Ryan Jajosky

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.

A model of acute renal allograft rejection in outbred Yorkshire piglets.

Pigs represent a desirable animal model for the study of rejection in kidney transplantation with inbred Yucatan miniature swine (YMS) the most commonly studied strain due to well defined swine leukocyte antigen (SLA) genotypes. However, limitations to YMS may include cost and availability. Outbred Yorkshire pigs are widely available and significantly cheaper than YMS. Recent advances in SLA genotyping have allowed its application to outbred strains. On this basis, we theorized that Yorkshire pigs would be a viable alternative to YMS for the study of rejection in kidney transplantation. To address this question, we performed auto (Auto) and allotransplants (Allo) in 24 Yorkshire pigs, and assessed SLA genotypes and acute rejection after 72h. At sacrifice, and when compared to autotransplants, allotransplants had significant elevations in serum creatinine (8.4±1.3 vs 2.8±2.0mg/dL for Allo vs autotransplants, respectively) and BUN (61±9 vs 19.2±15mg/dL for Allo vs autotransplants, respectively). Warm ischemia times between the two groups did not differ (24±2.3 vs 26.4±1.4min for Auto vs Allo, respectively). There were 16 distinct SLA haplotypes identified from pigs undergoing allotransplantion, no matched donor-recipient pairs, and all allografts demonstrated rejection. Type IIA cellular rejection (Banff) was the most common. One allograft demonstrated hyperacute rejection due a blood group incompatibility. Histologically, the expression of regulatory Tcells and dendritic cells was increased in allografts. These data suggest that Yorkshire pigs may be a useful model for the study of acute rejection in experimental kidney transplantation.

Is babesiosis the most common transfusion transmitted infection in the United States of America? The answer is not simple!

Babesiosis is an infectious disease caused by intraerythrocytic arasites of the Babesia species [1]. Babesia microti is the primary ause of babesiosis and transfusion-acquired babesiosis. Human ransmission usually occurs through the bite of an Ixodes scapuaris (deer) tick in the Northeast and upper Midwest regions of the nited States (US), especially in the warm months. There have been 65 cases of transfusion-acquired B. microti, with 32 deaths (19.4% ortality rate) [2]. This occurs because infected blood donors can emain asymptomatic and because there is no US Food and Drug dministration (FDA)-licensed laboratory test to detect Babesia n blood donors [3]. Having a medical history of babesiosis is an ndefinite deferral for blood donation in the US. Since Babesia parsites infect red blood cells (RBCs), hemolytic anemia can occur, n addition to flu-like symptoms, low and unstable blood presure, thrombocytopenia, disseminated intravascular coagulation DIC), and organ failure. Babesiosis can be life-threatening, espeially in the elderly, in individuals with a weakened immune system including those without a spleen), and in those with severe medcal conditions. We have read that babesiosis is, “the most frequent transfusionransmitted infection with approximately 162 cases reported since 980” [4]. Another article states that B. microti is, “the most comon transfusion-transmitted pathogen in the United States” [3]. different article claims that B. microti is, “the most commonly eported transfusion-transmitted pathogen” in the US [5]. There re similar claims in other articles [6]. Alternatively, the Centers or Disease Control and Prevention (CDC) website (www.cdc.gov) tates that, “babesiosis is the most frequently reported transfusionransmitted parasitic infection in the US”. So, is babesiosis the most ommon transfusion-acquired infection in the US? In order to make a claim about the most common transfusioncquired pathogen or transfusion-acquired infectious disease in given region, several statements must be provided. First, a ime-span needs to be clearly specified. Transfusion-transmitted ytomegalovirus (TT-CMV) was common in the 1980s before idespread use of CMV-seronegative and leukocyte-reduced blood roducts [7]. Since adoption of these mitigation strategies, there

