Dimensions of Uncertainty: A spatiotemporal review of five COVID-19 datasets.

COVID-19 surveillance across the U.S. is essential to tracking and mitigating the pandemic, but data representing cases and deaths may be impacted by attribute, spatial, and temporal uncertainties. COVID-19 case and death data are essential to understanding the pandemic and serve as key inputs for prediction models that inform policy-decisions; consistent information across datasets is critical to ensuring coherent findings. We implement an exploratory data analytic approach to characterize, synthesize, and visualize spatial-temporal dimensions of uncertainty across commonly used datasets for case and death metrics (Johns Hopkins University, the New York Times, USAFacts, and 1Point3Acres). We scrutinize data consistency to assess where and when disagreements occur, potentially indicating underlying uncertainty. We observe differences in cumulative case and death rates to highlight discrepancies and identify spatial patterns. Data are assessed using pairwise agreement (Cohen's kappa) and agreement across all datasets (Fleiss' kappa) to summarize changes over time. Findings suggest highest agreements between CDC, JHU, and NYT datasets. We find nine discrete type-components of information uncertainty for COVID-19 datasets reflecting various complex processes. Understanding processes and indicators of uncertainty in COVID-19 data reporting is especially relevant to public health professionals and policymakers to accurately understand and communicate information about the pandemic.

Evaluation of Efficacy of 2 Extended-release Bupivacaine Products in a Porcine Model of Incisional Pain.

Extended-release (ER) local anesthetics are often incorporated in multi-modal analgesia or as an alternative when the effect of systemic analgesics may confound research. In this study, we compared the analgesic efficacy of 2 ER bupivacaine anesthetics with different ER mechanisms, a slow-release bupivacaine-meloxicam polymer (BMP) and a sucrose acetate isobutyrate bupivacaine (SABER-B) system. We used a full-thickness unilateral skin incision porcine model to evaluate the efficacy of these 2 ER bupivacaine analgesics. Eighteen male swine were randomized into 3 groups: control (saline; n = 6), bupivacaine:meloxicam (10 mg/kg, 0.3 mg/kg; n = 6), and SABER-B (10 mg/kg; n = 6). After surgery, pigs were assessed for changes in body weight, salivary cortisol level, and response to von Frey testing at 1, 3, 6, 24, 48, 72, 96, 120, and 168 h. Body weight and salivary cortisol levels were not significantly different between groups. Based on the von Frey testing, the pigs that received analgesics showed a significantly higher withdrawal threshold of nociceptive stimulus than those that received saline at 1, 3, 6, and 24 h after the surgery. At 48 h after surgery, the SABER-B group had a significantly higher withdrawal threshold than the saline group. The withdrawal threshold was not significantly different from the baseline measurement on intact skin at 3 and 6 h after surgery in the BMP group or 1 and 3 h for the SABERB group. The analgesic effects of BMP were greatest at 3 and 6 h after surgery and that of SABER-B as 1 and 3 h SABER-B provided an earlier onset of analgesia and longer analgesia duration than did BMP. This study demonstrates that ER bupivacaine can provide pigs with 24 to 48 h of analgesia for incisional pain.

Mitochondrial genetic variation and risk of chronic kidney disease and acute kidney injury in UK Biobank participants.

