Current advances in 2022: A critical review of selected topics by the Association for the Advancement of Blood and Biotherapies (AABB) Clinical Transfusion Medicine Committee.

BACKGROUND: The Association for the Advancement of Blood and Biotherapies Clinical Transfusion Medicine Committee (CTMC) composes a summary of new and important advances in transfusion medicine (TM) on an annual basis. Since 2018, this has been assembled into a manuscript and published in Transfusion. STUDY DESIGN AND METHODS: CTMC members selected original manuscripts relevant to TM that were published electronically and/or in print during calendar year 2022. Papers were selected based on perceived importance and/or originality. References for selected papers were made available to CTMC members to provide feedback. Members were also encouraged to identify papers that may have been omitted initially. They then worked in groups of two to three to write a summary for each new publication within their broader topic. Each topic summary was then reviewed and edited by two separate committee members. The final manuscript was assembled by the first and senior authors. While this review is extensive, it is not a systematic review and some publications considered important by readers may have been excluded. RESULTS: For calendar year 2022, summaries of key publications were assembled for the following broader topics within TM: blood component therapy; infectious diseases, blood donor testing, and collections; patient blood management; immunohematology and genomics; hemostasis; hemoglobinopathies; apheresis and cell therapy; pediatrics; and health care disparities, diversity, equity, and inclusion. DISCUSSION: This Committee Report reviews and summarizes important publications and advances in TM published during calendar year 2022, and maybe a useful educational tool.

Red Blood Cell Transfusion: 2023 AABB International Guidelines.

Importance: Red blood cell transfusion is a common medical intervention with benefits and harms. Objective: To provide recommendations for use of red blood cell transfusion in adults and children. Evidence Review: Standards for trustworthy guidelines were followed, including using Grading of Recommendations Assessment, Development and Evaluation methods, managing conflicts of interest, and making values and preferences explicit. Evidence from systematic reviews of randomized controlled trials was reviewed. Findings: For adults, 45 randomized controlled trials with 20 599 participants compared restrictive hemoglobin-based transfusion thresholds, typically 7 to 8 g/dL, with liberal transfusion thresholds of 9 to 10 g/dL. For pediatric patients, 7 randomized controlled trials with 2730 participants compared a variety of restrictive and liberal transfusion thresholds. For most patient populations, results provided moderate quality evidence that restrictive transfusion thresholds did not adversely affect patient-important outcomes. Recommendation 1: for hospitalized adult patients who are hemodynamically stable, the international panel recommends a restrictive transfusion strategy considering transfusion when the hemoglobin concentration is less than 7 g/dL (strong recommendation, moderate certainty evidence). In accordance with the restrictive strategy threshold used in most trials, clinicians may choose a threshold of 7.5 g/dL for patients undergoing cardiac surgery and 8 g/dL for those undergoing orthopedic surgery or those with preexisting cardiovascular disease. Recommendation 2: for hospitalized adult patients with hematologic and oncologic disorders, the panel suggests a restrictive transfusion strategy considering transfusion when the hemoglobin concentration is less than 7 g/dL (conditional recommendations, low certainty evidence). Recommendation 3: for critically ill children and those at risk of critical illness who are hemodynamically stable and without a hemoglobinopathy, cyanotic cardiac condition, or severe hypoxemia, the international panel recommends a restrictive transfusion strategy considering transfusion when the hemoglobin concentration is less than 7 g/dL (strong recommendation, moderate certainty evidence). Recommendation 4: for hemodynamically stable children with congenital heart disease, the international panel suggests a transfusion threshold that is based on the cardiac abnormality and stage of surgical repair: 7 g/dL (biventricular repair), 9 g/dL (single-ventricle palliation), or 7 to 9 g/dL (uncorrected congenital heart disease) (conditional recommendation, low certainty evidence). Conclusions and Relevance: It is good practice to consider overall clinical context and alternative therapies to transfusion when making transfusion decisions about an individual patient.

MicroRNA-1270 Inhibits Cell Proliferation, Migration, and Invasion via Targeting IRF8 in Osteoblast-like Cell Lines.

