bluuebunny/crossref_metadata_2025 huggingface dataset:
Development of a Machine Learning Decision Support System for Clinical Flow Cytometry
Authors: Lownik Joseph , Mahov Simeon , Lopategui Jean , Alkan Serhan , Gibb David , Merchant Akil , Kitahara Sumire
Published: November 2023

High parameter flow cytometry is a highly utilized tool in both research and clinical settings for accurate immunophenotyping in immunology, oncology, and many other disciplines. With increasing dimensionality, manual analysis of data becomes more complex and time consuming. Over the past decade, several automated methods have been developed for cell population clustering and dimensionality reduction of high parameter flow cytometry data which have sped up and simplified the discovery of cell populations not observed by manual gating strategies. However, the input and output of such tools are stochastic in nature, thus making their results difficult to reuse with novel samples such as diagnostic patient samples. Several groups have recently attempted to utilize machine learning algorithms to analyze clinical flow cytometry data. These studies focused on training machine learning models with a goal of predicting a specific diagnosis for each sample. This approach can be limiting when the diagnostic features are not perfectly met to predict a specific diagnosis as well as the absence of the patient's clinical data. To our knowledge, no studies have utilized machine learning to identify and classify individual cells based on their raw fluorescence signature to various cellular populations, whether normal or abnormal, to aid a diagnostician to interpret their significance in a clinical context. In this study, we utilized a data set of ~240 million individual cells from ~9,500 flow cytometry files from 2,300 patients to train a machine learning model to predict cell population classifications as annotated by expert hematopathologists. These annotations were implemented into an end-to-end machine learning based decision support system allowing for rapid, automated analysis of high dimensional flow cytometry data with an output aiding the diagnostician in the generation of a diagnosis. A clinical validation highlighted the robustness of this methodology with 100% sensitivity and 94% specificity in the identification of abnormal B-cell populations on a cohort of 1,500 patients. This decision support system also identifies abnormal T-cell and myeloid cell populations with 100% sensitivity. Overall, the decision support system saves significant time as it removes the need for manual gating and analysis, and aids the diagnostician in identifying discrete cell populations and offering descriptive information about any abnormal populations identified.
Strategies for validation of a low-volume BCR::ABL p190 assay in the clinical laboratory
Authors: Hernandez Patricia , Kowalewski Rodney , Stroup Brooke , Hrabusicky Lori , Parikh Bijal
Published: November 2023

Background

The low prevalence of samples positive for the BCR::ABL p190 (e1a2) fusion transcript (<1/week) can be a barrier for molecular test validation. The Cepheid Xpert BCR-ABL Ultra p190 Assay is a single-use cartridge-based RUO assay designed for the quantitative detection of BCR::ABL p190 from fresh specimens. The following study describes our validation strategy to overcome this barrier for implementing a quantitative molecular LDT.

Methods

This study was conducted in a hospital clinical laboratory setting between 2019 to 2023. RNA was extracted and frozen from peripheral blood (PB) and bone marrow (BM) samples that were sent in parallel to a reference lab for BCR::ABL p190 testing. High positive diagnostic specimens (>10% p190/ABL1) were presumptively identified as BCR::ABL FISH positive and p210 negative. Diagnostic specimens were diluted in known negative PB or BM to achieve %p190/ABL1 in various quantitative ranges. Reverse transcription, amplification, and quantitative real-time PCR were performed in a single reaction format (Cepheid Xpert cartridge®). For accuracy determinations, reported results of clinical samples from the reference lab were compared to the obtained values from our validation using extracted RNA only. Banked proficiency testing (PT) material was used to supplement qualitative and quantitative accuracy. For precision, Invivoscribe (IVS) control material (San Diego, CA) diluted in seven levels (12.5% to 0.0031%; 4-fold increments) and Maine Molecular Quality Controls (MMQCI, Saco ME) at 10%, 1%, 0.1%, 0.02%, 0% were run by at least three technologists and rotated amongst the 16 instrument modules. To evaluate linearity, IVS controls at 15 levels (100% to 0.003%; 2-fold increments) were assayed in triplicate. Limit of detection (LoD) was the minimum concentration at which the detection rate is 100% in 10 independent runs. For analytical specificity, high-positive p210 specimens (>10%) were evaluated for detection of p190.

Results

a total of 169 samples were analyzed (33 BM, 32 PB, 5 PT samples, 73 IVS controls, and 26 MMQCI controls). We found a correlation (linearity) between reference lab results and clinical/ control samples (R-squared ~0.88, P < 0.01). Overall Cohen’s kappa concordance for qualitative accuracy analysis was 0.80 (CI 95% 0.65-0.95). Sensitivity, specificity, and accuracy were 91%, 92%, and 91%, respectively. This assay showed precision in all levels of dilution (IVS and MMQCI samples) as previously established. LoD was 0.02%. Samples with high level of p210 /ABL remained negative with the p190 assay.

