Specifications of the ACMG/AMP variant curation guidelines for the analysis of germline ATM sequence variants.

The ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer (HBOP) Variant Curation Expert Panel (VCEP) is composed of internationally recognized experts in clinical genetics, molecular biology and variant interpretation. This VCEP made specifications for ACMG/AMP guidelines for the ataxia telangiectasia mutated (ATM) gene according to the Food and Drug Administration (FDA)-approved ClinGen protocol. These gene-specific rules for ATM were modified from the American College of Medical Genetics and Association for Molecular Pathology (ACMG/AMP) guidelines and were tested against 33 ATM variants of various types and classifications in a pilot curation phase. The pilot revealed a majority agreement between the HBOP VCEP classifications and the ClinVar-deposited classifications. Six pilot variants had conflicting interpretations in ClinVar and reevaluation with the VCEP's ATM-specific rules resulted in four that were classified as benign, one as likely pathogenic and one as a variant of uncertain significance (VUS) by the VCEP, improving the certainty of interpretations in the public domain. Overall, 28 the 33 pilot variants were not VUS leading to an 85% classification rate. The ClinGen-approved, modified rules demonstrated value for improved interpretation of variants in ATM.

HUHgle: An Interactive Substrate Design Tool for Covalent Protein-ssDNA Labeling Using HUH-Tags.

HUH-tags have emerged as versatile fusion partners that mediate sequence specific protein-ssDNA bioconjugation through a simple and efficient reaction. Here we present HUHgle, a python-based interactive tool for the visualization, design, and optimization of substrates for HUH-tag mediated covalent labeling of proteins of interest with ssDNA substrates of interest. HUHgle streamlines design processes by integrating an intuitive plotting interface with a search function capable of predicting and displaying protein-ssDNA bioconjugate formation efficiency and specificity in proposed HUH-tag/ssDNA sequence combinations. Validation demonstrates that HUHgle accurately predicts product formation of HUH-tag mediated bioconjugation for single- and orthogonal-labeling reactions. In order to maximize the accessibility and utility of HUHgle, we have implemented it as a user-friendly Google Colab notebook which facilitates broad use of this tool, regardless of coding expertise.

Surface wear of PyroCarbon implant in metacarpophalangeal joint arthroplasty without radiographic abnormality: A case report.

CASE: A 54-year-old male with osteoarthritis of the right long finger metacarpophalangeal joint underwent PyroCarbon joint arthroplasty. Seven years later the patient presented for metacarpophalangeal joint swelling and pain. The workup was benign, without signs of implant complication or osseous abnormality. He underwent washout and two-stage revision, where gross implant wear and debris not demonstrated by radiograph were found. He then returned to the operating room for reimplantation of a PyroCarbon implant. CONCLUSION: This case demonstrates a novel presentation of aseptic PyroCarbon implant failure in the hand without radiographic abnormality that can alter operative management by reducing operating room returns.

Training simulated participants for role portrayal and feedback practices in communication skills training: A BEME scoping review: BEME Guide No. 86.

BACKGROUND: Providing feedback is a key aspect of simulated participants' (SPs) educational work. In teaching contexts, the ability to provide feedback to learners is central to their role. Suboptimal feedback practices may deny learners the valuable feedback they need to learn and improve. This scoping review systematically maps the evidence related to SPs' role as educators and identifies how SPs prepare for their role and feedback practices. METHODS: The authors conducted a scoping review and included a group of international stakeholders with experience and expertise in SP methodology. Five online databases were systematically searched and ERIC, MedEdPortal and MedEdPublish were hand searched to identify relevant studies. Inclusion/exclusion criteria were developed. Data screening and subsequently data charting were performed in pairs. The results of data charting were thematically analysed including categories relating to the Association of SP Educators (ASPE) Standards of Best Practice (SOBP). RESULTS: From 8179 articles identified for the title and abstract screening, 98 studies were included. Studies reported the benefit of SPs' authentic role portrayal and feedback interactions for learners and on the reported learning outcomes. Data was heterogeneous with a notable lack of consistency in the detail regarding the scenario formats for communication skills training interventions, SP characteristics, and approaches to training for feedback and role portrayal. CONCLUSIONS: The published literature has considerable heterogeneity in reporting how SPs are prepared for role portrayal and feedback interactions. Additionally, our work has identified gaps in the implementation of the ASPE SOBP, which promotes effective SP-learner feedback interactions. Further research is required to identify effective applications of SP methodology to prepare SPs for their role as educators.