Osteoporosis (OP) is the most common bone disease affecting elderly individuals. The diagnosis of this pathology is most commonly made on the basis of bone fractures. Several microRNAs (miRNAs/miRs) have been identified as possible biomarkers for the diagnosis and treatment of OP. miRNAs can regulate gene expression, and determining their functions can provide potential pharmacological targets for treating OP. A previous study showed that miR-1270 was upregulated in monocytes derived from postmenopausal women with OP. Therefore, the present study aimed to uncover the role of miR-1270 in regulating bone metabolism. To reveal the mechanism underlying the regulatory effect of miR-1270 on interferon regulatory factor 8 (IRF8) expression, luciferase assay, reverse transcription-quantitative PCR, and Western blot analysis were performed. The results suggest that miR-1270 could regulate the mRNA and protein expression levels of IRF8 by directly binding to its 3'-untranslated region. The effects of miR-1270 overexpression and IRF8 silencing on cell proliferation, migration, and invasion were also evaluated. To the best of our knowledge, the current study was the first to support the crucial role of miR-1270 in bone metabolism via modulation of IRF8 expression. In addition, miR-1270 overexpression could attenuate human osteoblast-like cells' proliferation and migration ability.

Significantly Decreased Mortality in a Large Cohort of Coronavirus Disease 2019 (COVID-19) Patients Transfused Early with Convalescent Plasma Containing High-Titer Anti-Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Spike Protein IgG.

Coronavirus disease 2019 (COVID-19) convalescent plasma has emerged as a promising therapy and has been granted Emergency Use Authorization by the US Food and Drug Administration for hospitalized COVID-19 patients. We recently reported results from interim analysis of a propensity score-matched study suggesting that early treatment of COVID-19 patients with convalescent plasma containing high-titer anti-spike protein receptor binding domain (RBD) IgG significantly decreases mortality. We herein present results from a 60-day follow-up of a cohort of 351 transfused hospitalized patients. Prospective determination of enzyme-linked immunosorbent assay anti-RBD IgG titer facilitated selection and transfusion of the highest titer units available. Retrospective analysis by the Ortho VITROS IgG assay revealed a median signal/cutoff ratio of 24.0 for transfused units, a value far exceeding the recent US Food and Drug Administration-required cutoff of 12.0 for designation of high-titer convalescent plasma. With respect to altering mortality, our analysis identified an optimal window of 44 hours after hospitalization for transfusing COVID-19 patients with high-titer convalescent plasma. In the aggregate, the analysis confirms and extends our previous preliminary finding that transfusion of COVID-19 patients soon after hospitalization with high-titer anti-spike protein RBD IgG present in convalescent plasma significantly reduces mortality.

Analysis of College of American Pathologists von Willebrand Factor Proficiency Testing Program.

Von Willebrand factor (VWF) level and/or function is altered in von Willebrand disease (VWD), the most common heritable bleeding disorder worldwide. Laboratory assessment of VWF is continually evolving. Historically, the primary method for the assessment of VWF platelet-binding activity was the ristocetin cofactor assay (VWF:RCo). Contemporary alternative measures of VWF platelet-binding activity include VWF:GPIbR (recombinant; using ristocetin), VWF:GPIbM (recombinant; gain-of-function mutant), and monoclonal antibody. Recently, the American Society of Hematology, International Society on Thrombosis and Haemostasis, National Hemophilia Foundation, and World Federation of Hemophilia collaboration issued guidelines recommending the use of newer assays of VWF platelet-binding activity (VWF: GPIbM, VWF: GPIbR) over VWF:RCo, given known limitations of the VWF:RCo assay. Despite this recommendation, the newer VWF:GPIbM and VWF:GPIbR assays are not United States Food and Drug Administration cleared, limiting their availability in the United States. We sought to assess assay utilization trends, agreement of VWF testing methods, and imprecision of VWF testing (based on assigned sample type) from the College of American Pathologists Proficiency Testing Surveys. The analysis confirms that, while VWF antigen testing has low imprecision, the various VWF activity assays have significant interassay variability, with VWF:RCo showing greater imprecision than the newer GPIb-binding assays. The overall trends in assay utilization reflect the barriers to complete compliance with modern VWD diagnostic guidelines in North America.

Analysis of College of American Pathologists von Willebrand Factor Proficiency Testing Program.

