Manipulating the selection forces during affinity maturation to generate cross-reactive HIV antibodies.

Generation of potent antibodies by a mutation-selection process called affinity maturation is a key component of effective immune responses. Antibodies that protect against highly mutable pathogens must neutralize diverse strains. Developing effective immunization strategies to drive their evolution requires understanding how affinity maturation happens in an environment where variants of the same antigen are present. We present an in silico model of affinity maturation driven by antigen variants which reveals that induction of cross-reactive antibodies often occurs with low probability because conflicting selection forces, imposed by different antigen variants, can frustrate affinity maturation. We describe how variables such as temporal pattern of antigen administration influence the outcome of this frustrated evolutionary process. Our calculations predict, and experiments in mice with variant gp120 constructs of the HIV envelope protein confirm, that sequential immunization with antigen variants is preferred over a cocktail for induction of cross-reactive antibodies focused on the shared CD4 binding site epitope.

The joy of surgery: how surgeons experience joy, time, and support.

BACKGROUND: Burnout is a crisis in medicine, and especially in surgery it has serious implications not only for physician well-being but also for patient outcomes. This study builds on previous SAGES Reimagining the Practice of Surgery Task Force work to better understand how organizations might intervene to increase the "joy in surgery." METHODS: This was a cross-sectional, descriptive study utilizing a REDCap survey with closed-ended questions for data collection across 5 domains: facilitators of joy, support for best work, time for work tasks, barriers to joy, and what they would do with more time. We calculated average scores and "percentage of respondents giving a high score" for each item. RESULTS: There were 307 individuals who started the survey; 223 completed it and were surgeons who met the inclusion criteria. The majority (85.7%) were trained in general surgery, regardless of sub-specialty. Surgeons found joy in operating and its technical skills, curing disease, patient relationships, and working with a good team. They reported usually having what they needed to deliver care. A majority felt valued and respected. Most were dissatisfied with reimbursement, perceiving it as unfair. The most commonly worked range of hours was 51-70 per week. They reported having little time for paperwork and documentation, and if they had more time, they would spend it with friends and family. CONCLUSION: Organizations should consider interventions to address the operative environment, provide appropriate staff support, and foster good teamwork. They can also consider interventions that alleviate time pressures and administrative burden while at the same time promoting sustainable workloads.

The joy of surgery: how gender influences surgeons' experiences.

INTRODUCTION: Burnout in medicine is an epidemic, and surgeons are not immune. Studies often focus on negative factors leading to burnout, with less emphasis on optimizing joy. The purpose of this study, conducted by the SAGES Reimagining the Practice of Surgery Task Force, was to explore how gender may influence surgeon well-being to better inform organizational change. METHODS: The study team developed a survey with the domains: facilitators of joy, support for best work, time for work tasks, barriers to joy, and what they would do with more time. The survey was emailed to 5777 addresses on the SAGES distribution list. Results were analyzed by calculating summary statistics. RESULTS: 223 surgeons completed the survey; 62.3% identified as men, 32.3% as women, and 5.4% did not indicate gender. Female compared to male respondents were younger (41.6 vs 52.5 years) and had practiced for fewer years (8.4 vs 19.4 years). The three greatest differences in facilitators of joy were being a leader in the field, leading clinical teams, and teaching, with a > 10 percentage point difference between men/women rating these highly (score of ≥ 8). Women generally perceived less support from their institutions than men. The greatest gender difference was in support for teaching, with 52.8% of men rating this highly compared to 30.2% of women. Only 52% of women felt respected by coworkers most of the time compared to 68.3% of men. Most (96.0%) respondents (men 95.7% and women 98.6%) reported wanting more time with family and friends. CONCLUSION: This study demonstrates the complexity of the personal and professional factors that influence joy in surgery, highlight gender differences that impact joy and suggests opportunities for improved gender-based support. These results can inform potential organization-level changes and further research to better understand emerging differences in joy across gender identities.

