CTLA4Ig prevents alloantibody formation following nonhuman primate islet transplantation using the CD40-specific antibody 3A8.

Islet transplantation to treat type 1 diabetes has been limited in part by toxicities of current immunosuppression and recipient humoral sensitization. Blockade of the CD28/CD80/86 and CD40/CD154 pathways has shown promise to remedy both these limitations, but translation has been hampered by difficulties in translating CD154-directed therapies. Prior CD40-directed regimens have led to prolonged islet survival, but fail to prevent humoral allosensitization. We therefore evaluated the addition of CTLA4Ig to a CD40 blockade-based regimen in nonhuman primate (NHP) alloislet transplantation. Diabetic rhesus macaques were transplanted allogeneic islets using the CD40-specific antibody 3A8, basiliximab induction, and sirolimus with or without CTLA4Ig maintenance therapy. Allograft survival was determined by fasting blood glucose levels and flow cytometric techniques were used to test for donor-specific antibody (DSA) formation. CTLA4Ig plus 3A8, basiliximab and sirolimus was well tolerated and induced long-term islet allograft survival. The addition of CTLA4Ig prevented DSA formation, but did not facilitate withdrawal of the 3A8-based regimen. Thus, CTLA4Ig combines with a CD40-specific regimen to prevent DSA formation in NHPs, and offers a potentially translatable calcineurin inhibitor-free protocol inclusive of a single investigational agent for use in clinical islet transplantation without relying upon CD154 blockade.

CD40-specific costimulation blockade enhances neonatal porcine islet survival in nonhuman primates.

The widespread clinical implementation of alloislet transplantation as therapy for type 1 diabetes has been hindered by the lack of suitable islet donors. Pig-to-human islet xenotransplantation is one strategy with potential to alleviate this shortage. Long-term survival of porcine islets has been achieved using CD154-specific antibodies to interrupt the CD40/CD154 costimulation pathway; however, CD154-specific antibodies seem unlikely candidates for clinical translation. An alternative strategy for CD40/CD154 pathway interruption is use of CD40-specific antibodies. Herein, we evaluate the ability of a chimeric CD40-specific monoclonal antibody (Chi220) to protect islet xenografts. Neonatal porcine islets (~50,000 IEQ/kg) were transplanted intraportally into pancreatectomized diabetic macaques. Immunosuppression consisted of induction therapy with Chi220 and the IL-2 receptor-specific antibody basiliximab, and maintenance therapy with sirolimus and the B7-specific fusion protein belatacept. Chi220 effectively promoted xenoislet engraftment and survival, with five of six treated recipients achieving insulin-independent normoglycemia (median rejection-free survival 59 days; mean 90.8 days, maximum 203 days). No thromboembolic phenomena were observed. CD40 represents a promising alternative to CD154 as a therapeutic target, and the efficacy of CD40-specific antibodies in islet xenotransplantation warrants further investigation.

Sirolimus enhances the magnitude and quality of viral-specific CD8+ T-cell responses to vaccinia virus vaccination in rhesus macaques.

Sirolimus is a potent antiproliferative agent used clinically to prevent renal allograft rejection. However, little is known about the effects of maintenance immunosuppressive agents on the immune response to potentially protective vaccines. Here we show that sirolimus paradoxically increases the magnitude and quality of the CD8+ T-cell response to vaccinia vaccination in nonhuman primates, fostering more robust recall responses compared to untreated and tacrolimus-treated controls. Enhancement of both the central and effector memory compartments of the vaccinia-specific CD8+ T-cell response was observed. These data elucidate new mechanistic characteristics of sirolimus and suggest immune applications extending beyond its role as an immunosuppressant.

Frequency and severity of sexual harassment in pharmacy practice in Ohio.

OBJECTIVE: To determine the frequency and severity of sexual harassment in the pharmacy workplace for both male and female pharmacists, and to identify: (1) instigators, (2) places of occurrence, and (3) pharmacists' responses. DESIGN: Mailed survey using elements of the Sexual Experience Questionnaire (SEQ). One repeat mailing to nonrespondents. SETTING: Community pharmacies, hospital pharmacies, other pharmacies in the state of Ohio. PATIENTS AND OTHER PARTICIPANTS: 789 randomly selected pharmacists registered in Ohio. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Amount of gender harassment, unwanted sexual attention, and sexual coercion; differences in occurrences of sexual harassment between men and women; identification of instigators as colleagues, patients, or supervisors; identification of place of occurrence as community pharmacy, hospital pharmacy, or elsewhere; pharmacists' responses and reactions. RESULTS: After two mailings, 265 usable surveys were returned for a response rate of 34%. Women differed significantly from men in total occurrences of sexual harassment, with men reporting 183 instances of sexual harassment and women reporting 281 such experiences. Instigators were colleagues (43%), patients (30%), and superiors (27%). Men reported 143 experiences of unwanted sexual attention, whereas women reported 272 such occurrences. Colleagues were responsible for 47% of instances of unwanted sexual attention, patients were responsible for 37%, and superiors 16%. No significant differences were found between men and women in total number of occurrences of sexual coercion. CONCLUSION: Sexual harassment in the workplace has been experienced by both male and female pharmacists. Women experienced more hostile work environment harassment than did men. However, quid pro quo harassment did not differ significantly between the sexes.