Validation of the PLASMIC score at a University Medical Center

BACKGROUNDnThe PLASMIC score was recently described as a convenient tool for predicting ADAMTS13 activity ≤10% in patients with possible thrombotic thrombocytopenic purpura (TTP), while awaiting the results of this send-out test. The purpose of this study was to validate the PLASMIC score at our University Medical Center.nnnMETHODSnApheresis records were reviewed from 2008 to 2017 to identify patients who received plasma exchange (PLEX) for suspected TTP. The ADAMTS13 activity and PLASMIC scoring criteria were recorded, and the PLASMIC score was calculated.nnnRESULTSnOf the 41 patients identified, 20 met inclusion criteria, of which 7 patients had ADAMTS13 activity ≤10%. Intermediate and high PLASMIC scores had 100% sensitivity, 46.2% specificity, 50% positive predictive value (PPV), and 100% negative predictive value (NPV).nnnCONCLUSIONnThese results are consistent with the original validation study of the PLASMIC score, supporting the efficacy of the PLASMIC score and validating its use at our institution.

Optimiser la transfusion d'échange chez les patients atteints de Babesia divergens sévère La babésiose: l'échange thérapeutiquement rationnel (T-REX) de globules rouges à antigène M et / ou à antigène S négatif doit être évalué maintenant

Babesia divergens is an intraerythrocytic parasite, which is the major cause of babesiosis in Europe. For years, clinicians have been publishing stunning case reports that describe how some - but not all - conventional red blood cell (RBC) exchange transfusions have saved the lives of severely ill babesiosis patients. Due to markedly different patient outcomes, clinicians agree that new treatments and additional studies are needed. Here we argue that we should evaluate therapeutically-rational exchange (T-REX) in which the RBCs used to replace Babesia-parasitized RBCs are special disease-resistant RBC genetic variants (instead of the nondescript, standard issue RBCs used in conventional exchanges). T-REX seems prudent because with conventional exchange only some units of standard issue RBCs may be disease-resistant, while other units may not protect or may even promote disease. The random selection of RBCs for conventional RBC exchange may explain why clinical outcomes can vary dramatically. Fortunately, researchers have found that M antigen-negative (M-) and S antigen-negative (S-) RBCs resist invasion by B.xa0divergens. Thus, we recommend evaluating T-REX of RBC variants that are B. divergens invasion-resistant: RBCs that are (1) M-, (2) S-, or (3) both M- and S-. By using only Babesia-resistant RBCs, T-REX eliminates the risk of unintentionally infusing Babesia-susceptible RBCs that might increase the severity of babesiosis. Because the T-REX variation of the conventional RBC exchange procedure is feasible, safe, and biologically plausible, we feel T-REX of Babesia-resistant RBCs should now be evaluated.

Regulation of indoleamine 2,3 dioxygenase and its role in a porcine model of acute kidney allograft rejection

In kidney transplantation acute allograft rejection is the most common cause of late allograft loss. Changes in indoleamine 2,3 dioxygenase (IDO) activity, which catabolizes the degradation of tryptophan to kynurenine, may predict rejection. However, exogenous IDO is immunosuppressive in rodent kidney transplantation. Thus, the increase in IDO activity observed in acute allograft rejection is insufficient to prevent rejection. To address this question, we assessed the regulation of IDO and its role in acute rejection in a porcine model of kidney transplant. In tissue samples from rejecting kidney allografts, we showed a 13-fold increase in IDO gene transcription and 20-fold increase in IDO enzyme activity when compared with autotransplanted kidneys. Allografts also demonstrated an over fourfold increase in tissue interferon (IFN)-γ, with marked increases in tumor necrosis factor (TNF)-α, TNF-β and interleukin 1β. Gene transcription and protein levels of kynurenine 3-monooxygenase (KMO) were decreased. KMO generates the immunosuppressive kynurenine, 3-hydroxykynurenine. The results of these studies demonstrate a clear association between rejection and increased allograft IDO expression, likely driven in part by IFN-γ and facilitated by other cytokines of the allogeneic response. Moreover, the loss of downstream enzymatic activity in the IDO metabolic pathway may suggest novel mechanisms for the perpetuation of rejection.