Factors influencing surgeon well-being: qualitatively exploring the joy of surgery.

BACKGROUND: There has been considerable research into burnout but much less into how surgeons thrive and find joy. This study, conducted by the SAGES Reimagining the Practice of Surgery Task Force, explored factors influencing surgeon well-being, the eventual goal being translating findings into tangible changes to help restore the joy in surgery. METHODS: This was a qualitative, descriptive study. Purposive sampling ensured representation across ages, genders, ethnicities, practice types, and geographies. Semi-structured interviews were recorded and transcribed. We coded inductively, finalized the codebook by consensus, and then constructed a thematic network. Global themes formed our conclusions; organizing themes gave additional detail. Analysis was facilitated by NVivo. RESULTS: We interviewed 17 surgeons from the US and Canada. Total interview time was 15 hours. Our global and organizing themes were: Stressors (Work-life Integration, Administration-related Concerns, Time and Productivity Pressures, Operating Room Factors, and Lack of Respect). Satisfaction (Service, Challenge, Autonomy, Leadership, and Respect and Recognition). Support (Team, Personal Life, Leaders, and Institutions). Values (Professional and Personal). Suggestions (Individual, Practice, and System level). Values, stressors, and satisfaction influenced perspectives on support. Experiences of support shaped suggestions. All participants reported stressors and satisfiers. Surgeons at all stages enjoyed operating and being of service. Supports and suggestions included compensation and infrastructure, but human resources were most critical. To experience joy, surgeons needed high-functioning clinical teams, good leaders/mentors, and supportive family/social networks. CONCLUSIONS: Our results indicated organizations could (1) better understand surgeons' values, like autonomy; (2) provide more time for satisfiers, like patient relationship building; (3) minimize stressors, like time and financial pressures; and (4) at all levels focus on (4a) building teams and leaders and (4b) giving surgeons time and space for healthy family/social lives. Next steps include developing an assessment tool for individual institutions to build "joy improvement plans" and to inform surgical associations' advocacy efforts.

Implementation of entrustable professional activities into fellowship council accredited programs: a pilot project.

OBJECTIVE: The Fellowship Council (FC) is transitioning to a competency-based medical education (CBME) model, including the introduction of Entrustable Professional Activities (EPAs) for training and assessment of Fellows. This study describes the implementation process employed by the FC during a ten-month pilot project and presents data regarding feasibility and perceived value. METHODS: The FC coordinated the development of EPAs in collaboration with the sponsoring societies for Advanced GI/MIS, Bariatrics, Foregut, Endoscopy and Hepatopancreaticobiliary (HPB) fellowships encompassing the preoperative, intraoperative, and postoperative phases of care for key competencies. Fifteen accredited fellowship programs participated in this project. The assessments were collected through a unique platform on the FC website. Programs were asked to convene a Clinical Competency Committee (CCC) on a quarterly basis. The pilot group met monthly to support and improve the process. An exit survey evaluated the perceived value of EPAs. RESULTS: The 15 participating programs included 18 fellows and 106 faculty. A total of 655 assessments were initiated with 429 (65%) completed. The average (SD) number of EPAs completed for each fellow was 24(18); range 0-72. Intraoperative EPAs were preferentially completed (71%). The average(SD) time for both the fellow and faculty to complete an EPA was 27(78) hours. Engagement increased from 39% of fellows completing at least one EPA in September to 72% in December and declining to 50% in May. Entrustment level increased from 6% of EPAs evaluated as "Practice Ready" in September to 75% in June. The exit survey was returned by 63% of faculty and 72% of fellows. Overall, 46% of fellows and 74% of program directors recommended full-scale implementation of the EPA framework. CONCLUSION: A competency-based assessment framework was developed by the FC and piloted in several programs. Participation was variable and required ongoing strategies to address barriers. The pilot project has prepared the FC to introduce CBME across all FC training programs.

