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I’ve seen a recent opinion on social media amongst medical trainees that research is boring, something done only to check the boxes to advance in one’s career. I don’t know the penetrance of this opinion and it may be isolated, but I see a link between this dispassionate description of research activities by trainees and a recent paper discussing the decline of disruptive science. Hear me out.   In 2016, Funk and Owen-Smith published something called the consolidation-disruption index (CDI) [1]. Essentially, this index expresses whether a new study consolidates scientific understanding, that is whether it reinforces current understanding of a subject, versus disruption, which is whether it brings new ideas and updates to understanding of a subject. The CDI is calculated based on the number of citations a study has in the 5 years following its publication and expressed on a scale from -1 (most consolidating) to 1 (most disruptive).   Earlier this year, Park et al. applied this formula to 45 million scientific papers and 3.9 million patents published across a 60-year span in 4 disciplines – life sciences, physical sciences, social sciences, and technology [2]. They found an astounding and alarmingly steady decline in the average CDI across all disciplines studied from 1950 to 2010. Life sciences experienced the greatest decline in disruptive papers, while technology experienced the least.   Of course, this study made a big impact in scientific circles, and ignited a chorus of think pieces addressing why disruptive science is declining. One common theme among these was the corporatization of science and the emphasis on volume of citations for young scientists to obtain grant funding and promotion. As pointed out by Bhattacharya et al., the push for evidence of productivity incentivizes scientists to publish incremental work and concentrates the volume of scientific effort on ideas that have already been established [3]. Similarly, Derek Thompson points out that scientists are not incentivized to submit grant proposals on entirely new ideas given the tight competition to obtain a grant and the high risk of failure [4]. Instead, scientists submit grants that are ‘optimally new’: new enough to secure a grant, but safe enough to secure publication.   Together, all these influences have created a surplus of papers designed to advance careers, not science, and it seems that medical trainees have certainly picked up on this trend. There’s been a steady decline in the number of trainees opting for the physician-scientist pathway, as well as a decline in the number of physician-scientists participating in biomedical research in their careers [5]. At the same time, there’s been increasing interest among PhD graduate students in leaving academia entirely [6-8].   I would argue that for a large percentage of trainees, corporatization has sucked the joy from science. The maxim to ‘publish or perish’ and exhausting competition over limited funding makes it almost impossible to enjoy the process of discovery and keep joyful curiosity about the work of science. Small wonder then that medical trainees view research as a box to check for their application, a menial task for career enhancement rather than an exploration of the human condition. As one trainee put it, research has indeed become ‘boring’.   So how do we put the joy back into science? Revision of the funding model would certainly help. Calls to fund careers of promising young scientists without ties to the success of a specific project abound. Increased support from institutions to cover gaps in grant funding and less emphasis on citations for promotion, among many others, have been proposed. Whether there is the will power to enact these changes remains to be seen.   1.       Russell J. Funk, Jason Owen-Smith (2016) A Dynamic Network Measure of Technological Change. Management Science 63(3):791-817. https://doi.org/10.1287/mnsc.2015.2366 2.       Park, M., Leahey, E. & Funk, R.J. Papers and patents are becoming less disruptive over time. Nature 613, 138–144 (2023). https://doi.org/10.1038/s41586-022-05543-x 3.       Bhattacharya, Jayanta and Packalen, Mikko. Stagnation and Scientific Incentives (February 2020). NBER Working Paper No. w26752, Available at SSRN: https://ssrn.com/abstract=3539319 4.       Thompson, D. The Consolidation-Disruption Index is Alarming. https://www.theatlantic.com/newsletters/archive/2023/01/academia-research-scientific-papers-progress/672694/ 5.       Garrison, H. H., & Ley, T. J. (2022). Physician‐scientists in the United States at 2020: Trends and concerns.  The FASEB Journal ,  36 (5). 6.       Chen, S. (2021). Leaving academia: why do doctoral graduates take up non-academic jobs and to what extent are they prepared?.  Studies in Graduate and Postdoctoral Education ,  12 (3), 338-352. 7.       Hunter, K. H., & Devine, K. (2016). Doctoral students’ emotional exhaustion and intentions to leave academia.  International Journal of doctoral studies ,  11 (2), 35-61. 8.       Kis, A., Tur, E. M., Lakens, D., Vaesen, K., & Houkes, W. (2022). Leaving academia: PhD attrition and unhealthy research environments.  Plos one ,  17 (10), e0274976.

