bluuebunny/crossref_metadata_2025 huggingface dataset:
Driver gene detection through Bayesian network integration of mutation and expression profiles
Authors: Chen Zhong , Lu You , Cao Bo , Zhang Wensheng , Edwards Andrea , Zhang Kun
Published: April 2022

Motivation

The identification of mutated driver genes and the corresponding pathways is one of the primary goals in understanding tumorigenesis at the patient level. Integration of multi-dimensional genomic data from existing repositories, e.g., The Cancer Genome Atlas (TCGA), offers an effective way to tackle this issue. In this study, we aimed to leverage the complementary genomic information of individuals and create an integrative framework to identify cancer-related driver genes. Specifically, based on pinpointed differentially expressed genes, variants in somatic mutations and a gene interaction network, we proposed an unsupervised Bayesian network integration (BNI) method to detect driver genes and estimate the disease propagation at the patient and/or cohort levels. This new method first captures inherent structural information to construct a functional gene mutation network and then extracts the driver genes and their controlled downstream modules using the minimum cover subset method.

Results

Using other credible sources (e.g. Cancer Gene Census and Network of Cancer Genes), we validated the driver genes predicted by the BNI method in three TCGA pan-cancer cohorts. The proposed method provides an effective approach to address tumor heterogeneity faced by personalized medicine. The pinpointed drivers warrant further wet laboratory validation.

Availability and implementation

The supplementary tables and source code can be obtained from https://xavieruniversityoflouisiana.sharefile.com/d-se6df2c8d0ebe4800a3030311efddafe5.

Supplementary information

Supplementary data are available at Bioinformatics online.
Relational graph convolutional networks for predicting blood–brain barrier penetration of drug molecules
Authors: Ding Yan , Jiang Xiaoqian , Kim Yejin
Published: April 2022

Motivation

Evaluating the blood–brain barrier (BBB) permeability of drug molecules is a critical step in brain drug development. Traditional methods for the evaluation require complicated in vitro or in vivo testing. Alternatively, in silico predictions based on machine learning have proved to be a cost-efficient way to complement the in vitro and in vivo methods. However, the performance of the established models has been limited by their incapability of dealing with the interactions between drugs and proteins, which play an important role in the mechanism behind the BBB penetrating behaviors. To address this limitation, we employed the relational graph convolutional network (RGCN) to handle the drug–protein interactions as well as the properties of each individual drug.

Results

The RGCN model achieved an overall accuracy of 0.872, an area under the receiver operating characteristic (AUROC) of 0.919 and an area under the precision-recall curve (AUPRC) of 0.838 for the testing dataset with the drug–protein interactions and the Mordred descriptors as the input. Introducing drug–drug similarity to connect structurally similar drugs in the data graph further improved the testing results, giving an overall accuracy of 0.876, an AUROC of 0.926 and an AUPRC of 0.865. In particular, the RGCN model was found to greatly outperform the LightGBM base model when evaluated with the drugs whose BBB penetration was dependent on drug–protein interactions. Our model is expected to provide high-confidence predictions of BBB permeability for drug prioritization in the experimental screening of BBB-penetrating drugs.

Availability and implementation

The data and the codes are freely available at https://github.com/dingyan20/BBB-Penetration-Prediction.

Supplementary information

Supplementary data are available at Bioinformatics online.
The ENDS of assumptions: an online tool for the epistemic non-parametric drug–response scoring
Authors: Amiryousefi Ali , Williams Bernardo , Jafari Mohieddin , Tang Jing
Published: April 2022

Motivation

The drug sensitivity analysis is often elucidated from drug dose–response curves. These curves capture the degree of cell viability (or inhibition) over a range of induced drugs, often with parametric assumptions that are rarely validated.

Results

We present a class of non-parametric models for the curve fitting and scoring of drug dose–responses. To allow a more objective representation of the drug sensitivity, these epistemic models devoid of any parametric assumptions attached to the linear fit, allow the parallel indexing such as half-maximal inhibitory concentration and area under curve. Specifically, three non-parametric models including spline (npS), monotonic and Bayesian and the parametric logistic are implemented. Other indices including maximum effective dose and drug–response span gradient pertinent to the npS are also provided to facilitate the interpretation of the fit. The collection of these models is implemented in an online app, standing as useful resource for drug dose–response curve fitting and analysis.

Availability and implementation

The ENDS is freely available online at https://irscope.shinyapps.io/ENDS/ and source codes can be obtained from https://github.com/AmiryousefiLab/ENDS.

Supplementary information

Supplementary data are available at Bioinformatics online.
A transdiagnostic review of neuroimaging studies of apathy and disinhibition in dementia
Authors: Jenkins Lisanne M , Wang Lei , Rosen Howie , Weintraub Sandra
Published: April 2022

Apathy and disinhibition are common and highly distressing neuropsychiatric symptoms associated with negative outcomes in persons with dementia. This paper is a critical review of functional and structural neuroimaging studies of these symptoms transdiagnostically in dementia of the Alzheimer type, which is characterized by prominent amnesia early in the disease course, and behavioural variant frontotemporal dementia, characterized by early social-comportmental deficits. We describe the prevalence and clinical correlates of these symptoms and describe methodological issues, including difficulties with symptom definition and different measurement instruments. We highlight the heterogeneity of findings, noting however, a striking similarity of the set of brain regions implicated across clinical diagnoses and symptoms. These regions involve several key nodes of the salience network, and we describe the functions and anatomical connectivity of these brain areas, as well as present a new theoretical account of disinhibition in dementia. Future avenues for research are discussed, including the importance of transdiagnostic studies, measuring subdomains of apathy and disinhibition, and examining different units of analysis for deepening our understanding of the networks and mechanisms underlying these extremely distressing symptoms.
Metaboloepigenetics in cancer, immunity, and cardiovascular disease
Authors: Keating Samuel T , El-Osta Assam
Published: April 2022