EVALUATION OF ß-HYDROXYBUTYRATE, AMINO ACIDS, AND SELECTED CHEMISTRY VALUES IN THE PLASMA OF FREE-RANGING RED-TAILED HAWKS (BUTEO JAMAICENSIS).

The red-tailed hawk (Buteo jamaicensis) is a raptor species native to North America that is commonly presented to wildlife rehabilitators and veterinarians, but little is known about biomarkers of metabolic status in this species. This study evaluates plasma ß-hydroxybutyrate (BHB) and free amino acids in 24 free-ranging red-tailed hawks in good body condition in order to establish reference intervals for these values. Standard biochemical analytes were also measured. The mean plasma BHB level measured was 13.9 mg/dl. Plasma amino acids were not similar to the few available reports in avian species. Standard biochemical analytes were similar to those previously reported for red-tailed hawks. These data serve as a foundation for further investigation into the use of these biomarkers to assess metabolic status of this species in health and disease.

The association between video-based assessment of intraoperative technical performance and patient outcomes: a systematic review.

BACKGROUND: Efforts to improve surgical safety and outcomes have traditionally placed little emphasis on intraoperative performance, partly due to difficulties in measurement. Video-based assessment (VBA) provides an opportunity for blinded and unbiased appraisal of surgeon performance. Therefore, we aimed to systematically review the existing literature on the association between intraoperative technical performance, measured using VBA, and patient outcomes. METHODS: Major databases (Medline, Embase, Cochrane Database, and Web of Science) were systematically searched for studies assessing the association of intraoperative technical performance measured by tools supported by validity evidence with short-term (≤ 30 days) and/or long-term postoperative outcomes. Study quality was assessed using the Newcastle-Ottawa Scale. Results were appraised descriptively as study heterogeneity precluded meta-analysis. RESULTS: A total of 11 observational studies were identified involving 8 different procedures in foregut/bariatric (n = 4), colorectal (n = 4), urologic (n = 2), and hepatobiliary surgery (n = 1). The number of surgeons assessed ranged from 1 to 34; patient sample size ranged from 47 to 10,242. High risk of bias was present in 5 of 8 studies assessing short-term outcomes and 2 of 6 studies assessing long-term outcomes. Short-term outcomes were reported in 8 studies (i.e., morbidity, mortality, and readmission), while 6 reported long-term outcomes (i.e., cancer outcomes, weight loss, and urinary continence). Better intraoperative performance was associated with fewer postoperative complications (6 of 7 studies), reoperations (3 of 4 studies), and readmissions (1 of 4 studies). Long-term outcomes were less commonly investigated, with mixed results. CONCLUSION: Current evidence supports an association between superior intraoperative technical performance measured using surgical videos and improved short-term postoperative outcomes. Intraoperative performance analysis using video-based assessment represents a promising approach to surgical quality-improvement.

Disseminated coelomic xanthogranulomatosis in eclectus parrots (Eclectus roratus) and budgerigars (Melopsittacus undulatus).

Xanthogranulomatosis is an inflammatory lesion characterized by lipid-containing macrophages, extracellular lipid, hemorrhage, and necrosis. We describe disseminated intracoelomic xanthogranulomatosis in 5 eclectus parrots (Eclectus roratus) and 2 budgerigars (Melopsittacus undulatus). Postmortem, clinicopathologic, and historical case material was reviewed. Ages ranged from 3 to 24 years; there were 5 males and 2 females. Table food was included in the diet of 3/5 cases, and animal products were included in 2/3 cases. Common clinicopathologic abnormalities included leukocytosis (4/5 cases) and elevated concentrations of bile acids (3/4 cases) and cholesterol within 6 months prior to death (2/4 cases). At postmortem examination, all 7 birds had grossly visible, irregular, soft, tan to yellow, amorphous plaques distributed on the surfaces of the viscera and body wall. Histologic evaluation and oil red O stain revealed xanthogranulomatous inflammation with phagocytized and extracellular lipid, necrosis, cholesterol clefts, fibrosis, and mineralization. Infectious agents were not identified with special stains in all cases. Concurrent hepatobiliary disease was present in 6/7 cases, and 6/7 had lipid accumulation within the parenchyma of various visceral organs. Five cases had atherosclerosis of great vessels. We describe a unique form of disseminated coelomic xanthogranulomatosis in 2 psittacine species. This condition should be recognized as a differential diagnosis in cases of disseminated coelomic mass formation and coelomic distension in psittacine birds, particularly in eclectus parrots and budgerigars.

