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.

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 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.

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.

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.

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.

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.

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.

Improving cytopenia with splenic artery embolization in a patient with paroxysmal nocturnal hemoglobinuria on eculizumab.

Paroxysmal nocturnal hemoglobinuria is a rare acquired stem cell disorder characterized by intravascular hemolysis, aplasia and an increased risk of thrombosis. We describe a patient under treatment with the anti-complement antibody eculizumab who developed pancytopenia, requiring blood transfusions, due to massive splenomegaly. The patient underwent two separate splenic embolizations, which reduced the size of the spleen and improved his blood count to the point that blood transfusions were no longer necessary. Splenic embolization was chosen over splenectomy due to the potential postoperative complications of splenectomy, especially that of thrombosis.

The scope and variety of combined baccalaureate-MD programs in the United States.

The landscape of combined baccalaureate-MD programs has changed substantially in the last two decades but has not been documented in detail. The authors review the current state of these programs and discuss opportunities for future study of their evolving role and potential impact.In 2011, using a definition of baccalaureate-MD program built on prior research, the authors reviewed Association of American Medical Colleges sources and medical school Web sites to identify and characterize 81 active programs. In addition, they surveyed the 57 medical schools offering those programs; 31 schools with 39 programs responded. The resulting database inventories the number and distribution of programs; institutional affiliations; missions or goals; length; size; admissions criteria; curricula; and retention requirements.Since the inception of combined programs in 1961, their number and curricular length have increased. Pressures that spurred earlier programs remain evident in the goals of today's programs: attract talented high school or early college students, especially from diverse backgrounds; prepare physicians to meet societal needs; and offer an enriched premedical environment. Baccalaureate educational activities achieve program goals through special courses, medical experiences, community service, and learning communities tailored to students' needs. Admission and retention criteria are comparable to those of traditional medical schools.Combined baccalaureate-MD programs have evolved along several paths during the last half century and have enriched the baccalaureate experiences of medical students. Shifting expectations for the selection and education of future physicians warrant focused research on these programs to document their effectiveness in addressing those expectations.

Management of transfusion-related iron overload in patients with myelodysplastic syndromes.

Anemia is a common symptom for patients with myelodysplastic syndromes (MDS), a spectrum of hematopoietic malignancies characterized by ineffective hematopoiesis; 90% of these patients will become transfusion dependent (TD). Because of the closed nature of iron metabolism, the repeated input of packed red blood cells during transfusions inevitably leads to iron overload. Iron overload can cause iron-related toxicity as well as end-organ damage from iron deposition in tissues. Studies have shown that patients with MDS who are TD have shorter overall survival, shorter leukemia-free survival, and higher healthcare costs compared with patients who are not TD, suggesting that iron overload has a significant clinical and economic impact. Iron chelation therapy can bind and eliminate free iron from the body. Although studies in genetic anemias have shown improved clinical outcomes, clinical trials with patients with MDS are ongoing. Because iron chelation therapy can be toxic, the risks, benefits, and therapy-related costs must be weighed for each patient.

Peer nominations as related to academic attainment, empathy, personality, and specialty interest.

PURPOSE: To test the hypotheses that peer nomination is associated with measures of (1) academic performance, (2) empathy, (3) personality, and (4) specialty interest. METHOD: In 2007-2008, 255 third-year medical students at Jefferson Medical College were asked to nominate classmates they considered the best in six areas of clinical and humanistic excellence. The authors compared students who received nominations with those who did not, analyzing differences in academic performance, personality factors (empathy as measured by the Jefferson Scale of Empathy and personality qualities as measured by the Zuckerman-Kuhlman Personality Questionnaire), and specialty interests. RESULTS: A comparison of the 155 students who received at least one peer nomination with the 100 students who received none found no significant difference in scores on objective examinations; nominated students, however, were rated significantly higher in clinical competence by faculty in six core third-year clerkships. Nominated students were also significantly more empathic and "active." In addition, a larger proportion of nominated students choose "people-oriented" (rather than "technology- or procedure-oriented") specialties. CONCLUSIONS: These results confirmed the hypotheses that peer nomination can predict clinical competence, empathy and other positive personal qualities, and interest in people-oriented specialties. Thus, in the assessment of medical students, peer nomination holds promise as a valid indicator of positive dimensions of professionalism.

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.

What factors create a humanistic doctor? A nationwide survey of fourth-year medical students.

PURPOSE: The authors sought to develop a conceptual framework of the factors that most influence medical students' development of humanism and to explore students' opinions regarding the role these factors play in developing or inhibiting humanism. METHOD: In 2006-2007, the authors conducted 16 focus groups with fourth-year students and first-year residents at four universities to design a conceptual framework. They used the framework to develop a survey, which they administered to fourth-year medical students at 20 U.S. medical schools in 2007-2008. RESULTS: Data from 80 focus-group participants suggested that the key influences on students' development of humanism were their authentic, unique, and participatory experiences before and during medical school, and the opportunity to process these experiences. Students who completed the survey (N = 1,170) reported that experiences of greatest intensity (e.g., being involved in a case where the patient dies), participatory learning experiences (e.g., volunteer work, international clinical rotations), and positive role models had the greatest effect on their development of humanism, whereas stressful conditions, such as a busy workload or being tired or postcall, inhibited their humanism. Women and students going into primary care placed significantly greater importance on experiences promoting humanism than did men and those not going into primary care. In addition, students with lower debt burdens viewed such experiences as more important than did those with higher debt burdens. CONCLUSIONS: Students viewed a variety of factors as influencing their development of humanism. This research provides a starting point for enhancing curricula to promote humanism.