Peer review journal publication rates of award-winning presentations from a multi-disciplinary multi-institutional medical education consortium annual research forum: 40-year experience.

INTRODUCTION: Resident research has been mandated by the Accreditation Council of Graduate Medical Education across all specialties. Southeast Michigan Center for Medical Education (SEMCME) has an annual Research Forum for resident competition, and we assessed the publication status of award-winning presentations. METHODS: The SEMCME Research Forum's winning presentations from 1978 to 2018 were reviewed. The author's information and keywords from the abstract's title were used to search PubMed and Google Scholar databases for publications. Descriptive statistics were generally used to characterize the data. RESULTS: Of 147 winning projects, 62% (78/126) were oral and 48% (10/21) were poster presentations; 88 (60%) were published. Obstetrics and gynecology had the highest publication rate (71%), followed by surgical (61%) and medical specialties (48%). CONCLUSION: While 60% of the award-winning presentations at the SEMCME Research Forum were published, more work needs to be done to examine the barriers preventing the publication of the remaining projects.

Incentives as a Driving Force for Scholarly Activity in General Surgery Training: Survey of Program Directors and our Institution's Experience.

INTRODUCTION: Scholarly activity in a few of the domains is required for both residents and faculty per Accreditation Council for Graduate Medical Education's Common Program Requirements. Increased burden in clinical activities and economic changes in the health care environment have created new challenges, which have negatively affected faculty and residents to participate in scholarly activity. Various avenues are being sought which might help in improving the scholarly activity in an institution by providing dedicated time, salaried positions, grants, paid conferences, and financial incentives. METHODS: A survey was sent to program directors of surgery residency programs in 2020 to evaluate the impact of financial incentives on scholarly activity. Data was analyzed on SPSS 20, and descriptive statistics using frequencies and percentages were done. RESULTS: Out of 230 surveys sent, 80 (35%) program directors responded (35%). 52 (65%) of respondents were from university hospitals and 28 (35%) were from community hospitals. Both the faculty and residents were required to publish in 56 (70%) of the institutions surveyed. 59 (73.7%) considered a PubMed publication as a scholarly activity. Only 9 (11%) programs were supportive of residents being involved in research activities that had a designated rotation. 48 (60%) respondents stated that residents and faculty would be more likely to pursue research endeavors if they were provided some form of financial incentive, but only 9 (11%) had some sort of incentive program in place. CONCLUSION: Given the results of the survey, there is a need to seek uniform, acceptable, and sustainable alternative incentive programs to help promote and increase the scholarly activity of residents and faculty.

Disruption of Cross-Feeding Inhibits Pathogen Growth in the Sputa of Patients with Cystic Fibrosis.

A critical limitation in the management of chronic polymicrobial infections is the lack of correlation between antibiotic susceptibility testing (AST) and patient responses to therapy. Underlying this disconnect is our inability to accurately recapitulate the in vivo environment and complex polymicrobial communities in vitro However, emerging evidence suggests that, if modeled and tested accurately, interspecies relationships can be exploited by conventional antibiotics predicted to be ineffective by standard AST. As an example, under conditions where Pseudomonas aeruginosa relies on cocolonizing organisms for nutrients (i.e., cross-feeding), multidrug-resistant P. aeruginosa may be indirectly targeted by inhibiting the growth of its metabolic partners. While this has been shown in vitro using synthetic bacterial communities, the efficacy of a "weakest-link" approach to controlling host-associated polymicrobial infections has not yet been demonstrated. To test whether cross-feeding inhibition can be leveraged in clinically relevant contexts, we collected sputa from cystic fibrosis (CF) subjects and used enrichment culturing to isolate both P. aeruginosa and anaerobic bacteria from each sample. Predictably, both subpopulations showed various antibiotic susceptibilities when grown independently. However, when P. aeruginosa was cultured and treated under cooperative conditions in which it was dependent on anaerobic bacteria for nutrients, the growth of both the pathogen and the anaerobe was constrained despite their intrinsic antibiotic resistance profiles. These data demonstrate that the control of complex polymicrobial infections may be achieved by exploiting obligate or facultative interspecies relationships. Toward this end, in vitro susceptibility testing should evolve to more accurately reflect in vivo growth environments and microbial interactions found within them.IMPORTANCE Antibiotic efficacy achieved in vitro correlates poorly with clinical outcomes after treatment of chronic polymicrobial diseases; if a pathogen demonstrates susceptibility to a given antibiotic in the lab, that compound is often ineffective when administered clinically. Conversely, if a pathogen is resistant in vitro, patient treatment with that same compound can elicit a positive response. This discordance suggests that the in vivo growth environment impacts pathogen antibiotic susceptibility. Indeed, here we demonstrate that interspecies relationships among microbiotas in the sputa of cystic fibrosis patients can be targeted to indirectly inhibit the growth of Pseudomonas aeruginosa The therapeutic implication is that control of chronic lung infections may be achieved by exploiting obligate or facultative relationships among airway bacterial community members. This strategy is particularly relevant for pathogens harboring intrinsic multidrug resistance and is broadly applicable to chronic polymicrobial airway, wound, and intra-abdominal infections.

