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1.  Optimizing Porcine Islet Isolation to Markedly Reduce Enzyme Consumption Without Sacrificing Islet Yield or Function 
Transplantation Direct  2016;2(7):e86.
Human allogeneic islet transplantation for treatment of type 1 diabetes provides numerous clinical benefits, such as fewer episodes of hypoglycemic unawareness and tighter control of blood glucose levels. Availability of human pancreas for clinical and research use, however, is severely limited. Porcine pancreas offers an abundant source of tissue for optimization of islet isolation methodology and future clinical transplantation, thereby increasing patient access to this potentially lifesaving procedure.
Porcine islet isolations were performed using varying amounts of collagenase (7.5, 3.75, or 2.5 Wunsch units per gram tissue) and neutral protease activity (12 000, 6000, or 4000 neutral protease units per gram tissue) and perfusion volumes (1.7 or 0.85 mL/g tissue) to assess their effects on isolation outcomes. Retention of dissociative enzymes within the pancreas during perfusion and digestion was evaluated, along with distribution of the perfusion solution within the tissue.
Reducing enzyme usage by as much as 67% and perfusion volume by 50% led to equally successful islet isolation outcomes when compared with the control group (48 ± 7% of tissue digested and 1088 ± 299 islet equivalents per gram of pancreas vs 47 ± 11% and 1080 ± 512, respectively). Using margin-marking dye in the perfusion solution to visualize enzyme distribution demonstrated that increasing perfusion volume did not improve tissue infiltration.
Current protocols for porcine islet isolation consume excessive amounts of dissociative enzymes, elevating cost and limiting research and development. These data demonstrate that islet isolation protocols can be optimized to significantly reduce enzyme usage while maintaining yield and function and thus accelerating progress toward clinical application.
PMCID: PMC5087567  PMID: 27830180
2.  Identifying Effective Enzyme Activity Targets for Recombinant Class I and Class II Collagenase for Successful Human Islet Isolation 
Transplantation Direct  2015;2(1):e54.
Isolation following a good manufacturing practice-compliant, human islet product requires development of a robust islet isolation procedure where effective limits of key reagents are known. The enzymes used for islet isolation are critical but little is known about the doses of class I and class II collagenase required for successful islet isolation.
We used a factorial approach to evaluate the effect of high and low target activities of recombinant class I (rC1) and class II (rC2) collagenase on human islet yield. Consequently, 4 different enzyme formulations with divergent C1:C2 collagenase mass ratios were assessed, each supplemented with the same dose of neutral protease. Both split pancreas and whole pancreas models were used to test enzyme targets (n = 20). Islet yield/g pancreas was compared with historical enzymes (n = 42).
Varying the Wunsch (rC2) and collagen degradation activity (CDA, rC1) target dose, and consequently the C1:C2 mass ratio, had no significant effect on tissue digestion. Digestions using higher doses of Wunsch and CDA resulted in comparable islet yields to those obtained with 60% and 50% of those activities, respectively. Factorial analysis revealed no significant main effect of Wunsch activity or CDA for any parameter measured. Aggregate results from 4 different collagenase formulations gave 44% higher islet yield (>5000 islet equivalents/g) in the body/tail of the pancreas (n = 12) when compared with those from the same segment using a standard natural collagenase/protease mixture (n = 6). Additionally, islet yields greater than 5000 islet equivalents/g pancreas were also obtained in whole human pancreas.
A broader C1:C2 ratio can be used for human islet isolation than has been used in the past. Recombinant collagenase is an effective replacement for the natural enzyme and we have determined that high islet yield can be obtained even with low doses of rC1:rC2, which is beneficial for the survival of islets.
PMCID: PMC4946501  PMID: 27500247
3.  Charting the Road to Competence: Developmental Milestones for Internal Medicine Residency Training 
The Accreditation Council for Graduate Medical Education (ACGME) Outcome Project requires that residency program directors objectively document that their residents achieve competence in 6 general dimensions of practice.