Von Willebrand factor (VWF) level and/or function is altered in von Willebrand disease (VWD), the most common heritable bleeding disorder worldwide. Laboratory assessment of VWF is continually evolving. Historically, the primary method for the assessment of VWF platelet-binding activity was the ristocetin cofactor assay (VWF:RCo). Contemporary alternative measures of VWF platelet-binding activity include VWF:GPIbR (recombinant; using ristocetin), VWF:GPIbM (recombinant; gain-of-function mutant), and monoclonal antibody. Recently, the American Society of Hematology, International Society on Thrombosis and Haemostasis, National Hemophilia Foundation, and World Federation of Hemophilia collaboration issued guidelines recommending the use of newer assays of VWF platelet-binding activity (VWF: GPIbM, VWF: GPIbR) over VWF:RCo, given known limitations of the VWF:RCo assay. Despite this recommendation, the newer VWF:GPIbM and VWF:GPIbR assays are not United States Food and Drug Administration cleared, limiting their availability in the United States. We sought to assess assay utilization trends, agreement of VWF testing methods, and imprecision of VWF testing (based on assigned sample type) from the College of American Pathologists Proficiency Testing Surveys. The analysis confirms that, while VWF antigen testing has low imprecision, the various VWF activity assays have significant interassay variability, with VWF:RCo showing greater imprecision than the newer GPIb-binding assays. The overall trends in assay utilization reflect the barriers to complete compliance with modern VWD diagnostic guidelines in North America.

Current advances in transfusion medicine 2021: A critical review of selected topics by the AABB Clinical Transfusion Medicine Committee.

BACKGROUND: Each year the AABB Clinical Transfusion Medicine Committee (CTMC) procures a synopsis highlighting new, important, and clinically relevant studies in the field of transfusion medicine (TM). This has been made available as a publication in Transfusion since 2018. METHODS: CTMC members reviewed and identified original manuscripts covering TM-related topics published electronically (ahead-of-print) or in print from December 2020 to December 2021. Selection of publications was discussed at committee meetings and chosen based on perceived relevance and originality. Next, committee members worked in pairs to create a synopsis of each topic, which was then reviewed by additional committee members. The first and senior authors assembled the final manuscript. Although this synopsis is extensive, it is not exhaustive, and some articles may have been excluded or missed. RESULTS: The following topics are included: blood products; convalescent plasma; donor collections and testing; hemoglobinopathies; immunohematology and genomics; hemostasis; patient blood management; pediatrics; therapeutic apheresis; and cell therapy. CONCLUSIONS: This synopsis highlights and summarizes recent key developments in TM and may be useful for educational purposes.

Apixaban and Rivaroxaban Anti-Xa Level Monitoring Versus Standard Monitoring in Hospitalized Patients With Acute Kidney Injury.

BACKGROUND: Oral direct factor Xa inhibitors (FxaIs) are renally eliminated; thus, acute kidney injury (AKI) may increase the risk for drug accumulation and bleeding. There is minimal data describing the effects of AKI on FxaI anti-Xa levels or clinical outcomes. OBJECTIVE: To compare anti-Xa level monitoring with standard monitoring in patients who experience AKI on apixaban or rivaroxaban. METHODS: This retrospective study included patients admitted within a large hospital system from May 2016 to October 2020. Patients were included if they received apixaban or rivaroxaban prior to AKI. Patients were stratified into 1 of 2 groups: those with anti-Xa level monitoring or those who received standard monitoring. The primary outcome was major bleeding as defined by the International Society of Thrombosis and Haemostasis. RESULTS: A total of 196 patients were included in the final analysis. Major bleeding occurred in 2 patients who received anti-Xa level monitoring, compared with 14 patients who received standard monitoring (2.1% vs 14%; P < 0.01). Variables identified as predictors of major bleeding included a documented history of liver disease (adjusted odds ratio = 3.17; 95% CI = 1.04-9.67; P = 0.04) and antiplatelet use (adjusted odds ratio = 4.18; 95% CI = 1.28-13.7; P = 0.02). CONCLUSION AND RELEVANCE: This is the first study to demonstrate that anti-Xa level monitoring was associated with a significant reduction in major bleeding compared with standard monitoring in patients with AKI who received apixaban or rivaroxaban. The optimal management of antithrombotic medications in patients with AKI and recent exposure to an FxaI requires further investigation.

Evaluation of outcomes with apixaban use for venous thromboembolism in hospitalized patients with end-stage renal disease receiving renal replacement therapy.