Cross-feeding modulates antibiotic tolerance in bacterial communities.

Microbes frequently rely on metabolites excreted by other bacterial species, but little is known about how this cross-feeding influences the effect of antibiotics. We hypothesized that when species rely on each other for essential metabolites, the minimum inhibitory concentration (MIC) for all species will drop to that of the "weakest link"-the species least resistant in monoculture. We tested this hypothesis in an obligate cross-feeding system that was engineered between Escherichia coli, Salmonella enterica, and Methylobacterium extorquens. The effect of tetracycline and ampicillin were tested on both liquid and solid media. In all cases, resistant species were inhibited at significantly lower antibiotic concentrations in the cross-feeding community than in monoculture or a competitive community. However, deviation from the "weakest link" hypothesis was also observed in cross-feeding communities apparently as result of changes in the timing of growth and cross-protection. Comparable results were also observed in a clinically relevant system involving facultative cross-feeding between Pseudomonas aeruginosa and an anaerobic consortium found in the lungs of cystic fibrosis patients. P. aeruginosa was inhibited by lower concentrations of ampicillin when cross-feeding than when grown in isolation. These results suggest that cross-feeding significantly alters tolerance to antibiotics in a variety of systems.

Relationship of Blood Metal Ion Levels and Leukocyte Profiles in Patients With Articular Surface Replacement Metal-on-Metal Hip Replacement.

The purpose of this study was to compare blood leukocyte profiles and metal ion concentrations between hip resurfacing arthroplasty (articular surface replacement) patients with and without revision. A total of 25 articular surface replacement patients were recruited (10 with stable implants and 15 undergoing revision). Blood concentrations of chromium (Cr) and cobalt (Co) were measured. Flow cytometry was used to quantify the subpopulations of leukocytes, including CD14+ monocytes, CD16+ monocytes, CD3+ T-lymphocytes, CD19+ B-lymphocytes, CD4+ helper T-cells, and CD45+RA memory vs naïve T-cells. Patients undergoing revision had higher blood Co (mean, 10.85 µg/L) and Cr (mean, 3.19 µg/L) levels than patients with stable implants (mean Co, 3.06 µg/L; mean Cr, 1.07 µg/L) (P<.05). The number of CD4+ helper T-cells was higher in patients with stable implants (mean, 842±311 cells/µL) than in patients undergoing revision (mean, 591±208 cells/µL) (P<.05). There was a significant association between total metal ion levels (Co+Cr) and the number of CD14+ monocytes (P=.045) and inflammatory CD16+ monocytes (P=.046). The authors observed that the increase in blood metal ions was associated with an increase in CD16+ monocytes. They believe that continued analysis of blood leukocyte profiles may be helpful in defining differences among failed articular surface replacement, stable articular surface replacement, and failed metal-on-polyethylene implants. [Orthopedics. 2018; 41(3):e424-e431.].

Genome-Wide Survey of Pseudomonas aeruginosa PA14 Reveals a Role for the Glyoxylate Pathway and Extracellular Proteases in the Utilization of Mucin.