Experimental models suggest an important role for mitochondrial dysfunction in the pathogenesis of chronic kidney disease (CKD) and acute kidney injury (AKI), but little is known regarding the impact of common mitochondrial genetic variation on kidney health. We sought to evaluate associations of inherited mitochondrial DNA (mtDNA) variation with risk of CKD and AKI in a large population-based cohort. We categorized UK Biobank participants who self-identified as white into eight distinct mtDNA haplotypes, which were previously identified based on their associations with phenotypes associated with mitochondrial DNA copy number, a measure of mitochondrial function. We used linear and logistic regression models to evaluate associations of these mtDNA haplotypes with estimated glomerular filtration rate by serum creatinine and cystatin C (eGFRCr-CysC, N = 362,802), prevalent (N = 416 cases) and incident (N = 405 cases) end-stage kidney disease (ESKD), AKI defined by diagnostic codes (N = 14,170 cases), and urine albumin/creatinine ratio (ACR, N = 114,662). The mean age was 57 ± 8 years and the mean eGFR was 90 ± 14 ml/min/1.73 m2. MtDNA haplotype was significantly associated with eGFR (p = 2.8E-12), but not with prevalent ESKD (p = 5.9E-2), incident ESKD (p = 0.93), AKI (p = 0.26), or urine ACR (p = 0.54). The association of mtDNA haplotype with eGFR remained significant after adjustment for diabetes mellitus and hypertension (p = 1.2E-10). When compared to the reference haplotype, mtDNA haplotypes I (ß = 0.402, standard error (SE) = 0.111; p = 2.7E-4), IV (ß = 0.430, SE = 0.073; p = 4.2E-9), and V (ß = 0.233, SE = 0.050; p = 2.7E-6) were each associated with higher eGFR. Among self-identified white UK Biobank participants, mtDNA haplotype was associated with eGFR, but not with ESKD, AKI or albuminuria.

A History of Umbilical Vein Catheterization Does Not Preclude Children from a Successful Meso-Rex Bypass.

INTRODUCTION: Umbilical vein catheterization (UVC) can cause portal venous thrombosis, leading to the development of extrahepatic portal venous obstruction (EHPVO) and portal hypertension (PHT). The feasibility of the Meso-Rex bypass (MRB) for the treatment of EHPVO in patients with a history of UVC has been questioned. We compared the feasibility of performing an MRB in patients with or without a history of previous UVC. METHODS: A retrospective review of patients with EHPVO and known UVC status explored for a possible MRB at our institution was performed (1997-2022). Patients were categorized in two groups: with (UVC(+)) or without (UVC(-)) a history of UVC for comparison. A p-value less than 0.05 was considered significant. RESULTS: One hundred and eighty-seven patients were included (n = 57 in UVC(+); n = 130 in UVC(-)). Patients in the UVC group were significantly younger at surgery and the incidence of prematurity was higher. Other risk factors for the development of EHPVO were similar between the groups, but only history of UVC could predict the ability to receive MRB (odds ratio [OR]: 7.4 [3.5-15.4]; p < 0.001). The success rate of MRB was significantly higher in patients with no history of UVC (28/57 [49.1%] in UVC(+) vs. 114/130 [87.7%] in UVC(-); p < 0.001). However, MRB patency at discharge (25/28 [89.3%] in UVC(+) vs. 106/114 [94.7%] in UVC(-); p = 0.3) was equally high in both groups. CONCLUSION: Our results indicate that a history of UVC is not a contraindication to MRB. Half of the patients were able to successfully receive an MRB. Patients with symptomatic PHT from EHPVO should not be excluded from consideration for MRB based on UVC history.

Complete genome sequences of cluster F1 and cluster B1 Mycobacterium smegmatis phages Karhdo and Basato.

We present the complete genome sequences of Mycobacterium smegmatis phages Karhdo and Basato, isolated in Clark County, Nevada. The phages were isolated and annotated by students enrolled in undergraduate research courses over two semesters at the University of Nevada, Las Vegas.

Evaluation of Dental Root Development Regarding Maxillary Canine Eruption Status after Secondary Alveolar Bone Grafting in Patients with Cleft Lip and Palate.

In children born with cleft lip and palate, the timing of the secondary alveolar bone graft (SABG) is crucial to its success; this involves estimating the eruption of the permanent maxillary canine. Altered dental eruption in this patient group gives impetus to the identification of dental developmental factors concerning maxillary canine eruption, which may steer the clinical decision of SABG timing. Records of over nine hundred patients who received SABG with pre- and post-operative cone beam computed tomography (CBCT) scans were analyzed for inclusion and divided into two groups (erupting or non-erupting canine after SABG). Roots of the maxillary canines and premolars were segmented from the cementoenamel junction then linear and volumetric measurements were performed. The pre- and post-operative root length and volume differences were calculated and compared statistically using independent sample tests and paired t-tests. No statistically significant differences were found in the volume change (%), or reciprocal of mean root length in the erupted and unerupted groups in the canine, first premolar, or second premolar roots except for an association between the post-operative dental root length of the canine and the maxillary canine eruption status. Therefore, assessment of root development from pre-treatment CBCT scans was not deemed worthy from a diagnostic perspective.

