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The United States Food and Drug Administration Final Guidance for Industry titled, "Bacterial Risk Control Strategies for Blood Collection Establishments and Transfusion Services to Enhance the Safety and Availability of Platelets for Transfusion" provides nine strategies for platelet bacterial risk mitigation. Even if it is assumed all strategies are comparable in terms of safety and efficacy, the decision of which to implement remains challenging. Some additional factors that warrant evaluation before selecting a strategy include the financial impact, process for implementation, logistics upon implementation, institutional acceptance by blood bank staff, administration and clinicians, and effect on platelet availability. To assist with this difficult choice, a panel of transfusion service physicians who have expertise on the topic and have already selected strategies for their transfusion services were recruited to provide varied perspectives. In addition, the use of a decision-making tool that objectively evaluates defined criteria for assessment of the nine strategies is described.

Large-scale multi-ethnic cohorts offer unprecedented opportunities to elucidate the genetic factors influencing complex traits related to health and disease among minority populations. At the same time, the genetic diversity in these cohorts presents new challenges for analysis and interpretation. We consider the utility of race and/or ethnicity categories in genome-wide association studies (GWASs) of multi-ethnic cohorts. We demonstrate that race/ethnicity information enhances the ability to understand population-specific genetic architecture. To address the practical issue that self-identified racial/ethnic information may be incomplete, we propose a machine learning algorithm that produces a surrogate variable, termed HARE. We use height as a model trait to demonstrate the utility of HARE and ethnicity-specific GWASs.

The need for accurate antibody testing in patients following symptomatic or asymptomatic infections with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is well documented. How we best utilize the data obtained from these antibody studies is still a haunting question ([1][1]). There are

Moderate alcohol consumption has been associated with a lower risk of coronary artery disease (CAD) in the general population but has not been well studied in US veterans. We obtained self-reported alcohol consumption from Million Veteran Program participants. Using electronic health records, CAD events were defined as 1 inpatient or 2 outpatient diagnosis codes for CAD, or 1 code for a coronary procedure. We excluded participants with prevalent CAD (n = 69,995) or incomplete alcohol information (n = 8,449). We used a Cox proportional hazards model to estimate hazard ratios and 95% confidence intervals for CAD, adjusting for age, gender, body mass index, race, smoking, education, and exercise. Among 156,728 participants, the mean age was 65.3 years (standard deviation = 12.1) and 91% were men. There were 6,153 CAD events during a mean follow-up of 2.9 years. Adjusted hazard ratios (95% confidence intervals) for CAD were 1.00 (reference), 1.02 (0.92 to 1.13), 0.83 (0.74 to 0.93), 0.77 (0.67 to 0.87), 0.71 (0.62 to 0.81), 0.62 (0.51 to 0.76), 0.58 (0.46 to 0.74), and 0.95 (0.85 to 1.06) for categories of never drinker; former drinker; current drinkers of ≤0.5 drink/day, >0.5 to 1 drink/day, >1 to 2 drinks/day, >2 to 3 drinks/day, and >3 to 4 drinks/day; and heavy drinkers (>4 drinks/day) or alcohol use disorder, respectively. For a fixed amount of ethanol, intake at ≥3 days/week was associated with lower CAD risk compared with ≤1 day/week. Beverage preference (beer, wine, or liquor) did not influence the alcohol-CAD relation. Our data show a lower risk of CAD with light-to-moderate alcohol consumption among US veterans, and drinking frequency may provide a further reduction in risk.

Mycosis fungoides in palmoplantar localization (MFPP) is a rare variant of MF that is confined to the hands and feet. Patients commonly receive treatment over many years for suspected palmoplantar dermatitis before the diagnosis is made. Most MFPP patients remain at patch or plaque stage, and often respond to treatment with radiotherapy. Herein, we describe a 77-year-old man who suffered 6 years of hand and foot dermatitis that failed multiple treatments, most notably TNF-α inhibitors and mycophenolate mofetil. He eventually developed a tumor on the hand, which was biopsied to reveal a dense dermal infiltrate of large lymphocytes (CD3+/CD4-/CD8-/TCR-BetaF1+/partial CD30+). A subsequent biopsy of an eczematous patch from his hand revealed an epidermotropic and syringotropic infiltrate comprised of smaller lymphocytes with a concordant immunophenotype and matching clonal peak with TCR gene rearrangement. He was diagnosed with MFPP and started on radiotherapy with a modest response; therefore, a decision was made to start brentuximab vedotin, which resulted in a complete response. MFPP is an exceedingly rare variant of MF that can show large-cell transformation and progress in stage. We highlight a possible association between disease progression and immunosuppressants and the potential role for treatment with brentuximab.

