Treatment outcomes of complement protein C5 inhibition in 509 UK patients with paroxysmal nocturnal hemoglobinuria.

ABSTRACT: Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired clonal hematopoietic disorder that occurs on a background of bone marrow failure (BMF). In PNH, chronic intravascular hemolysis causes an increase in morbidity and mortality, mainly because of thromboses. Over the last 20 years, treatment of PNH has focused on the complement protein C5 to prevent intravascular hemolysis using the monoclonal antibody eculizumab and more recently ravulizumab. In the United Kingdom, all patients are under review at 1 of 2 reference centers. We report on all 509 UK patients with PNH treated with eculizumab and/or ravulizumab between May 2002 and July 2022. The survival of patients with eculizumab and ravulizumab was significantly lower than that of age- and sex-matched controls (P = .001). Only 4 patients died of thromboses. The survival of patients with PNH (n = 389), when those requiring treatment for BMF (clonal evolution to myelodysplastic syndrome or acute leukemia or had progressive unresponsive aplastic anemia) were excluded, was not significantly different from that of age- and sex-matched controls (P = .12). There were 11 cases of meningococcal sepsis (0.35 events per 100 patient-years). Extravascular hemolysis was evident in patients who received treatment, with 26.7% of patients requiring transfusions in the most recent 12 months on therapy. Eculizumab and ravulizumab are safe and effective therapies that reduce mortality and morbidity in PNH, but further work is needed to reduce mortality in those with concomitant BMF.

The incidence and prevalence of patients with paroxysmal nocturnal haemoglobinuria and aplastic anaemia PNH syndrome: A retrospective analysis of the UK's population-based haematological malignancy research network 2004-2018.

OBJECTIVES: A retrospective population-based study to determine the incidence and prevalence of patients with the rare blood disease paroxysmal nocturnal haemoglobinuria (PNH). METHODS: All patients were identified by flow cytometric detection of blood cells deficient in glycosylphosphatidylinositol (GPI) linked proteins at a single diagnostic reference laboratory that serves the Yorkshire based, Haematological Malignancy Research Network (HMRN) with a population of 3.8 million. RESULTS: One hundred and ninety-seven patients with detectable PNH clones at a level of >0.01% in at least two lineages of cells (neutrophils, monocytes and/or red cells) were identified over a 15-year period (2004-2018). Of these, 88% had aplastic anaemia (AA), 8% classical PNH and 3% myelodysplastic syndrome. The overall incidence rate was estimated at 0.35 cases per 100 000 people per year. This equates to 220 cases newly diagnosed in the United Kingdom each year. The overall prevalence rate was 3.81 per 100 000, this equates to an estimated 2400 prevalent cases in the UK. The overall and relative 5-year survival rates were 72% and 82.7%, respectively. CONCLUSIONS: This study showed that classical haemolytic PNH is a rare disease and represents only a small proportion overall of patients with detectable PNH cells, the majority of which have aplastic anaemia.

Presentation clinical, haematological and immunophenotypic features of 1081 patients with GPI-deficient (paroxysmal nocturnal haemoglobinuria) cells detected by flow cytometry.

A retrospective analysis of presentation clinical, laboratory and immunophenotypic features of 1 081 patients with paroxysmal nocturnal haemoglobinuria (PNH) clones [glycosylphosphatidylinositol (GPI)-deficient blood cells] identified at our hospital by flow cytometry over the past 25 years was undertaken. Three distinct clusters of patients were identified and significant correlations between presentation disease type and PNH clone sizes were evident. Smaller PNH clones predominate in cytopenic and myelodysplastic subtypes; large PNH clones were associated with haemolytic, thrombotic and haemolytic/thrombotic subtypes. Rare cases with an associated chronic myeloproliferative disorder had either large or small PNH clones. Cytopenia was a frequent finding, highlighting bone marrow failure as the major underlying feature associated with the detection of PNH clones in the peripheral blood. Red cell PNH clones showed significant correlations between the presence of type II (partial GPI deficiency) red cells and thrombotic disease. Haemolytic PNH was associated with type III (complete GPI deficiency) red cell populations of >20%. Those with both haemolytic and thrombotic features had major type II and type III red cell populations. Distinct patterns of presentation age decade were evident for clinical subtypes with a peak incidence of haemolytic PNH in the 30-49 year age group and a biphasic age distribution for the cytopenia group.