Conclusion

in the setting of low-volume assays optimized for fresh samples, such as for the detection of BCR::ABL p190, dilutions of clinical samples, banked frozen RNA extracts, PT samples, and commercial controls are important tools for validation of a quantitative LDT.
A stochastic multicompartment model of hemostasis and oxygenation during trauma resuscitation as a platform for in silico trials of transfusion
Authors: Vieni Casey , Yazer Mark , Seheult Jansen
Published: November 2023

Uncontrolled hemorrhage accounts for up to 40% of trauma related mortality, and approximately 30% of trauma related deaths occur in the hospital within the first 1-4 hours of injury. The Advanced Trauma Life Support (ATLS) guidelines still recommend initial resuscitation with crystalloid fluid as an integral part of maintaining or restoring hemodynamic stability, but are starting to recognize the role of early resuscitation with blood products in patients with evidence of Class III and IV hemorrhage, in line with recent clinical trial and observational data. Although there is a growing body of evidence that early transfusion with blood products may be associated with improved survival compared with crystalloid infusion, the optimal transfusion strategy still remains unclear and is being actively investigated in clinical trials. In silico models of resuscitation offer a means to evaluate the effectiveness and safety of resuscitation protocols, including effects on body fluid compartment volumes, tissue oxygenation, and hemostatic factors. Here we describe our work extending earlier deterministic models of trauma resuscitation to incorporate hemodynamic, hemostatic, resuscitation, biomarker, and tissue-oxygenation domains into a single comprehensive model. Additionally, this model expands upon previous deterministic models to create a stochastic computational model of hemostatic resuscitation that accounts for variations in blood component composition and temporal features of transfusion therapy. Using this stochastic model, an in silico trial was piloted to compare conventional component therapy, i.e. red cell, platelet and plasma components, to cold-stored whole blood using the following starting assumptions: patient weight of 81.3±21.8 kg, hematocrit of 41.8±4.3%, initial bleeding rate between 50 and 150 mL/min, systolic blood pressure of 125±18 mmHg, fibrinogen of 293±88 mg/dL, international normalized ratio of 1.0±0.1 and platelet count of 239±62x109/L, with blood component and whole blood constituent distributions based on laboratory quality control data. This in silico trial demonstrated that resuscitation with whole blood was associated with a 28-minute reduction in the time spent in the critical window defined by platelet count <50x109/L, INR≥2, hemoglobin <9 g/dL and fibrinogen <150 mg/dL compared with conventional component resuscitation over the course of a 4 hour simulation (p<0.001 based on median regression). We demonstrate how stochastic models of hemostatic resuscitation can be used to perform in silico trials of resuscitation strategies. Our work can guide inclusion and exclusion criteria for future clinical trials and facilitate identification of patient subgroups most likely to benefit from certain resuscitation strategies. This work was partially funded by the AABB Foundation (formerly the National Blood Foundation).
Recycling Opportunities in a High Volume Academic Clinical Chemistry Laboratory
Authors: Glover Raeshun , Booth Garrett , Wiencek Joesph R
Published: November 2023

Many sectors of industry, including the biomedical sector, have quantified waste, and created sustainability strategies to mitigate its environmental impact. One of these strategies utilizes the waste hierarchy, a model which ranks the concepts reduce, re-use and recycle in order of the most to least sustainable practice. However, to date, the clinical laboratory has seldom been evaluated for total waste production and mitigation strategies and additional public reporting of the physical amount of waste produced in these areas are lacking in the literature. In this study, we aimed to identify specific wastes produced from performing the CMP over the course of a year in our automated clinical chemistry laboratory and what proportion would be recyclable. The total in- and outpatient testing volumes as well as volumes of quality control and calibrations needed to perform the CMP at our institution were collected retrospectively from 07/14/2021 - 07/14/2022. We further identified disposables waste items such as calibrator kits, quality control kits, patient blood specimen tubes, shipping packaging and reagent wedge kits that are necessary to perform the CMP. In addition, to obtain a conservative and consistent evaluation to the total amount of waste produced from the CMP, the average weights for components of the reagent test wedge kits which includes plastic wedges, cardboard shipping boxes, and paper package inserts were calculated. These weights in conjunction with total testing volumes was used to determine the total, recyclable, and non-recyclable waste produced from these disposable items. A total of 1089.2 kg of reagent kit wastes were estimated to be produced by performing the CMP over the course of a year. Of this waste, cardboard shipping boxes and paper package inserts were determined to be recyclable (233.6 kg) and the plastic reagent wedges were determined to be non-recyclable (855.5 kg) as they were not labelled with the universally recognized recycling code, were composed of proprietary plastic material, and contained biohazardous contaminants. Overall, 21.4 % of the total specific waste weight was found to be recyclable. The CMP is a small subset of the clinical chemistry test menu that produces a considerable amount of recyclable and non-recyclable waste.
Did interventions in a massive transfusion protocol program change transfusion practice?
Authors: Devera Ronald , Gorham Jim
Published: November 2023

Current literature supports improved clinical outcomes in the setting of trauma when a Massive Transfusion Protocol (MTP) adheres to transfusion at, or close, to a 1:1 ratio (RBC:Plasma). At our institution, between 2008 and 2015, the number of MTP activations increased ten-fold, accompanied by increased wastage of blood products and stress on the transfusion service. In response, in 2016-2018, we undertook an extensive root-cause analysis, and deployed multiple interventions, including clinician education and multiple process changes to the MTP, which succeeded in reining in inappropriate activation of the MTP, as we have previously published.