In November 2007, the American Board of Internal Medicine (ABIM) and the ACGME initiated the development of milestones for internal medicine residency training. ABIM and ACGME convened a 33-member milestones task force made up of program directors, experts in evaluation and quality, and representatives of internal medicine stakeholder organizations. This article reports on the development process and the resulting list of proposed milestones for each ACGME competency.
The task force adopted the Dreyfus model of skill acquisition as a framework the internal medicine milestones, and calibrated the milestones with the expectation that residents achieve, at a minimum, the “competency” level in the 5-step progression by the completion of residency. The task force also developed general recommendations for strategies to evaluate the milestones.
The milestones resulting from this effort will promote competency-based resident education in internal medicine, and will allow program directors to track the progress of residents and inform decisions regarding promotion and readiness for independent practice. In addition, the milestones may guide curriculum development, suggest specific assessment strategies, provide benchmarks for resident self-directed assessment-seeking, and assist remediation by facilitating identification of specific deficits. Finally, by making explicit the profession's expectations for graduates and providing a degree of national standardization in evaluation, the milestones may improve public accountability for residency training.
PMCID: PMC2931179  PMID: 21975701
4.  Surgical versus non-surgical treatment of feline small intestinal adenocarcinoma and the influence of metastasis on long-term survival in 18 cats (2000–2007) 
The Canadian Veterinary Journal  2011;52(10):1101-1105.
This study retrospectively evaluated long-term outcomes of 18 cats diagnosed with small intestinal adenocarcinoma, based on surgical versus non-surgical treatment and the presence or absence of metastasis at the time of surgery. Ten cats had surgery and histopathologic confirmation of adenocarcinoma and 8 cats did not have surgery but had cytologic diagnosis of adenocarcinoma. Median survival of cats with adenocarcinoma that underwent surgical excision was 365 days and 22 days for those with suspected adenocarcinoma that did not undergo surgery (P = 0.019). Median survival of cats was 843 days for those without evidence of metastatic disease at the time of surgery and 358 days for those that had (P = 0.25). In conclusion, surgical excision is beneficial in the treatment of small intestinal adenocarcinoma in the cat, including those patients with metastasis, and may result in a significantly longer survival time compared with patients which do not have their mass surgically excised.
PMCID: PMC3174506  PMID: 22467965
5.  Transforming Primary Care Training—Patient-Centered Medical Home Entrustable Professional Activities for Internal Medicine Residents 
The U.S. faces a critical gap between residency training and clinical practice that affects the recruitment and preparation of internal medicine residents for primary care careers. The patient-centered medical home (PCMH) represents a new clinical microsystem that is being widely promoted and implemented to improve access, quality, and sustainability in primary care practice.
We address two key questions regarding the training of internal medicine residents for practice in PCMHs. First, what are the educational implications of practice transformations to primary care home models? Second, what must we do differently to prepare internal medicine residents for their futures in PCMHs?
The 2011 Society of General Internal Medicine (SGIM) PCMH Education Summit established seven work groups to address the following topics: resident workplace competencies, teamwork, continuity of care, assessment, faculty development, ‘medical home builder’ tools, and policy. The output from the competency work group was foundational for the work of other groups. The work group considered several educational frameworks, including developmental milestones, competencies, and entrustable professional activities (EPAs).
The competency work group defined 25 internal medicine resident PCMH EPAs. The 2011 National Committee for Quality Assurance (NCQA) PCMH standards served as an organizing framework for EPAs.
The list of PCMH EPAs has the potential to begin to transform the education of internal medicine residents for practice and leadership in the PCMH. It will guide curriculum development, learner assessment, and clinical practice redesign for academic health centers.
PMCID: PMC3663955  PMID: 22997002
patient-centered medical home; entrustable professional activities; graduate medical education; internal medicine; primary care
6.  Tissue dissociation enzymes for isolating human islets for transplantation: factors to consider in setting enzyme acceptance criteria 
Transplantation  2011;91(2):137-145.
