Dana W. Dunne

Fungal peritonitis in a large chronic peritoneal dialysis population: a report of 55 episodes

Fungal peritonitis (FP) is a rare but serious complication of chronic peritoneal dialysis (CPD) therapy and is associated with high morbidity and CPD drop-out. Risk factors and management of FP remain controversial. We reviewed our experience with FP in an attempt to identify risk factors and to examine outcome in relation to treatment strategies. Between March 1984 and August 1994, 704 patients were maintained on CPD therapy in our unit. A total of 1,712 episodes of peritonitis were identified among these patients. Fungal peritonitis accounted for 55 (3.2%) of these episodes. The patients on CPD therapy who developed FP were similar to those who did not develop FP with regard to age, gender, underlying etiology for end-stage renal disease, and comorbid disease. Prior antibiotic use was noted in 87.3% of episodes of FP. The peritonitis rate in the patients who developed FP was one episode every 5.1 months compared with one episode every 9.9 patient-months in the CPD patients who did not develop this infection. Candida sp caused 74.5% of the episodes of FP. All patients were treated with antifungal drugs. In 85.5% of infections the Tenckhoff catheter was removed within 1 week of the diagnosis of FP; 31.9% of the patients who had the Tenckhoff catheter removed did not have the catheter replaced because of death or transfer to hemodialysis. In the patients who developed FP, 68.1% had the Tenckhoff catheter replaced; of these patients, 90.6% and 59.4% were on CPD therapy 1 and 6 months after catheter replacement, respectively. We conclude that risk factors identified in our population include peritonitis rate and prior antibiotic use. Fungal peritonitis is rare in our CPD population, and although it leads to significant CPD drop-out, it can be managed in many patients with antifungal therapy, early catheter removal, and temporary hemodialysis. Of the catheters replaced between 2 and 8 weeks after the diagnosis of FP, 91% functioned successfully, allowing continuation of CPD.

Lifestyle factors and primary care specialty selection: comparing 2012-2013 graduating and matriculating medical students' thoughts on specialty lifestyle.

Purpose To compare how first-year (MS1) and fourth-year students (MS4) ascribe importance to lifestyle domains and specialty characteristics in specialty selection, and compare students’ ratings with their primary care (PC) interest. Method In March 2013, MS4s from 11 U.S. MD-granting medical schools were surveyed. Using a five-point Likert-type scale (1 = not important at all; 5 = extremely important), respondents rated the importance of 5 lifestyle domains and 21 specialty selection characteristics. One-way analysis of variance was used to assess differences by PC interest among MS4s. Using logistic regression, ratings from MS4s were compared with prior analyses of ratings by MS1s who matriculated to the same 11 schools in 2012. Results The response rate was 57% (965/1,701). MS4s, as compared with MS1s, rated as more important to good lifestyle: time off (4.3 versus 4.0), schedule control (4.2 versus 3.9), and financial compensation (3.4 versus 3.2). More MS4s than MS1s selected “time-off” (262/906 [30%] versus 136/969 [14%]) and “control of work schedule” (169/906 [19%] versus 146/969 [15%]) as the most important lifestyle domains. In both classes, PC interest was associated with higher ratings of working with the underserved and lower ratings of prestige and salary. Conclusions In the 2012–2013 academic year, matriculating students and graduating students had similar perceptions of lifestyle and specialty characteristics associated with PC interest. Graduating students placed more importance on schedule control and time off than matriculating students. Specialties should consider addressing a perceived lack of schedule control or inadequate time off to attract students.

Primary Care, the ROAD Less Traveled: What First-Year Medical Students Want in a Specialty

Purpose Medical students are increasingly choosing non-primary-care specialties. Students consider lifestyle in selecting their specialty, but how entering medical students perceive lifestyle is unknown. This study investigates how first-year students value or rate lifestyle domains and specialty-selection characteristics and whether their ratings vary by interest in primary care (PC). Method During the 2012–2013 academic year, the authors conducted a cross-sectional survey of first-year medical students from 11 MD-granting medical schools. Using a five-point Likert-type scale (1 = not important at all; 5 = extremely important), respondents rated the importance of 5 domains of good lifestyle and 21 characteristics related to specialty selection. The authors classified students into five groups by PC interest and assessed differences by PC interest using one-way analysis of variance. Results Of 1,704 participants, 1,020 responded (60%). The option “type of work I am doing” was the highest-rated lifestyle domain (mean 4.8, standard deviation [SD] 0.6). “Being satisfied with the job” was the highest-rated specialty-selection characteristic (mean 4.7, SD 0.5). “Availability of practice locations in rural areas” was rated lowest (mean 2.0, SD 1.1). As PC interest decreased, the importance of “opportunities to work with underserved populations” also decreased, but importance of “average salary earned” increased (effect sizes of 0.98 and 0.94, respectively). Conclusions First-year students valued enjoying work. The importance of financial compensation was inversely associated with interest in PC. Examining the determinants of enjoyable work may inform interventions to help students attain professional fulfillment in PC.

