Galectin-4 Antimicrobial Activity Primarily Occurs Through its C-Terminal Domain.

Although immune tolerance evolved to reduce reactivity with self, it creates a gap in the adaptive immune response against microbes that decorate themselves in self-like antigens. This is particularly apparent with carbohydrate-based blood group antigens, wherein microbes can envelope themselves in blood group structures similar to human cells. In this study, we demonstrate that the innate immune lectin, galectin-4 (Gal-4), exhibits strain-specific binding and killing behavior towards microbes that display blood group-like antigens. Examination of binding preferences using a combination of microarrays populated with ABO(H) glycans and a variety of microbial strains, including those that express blood group-like antigens, demonstrated that Gal-4 binds mammalian and microbial antigens that have features of blood group and mammalian-like structures. Although Gal-4 was thought to exist as a monomer that achieves functional bivalency through its two linked carbohydrate recognition domains, our data demonstrate that Gal-4 forms dimers and that differences in the intrinsic ability of each domain to dimerize likely influences binding affinity. While each Gal-4 domain exhibited blood group-binding activity, the C-terminal domain (Gal-4C) exhibited dimeric properties, while the N-terminal domain (Gal-4N) failed to similarly display dimeric activity. Gal-4C not only exhibited the ability to dimerize but also possessed higher affinity toward ABO(H) blood group antigens and microbes expressing glycans with blood group-like features. Furthermore, when compared to Gal-4N, Gal-4C exhibited more potent antimicrobial activity. Even in the context of the full-length protein, where Gal-4N is functionally bivalent by virtue of Gal-4C dimerization, Gal-4C continued to display higher antimicrobial activity. These results demonstrate that Gal-4 exists as a dimer and exhibits its antimicrobial activity primarily through its C-terminal domain. In doing so, these data provide important insight into key features of Gal-4 responsible for its innate immune activity against molecular mimicry.

Blood group A enhances SARS-CoV-2 infection.

Among the risk factors for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), ABO(H) blood group antigens are among the most recognized predictors of infection. However, the mechanisms by which ABO(H) antigens influence susceptibility to COVID-19 remain incompletely understood. The receptor-binding domain (RBD) of SARS-CoV-2, which facilitates host cell engagement, bears significant similarity to galectins, an ancient family of carbohydrate-binding proteins. Because ABO(H) blood group antigens are carbohydrates, we compared the glycan-binding specificity of SARS-CoV-2 RBD with that of galectins. Similar to the binding profile of several galectins, the RBDs of SARS-CoV-2, including Delta and Omicron variants, exhibited specificity for blood group A. Not only did each RBD recognize blood group A in a glycan array format, but each SARS-CoV-2 virus also displayed a preferential ability to infect blood group A-expressing cells. Preincubation of blood group A cells with a blood group-binding galectin specifically inhibited the blood group A enhancement of SARS-CoV-2 infection, whereas similar incubation with a galectin that does not recognize blood group antigens failed to impact SARS-CoV-2 infection. These results demonstrated that SARS-CoV-2 can engage blood group A, providing a direct link between ABO(H) blood group expression and SARS-CoV-2 infection.

Marginal zone B cells mediate a CD4 T-cell-dependent extrafollicular antibody response following RBC transfusion in mice.

Red blood cell (RBC) transfusions can result in alloimmunization toward RBC alloantigens that can increase the probability of complications following subsequent transfusion. An improved understanding of the immune mechanisms that underlie RBC alloimmunization is critical if future strategies capable of preventing or even reducing this process are to be realized. Using the HOD (hen egg lysozyme [HEL] and ovalbumin [OVA] fused with the human RBC antigen Duffy) model system, we aimed to identify initiating immune factors that may govern early anti-HOD alloantibody formation. Our findings demonstrate that HOD RBCs continuously localize to the marginal sinus following transfusion, where they colocalize with marginal zone (MZ) B cells. Depletion of MZ B cells inhibited immunoglobulin M (IgM) and IgG anti-HOD antibody formation, whereas CD4 T-cell depletion only prevented IgG anti-HOD antibody development. HOD-specific CD4 T cells displayed similar proliferation and activation following transfusion of HOD RBCs into wild-type or MZ B-cell-deficient recipients, suggesting that IgG formation is not dependent on MZ B-cell-mediated CD4 T-cell activation. Moreover, depletion of follicular B cells failed to substantially impact the anti-HOD antibody response, and no increase in antigen-specific germinal center B cells was detected following HOD RBC transfusion, suggesting that antibody formation is not dependent on the splenic follicle. Despite this, anti-HOD antibodies persisted for several months following HOD RBC transfusion. Overall, these data suggest that MZ B cells can initiate and then contribute to RBC alloantibody formation, highlighting a unique immune pathway that can be engaged following RBC transfusion.