Counting the cost of an NRSA Primary Care Research Fellowship Program.

BACKGROUND AND OBJECTIVES: Concerns are often raised about the potential financial and logistical burdens that fellows (even those who receive federal funding) add to departmental budgets. METHODS: We collected data on patient care income, financial values of teaching, on-call and attending duties, and departmental costs for patient care overhead, administration, and supervision over a 1-year period for six fellows in the National Research Service Award (NRSA) Primary Care Research Fellowship Program at the University of North Carolina at Chapel Hill. RESULTS: Net receipts for clinical services ranged from $4,023 to $15,742, which, when adjusted for overhead costs, led to financial loss. However, assuming an academic dollar value of $15/hour, teaching, precepting, and on-call coverage were worth from $3,330 to $9,780 to a department, depending on level and specialty of the fellow. Overall, NRSA fellows imposed a financial burden consisting of practice-related costs and uncompensated faculty supervision and administration. Three factors can modify the estimate of this burden, including the calculation of patient care overhead, the estimated value of academic work, and whether fellows provide "replacement" or "additive" clinical functions to their departments. CONCLUSIONS: The NRSA Fellowship Training Program can be a cost-neutral but valuable resource for developing highly trained primary care researchers and new faculty. Increased administrative funding for these programs would be a low-cost strategy to compensate faculty time and program management in generalist departments.

Trauma care reimbursement in rural hospitals: implications for triage and trauma system design.

UNLABELLED: American College of Surgeons triage guidelines recommend rapid identification and transfer of seriously injured patients to regional trauma centers, bypassing local hospitals if necessary. This approach raises concerns about the potential negative financial impact of implementing such triage strategies on already strained rural hospitals. OBJECTIVE: The purpose of this study was to determine the association between injury severity and reimbursement for trauma care in rural hospitals. It was our hypothesis that the seriously injured would be high cost and relatively low reimbursement patients, and thus be a significant financial liability to the rural hospital. This would imply that concerns by the rural hospital about triage of such patients to trauma centers would be unfounded. METHODS: Data on every injured patient seen in the emergency department during two 3-month periods were obtained from three rural hospitals in the state using the American College of Surgeons Trauma Registry data base. RESULTS: One thousand six hundred thirty patients had complete data available for analysis. The analyses demonstrated that as the injury severity increased, there was an increase in hospital charges, length of stay, and risk of dying. In contrast, the reimbursement changed little as the charges and severity increased. Thus, hospital losses increased in an exponential fashion as injury severity increased above 15. CONCLUSION: The study demonstrates that as injury severity increases, costs and charges increase, but reimbursement does not keep pace with these increased charges. The rural hospital was projected to lose an average of $25,000 for each patient with an Injury Severity Score over 15. This study supports the rapid triage and transport of the seriously injured patient from the rural hospital to the regional trauma center both for improved patient outcome and for the hospital's best interest. The potential impact of such a system on the trauma center also needs to be addressed.

Improving pharmacy and therapeutics committee operations.

A panel discussion of various aspects of the operations of pharmacy and therapeutics (P & T) committees is presented. Pharmacy and therapeutics committee operations in various types and sizes of hospitals are described. Ways of stimulating physicians' interest in P & T committee activities, difficult problems faced, scope of issues dealt with by P & T committees, functions of P & T subcommittees, the value of drug information from pharmaceutical representatives, and the influence of research funds from the pharmaceutical industry on committee decisions are discussed. Panel members also present their views on therapeutic alternates, FDA-nonapproved use of drugs, and counter-detailing. Finally, suggestions for improving P & T drug evaluations, cost-containment issues, and the authority of P & T committees are discussed. A well-prepared agenda, good educational material, active members, and strong leadership are important for successful P & T committee operations.