Chronic airway infections by the opportunistic pathogen Pseudomonas aeruginosa are a major cause of mortality in cystic fibrosis (CF) patients. Although this bacterium has been extensively studied for its virulence determinants, biofilm growth, and immune evasion mechanisms, comparatively little is known about the nutrient sources that sustain its growth in vivo Respiratory mucins represent a potentially abundant bioavailable nutrient source, although we have recently shown that canonical pathogens inefficiently use these host glycoproteins as a growth substrate. However, given that P. aeruginosa, particularly in its biofilm mode of growth, is thought to grow slowly in vivo, the inefficient use of mucin glycoproteins may be relevant to its persistence within the CF airways. To this end, we used whole-genome fitness analysis, combining transposon mutagenesis with high-throughput sequencing, to identify genetic determinants required for P. aeruginosa growth using intact purified mucins as a sole carbon source. Our analysis reveals a biphasic growth phenotype, during which the glyoxylate pathway and amino acid biosynthetic machinery are required for mucin utilization. Secondary analyses confirmed the simultaneous liberation and consumption of acetate during mucin degradation and revealed a central role for the extracellular proteases LasB and AprA. Together, these studies describe a molecular basis for mucin-based nutrient acquisition by P. aeruginosa and reveal a host-pathogen dynamic that may contribute to its persistence within the CF airways.

The Effect of Comorbidities on Discharge Disposition and Readmission for Total Joint Arthroplasty Patients.

BACKGROUND: As the annual demand and number of total joint arthroplasty cases increase, so do concerns of outcomes of patient with specific comorbidities relative to outcomes and costs of care. METHODS: The study cohort included 2009 primary total knee arthroplasty (TKA) patients and 905 total hip arthroplasty patients. Discharge disposition was classified as discharge to any facility or home. The comorbidities of the patients who were readmitted and those without a 90-day event were also evaluated. RESULTS: In the TKA population, age, female gender, nonsmoking status, venous thromboembolism (VTE) history, and diabetes were significantly associated with discharge to extended care facility (ECF) on univariate analysis, unlike body mass index. With multivariate analyses, female gender, age, VTE history, and diabetes were associated with ECF placement, but smoking was not. In the total hip arthroplasty population, age, female gender, and nonsmoking status were significantly associated with discharge to ECF on univariate analysis, whereas body mass index, diabetes, and VTE history were not. On multivariate analyses, female gender and age were associated with ECF, but smoking was not. The only significant finding for the readmission data was an increased rate of readmission for TKA patients of older age. CONCLUSION: The potential of projecting patient discharge and readmission allows physicians to counsel patients and improve patient expectations.

Evidence and Role for Bacterial Mucin Degradation in Cystic Fibrosis Airway Disease.

Chronic lung infections in cystic fibrosis (CF) patients are composed of complex microbial communities that incite persistent inflammation and airway damage. Despite the high density of bacteria that colonize the lower airways, nutrient sources that sustain bacterial growth in vivo, and how those nutrients are derived, are not well characterized. In this study, we examined the possibility that mucins serve as an important carbon reservoir for the CF lung microbiota. While Pseudomonas aeruginosa was unable to efficiently utilize mucins in isolation, we found that anaerobic, mucin-fermenting bacteria could stimulate the robust growth of CF pathogens when provided intact mucins as a sole carbon source. 16S rRNA sequencing and enrichment culturing of sputum also identified that mucin-degrading anaerobes are ubiquitous in the airways of CF patients. The collective fermentative metabolism of these mucin-degrading communities in vitro generated amino acids and short chain fatty acids (propionate and acetate) during growth on mucin, and the same metabolites were also found in abundance within expectorated sputum. The significance of these findings was supported by in vivo P. aeruginosa gene expression, which revealed a heightened expression of genes required for the catabolism of propionate. Given that propionate is exclusively derived from bacterial fermentation, these data provide evidence for an important role of mucin fermenting bacteria in the carbon flux of the lower airways. More specifically, microorganisms typically defined as commensals may contribute to airway disease by degrading mucins, in turn providing nutrients for pathogens otherwise unable to efficiently obtain carbon in the lung.

Opportunistic Autoimmune Disorders Potentiated by Immune-Checkpoint Inhibitors Anti-CTLA-4 and Anti-PD-1.