Does Bernard-Soulier syndrome protect against thrombotic thrombocytopenic purpura?

Thrombotic thrombocytopenic purpura (TTP) is a thrombotic microangiopathy which is either congenital (Upshaw-Schulman syndrome) due to genetic mutations causing deficient function of ADAMTS-13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13), or acquired due to antibodies against ADAMTS-13.1–4 TTP is characterized by severe thrombocytopenia and microangiopathic hemolytic anemia (detected by identifying significant numbers of schistocytes on a peripheral blood smear) and is associated with mental status changes, renal failure, and fever. Plasma transfusion is first-line therapy for patients with congenital TTP, while plasma exchange (PLEX) is first-line treatment for acquired TTP patients. PLEX has increased the survival rate among patients with acquired TTP to >80%. The pathophysiology of TTP has been attributed to an increase in ultra-large von Willebrand factor (UL-vWF) multimers, which are produced by endothelial cells and stored in Weibel-Palade bodies. UL-vWF multimers are released by endothelial cells and are normally cleaved by ADAMTS-13. In TTP patients, UL-vWF multimers either remain adherent to endothelial cells or circulate in the blood. The UL-vWF multimers are highly adhesive to platelets through binding of the A1 domain of vWF to platelet glycoprotein (GP)Ib receptors. The attachment of ADAMTS-13 to platelets leads to microthrombosis, leading to ischemia and formation of schistocytes. The importance of platelet GPIb binding to the A1 domain of UL-vWF multimers has been shown through the evaluation of candidate anti-vWF therapies. Aptamer ARC1779, humanized mAb GBR600, and the anti-vWF humanized single-variable-domain immunoglobulin (Nanobody) caplacizumab are three candidate therapies being tested for TTP.5–7 These compounds bind to the A1 domain of vWF, which prevents attachment to GPIb on platelets.5–7 Caplacizumab is the most successful of these drugs. In a recent phase 2 TITAN study, caplacizumab was shown to induce faster resolution of acquired TTP in the acute setting, compared to a placebo. The pathophysiology of Bernard-Soulier syndrome (BSS) and TTP both involve platelet GPIb. BSS is usually an inherited autosomal recessive (rarely autosomal dominant) condition characterized by prolonged bleeding time and macrothrombocytopenia.8–10 BSS is often associated with epistaxis, gingival and cutaneous bleeding, and hemorrhage following trauma. BSS is caused by mutations in the GPIbIX-V complex, which is encoded by four genes (GP1BA, GP1BB, GP9, and GP5). The mutations are most common in GP9, but may also occur in GP1BA or GP1BB, but have not been reported in GP5. This is because GP5 expression is not needed for expression of the other subunits of the GPIb-IX-V complex. These mutations almost always result in either very low or undetectable levels of GPIb-IX-V. An exception is the Bolzano variant of BSS, caused by an A156V mutation in GP1BA, in which platelets express GPIb-IX-V in normal levels, but are unable to bind vWF. An examination of how TTP would be affected by BSS has not been performed. This can be attributed to the extreme unlikeliness of a single patient having two exceptionally rare medical conditions. The incidence of BSS is estimated to be 1 in a million persons. The incidence of TTP is estimated to be 3.7 in a million persons in the USA. Thus, only 3.7 in a trillion persons are estimated to have both medical conditions. In other words, only one person in 270 billion persons would have both conditions. To put this in perspective, the US Census Bureau (www.census.gov/popclock) estimates that the current global population is approximately 7.4 billion persons. Furthermore, the Population Reference Bureau (www.prb.org) estimated in 2011 that approximately 108 billion persons have ever lived. This number is still less than the 270 billion persons which would be needed to have one person with both BSS and TTP. Therefore, it is extremely unlikely that a person has ever had both conditions. Although patients with BSS could have a congenital or acquired deficiency of ADAMTS-13, they should be protected against the clinical severity of TTP. Patients with BSS have platelets that should not be able to strongly bind to ULvWF multimers due to the lack of functional platelet GPIb. To further explore this topic, PubMed searches were performed for “Bernard-Soulier” AND “TTP”. Two search results were identified. However, neither article described a patient with both conditions, nor discussed the relationship between TTP and BSS. In the unlikely event that a patient