An octogenarian woman with past medical history of coronary artery disease on aspirin and Plavix presents from an assisted living facility with complaints of blood in her diaper. Hemoglobin is 5.8 g/dL, and a unit of O negative blood is given on emergency release, meaning the blood was transfused before a full type and screen and crossmatch could be performed. Two hours following transfusion, information is obtained from an outside hospital significant for a history of anti-E. Upon completion of testing, the emergency release unit was found to be incompatible on crossmatch, and antigen typing of the unit was significant for the presence of E antigen.   What are you concerned about? Hemolysis!   Hemolytic transfusion reactions occur when a patient antibody binds to antigen on a transfused red blood cell (RBC). The bound antibody may then fix complement to the surface of the transfused RBC and initiate lysis, which releases the contents of the RBC into the blood stream. Contents of the RBC include lactate dehydrogenase (LDH) and bilirubin, and monitoring for elevations in these analytes helps determine a diagnosis of hemolysis. Similarly, hemoglobin is released from the lysed RBC which is then bound by haptoglobin. The haptoglobin-hemoglobin complex is then taken up and digested by macrophages, which prevents accumulation of hemoglobin in the kidneys and reduces the potential for renal injury. Thus, hemolysis involves a decrease in circulating haptoglobin, and reduced haptoglobin levels help determine a diagnosis of hemolysis.   Hemolysis can occur in two compartments in the body. Intravascular hemolysis occurs within blood vessels and generally causes a more severe syndrome. Because the contents of RBCs are being released directly into the blood stream, the classic triad of elevated LDH and bilirubin, and reduced haptoglobin, is commonly seen. The body’s natural defenses against hemolysis – namely haptoglobin – can be easily overwhelmed, and excess circulating hemoglobin can accumulate in the kidneys, causing both renal injury and hemoglobinuria. This is an important way to distinguish intravascular hemolysis from extravascular hemolysis. Extravascular hemolysis occurs when antibody-coated RBCs are taken up by macrophages in the reticuloendothelial system (i.e. the spleen), which then digests the RBC and its contents. Some of the RBC contents may spill out of macrophages, but because RBC destruction is largely occurring inside macrophages, extravascular hemolysis tends to feature less severe elevations in LDH and bilirubin, less severe reductions in haptoglobin, and less severe symptoms all around. It’s important to note that there are exceptions, and severe cases of extravascular hemolysis have been reported.   Hemolytic transfusion reactions can be acute, meaning they occur within 24 hours of transfusion, or delayed, meaning they occur between 1- and 28-days following transfusion. Acute hemolytic transfusion reactions involve a pre-existing antibody, and are typically more severe, whereas delayed transfusion reactions can involve either a pre-existing or newly made antibody and tend to be less severe. Hemolytic transfusion reactions can also be divided into two categories based on the type of antibody involved. ABO antibodies are naturally occurring largely IgM antibodies. IgM antibodies are very good at fixing complement, and ABO-incompatibility tends to cause severe, intravascular hemolytic transfusion reactions. Non-ABO antibodies typically develop in response to antigen exposure and are largely IgG. They may or may not fix compliment, may cause either intravascular or extravascular hemolysis, and tend to cause less severe reactions than ABO antibodies. Again, there are exceptions to this, with non-ABO antibodies causing severe hemolysis.   