While direct oral anticoagulants (DOACs) received expanded labeling for use in atrial fibrillation (AF) for end-stage renal disease (ESRD) based on pharmacokinetic trials, little data exist regarding the use of DOACs for venous thromboembolism (VTE) in ESRD patients requiring renal replacement therapy (RRT). This retrospective, descriptive cohort study evaluated adult patients with a diagnosis of ESRD on RRT and with a VTE diagnosis receiving apixaban therapy prior to or during admission. The primary outcome was to identify major bleeding events within 72 h of last apixaban dose administration. Secondary outcomes included new VTE while on apixaban, appropriateness of anticoagulation regimen with regards to FDA labeled dosing and frequency, anticoagulation regimen adjustments, and factor Xa inhibitor-specific anti-Xa levels if available. A total of 68 patients met criteria for inclusion in the final analysis. Major bleeding events occurred in 13.2% of patients receiving apixaban within the last 72 h. Recurrent thrombosis occurred in 7.4% of patients. The use of apixaban for VTE in patients with ESRD on RRT led to a higher risk of bleeding compared to that of landmark trials. Therefore, apixaban use should occur following shared decision making especially if there is no contraindication to warfarin.

Apixaban and rivaroxaban anti-Xa level utilization for guidance of administration of andexanet alfa: a case series.

BACKGROUND: Andexanet alfa, a modified recombinant factor Xa (FXa), was FDA approved in 2018 for anticoagulant reversal in patients with life-threatening bleeding associated with FXa inhibitors (FXaI). The ANNEXA-4 investigators administered andexanet alfa to patients within an 18-h from last dose of oral FXaI. In practice, time from last dose is often unknown. Previous studies have shown that clearance of these agents may be impaired by renal and hepatic dysfunction, as well as drug-drug interactions. Decision for use of andexanet alfa is also complicated by its high cost, limited drug availability, and thrombotic risk. This study aimed to describe the utility of anti-Xa DOAC levels as a decision point to administer andexanet alfa. METHODS: This is a case series of four patients with an anti-Xa DOAC level that received andexanet alfa for oral FXaI reversal in the setting of life-threatening bleeding or prior to procedure. RESULTS: Four patients were included in the study. Two patients had a known time since last dose of oral FXaI. All patients had a detectable anti-Xa DOAC levels prior to administration of andexanet alfa. Two patients had levels within the peak range, one patient had a level below the peak range, and one patient had a level above the peak range. Andexanet alfa was administered after anti-Xa DOAC level return in all patients. CONCLUSION: In our case series, obtaining anti-Xa DOAC levels prior to administration of andexanet alfa was achievable and facilitated use of reversal agents in patients with major bleeding or emergent procedural need.

Treatment of Coronavirus Disease 2019 Patients with Convalescent Plasma Reveals a Signal of Significantly Decreased Mortality.

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2, has spread globally, and proven treatments are limited. Transfusion of convalescent plasma collected from donors who have recovered from COVID-19 is among many approaches being studied as potentially efficacious therapy. We are conducting a prospective, propensity score-matched study assessing the efficacy of COVID-19 convalescent plasma transfusion versus standard of care as treatment for severe and/or critical COVID-19. We present herein the results of an interim analysis of 316 patients enrolled at Houston Methodist hospitals from March 28 to July 6, 2020. Of the 316 transfused patients, 136 met a 28-day outcome and were matched to 251 non-transfused control COVID-19 patients. Matching criteria included age, sex, body mass index, comorbidities, and baseline ventilation requirement 48 hours from admission, and in a second matching analysis, ventilation status at day 0. Variability in the timing of transfusion relative to admission and titer of antibodies of plasma transfused allowed for analysis in specific matched cohorts. The analysis showed a significant reduction (P = 0.047) in mortality within 28 days, specifically in patients transfused within 72 hours of admission with plasma with an anti-spike protein receptor binding domain titer of ≥1:1350. These data suggest that treatment of COVID-19 with high anti-receptor binding domain IgG titer convalescent plasma is efficacious in early-disease patients.

Treatment of Coronavirus Disease 2019 (COVID-19) Patients with Convalescent Plasma.