Specifications of the ACMG/AMP Variant Classification Guidelines for Germline DICER1 Variant Curation.

Germline pathogenic variants in DICER1 predispose individuals to develop a variety of benign and malignant tumors. Accurate variant curation and classification is essential for reliable diagnosis of DICER1-related tumor predisposition and identification of individuals who may benefit from surveillance. Since 2015, most labs have followed the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) sequence variant classification guidelines for DICER1 germline variant curation. However, these general guidelines lack gene-specific nuances and leave room for subjectivity. Consequently, a group of DICER1 experts joined ClinGen to form the DICER1 and miRNA-Processing Genes Variant Curation Expert Panel (VCEP), to create DICER1- specific ACMG/AMP guidelines for germline variant curation. The VCEP followed the FDA-approved ClinGen protocol for adapting and piloting these guidelines. A diverse set of 40 DICER1 variants were selected for piloting, including 14 known Pathogenic/Likely Pathogenic (P/LP) variants, 12 known Benign/Likely Benign (B/LB) variants, and 14 variants classified as variants of uncertain significance (VUS) or with conflicting interpretations in ClinVar. Clinically meaningful classifications (i.e., P, LP, LB, or B) were achieved for 82.5% (33/40) of the pilot variants, with 100% concordance among the known P/LP and known B/LB variants. Half of the VUS or conflicting variants were resolved with four variants classified as LB and three as LP. These results demonstrate that the DICER1-specific guidelines for germline variant curation effectively classify known pathogenic and benign variants while reducing the frequency of uncertain classifications. Individuals and labs curating DICER1 variants should consider adopting this classification framework to encourage consistency and improve objectivity.

Zone I Revision Finger Amputations Performed in the Emergency Department Compared With Those Performed in the Operating Room.

Finger amputations are commonly encountered. These may be revised in the emergency department (ED) or the operating room (OR). Previous studies have demonstrated the cost-effectiveness associated with procedures performed in the ED. Patient outcomes have not been described. We retrospectively reviewed patients who presented to our level 1 trauma center with a traumatic partial or complete finger amputation through flexor tendon zone I. All were treated with revision amputation performed in either the ED or the OR between January 2012 and December 2017. A total of 172 patient charts were included. Ninety-three of the revision amputations were performed in the ED, while 79 were performed in the OR. There was no difference in age, race, sex, having a manual labor job, medical comorbidities, or mechanism of injury between the groups. Compared with procedures performed in the ED, procedures performed in the OR had a higher rate of delayed healing, a longer stay in the hospital, and a higher referral to therapy postoperatively. Length of follow-up and number of follow-up visits were not statistically different based on location of procedure. There was no difference in post-procedural infection rate or need for revision procedure between the groups. Our data support the efficacy of performing revision amputation procedures in the ED. Recorded patient complications and subsequent treatment after revision amputations performed in the ED vs the OR were comparable. Those performed in the ED potentially decrease the burden placed on the patient and the health care system. [Orthopedics. 202x;4x(x):xx-xx.].

Retrospective Cohort Study on the Limitations of Direct-to-Consumer Genetic Screening in Hereditary Breast and Ovarian Cancer.