Seniors from United States allopathic medical schools matching into pathology residency, 2018-2022.

BACKGROUND: From 2008 to 2017, 28.8 % fewer United States allopathic medical students (MD seniors) applied to pathology residency in the Main Residency Match (MRM) and 27.5 % fewer matched. This study is a 5-year follow-up. METHODS: MRM data from 2018 to 2022 were reviewed to determine the numbers of MD seniors that applied and matched to pathology residency and other major medical specialties. RESULTS: From 2018 to 2022, the number of MD seniors applying to pathology increased 4.6 % from 237 to 248, while MD seniors matching to pathology increased 5.0 % from 220 to 231. For the 4 years from 2018 to 2021, there was a slight decline in MD seniors filling pathology positions, followed by a substantial 16.7 % spike in 2022. For the entire 5-year interval, because the number of filled pathology residency positions increased by 9.0 %, the percentage of filled positions taken by MD seniors declined from 38.7 % to 37.3 %. Of the 15 major medical specialties evaluated, pathology now has the 14th lowest percentage of filled positions taken by MD seniors. CONCLUSIONS: The number of MD seniors applying and matching to pathology residency increased over the past 5-years, in contrast to the timespan of 2008 to 2017. However, the percentage of pathology residency positions taken by MD seniors continued to decline and remains low compared to other major medical specialties. MRM data should be continually monitored to study trends in MD seniors filling pathology residency positions in the context of new recruitment efforts and the pandemic.

The medical student's guide to pathology residency, fellowships, and careers.

Recent studies have shown that relatively few MD, DO, and underrepresented in medicine (URM) students and physicians are matching into pathology residency in the United States (US). In the 2021 Main Residency Match, just 33.6% of filled pathology residency positions were taken by senior year students at US allopathic medical schools. This has been attributed to the fact that pathology is not a required rotation in most US medical schools, pathology is often taught in an integrated curriculum in the US where is does not stand out as a distinct field, and because the COVID-19 pandemic led to a suspension of in-person pathology rotations and electives. Ultimately, many US medical students fail to consider pathology as a career pathway. The objective of this article is to provide medical students with basic information, in the form of frequently asked questions (FAQs), about pathology training and career opportunities. This was accomplished by forming a team of MD and DO pathology attendings, pathology trainees, and a medical student from multiple institutions to create a pathology guide for medical students. This guide includes information about post-sophomore fellowships, 5 major pathology residency tracks, more than 20 fellowship pathways, and allopathic and osteopathic board examinations. This guide also contains photographs and descriptions of major pathology sub-specialties, including the daily and on-call duties and responsibilities of pathology residents. The exciting future of pathology is also discussed. This guide supports the agenda of the College of American Pathologists' (CAP) Pathologist Pipeline Initiative to improve student recruitment into pathology.

"Dual-gene" malaria-resistance: Therapeutically-rational exchange (T-REX) of group-O sickle trait and group-O C-traittrait red blood cells can be evaluated in Benin and Nigeria.

BACKGROUND: Using indicators of disease severity, clinicians can predict which Plasmodium falciparum (Pf) malaria patients being treated with artesunate or quinine are likely to die despite these drugs. Effective "rescue adjuncts" are needed when drugs alone are inadequate. "Therapeutically-rational exchange" (T-REX) of special malaria-resistant red blood cells (RBCs) has been proposed to optimize adjunctive exchange transfusion. METHODS: Studies were reviewed that (1) quantified how group-O status and "sickle-trait" (HbAS) and "C-trait" (HbAC) hemoglobins affect Pf mortality, risk of thrombosis, or birth outcomes for women with pregnancy associated malaria (PAM), (2) reported prevalences of "dual-gene" malaria-resistant RBCs, or (3) reflected the level of exchange-transfusion and malaria-related expertise in Benin and Nigeria. RESULTS: Data show that the malaria- and thrombosis-resistance of RBCs depend on specific genes and the patient's clinical status and medical history. In malaria-endemic Benin and Nigeria, prevalences of "dual-gene" malaria-resistant group-O HbAS and group-O HbAC RBCs are substantial, and both malaria- and exchange-related expertise are outstanding. CONCLUSIONS: T-REX of "dual-gene" malaria-resistant RBCs is feasible in Benin and Nigeria and warrants evaluation as a rescue adjunct for 3 subsets of Pf-malaria patients. For therapeutic use, group-O HbAS RBCs are likely to be more effective than non-O HbAS RBCs for Pf-infected patients who (1) have a history of thrombosis or (2) are taking birth-control hormones while group-O HbAC RBCs may substantially improve birth outcomes for women with PAM. Studies suggest it is prudent to assume - until proven otherwise - that T-REX of "dual-gene" malaria-resistant RBCs can improve ("personalize") rescue of these patient subsets.