To improve the efficacy of immunotherapy for cancer and autoimmune diseases, recent ongoing and completed clinical trials have focused on specific targets to redirect the immune network toward eradicating a variety of tumors and ameliorating the self-destructive process. In a previous review, both systemic immunomodulators and monoclonal antibodies (mAbs), anti-CTLA-4, and anti-CD52, were discussed regarding therapeutics and autoimmune sequelae, as well as predisposing factors known to exacerbate immune-related adverse events (irAEs). This review will focus on immune-checkpoint inhibitors, and the data from most clinical trials involve blockade with anti-CTLA-4 such as ipilimumab. However, despite the mild to severe irAEs observed with ipilimumab in ~60% of patients, overall survival (OS) averaged ~22-25% at 3-5 years. To boost OS, other mAbs targeting programed death-1 and its ligand are undergoing clinical trials as monotherapy or dual therapy with anti-CTLA-4. Therapeutic combinations may generate different spectrum of opportunistic autoimmune disorders. To simulate clinical scenarios, we have applied regulatory T cell perturbation to murine models combined to examine the balance between thyroid autoimmunity and tumor-specific immunity.

Implant wear induced inflammation is mitigated in CX3CR1(-/-) mice.

Wear debris-induced monocyte recruitment plays a key role in the formation of chronic periprosthetic tissue inflammation associated with aseptic loosening. The purpose of this study was to investigate the role(s) of chemokine receptor CX3CR1 in ultra high molecular weight polyethylene (UHMWPE) particle-induced tissue inflammation using a murine air pouch model developed in CX3CR1 knockout (CX3CR1(-/-) ) mice. UHMWPE debris or saline were introduced into established air pouches on CX3CR1(-/-) and CX3CR1(+/+) mice. Pouch tissues were collected 7 days after UHMWPE inoculation. Results showed that UHMWPE stimulation induced strong pouch tissue inflammation in CX3CR1(+/+) mice, as manifested by inflammatory cellular infiltration (mainly macrophages), pouch tissue proliferation, and increased gene expression of IL-1ß and TNFα. UHMWPE-induced inflammation was significantly mitigated in CX3CR1(-/-) mice, as manifested by reduction of tissue inflammation (pouch thickness and cell density), inflammatory cytokine production (IL-1ß and TNFα) and macrophage accumulation. The observations support the hypothesis that the activation of the CX3CR1 chemokine pathway contributes to the severity of UHMWPE particle-induced tissue inflammation, and suggests that CX3CR1 signaling is involved in the recruitment of monocytes to the wear debris-containing inflammatory tissues. Blocking of CX3CR1 pathway may represent a viable therapeutic approach to the prevention and treatment of patients with aseptic loosening.

Immunological response to bolus versus multiple injections of hylan G-F 20 (Synvisc) in a murine biocompatibility model.

Local tissue reactivity to intra-articular injections of hyaluronic acid hylan G-F 20 (Synvisc) has been described. We used a murine biocompatibility model to study the inflammatory response to Synvisc after a single bolus injection versus the traditional three shot series of injections. Air pouches were established subcutaneously in BALB/c mice, which were injected with phosphate-buffered saline (PBS), 5 mg ultra-high molecular weight polyethylene particles (to simulate synthetic joint wear debris, positive control), 0.5 mL Synvisc (one injection/week for three weeks, harvested 14 days after last injection), or 1.5 mL Synvisc bolus (harvested either 14 or 28 days after last injection). Inflammatory gene expression and inflammation of air pouch tissue, and serum antibody titers to Synvisc were determined. Inflammation was observed with all Synvisc treatments relative to PBS (p < 0.01). However, the three injection series of Synvisc resulted in significantly (p < 0.05) greater tumor necrosis factor-alpha gene expression compared to both PBS and bolus single shot Synvisc harvested after 14 or 28 days. While all Synvisc treatments resulted in serum antibodies to Synvisc (p < 0.02 compared to PBS control group), mice that received three injections of Synvisc had higher levels than mice receiving a single injection (p < 0.01). These results demonstrate that a single bolus injection of Synvisc led to less inflammation and a lower antibody response when compared to the three-shot series of injections, supporting the current change in treatment from multiple injections to a single injection of Synvisc .

Enhanced autoimmunity associated with induction of tumor immunity in thyroiditis-susceptible mice.