Micro-relational interdependencies are the essence of teaching and learning in the OR.

CONTEXT: In the high-stakes, time-critical environment of the operating room (OR), attendings and residents strive to complete safe, effective surgeries and ensure that learning occurs. Yet meaningful resident participation often receives less attention, and that impedes residents' ability to learn and achieve autonomous operative practice. We need a new conceptual framework for understanding progression to autonomous practice that can guide both faculty and residents. Thus, we sought a new conceptualisation of intraoperative teaching and learning (IOT&L) through the lens of Eraut's notion of informal workplace learning and Billett's theory of relational interdependence between social and individual agency. METHODS: We viewed authentic examples of IOT&L in video and transcripts of live OR cases and interviews with participating attendings and residents. By systematically applying Eraut and Billet's theories to the transcripts and interviews, we developed concrete descriptions about how IOT&L occurs, categorised them into theory-based principles and derived a conceptualisation and related research ideas about IOT&L. RESULTS: Established workplace learning theories frame IOT&L as socially negotiated processes transpiring in distinct interdependent interactions between residents' individual cognitive experiences and their OR social experiences that direct their learning. As the surgery unfolds, spontaneous events and the rules of surgery create opportunities for unplanned and informal learning. These authentic interrelated cognitive and social experiences are stimulated when residents reveal a learning need or attendings recognise a learning gap, and efforts ensue to bridge that gap. Through these minute distinct exchanges, labelled here as 'atomic' IOT&L, residents gain crucial knowledge and skill. CONCLUSION: Framing authentic OR interactions between attendings and residents in terms of micro-relational interdependencies shows how granular teaching/learning exchanges yield high-value informal learning. To improve IOT&L, we must examine and change it at this fundamental level by using and testing this new theoretical conceptualisation. These insights produced ideas about IOT&L to test and research.

Long-term treatment with eculizumab in paroxysmal nocturnal hemoglobinuria: sustained efficacy and improved survival.

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired clonal hematopoietic disorder with increased mortality and morbidity resulting from intravascular hemolysis. Eculizumab, a monoclonal antibody against the complement protein 5, stops the intravascular hemolysis in PNH. We evaluated 79 consecutive patients treated with eculizumab in Leeds between May 2002 and July 2010. The survival of patients treated with eculizumab was not different from age- and sex-matched normal controls (P = .46) but was significantly better than 30 similar patients managed before eculizumab (P = .030). Three patients on eculizumab, all over 50 years old, died of causes unrelated to PNH. Twenty-one patients (27%) had a thrombosis before starting eculizumab (5.6 events per 100 patient-years) compared with 2 thromboses on eculizumab (0.8 events per 100 patient-years; P < .001). Twenty-one patients with no previous thrombosis discontinued warfarin on eculizumab with no thrombotic sequelae. Forty of 61 (66%) patients on eculizumab for more than 12 months achieved transfusion independence. The 12-month mean transfusion requirement reduced from 19.3 units before eculizumab to 5.0 units in the most recent 12 months on eculizumab (P < .001). Eculizumab dramatically alters the natural course of PNH, reducing symptoms and disease complications as well as improving survival to a similar level to that of the general population.

Optimizing surgical teaching through the lens of sociocultural learning theory.

BACKGROUND: The objective of this study was to identify intraoperative instructional strategies that embody the ways that learning occurs in the social contexts of surgery. METHODS: We performed a qualitative review of examples of intraoperative teaching from transcripts of ten videotaped surgeries, coupled with interviews with surgical attendings and residents. We coded the examples according to the key tenets of sociocultural learning theories and used these codes to develop instructional strategies aimed at improving resident surgical autonomy. RESULTS: The sociocultural learning theories prompted six intraoperative teaching strategies (Assess Learner Needs, Inquire, Coach, Permit, Entrust, and Debrief) to address residents' learning needs in specific surgical tasks. The six strategies involve identifying procedure-specific learning needs; discussing interventions based on strategies successful with other learners; providing in-the-moment, interactive coaching; allowing the resident to struggle; increasing the resident's graduated responsibility; debriefing about successes and struggles. CONCLUSIONS: We argue that these six strategies should improve the quality of intraoperative teaching, and therefore, enhance progression to autonomous practice.