Heretofore, we have not addressed whether these interventions also affected the ratio of blood products transfused during MTPs activated at our institution. Here, we test the hypothesis that the changes deployed in 2016-2018 were associated with improved adherence to the desired 1:1 ratio.

The study is a retrospective analysis of massive transfusion data collected from 2008 to 2022. We reviewed RBC and Plasma units transfused to all patients receiving blood products through the MTP during this period. All patients transfused seven or more RBC and/or Plasma units following MTP activation were included in the study (total n = 443). Activations were classified by year. For each patient, the (RBC:Plasma) ratio transfused was calculated and assessed for adherence to a 1:1 ratio, with a ratio of 2:1 or greater classified as “suboptimal”. Our institution does not use Whole Blood.

MTP usage at our institution gradually increased from 2008, when the MTP was established, to 2016, when the MTP procedure was revised. Suboptimal transfusion ratios (RBC:Plasma) also increased from 2008-2016. Between 2008 and 2013, 15% of patients received suboptimal ratios following MTP activation. In 2014-2016, suboptimal ratios were observed in 25% of MTPs. Following multiple interventions, the frequency of MTP activation dropped precipitously, as described, and was accompanied by a decrease in the percentage of suboptimal ratios; in 2020 to 2022, 11% of MTPs involving seven or more transfused units had a suboptimal ratio.

In summary, the dramatic increase in activations of the MTP observed between 2008 and 2016 at our medical center was accompanied by an increase in suboptimal RBC:Plasma transfusion ratios. Interventions deployed between 2016 and 2018 led not only to reduced blood wastage, and lower stress of BB staff, but also to improved adherence to best transfusion practices, in the form of appropriate (RBC:Plasma) ratios transfused during MTPs.
Antimicrobial Susceptibility Patterns Among a Large, Nationwide Cohort of Chryseobacterium Species Clinical Isolates
Authors: Pham Jonathan , Calvaresi Emilia , Fisher Mark
Published: November 2023

Background

Chryseobacterium species are ubiquitous in nature that can be found in soil, water, sinks, and medical devices. They have been implicated in various infections including ventilator-associated pneumonia, catheter-related bloodstream infections (CRBSI), skin and soft tissue infections, and meningitis. C. indologenes has been shown to possess an extended-spectrum beta-lactamase (ESBL) and metallo-β-lactamase (MBL) that render it resistant to most antibiotics. Antimicrobial susceptibility testing (AST) data are required to help clinicians choose effective empiric antibiotics and to investigate potential resistance mechanisms.

Methods

Chryseobacterium spp. identification was determined prior to submission by client laboratories or performed in our laboratory by MALDI-TOF (Bruker Biotyper) or 16S rRNA gene sequencing. AST was performed on Chryseobacterium species isolates received from across the United States between April 2004 and December 2018. AST was performed using custom-made broth microdilution panels, and minimal inhibitory concentrations (MICs) were interpreted using CLSI M100 MIC breakpoints for non-Enterobacterales organisms. Isolates from a range of clinical specimens including blood, respiratory, wound, tissue, bone, and body fluids were included. Quality control was performed using Escherichia coli ATCC 25922 and Pseudomonas aeruginosa ATCC 27853. Results were included only if the QC values were within range. The MIC50, MIC90, and MIC ranges for antimicrobials for frequently tested Chryseobacterium species were determined.

Results

AST was completed for 245 Chryseobacterium species clinical isolates, and the most frequently tested species were C. gleum/ indologenes (n = 78), C. hominis (n = 25), C. taklimakanense (n = 14), C. anthropi/ haifense (n = 12), C. arthrospharae (n = 12), C. bernardetii/jejuense (n = 3), C. pallidum (n = 3), and C. solincola/treverense (n = 3). 84 isolates were unable to be identified to species level, and were grouped as “Chryseobacterium spp.” Regarding susceptibility, across all Chryseobacterium species, the antibiotics with the most activity included minocycline (97.8%), trimethoprim-sulfamethoxazole (TMP-SMX; 95.5%), levofloxacin (92.3%), and ciprofloxacin (82.8%). Comparing the β-lactams, piperacillin-tazobactam had the most activity (59.7%), whereas ceftazidime (42.2%), cefepime (44.3%), meropenem (41.2%), and imipenem (46.3%) had similar low activity. The highest resistance rates were found for tobramycin (96%), aztreonam (94.6%), and gentamicin (62.7%). Among the Chryseobacterium isolates, certain species were found to be largely pan-susceptible, including C. anthropic/haifense, C. hominis, and C. taklimakanense.

Conclusions

Chryseobacterium species display significant resistance against β-lactam antibiotics, which are often used for empiric therapy. Minocycline, TMP-SMX, and fluoroquinolones have the most activity against Chryseobacterium species clinical isolates.
IMPACT OF CMA ON DIAGNOSIS AND CLINICAL MANAGEMENT OF NEONATES: A RETROSPECTIVE SINGLE CENTER STUDY OF A 10-YEAR COHORT
Authors: Rosti Ozgur , Williams Eli , Fan Jinbo
Published: November 2023

Introduction

Congenital anomalies are one of the leading causes of mortality in neonatal period. The burden of genetic disease is high in neonates with congenital anomalies. Chromosomal microarray analysis (CMA) is the “first-tier” cytogenetic diagnostic test for individuals with multiple congenital anomalies. The aim of this study is to assess the diagnostic yield and clinical management impact of CMA in a large neonatal cohort over a 10-year period at a single medical center.