Hydrogel viscoelasticity modulates migration and fusion of mesenchymal stem cell spheroids.

Multicellular spheroids made of stem cells can act as building blocks that fuse to capture complex aspects of native in vivo environments, but the effect of hydrogel viscoelasticity on cell migration from spheroids and their fusion remains largely unknown. Here, we investigated the effect of viscoelasticity on migration and fusion behavior of mesenchymal stem cell (MSC) spheroids using hydrogels with a similar elasticity but different stress relaxation profiles. Fast relaxing (FR) matrices were found to be significantly more permissive to cell migration and consequent fusion of MSC spheroids. Mechanistically, inhibition of ROCK and Rac1 pathways prevented cell migration. Moreover, the combination of biophysical and biochemical cues provided by fast relaxing hydrogels and platelet-derived growth factor (PDGF) supplementation, respectively, resulted in a synergistic enhancement of migration and fusion. Overall, these findings emphasize the important role of matrix viscoelasticity in tissue engineering and regenerative medicine strategies based on spheroids.

Septicemia caused by an emerging pathogen, Elizabethkingia miricola, in a laboratory colony of African dwarf frogs (Hymenochirus curtipes).

An outbreak of morbidity and mortality in an African dwarf frog (Hymenochirus curtipes) colony was reported following arrival at an animal research facility. Animals were found dead on arrival or became moribund shortly thereafter, and additional animals showed clinical signs of lethargy, weight loss, and anorexia over the following 3 weeks. Externally, some affected animals presented with multifocal areas of hyperemia in the inguinal and axillary areas and on the limbs, and mottled tan discoloration along the ventral abdomen. Histologically, lesions were consistent with generalized septicemia, characterized by granulomatous meningitis, otitis media, peritonitis (coelomitis), myocarditis and pericarditis, nephritis, pneumonia, and arthritis. Gram staining identified gram-negative rod-shaped bacteria free within tissues and within macrophages. Culture results of coelomic swabs identified moderate to numerous Elizabethkingia miricola. Testing of water from tanks housing affected animals showed elevated levels of nitrites and ammonia, and the presence of Citrobacter, Aeromonas, Pseudomonas, and Staphylococcus spp. cultured from several tank biofilters. E miricola is a newly recognized and rapidly emerging opportunistic pathogen in anurans and has been reported as a cause of septicemia in humans. This report documents the first occurrence of E. miricola septicemia in African dwarf frogs and illustrates the importance of this potential pathogen in the laboratory setting for amphibian research colonies, as well as those individuals directly working with them.

Direct delivery of plasmin using clot-anchoring thrombin-responsive nanoparticles for targeted fibrinolytic therapy.

BACKGROUND: Fibrin-rich clot formation in thrombo-occlusive pathologies is currently treated by systemic administration of plasminogen activators (e.g. tPA), to convert fibrin-associated plasminogen to plasmin for fibrinolytic action. However, this conversion is not restricted to clot site only but also occurs on circulating plasminogen, causing systemic fibrinogenolysis and bleeding risks. To address this, past research has explored tPA delivery using clot-targeted nanoparticles. OBJECTIVES: We designed a nanomedicine system that can (1) target clots via binding to activated platelets and fibrin, (2) package plasmin instead of tPA as a direct fibrinolytic agent, and (3) release this plasmin triggered by thrombin for clot-localized action. METHODS: Clot-targeted thrombin-cleavable nanoparticles (CTNPs) were manufactured using self-assembly of peptide-lipid conjugates. Plasmin loading and its thrombin-triggered release from CTNPs were characterized by UV-visible spectroscopy. CTNP-targeting to clots under flow was studied using microfluidics. Fibrinolytic effect of CTNP-delivered plasmin was studied in vitro using BioFlux imaging and D-dimer analysis and in vivo in a zebrafish thrombosis model. RESULTS: Plasmin-loaded CTNPs significantly bound to clots under shear flow and showed thrombin-triggered enhanced release of plasmin. BioFlux studies confirmed that thrombin-triggered plasmin released from CTNPs rendered fibrinolysis similar to free plasmin, further corroborated by D-dimer analysis. In the zebrafish model, CTNP-delivered plasmin accelerated time-to-recanalization, or completely prevented occlusion when infused before thrombus formation. CONCLUSION: Considering that the very short circulation half-life (<1 second) of plasmin prevents its systemic use but also makes it safer without off-target drug effects, clot-targeted delivery of plasmin using CTNPs can enable safer and more efficacious fibrinolytic therapy.