The influence of cellular metabolism on epigenetic pathways is well documented but misunderstood. Scientists have long known of the metabolic impact on epigenetic determinants. More often than not, that title role for DNA methylation was portrayed by the metabolite S-adenosylmethionine. Technically speaking, there are many other metabolites that drive epigenetic processes that instruct seemingly distant—yet highly connect pathways—and none more so than our understanding of the cancer epigenome. Recent studies have shown that available energy links the extracellular environment to influence cellular responses. This focused review examines the recent interest in epigenomics and casts cancer, metabolism, and immunity in unfamiliar roles—cooperating. There are not only language lessons from cancer research, we have come round to appreciate that reaching into areas previously thought of as too distinct are also object lessons in understanding health and disease. The Warburg effect is one such signature of how glycolysis influences metabolic shift during oncogenesis. That shift in metabolism—now recognized as central to proliferation in cancer biology—influences core enzymes that not only control gene expression but are also central to replication, condensation, and the repair of nucleic acid. These nuclear processes rely on metabolism, and with glucose at centre stage, the role of respiration and oxidative metabolism is now synonymous with the mitochondria as the powerhouses of metaboloepigenetics. The emerging evidence for metaboloepigenetics in trained innate immunity has revealed recognizable signalling pathways with antecedent extracellular stimulation. With due consideration to immunometabolism, we discuss the striking signalling similarities influencing these core pathways. The immunometabolic-epigenetic axis in cardiovascular disease has deeply etched connections with inflammation, and we examine the chromatin template as a carrier of epigenetic indices that determine the expression of genes influencing atherosclerosis and vascular complications of diabetes.
Outcomes of Children with Inflammatory Bowel Disease who Develop Anti-tumour Necrosis Factor-induced Skin Reactions
Authors: Dolinger Michael T , Rolfes Priya , Spencer Elizabeth , Stoffels Guillaume , Dunkin David , Dubinsky Marla C
Published: April 2022

Background and Aims

Anti-tumour necrosis factor [anti-TNF] induced skin reactions are common adverse events in paediatric inflammatory bowel disease [IBD]. We aimed to report on outcomes of children with anti-TNF induced skin reactions who switched to ustekinumab [UST] vs. continued anti-TNF therapy.

Methods

Charts were reviewed for paediatric IBD patients with anti-TNF induced skin reactions. Skin reactions, including psoriasiform dermatitis [PD], were classified as mild or severe based on a severity score. Primary outcome was frequency of skin resolution at 6 months. Secondary outcomes were combined clinical remission and skin resolution at 6 months and skin resolution at latest follow-up.

Results

A total of 111/638 [17%] children ([85, 21%] infliximab [IFX]; [26, 11%] adalimumab [ADA]) developed skin reactions. Eighty [72%] had PD, 25 [23%] infections, and four [4%] alopecia areata; 71 [64%] continued anti-TNF; and 40 [36%] switched to UST. In all, 73 [66%] had severe reactions and were more likely to switch to UST than if mild (37 [51%] vs. 3 [8%]; p <0.0001). Switching to UST had a higher rate and odds of resolution (29 [73%] vs. 24 [34%]; p <0.0001; odds ratio [OR] = 19.7, 95% confidence interval [CI]: 5.6, 69.5; p <0.0001) and combined remission (21 [52%] vs. 22 [31%]; p = 0.03; OR = 8.5, 95% CI: 2.5, 28.4; p = 0.0005] vs. continuing anti-TNF at 6 months.

Conclusions

Children who switched to UST after anti-TNF induced skin reactions were more likely to have improved outcomes than those who continued anti-TNF therapy. Future studies are needed to determine immune mechanisms of anti-TNF induced skin reactions and treatment response.
Perioperative management of P2Y12 inhibitors in patients undergoing cardiac surgery within 1 year of PCI
Authors: Cao Davide , Swain Julie A , Sartori Samantha , Nardin Matteo , Zhang Zhongjie , Roumeliotis Anastasios , Nicolas Johny , Chiarito Mauro , Chandiramani Rishi , Pivato Carlo A , Spirito Alessandro , Giustino Gennaro , Stefanini Giulio G , Dangas George D , Baber Usman , Bhatt Deepak L , Adams David H , Sharma Samin K , Kini Annapoorna S , Mehran Roxana
Published: April 2022

Aims

To evaluate the impact of perioperative P2Y12 receptor inhibitor therapy among patients undergoing cardiac surgery within 1 year of percutaneous coronary intervention (PCI).