Methods

This is a retrospective study of a cohort of neonates tested by CMA at UVA Cytogenetics Laboratory between the years of 2013-2022. All individuals had either an isolated (major) congenital anomaly (CA) or multiple congenital malformations (MCA). We evaluated the diagnostic yield of the CMA in this neonate cohort and the frequency of positive CMA findings for specific phenotypes, as well as impact of CMA findings in the clinical management of patients.

Results

Of the 965 patients analyzed, 656 (68%) had normal results, 166 (17%) patients only had variants of uncertain significance (VUS), 128 (13%) patients had pathogenic alterations (thus confirmed genetic diagnosis), and 15 (2%) patients only had absence of heterozygosity (AOH) regions meeting our reporting criteria. Further details on presence of specific CNVs in the cohort and, positivity per presence/absence of multiple and specific anomalies is still ongoing and will be given in the presentation. For patients received a genetic diagnosis through CMA analysis, genetic findings were considered beneficial for clinical management, and a direct change to medical management occurred.

Conclusion

s: In this study, we found that the overall diagnostic yield for CMA in this neonate cohort is at approximately 13%. The confirmed genetic diagnosis affected the clinical management/treatment plan of this subset of neonatal patients. While first-tier testing for MCA and other indications is increasingly moving to ES/GS approaches, CMA continues to offer diagnostic and actionable genetic information in a timely matter. Overall, the implementation of CMA to a neonatal cohort at our center has increased the proportion of patients receiving a confirmed genetic diagnosis and affected the management/treatment plan of a subset of neonatal patients.
CytogeneticsPlatelet inhibition testing: whole blood point-of-care vs traditional platelet aggregometry
Authors: Achram Robert , Barrette Eileen , Guarner Jeannette , Smith Geoffrey , Maier Cheryl L
Published: November 2023

Monitoring drug response to ensure optimal platelet suppression is necessary in select patients on dual antiplatelet therapy (DAPT). At our institution, responses to aspirin (ASA) and P2Y12 inhibitors (P2Y12-Is) are assessed by light transmission aggregometry (LTA) using the Helena AggRAM assay. This method requires platelet-rich plasma (PRP) and is labor intensive. Platelet mapping using thromboelastography (TEG) is an alternate method, which offers point-of-care testing on whole blood. Here, we aimed to evaluate the concordance of our LTA assay with TEG, as well as the VerifyNow® PRUTest. We aimed to run testing on at least 20 patient samples; however, at the time of abstract submission, only 10 samples were available. Ten blood samples from 8 patients on dual anti-platelet therapy were collected in preparation for neurologic stent placement. Prepared PRP was analyzed by LTA on the Helena AggRAM assay. The maximal amplitude of the aggregation curves was recorded in the presence of high dose (HD) ADP, low dose (LD) ADP, and arachidonic acid (AA). Whole blood was analyzed by TEG using PlateletMapping ADP & AA assay cartridges on the Haemonetics® TEG 6s analyzer, and by the VerifyNow® PRUTest. Thresholds to qualify platelet suppression as optimal or suboptimal were defined a priori following established guidelines. Concordance between methods was calculated using the following formula: (optimal/optimal + suboptimal/suboptimal) / total number of samples. Pearson correlation between units of measure was also determined. For P2Y12-I response, concordance between LTA and TEG was 70% (correlation was r = 0.76 between TEG and LTA with HD ADP, and r = 0.70 between TEG and LTA with LD ADP). Concordance between VerifyNow® and LTA was 60% (correlation was r = 0.84 between VerifyNow® and LTA with HD ADP, and r = 0.78 between VerifyNow® and LTA with LD ADP). Finally, concordance between VerifyNow® and TEG was 30% (correlation was r = 0.81). Regarding ASA response, concordance was 80% between LTA and TEG (correlation was r = 0.31). To summarize, overall concordance ranged from 30 to 80% across platforms. For P2Y12 inhibition, results obtained from LTA with HD ADP and VerifyNow® had the strongest correlation (r = 0.84). Interestingly, the correlation between VerifyNow® and TEG was similarly elevated (r = 0.81), but concordance was poor (30%). When comparing TEG to LTA, the strongest correlation was between LTA with HD ADP and TEG (r value = 0.76). Concerning ASA inhibition, concordance between LTA and TEG was acceptable; however, correlation was weak (80%; r = 0.31). Results from this preliminary study support the potential use of TEG to monitor platelet response to therapy. We plan to continue our testing to include a minimum of 20 samples, and also consider patient outcomes, before implementing any laboratory workflow changes.
The Million Patient Labset: A large, de-identified dataset of longitudinal clinical laboratory results from one million patients
Authors: Spies Nicholas , Zhang Ray , Jackups Ronald
Published: November 2023