PURPOSE: Among cancer predisposition genes, most direct-to-consumer (DTC) genetic tests evaluate three Ashkenazi Jewish (AJ) founder mutations in BRCA1/2, which represent a small proportion of pathogenic or likely pathogenic variants (PLPV) in cancer predisposing genes. In this study, we investigate PLPV in BRCA1/2 and other cancer predisposition genes that are missed by testing only AJ founder BRCA1/2 mutations. METHODS: Individuals were referred to genetic testing for personal diagnoses of breast and/or ovarian cancer (clinical cohort) or were self-referred (nonindication-based cohort). There were 348,692 participants in the clinical cohort and 7,636 participants in the nonindication-based cohort. Both cohorts were analyzed for BRCA1/2 AJ founder mutations. Full sequence analysis was done for PLPV in BRCA1/2, CDH1, PALB2, PTEN, STK11, TP53, ATM, BARD1, BRIP1, CHEK2 (truncating variants), EPCAM, MLH1, MSH2/6, NF1, PMS2, RAD51C/D, and 22 other genes. RESULTS: BRCA1/2 AJ founder mutations accounted for 10.8% and 29.7% of BRCA1/2 PLPV in the clinical and nonindication-based cohorts, respectively. AJ founder mutations accounted for 89.9% of BRCA1/2 PLPV in those of full AJ descent, but only 69.6% of those of partial AJ descent. In total, 0.5% of all individuals had a BRCA1/2 AJ founder variant, while 7.7% had PLPV in a high-risk breast/ovarian cancer gene. For non-AJ individuals, limiting evaluation to the AJ founder BRCA1/2 mutations missed >90% of mutations in actionable cancer risk genes. Secondary analysis revealed a false-positive rate of 69% for PLPV outside of non-AJ BRCA 1/2 founder mutations. CONCLUSION: DTC genetic testing misses >90% of BRCA1/2 PLPV in individuals of non-AJ ancestry and about 10% of BRCA1/2 PLPV among AJ individuals. There is a high false-positivity rate for non-AJ BRCA 1/2 PLPV with DTC genetic testing.

Serum Cytomegalovirus Polymerase Chain Reaction Test Is a Valuable Negative Predictor of Infection in Acute Severe Ulcerative Colitis.

BACKGROUND: Diagnosis of cytomegalovirus (CMV) colitis in the setting of severe ulcerative colitis (UC) remains a clinical challenge. This study aimed to determine the utility of serum CMV polymerase chain reaction (PCR) as a non-invasive test for the diagnosis of CMV superinfection in patients hospitalized with UC. METHODS: This retrospective study included consecutive admitted patients with UC who had serum testing for CMV completed as part of standard hospital procedure and CMV colitis diagnosed by expert pathologists. RESULTS: Two hundred and six patients with UC were included; 13 patients (6%) had histologically confirmed CMV colitis. Eleven of 13 patients with CMV colitis (84%) and 3 of 193 (1.5%) patients without CMV colitis had a positive serum PCR test (p < 0.0001). ROC analysis showed that a CMV PCR level of 259 IU/mL had a sensitivity and specificity of 77% and 99%, respectively, for diagnosis of CMV colitis with an AUC of 0.9 (p < 0.0001). Serum CMV PCR level significantly correlated to the number of inclusion bodies on biopsy specimens with data available (n = 8) (r = 0.8, p = 0.02). CMV positivity did not predict the need for salvage therapy, admission or 1-year colectomy rates. CONCLUSION: Serum CMV PCR has an excellent negative predictive value and demonstrates a strong correlation with CMV positivity on histology. This work supports a rationale for serum CMV PCR testing on admission to assess the risk of CMV colitis in patients with severe UC.

Dystrophin missense mutations alter focal adhesion tension and mechanotransduction.

Dystrophin is an essential muscle protein that contributes to cell membrane stability by mechanically linking the actin cytoskeleton to the extracellular matrix via an adhesion complex called the dystrophin-glycoprotein complex. The absence or impaired function of dystrophin causes muscular dystrophy. Focal adhesions (FAs) are also mechanosensitive adhesion complexes that connect the cytoskeleton to the extracellular matrix. However, the interplay between dystrophin and FA force transmission has not been investigated. Using a vinculin-based bioluminescent tension sensor, we measured FA tension in transgenic C2C12 myoblasts expressing wild-type (WT) dystrophin, a nonpathogenic single nucleotide polymorphism (SNP) (I232M), or two missense mutations associated with Duchenne (L54R), or Becker muscular dystrophy (L172H). Our data revealed cross talk between dystrophin and FAs, as the expression of WT or I232M dystrophin increased FA tension compared to dystrophin-less nontransgenic myoblasts. In contrast, the expression of L54R or L172H did not increase FA tension, indicating that these disease-causing mutations compromise the mechanical function of dystrophin as an FA allosteric regulator. Decreased FA tension caused by these mutations manifests as defective migration, as well as decreased Yes-associated protein 1 (YAP) activation, possibly by the disruption of the ability of FAs to transmit forces between the extracellular matrix and cytoskeleton. Our results indicate that dystrophin influences FA tension and suggest that dystrophin disease-causing missense mutations may disrupt a cellular tension-sensing pathway in dystrophic skeletal muscle.