Methods and results

Patients undergoing cardiac surgery in the year post-PCI at three tertiary care centres between 2011 and 2018 were stratified into those who had received at least one dose of P2Y12 inhibitor prior to surgery (within 5 days for clopidogrel or prasugrel, or within 3 days for ticagrelor) and those who had not. The outcomes of interest were major adverse cardiac and cerebrovascular events (MACCEs) and bleeding. Among 20 279 PCI patients, 359 (1.8%) underwent cardiac surgery in the ensuing year, 76.3% of whom received coronary artery bypass grafts. Overall, 33 (9.2%) MACCEs and 85 (23.7%) bleeding events occurred within 30 days post-cardiac surgery. Perioperative P2Y12 inhibition (N = 133, 37%) was not associated with the risk of MACCEs or bleeding, despite numerically lower rates of myocardial infarction or stent thrombosis (0.0% vs. 2.6%; P = 0.089). Patients who continued the P2Y12 inhibitor until the day of surgery (N = 60, 17%) had significantly higher bleeding risk [adjusted odds ratio 2.93, 95% confidence interval 1.53–5.59)]. Predictors of MACCEs included a time interval from PCI to cardiac surgery of ≤30 days and reduced ejection fraction, whereas urgent/emergent surgery predicted bleeding. Chronic kidney disease and myocardial infarction as indication for PCI predicted both MACCEs and bleeding.

Conclusion

Among patients undergoing cardiac surgery in the year after PCI, the perioperative risk of ischaemic and bleeding events might be influenced by P2Y12 inhibitor therapy in addition to other risk parameters, including the timing and urgency of the procedure.
Population genetics of polymorphism and divergence in rapidly evolving populations
Authors: Melissa Matthew J , Good Benjamin H , Fisher Daniel S , Desai Michael M
Published: April 2022

In rapidly evolving populations, numerous beneficial and deleterious mutations can arise and segregate within a population at the same time. In this regime, evolutionary dynamics cannot be analyzed using traditional population genetic approaches that assume that sites evolve independently. Instead, the dynamics of many loci must be analyzed simultaneously. Recent work has made progress by first analyzing the fitness variation within a population, and then studying how individual lineages interact with this traveling fitness wave. However, these “traveling wave” models have previously been restricted to extreme cases where selection on individual mutations is either much faster or much slower than the typical coalescent timescale Tc. In this work, we show how the traveling wave framework can be extended to intermediate regimes in which the scaled fitness effects of mutations (Tcs) are neither large nor small compared to one. This enables us to describe the dynamics of populations subject to a wide range of fitness effects, and in particular, in cases where it is not immediately clear which mutations are most important in shaping the dynamics and statistics of genetic diversity. We use this approach to derive new expressions for the fixation probabilities and site frequency spectra of mutations as a function of their scaled fitness effects, along with related results for the coalescent timescale Tc and the rate of adaptation or Muller’s ratchet. We find that competition between linked mutations can have a dramatic impact on the proportions of neutral and selected polymorphisms, which is not simply summarized by the scaled selection coefficient Tcs. We conclude by discussing the implications of these results for population genetic inferences.
Retinoids rescue ceruloplasmin secretion and alleviate oxidative stress in Wilson’s disease-specific hepatocytes
Authors: Song Dan , Takahashi Gou , Zheng Yun-Wen , Matsuo-Takasaki Mami , Li Jingyue , Takami Miho , An Yuri , Hemmi Yasuko , Miharada Natsumi , Fujioka Tsuyoshi , Noguchi Michiya , Nakajima Takashi , Saito Megumu K , Nakamura Yukio , Oda Tatsuya , Miyaoka Yuichiro , Hayashi Yohei
Published: April 2022

Wilson’s disease (WD) is a copper metabolic disorder caused by a defective ATP7B function. Conventional therapies cause severe side effects and significant variation in efficacy, according to cohort studies. Thus, exploring new therapeutic approaches to prevent progression to liver failure is urgent. To study the physiology and pathology of WD, immortalized cell lines and rodent WD models have been used conventionally; however, a large gap remains among different species as well as in genetic backgrounds among individuals. We generated induced pluripotent stem cells (iPSCs) from four WD patients carrying compound heterozygous mutations in the ATP7B gene. ATP7B loss- and gain-of-functions were further manifested with ATP7B-deficient iPSCs and heterozygously corrected R778L WD patient-derived iPSCs using CRISPR-Cas9-based gene editing. Although the expression of ATP7B protein varied among WD-specific hepatocytes differentiated from these iPSCs, the expression and secretion of ceruloplasmin (Cp), a downstream copper carrier in plasma, were consistently decreased in WD patient-derived and ATP7B-deficient hepatocytes. A transcriptome analysis detected abnormalities in the retinoid signaling pathway and lipid metabolism in WD-specific hepatocytes. Drug screening using WD patient-derived hepatocytes identified retinoids as promising candidates for rescuing Cp secretion. All-trans retinoic acid also alleviates reactive oxygen species production induced by lipid accumulation in WD-specific hepatocytes treated with oleic acid. These patient-derived iPSC-based hepatic models function as effective platforms for the development of potential therapeutics for hepatic steatosis in WD and other fatty liver diseases.
Organizations Involved in Humanitarian Action: Introducing a New Dataset
Authors: Egger Clara , Schopper Doris
Published: April 2022