Laboratory testing is integral to the diagnosis and treatment of disease. Advances in electronic medical records and computation have initiated an era of ‘big data’ for laboratory medicine. However, most health data continues to exist in isolated and inaccessible information silos, limiting public utility. To address this gap, we have developed a large, de-identified, longitudinal dataset of laboratory results from over one million patients, called the Million Patient Labset (MPL), which is free and open to the public. The MPL was produced from the combination of two large healthcare systems with IRB and information security approvals. It includes 1,112,550 patients from across 1,920 healthcare sites in two states from 2017 through 2021, with 4,404 different clinical assays represented. Sites included primary care clinics, secondary care facilities for dialysis, infusions, rehabilitation, and other subspecialties, and tertiary centers for major surgery, trauma care, cancer care, and other complex medical services. Assays having fewer than 100 results were excluded. Limited patient demographic and encounter metadata are also included. Protected health information was de-identified in accordance with Health Insurance Portability and Accountability Act of 1996 (HIPAA) safe harbor standards. Service dates and times were altered to obscure absolute timestamps, while approximately preserving interval lengths between test results of the same patient, and general age and time of testing averages across patients. Time of day, day of week, and seasonality were approximately preserved. Data were validated through randomly selected comparisons against the original patient records, prior to destroying re-identification keys. In conclusion, we have produced a large de-identified open-access dataset of clinical laboratory results from over one million real patients. We hope this resource will be valuable for researchers exploring human clinical variation, medical artificial intelligence, reference interval optimization, and other data-driven studies.
CytogeneticsPathBrowser: an educational tool to convert textbook images and captions into flashcards
Authors: Hung Stevephen , Woddor Navitha , Barzaga Maikel Benitez , Prado Ilianne Vega , Soriano Carla Ayala , Mamilla Divya , Sepulveda Jorge
Published: November 2023

Background

Competence in reaching the correct diagnosis from analysis of clinical pathology specimens requires exposure to a large volume and breadth of cases. Images from textbooks are critical resources that supplement actual cases with well curated information. However, learning from textbooks has several setbacks. Images from individual textbooks are limited in number and often do not adequately capture variation of the disease entity. Textbooks also do not usually provide a platform for learners to assess their diagnostic abilities. This burdens the learner with creating flashcards for self-assessment, which is manually intensive.

Methods

To address these limitations, we developed PathBrowser, a web browser-accessible program that leverages the PyMuPDF Python package (Artifex) to extract images and captions from textbooks in PDF format. Captions are written to the image files using ExifTool (Phil Harvey), making the images searchable by keywords. The program then displays the image while hiding the caption, challenging the user to enter the appropriate diagnosis. To minimize work by the user to prepare flashcard questions and answers, the program can automatically generate quiz questions by using natural language processing tools and a Naïve Bayes (NB) classifier (NLTK and SpaCy packages) to identify important terms from the caption as either diagnoses or cytologic features.

Results

As a proof of principle, we used PathBrowser to build an image repository of myeloblasts and common mimickers, including reactive lymphocytes and chronic lymphoid leukemias, towards training junior pathology residents to identify blasts in peripheral blood and body fluids. In total, PathBrowser extracted 173 images (63 myeloblasts and 110 non-blasts) from 2 textbook sources (Atlas of Diagnostic Hematology by Salama et al., and Hematopathology by Jaffe et al.). We trained a NB classifier to label images as “myeloblast” or “non-myeloblast,” based on keywords in the caption. We manually ascertained that PathBrowser extracted the appropriate caption from 30/30 (100%) images of myeloblasts. Of these, the NB classifier correctly extracted the term “myeloblast” in 28 (93%) images. A survey of pathology residents showed that 89% of respondents agreed the program is a useful pathology learning tool.

Conclusions

We developed a program that makes reading from textbooks an interactive learning experience. By automating the manual-intensive steps of extracting images and captions and preparing flashcards with quiz questions using caption terms classified by machine learning tools, learners can focus on recognizing the diagnostic features represented by the images. Finally, our program enables the rapid generation of a repository of images from diverse sources, so that learners can browse a wide spectrum of disease entities and their variants.
State-of-the-Art Review: Persistent Enterococcal Bacteremia
Authors: Rogers Ralph , Rice Louis B
Published: November 2023

Persistent enterococcal bacteremia is a commonly encountered and morbid syndrome without a strong evidence base for optimal management practices. Here we highlight reports on the epidemiology of enterococcal bacteremia to better describe and define persistent enterococcal bacteremia, discuss factors specific to Enterococcus species that may contribute to persistent infections, and describe a measured approach to diagnostic and therapeutic strategies for patients with these frequently complicated infections. The diagnosis of persistent enterococcal bacteremia is typically clinically evident in the setting of repeatedly positive blood culture results; instead, the challenge is to determine in an accurate, cost-effective, and minimally invasive manner whether any underlying nidus of infection (eg, endocarditis or undrained abscess) is present and contributing to the persistent bacteremia. Clinical outcomes for patients with persistent enterococcal bacteremia remain suboptimal. Beyond addressing host immune status if relevant and pursuing source control for all patients, management decisions primarily involve the selection of the proper antimicrobial agent(s). Options for antimicrobial therapy are often limited in the setting of intrinsic and acquired antimicrobial resistance among enterococcal clinical isolates. The synergistic benefit of combination antimicrobial therapy has been demonstrated for enterococcal endocarditis, but it is not clear at present whether a similar approach will provide any clinical benefit to some or all patients with persistent enterococcal bacteremia.
Spatial differencing for sample selection models with ‘site-specific’ unobserved local effects
Authors: Klein Alexander , Tchuente Guy
Published: November 2023