Toxicity of Refugio Beach Oil to Sand Crabs (Emerita analoga), Blue Mussels (Mytilus sp.), and Inland Silversides (Menidia beryllina).

Monterey formation crude oil spilled from an onshore pipeline and entered the surf zone near Refugio State Beach, Santa Barbara County, California (USA) on 19 May 2015. During this season, early life stages of many marine fish and invertebrates were present. Surf zone water and beach porewater samples were collected during the 4 mo after the spill and 2 yr later for chemical analyses. Elevated polycyclic aromatic hydrocarbon (PAH) and total petroleum hydrocarbon concentrations were observed in surf zone water and porewater near the release point, declining with distance and time. Early life stage toxicity was investigated by conducting 6- and 7-d static renewal bioassays with sand crab (Emerita analoga) post larvae (megalopae) and inland silverside larvae (Menidia beryllina), respectively, and a 48-h blue mussel (Mytilus sp.) embryo development bioassay. Dilutions of a high-energy water accommodated fraction of the Refugio Beach oil and a seawater control were prepared to simulate surf zone PAH concentrations (nominal PAH45 ; 0, 0.5, 1, 5, 10, 50, 100, and 500 µg/L). The PAH45 median lethal concentrations (LC50s), based on measured concentrations, were 381 µg/L for Mytilus sp., 75.6 µg/L for Menidia, and 40.9 µg/L for Emerita. Our results suggest that PAH concentrations in coastal waters of the spill-affected area were potentially lethal to early life stages of fish and invertebrates. Environ Toxicol Chem 2021;40:2578-2586. © 2021 SETAC.

BrainIAK: The Brain Imaging Analysis Kit.

Functional magnetic resonance imaging (fMRI) offers a rich source of data for studying the neural basis of cognition. Here, we describe the Brain Imaging Analysis Kit (BrainIAK), an open-source, free Python package that provides computationally optimized solutions to key problems in advanced fMRI analysis. A variety of techniques are presently included in BrainIAK: intersubject correlation (ISC) and intersubject functional connectivity (ISFC), functional alignment via the shared response model (SRM), full correlation matrix analysis (FCMA), a Bayesian version of representational similarity analysis (BRSA), event segmentation using hidden Markov models, topographic factor analysis (TFA), inverted encoding models (IEMs), an fMRI data simulator that uses noise characteristics from real data (fmrisim), and some emerging methods. These techniques have been optimized to leverage the efficiencies of high-performance compute (HPC) clusters, and the same code can be se amlessly transferred from a laptop to a cluster. For each of the aforementioned techniques, we describe the data analysis problem that the technique is meant to solve and how it solves that problem; we also include an example Jupyter notebook for each technique and an annotated bibliography of papers that have used and/or described that technique. In addition to the sections describing various analysis techniques in BrainIAK, we have included sections describing the future applications of BrainIAK to real-time fMRI, tutorials that we have developed and shared online to facilitate learning the techniques in BrainIAK, computational innovations in BrainIAK, and how to contribute to BrainIAK. We hope that this manuscript helps readers to understand how BrainIAK might be useful in their research.

Loss-of-function variants in CTNNA1 detected on multigene panel testing in individuals with gastric or breast cancer.

PURPOSE: CTNNA1 is a potential diffuse gastric cancer risk gene, however CTNNA1 testing on multigene panel testing (MGPT) remains unstudied. METHODS: De-identified data from 151,425 individuals who underwent CTNNA1 testing at a commercial laboratory between October 2015 and July 2019 were reviewed. Tissue α-E-catenin immunohistochemistry was performed on CTNNA1 c.1351C>T (p.Arg451*) carriers. RESULTS: Fifty-two individuals (0.03% tested) had CTNNA1 loss-of-function (LOF) variants and 1057 individuals (0.7% tested) had a total of 302 distinct missense variants of uncertain significance. Detailed history was available on 33 CTNNA1 LOF carriers, with 21 unique CTNNA1 LOF variants. Four (12%) individuals had diffuse gastric cancer and 22 (67%) had breast cancer. Six (21%) and 24 (83%) of the 29 families reported a history of gastric or breast cancer, respectively. The CTNNA1 c.1351C>T nonsense variant was identified in three separate families with early-onset diffuse gastric cancer or breast cancer. Immunohistochemistry showed decreased α-E-catenin expression in gastric cancers. CONCLUSION: CTNNA1 LOF variants are detected on MGPT with a majority of these individuals having gastric or breast cancer. The overall risk of gastric cancer for CTNNA1 LOF carriers may be lower than expected. Given the uncertain phenotype and penetrance, management of individuals with CTNNA1 LOF variants remains challenging.