BACKGROUND: Immunotherapeutic modalities to bolster tumor immunity by targeting specific sites of the immune network often result in immune dysregulation with adverse autoimmune sequelae. To understand the relative risk for opportunistic autoimmune disorders, we studied established breast cancer models in mice resistant to experimental autoimmune thyroiditis (EAT). EAT is a murine model of Hashimoto's thyroiditis, an autoimmune syndrome with established MHC class II control of susceptibility. The highly prevalent Hashimoto's thyroiditis is a prominent autoimmune sequela in immunotherapy, and its relative ease of diagnosis and treatment could serve as an early indicator of immune dysfunction. Here, we examined EAT-susceptible mice as a combined model for induction of tumor immunity and EAT under the umbrella of disrupted regulatory T cell (Treg) function. METHODS: Tumor immunity was evaluated in female CBA/J mice after depleting Tregs by intravenous administration of CD25 monoclonal antibody and/or immunizing with irradiated mammary adenocarcinoma cell line A22E-j before challenge; the role of T cell subsets was determined by injecting CD4 and/or CD8 antibodies after tumor immunity induction. Tumor growth was monitored 3×/week by palpation. Subsequent EAT was induced by mouse thyroglobulin (mTg) injections (4 daily doses/week over 4 weeks). For some experiments, EAT was induced before establishing tumor immunity by injecting mTg+interleukin-1, 7 days apart. EAT was evaluated by mTg antibodies and thyroid infiltration. RESULTS: Strong resistance to tumor challenge after Treg depletion and immunization with irradiated tumor cells required participation of both CD4(+) and CD8(+) T cells. This immunity was not altered by induction of mild thyroiditis with our protocol of Treg depletion and adjuvant-free, soluble mTg injections. However, the increased incidence of mild thyroiditis can be directly related to Treg depletion needed to achieve strong tumor immunity. Moreover, when a subclinical, mild thyroiditis was induced with soluble mTg and low doses of interleukin-1, to simulate pre-existing autoimmunity in patients subjected to cancer immunotherapy, mononuclear infiltration into the thyroid was enhanced. CONCLUSIONS: Our current findings indicate that genetic predisposition to autoimmune disease could enhance autoimmunity during induction of tumor immunity in thyroiditis-susceptible mice. Thus, HLA genotyping of cancer patients should be part of any risk assessment.

Analysis and implications of changing hepatopancreatobiliary (HPB) case loads in general surgery residency training for HPB surgery accreditation.

OBJECTIVE: This study was conducted to determine whether residents are receiving enough hepatopancreatobiliary (HPB) training during general surgery residencies to exclude the necessity of pursuing formal fellowships in HPB surgery. METHODS: Trends in HPB surgery training were examined using Accreditation Council for Graduate Medical Education (ACGME) operative log data for the academic years 1999/2000 to 2009/2010. RESULTS: Of 800,000 HPB operations performed annually in the USA, the proportion of HPB procedures performed by general surgery residents increased from 15% (122,007) to 18% (143,000) between the periods under study. Numbers of pancreatic, liver and biliary procedures performed by graduating general surgery residents increased by 47% (from 8185 to 12,006), 31% (from 7468 to 9765), and 14% (from 106,354 to 121,239), respectively. The mean number of operations undertaken by a graduating resident increased from 8.3 to 11.5 (38% increase) for pancreatic surgeries, from 7.6 to 9.4 (24% increase) for liver surgeries, and from 107.5 to 116.6 (8% increase) for biliary surgeries. Total numbers of complex pancreatic, liver and biliary procedures increased by 91% (from 4768 to 9129) and 24% (from 6649 to 8233), and decreased by 29% (from 6581 to 4648), respectively. CONCLUSIONS: The overall trend shows an increase in the number of HPB procedures undertaken by graduating general surgery residents. The mean number of procedures exceeds ACGME requirements, but falls short of association guidelines. However, certain residents exceed International Hepato-Pancreato-Biliary Association (IHPBA) fellowship requirements for total and complex procedures during residency. Consideration should be given to those residents to allow them to bypass fellowship training provided that they meet other IHPBA standards.

Colorectal cancer: are the "young" being overlooked?

BACKGROUND: Colorectal cancer (CRC) is increasing in young patients. We aimed to assess the trends of CRC and its corresponding clinical presentation in the young. METHODS: Cancer registry patients were divided into 3 groups according to age:<50, 50-75, and >75 years. Charts were reviewed for average-risk patients <50 years of age to assess clinicopathological data. RESULTS: We identified 3,599 patients between 1982 and 2010. Patients aged <50 years increased from 6.8% in (1982-1990) to 8.5% in (2000-2010) with a decrease in the 50-75-year age group from 45.5% to 43.4% (P = .03). One hundred eighty-eight patients were <50 years of age at the time of diagnosis. None had screening tests. Eighty-four percent had symptoms including rectal bleeding (76.5%), abdominal pain (58%), and an altered bowel pattern (71%). Twenty-one percent had symptoms for >6 months before diagnosis. Forty percent had stage III and 20% stage IV disease. This is unlike the 50-75-year age group in which the majority of patients had stage I disease. CONCLUSIONS: Young CRC patients are mostly symptomatic. Advanced disease at presentation could be caused by a delay in investigating these patients. Colonoscopy should be offered early to young patients presenting with warning symptoms.