Although the humanitarian sector has gained prominence in the management of contemporary conflicts, data on the diversity of organizations involved in humanitarian aid are scarce and do not rely on well-founded inclusion criteria. This lack of data limits not only our knowledge of humanitarian action but also our understanding of international security and of non-state actors’ role in foreign aid. The Humanitarian Organisations Dataset (HOD) seeks to fill these gaps. Based on clear and reproducible criteria, 2,505 organizations active in the humanitarian sector have been identified while information on their history, nature, activities, and geographical location has been collected. Our analyses depart from prevailing Western-centered accounts of humanitarian, show regional variations in types of organizations, and identify distinct historical patterns by region and by type of organization. They also document a large span of humanitarian activities, going beyond the current exclusive focus on in-kind assistance. We illustrate how the dataset can contribute to further research through its combination with other data and explore the relationship between NGOs and governments in humanitarian aid funding. Beyond its value for scholars, we anticipate that the HOD will also be of interest to policymakers and nonacademic users concerned with humanitarian action and crisis-management issues.
Quantitative Changes in Intratumoral Habitats on MRI Correlate With Pathologic Response in Early-stage ER/PR+ HER2− Breast Cancer Treated With Preoperative Stereotactic Ablative Body Radiotherapy
Authors: Jared Weinfurtner R , Abdalah Mahmoud , Stringfield Olya , Ataya Dana , Williams Angela , Mooney Blaise , Rosa Marilin , Lee Marie C , Khakpour Nazanin , Laronga Christine , Czerniecki Brian , Diaz Roberto , Ahmed Kamran , Washington Iman , Latifi Kujtim , Niell Bethany L , Montejo Michael , Raghunand Natarajan
Published: April 2022

Objective

To quantitatively evaluate intratumoral habitats on dynamic contrast-enhanced (DCE) breast MRI to predict pathologic breast cancer response to stereotactic ablative body radiotherapy (SABR).

Methods

Participants underwent SABR treatment (28.5 Gy x3), baseline and post-SABR MRI, and breast-conserving surgery for ER/PR+ HER2− breast cancer. MRI analysis was performed on DCE T1-weighted images. MRI voxels were assigned eight habitats based on high (H) or low (L) maximum enhancement and the sequentially numbered dynamic sequence of maximum enhancement (H1−4, L1−4). MRI response was analyzed by percent tumor volume remaining (%VR = volume post-SABR/volume pre-SABR), and percent habitat makeup (%HM of habitat X = habitat X voxels/total voxels in the segmented volume). These were correlated with percent tumor bed cellularity (%TC) for pathologic response.

Results

Sixteen patients completed the trial. The %TC ranged 20%–80%. MRI %VR demonstrated strong correlations with %TC (Pearson R = 0.7–0.89). Pre-SABR tumor %HMs differed significantly from whole breasts (P = 0.005 to <0.00001). Post-SABR %HM of tumor habitat H4 demonstrated the largest change, increasing 13% (P = 0.039). Conversely, combined %HM for H1−3 decreased 17% (P = 0.006). This change correlated with %TC (P < 0.00001) and distinguished pathologic partial responders (≤70 %TC) from nonresponders with 94% accuracy, 93% sensitivity, 100% specificity, 100% positive predictive value, and 67% negative predictive value.

Conclusion

In patients undergoing preoperative SABR treatment for ER/PR+ HER2− breast cancer, quantitative MRI habitat analysis of %VR and %HM change correlates with pathologic response.
Improved chemical fixation of lipid-secreting plant cells for transmission electron microscopy
Authors: Kiyoto Shingo , Ichino Takuji , Awano Tatsuya , Yazaki Kazufumi
Published: April 2022

Cultured Lithospermum erythrorhizon cells were fixed with a new fixation method to visualize the metabolism of shikonin derivatives, the lipophilic naphthoquinone pigments in Boraginaceae. The new fixation method combined glutaraldehyde containing malachite green, imidazole–osmium and p-phenylenediamine treatments, and cells were then observed with a transmission electron microscope. The method prevented the extraction of lipids, including shikonin derivatives, and improved the visualization of subcellular structures, especially the membrane system, when compared with that of conventional fixation. The improved quality of the transmission electron micrographs is because malachite green ionically binds to the plasma membrane, organelles and lipids and acts as a mordant for electron staining with osmium tetroxide. Imidazole promotes the reaction of osmium tetroxide, leading to enhanced electron staining. p-Phenylenediamine reduces osmium tetroxide bound to cellular materials and increases the electron density. This protocol requires only three additional reagents over conventional chemical fixation using glutaraldehyde and osmium tetroxide.
Gastrointestinal Biopsy Obtained During Cancer Screening, a Biological Marker for α-Synucleinopathy?
Authors: Jotanovic Jelena , Milin-Lazovic Jelena , Alafuzoff Irina
Published: April 2022

The hallmark alteration in α-synucleinopathies, α-synuclein, is observed not only in the brain but also in the peripheral tissues, particularly in the intestine. This suggests that endoscopic biopsies performed for colon cancer screening could facilitate the assessment of α-synuclein in the gastrointestinal (GI) tract. Using immunohistochemistry for α-synuclein, we assessed whether GI biopsies could be used to confirm an ongoing α-synucleinopathy. Seventy-four subjects with cerebral α-synucleinopathy in various Braak stages with concomitant GI biopsies were available for study. In 81% of the subjects, α-synuclein was seen in the mucosal/submucosal GI biopsies. Two subjects with severe cerebral α-synucleinopathy and a long delay between biopsy and death displayed no α-synuclein pathology in the gut, and 11 subjects with sparse cerebral α-synucleinopathy displayed GI α-synuclein up to 36 years prior to death. The finding that there was no GI α-synuclein in 19% of the subjects with cerebral α-synucleinopathy, and α-synuclein was observed in the gut of 11 subjects (15%) with sparse cerebral α-synucleinopathy even many years prior to death is unexpected and jeopardizes the use of assessment of α-synuclein in the peripheral tissue for confirmation of an ongoing cerebral α-synucleinopathy.
Dismantling or Disguising Racialization?: Defining Racialized Change Work in the Context of Postsecondary Grantmaking
Authors: McCambly Heather , Colyvas Jeannette A
Published: April 2022