Targeted rapid knee MRI exam using T2 shuffling.

BACKGROUND: MRI is commonly used to evaluate pediatric musculoskeletal pathologies, but same-day/near-term scheduling and short exams remain challenges. PURPOSE: To investigate the feasibility of a targeted rapid pediatric knee MRI exam, with the goal of reducing cost and enabling same-day MRI access. STUDY TYPE: A cost effectiveness study done prospectively. SUBJECTS: Forty-seven pediatric patients. FIELD STRENGTH/SEQUENCE: 3T. The 10-minute protocol was based on T2 Shuffling, a four-dimensional acquisition and reconstruction of images with variable T2 contrast, and a T1 2D fast spin-echo (FSE) sequence. A distributed, compressed sensing-based reconstruction was implemented on a four-node high-performance compute cluster and integrated into the clinical workflow. ASSESSMENT: In an Institutional Review Board-approved study with informed consent/assent, we implemented a targeted pediatric knee MRI exam for assessing pediatric knee pain. Pediatric patients were subselected for the exam based on insurance plan and clinical indication. Over a 2-year period, 47 subjects were recruited for the study and 49 MRIs were ordered. Date and time information was recorded for MRI referral, registration, and completion. Image quality was assessed from 0 (nondiagnostic) to 5 (outstanding) by two readers, and consensus was subsequently reached. STATISTICAL TESTS: A Wilcoxon rank-sum test assessed the null hypothesis that the targeted exam times compared with conventional knee exam times were unchanged. RESULTS: Of the 49 cases, 20 were completed on the same day as exam referral. Median time from registration to exam completion was 18.7 minutes. Median reconstruction time for T2 Shuffling was reduced from 18.9 minutes to 95 seconds using the distributed implementation. Technical fees charged for the targeted exam were one-third that of the routine clinical knee exam. No subject had to return for additional imaging. DATA CONCLUSION: The targeted knee MRI exam is feasible and reduces the imaging time, cost, and barrier to same-day MRI access for pediatric patients. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 6 J. Magn. Reson. Imaging 2019.

Specifications of the ACMG/AMP variant curation guidelines for the analysis of germline CDH1 sequence variants.

The variant curation guidelines published in 2015 by the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) provided the genetics community with a framework to assess variant pathogenicity; however, these rules are not gene specific. Germline pathogenic variants in the CDH1 gene cause hereditary diffuse gastric cancer and lobular breast cancer, a clinically challenging cancer predisposition syndrome that often requires a multidisciplinary team of experts to be properly managed. Given this challenge, the Clinical Genome Resource (ClinGen) Hereditary Cancer Domain prioritized the development of the CDH1 variant curation expert panel (VCEP) to develop and implement rules for CDH1 variant classifications. Here, we describe the CDH1 specifications of the ACMG/AMP guidelines, which were developed and validated after a systematic evaluation of variants obtained from a cohort of clinical laboratory data encompassing ∼827,000 CDH1 sequenced alleles. Comparing previously reported germline variants that were classified using the 2015 ACMG/AMP guidelines to the CDH1 VCEP recommendations resulted in reduced variants of uncertain significance and facilitated resolution of variants with conflicted assertions in ClinVar. The ClinGen CDH1 VCEP recommends the use of these CDH1-specific guidelines for the assessment and classification of variants identified in this clinically actionable gene.

Warming of Irrigation Fluids for Prevention of Perioperative Hypothermia During Arthroscopy: A Systematic Review and Meta-analysis.