Pelvic Reconstruction following Abdominoperineal Resection and Pelvic Exenteration: Management Practices among Plastic and Colorectal Surgeons.

BACKGROUND: Pelvic reconstruction with a muscle flap significantly improves postoperative outcomes following abdominoperineal resection (APR). Despite it being the gold standard, significant surgeon-selection bias remains with respect to the necessity of pelvic obliteration, flap choice, and ostomy placement. The objective of the study was to characterize management practices among colorectal surgeons (CSs) and plastic surgeons (PSs). METHODS: Specialty-specific surveys were distributed electronically to CSs and PSs via surgical societies. Surveys were designed to illustrate geographic and specialty-specific differences in management. RESULTS: Of 106 (54 CSs and 52 PSs) respondents (58% Canada, 21% Europe, 14% the United States, and 6% Asia/Africa), significant interdisciplinary differences in practices were observed. Most respondents indicated that multidisciplinary meetings were not performed (74% of CSs and 78% of PSs). For a nonradiated pelvic dead space with small perineal defect, 91% of CSs and 56% of PSs indicated that flap reconstruction was not required. For a radiated pelvic dead space with small perineal defect, only 54% of CSs and 6% of PSs indicated that there was no need for flap reconstruction. With respect to ostomy placement, 87% of CSs and 21% of PSs indicated that stoma placement through the rectus was superior. When two ostomies were required, most CSs preferred exteriorizing ostomies through bilateral recti and requesting thigh-based reconstruction. PSs favored the vertical rectus abdominis muscle (VRAM; 52%) over the gracilis (23%) and inferior gluteal artery perforator (IGAP; 23%) flaps. Among PSs, North Americans favor abdominally based flaps (VRAM 60%), while Europeans favor gluteal-based flaps (IGAP 78%). CONCLUSION: A lack of standardization continues to exist with respect to the reconstruction of pelvic defects following APR and pelvic exenteration. Geographic and interdisciplinary biases with respect to ostomy placement, flap choice, and role for pelvic obliteration continues to influence reconstructive practices. These cases should continue to be approached on a case by case basis, driven by pathology, presence of radiation, comorbidities, and the size of the pelvic and perineal defect.

Imaging features of disseminated xanthogranulomatous inflammation in eclectus parrots (Eclectus roratus).

Xanthogranulomatous disease is a rare condition, which can be caused by infection, inflammation, hemorrhage, immunologic disease, or inherited lysosomal disorders. It is characterized by non-intracellular lipid and cholesterol deposits among an inflammatory infiltrate of vacuolated macrophages and giant cells. The diagnosis of xanthogranulomatous disease is challenging, with nonspecific imaging findings often misinterpreted as aggressive neoplastic processes in humans. In this retrospective case series study, we describe the diagnostic imaging characteristics of a disseminated xanthogranulomatous condition identified in five eclectus parrots (Eclectus roratus). Decreased serosal detail and celomic distension were present in all three birds radiographed, with multifocal variably sized celomic mineralization (3/3 birds), and extracelomic mineralized masses (1/3 birds). Celomic effusion with foci of celomic mineralization and hepatomegaly were identified in all birds (3/3) imaged with ultrasound. Finally, a mineralized mural ventricular mass was present in one of three patients imaged with CT, multifocal celomic mineralization with moderate to severe celomic effusion in two of three patients, diffuse severe proventricular and intestinal dilation in all three patients, and atherosclerosis of the major arterial trunks in all three patients. Veterinary radiologists should be aware of this inflammatory condition in birds, especially in eclectus parrots, and should be able to recognize the imaging features of xanthogranulomatous inflammation.