Changing paradigms in minimally invasive surgery training.

BACKGROUND: Realizing the trends toward minimally invasive procedures, the Accreditation Council for Graduate Medical Education (ACGME) increased the requirements for laparoscopic procedures effective 2007 to 2008. Our purpose was to analyze the trend of laparoscopic versus open cases. METHODS: We analyzed national ACGME general surgery operative log program data for basic and advanced open and laparoscopic procedures performed by graduating surgical residents between academic years 1996 to 1997 and 2009 to 2010. RESULTS: From 1997 to 2010, the average number of procedures performed by graduating residents increased for appendectomies (36.5 to 59.3), cholecystectomies (90.9 to 112), hernia repairs (58.9 to 67.4), and colectomies (40.1 to 60.2). These increases have been accompanied by decreases in the percentage of open procedures for appendectomies (84% to 30%), cholecystectomies (24% to 9%), hernia repairs (90% to 70%), and colectomies (97% to 71%), which have resulted primarily from a decrease in open procedures (basic) or an increase in laparoscopic procedures (advanced). CONCLUSIONS: The rising number of laparoscopic procedures performed by surgical residents is associated with a drastic decrease in the number of basic open procedures. Although the number of open procedures is sufficient to meet ACGME requirements for now, this is an area of concern for the adequacy of training in the future.

Differentiation of septic and aseptic loosening by PET with both 11C-PK11195 and 18F-FDG in rat models.

PURPOSE: This study aims to determine the value of PET with C-isoquinoline carboxamide (C-PK11195) and F-fluorodeoxyglucose (F-FDG) in assisting the differentiation of aseptic loosening (AL) from septic loosening (SL) in rat models. PROCEDURES: Initially, the histological profiles of SL and AL (cellular infiltration and the number of CD68 macrophage and PBR cells) were compared. Subsequently, we investigated whether C-PK11195 alone and also in combination with F-FDG increases the sensitivity and specificity of PET imaging for distinguishing SL from AL. RESULTS: There were distinguishable features between the histological profiles of the SL and AL rat groups. The number of CD68/PBR cells in AL rats was significantly higher than that seen in SL rats (P<0.05). The uptake of C-PK1195 was higher in AL and lower in SL rats. The uptake of F-FDG was higher in SL and lower in AL rats. CONCLUSION: PET with a C-PK11195 and F-FDG imaging protocol is helpful in the clinical differential diagnosis of AL from SL.

Efficacy of HLA-DRB1∗03:01 and H2E transgenic mouse strains to correlate pathogenic thyroglobulin epitopes for autoimmune thyroiditis.

Thyroglobulin (Tg), a homodimer of 660 kD comprising 2748 amino acids, is the largest autoantigen known. The prevalence of autoimmune thyroid disease, including Hashimoto's thyroiditis and Graves' disease, has provided the impetus for identifying pathogenic T cell epitopes from human Tg over two decades. With no known dominant epitopes, the search has long been a challenge for investigators. After identifying HLA-DRB1∗03:01 (HLA-DR3) and H2E(b) as susceptibility alleles for Tg-induced experimental autoimmune thyroiditis in transgenic mouse strains, we searched for naturally processed T cell epitopes with MHC class II-binding motif anchors and tested the selected peptides for pathogenicity in these mice. The thyroiditogenicity of one peptide, hTg2079, was confirmed in DR3 transgenic mice and corroborated in clinical studies. In H2E(b)-expressing transgenic mice, we identified three T cell epitopes from mouse Tg, mTg179, mTg409 and mTg2342, based on homology to epitopes hTg179, hTg410 and hTg2344, respectively, which we and others have found stimulatory or pathogenic in both DR3- and H2E-expressing mice. The high homology among these peptides with shared presentation by DR3, H2E(b) and H2E(k) molecules led us to examine the binding pocket residues of these class II molecules. Their similar binding characteristics help explain the pathogenic capacity of these T cell epitopes. Our approach of using appropriate human and murine MHC class II transgenic mice, combined with the synthesis and testing of potential pathogenic Tg peptides predicted from computational models of MHC-binding motifs, should continue to provide insights into human autoimmune thyroid disease.