Grantmaking organizations (GMOs) exert considerable influence on education systems, public policy, and its administration. We position the work of GMOs—in the distribution and management of funds for the public good—as a form of public management. Using recent work on racialized organizations from sociology, critical theories of race, and institutional theory, we address the role of GMOs in dismantling or reproducing inequalities. In doing so, we develop a new construct—racialized change work—to refer to the purposive action that organizations take to build new, equitable organizational arrangements or tear down old, inequitable ones. We develop quantifiable and testable propositions for how racialized change work might spread (engagement), how it might stick (institutionalization), and what effects it may have on producing equitable outcomes (impact). We build these propositions in the context of US higher education and demonstrate their portability across areas of public policy and administration. We conclude with a discussion of our contributions back to the theories from which we draw and their relationship to public administration.
Formation of carboxylated and decarboxylated betalains in ripening grains of Chenopodium quinoa by a dual dioxygenase
Authors: Henarejos-Escudero Paula , Martínez-Rodríguez Pedro , Gómez-Pando Luz Rayda , García-Carmona Francisco , Gandía-Herrero Fernando
Published: April 2022

Chenopodium quinoa (quinoa) is a pseudo-cereal that forms part of the cultural heritage of Andean countries, and its grains have high nutritional value and potential health benefits. Betalains are nitrogenous water-soluble pigments and bioactive molecules that contribute to these health-promoting properties. Betalains are restricted to plants of the order Caryophyllales, to which quinoa belongs. A new family of betalains has been discovered in the form of unconventional decarboxylated pigments. Here, we show that these pigments accumulate in ripening quinoa grains of fluorescent nature, and are putatively based on a dopamine-cleaving activity. This study describes for the first time the purification and molecular and functional characterization of a 4,5-dopamine extradiol dioxygenase enzyme from plants. It is a monomeric protein with a molecular mass of 34.5 kDa characterized by chromatography, electrophoresis, and time-of-flight mass spectrometry. We demonstrate that this key enzyme has a dual function in a square-shaped biosynthetic pathway towards the formation of both carboxylated and decarboxylated pigments. Enzyme kinetic properties are characterized for the production of 6-decarboxy-betalamic acid and 3,4-dihydroxy-l-phenylalanine-derived betalamic acid, the two structural units of plant pigment in nature. The profile of multiple betalains present in quinoa grains has been reproduced in one-pot bioreactors containing the novel enzyme and two competing substrates.
Anterior Cruciate Ligament Reconstruction Surgery: Creating a Permissive Healing Phenotype in Military Personnel and Civilians for Faster Recovery
Authors: Morris Jodie L , McEwen Peter , Letson Hayley L , Dobson Geoffrey P
Published: April 2022

Introduction

Anterior cruciate ligament (ACL) rupture in military personnel and civilians can be a devastating injury. A service member is 10 times more likely to suffer an ACL injury than their civilian counterparts, and despite successful surgical stabilization, 4%-35% will develop arthrofibrosis, over 50% will not return to full active duty, and up to 50% will develop post-traumatic osteoarthritis (PTOA) within 15 years. Equally concerning, woman are 2 to 8 times more likely to experience ACL injuries than men, which represents a major knowledge gap.

Materials and Methods

A comprehensive literature search was performed in December 2021 using structured search terms related to prevalence, risk factors, disease progression, and treatment of ACL injury and reconstruction. The literature search was conducted independently by two researchers using PubMed, Cochrane, and Embase databases, with inclusion of articles with military, civilian, and sex relevance, and exclusion of most papers with a publication date greater than 10 years. The resources used for the review reflect the most current data, knowledge, and recommendations associated with research and clinical findings from reliable international sources.

Results

Currently, there is no effective system-based drug therapy that creates a “permissive environment” to reduce synovial and cartilage stress after ACL injury and reconstruction and prevent secondary complications. We argue that progress in this area has been hampered by researchers and clinicians failing to recognize that (1) an ACL injury is a system’s failure that affects the whole joint, (2) the early molecular events define and perpetuate different injury phenotypes, (3) male and female responses may be different and have a molecular basis, (4) the female phenotype continues to be under-represented in basic and clinical research, and (5) the variable outcomes may be perpetuated by the trauma of surgery itself. The early molecular events after ACL injury are characterized by an overexpression of joint inflammation, immune dysfunction, and trauma-induced synovial stress. We are developing an upstream adenosine, lidocaine, and magnesium therapy to blunt these early molecular events and expedite healing with less arthrofibrosis and early PTOA complications.