Pathology's historic 2019 incoming residents: Why "the internationalization of pathology" may markedly advance transfusion medicine and cellular therapeutics.

OBJECTIVES: This study had two objectives: (1) to determine if, in the United States of America (US), the proportion of non-US citizen international medical graduates (non-US IMGs) entering pathology residencies had increased (again) in 2019 and (2) to assess how this multi-year trend might impact transfusion medicine in the US. METHODS: The most recent (2019) "National Resident Matching Program" (NRMP) data were analyzed. To assess potential future impact, using controversies related to Plasmodium falciparum (Pf) malaria, conflicting US and non-US perspectives were reviewed. Differences between published US and non-US views were identified regarding, for example, the value of Pf-resistant ("variant") red blood cells (RBCs) and exchange transfusions. RESULTS: Year 2019 is the first year non-US IMGs were the largest group to fill residency-training positions for a major US specialty via the "Main Residency Match." Also notable, US and non-US views were found to differ markedly regarding (1) the value and safety of Pf-resistant RBC variants and exchange transfusions, and (2) the threat of drug-resistant Pf-malaria parasites. Non-US clinicians and researchers seem more concerned about Pf-malaria, and their interest in cellular therapies seems greater and more optimistic. CONCLUSIONS: In 2019, the historically high proportion of non-US IMGs among incoming pathology residents dramatically highlights the steady demographic shift that began years ago: "the internationalization of pathology" in the US. Fortunately, a review of publications related to exchange transfusion, Pf-malaria, and variant RBCs suggests non-US IMGs may markedly promote and advance cell therapies such as therapeutically-rational exchange (T-REX) of disease-resistant RBCs.

Plasmodium knowlesi (Pk) Malaria: A Review & Proposal of Therapeutically Rational Exchange (T-REX) of Pk-Resistant Red Blood Cells.

Plasmodium knowlesi (Pk) causes zoonotic malaria and is known as the "fifth human malaria parasite". Pk malaria is an emerging threat because infections are increasing and can be fatal. While most infections are in Southeast Asia (SEA), especially Malaysia, travelers frequently visit this region and can present with Pk malaria around the world. So, clinicians need to know (1) patients who present with fever after recent travel to SEA might be infected with Pk and (2) Pk is often misdiagnosed as P. malariae (which typically causes less severe malaria). Here we review the history, pathophysiology, clinical features, diagnosis, and treatment of Pk malaria. Severe disease is most common in adults. Signs and symptoms can include fever, abdominal pain, jaundice, acute kidney injury, acute respiratory distress syndrome, hyponatremia, hyperparasitemia, and thrombocytopenia. Dengue is one of the diseases to be considered in the differential. Regarding pathophysiologic mechanisms, when Pk parasites invade mature red blood cells (RBCs, i.e., normocytes) and reticulocytes, changes in the red blood cell (RBC) surface can result in life-threatening cytoadherence, sequestration, and reduced RBC deformability. Since molecular mechanisms involving the erythrocytic stage are responsible for onset of severe disease and lethal outcomes, it is biologically plausible that manual exchange transfusion (ET) or automated RBC exchange (RBCX) could be highly beneficial by replacing "sticky" parasitized RBCs with uninfected, deformable, healthy donor RBCs. Here we suggest use of special Pk-resistant donor RBCs to optimize adjunctive manual ET/RBCX for malaria. "Therapeutically-rational exchange transfusion" (T-REX) is proposed in which Pk-resistant RBCs are transfused (instead of disease-promoting RBCs). Because expression of the Duffy antigen on the surface of human RBCs is essential for parasite invasion, T-REX of Duffy-negative RBCs-also known as Fy(a-b-) RBCs-could replace the majority of the patient's circulating normocytes with Pk invasion-resistant RBCs (in a single procedure lasting about 2 h). When sequestered or non-sequestered iRBCs rupture-in a 24 h Pk asexual life cycle-the released merozoites cannot invade Fy(a-b-) RBCs. When Fy(a-b-) RBC units are scarce (e.g., in Malaysia), clinicians can consider the risks and benefits of transfusing plausibly Pk-resistant RBCs, such as glucose-6-phosphate dehydrogenase deficient (G6PDd) RBCs and Southeast Asian ovalocytes (SAO). Patients typically require a very short recovery time (<1 h) after the procedure. Fy(a-b-) RBCs should have a normal lifespan, while SAO and G6PDd RBCs may have mildly reduced half-lives. Because SAO and G6PDd RBCs come from screened blood donors who are healthy and not anemic, these RBCs have a low-risk for hemolysis and do not need to be removed after the patient recovers from malaria. T-REX could be especially useful if (1) antimalarial medications are not readily available, (2) patients are likely to progress to severe disease, or (3) drug-resistant strains emerge. In conclusion, T-REX is a proposed optimization of manual ET/RBCX that has not yet been utilized but can be considered by physicians to treat Pk malaria patients.