Tissue dissociation enzymes are critical reagents that affect the yield and quality of human pancreatic islets required for islet transplantation. The FDA’s oversight of this procedure recommends laboratories set acceptance criteria for enzymes used in the manufacture of islet products for transplantation. Presently, many laboratories base this selection on personal experience since biochemical analysis is not predictive of success of the islet isolation procedure. This review identifies the challenges of correlating results from enzyme biochemical analysis to their effectiveness in human islet isolation and suggests a path forward to address these challenges to improve control of the islet manufacturing process.
PMCID: PMC3022104  PMID: 21116222
tissue dissociation; collagenase; islet isolation; protease; biochemical characterization; type 1 diabetes
7.  Development and Implementation of an Oral Sign-out Skills Curriculum 
Journal of General Internal Medicine  2007;22(10):1470-1474.
Imperfect sign-out of patient information between providers has been shown to contribute to medical error, but there are no standardized curricula to teach sign-out skills. At our institution, we identified several deficiencies in skills and a lack of any existing training.
To develop a sign-out curriculum for medical house staff. Setting: Internal medicine residency program.
Program description
We developed a 1-h curriculum and implemented it in August of 2006 at three hospital sites. Teaching strategies included facilitated discussion, modeling, and observed individual practice with feedback. We emphasized interactive communication, a structured sign-out format summarized by an easy-to-remember mnemonic (“SIGNOUT”), consistent inclusion of key content items such as anticipatory guidance, and use of concrete language.
Program evaluation
We received 34 evaluations. The mean score for the course was 4.44 ± 0.61 on a 1–5 scale. Perceived usefulness of the structured oral communication format was 4.46 ± 0.78. Participants rated their comfort with providing oral sign-out significantly higher after the session than before (3.27 ± 1.0 before vs. 3.94 ± 0.90 after; p < .001).
We developed an oral sign-out curriculum that was brief, structured, and well received by participants. Further study is necessary to determine the long-term impact of the curriculum.
PMCID: PMC2305855  PMID: 17674110
medical student and residency education; communication skills; curriculum development/evaluation
8.  Internal Medicine Residents' Clinical and Didactic Experiences After Work Hour Regulation 
Work hour regulations for house staff were intended in part to improve resident clinical and educational performance.
To characterize the effect of work hour regulation on internal medicine resident inpatient clinical experience and didactic education.
Cross-sectional mail survey.
Chief residents at all accredited U.S. internal medicine residency programs outside New York.
The response rate was 62% (202/324). Most programs (72%) reported no change in average patient load per intern after work hour regulation. Many programs (48%) redistributed house staff admissions through the call cycle. The number of admissions per intern on long call (the day interns have the most admitting responsibility) decreased in 31% of programs, and the number of admissions on other days increased in 21% of programs. Residents on outpatient rotations were given new ward responsibilities in 36% of programs. Third-year resident ward and float time increased in 34% of programs, while third-year elective time decreased in 22% of programs. The mean weekly hours allotted to educational activities did not change significantly (12.7 vs 12.4, P = .12), but 56% of programs reported a decrease in intern attendance at educational activities.
In response to work hour regulation, many internal medicine programs redistributed rather than reduced residents' inpatient clinical experience. Hours allotted to educational activities did not change; however, most programs saw a decrease in intern attendance at conferences, and many reduced third-year elective time.
PMCID: PMC1831597  PMID: 16918742
internship and residency; workload; education; personnel staffing; scheduling
9.  Evaluation of a Women's Safe Shelter Experience to Teach Internal Medicine Residents About Intimate Partner Violence 
Although intimate partner violence (IPV) remains a major public health problem, physicians often fail to screen female patients. Reported IPV training approaches suffer from weak study designs and limited outcome assessments. We hypothesized that an educational experience for residents at a women's safe shelter would have significantly greater impact on IPV competencies, screening, and care for victims than a workshop seminar alone. In a pre-post randomized controlled trial, we compared residents exposed to the workshop seminar alone (controls) to residents exposed to these methods plus an experience at a women's safe shelter (cases). Competencies were assessed by written questionnaire and included knowledge, skills, attitudes, resource awareness, and screening behaviors. Of the 36 residents in the trial, 22 (61%) completed both pre- and postquestionnaires. Compared to controls, cases showed significantly greater pre-post improvement in the knowledge composite subscale. There were no significant differences between cases and controls in the subscales of skills, attitudes, or resource awareness. Cases increased their self-reported screening frequency but this did not differ significantly from the controls. Enhancing traditional IPV curriculum with a women's safe shelter educational experience may result in small improvements in residents' knowledge about IPV.