Conclusions

ACL injuries continue to be a major concern among military personnel and civilians and represent a significant loss in command readiness and quality of life. The lack of predictability in outcomes after ACL repair or reconstruction underscores the need for new joint protection therapies. The male–female disparity requires urgent investigation.
Transposon Insertion Drove the Loss of Natural Seed Shattering during Foxtail Millet Domestication
Authors: Liu Hangqin , Fang Xiaojian , Zhou Leina , Li Yan , Zhu Can , Liu Jiacheng , Song Yang , Jian Xing , Xu Min , Dong Li , Lin Zhongwei
Published: April 2022

Loss of seed shattering was a key step during cereal domestication, and it greatly facilitated seed harvest of the staple cereal foxtail millet (Setaria italica) because the cereal has very small seeds. However, the genetic basis for this loss has been largely unknown. Here, we combined comparative and association mapping to identify an 855-bp Harbinger transposable element insertion in the second exon of the foxtail millet gene shattering1 (sh1) that was responsible for the loss of seed shattering. The sh1 gene encodes zinc finger and YABBY domains. The insert prevents transcription of the second exon, causing partial loss of the zinc finger domain and then loss of natural seed shattering. Specifically, sh1 functions as a transcription repressor and represses the transcription of genes associated with lignin synthesis in the abscission zone, including CAD2. The diversity of sh1 is highly reduced in foxtail millet, consistent with either a severe domestication bottleneck or a selective sweep. Phylogenetic analysis of sh1 further revealed a single origin of foxtail millet in China. Our results support the theories that transposons were the most active factors in genome evolution driving loss of natural seed shattering during foxtail millet domestication and that sh1 underwent parallel selection during domestication across different cereal species.
SPATULA and ALCATRAZ confer female sterility and fruit cavity via mediating pistil development in cucumber
Authors: Cheng Zhihua , Song Xiaofei , Liu Xiaofeng , Yan Shuangshuang , Song Weiyuan , Wang Zhongyi , Han Lijie , Zhao Jianyu , Yan Liying , Zhou Zhaoyang , Zhang Xiaolan
Published: April 2022

Fruits and seeds play essential roles in plant sexual reproduction and the human diet. Successful fertilization involves delivery of sperm in the pollen tube to the egg cell within the ovary along the transmitting tract (TT). Fruit cavity is an undesirable trait directly affecting cucumber (Cucumis sativus) commercial value. However, the regulatory genes underlying fruit cavity formation and female fertility determination remain unknown in crops. Here, we characterized a basic Helix-Loop-Helix (bHLH) gene C. sativus SPATULA (CsSPT) and its redundant and divergent function with ALCATRAZ (CsALC) in cucumber. CsSPT transcripts were enriched in reproductive organs. Mutation of CsSPT resulted in 60% reduction in female fertility, with seed produced only in the upper portion of fruits. Csspt Csalc mutants displayed complete loss of female fertility and fruit cavity due to carpel separation. Further examination showed that stigmas in the double mutant turned outward with defective papillae identity, and extracellular matrix contents in the abnormal TT were dramatically reduced, which resulted in no path for pollen tube extension and no ovules fertilized. Biochemical and transcriptome analysis showed that CsSPT and CsALC act in homodimers and heterodimers to confer fruit cavity and female sterility by mediating genes involved in TT development, auxin-mediated signaling, and cell wall organization in cucumber.
Inappropriate Empiric Therapy Impacts Complications and Hospital Resource Utilization Differentially Among Different Types of Bacterial Nosocomial Pneumonia: A Cohort Study, United States, 2014–2019
Authors: Zilberberg Marya D. , Nathanson Brian H. , Puzniak Laura A. , Zilberberg Noah W. D. , Shorr Andrew F.
Published: April 2022

OBJECTIVES:

Nosocomial pneumonia (NP) remains a costly complication of hospitalization fraught with subsequent complications and augmented resource utilization. Consisting of ventilated hospital-acquired bacterial pneumonia (vHABP), nonventilated hospital-acquired bacterial pneumonia (nvHABP), and ventilator-associated bacterial pneumonia (VABP), each may respond differently to inappropriate empiric treatment (IET). We explored whether IET affects the three pneumonia types differently.

DESIGN:

A multicenter, retrospective cohort study within the Premier Research database.

SETTING:

Acute care hospitals in the United States.

PATIENTS:

Patients with three types of NP were identified based on a previously published International Classification of Diseases, 9th Edition/International Classification of Diseases, 10th Edition Clinical Modification algorithm.

INTERVENTIONS:

None.

MEASUREMENTS AND MAIN RESULTS:

We compared the impact of IET on hospital costs, length of stay (LOS), and development of Clostridium difficile infection (CDI), extubation failure (EF), and reintubation (RT). Marginal effects were derived from multivariable regression analyses. IET was present if no drug covering the organism recovered from the index culture was administered within 2 days of the culture date. Among 17,819 patients who met the enrollment criteria, 26.5% had nvHABP, 25.6% vHABP, and 47.9% VABP. Compared with non-IET, IET was associated with increased mean unadjusted hospital LOS across all NP types: nvHABP 12.5 versus 21.1, vHABP 16.7 versus 19.2, and VABP 18.6 versus 21.4 days. The adjusted marginal hospital LOS (4.9 d) and costs ($13,147) with IET were the highest in nvHABP. Incident CDI was rare and similar across NP types (2.4% nvHABP to 3.6% VABP). Both EF and RT were more common with IET in VABP (EF, 15.4% vs 19.2%; RT, 6.2% vs 10.4%), but not vHABP (EF, 15.1% vs 17.7%; RT, 8.1% vs 9.1%).