This paper proposes an estimator which combines spatial differencing with a two-step sample selection estimator. We derive identification, estimation, and inference results from ‘site-specific’ unobserved effects. These effects operate at a spatial scale that cannot be captured by administrative borders. Therefore, we use spatial differencing. We show that under justifiable assumptions, the estimator is consistent and asymptotically normal. A Monte Carlo experiment illustrates the small sample properties of our estimator. We apply our procedure to the estimation of a female wage offer equation in the United States and the results show the relevance of spatial differencing to account for ‘site-specific’ unobserved effects.
Teaching positive psychology lessons in an intensive English program
Authors: Rogers Carolee , McMurry Benjamin L , Dewey Dan P
Published: November 2023

This article investigates the effectiveness of positive psychology interventions (PPIs) in an intensive English program for non-matriculated university students. Interventions based on the PERMA model were implemented through weekly 65-minute lessons given during the first class of each week. These were followed by short daily activities during the rest of the week. Using positive psychology topics as the content, students concurrently engaged in language learning activities. Each participant was asked to complete a questionnaire at the end of the semester consisting of five open-ended questions relating to the PPIs, the lessons, the activities, the topics, and how they felt the PPIs affected their language learning and their life outside of class. Two raters individually reviewed each student response and marked them as positive, neutral, or negative. On the whole, the learners viewed the PPIs as being helpful for their well-being without detracting from their linguistic development.
Language teacher wellbeing: an individual–institutional pact
Authors: Gregersen Tammy , MacIntyre Peter
Published: November 2023

Although positive psychology (PP) is characterized as a tripartite approach to human flourishing that considers emotions, traits, and institutions, to date the role of institutions has been relatively overlooked. This is particularly problematic when exploring language teacher wellbeing because a teacher’s ability to thrive is also dependent upon the context in which they work. Combining the results of a web survey on teacher wellbeing with relevant concepts from PP on the collective responsibility of individuals and institutions, this study provides a podium from which teachers’ voices can be heard. When asked for specific advice on positively confronting challenges (particularly stemming from the Covid-19 pandemic), teachers’ recommendations coalesced around the four themes of doing your best: teaching practices, positive leadership, and positive attitudes and gratitude. The purpose of this study is to listen to teachers’ voices and provide implications for making more positive institutions.
ORFans in Mitochondrial Genomes of Marine Polychaete Polydora
Authors: Selifanova Maria , Demianchenko Oleg , Noskova Elizaveta , Pitikov Egor , Skvortsov Denis , Drozd Jana , Vatolkina Nika , Apel Polina , Kolodyazhnaya Ekaterina , Ezhova Margarita A , Tzetlin Alexander B , Neretina Tatiana V , Knorre Dmitry A
Published: November 2023

Most characterized metazoan mitochondrial genomes are compact and encode a small set of proteins that are essential for oxidative phosphorylation, as well as rRNA and tRNA for their expression. However, in rare cases, invertebrate taxa have additional open reading frames (ORFs) in their mtDNA sequences. Here, we sequenced and analyzed the mitochondrial genome of a polychaete worm, Polydora cf. ciliata, part of whose life cycle takes place in low-oxygen conditions. In the mitogenome, we found three “ORFan” regions (544, 1,060, and 427 bp) that have no resemblance to any standard metazoan mtDNA gene but lack stop codons in one of the reading frames. Similar regions are found in the mitochondrial genomes of three other Polydora species and Bocardiella hamata. All five species share the same gene order in their mitogenomes, which differ from that of other known Spionidae mitogenomes. By analyzing the ORFan sequences, we found that they are under purifying selection pressure and contain conservative regions. The codon adaptation indices (CAIs) of the ORFan genes were in the same range of values as the CAI of conventional protein-coding genes in corresponding mitochondrial genomes. The analysis of the P. cf. ciliata mitochondrial transcriptome showed that ORFan-544, ORFan-427, and a portion of the ORFan-1060 are transcribed. Together, this suggests that ORFan-544 and ORFan-427 encode functional proteins. It is likely that the ORFans originated when the Polydora/Bocardiella species complex separated from the rest of the Spionidae, and this event coincided with massive gene rearrangements in their mitochondrial genomes and tRNA-Met duplication.
Associations of Folate/Folic Acid Supplementation Alone and in Combination With Other B Vitamins on Dementia Risk and Brain Structure: Evidence From 466 224 UK Biobank Participants
Authors: Ling Yitong , Yuan Shiqi , Huang Xiaxuan , Tan Shanyuan , Cheng Hongtao , Xu Anding , Lyu Jun
Published: November 2023