The management of pregnancy in paroxysmal nocturnal haemoglobinuria on long term eculizumab.

In Paroxysmal nocturnal haemoglobinuria (PNH), pregnancy is associated with increased maternal and foetal complications to such an extent that the condition has been considered relatively contra-indicated in PNH. Eculizumab has revolutionized the treatment of PNH. We evaluate its use in pregnancy to date. We report on seven patients exposed to eculizumab at different stages of pregnancy including the first two patients to receive the drug from conception to delivery. There was no evidence of complement blockade from cord blood samples taken at delivery. Eculizumab appears safe to use in this setting and is likely to prevent many of the complications usually observed.

Eculizumab prevents intravascular hemolysis in patients with paroxysmal nocturnal hemoglobinuria and unmasks low-level extravascular hemolysis occurring through C3 opsonization.

BACKGROUND: Paroxysmal nocturnal hemoglobinuria is an acquired hemolytic anemia characterized by intravascular hemolysis which has been demonstrated to be effectively controlled with eculizumab. However, lactate dehydrogenase levels remain slightly elevated and haptoglobin levels remain low in some patients suggesting residual low-level hemolysis. This may be due to C3-mediated clearance of paroxysmal nocturnal hemoglobinuria red blood cells through the reticuloendothelial system. DESIGN AND METHODS: Thirty-nine samples from patients not treated with eculizumab and 31 samples from patients treated with eculizumab were obtained (for 17 of these 31 samples there were also samples taken prior to eculizumab treatment). Membrane bound complement was assessed by flow cytometry. Direct antiglobulin testing was carried out using two methods. Lactate dehydrogenase was assayed to assess the degree of hemolysis. RESULTS: Three of 39 patients (8%) with paroxysmal nocturnal hemoglobinuria not on eculizumab had a positive direct antiglobulin test, while the test was positive in 21 of 31 (68%) during eculizumab treatment. Of these 21 patients who had a positive direct antiglobulin test during eculizumab treatment, 17 had been tested prior to treatment; only one was positive. Flow cytometry using anti-C3 monoclonal antibodies was performed on the 21 direct antiglobulin test-positive, eculizumab-treated patients; the median proportion of C3-positive total red blood cells was 26%. Among the eculizumab-treated patients, 16 of the 21 (76.2%) with a positive direct antiglobulin test received at least one transfusion compared with one of ten (10.0%) of those with a negative test (P<0.01). Among the eculizumab-treated patients, the mean hemoglobin value for the 21 with a positive direct antiglobulin test was 9.6+/-0.3 g/dL, whereas that in the ten patients with a negative test was 11.0+/-0.4 g/dL (P=0.02). CONCLUSIONS: These data demonstrate a previously masked mechanism of red cell clearance in paroxysmal nocturnal hemoglobinuria and suggests that blockade of complement at C5 allows C3 fragment accumulation on some paroxysmal nocturnal hemoglobinuria red cells, explaining the residual low-level hemolysis occurring in some eculizumab-treated patients.

Medical students' interviews with older adults: an examination of their performance.

During a geriatrics/gerontology curriculum designed to develop positive attitudes toward older adults, promote understanding about the psychosocial aspects of normal aging, and provide experience with intergenerational communication, students in a combined BA/MD degree program participated in learning activities that focused on interacting with and interviewing older adults. This article describes medical students' performance during an intergenerational interview, examines differences between students' self-assessments and evaluators' ratings of students' performance, and presents statistical relationships among communication apprehension, situation anxiety, competence, and performance. Data analysis indicates that the majority of students demonstrated competent intergenerational interviewing skills during their standardized communication assessment. The discussion elaborates on the study findings, acknowledges limitations, and addresses practical implications of the study.

Development of a communication curriculum for emergency medicine residents.