CONCLUSIONS:

Although IET is relatively uncommon, it affects resource utilization and the risk of complications differently across NP types. The impact of IET is greatest on both LOS and costs in nvHABP and is greater on VABP than vHABP in terms of EF and RT.
Lupus Erythematosus Tumidus Associated With Hemophagocytosis
Authors: Georgiadou Nikki , Singh Sarita , Singh Manuraj
Published: April 2022

A case of lupus erythematosus tumidus (LET), a subtype of chronic cutaneous lupus erythematosus, in an 85-year-old woman who presented with discrete indurated erythematous plaques over the face and upper chest is described. A skin biopsy showed features in keeping with a diagnosis of LET. Unusually however, the lymphocytic infiltrate contained frequent macrophages that demonstrated hemophagocytosis. Most of the phagocytosed cells were lymphocytes, but there was also evidence of erythrophagocytosis. The presence of conspicuous hemophagocytosis has only rarely been reported in skin biopsies of patients with autoimmune conditions. These include systemic lupus, neonatal lupus and dermatomyositis, and on 2 occasions in cases of nonspecified cutaneous lupus erythematosus. To the best of our knowledge, hemophagocytosis as a feature of LET has not been previously described in the literature.
A Case of Indeterminate Cutaneous Dendritic Cell Tumors in the Setting of Chronic Myelomonocytic Leukemia
Authors: Nyckowski Timothy , Vance Paul , Marks Etan
Published: April 2022

Chronic myelomonocytic leukemia (CMML) is a rare hematopoietic stem cell neoplasm. Indeterminate dendritic cell neoplasm (IDCN) is an extraordinarily rare histiocytosis that may manifest secondarily to CMML. A 75-year-old man with a 2-year history of CMML presented for multiple cutaneous lesions on his head and neck. Biopsy results yielded a dense diffuse infiltrate of large pleomorphic cells, which were positive for CD1a, S100, and CD56 with weak positivity for CD43 and CD68. Given his history of CMML, the patient was diagnosed with IDCN. This may indicate a progression of his CMML or transformation to acute leukemia; therefore, a systemic workup was recommended. IDCN may manifest secondary to a wide number of hematopoietic malignancies, with CMML being a rare occurrence. Recorded responses to phototherapy are reassuring, whereas systemic therapy may be appropriate for widespread cases. Remaining vigilant for cutaneous changes in patients with CMML will help prevent misdiagnosis and encourage prompt initiation of appropriate treatment.
Long-Term Zonal Average Analysis of Corneal Tomography in Keratoconus Eyes
Authors: Lombardo Giuseppe , Serrao Sebastiano , Lombardo Marco
Published: April 2022

Purpose:

The scope of this study was to investigate keratoconus progression using zonal average analysis of corneal tomography.

Methods:

The corneal tomographies of patients participating in initial baseline and all scheduled follow-up visits up to 4 years were analyzed. Data were exported in custom software, which delineated 4 zones of analysis and calculated the average values of the anterior and posterior curvature and the average thickness for each zone at each visit. In particular, a 3.1 mm2 area containing the Kmax, termed “keratoconus cone zone,” was defined for assessing disease progression during the follow-up.

Results:

A total of 201 patients were enrolled in this prospective study. At 4 years, 31% of the eyes (n = 62) had an average increase of ≥1.0 D in the keratoconus cone zone in baseline visit, whereas only 11% of the eyes (n = 22) had ≥1.0 D Kmax increase in the same period. The zonal anterior average curvature (+1.1 D; P < 0.001) and thickness (−14 μm; P < 0.001) values of the keratoconus cone zone progressed significantly during the follow-up. A high correlation was found between the 4-year changes of Kmax and central corneal thickness values and the change of the average anterior curvature and thickness values in the keratoconus cone zone. The posterior cornea did not show significant average changes (<−0.2 D; P > 0.05) during the follow-up.

Conclusions:

Single-point tomography indexes for keratoconus progression did not capture the overall structure and shape changes of the cornea. It would be recommended to update criteria for keratoconus management including the zonal average analysis of curvature and thickness values for tracking disease progression over observation periods longer than 1 year.
Multivalvular Endocarditis With Abscess: A Wild Goose Chase
Authors: Abuso Stephanie , Rubin Lily , Geraghty Brian , Hoque Tasneem , Better Donna , Kumar T. K. Susheel , Small Adam , Halpern Dan , Weisenberg Scott , Fiorito Theresa M.
Published: April 2022

We report a case of Streptococcus mutans multivalvular infective endocarditis complicated by aortic root abscess and septic emboli in a 19-year-old male with a bicuspid aortic valve. This case illustrates the progression of untreated subacute bacterial endocarditis and highlights the importance of ongoing clinical suspicion for infective endocarditis in patients with underlying valvular defects.
Expert-Identified Practices for Achieving Measurable Performance Improvements With Lean Implementation
Authors: Reponen Elina , Rundall Thomas G. , Shortell Stephen M. , Blodgett Janet C. , Jokela Ritva , Mäkijärvi Markku , Torkki Paulus
Published: April 2022

Background and Objectives:

Despite the rapid spread of Lean management in health care, few organizations have achieved measurable overall performance improvements with Lean. What differentiates these organizations from those that struggle with realizing the potential benefits of Lean management is unclear. In this qualitative study we explore measuring the impact of Lean and the recommended practices for achieving measurable performance improvements with Lean in health care organizations.

Methods:

Informed by preliminary quantitative results from analyses of high- and low-performing Lean hospitals, we conducted 17 semi-structured interviews with Lean health care experts on the Lean principles and practices associated with better performance. We conducted qualitative content analyses of the interview transcripts based on grounded theory and linking to core principles and practices of the Lean management system.