PMCID: PMC1490142  PMID: 15987330
intimate partner violence; medical education; curriculum; randomized controlled trial
11.  The fool wonders, the wise (women) ask... about tropical diseases in their practice 
BMJ : British Medical Journal  2004;329(7473):1023.
PMCID: PMC524558  PMID: 15514350
12.  Evaluating the teaching of evidence based medicine: conceptual framework 
BMJ : British Medical Journal  2004;329(7473):1029-1032.
Although evidence for the effectiveness of evidence based medicine has accumulated, there is still little evidence on what are the most effective methods of teaching it.
PMCID: PMC524561  PMID: 15514352
13.  Integrating Teaching Skills and Clinical Content in a Faculty Development Workshop 
Incorporating clinical content into medical education faculty development programs has been proposed as a strategy to consolidate faculty continuing medical education time and enhance learning. We developed a faculty development program for ambulatory internal medicine preceptors that integrated primary care genetics with ambulatory precepting. The instructional strategies addressed both areas simultaneously and included facilitated discussions, mini-lectures, trigger tapes, and role plays. To evaluate the program, we conducted a pre-post trial. Skills were measured by retrospective pre-post self-reported ratings and behaviors by self-reported implementation of commitment to change (CTC) statements. Participants' (N = 26) ambulatory precepting and primary care genetics skill ratings improved after the intervention. They listed an average of 2.4 clinical teaching CTC statements and 2.0 clinical practice CTC statements. By 3 months after the workshop, preceptors, as a group, fully implemented 32 (38%), partially implemented 35 (41%), and failed to implement 18 (21%) CTC statements. The most common barrier to clinical teaching change was insufficient skills (8 of 25; 32%) and to clinical practice change was lack of a suitable patient (15 of 25; 60%). Integrating clinical content with clinical teaching in a faculty development workshop is feasible, can improve clinical and teaching skills, and can facilitate behavior change.
PMCID: PMC1494873  PMID: 12823654
faculty development; curriculum; evaluation; integration
14.  Evaluation and Management of Dyslipidemia in Patients with HIV Infection 
Persons with HIV infection develop metabolic abnormalities related to their antiretroviral therapy and HIV infection itself. The objective of this study was to summarize the emerging evidence for the incidence, etiology, health risks, and treatment of dyslipidemias in HIV disease.
Systematic review of original research with quantitative synthesis.
Dyslipidemia is common in persons with HIV infection on highly active antiretroviral therapy (HAART), but methodologic differences between studies preclude precise estimates of prevalence and incidence. The typical pattern includes elevated total cholesterol, low-density lipoprotein cholesterol, and triglycerides, which may be markedly elevated. The dyslipidemia may be associated with lipodystrophy, insulin resistance, and, rarely, frank diabetes mellitus. Exposure to protease inhibitors (PIs) is associated with this entire range of metabolic abnormalities. PI-naïve patients on nucleoside reverse transcriptase inhibitors (NRTIs) may develop lipodystrophy, insulin resistance, hypercholesterolemia, and possibly modest elevations in triglycerides but not severe hypertriglyceridemia, which appears to be linked to PIs alone. Most studies have not found an association between CD4 lymphocyte count or HIV viral load and lipid abnormalities. The pathogenesis is incompletely understood and appears to be multifactorial. There are insufficient data to definitively support an increased coronary heart disease risk in patients with HIV-related dyslipidemia. However, some of the same metabolic abnormalities remain firmly established risk factors in other populations. Patients on HAART with severe hypertriglyceridemia may develop pancreatitis or other manifestations of the chylomicronemia syndrome. Some of the metabolic derangements (particularly hypertriglyceridemia) may improve upon replacing a PI with a non-nucleoside reverse transcriptase inhibitor. The limited experience suggests that fibrates, pravastatin, and atorvastatin can safely treat lipid abnormalities in HIV-infected patients.