The impact of ABO and RhD blood types on Babesia microti infection.

BACKGROUND: Babesiosis is an emerging infectious disease caused by intraerythrocytic Babesia parasites that can cause severe disease and death. While blood type is known to affect the mortality of Plasmodium falciparum malaria patients, associations between red blood cell (RBC) antigens and Babesia microti infection and disease severity are lacking. METHODS: We evaluated RhD and ABO blood types of Babesia-infected (18S rRNA reactive) blood donors in 10 endemic states in the Northeastern and northern Midwestern United States. We also assessed possible associations between RhD and ABO blood types and disease severity among hospitalized babesiosis patients in Connecticut. RESULTS: A total of 768 Babesia-infected blood donors were analyzed, of which 750 (97.7%) had detectable B. microti-specific antibodies. B. microti-infected blood donors were more likely to be RhD- (OR of 1.22, p-value 0.024) than RhD+ donors. Hospitalized RhD- babesiosis patients were more likely than RhD+ patients to have high peak parasitemia (p-value 0.017), which is a marker for disease severity. No differences in RhD+ blood type were noted between residents of the Northeast (OR of 0.82, p-value 0.033) and the Midwest (OR of 0.74, p-value 0.23). Overall, ABO blood type was not associated with blood donor B. microti infection, however, B. microti-infected donors in Maine and New Jersey were more likely to be blood type B compared to non-type B (OR 2.49 [p = 0.008] and 2.07 [p = 0.009], respectively), while infected donors from Pennsylvania were less likely to be type B compared to non-type B (OR 0.32 [p = 0.02]). CONCLUSIONS: People expressing RhD antigen may have a decreased risk of B. microti infection and babesiosis severity. The association of B antigen with B. microti infection is less clear because the antigen appeared to be less prevalent in infected Pennsylvania blood donors but more prevalent in Maine and New Jersey infected donors. Future studies should quantify associations between B. microti genotypes, RBC antigens, and the frequency and severity of B. microti infection to increase our understanding of human Babesia pathogenesis and improve antibody, vaccine, and RBC exchange transfusion strategies.

ABO blood group antigens and differential glycan expression: Perspective on the evolution of common human enzyme deficiencies.

Enzymes catalyze biochemical reactions and play critical roles in human health and disease. Enzyme variants and deficiencies can lead to variable expression of glycans, which can affect physiology, influence predilection for disease, and/or directly contribute to disease pathogenesis. Although certain well-characterized enzyme deficiencies result in overt disease, some of the most common enzyme deficiencies in humans form the basis of blood groups. These carbohydrate blood groups impact fundamental areas of clinical medicine, including the risk of infection and severity of infectious disease, bleeding risk, transfusion medicine, and tissue/organ transplantation. In this review, we examine the enzymes responsible for carbohydrate-based blood group antigen biosynthesis and their expression within the human population. We also consider the evolutionary selective pressures, e.g. malaria, that may account for the variation in carbohydrate structures and the implications of this biology for human disease.