Venous thromboembolism: management by American Association of Hip and Knee Surgeons.

A 2008 survey of American Association of Hip and Knee Surgeons membership explored current venous thromboembolism (VTE) protocols for lower-extremity total joint surgery. Fifty-three percent reported a change in VTE-related practices in the last 5 years. More than 70% reported that their primary hospital now mandates VTE prophylaxis. Although 74% of their primary hospitals recognized the American College of Chest Physicians guidelines, 68% of surgeons felt the American Academy of Orthopaedic Surgeons guidelines were more relevant to their practice. Respondents believe low molecular weight heparin to be the most efficacious but aspirin to be the easiest to use and has the lowest risks of bleeding and wound drainage. Warfarin was the most used in hospital prophylaxis, and 90% of respondents targeted an international normalized ratio of 1.6 to 2.5. Practice patterns continue to evolve, and there remains no consensus on specific treatment protocols or preferences.

Autoimmune thyroiditis: a model uniquely suited to probe regulatory T cell function.

Murine experimental autoimmune thyroiditis (EAT) is a model for Hashimoto's thyroiditis that has served as a prototype of T cell-mediated autoimmunity for more than three decades. Key roles for MHC restriction and autoantigen influence on susceptibility to autoimmunity have been demonstrated in EAT. Moreover, it has served a unique role in investigations of self tolerance. In the early 1980s, self tolerance and resistance to EAT induction could be enhanced by increasing circulating levels of the autoantigen, thyroglobulin (Tg), by exogenous addition as well as endogenous release. This observation, directly linking circulating self antigen to self tolerance, led to subsequent investigations of the role of regulatory T cells (Tregs) in self tolerance. These studies revealed that protection against autoimmunity, in both naive and tolerized mice, was mediated by thymically-derived CD4(+)CD25(+)Foxp3(+) Tregs. Moreover, these naturally-existing Tregs required proper costimulation, in context with autoantigen presentation, to maintain and enhance self tolerance. In particular was the selected use of MHC- and heterologous Tg-restricted models from both conventional and transgenic mice. These models helped to elucidate the complex interplay between autoantigen presentation and MHC class II-mediated T cell selection in the development of Treg and autoreactive T cell repertoires determining susceptibility to autoimmunity. Here we describe these investigations in further detail, providing a context for how EAT has helped shape our understanding of self tolerance and autoimmunity.

Autoimmune thyroiditis as an indicator of autoimmune sequelae during cancer immunotherapy.

Improving cancer immunotherapy by targeting T cell network also triggers autoimmunity. We disrupted regulatory T cell (Treg) function to probe the balance between breast cancer vaccination and autoimmune thyroiditis (EAT) in four models, with particular attention to MHC-associated susceptibility, EAT induction with mouse thyroglobulin (mTg) without adjuvant, and tolerance to Her-2/neu in transgenic mice. 1) In EAT-resistant BALB/c mice, Treg depletion enhanced tumor regression, and facilitated mild thyroiditis induction. 2) In Her-2 tolerant C57BL/6 mice expressing HLA-DR3, an EAT-susceptibility allele, Her-2 DNA vaccinations must follow Treg depletion for (Her-2xDR3)F(1) mice to resist tumor challenge; thyroiditis incidence was moderated by the EAT-resistant IA(b) allele. 3) In neu tolerant, EAT-resistant BALB/c mice, implanted neu(+) tumor also regressed only after Treg depletion and DNA vaccinations. Tumor immunity was long-term, providing protection from spontaneous tumorigenesis. In all three, immune stimuli from concurrent tumor regression and EAT development have a noticeable, mutually augmenting effect. 4) In Treg-depleted, EAT-susceptible CBA/J mice, strong tumor protection was established by immunization with a cell vaccine. mTg injections led to greater thyroiditis incidence and severity. Combination models with MHC class II diversity should facilitate autoimmunity risk assessment and management while generating tumor immunity.