Previous researchers have tried to explore the association between folate/folic acid intake and dementia incidence, but the results remain controversial. We evaluated the associations of folate/folic acid supplementation alone and in combination with other B vitamins on dementia risk and brain structure. A total of 466 224 UK Biobank participants were investigated. Cox proportional hazards models were used to assess the associations between folate/folic acid supplementation status and the risk of Alzheimer’s disease (AD) and vascular dementia (VD). Multivariable linear regression models were employed to evaluate the association between folate/folic acid supplementation status and brain structure. In the final model, folate/folic acid supplementation alone was significantly associated with a higher risk of AD (hazard ratio [HR] = 1.34, 95% confidence interval [CI] = 1.06–1.69, p = .015) and VD (HR = 1.61, 95% CI = 1.21–2.13, p = .001). Folate/folic acid supplementation alone was associated with a reduction in the hippocampus (β = −95.25 mm3, 95% CI = −165.31 to −25.19 mm3, p = .014) and amygdala (β = −51.85 mm3, 95% CI = −88.02 to −15.68 mm3, p = .012). The risk of AD and VD, as well as brain structure, in the group with combined folate/folic acid supplementation and other B vitamins did not show a statistically significant difference compared to the reference group (all p > .05). Folate/folic acid supplementation alone is significantly associated with a higher risk of AD and VD, as well as adverse alterations in brain structure. However, when combined with other B vitamins, these detrimental effects can be counteracted.
Long-stranded non-coding RNAs temporal-specific expression profiles reveal longissimus dorsi muscle development and intramuscular fat deposition in Tianzhu white yak
Authors: He Zhaohua , Wang Xiangyan , Qi Youpeng , Zhu Chune , Zhao Zhidong , Zhang Xiaolan , Liu Xiu , Li Shaobin , Zhao Fangfang , Wang Jiqing , Shi Bingang , Hu Jiang
Published: November 2023

The process of muscle development and intramuscular fat (IMF) deposition is quite complex and controlled by both mRNAs and ncRNAs. Long-stranded non-coding RNAs (LncRNAs) are involved in various biological processes in mammals while also playing a critical role in muscle development and fat deposition. In the present study, RNA-Seq was used to comprehensively study the expression of lncRNAs and mRNAs during muscle development and intramuscular fat deposition in postnatal Tianzhu white yaks at three stages, including 6 mo of age (calve, n = 6), 30 mo of age (young cattle, n = 6) and 54 mo of age (adult cattle, n = 6). The results indicated that a total of 2,101 lncRNAs and 20,855 mRNAs were screened across the three stages, of which the numbers of differential expression (DE) lncRNAs and DE mRNAs were 289 and 1,339, respectively, and DE lncRNAs were divided into eight different expression patterns based on expression trends. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis revealed that some DE mRNAs overlapped with target genes of lncRNAs, such as NEDD4L, SCN3B, AGT, HDAC4, DES, MYH14, KLF15 (muscle development), ACACB, PCK2, LIPE, PIK3R1, PNPLA2, and MGLL (intramuscular fat deposition). These DE mRNAs were significantly enriched in critical muscle development and IMF deposition-related pathways and GO terms, such as AMPK signaling pathway, PI3K-Akt signaling pathway, PPAR signaling pathway, etc. In addition, lncRNA-mRNA co-expression network analysis revealed that six lncRNAs (MSTRG.20152.2, MSTRG.20152.3, XR_001351700.1, MSTRG.8190.1, MSTRG.4827.1, and MSTRG.11486.1) may play a major role in Tianzhu white yak muscle development and lipidosis deposition. Therefore, this study enriches the database of yak lncRNAs and could help to further explore the functions and roles of lncRNAs in different stages of muscle development and intramuscular fat deposition in the Tianzhu white yak.
From Theory to Practice: Reflections on How We Can Meaningfully Measure Human Rights Impact
Authors: Gubbioni Natalia , Vannucchi Danny
Published: November 2023

What are the biggest challenges and opportunities when an organization is trying to understand the human rights impact it has achieved? Building on more than 12 years combined years of practical evaluation and impact assessment experience across various organizations in the human rights field, the authors reflect on the key lessons learnt while trying to balance organizational needs of reporting, planning, and accountability with the substantive need of understanding how to break down human rights progress and how it happens. Reflections will be articulated in four key challenges, each with practical ideas to build on: the data challenge—what kind of information can give us the most meaningful view of human rights impact; the progress challenge—how we might capture the incremental nature and gradual pace of human rights impact; the target challenge—how best to balance the need to work towards realistic targets with setting an ambitious agenda for change; and finally, the context challenge—how we might compare human rights impact across countries and acknowledge different operating contexts.
Nord-Ost: Russia’s Medical Failure in the 2002 Crisis
Authors: Turner Matthew D , Sapp Jason
Published: November 2023

The 2002 hostage crisis at a Moscow theater transfixed the attention of the world. While the initial assault, led by Spetsnaz commandos, successfully secured the building, the Russian security force’s utter failure at coordinating with medical services led to the preventable deaths of over 100 hostages.
Embrace open-environment machine learning for robust AI
Authors: Li Gang , Cherukuri Aswani Kumar
Published: November 2023

Dive into the novel OpenML paradigm, unveiling its transformative approach to robust AI in dynamic environment, shaping Automated Machine Learning with adaptability for ground breaking advancements towards Artificial General Intelligence.
Passive Movements Do Not Appear to Prevent or Reduce Joint Stiffness in Medium to Long-Stay ICU Patients: A Randomized, Controlled, Within-Participant Trial
Authors: Stiller Kathy R. , Dafoe Simone , Jesudason Christabel S. , McDonald Tony M. , Callisto Rocky J.
Published: November 2023

OBJECTIVES:

ICU patients have an increased risk of joint stiffness because of their critical illness and reduced mobility. There is a paucity of evidence evaluating the efficacy of passive movements (PMs). We investigated whether PMs prevent or reduce joint stiffness in ICU patients.