IMPORTANCE: Electronic health record (EHR) biobanks containing clinical and genomic data on large numbers of individuals have great potential to inform drug discovery. Individuals with interleukin 6 receptor (IL6R) single-nucleotide polymorphisms (SNPs) who are not receiving IL6R blocking therapy have biomarker profiles similar to those treated with IL6R blockers. This gene–drug pair provides an example to test whether associations of IL6R SNPs with a broad range of phenotypes can inform which diseases may benefit from treatment with IL6R blockade. OBJECTIVE: To determine whether screening for clinical associations with the IL6R SNP in a phenome-wide association study (PheWAS) using EHR biobank data can identify drug effects from IL6R clinical trials. DESIGN, SETTING, AND PARTICIPANTS: Diagnosis codes and routine laboratory measurements were extracted from the VA Million Veteran Program (MVP); diagnosis codes were mapped to phenotype groups using published PheWAS methods. A PheWAS was performed by fitting logistic regression models for testing associations of the IL6R SNPs with 1342 phenotype groups and by fitting linear regression models for testing associations of the IL6R SNP with 26 routine laboratory measurements. Significance was reported using a false discovery rate of 0.05 or less. Findings were replicated in 2 independent cohorts using UK Biobank and Vanderbilt University Biobank data. The Million Veteran Program included 332 799 US veterans; the UK Biobank, 408 455 individuals from the general population of the United Kingdom; and the Vanderbilt University Biobank, 13 835 patients from a tertiary care center. EXPOSURES: IL6R SNPs (rs2228145; rs4129267). MAIN OUTCOMES AND MEASURES: Phenotypes defined by International Classification of Diseases, Ninth Revision codes. RESULTS: Of the 332 799 veterans included in the main cohort, 305 228 (91.7%) were men, and the mean (SD) age was 66.1 (13.6) years. The IL6R SNP was most strongly associated with a reduced risk of aortic aneurysm phenotypes (odds ratio, 0.87-0.90; 95% CI, 0.84-0.93) in the MVP. We observed known off-target effects of IL6R blockade from clinical trials (eg, higher hemoglobin level). The reduced risk for aortic aneurysms among those with the IL6R SNP in the MVP was replicated in the Vanderbilt University Biobank, and the reduced risk for coronary heart disease was replicated in the UK Biobank. CONCLUSIONS AND RELEVANCE: In this proof-of-concept study, we demonstrated application of the PheWAS using large EHR biobanks to inform drug effects. The findings of an association of the IL6R SNP with reduced risk for aortic aneurysms correspond with the newest indication for IL6R blockade, giant cell arteritis, of which a major complication is aortic aneurysm.

Background While adherence to healthful dietary patterns has been associated with a lower risk of coronary artery disease (CAD) in the general population, limited data are available among US veterans. We tested the hypothesis that adherence to Dietary Approach to Stop Hypertension (DASH) food pattern is associated with a lower risk of developing CAD among veterans. Methods and Results We analyzed data on 153 802 participants of the Million Veteran Program enrolled between 2011 and 2016. Information on dietary habits was obtained using a food frequency questionnaire at enrollment. We used electronic health records to assess the development of CAD during follow‐up. Of the 153 802 veterans who provided information on diet and were free of CAD at baseline, the mean age was 64.0 (SD=11.8) years and 90.4% were men. During a mean follow‐up of 2.8 years, 5451 CAD cases occurred. The crude incidence rate of CAD was 14.0, 13.1, 12.6, 12.3, and 11.1 cases per 1000 person‐years across consecutive quintiles of Dietary Approach to Stop Hypertension score. Hazard ratios (95% confidence interval) for CAD were 1.0 (ref), 0.91 (0.84–0.99), 0.87 (0.80–0.95), 0.86 (0.79–0.94), and 0.80 (0.73–0.87) from the lowest to highest quintile of Dietary Approach to Stop Hypertension score controlling for age, sex, body mass index, race, smoking, exercise, alcohol intake, and statin use ( P linear trend, Conclusions Our data are consistent with an inverse association between Dietary Approach to Stop Hypertension diet score and incidence of CAD among US veterans.