Increased TLR4 Expression and Downstream Cytokine Production in Immunosuppressed Adults Compared to Non-Immunosuppressed Adults

Background An increasing number of patients have medical conditions with altered host immunity or that require immunosuppressive medications. While immunosuppression is associated with increased risk of infection, the precise effect of immunosuppression on innate immunity is not well understood. We studied monocyte Toll-like receptor (TLR) expression and cytokine production in 137 patients with autoimmune diseases who were maintained on immunosuppressive medications and 419 non-immunosuppressed individuals. Methodology/Principal Findings Human peripheral blood monocytes were assessed for surface expression of TLRs 1, 2, and 4. After incubation with TLR agonists, in vitro production of the cytokines IL-8, TNFα, and MIF were measured by ELISA as a measure of TLR signaling efficiency and downstream effector responsiveness. Immunosuppressed patients had significantly higher TLR4 surface expression when compared to non-immunosuppressed adults (TLR4 %-positive 70.12±2.28 vs. 61.72±2.05, p = 0.0008). IL-8 and TNF-α baseline levels did not differ, but were significantly higher in the autoimmune disease group following TLR stimulation. By contrast, baseline MIF levels were elevated in monocytes from immunosuppressed individuals. By multivariable analyses, IL-8 and TNFα, but not MIF levels, were associated with the diagnosis of an underlying autoimmune disease. However, only MIF levels were significantly associated with the use of immunosuppressive medications. Conclusions/Significance Our results reveal that an enhanced innate immune response is a feature of patients with autoimmune diseases treated with immunosuppressive agents. The increased risk for infection evident in this patient group may reflect a dysregulation rather than a simple suppression of innate immunity.

MyD88 Deficiency Markedly Worsens Tissue Inflammation and Bacterial Clearance in Mice Infected with Treponema pallidum, the Agent of Syphilis

Research on syphilis, a sexually transmitted infection caused by the non-cultivatable spirochete Treponema pallidum, has been hampered by the lack of an inbred animal model. We hypothesized that Toll-like receptor (TLR)-dependent responses are essential for clearance of T. pallidum and, consequently, compared infection in wild-type (WT) mice and animals lacking MyD88, the adaptor molecule required for signaling by most TLRs. MyD88-deficient mice had significantly higher pathogen burdens and more extensive inflammation than control animals. Whereas tissue infiltrates in WT mice consisted of mixed mononuclear and plasma cells, infiltrates in MyD88-deficient animals were predominantly neutrophilic. Although both WT and MyD88-deficient mice produced antibodies that promoted uptake of treponemes by WT macrophages, MyD88-deficient macrophages were deficient in opsonophagocytosis of treponemes. Our results demonstrate that TLR-mediated responses are major contributors to the resistance of mice to syphilitic disease and that MyD88 signaling and FcR-mediated opsonophagocytosis are linked to the macrophage-mediated clearance of treponemes.

A Multi-Institutional Longitudinal Faculty Development Program in Humanism Supports the Professional Development of Faculty Teachers

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Healthcare at the Crossroads: The Need to Shape an Organizational Culture of Humanistic Teaching and Practice