BACKGROUND: The Accreditation Council for Graduate Medical Education requires residency training programs to develop methods to teach and assess communication skills in residents to ensure competence as a practitioner. In response, we piloted a communication curriculum for emergency medicine residents. We describe the curriculum and suggest future directions for development based on the strengths and weaknesses of residents' performance and their reactions to the curriculum. DESCRIPTION: Twenty-six residents in a 3-year program at a university-affiliated county hospital participated. Curriculum components were an introductory session, a single standardized patient encounter using a locally written, unvalidated checklist assessing residents' communication skills, a videotape-facilitated self-assessment, and a private feedback session. EVALUATION: Residents demonstrated greatest strengths in basic interpersonal skills and efficient information gathering and greatest weakness in empathy. Residents rated the curriculum favorably. CONCLUSION: The curriculum as implemented offers an initial foundation for teaching and learning critical care communication. Instruction in empathy requires improvement.

Medical Leaders Identify Personal Characteristics and Experiences that Contribute to Leadership Success in Medicine.

This article was migrated. The article was marked as recommended. Introduction: The approach of medical educators to preparing learners for leadership reflects the emphasis leadership theories once placed on experiential learning. But, contemporary theories now also show a renewed interest in the role of personal characteristics in effective leadership. This shift raises questions explored here: What characteristics mark top medical leaders? What experiences nurture those characteristics? Method: In a 2015 qualitative study, 48 University of Missouri-Kansas City (UMKC) medical graduates who met criteria for outstanding leadership participated in semi-structured interviews. Investigators applied directed content-analysis to their responses. Then, using iterative open-coding, investigators identified personal characteristics leaders said contributed to their leadership, clustered them into types, and counted the number of leaders who spoke to each type. Next, they coded and categorized experiences leaders discussed and counted the number of leaders who mentioned each type of experience. Finally, they identified leaders' comments about which types of experiences helped develop which types of characteristics. Results: Most leadersmentioned four types of characteristics: openness to new ideas/opportunities/astute risk-taking; intense motivation/active involvement/commitment; people-orientation; and capability/competence/ intelligence. Many discussed two additional types: self-awareness and service-orientation. Leaders said these types of experiences nurtured their characteristics: family traditions, high-school co-curricular activities, participation in medical school learning communities plus interaction with role models/mentors and authentic opportunities to practice leadership, innovation, and excellence throughout their education and in the workplace. Conclusions: Medical leaders' views of the role of personal characteristics in outstanding leadership and the power of educational and workplace experiences, especially informal ones, to mold those characteristics have enriched understanding how to prepare tomorrow's leaders.

Critical care recognition, management and communication skills during an emergency medicine clerkship.

BACKGROUND: Medical students need to learn how to recognize and manage critically ill patients; to communicate in critical situations with patients, families, and the healthcare team; and finally, to integrate technical knowledge with communication skills in caring for these patients. Meeting their needs will help prepare them to demonstrate, as physicians, the ability to synthesize information while simultaneously caring for patients, that the American Medical Association recently characterized as vital. AIMS: Responding to these needs, we developed and implemented a curriculum to enable students in a required emergency medicine clerkship to recognize, manage, and simultaneously communicate with critically ill patients. METHODS: The curriculum consisted of lectures and exercises on caring for the critically ill including: an introduction to the systematic approach; an interactive lecture on comprehensive communication; observation and discussion of real patients in the emergency department; participation in a single standardized patient encounter while peers and a faculty member observed them; assessment of students' own videotaped performance of the examination by using critical care and communication/interpersonal skills checklists; and receipt of private feedback based on the checklists from the faculty and the standardized patient. Students evaluated the curriculum at the end of the clerkship. RESULTS: Complete performance data for 46 students and curriculum evaluation data from 42 students were available. According to faculty assessment, students as a group performed 79.6% (SD 0.15) of the critical care and 70.9% (SD 11.5%) of the communication skills. Students most often demonstrated Basic Interpersonal Skills (97.9%, SD 0.056) and least often demonstrated Empathy skills (41.7%, SD 0.235). Students rated the curriculum positively. CONCLUSIONS: It is feasible to integrate the teaching of communication skills with the recognition and management of critically ill patients. The next step will be to revise the curriculum to address student deficiencies and to evaluate its effectiveness more rigorously.