The National Heart, Lung, and Blood Institute in collaboration with the American Society for Apheresis, convened a State of the Science Symposium in November of 2012 due to the expanding application of therapeutic apheresis despite the lack of well-designed research to address its efficacy. This article reviews the opportunities that were presented at this meeting in the area of cardiovascular disease (CVD), specifically the use of columns to adsorb autoantibodies in dilated cardiomyopathy or damaging lipids in peripheral vascular disease. Understanding how absorption of these pathologic substances alters the inflammatory response in these disorders is important for the application of these technologies to the treatment of CVD.

Increasing the pool of cells at early T-cell developmental stages enhances thymopoiesis and is especially beneficial when T-cell production is compromised by radiation or aging. Within the immature double-negative (DN; CD4(-)CD8(-)) thymocyte subpopulation, the DN1 subset contains the most primitive cells including the rare early T-cell progenitors (ETPs). In the present study, a human MCL1 transgene, under the control of its endogenous promoter, resulted in enlargement of an undistorted thymus in C57/BL6 mice. Enlargement occurred in females but not males, being seen at 1 month of age and maintained during progression into adulthood as the thymus underwent involution. The small DN1 subset was expanded disproportionally (ETPs increasing from ∼0.016 to 0.03% of thymocytes), while more mature thymocytes were increased proportionally (1.5-fold) along with the stroma. DN1 cells from transgenic females exhibited increased viability with maintained proliferation, and their survival in primary culture was extended. Exposure of transgenic females to γ-irradiation also revealed an expanded pool of radioresistant DN1 cells exhibiting increased viability. While the viability of DN1 cells from transgenic males was equivalent to that of their non-transgenic counterparts directly after harvest, it was enhanced in culture-suggesting that the effect of the transgene was suppressed in the in vivo environment of the male. Viability was increased in ETPs from transgenic females, but unchanged in more mature thymocytes, indicating that primitive cells were affected selectively. The MCL1 transgene thus increases the viability and pool size of primitive ETP/DN1 cells, promoting thymopoiesis and radioresistance in peripubescent females and into adulthood.

Lansoprazole is a potent proton pump inhibitor that has been well tolerated with minimal serious adverse events. One of the most commonly reported side effects is diarrhea in 3-8% of study patients. During 1997, approximately 850 veterans at our institution had their proton pump inhibitor converted from omeprazole to lansoprazole because of a formulary change. A number of patients subsequently developed chronic watery diarrhea. While evaluating six of these patients, we discovered microscopic colitis that resolved with discontinuation of lansoprazole. The diarrhea was described as three to 10 loose, nonbloody bowel movements per day with some abdominal cramping. Colonoscopy in five patients and flexible sigmoidoscopy in one patient revealed normal colonic mucosa, but random biopsies all supported microscopic colitis (five cases of lymphocytic colitis and one case of collagenous colitis). Complete symptom resolution occurred in all patients within 4 to 10 days of discontinuing lansoprazole. In all patients, follow-up biopsies demonstrated normalization of the colonic histology. This is the first published case series of patients with microscopic colitis that correlated clinically and histologically with the initiation and discontinuation of lansoprazole.