ABSTRACTBackgroundChanges in the organization of medical practice have impeded humanistic practice and resulted in widespread physician burnout and dissatisfaction.ObjectiveTo identify organizational factors that promote or inhibit humanistic practice of medicine by faculty physicians.DesignFrom January 1, 2015, through December 31, 2016, faculty from eight US medical schools were asked to write reflectively on two open-ended questions regarding institutional-level motivators and impediments to humanistic practice and teaching within their organizations.ParticipantsSixty eight of the 92 (74%) study participants who received the survey provided written responses. All subjects who were sent the survey had participated in a year-long small-group faculty development program to enhance humanistic practice and teaching. As humanistic leaders, subjects should have insights into motivating and inhibiting factors.ApproachParticipants’ responses were analyzed using the constant comparative method.Key ResultsMotivators included an organizational culture that enhances humanism, which we judged to be the overarching theme. Related themes included leadership supportive of humanistic practice, responsibility to role model humanism, organized activities that promote humanism, and practice structures that facilitate humanism. Impediments included top down organizational culture that inhibits humanism, along with related themes of non-supportive leadership, time and bureaucratic pressures, and non-facilitative practice structures.ConclusionsWhile healthcare has evolved rapidly, efforts to counteract the negative effects of changes in organizational and practice environments have largely focused on cultivating humanistic attributes in individuals. Our findings suggest that change at the organizational level is at least equally important. Physicians in our study described the characteristics of an organizational culture that supports and embraces humanism. We offer suggestions for organizational change that keep humanistic and compassionate patient care as its central focus.

O4-S2.05 Myd-88 deficient mice show evidence of productive T pallidum infection"

Background Syphilis rates are again increasing in the US and globally and are associated with HIV transmission and rising rates of congenital syphilis. Humans serve as the only natural reservoir of the causative agent, Treponema pallidum, and no in vitro cultivation systems are available. Progress towards a vaccine and a better understanding of immune response to syphilis has been hampered over the last half century by lack of a murine model. We hypothesised that previous attempts to establish T pallidum infection in mice were unsuccessful because of rapid clearance of the organism by an intact innate immune response. Myd-88 serves as a common signalling molecule stimulated by most toll-like receptors TLRs; pattern recognition receptors of the innate immune system found on most innate immune cells, for example, monocytes, macrophages, and dentritic cells) and is responsible for downstream cytokine responses. We utilised mice bred to be Myd-88 deficient to test this hypothesis and to ascertain whether this mouse strain could be used to study persistent syphilis infection, immune response mechanisms, and eventually vaccine candidates. Methods T pallidum, Nicohols strain, was cultivated by intratesticular infection of New Zealand male rabbits housed at 62°C as per protocol. After 12 day incubation, T pallidum was extracted and the concentration adjusted to 7×108 organisms/ml. Myd-88 −/− mice and equally-aged C57BL/6 mice were inoculated intradermally, intraperitoneally, intravaginally or in testicles, and intrarectally each mouse receiving total dose of 1×108 organisms divided into the four body site aliquots). Mice were observed daily for signs or cutaneous disease and/or systemic illness and were sacrificed at day 10 and 21. DNA and RNA were extracted from skin, spleen, genitals, rectum, lymph nodes, spinal cord and blood for use in real-time quantitative PCR and RT-PCR, respectively. Corresponding tissue types were also evaluated by histopathology and immunohistochemical staining T pallidum Ab, BioCare, Concord, California, USA). The experiment was repeated three times with variable number of mice per experiment. Results A total of 18 Myd-88 mice and 19 C57BL/6 mice were infected. MyD-88 −/− mice were more likely than B6 control mice to have detectable RNA at day 10 and 21 (day 10, 12/35 sites (35%) +RNA in Myd-88 −/− ; 3/35 sites (8.5%) +RNA in WT. Day 21, 11/40 sites (27.5%) +RNA in Myd-88−/−; 3/40 (7.5%) +RNA in B6). One experiment ongoing past 42 day post-infection reveals at day 42 sacrifice Myd-88 −/− mice with 6/15 sites (40%) +RNA; B6 0/15 sites (0%) +RNA. Histopathology revealed mild to moderate inflammation in MyD88−/− mice and demonstrable organisms by IHC Abstract O4-S2.05 figure 1). Abstract O4-S2.05 Figure 1 Day 21 Post T.pallidum infection Epididymis. Conclusion These preliminary experiments suggest that the immune recognition impairment caused by deleting Myd88 signalling protein results in productive and longer-lasting T pallidum infection in this murine strain compared to wild-type mice. Further experiments are necessary to further elucidate the kinetics of T pallidum-infected Myd-88 −/− mice (relative DNA burden in tissue compartments, carrying out infection to 3 and 6 months and beyond to assess chronicity). MyD-88 deficient mice may hold the promise of serving as one of the first useful murine models to study immunopathogenesis of T pallidum infection. Abstract O4-S2.05 figure 1: representative epididymus sections from Day 21 sacrifice. Formalin-fixed tissues were stained with H&E as well as T pallidum-specific immunohistochemical stain (IHC).