African Americans (28 outcomes), Hispanics (18 outcomes), and Asian/Pacific Islanders (10 outcomes)., Results: Using the random effects model, results showed that African Americans were screened less than white non-Hispanics at a marginal level (OR 0.87, 95% CI 0.75, 1.00). Larger and significant discrepancies were observed for Hispanics (OR 0.65, 95% CI 0.50, 0.85) and Asian/Pacific Islanders (OR 0.63, 95% CI 0.39, 0.99) compared to white non-Hispanics. However, among studies controlling for socioeconomic status, ethnic differences in mammography screening were no longer significant for African Americans (OR 1.05, 95% CI 0.71, 1.76), Hispanics (OR 1.08, 95% CI 0.64, 1.93), or Asian/Pacific Islanders (OR 1.08, 95% CI 0.64, 1.93). Subgroup analyses further showed that geographical region, sampling method, and data collection strategy significantly impacted results., Conclusions: This study found evidence that ethnic minority-screening mammography differences exist but were impacted by socioeconomic status. Implications for interpreting existing knowledge and future research needs are discussed.

Environmental monitoring indicates that the distribution of alcohol ethoxylate (AE) homologues in wastewater treatment plant (WWTP) effluents differs from the distribution in commercial AE products, with a relative higher proportion of fatty alcohol (AOH, which is AE with zero ethoxylation). To determine the contribution of AE-derived AOH to the total concentration of AE and AOH in WWTP effluents, we conducted a laboratory continuous activated-sludge study (CAS). This consisted of a test unit fed with AE-amended synthetic sewage and a control unit fed with only synthetic sewage to avoid AE contamination from the feed. The removal efficiencies of some 114 AE homologues were determined by the application of a specific and sensitive analytical method. The extent of the removal of AE ranged from 99.70% for C18 compounds to > 99.98% for C12-16. Relatively high-AOH concentrations were observed in the effluents from blank and test units. By building the concentration difference from the test minus the control unit, the AE in the CAS effluent originating from AE in the influent was determined. Thus, it could be shown that AOH represented only 19% of the total AE (EO0-18) in the CAS, while monitoring in 29 WWTP effluents (European, Canadian, and US) revealed in total a mean AOH fraction of 55% (5-82%) of the total AE (EO0-18). This shows that only a small fraction of AOH in WWTP effluents originates from AE entering the WWTP.

Twenty-one postoperative patients with transposition of the great arteries (TGA) underwent graded exercise testing 4 to 15 years (mean 9) after the Mustard operation. No patient had subjective exercise intolerance before testing, although some had symptomatic resting arrhythmias. Correlations were made between cardiac catheterization data and 24-hour ambulatory monitoring. Exercise tolerance was diminished in nearly half of the patients. No statistically significant differences were found in heart rate or blood pressure responses, but maximal oxygen consumption values were lower than the control values (p less than 0.001) in the larger patients. Arrhythmias were present or provoked in most patients during exercise testing. Only 28% remained in normal sinus rhythm during and after exercise. Multifocal premature contractions were the most serious arrhythmias demonstrated. Some long-term survivors of the Mustard operation may have abnormal exercise dynamics, even though they may be asymptomatic and have normal physical activities and endurance. Mean maximal systolic blood pressure, heart rate, oxygen consumption, and maximal treadmill times were consistently in the low-normal range or were statistically lower than normal.