Patients with HIV infection on HAART should be screened for lipid disorders, given their incidence, potential for morbidity, and possible long-term cardiovascular risk. Treatment decisions are complex and must include assessments of cardiac risk, HIV infection status, reversibility of the dyslipidemia, and the effectiveness and toxicities of lipid-lowering medications. The multiple potential drug interactions with antiretroviral or other HIV-related medications should be considered in lipid-lowering drug selection and monitoring.
PMCID: PMC1495116  PMID: 12390557
hyperlipidemia; triglycerides; HIV; lipodystrophy; protease inhibitors; HAART
15.  Evidence-Based Medicine Training in Internal Medicine Residency Programs 
To characterize evidence-based medicine (EBM) curricula in internal medicine residency programs, a written survey was mailed to 417 program directors of U.S. internal medicine residency programs. For programs offering a freestanding (dedicated curricular time) EBM curriculum, the survey inquired about its objectives, format, curricular time, attendance, faculty development, resources, and evaluation. All directors responded to questions regarding integrating EBM teaching into established educational venues. Of 417 program directors, 269 (65%) responded. Of these 269 programs, 99 (37%) offered a freestanding EBM curriculum. Among these, the most common objectives were performing critical appraisal (78%), searching for evidence (53%), posing a focused question (44%), and applying the evidence in decision making (35%). Although 97% of the programs provided medline, only 33% provided Best Evidence or the Cochrane Library. Evaluation was performed in 37% of the freestanding curricula. Considering all respondents, most programs reported efforts to integrate EBM teaching into established venues, including attending rounds (84%), resident report (82%), continuity clinic (76%), bedside rounds (68%), and emergency department (35%). However, only 51% to 64% of the programs provided on-site electronic information and 31% to 45% provided site-specific faculty development. One third of the training programs reported offering freestanding EBM curricula, which commonly targeted important EBM skills, utilized the residents' experiences, and employed an interactive format. Less than one half of the curricula, however, included curriculum evaluation, and many failed to provide important medical information sources. Most programs reported efforts to integrate EBM teaching, but many of these attempts lacked important structural elements.
PMCID: PMC1495338  PMID: 10672117
evidence-based medicine; residency programs; curriculum; graduate medical education; survey
16.  Impact of an Evidence-Based Medicine Curriculum Based on Adult Learning Theory 
To develop and implement an evidence-based medicine (EBM) curriculum and determine its effectiveness in improving residents' EBM behaviors and skills.
Description of the curriculum and a multifaceted evaluation, including a pretest-posttest controlled trial.
University-based primary care internal medicine residency program.
Second- and third-year internal medicine residents (N =34).
A 7-week EBM curriculum in which residents work through the steps of evidence-based decisions for their own patients. Based on adult learning theory, the educational strategy included a resident-directed tutorial format, use of real clinical encounters, and specific EBM facilitating techniques for faculty.
Behaviors and self-assessed competencies in EBM were measured with questionnaires. Evidence-based medicine skills were assessed with a 17-point test, which required free text responses to questions based on a clinical vignette and a test article. After the intervention, residents participating in the curriculum (case subjects) increased their use of original studies to answer clinical questions, their examination of methods and results sections of articles, and their self-assessed EBM competence in three of five domains of EBM, while the control subjects did not. The case subjects significantly improved their scores on the EBM skills test (8.5 to 11.0, p =.001), while the control subjects did not (8.5 to 7.1, p =.09). The difference in the posttest scores of the two groups was 3.9 points (p =.001, 95% confidence interval 1.9, 5.9).
An EBM curriculum based on adult learning theory improves residents' EBM skills and certain EBM behaviors. The description and multifaceted evaluation can guide medical educators involved in EBM training.
PMCID: PMC1497200  PMID: 9436893
evidence-based medicine (EBM); curriculum; residents; medical education; adult learning theory

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