The clinical use of extracorporeal photopheresis (ECP) for accepted indications such as graft-versus-host disease, transplant rejection, and cutaneous T-cell lymphoma continues to increase. Expanded applications for ECP, such as the treatment of select autoimmune diseases, are being explored. Extracorporeal photopheresis's capacity to both immunotolerize in the autoreactive setting, while immunizing against a lymphoma is unusual and suggestive of a unique mechanism. It is likely that ECP's induction of dendritic cells is key to its efficacy in both of these settings, but exactly how ECP impacts other immune components and their interactions is not fully understood. Further basic science research is necessary to elucidate how these dissimilar cellular activities are functionally integrated. On the clinical side, collaborative multicenter trials designed to recognize the principal variables controlling therapeutic responses and improve prognostic indicators may enable tailoring devices, treatment schedules, and doses to the needs of the individual patients or diseases. This review describes our current understanding of how ECP influences the immune system, reviews the existing clinical applications of ECP, and explores areas for future basic science and clinical research as presented at the National Institutes of Health State of the Science Symposium in Therapeutic Apheresis in November 2012.

Abundant, sustained expression of prosurvival Mcl-1 is an important determinant of viability and drug resistance in cancer cells. The Mcl-1 protein contains PEST sequences (enriched in proline, glutamic acid, serine, and threonine) and is normally subject to rapid turnover via multiple different pathways. One of these pathways involves a phosphodegron in the PEST region, where Thr-163 phosphorylation primes for Ser-159 phosphorylation by glycogen synthase kinase-3. Turnover via this phosphodegron-targeted pathway is reduced in Mcl-1-overexpressing BL41-3 Burkitt lymphoma and other cancer cells; turnover is further slowed in the presence of phorbol ester-induced ERK activation, resulting in Mcl-1 stabilization and an exacerbation of chemoresistance. The present studies focused on Mcl-1 dephosphorylation, which was also found to profoundly influence turnover. Exposure of BL41-3 cells to an inhibitor of protein phosphatase 2A (PP2A), okadaic acid, resulted in a rapid increase in phosphorylation at Thr-163 and Ser-159, along with a precipitous decrease in Mcl-1 expression. The decline in Mcl-1 expression preceded the appearance of cell death markers and was not slowed in the presence of phorbol ester. Upon exposure to calyculin A, which also potently inhibits PP2A, versus tautomycin, which does not, only the former increased Thr-163/Ser-159 phosphorylation and decreased Mcl-1 expression. Mcl-1 co-immunoprecipitated with PP2A upon transfection into CHO cells, and PP2A/Aα knockdown recapitulated the increase in Mcl-1 phosphorylation and decrease in expression. In sum, inhibition of PP2A prevents Mcl-1 dephosphorylation and results in rapid loss of this prosurvival protein in chemoresistant cancer cells.

The National Heart, Lung, and Blood Institute in collaboration with the American Society for Apheresis, convened a State of the Science Symposium in November of 2012 due to the expanding application of therapeutic apheresis despite the lack of well-designed research to address its efficacy. This article reviews the opportunities that were presented at this meeting in the area of cardiovascular disease (CVD), specifically the use of columns to adsorb autoantibodies in dilated cardiomyopathy or damaging lipids in peripheral vascular disease. Understanding how absorption of these pathologic substances alters the inflammatory response in these disorders is important for the application of these technologies to the treatment of CVD.

Much evidence indicates that atherosclerotic lesions are largely of an inflammatory nature. Activated macrophages and macrophage-derived foam cells laden with cholesterol esters are a major constituent of these lesions and can influence lesion formation via several potential mechanisms. One such mechanism is Fcgamma receptor activation and/or Fcgamma receptor-mediated clearance of immune complexes containing cholesterol, such as lipoprotein immune complexes. That this mechanism contributes to lesion formation would be further supported if Fcgamma receptor expression in arterial lesions were demonstrated. We therefore used monoclonal antibodies and immunocytochemical methods to analyze frozen sections of human arterial lesions for expression of each of the three primary classes of mononuclear phagocyte Fcgamma receptors. Approximately 800 sections of aorta, carotid, and coronary arteries obtained from five elderly donors were analyzed. The presence of macrophages was determined by assaying reactivity of a monoclonal antibody specific to CD163, which is expressed only on cells of the human mononuclear phagocyte lineage. Results indicate that highly cellular preatheromatous lesions contained numerous macrophages in the zone of proliferation that expressed each class of Fcgamma receptor (FcgammaRIA, FcgammaRIIA, and FcgammaRIIIA). Fcgamma receptor-positive cells were also present in medial and adventitial areas. Fcgamma receptor staining was both punctate and diffuse, the latter suggesting that soluble receptors were present in the extracellular matrix. These data further support that Fcgamma receptor-mediated clearance of immune complexes can occur in arterial lesions during atherogenesis. Expression of both the high affinity (FcgammaRIA) and lower affinity (FcgammaRIIA/FcgammaRIIIA) receptors indicates that mono- and multivalent IgG-containing immune complexes could engage Fcgamma receptors and influence lesion formation through several different inflammatory mechanisms triggered by receptor activation.