Results:

The qualitative data revealed 3 categories of metrics for measuring the impact of Lean: currently used institutional measures, measures tailored to Lean initiatives, and population-level measures. Leadership engagement/commitment and clear organizational focus/prioritization/alignment had the highest weighted averages of success factors. The lack of these 2 factors had the highest weighted averages of biggest barriers for achieving measurable performance improvements with Lean implementation.

Conclusions:

Leadership engagement and organizational focus can facilitate achieving the organization's performance improvement goals, whereas their absence can considerably hinder performance improvement efforts. Many different approaches have been used to quantify the impact of Lean, but currently used institutional performance measures are preferred by the majority of Lean experts.
What Cardiothoracic Radiologists Should Know About Imaging in Transgender Patients
Authors: Carroll Evelyn F. , Massoth Lucas R. , Stowell Justin T.
Published: April 2022

Transgender and gender diverse (TGD) individuals may undergo a wide range of care during gender transition including mental health counseling, gender-affirming hormonal therapy, and various surgeries. Hormone therapy effectively converts the hormonal milieu into that of the affirmed gender and produces measurable alterations in serum markers for coronary artery disease and other hematologic conditions (eg, erythrocytosis, venous thrombosis). Although illegal in the United States, some transgender women may receive silicone injections for breast and soft tissue augmentation, which can lead to devastating local complications, as well as silicone migration, pulmonary embolism, systemic reactions, and death. Smoking rates are higher among transgender and sexual minority populations, placing them at elevated risk of smoking-related diseases, including lung cancer. Some opportunistic infections may be more common in the TGD populations, attributable to higher rates of coexisting infection with human immunodeficiency virus. Radiologists should be aware that these patients may develop cancer of their natal organs (eg, breast, prostate), especially as some of these tissues are not completely removed during gender-affirming surgery, which may manifest with thoracic involvement by secondary neoplasia. As more TGD patients seek medical care, thoracic radiologists can reasonably expect to interpret imaging performed in this population and should be aware of possible disease processes and potential complications of hormonal and surgical therapies.
Cytomegalovirus-related Complications and Management in Facial Vascularized Composite Allotransplantation: An International Multicenter Retrospective Cohort Study
Authors: Kauke-Navarro Martin , Panayi Adriana C. , Formica Richard , Marty Francisco , Parikh Neil , Foroutanjazi Sina , Safi Ali-Farid , Mardini Samir , Razonable Raymund R. , Morelon Emmanuel , Gelb Bruce , Rodriguez Eduardo , Lassus Patrik , Pomahac Bohdan
Published: April 2022

Background.

There is a paucity of data on the impact of cytomegalovirus (CMV) serostatus and CMV infection on outcomes in facial vascularized composite allotransplantation.

Methods.

This international, multicenter, retrospective cohort study presents data on CMV and basic transplant-related demographics, including pretransplant viral D/R serostatus, and duration of antiviral prophylaxis. CMV-related complications (viremia, disease), allograft-related complications (rejection episodes, loss), and mortality were analyzed.

Results.

We included 19 patients, 4 of whom received CMV high-risk transplants (D+/R−). CMV viremia was noted in 6 patients (all 4 D+/R− patients and 2 D−/R+), mostly within the first-year posttransplant, shortly after discontinuation of antiviral prophylaxis (median 2 mo). CMV disease occurred in 2 D+/R− patients. The high-risk group experienced relatively more rejection episodes per month follow-up. None of D+/R− patients suffered allograft loss due to rejection (longest follow-up: 121 mo).

Conclusions.

D+/R− patients were at increased risk of CMV-related complications. Although a higher number of rejections was noted in this group, none of the D+/R− patients lost their allograft or died because of CMV or rejection. Thus, CMV D+/R− face transplantation can likely be safely performed with prophylaxis, active surveillance, and prompt treatment.
Development of a Comprehensive Battery to Collect Social and Structural Determinants of Health (SSDOH) in Cognitively Normal or Very Mildly Impaired Persons
Authors: Streitz Marissa L. , Denny Andrea , Xiong Chengjie , McCue Lena , Stites Shana D. , Midgett Sharnita , Mechanic-Hamilton Dawn , Moulder Krista L. , Morris John C. , Balls-Berry Joyce
Published: April 2022

Introduction:

Research addressing Alzheimer disease and related dementias must examine nonbiological factors influencing the risk for and expression of Alzheimer disease and related dementias. These factors address the interplay of cognition with lived experiences and social and structural determinants of health (SSDOH). However, coordinated measures of SSDOH are limited.

Methods:

The Knight Alzheimer Disease Research Center (ADRC) at Washington University in St. Louis developed and piloted a comprehensive battery to measure SSDOH. One hundred and twelve participants, very mildly cognitively impaired or unimpaired, enrolled in memory studies completed the electronic SSDOH battery. The Clinical Dementia Rating (CDR) determined the presence or absence of cognitive impairment.

Results:

Four domains demonstrated above acceptable intraclass correlation scores for test-retest reliability (≥0.70), including adverse childhood events, discrimination, social status, and early education. Twenty very mildly impaired participants completed the electronic pilot study.

Conclusion:

Our findings indicate that participants with early-stage symptomatic Alzheimer disease are able to participate in electronic SSDOH data collection. In collaboration with the University of Pennsylvania ADRC, we replaced/modified certain assessments to increase intraclass correlation. The resulting battery, Social and Structural Life-courses Influencing Aging and Dementia (SS-DIAD), can serve as a SSDOH collection tool and is currently utilized in cognitively impaired and unimpaired research participants at both ADRCs.