Adding neonatal hyperbilirubinemia/bilirubin encephalopathy to the American Society for Apheresis Guidelines on Therapeutic Apheresis

Dear Editor, Acute bilirubin encephalopathy describes bilirubin toxicity in the “first weeks after birth”, which is likely caused by unbound bilirubin (not bound to albumin) crossing the bloodbrain barrier and causing neurotoxicity. Acute bilirubin encephalopathy first manifests with severe jaundice, lethargy, hypotonia, and poor sucking. It then progresses to an intermediate stage which may include moderate stupor, hypertonia, fever, and a high-pitched cry. The advanced phase of acute bilirubin encephalopathy is likely irreversible and may involve pronounced retrocollis-opisthotonus, a shrill cry, the absence of feeding, apnea, coma, seizure, and death. Those surviving acute bilirubin encephalopathy may develop chronic bilirubin encephalopathy and permanent sequalae (together known as “kernicterus”), which may involve deafness, cerebral palsy, paralysis of upper gaze, and other manifestations. In 2004, the American Academy of Pediatrics (AAP) published guidelines for the management of newborn infants with hyperbilirubinemia. In 2009, an update was published because “kernicterus is still occurring in the United States,” but should be a “never event”. The guidelines include primary and secondary prevention measures and treatment algorithms. Phototherapy treatment reduces the bilirubin level by converting trans-bilirubin to water-soluble cis-bilirubin, which is more easily excreted into bile. Intravenous immunoglobulin (IVIG) can be used in cases of hemolytic disease (HDFN) caused by ABO and Rh antibodies. Modified whole blood exchange transfusion (using red blood cells and plasma) is still recommended, although total serum bilirubin (TSB) levels for initiating exchange transfusion are higher than for phototherapy. The AAP recommends exchange transfusion as “immediate” therapy for the following: (1) patients with signs of acute bilirubin encephalopathy or (2) TSB levels 5 mg/dL above the risk-appropriate line on the “exchange transfusion bilirubin nomogram”. Still, most patients who receive exchange transfusion failed phototherapy. We feel that it is imperative that the American Society for Apheresis (ASFA) include severe hyperbilirubinemia/ bilirubin encephalopathy in their Guidelines for Therapeutic Apheresis. Phototherapy has not eliminated the need for modified whole blood exchange, and debilitating cases of kernicterus are still occurring. The ASFA Therapeutic Apheresis Guidelines include pediatric indications for apheresis and information about manual exchange transfusion for malaria and sickle cell disease, thus neonatal hyperbilirubinemia should also be included. While there is an ASFA guideline for “autoimmune hemolytic anemia, severe”, it describes therapeutic plasma exchange (TPE) for warm autoimmune hemolytic anemia (WAIHA) and cold agglutinin disease (CAD)/cold autoimmune hemolytic anemia (CAIHA). The ASFA guideline for “red cell alloimmunization in pregnancy” is for managing hemolytic disease of the fetus and newborn (HDFN) in pregnant women using TPE. Thus, these two ASFA guidelines do not describe the apheresis management of neonatal hyperbilirubinemia. Furthermore, the AAP guidelines do not provide detailed recommendations about modified whole blood exchange (ex. the composition of modified whole blood or the volumes of modified whole blood to be exchanged). In conclusion, neonatal hyperbilirubinemia/bilirubin encephalopathy remains a serious clinical problem. The eighth edition of the ASFA Therapeutic Apheresis Guidelines should include this condition to help physicians provide the most appropriate whole blood exchange transfusion regimen for these patients.