Prior to 1985, ABO-incompatibility was responsible for ~15% of all deaths from hemolytic transfusion reactions [1]. Investigations showed that erroneous patient identification on blood samples for type and screen was a common underlying culprit, and the term ‘wrong blood in tube’ (WBIT) was coined. Between 1985 and 2005 a bevy of initiatives to increase blood safety were launched, including two-factor patient identification, bar code scanning of sample labels and patient wrist bands, bar code scanning on blood product labels, and administrative systems for tracking of patient blood type and antibody history [1]. These efforts had good effect, and from 2005-2008 ABO-incompatibility accounted for only 5.5% of deaths from hemolytic transfusion reactions [1].   In line with innovations to prevent hemolysis came innovations in treating hemolysis. First line treatment remains supportive, such as maintaining normokalemia, normotension, and urine pH > 6.5. The options for second line treatment have expanded, and now include steroids, plasma exchange, and continuous dialysis [2]. There are now even third line options for refractory cases of hemolysis. Ruxolotinib is a JAK-STAT inhibitor that serves to inhibit downstream cytokine activity in severe cases of hemolysis, and eculizumab is a monoclonal antibody against C5 in the complement cascade that can inhibit formation of the membrane attack complex and destruction of RBCs [2].   Now that we know so much about hemolysis, let’s come back to our patient with a history of anti-E who was transfused an E positive unit on emergency release. She was briefly managed in the ICU where it was determined she was bleeding from her bladder. Aspirin and Plavix were held, and the patient underwent bladder irrigation. Notably, she developed no signs or symptoms of acute or delayed hemolysis during her hospital stay. She did well and was discharged to follow up outpatient.   So why didn’t this patient have hemolysis? Because hemolysis is influenced by a number of factors: how much antigen the patient is exposed to, how antigenic the antigen is, the titer of the alloantibody, and whether the antibody fixes complement can all influence whether a hemolytic transfusion reaction develops. In this case, anti-E is described as producing mild to moderate hemolysis, so is less antigenic than other antigens, and the patient’s DAT was negative for C3d, which means her anti-E antibody was not very good at fixing complement. These are both possible explanations for why this patient escaped hemolysis even though she was exposed to E antigen. Hemolysis does not occur 100% of the time, and is not 100% fatal.   Take away points: Hemolytic transfusion reactions can be acute or delayed. ABO incompatibility is generally more severe than non-ABO incompatibility. Treatment for hemolytic reactions is largely supportive, but there are also fancier options. Hemolysis does not happen 100% of the time, and is not 100% fatal. A DAT helps you determine what type of antibody is on the patient’s RBC, and whether it fixes complement.    References: 1.       Vamvakas, E. C., & Blajchman, M. A. (2010). Blood still kills: six strategies to further reduce allogeneic blood transfusion-related mortality. Transfusion medicine reviews, 24(2), 77-124. 2.       Ackfeld, T., Schmutz, T., Guechi, Y., & Le Terrier, C. (2022). Blood transfusion reactions—a comprehensive review of the literature including a swiss perspective. Journal of Clinical Medicine, 11(10), 2859.