PURPOSE: To determine whether warming of irrigation fluids (32°C-40°C) compared with using room-temperature irrigation fluids (20°C-22°C) decreases the risk of perioperative hypothermia (<36°C) for patients undergoing shoulder, hip, or knee arthroscopy. METHODS: One reviewer, with the assistance of a medical librarian, searched the following databases: PubMed, Embase, Cochrane Central, SPORTDiscus, Web of Science, and CINAHL (Cumulative Index to Nursing and Allied Health Literature). Level I and II studies involving shoulder, hip, or knee arthroscopy were included. Two reviewers screened the abstracts and titles. Two reviewers assessed the risk of bias of selected studies using The Cochrane Collaboration tool. Meta-analyses were conducted on the following outcomes: hypothermia, lowest temperature, maximum temperature drop, and shivering. RESULTS: Seven studies of patients undergoing arthroscopy were included in the qualitative synthesis (5 shoulder studies, 1 hip study, and 1 knee study; 501 patients). The study involving knee arthroscopy was excluded from the meta-analyses because of insufficient data and high clinical heterogeneity (surgical site distal to the core, not involving extravasation of large amounts of fluid). The remaining 6 studies were included in 1 or more meta-analyses: hypothermia (5 shoulder and 1 hip study), lowest temperature (3 shoulder and 1 hip study), maximum temperature drop (2 shoulder and 1 hip study), and shivering (5 shoulder and 1 hip study). Warming of irrigation fluids for shoulder or hip arthroscopy significantly decreased the risk of hypothermia (odds ratio, 0.15; 95% confidence interval [CI], 0.06-0.40; P = .0001), increased the lowest mean temperature (mean difference, 0.46°C; 95% CI, 0.11°C-0.81°C; P = .01), decreased the maximum temperature drop (mean difference, -0.64°C; 95% CI, -0.94°C to -0.35°C; P < .0001), and decreased the risk of shivering (odds ratio, 0.25; 95% CI, 0.07-0.86; P = .03). CONCLUSIONS: When irrigation fluids are warmed for shoulder and hip arthroscopy, the risk of hypothermia is less, the drop in intraoperative temperature is less, the lowest body temperature is higher, and the risk of postoperative shivering is reduced. LEVEL OF EVIDENCE: Level II, systematic review of Level I and II studies.

Development of a novel longitudinal postgraduate year 1 residency training model.

PURPOSE: A longitudinal program design for a postgraduate year 1 (PGY1) pharmacy residency that has enhanced residents' ability to adapt to decentralized pharmacy practice roles is described. SUMMARY: Historically, like most 12-month PGY1 residency programs, the program at Baptist Health Lexington, a 383-bed community hospital in Kentucky, offered month-long rotational learning experiences across the various service lines within the institution. As the core philosophy of the program matured, the focus of the residency program's preceptor group moved toward maximizing a facilitated learning experience for residents. Beginning in 2015, the program structure was redesigned to implement a longitudinal structure for all learning experiences. Residents now cycle through experiences every 2 weeks for the duration of the program. These shorter and more frequently varied learning experiences allow residents to focus on completing meaningful work in the pharmacy department and develop independent practice skills as they learn how to manage the daily tasks and workflow of a decentralized pharmacist within the institution. The change from a rotational model to a longitudinal design has allowed earlier realization of resident independence, allowing trainees to focus on their individual professional growth. The revised program structure has allowed integration of the PGY1 program into departmental activities. CONCLUSION: Changing a PGY1 program design from a rotational model to a longitudinal design has aligned resident development with departmental goals and accelerated achievement of resident independence.

Vegetation effects on impulsive events in the acoustic signature of fires.

Acoustic impulse events have long been used as diagnostics for discrete phenomena in the natural world, including the detection of meteor impacts and volcanic eruptions. Wildland fires display an array of such acoustic impulse events in the form of crackling noises. Exploratory research into the properties of these impulse events revealed information regarding the specific properties of plant material. Unique acoustic frequency bands in the upper end of the sonic spectrum correlated to changes in vegetation properties. The signature of acoustic impulse events as they relate to plant species and plant water stress, were investigated in controlled laboratory combustion experiments. Correlation in the frequency range of 6.0-15.0 kHz was found for both species and water stress, indicating the possibility that a digital filter may be capable of identifying vegetation properties during wildland fire events.

Comparing ε-Aminocaproic Acid and Tranexamic Acid in Reducing Postoperative Transfusions in Total Knee Arthroplasty.