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2, has spread globally, and no proven treatments are available. Convalescent plasma therapy has been used with varying degrees of success to treat severe microbial infections for >100 years. Patients (n = 25) with severe and/or life-threatening COVID-19 disease were enrolled at the Houston Methodist hospitals from March 28, 2020, to April 14, 2020. Patients were transfused with convalescent plasma, obtained from donors with confirmed severe acute respiratory syndrome coronavirus 2 infection who had recovered. The primary study outcome was safety, and the secondary outcome was clinical status at day 14 after transfusion. Clinical improvement was assessed on the basis of a modified World Health Organization six-point ordinal scale and laboratory parameters. Viral genome sequencing was performed on donor and recipient strains. At day 7 after transfusion with convalescent plasma, nine patients had at least a one-point improvement in clinical scale, and seven of those were discharged. By day 14 after transfusion, 19 (76%) patients had at least a one-point improvement in clinical status, and 11 were discharged. No adverse events as a result of plasma transfusion were observed. Whole genome sequencing data did not identify a strain genotype-disease severity correlation. The data indicate that administration of convalescent plasma is a safe treatment option for those with severe COVID-19 disease.

Evaluation of characteristics and dosing regimens in patients with new or recurrent thrombosis on apixaban and rivaroxaban.

Direct factor Xa inhibitors, such as apixaban and rivaroxaban, are widely used for treatment and prevention of venous thromboembolism; however, recent cases of therapeutic failure have been reported. Potential risk factors associated with therapeutic failure such as dose deviations outside of package labeling recommendations, and the use of direct factor Xa-specific inhibitor levels to guide clinical decision making continue to be areas of further investigation. Our study aimed to describe characteristics and dosing regimens in patients on apixaban or rivaroxaban who experienced a new or recurrent thrombosis. We performed a retrospective chart review on 190 patients on either apixaban or rivaroxaban presenting to our institution with new or breakthrough thromboembolism. Evaluation of prescribed anticoagulation regimens compared to package labeling recommendations, direct factor Xa inhibitor-specific anti-Xa levels, anticoagulation interruptions, use of parenteral bridge anticoagulation, final anticoagulation regimen disposition, and thrombosis-associated mortality were recorded. In patients presenting with breakthrough thromboembolism, 78% were on a regimen that matched package labeling recommendations. Anti-Xa levels were documented in 66 patients, the majority of which fell within institutional expected ranges at time of thrombosis. Therapy interruptions immediately prior to thrombosis were observed in 22% of patients and 21% of those patients received parenteral anticoagulation during interruption. Upon discharge, 46% of patients continued the same anticoagulation regimen with no changes. The mortality rate was 6%. In patients who present with new thromboembolism on apixaban or rivaroxaban, a thorough review of risks and benefits should be conducted to mitigate future risk of recurrent thrombosis.

Ultrasound-based criteria for adequate peripheral venous access in therapeutic apheresis procedures.

BACKGROUND: Apheresis procedures require adequate vascular access to achieve adequate inlet flow rates. Central dialysis-type catheters are often used in apheresis, despite their multiple risks. Peripheral venous access is a safe and effective option for many patients. AIM: We previously demonstrated that ultrasound guidance reduces central venous catheter use in apheresis patients; however, no validated criteria for preprocedural evaluation of peripheral veins exist. Here, we hypothesized that ultrasound-based criteria could predict the adequacy of a peripheral vein for apheresis procedures. PATIENTS/METHODS: In this pilot cohort study, we reviewed the procedural outcomes for 50 cases of peripheral venous procedures that used our ultrasound-based criteria. RESULTS: Of the procedures that met our criteria, 96% (46/48) were successfully completed. Overall, our criteria had 100% sensitivity, 50% specificity, 96% positive predictive value, and 100% negative predictive value. CONCLUSION: Our criteria justify an evidence-based ultrasound-guided standard for evaluation of peripheral venous access for apheresis procedures.

Neutralizing Aptamers Block S/RBD-ACE2 Interactions and Prevent Host Cell Infection.