Contribution of Family Relatedness to Neurobehavioral Comorbidities in Idiopathic Childhood Epilepsies.

OBJECTIVES: Rates of cognitive, academic and behavioral comorbidities are elevated in children with epilepsy. The contribution of environmental and genetic influences to comorbidity risk is not fully understood. This study investigated children with epilepsy, their unaffected siblings, and controls to determine the presence and extent of risk associated with family relatedness across a range of epilepsy comorbidities. METHODS: Participants were 346 children (8-18 years), n=180 with recent-onset epilepsy, their unaffected siblings (n=67), and healthy first-degree cousin controls (n=99). Assessments included: (1) Child Behavior Checklist/6-18 (CBCL), (2) Behavior Rating Inventory of Executive Function (BRIEF), (3) history of education and academic services, and (4) lifetime attention deficit hyperactivity disorder (ADHD) diagnosis. Analyses consisted of linear mixed effect models for continuous variables, and logistic mixed models for binary variables. RESULTS: Differences were detected between the three groups of children across all measures (p<.001). For ADHD, academic problems, and executive dysfunction, children with epilepsy exhibited significantly more problems than unaffected siblings and controls; siblings and controls did not differ statistically significantly from each other. For social competence, children with epilepsy and their unaffected siblings displayed more abnormality compared with controls, with no statistically significant difference between children with epilepsy and unaffected siblings. For behavioral problems, children with epilepsy had more abnormality than siblings and controls, but unaffected siblings also exhibited more abnormalities than controls. CONCLUSIONS: The contribution of epilepsy and family relatedness varies across specific neurobehavioral comorbidities. Family relatedness was not significantly associated with rates of ADHD, academic problems and executive dysfunction, but was associated with competence and behavioral problems. (JINS, 2018, 24, 653-661).

Generation of Long-Lived Bone Marrow Plasma Cells Secreting Antibodies Specific for the HIV-1 gp41 Membrane-Proximal External Region in the Absence of Polyreactivity.

UNLABELLED: An effective preventive vaccine is highly sought after in order to stem the current HIV-1 pandemic. Both conservation of contiguous gp41 membrane-proximal external region (MPER) amino acid sequences across HIV-1 clades and the ability of anti-MPER broadly neutralizing antibodies (BNAbs) to block viral hemifusion/fusion establish the MPER as a prime vaccination target. In earlier studies, we described the development of an MPER vaccine formulation that takes advantage of liposomes to array the MPER on a lipid bilayer surface, paralleling its native configuration on the virus membrane while also incorporating molecular adjuvant and CD4 T cell epitope cargo. Here we demonstrate that several immunizations with MPER/liposomes induce high levels of bone marrow long-lived plasma cell (LLPC) antibody production. Single-cell immunoglobulin gene retrieval analysis shows that these plasma cells are derived from a germ line repertoire of B cells with a diverse representation of immunoglobulin genes, exhibiting antigen-driven positive selection. Characterization of LLPC recombinant monoclonal antibodies (rMAbs) indicates that antigen recognition is achieved through convergence on a common epitopic focus by utilizing various complementarity-determining region H3 (CDRH3) lengths. Importantly, the vast majority of rMAbs produced from these cells lack polyreactivity yet manifest antigen specificity in the context of lipids, shaping MPER-specific paratopes through selective pressure. Taken together, these findings demonstrate that the MPER is a vaccine target with minimal risk of generating off-target autoimmunity. IMPORTANCE: A useful vaccine must generate desired long-term, antigen-specific antibody responses devoid of polyreactivity or autoreactivity. The common polyreactive features of some HIV-1 BNAbs have raised concern about elicitation of anti-MPER antibodies. Utilizing single-LLPC repertoire analysis and biophysical characterization of anti-MPER rMAbs, we show that their fine specificities require a structural fitness of the antibody combining site involving heavy and light chain variable domains shaped by somatic hypermutation and affinity maturation of B cells in the germinal center. Perhaps more importantly, our results demonstrate that the majority of MPER-specific antibodies are not inherently polyspecific and/or autoreactive, suggesting that polyreactivity of MPER-specific antibodies is separable from their antigen specificity.