DESIGN:

A randomized, controlled, within-participant, assessor-blinded study.

SETTING:

A 48-bed tertiary care adult ICU.

PATIENTS:

Intubated patients who were expected to be invasively mechanically ventilated for greater than 48 hours with an ICU length of stay greater than or equal to 5 days, and unable to voluntarily move their limbs through full range of motion (ROM).

INTERVENTIONS:

The ankle and elbow on one side of each participant’s body received PMs (10 min each joint, morning and afternoon, 5 d/wk). The other side acted as the control. The PMs intervention continued for as long as clinically indicated to a maximum of 4 weeks.

MEASUREMENTS:

The primary outcome was ankle dorsiflexion ROM at cessation of PMs. Plantarflexion, elbow flexion and extension ROM, and participant-reported joint pain and stiffness (verbal analog scale [VAS]) were also measured. Outcomes were recorded at baseline and cessation of PMs. For participants whose PMs intervention ceased early due to recovery, additional post-early-cessation of PMs review measurements were undertaken as near as possible to 4 weeks.

MAIN RESULTS:

We analyzed data from 25 participants with a median (interquartile range) ICU stay of 15.6 days (11.3–25.4). The mean (95% CI) between-side difference for dorsiflexion ROM (with knee extension) at cessation of PMs was 0.4 degrees (–4.4 to 5.2; p = 0.882), favoring the intervention side, indicating there was not a clinically meaningful effect of 5 degrees. No statistically significant differences were found between the intervention and control sides for any ROM or VAS data.

CONCLUSIONS:

PMs, as provided to this sample of medium to long-stay ICU patients, did not prevent or reduce joint stiffness.
A Population Pharmacokinetic Model to Predict the Individual Starting Dose of Tacrolimus for Tunisian Adults after Renal Transplantation
Authors: Abderahmene Amani , Francke Marith I. , Andrews Louise M. , Hesselink Dennis A. , Amor Dorra , Sahtout Wissal , Ajmi Marwa , Mastouri Hayfa , Bouslama Ali , Zellama Dorsaf , Omezzine Asma , De Winter Brenda C. M.
Published: November 2023

Background:

Tacrolimus is the most frequently used immunosuppressive drug for preventing renal rejection. However, its use is hampered by its narrow therapeutic index and large intra and interpatient variability in pharmacokinetics. The objective of this study was to externally validate a tacrolimus population pharmacokinetic model developed for the Dutch population and adjust the model for the Tunisian population for use in predicting the starting dose requirement after kidney transplantation.

Methods:

Data on tacrolimus exposure were obtained from kidney transplant recipients (KTRs) during the first 3 months post-transplantation. External validation of the Dutch model and its adjustment for the Tunisian population was performed using nonlinear mixed-effects modeling.

Results:

In total, 1901 whole-blood predose tacrolimus concentrations from 196 adult KTRs were analyzed. According to a visual predictive check, the Dutch model underestimated the starting dose for the Tunisian adult population. The effects of age, together with the CYP3A5*3 and CYP3A4*22 genotypes on tacrolimus clearance were significantly different in the Tunisian population than in the Dutch population. Based on a bodyweight-based dosing, only 21.9% of tacrolimus concentrations were within the target range, whereas this was estimated to be 54.0% with the newly developed model-based dosing. After adjustment, the model was successfully validated internally in a Tunisian population.

Conclusions:

A starting-dose population pharmacokinetic model of tacrolimus for Tunisian KTRs was developed based on a previously published Dutch model. Using this starting dose could potentially increase the percentage of patients achieving target tacrolimus concentrations after the initial starting dose.
Assessing health care leadership and management for resilience and performance during crisis: The HERO-36
Authors: Atkinson Mariam Krikorian , Biddinger Paul D. , Chughtai Mah-Afroze , Hayirli Tuna C. , Hick John L. , Cagliuso Nicholas V. , Singer Sara J.
Published: November 2023

Background

Whereas organizational literature has provided much insight into the conceptual and theoretical underpinnings of organizational leadership and management during emergencies, measures to operationalize related effective practices during crises remain sparse.

Purpose

To address this need, we developed the Healthcare Emergency Response Optimization survey, which set out to examine the leadership and management practices in health care organizations that support resilience and performance during crisis.

Methodology

We administered an online survey in April to May 2022 to health care administrators and frontline staff intimately involved in their hospital’s emergency response during the COVID-19 pandemic, which included a sample of 379 respondents across nine rural and urban hospitals (response rate: 44.4%). We used confirmatory factor analysis and quantile regressions to examine the results.

Results

Applying confirmatory factor analysis, we retained 36 items in our survey that comprised eight measures for formal and informal practices to assess crisis leadership and management. To test effectiveness of the specified practices, we regressed self-reported resilience and performance measures on the formality and informality scores. Findings show that informal practices mattered most for resilience, whereas formal practices mattered most for performance. We also identified specific practices (anticipation, transactional and relational interactions, and ad hoc collaborations) for resilience and performance.

Practice Implications

These validated measures of organizational practices assess emergency response during crisis, with an emphasis on the actions and decisions of leadership as well as the management of organizational structures and processes. Organizations using these measures may subsequently modify preparedness and planning approaches to better manage future crises.