The receptor-binding domain (RBD) of the severe acute respiratory syndrome coronavirus 2 spike (S) protein plays a central role in mediating the first step of virus infection to cause disease: virus binding to angiotensin-converting enzyme 2 (ACE2) receptors on human host cells. Therefore, S/RBD is an ideal target for blocking and neutralization therapies to prevent and treat coronavirus disease 2019 (COVID-19). Using a target-based selection approach, we developed oligonucleotide aptamers containing a conserved sequence motif that specifically targets S/RBD. Synthetic aptamers had high binding affinity for S/RBD-coated virus mimics (KD ≈7 nM) and also blocked interaction of S/RBD with ACE2 receptors (IC50 ≈5 nM). Importantly, aptamers were able to neutralize S protein-expressing viral particles and prevent host cell infection, suggesting a promising COVID-19 therapy strategy.

Single-nucleotide polymorphism rs10036727 in the SLIT3 gene is associated with osteoporosis at the femoral neck in older Mexican postmenopausal women.

AIMS: Osteoporosis (OP) remains a major public health problem worldwide. The most serious complications of this disease are fragility fractures, which increase morbidity and mortality. Management of OP represents an economic burden for health systems. Therefore, it is necessary to develop new screening strategies to identify the population at risk and implement preventive measures. We previously identified the SNPs rs3801387 in WNT16, rs7108738 in SOX6, rs10036727 in SLIT3 and rs7584262 in PKDCC as associated with bone mineral density in postmenopausal women through a genome-wide association study. The aim of this study was to validate those SNPs in two independent cohorts of non-related postmenopausal women. MATERIALS AND METHODS: We included 1160 women classifying them as normal, osteopenic or osteoporotic and a group with hip fragility fracture. Genotyping was performed using predesigned TaqMan assays. RESULTS: The variants rs10036727 and rs7108738 showed a significant association with BMD at the femoral neck. SLIT3 has been previously proposed as a potential biomarker and therapeutic resource. CONCLUSIONS: Our results provide new evidence regarding a possible involvement of SLIT3 in bone metabolisms and encourage the development of more studies in different populations to support these observations.

Evaluation of postoperative clinical outcomes in Jehovah's Witness patients who receive prothrombin complex concentrate during cardiac surgery.

BACKGROUND: Patients who refuse allogeneic blood transfusions (alloBT) on the basis of religious doctrine, such as Jehovah's Witnesses (JWs), can pose a challenge when undergoing surgical procedures. During cardiac surgery, special considerations regarding surgical techniques and blood loss minimization strategies can lead to improved outcomes. Limited literature exists to guide the use of four-factor prothrombin complex concentrate (4PCC) in this patient population undergoing cardiac surgery. STUDY DESIGN AND METHODS: This retrospective, single-center study evaluated the impact of 4PCC on hemoglobin (Hgb) change from baseline to postoperative nadir within a 7-day period among patients who refused alloBT during cardiac surgery. This study identified patients who refused alloBT from January 2011 to June 2017. Multivariable linear regression was used to control for confounding variables to evaluate the effectiveness of 4PCC. RESULTS: During the study timeframe, 79 patients met inclusion criteria, all of whom identified as JWs, and underwent cardiac surgery. Of these, 19 received intraoperative 4PCC. Multivariable linear regression found no difference in Hgb change in patients who received 4PCC vs those who did not. No significant differences were found in mortality, thromboembolic complications, or in-hospital postoperative events. CONCLUSIONS: In JWs undergoing cardiac surgery who refuse alloBT, intraoperative use of 4PCC was not associated with a difference in Hgb change within 7 days postoperatively when adjusting for confounding variables. In the event of excessive blood loss, the utilization of 4PCC may provide a viable option in JW patients who undergo cardiac surgery where few options exist to mitigate blood loss.

Control of Heterologous Simian Immunodeficiency Virus SIVsmE660 Infection by DNA and Protein Coimmunization Regimens Combined with Different Toll-Like-Receptor-4-Based Adjuvants in Macaques.