Informed consent for surgery: risk discussion and documentation.

SUMMARY: Informed consent for surgery has become a critical component of surgical practice. There are specific legal requirements for what has to be disclosed to patients and for the accompanying documentation. The hospital consent for surgery form with the patient's signature is a small part of the process. A quality assurance review of the documentation of informed consent by our surgical group indicated major deficiencies and prompted this article (and its Appendix containing further information). Our intent was to inform surgeons about modern standards and to discuss particular challenges. Informed consent for surgery entails what surgeons communicate to their patients about the proposed surgery and is a key element in the trust patients have in surgeons. It is of increasing importance, and we must keep up to date with patient and legal expectations.

A Matter of Life and Death: End-of-Life Simulation to Develop Confidence in Nursing Students.

The use of simulation to provide end-of-life (EOL) education is a means to enhance self-efficacy levels among nursing students. The purpose of this exploratory study was to evaluate self-efficacy levels of nursing students and recent graduate nurses following an EOL simulation experience. Data were obtained using the Simulation Effectiveness Tool developed by Medical Education Technologies, Inc.; 72 participants in three groups completed the study. Moderate to strong levels of confidence in providing EOL care were found following the simulation experience; observations by the researcher and unsolicited participant statements supported the findings. Results of the study support EOL simulation as an effective and sustainable teaching modality for enhancing self-efficacy levels when managing EOL events.

Hair epilation versus surgical excision as primary management of pilonidal disease in the pediatric population.

Pilonidal disease is a chronic, acquired inflammatory process of the skin due to entrapped hair at the natal cleft. Reported recurrence rates are as high as 30%, and recurrence has been attributed to persistent hair near the surgical site. Although conservative measures, such as meticulous hair control and improved perineal hygiene, have been shown to be effective, these techniques typically require much effort on behalf of the patient. Laser hair epilation (LE) might solve this issue of poor patient compliance while helping patients to avoid surgical excision. In this article, we discuss recurrence rates of pilonidal disease in children treated with LE versus surgical excision in relation to findings from our institution between 2005 and 2013 as well as patient satisfaction with the treatment method.

Immunogenicity of membrane-bound HIV-1 gp41 membrane-proximal external region (MPER) segments is dominated by residue accessibility and modulated by stereochemistry.

Structural characterization of epitope-paratope pairs has contributed to the understanding of antigenicity. By contrast, few structural studies relate to immunogenicity, the process of antigen-induced immune responses in vivo. Using a lipid-arrayed membrane-proximal external region (MPER) of HIV-1 glycoprotein 41 as a model antigen, we investigated the influence of physicochemical properties on immunogenicity in relation to structural modifications of MPER/liposome vaccines. Anchoring the MPER to the membrane via an alkyl tail or transmembrane domain retained the MPER on liposomes in vivo, while preserving MPER secondary structure. However, structural modifications that affected MPER membrane orientation and antigenic residue accessibility strongly impacted induced antibody responses. The solvent-exposed MPER tryptophan residue (Trp-680) was immunodominant, focusing immune responses, despite sequence variability elsewhere. Nonetheless, immunogenicity could be readily manipulated using site-directed mutagenesis or structural constraints to modulate amino acid surface display. These studies provide fundamental insights for immunogen design aimed at targeting B cell antibody responses.