Recent recognition that an autoimmune myocarditis may precede, and result in, dilated cardiomyopathy has focused attention on immune mechanisms of myocardial injury. In this paper, we describe a model of chronic autoimmune myocarditis in the Lewis rat. The production of myocarditis has been previously described by this group and in brief is accomplished by a single tail vein infusion of activated T cells specific for a 17-amino acid peptide from rat cardiac myosin. In this report, animals were followed for approximately 6 months post-T-cell infusion. Hearts from animals which received cardiac myosin specific T cells all showed extensive fibrosis associated with ongoing inflammation. Apoptosis, identified by TdT-mediated dUTP nick end labelling (TUNEL), was identified as a mode of myocyte death in hearts with acute and chronic myocarditis but not in age- and sex-matched controls. Immunohistochemistry was used to characterize the immune infiltrate and adhesion molecules in hearts with chronic myocarditis and these findings were compared to hearts with acute myocarditis. We propose that this rat model of chronic myocarditis mimics human disease, since inflammation results in ventricular dilatation and myocyte hypertrophy reminiscent of dilated cardiomyopathy. This model offers potential for further investigation of immune, functional and possible therapeutic aspects of autoimmune related cardiomyopathies.

In the rat, autoimmune myocarditis can be produced by the infusion of activated myosin peptide specific, CD4 + , class II restricted, effector T cells. Whether antigen presenting cells (APCs), which interact with these effector T cells in the heart, are a fixed population of cells (resident dendritic, macrophage, or endothelial cells), or a dynamic bone marrow derived population has not yet been demonstrated in vivo . To study this question, bone marrow chimeras were generated using inbred Brown Norway (BN) rats, which are resistant to autoimmune myocarditis, and transplanting them after lethal irradiation with (Lewis×BN) F1 bone marrow. BN rats differ at both MHC loci from the susceptible inbred Lewis rats. Two months after bone marrow transplantation, chimeric animals received Lewis T cells specific for a myocarditogenic peptide antigen. To characterize the cardiac APCs, immunohistochemistry using a battery of antibodies including Lewis-specific and broadly reactive antibodies for both MHC class I and class II, was performed on chimeric hearts, with and without infused Lewis T cells, and non-transplanted BN control hearts. All chimeric rats infused with allogeneic (Lewis), anti-cardiac myosin peptide effector T cells displayed the lesions of myocarditis. Myocarditis was not present in non-transplanted BN controls given either Lewis or F1 derived myocarditogenic T cells, nor in chimeric animals which did not receive myocarditogenic T cells, thus excluding graft vs host disease as the explanation for the inflammation in chimeric hearts with myocarditis. Marrow derived cells expressing both Lewis class I and class II MHC molecules were demonstrated on perivascular cells in the myocardium of all chimeric animals, and on infiltrating cells in chimeric animals with myocarditis. Cells expressing Lewis-specific MHC antigens were not detected in the non-transplanted BN controls. Furthermore, immunohistochemistry using broadly reactive antibodies demonstrated MHC class II on perivascular cells with a dendritic morphology in all hearts but not on endothelial cells or cardiac myocytes. These results support the hypothesis that in vivo , cardiac APCs which result in MHC class II restricted, T cell induced myocarditis are a dynamic bone marrow derived population and not a fixed population. In order to address the potential requirement of MHC class I for the initiation of autoimmune myocarditis, myocarditogenic T cells derived from either Lewis or DA(RP) rats were infused into a member of the other strain. These strains share common MHC class II genes but differ at the MHC class I loci. Myocarditis identical to that produced in the syngeneic animal was successfully transferred by the MHC class I mismatched T cells, but only after the recipient animal's native immune system was mildly suppressed. These results further support the primary role for professional antigen presentation via MHC class II restriction to the effector T cells at the initiation of autoimmune myocarditis in the heart. Together, these experiments confirm that activated effector T cells, in order to produce myocarditis, require MHC class II compatible APCs in the heart, that these APCs are bone marrow derived, and will endogenously take up and present local antigens in the target organ after bone marrow reconstitution.