Therapeutically-rational exchange (T-REX) of Gerbich-negative red blood cells can be evaluated in Papua New Guinea as "a rescue adjunct" for patients with Plasmodium falciparum malaria.

"Conventional exchange transfusion"-that delivers nondescript "standard issue" units of red blood cells (RBCs)-is used worldwide to rescue dying Plasmodium falciparum (Pf) malaria patients. Recently, exchanging special malaria-resistant RBCs (T-REX) has been recommended to prevent random delivery of malaria-susceptible RBCs that promote Pf infection. Fortunately, Papua New Guinea (PNG) is well positioned to help optimize exchange as "a rescue adjunct" because (a) Gerbich-negative (GN) RBCs that resist Pf invasion are prevalent in PNG; (b) with international support, PNG has conducted outstanding malaria research; (c) PNG's scientists feel studies of GN RBCs can advance malaria therapeutics; and (d) with blood-bank support, evaluating exchange of GN RBCs is feasible in PNG. An exchange-transfusion study of GN RBCs might attract international sponsorship given the threat of expanding drug-resistance as well as growing recognition that advancing transfusion medicine and expanding blood donation could especially help Pf-infected children-immediately.

Osteopathic students and graduates matching into pathology residency, 2011-2020.

Context: In the past decade, two changes have affected the pathology residency match. First, the American Osteopathic Association (AOA) Match, which did not offer pathology residency, became accredited under a single graduate medical education (GME) system with the Main Residency Match (MRM), which offers pathology residency. Second, substantially fewer United States senior-year allopathic medical students (US MD seniors) matched into pathology residency. Objective: To determine whether there were major changes in the number and percentage of osteopathic students and physicians (DOs) matching into pathology residency programs over the past decade. Methods: Pathology match outcomes for DOs from 2011 to 2020 were obtained by reviewing AOA Match data from the National Matching Services and MRM data from the National Resident Matching Program (NRMP). The number of DOs that filled pathology positions in the MRM was divided by the total number of pathology positions filled in the MRM to calculate the percentage of pathology positions taken by DOs. Results: Over the past decade, there was a 109% increase in the total number of DOs matching into pathology residency (34 in 2011 vs. 71 in 2020). During this time, there was a 23.3% increase in the total number of pathology positions filled in the MRM (476 in 2011 vs. 587 in 2020). Thus, the percentage of pathology residency positions filled by DOs increased from 7.1% in 2011 to 12.1% in 2020. The substantial increase of DOs in pathology occurred simultaneously with a 94.2% increase in the total number of DOs filling AOA/MRM "postgraduate year 1" (PGY-1) positions (3201 in 2011 vs. 6215 in 2020). Thus, the percentage of DOs choosing pathology residency has remained steady (1.06% in 2011 and 1.14% in 2020). In 2020, pathology had the third lowest percentage of filled PGY-1 residency positions taken by DOs, out of 15 major medical specialties. Conclusion: The proportion of DOs choosing pathology residency was stable from 2011 to 2020 despite the move to a single GME accreditation system and the stark decline in US MD seniors choosing pathology. In 2020, a slightly higher percentage of DOs (1.14%) chose pathology residency than US MD seniors (1.13%). Overall, DOs more often choose other medical specialties, including primary care. Additional studies are needed to determine why fewer US MD seniors, but not fewer DOs, are choosing pathology residency.

ABO blood group should be considered and reported when red blood cell exchange transfusion is used to treat Plasmodiumfalciparum Malaria patients.