Donating blood is an essential community service that saves lives. Because donors are healthy volunteers, several safety precautions are put in place to maintain their well-being. For example, there are restrictions on how often one can donate different types of blood products, to ensure that the donor has adequate time to recover. Blood Product Donated Donation Interval Whole Blood 56 days/8 weeks 1 unit of red blood cells 56 days/8 weeks 2 units of red blood cells 112 days/16 weeks Platelets 7 days/1 week Plasma 48 hours/2 days (no more than twice in 7 days) One common issue of donor safety is iron depletion or deficiency. A donation of one unit of whole blood contains about 250 mg of iron, or about 25% of the iron stores in a typical adult male. For menstruating individuals, this percentage is higher. Loss of iron stores leads first to iron depletion, which is defined as iron levels <26 ng/dL, then to iron deficiency, which is defined as iron levels <19 ng/dL. If iron deficiency is not corrected, it can reduce production of red blood cells and lead to anemia, which is defined as hemoglobin levels < 13.5 g/dL in males and <12.0 g/dL in females.   Blood donation centers routinely test hemoglobin levels prior to blood donation. This can uncover anemia and an anemic donor will be deferred for donor safety. However, iron levels are generally determined with a ferritin level, which is not routinely performed at donor centers. Studies show that while anemia is present in 4.2% of all donors and 6.2% of female donors, iron deficiency is more prevalent at 13.6% of all donors, and 22.6% of female donors [1].   As transfusion medicine physicians, we care about the iron levels of our donors for two main reasons. First, we want to maintain the well-being of our healthy volunteer donors. Iron is an essential nutrient and evidence suggests it is critical not just for the production of red blood cells, but also for brain maturation and development as well as healthy pregnancies [2]. Second, we want to act as good stewards of our blood supply. Approximately 8-12% of all potential blood donations are deferred due to iron deficiency, and mitigating iron deficiency could reduce deferrals by 66% [2].   A great deal of research has been done to investigate iron deficiency in donors. First, the HEIRS study found that iron supplementation in the first 8 weeks after donation can help donors recover faster [3]. Second, the STRIDE study found that testing for ferritin levels at donation and providing written documentation of the result is as effective as prescribing iron supplementation [4]. Finally, the CHILL study found that adolescent donors are more at risk of iron deficiency than their adult counterparts [5].   Currently, the AABB recommends that blood donation centers adopt the following three strategies to mitigate iron deficiency in their donors. First, that they provide educational materials about iron deficiency and discuss its impacts, particularly in at risk subgroups of donors like adolescents and individuals who menstruate. Second, that they provide direct intervention either to all donors or to at risk subgroups by testing for ferritin levels, providing iron tablets or vouchers for iron supplements, or spacing out donation intervals to allow for adequate recovery. Finally, that donor centers implement monitoring of donor iron deficiency after implementing one or both of the above strategies.   There remain some unanswered questions in the field of donor iron deficiency. First, what dose of iron supplementation is appropriate? In the original HEIRS study, donors were supplemented with daily iron doses. In the time since that study, evidence has emerged that daily iron dosing actually inhibits the absorption of iron by triggering the release of hepcidin [6, 7], and current recommendations are to dose iron every other day or even three times per week.   Another unanswered question is the risk of iron supplementation itself. Several recent studies have found a link between iron supplementation and increased risk of bacteremia and bacterial seeding [8]. However, these studies were done on healthy donors taking iron supplements and did not include those with iron deficiency in the study population. Whether these results can be extrapolated to iron deficient donors remains to be seen. To date, studies of donor iron deficiency have not tracked infection, hospitalization, or death as an outcome of donor iron supplementation.   In summary, blood donation can lead to iron deficiency, and iron supplementation of donors is a cost-effective intervention to maintain donor health and the blood supply. However, there may be room for improvement in the current guidelines and further studies would certainly be indicated.   