Myocarditis and progression to cardiomyopathy is associated with focal spasm and reperfusion of the coronary microcirculation. Experimental autoimmune myocarditis (EAM), induced with cardiomyosin peptide-specific T cells in Lewis rats, was hypothesized to cause acute hemodynamic and coronary vasculature changes. Fifteen experimental animals (5 each at 1, 2, and 3 weeks after T-cell injection) and eight controls were studied using the constant pressure variant of the isolated heart. Coronary resistant decreased while coronary flow increased (P < 0.05) in EAM hearts after the first week. Rate-pressure product, +dP/dt and -dP/dt, decreased while the heart/body weight ratio increased (P < 0.05) compared with controls at 1 week but not at 2 or 3 weeks. Mean local myocardial PO2, which reflects local oxygen delivery and consumption, and MVO2 were not different for EAM hearts. However, compared with controls EAM myocardial PO2 varied more widely and was often beyond the usual range, suggesting the occurrence of localized hypoxic and hyperoxic areas. In summary, after the first week there was a significant decrease in coronary resistance in the EAM animals, which required higher flow to maintain a similar perfusion pressure. These changes in coronary resistance and flow along with the heterogeneity and extremes of local myocardial PO2 levels without a significant change in MVO2 may be explained by postulating development of low-resistance, high-flow hyperoxic areas which steal flow, thus causing hypoxia in other areas.

Intraosseous epidermoid inclusion cysts are rare benign bone lesions that occur most commonly in the skull and in the distal phalanges of the fingers. Herein we report a case of an intraosseous epidermoid inclusion cyst occurring in the distal phalanx of the left hallux. Only six occurrences of this lesion have been described in the foot. This patient’s presentation, with active drainage (initially appearing as purulent discharge from an acutely tender ingrown hallux nail) and a known inoculation event accompanied by severe peripheral vascular disease, make this case unique. (J Am Podiatr Med Assoc 100(2): 133–137, 2010)

A lymphotoxin-β (LTβ) receptor-Ig fusion protein (LTβR-Ig) was used to evaluate the importance of the lymphotoxin/LIGHT axis in the development and perpetuation of arthritis. Prophylactic treatment with the inhibitor protein LTβR-Ig blocked the induction of collagen-induced arthritis in mice and adjuvant arthritis in Lewis rats. Treatment of mice with established collagen-induced arthritis reduced the severity of arthritic symptoms and joint tissue damage. However, in a passive model of anti-collagen Ab-triggered arthritis, joint inflammation was not affected by LTβR-Ig treatment precluding LT/LIGHT involvement in the very terminal immune complex/complement/FcR-mediated effector phase. Collagen-II and Mycobacterium-specific T cell responses were not impaired, yet there was evidence that the overall response to the mycobacterium was blunted. Serum titers of anti-collagen-II Abs were reduced especially during the late phase of disease. Treatment with LTβR-Ig ablated follicular dendritic cell networks in the draining lymph nodes, suggesting that impaired class switching and affinity maturation may have led to a decreased level of pathological autoantibodies. These data are consistent with a model in which the LT/LIGHT axis controls microenvironments in the draining lymph nodes. These environments are critical in shaping the adjuvant-driven initiating events that impact the subsequent quality of the anti-collagen response in the later phases. Consequently, blockade of the LT/LIGHT axis may represent a novel approach to the treatment of autoimmune diseases such as rheumatoid arthritis that involve both T cell and Ab components.