Laboratory and epidemiologic studies have clarified how persons born with malaria-resistant red blood cells (RBCs)-like group-O, sickle-trait, and C-trait RBCs-are protected against death or severe disease due to Plasmodiumfalciparum (Pf) infection. Compared to malaria-promoting RBCs-like non-O or hemoglobin-AA RBCs-inborn RBC protection against severe Pf malaria can be profound: up to 10-fold greater. Given that "the Berlin patient" success showed patients do not have to be born with disease-resistant cells to benefit from them, why have the biologically plausible benefits of exchange transfusion (ET) of malaria-resistant RBCs not yet been evaluated? Unfortunately, a 2013 ET-for-malaria meta-analysis could not quantify the impact on mortality of ET of malaria-resistant RBCs because RBC malaria resistance variables (ABO group, hemoglobin type, enzyme levels, etc.) had not been reported in any of the ET studies used in that meta-analysis. To promote evaluation of the therapeutic impact of specific malaria-resistant RBCs, we urge clinicians to always report ABO blood group (and all other RBC malaria-resistance variables they are aware of) when they use ET to rescue Pf-infected patients. Prudent selection of donor RBCs has successfully optimized ET for sickle cell disease patients, and this precedent suggests selection of special malaria-resistant donor RBCs may optimize ET for Pf-malaria patients. Given that ET is used worldwide as a rescue adjunct, we feel it is most prudent to now assume-until proven otherwise-that considering and reporting the Pf-malaria-resistance variables of the RBCs to be transfused-at least ABO status-will help optimize ET-for-malaria.

Concerns about the pathology job market dominate a popular online pathology forum and likely deterred American medical students from pursuing pathology residency.

From 2010 to 2019, 40.5% fewer senior students from United States (US) allopathic medical schools pursued pathology in the Main Residency Match. To possibly explain this trend, we sought to identify major concerns about pathology which were made during this time. Because the Student Doctor Network (SDN) website is widely used by students at American medical schools during the residency application process, SDN has been shown to influence career decisions. So, the 50 all-time most-viewed SDN pathology threads (as of February 2018) were analyzed. The words "job" and "jobs" were used in the title of 11 of the 50 (22%) threads, which altogether received more than 400,000 views. However, the term "job(s)" was rarely used by 14 other major medical specialties. Seven of the 11 (63.6%) job-related threads were created from 2009 to 2011, corresponding with the start of the decline in medical students pursuing pathology residency. It was reasoned that job-market concerns within SDN threads may have discouraged students from pursuing pathology. To test this hypothesis, 5 pathology residents were asked to read all 11 threads and then complete a survey. Most thread reviewers agreed that commenters, which included medical students, were concerned about the pathology job-market and that medical students who viewed the threads would be less likely to pursue pathology residency. Because more than 85% of SDN users are from the US, the threads likely had a greater impact on American medical students compared to foreign students. In conclusion, job-market concerns over the past decade are so prominent in the SDN pathology forum that they likely contributed to fewer seniors from US allopathic medical schools pursuing pathology residency. As of 2019, there are 12 job-related threads among the 50 all-time most-viewed, including threads created in 2016 and 2017. To improve recruitment, the pathology community should carefully review and address concerns about employment opportunities. Due to conflicting reports, additional studies are needed to determine if a mismatch in workforce supply and demand warrants prompt and thoughtful intervention.

Can the Therapeutically-rational Exchange (T-REX) of Glucose-6-phosphate Dehydrogenase Deficient Red Blood Cells Reduce Plasmodium falciparum Malaria Morbidity and Mortality?

NA.

Fewer seniors from United States allopathic medical schools are filling pathology residency positions in the Main Residency Match, 2008-2017.

Some pathologists have observed that fewer trainees from US medical schools are entering pathology residency. This trend was measured and further explored using Main Residency Match (MRM) data from 2008 to 2017, obtained from the National Resident Matching Program (NRMP). Over the past decade, there was an increase of 93 (508 in 2008 versus 601 in 2017, an 18.3% increase) pathology positions offered in the MRM. However, the proportion of pathology residency positions filled in the MRM which were taken by trainees from US medical schools decreased from 77.7% to 50.1% over this timespan. This was primarily due to fewer seniors from US allopathic medical schools filling pathology positions in the MRM (298 in 2008 versus 216 in 2017, a 27.5% decrease). Compared to 14 other medical specialties, pathology had the largest decline in the proportion of residency positions filled in the MRM which were taken by seniors from US allopathic medical schools (63.8% in 2008 versus 39.6% in 2017). Furthermore, pathology now has the lowest percentage of residency positions filled in the MRM, which were taken by seniors from US allopathic medical schools. The primary reason for this decline was because fewer seniors from US allopathic medical schools participated in the MRM for pathology positions (326 in 2008 versus 232 in 2017, a 28.8% decrease); however, the underlying reasons for this decline are unknown. In conclusion, over the past decade, substantially fewer seniors from US allopathic medical schools sought/filled pathology residency positions in the MRM. These findings are relevant for pathology residency recruitment, especially in the context of a projected decline in US pathologist workforce.