References: 1.       Salvin, H.E., Pasricha, S.R., Marks, D.C. and Speedy, J., 2014. Iron deficiency in blood donors: a national cross‐sectional study.  Transfusion ,  54 (10), pp.2434-2444. 2.       Smith GA, Fisher SA, Doree C, Di Angelantonio E, Roberts DJ. Oral or parenteral iron supplementation to reduce deferral, iron deficiency and/or anaemia in blood donors. Cochrane Database of Systematic Reviews. 2014(7). 3.       Kiss JE, Brambilla D, Glynn SA, Mast AE, Spencer BR, Stone M, Kleinman SH, Cable RG; National Heart, Lung, and Blood Institute (NHLBI) Recipient Epidemiology and Donor Evaluation Study–III (REDS-III). Oral iron supplementation after blood donation: a randomized clinical trial. JAMA. 2015 Feb 10;313(6):575-83. doi: 10.1001/jama.2015.119. PMID: 25668261; PMCID: PMC5094173. 4.       Mast AE, Bialkowski W, Bryant BJ, Wright DJ, Birch R, Kiss JE, D'Andrea P, Cable RG, Spencer BR. A randomized, blinded, placebo-controlled trial of education and iron supplementation for mitigation of iron deficiency in regular blood donors. Transfusion. 2016 Jun;56(6 Pt 2):1588-97. doi: 10.1111/trf.13469. Epub 2016 Jan 26. PMID: 26813849; PMCID: PMC4905782. 5.       Patel, E. U., White, J. L., Bloch, E. M., Grabowski, M. K., Gehrie, E. A., Lokhandwala, P. M., Brunker, P., Goel, R., Shaz, B. H., Ness, P. M., & Tobian, A. (2019). Association of blood donation with iron deficiency among adolescent and adult females in the United States: a nationally representative study.  Transfusion ,  59 (5), 1723–1733. https://doi.org/10.1111/trf.15179 6.       Moretti, D., Goede, J. S., Zeder, C., Jiskra, M., Chatzinakou, V., Tjalsma, H., ... & Zimmermann, M. B. (2015). Oral iron supplements increase hepcidin and decrease iron absorption from daily or twice-daily doses in iron-depleted young women. Blood, The Journal of the American Society of Hematology, 126(17), 1981-1989. 7.       Nicole U Stoffel, Colin I Cercamondi, Gary Brittenham, Christophe Zeder, Anneke J Geurts-Moespot, Dorine W Swinkels, Diego Moretti, Michael B Zimmermann. Iron absorption from oral iron supplements given on consecutive versus alternate days and as single morning doses versus twice-daily split dosing in iron-depleted women: two open-label, randomised controlled trials. The Lancet Haematology, Volume 4, Issue 11, 2017, Pages e524-e533, https://doi.org/10.1016/S2352-3026(17)30182-5 . 8.       Cross, J. H., Bradbury, R. S., Fulford, A. J., Jallow, A. T., Wegmüller, R., Prentice, A. M., & Cerami, C. (2015). Oral iron acutely elevates bacterial growth in human serum. Scientific reports, 5, 16670. https://doi.org/10.1038/srep16670

Unclear on Castleman's? Let's learn together in this bullet learning entry. A rare entity with unknown etiology, Castleman’s Disease (CD) is a non-clonal lymphoproliferative disorder that primarily affects lymph nodes and features abundant proliferation of B cells and plasma cells in lymphoid organs. Clinically, CD is classified as unicentric or multicentric, and pathologically it has 4 subtypes: hyaline vascular, plasma cell, mixed, and HHV-8 associated. Current theories are that immune dysregulation, found in chronic inflammation or viral infection, underlies CD, and there is evidence that upregulation of the IL-6 pathway, through over-secretion of IL-6 or over-production of IL-6 receptor, is critical to the pathogenesis of CD. Additionally, HIV is known to be associated with CD, especially the multicentric variant, and almost all cases of HIV-associated CD are HHV-8 positive. Non-HIV-associated CD, or idiopathic CD, features HHV-8 in ~50% of cases.  First line therapy for the more common unicentric CD is surgical resection of the affected lymph node +/- IL-6 inhibition through Tocilizumab, a monoclonal antibody to the IL-6 receptor, or Siltuximab, a monoclonal antibody to IL-6.   Antiviral therapy against HHV-8 has also shown benefit , as have immunomodulatory treatments such as rituximab and interferon-alpha.        References:  Yoshizaki K, et al. The Role of Interleukin-6 in Castleman Disease. Hematol Oncol Clin North Am. 2018 Feb;32(1):23-36. doi: 10.1016/j.hoc.2017.09.003. PMID: 29157617. Ehsan N, Zahra F. Castleman Disease. [Updated 2022 Nov 14]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK576394/ Oksenhendler, E., et al. "The full spectrum of Castleman disease: 273 patients studied over 20 years." British journal of haematology 180.2 (2018): 206-216. Fu, B., et al. Why tocilizumab could be an effective treatment for severe COVID-19?. J Transl Med 18, 164 (2020). https://doi.org/10.1186/s12967-020-02339-3