A Free-Market Approach to the Match: A Proposal Whose Time Has Not Yet Come.

The authors respond to a proposal in this issue of Academic Medicine by Ray, Bishop, and Dow, who recommend adopting a free-market approach to the Match in which applicants and programs negotiate directly with each other to find and fill residency positions year-round. This Invited Commentary examines and responds to the reasons Ray and colleagues give for changing the Match and explores their proposal's implications and likelihood of success.The authors question Ray and colleagues' argument that assumptions underlying the National Resident Matching Program algorithm have been violated. The authors suggest there is insufficient evidence for the "July effect" and that the possibility for improvement in physician supply due to the year-round entry of graduates into the workforce ultimately faces the rate-limiting step of caps on residency positions allocated to programs. Most important, competency-based medical education, on which the free-market proposal depends, is not yet sufficiently developed.Nonetheless, the imbalanced ratio of applicants to positions in the Match is contributing to a rise in the numbers of student applications and program interviews. Although the proposed free-market approach might, as Ray and colleagues envision, curtail applications as well as reduce time and financial resources currently expended on the process, it would require significant changes on the part of applicants, residency programs, medical schools, and other stakeholders.Because the proposed free-market approach could reduce some negative effects of the imbalance of applicants and positions, it merits ongoing discussion along with other more immediate practical solutions to issues with the Match.

Medical School Factors That Prepare Students to Become Leaders in Medicine.

PURPOSE: To identify medical school factors graduates in major leadership positions perceive as contributing to their leadership development. METHOD: Using a phenomenological, qualitative approach, in August-November 2015 the authors conducted semistructured interviews with 48 medical leaders who were 1976-1999 baccalaureate-MD graduates of the University of Missouri-Kansas City School of Medicine (UMKC). At UMKC, they participated in longitudinal learning communities, the centerpiece for learning professional values and behaviors plus clinical skills, knowledge, and judgment, but received no formal leadership instruction. The authors subjected interview comments to directed, largely qualitative content analysis with iterative coding cycles. RESULTS: Most graduates said their experiences and the people at UMKC positively influenced their leadership growth. Medical school factors that emerged as contributing to that growth were the longitudinal learning communities including docents, junior-senior partners, and team experiences; expectations set for students to achieve; a clinically oriented but integrated curriculum; admission policies seeking students with academic and nonacademic qualifications; supportive student-student and student-faculty relationships; and a positive overall learning environment. Graduates viewed a combination of factors as best preparing them for leadership and excellence in clinical medicine; together these factors enabled them to assume leadership opportunities after graduation. CONCLUSIONS: This study adds medical leaders' perspective to the leadership development literature and offers guidance from theory and practice for medical schools to consider in shaping leadership education: Namely, informal leadership preparation coupled with extensive longitudinal clinical education in a nurturing, authentic environment can develop students effectively for leadership in medicine.

The University of Missouri-Kansas City School of Medicine: thirty-five years of experience with a nontraditional approach to medical education.

The University of Missouri-Kansas City (UMKC) School of Medicine is a public medical school that opened in 1971 in response to a need to train more physicians in Missouri. As a six-year, integrated, combined-degree program leading to the baccalaureate and medical degrees, the school offers an innovative, nontraditional approach to medical education. In the past 35 years, UMKC has graduated over 2,400 physicians who are successful according to outcomes measures used at other medical schools. With recent interest in reforming medical education to prepare physicians for a changing world, a review of alternative models may be especially instructive.UMKC's academic plan offers a blueprint for the curriculum plan and governance of the school. The plan is built on four hallmarks: (1) a combined baccalaureate/MD program, (2) early exposure to clinical medicine, (3) small-group learning through the docent system, and (4) a continuing ambulatory care clinic experience for four years. This article catalogs the results of this plan including student, faculty, and graduates' perceptions of and satisfaction with the school's educational approach, students' achievement on licensing examinations and in the residency match, graduates' performance in residency programs, and their subsequent career patterns. The authors also discuss lessons learned and adjustments made in response to local needs in the context of a changing environment in education, health care, and health care delivery while continually improving the school's nontraditional approach to medical education. These include changes in basic and clinical science instruction, student assessment, faculty development, and funding and governance.