Antigen delivery by lipid-enveloped PLGA microparticle vaccines mediated by in situ vesicle shedding.

Lipid-coated poly(lactide-co-glycolide) microparticles (LCMPs) consist of a solid polymer core wrapped by a surface lipid bilayer. Previous studies demonstrated that immunization with LCMPs surface-decorated with nanograms of antigen elicit potent humoral immune responses in mice. However, the mechanism of action for these vaccines remained unclear, as LCMPs are too large to drain efficiently to lymph nodes from the vaccination site. Here, we characterized the stability of the lipid envelope of LCMPs and discovered that in the presence of serum the lipid coating of the particles spontaneously delaminates, shedding antigen-displaying vesicles. Lipid delamination generated 180 nm liposomes in a temperature- and lipid/serum-dependent manner. Vesicle shedding was restricted by inclusion of high-TM lipids or cholesterol in the LCMP coating. Administration of LCMPs bearing stabilized lipid envelopes generated weaker antibody responses than those of shedding-competent LCMPs, suggesting that in situ release of antigen-loaded vesicles plays a key role in the remarkable potency of LCMPs as vaccine adjuvants.

Nursing students' perspectives on being work-ready with electronic medical records: Intersections of rurality and health workforce capacity.

AIM: To explore nursing students' views on being prepared for using electronic medical records during clinical placement. BACKGROUND: The need for an undergraduate nursing curriculum to include electronic medical record training has been internationally recognised, however successful implementation has been inconsistent worldwide and limited in Australia. Many nursing students are unprepared to effectively provide care during clinical placement using electronic medical records and are therefore not work-ready as registered nurses. DESIGN: Online survey. METHODS: Third-year nursing students from two multi-campus universities were invited to complete the survey. RESULTS: Most students believed that learning electronic medical records during simulations would be extremely or very useful. Student confidence levels correlate with the amount and type of exposure to electronic medical records prior to clinical placement. Four themes emerged from qualitative analysis: Don't throw out the baby with the bathwater; Prepare us for practice; Mistakes - hardly any; and Universities need to catch up and put out. CONCLUSION: Students receiving hospital-based education on eMR and eObs can improve student confidence in preparation for clinical practice. First-year optional eMR university education had a limited impact on students' perception of preparedness for clinical practice. Shared responsibility between both the universities and health services on eMR education would provide improved student confidence and preparedness for clinical practice. This study supports the international research that eMR education needs to be scaffolded over the three years of study with increasing complexity of real-life scenarios.

An oral cholera vaccine in the prevention and/or treatment of inflammatory bowel disease.

The oral cholera vaccine WC-rBS consists of 4 different inactivated strains of Vibrio cholerae (LPS source) admixed with recombinant cholera toxin B subunit. Because of its unique composition and anti-inflammatory properties reported for both CTB and low doses of LPS from other Gram-negative bacteria, we speculated that WC-rBS might have anti-inflammatory potential in a chronic autoimmune disease such as inflammatory bowel diseases. First in vitro endotoxin tolerance experiments showed the surprising WC-rBS potential in the modulation of inflammatory responses on both PBMCs and THP1 cells. WC-rBS was further evaluated in the Dextran Sodium Sulfate colitis mouse model. Administrated orally at different dosages, WC-rBS vaccine was safe and showed immunomodulatory properties when administered in a preventive mode (before and during the induction of DSS colitis) as well as in a curative mode (after colitis induction); with improvement of disease activity index (from 27 to 73%) and histological score (from 65 to 88%). Interestingly, the highest therapeutic effect of WC-rBS vaccine was observed with the lowest dosage, showing even better anti-inflammatory properties than mesalamine; an approved 5-aminosalicylic acid drug for treating IBD patients. In summary, this is the first time that a prophylactic medicine, safe and approved for prevention of an infectious disease, showed a benefit in an inflammatory bowel disease model, potentially offering a novel therapeutic modality for IBD patients.