Multiple studies have shown tranexamic acid (TXA) to reduce blood loss and transfusion rates in patients undergoing total knee arthroplasty (TKA). Accordingly, TXA has become a routine blood conservation agent for TKA. In contrast, ε-aminocaproic acid (EACA), a similar acting antifibrinolytic to TXA, has been less frequently used. This study evaluated whether EACA is as efficacious as TXA in reducing postoperative blood transfusion rates and compared the cost per surgery between agents. A multicenter retrospective chart review of elective unilateral TKA from April 2012 through December 2014 was performed. Five hospitals within a health care system participated. Data collected included age, gender, severity of illness score, use of antifibrinolytic and dose, red blood cell (RBC) transfusions and the number of units, and preadmission and discharge hemoglobin (Hb). Dosing of the antifibrinolytic differed based on the agent used, 5 or 10 g (based on weight) for EACA versus 1 g for TXA. The institutional acquisition cost of each antifibrinolytic was obtained and averaged over the study period. Of 2,922 primary unilateral TKA cases, 820 patients received EACA, 610 patients received TXA, and 1,492 patients received no antifibrinolytic (control group). Compared with the control group both EACA and TXA groups had significantly fewer patients transfused (EACA 2.8% [p < 0.0001], TXA 3.2% [p < 0.0001] vs. control 10.8%) and lower mean RBC units transfused per patient (EACA 0.05 units/patient [pt] [p < 0.0001], TXA 0.05 units/pt [p < 0.0001] vs. control 0.19 units/pt]. There was no difference in mean RBC units transfused per patient, percentage of patients transfused, and discharge Hb levels between the EACA and TXA groups (p = 0.822, 0.236, and 0.322, respectively). Medication acquisition cost for EACA averaged $2.23 per surgery compared with TXA at $39.58 per surgery. Administration of EACA or TXA significantly decreased postoperative transfusion rates compared with no antifibrinolytic therapy. Utilization of EACA for unilateral TKA proved to be comparable to TXA in all studied aspects at a lower cost. The level of evidence for the study is Level 3.

A generalized framework for computational design and mutational scanning of T-cell receptor binding interfaces.

T-cell receptors (TCRs) have emerged as a new class of therapeutics, most prominently for cancer where they are the key components of new cellular therapies as well as soluble biologics. Many studies have generated high affinity TCRs in order to enhance sensitivity. Recent outcomes, however, have suggested that fine manipulation of TCR binding, with an emphasis on specificity may be more valuable than large affinity increments. Structure-guided design is ideally suited for this role, and here we studied the generality of structure-guided design as applied to TCRs. We found that a previous approach, which successfully optimized the binding of a therapeutic TCR, had poor accuracy when applied to a broader set of TCR interfaces. We thus sought to develop a more general purpose TCR design framework. After assembling a large dataset of experimental data spanning multiple interfaces, we trained a new scoring function that accounted for unique features of each interface. Together with other improvements, such as explicit inclusion of molecular flexibility, this permitted the design new affinity-enhancing mutations in multiple TCRs, including those not used in training. Our approach also captured the impacts of mutations and substitutions in the peptide/MHC ligand, and recapitulated recent findings regarding TCR specificity, indicating utility in more general mutational scanning of TCR-pMHC interfaces.

Using Aminocaproic Acid to Reduce Blood Loss After Primary Unilateral Total Knee Arthroplasty.

xtensive blood loss after total knee arthroplasty (TKA) is common, and affected patients often require blood transfusions. Studies suggest that antifibrinolytic agents such as aminocaproic acid (ACA) reduce blood loss and blood transfusion rates in patients undergoing TKA. We conducted a study to evaluate whether a single intravenous 10-g dose of ACA given during primary unilateral TKA would decrease perioperative blood loss, raise postoperative hemoglobin levels, and reduce postoperative blood transfusion rates. We retrospectively reviewed the charts of 50 comparable cemented primary unilateral TKAs. Twenty-five patients had been given a single intraoperative 10-g dose of ACA (antifibrinolytic group), and the other 25 had not been given ACA (control group). Postoperative drain output was decreased significantly (P < .0001) in the antifibrinolytic group (155 mL) compared with the control group (410 mL), as was the number of units of blood transfused after surgery (antifibrinolytic group, 0 units; control group, 10 units; P < .002). There were no adverse events in the antifibrinolytic group. In TKA, perioperative blood loss and blood transfusion rates were reduced significantly in patients given a single intraoperative intravenous 10-g dose of ACA compared with patients not given antifibrinolytics. The positive effects of ACA were obtained without adverse events or complications.