Comparing leukapheresis protocols for an AML patient with symptomatic leukostasis

Acute myeloid leukemia (AML) is a malignancy characterized by rapid clonal proliferation of myeloid precursors, which can result in hyperleukocytosis. Leukapheresis can be used to rapidly reduce the white blood cell count (WBC). However, the only FDA cleared device for WBC depletion, the COBE Spectra, will no longer be supported by the manufacturer in 2017, and there are few studies comparing different methods of leukapheresis.

Can Exchange Transfusions Using Red Blood Cells from Donors with Hemoglobin E Trait Prevent or Ameliorate Severe Malaria in Patients with Multi-drug Resistant Plasmodium falciparum?

Malaria continues to be a devastating parasitic disease. In 2015, an estimated 212 million new infections caused 429,000 deaths across the world—about 70% of these deaths were children less than 5-years-old [1]. The Plasmodium falciparum parasite was responsible for 99% of all deaths [1]. Unfortunately, in 2017, multi-drug resistant strains of P. falciparum are spreading throughout the Greater Mekong subregion. Because of multi-drug resistance, new therapeutic options are needed. We recently proposed that a selective or ‘‘therapeutically-rational red blood cell exchange’’ (T-REX) strategy using Southeast Asian ovalocytosis (SAO) RBCs may reduce the morbidity and mortality of patients infected with multi-drug resistant P. falciparum malaria [2]. Here we propose an alternative strategy using RBCs with hemoglobin E trait (HbAE), which may be feasible in regions where SAO is not prevalent. Hemoglobin E (HbE) is a hemoglobin variant caused by a point mutation in codon 26 of the b-globin gene which substitutes lysine for glutamic acid. HbAE is most common in Southeast Asia, especially northeast and eastern India and eastern Thailand [3] where more than 50% of some populations have HbAE [4]. In addition, HbAE is also prevalent in Myanmar, Indonesia, and Malaysia [3]. Fortunately, HbAE protects against severe P. falciparum malaria [5] and explains why this variant is common in malaria-endemic regions. HbAE is characterized by microcytosis without anemia and has no clinical significance for carriers. HbAE can be screened-for/diagnosed using high-pressure liquid chromatography (HPLC), acid/ alkaline hemoglobin electrophoresis, isoelectric focusing, or DNA-based tests. Instead of using routine, ‘‘standard-issue’’ RBC units for exchange transfusion to ameliorate severe malaria (by removing infected, cytoadherent RBCs and replacing them with ‘‘standard-issue’’ RBCs), we suggest evaluating the efficacy of selective HbAE-RBC T-REX. In hospitals without an automated RBC-exchange machine, manual RBC exchange can be performed. Fortunately, HbAE RBCs are already commonly and safely used to treat blood loss. Because clinical studies have shown that HbAE-RBCs are protective against severe P. falciparum malaria, HbAERBC T-REX could prove to be life-saving. Fortunately, HbAE-RBC T-REX is feasible because (1) individuals with HbAE are generally asymptomatic, not anemic, and qualify as blood donors, (2) up to 50% of individuals in regions of India and Thailand have HbAE, and (3) blood banks can identify units as HbAE by testing the donors or a bloodtubing segment for low mean corpuscular hemoglobin (MCV), followed by confirmatory testing. Of course, severely anemic patients could receive HbAE-RBC blood transfusions before undergoing HbAE-RBC T-REX. Because more than 400,000 P. falciparum malaria patients still die each year due to delayed drug administration or multi-drug resistance, non-drug cell therapies warrant serious consideration. Fortunately, compelling clinical data and modern public health infrastructures mean Ryan P. Jajosky, Audrey N. Jajosky, Philip G. Jajosky have equally contributed to the literature review and manuscript editing/ production.