We developed a method of simultaneous vaccination with DNA and protein resulting in robust and durable cellular and humoral immune responses with efficient dissemination to mucosal sites and protection against simian immunodeficiency virus (SIV) infection. To further optimize the DNA-protein coimmunization regimen, we tested a SIVmac251-based vaccine formulated with either of two Toll-like receptor 4 (TLR4) ligand-based liposomal adjuvant formulations (TLR4 plus TLR7 [TLR4+7] or TLR4 plus QS21 [TLR4+QS21]) in macaques. Although both vaccines induced humoral responses of similar magnitudes, they differed in their functional quality, including broader neutralizing activity and effector functions in the TLR4+7 group. Upon repeated heterologous SIVsmE660 challenge, a trend of delayed viral acquisition was found in vaccinees compared to controls, which reached statistical significance in animals with the TRIM-5α-resistant (TRIM-5α R) allele. Vaccinees were preferentially infected by an SIVsmE660 transmitted/founder virus carrying neutralization-resistant A/K mutations at residues 45 and 47 in Env, demonstrating a strong vaccine-induced sieve effect. In addition, the delay in virus acquisition directly correlated with SIVsmE660-specific neutralizing antibodies. The presence of mucosal V1V2 IgG binding antibodies correlated with a significantly decreased risk of virus acquisition in both TRIM-5α R and TRIM-5α-moderate/sensitive (TRIM-5α M/S) animals, although this vaccine effect was more prominent in animals with the TRIM-5α R allele. These data support the combined contribution of immune responses and genetic background to vaccine efficacy. Humoral responses targeting V2 and SIV-specific T cell responses correlated with viremia control. In conclusion, the combination of DNA and gp120 Env protein vaccine regimens using two different adjuvants induced durable and potent cellular and humoral responses contributing to a lower risk of infection by heterologous SIV challenge.IMPORTANCE An effective AIDS vaccine continues to be of paramount importance for the control of the pandemic, and it has been proven to be an elusive target. Vaccine efficacy trials and macaque challenge studies indicate that protection may be the result of combinations of many parameters. We show that a combination of DNA and protein vaccinations applied at the same time provides rapid and robust cellular and humoral immune responses and evidence for a reduced risk of infection. Vaccine-induced neutralizing antibodies and Env V2-specific antibodies at mucosal sites contribute to the delay of SIVsmE660 acquisition, and genetic makeup (TRIM-5α) affects the effectiveness of the vaccine. These data are important for the design of better vaccines and may also affect other vaccine platforms.

Genetic variants in COL13A1, ADIPOQ and SAMM50, in addition to the PNPLA3 gene, confer susceptibility to elevated transaminase levels in an admixed Mexican population.

Non-alcoholic fatty liver disease (NAFLD) is the accumulation of extra fat in liver cells not caused by alcohol. Elevated transaminase levels are common indicators of liver disease, including NAFLD. Previously, we demonstrated that PNPLA3 (rs738409), LYPLAL1 (rs12137855), PPP1R3B (rs4240624), and GCKR (rs780094) are associated with elevated transaminase levels in overweight/obese Mexican adults. We investigated the association between 288 SNPs identified in genome-wide association studies and risk of elevated transaminase levels in an admixed Mexican-Mestizo sample of 178 cases of NAFLD and 454 healthy controls. The rs2896019, rs12483959, and rs3810622 SNPs in PNPLA3 and rs1227756 in COL13A1 were associated with elevated alanine aminotransferase (ALT, ≥40IU/L). A polygenic risk score (PRS) based on six SNPs in the ADIPOQ, COL13A1, PNPLA3, and SAMM50 genes was also associated with elevated ALT. Individuals carrying 9-12 risk alleles had 65.8% and 48.5% higher ALT and aspartate aminotransferase (AST) levels, respectively, than those with 1-4 risk alleles. The PRS showed the greatest risk of elevated ALT levels, with a higher level of significance than the individual variants. Our findings suggest a significant association between variants in COL13A1, ADIPOQ, SAMM50, and PNPLA3, and risk of NAFLD/elevated transaminase levels in Mexican adults with an admixed ancestry. This is the first study to examine high-density single nucleotide screening for genetic variations in a Mexican-Mestizo population. The extent of the effect of these variations on the development and progression of NAFLD in Latino populations requires further analysis.

The utility of therapeutic plasma exchange for amphotericin B overdose.

Medication error is a preventable cause of morbidity and death in the inpatient population. We describe a patient with an antifungal overdose treated with therapeutic plasma exchange (TPE). The patient was diagnosed with cryptococcal meningitis and received an acute overdose of amphotericin B deoxycholate instead of the prescribed liposomal amphotericin B. Consequently, the patient developed clinical symptoms including tremors, hypertension, visual hallucinations, vertigo, fever, and acute renal failure. A series of four TPEs was emergently initiated, resulting in complete resolution of most symptoms.