Whole-exome sequencing in 415,422 individuals identifies rare variants associated with mitochondrial DNA copy number.

Inter-individual variation in the number of copies of the mitochondrial genome, called mitochondrial DNA copy number (mtDNA-CN), reflects mitochondrial function and has been associated with various aging-related diseases. We examined 415,422 exomes of self-reported White ancestry individuals from the UK Biobank and tested the impact of rare variants, at the level of single variants and through aggregate variant-set tests, on mtDNA-CN. A survey across nine variant sets tested enrichment of putatively causal variants and identified 14 genes at experiment-wide significance and three genes at marginal significance. These included associations at known mtDNA depletion syndrome genes (mtDNA helicase TWNK, p = 1.1 × 10-30; mitochondrial transcription factor TFAM, p = 4.3 × 10-15; mtDNA maintenance exonuclease MGME1, p = 2.0 × 10-6) and the V617F dominant gain-of-function mutation in the tyrosine kinase JAK2 (p = 2.7 × 10-17), associated with myeloproliferative disease. Novel genes included the ATP-dependent protease CLPX (p = 8.4 × 10-9), involved in mitochondrial proteome quality, and the mitochondrial adenylate kinase AK2 (p = 4.7 × 10-8), involved in hematopoiesis. The most significant association was a missense variant in SAMHD1 (p = 4.2 × 10-28), found on a rare, 1.2-Mb shared ancestral haplotype on chromosome 20. SAMHD1 encodes a cytoplasmic host restriction factor involved in viral defense response and the mitochondrial nucleotide salvage pathway, and is associated with Aicardi-Goutières syndrome 5, a childhood encephalopathy and chronic inflammatory response disorder. Rare variants were enriched in Mendelian mtDNA depletion syndrome loci, and these variants implicated core processes in mtDNA replication, nucleoid structure formation, and maintenance. These data indicate that strong-effect mutations from the nuclear genome contribute to the genetic architecture of mtDNA-CN.

Mitochondrial DNA copy number, metabolic syndrome, and insulin sensitivity: Insights from the Sugar, Hypertension, and Physical Exercise studies.

Mitochondrial DNA copy number (mtDNA-CN) measured in blood has been associated with many aging-related diseases, with higher mtDNA-CN typically associated with lower disease risk. Exercise training is an excellent preventative tool against aging-related disorders and has been shown to increase mitochondrial function in muscle. Using the Sugar, Hypertension, and Physical Exercise cohorts (N = 105), we evaluated the effect of 6-months of exercise intervention on mtDNA-CN measured in blood. Although there was no significant relationship between exercise intervention and mtDNA-CN change (P = 0.29), there was a nominally significant association between mtDNA-CN and metabolic syndrome (P = 0.04), which has been seen in previous literature. We also identified a nominally significant association between higher mtDNA-CN and higher insulin sensitivity (P = 0.02).

How Can High-Frequency Sensors Capture Collaboration? A Review of the Empirical Links between Multimodal Metrics and Collaborative Constructs.

This paper reviews 74 empirical publications that used high-frequency data collection tools to capture facets of small collaborative groups-i.e., papers that conduct Multimodal Collaboration Analytics (MMCA) research. We selected papers published from 2010 to 2020 and extracted their key contributions. For the scope of this paper, we focus on: (1) the sensor-based metrics computed from multimodal data sources (e.g., speech, gaze, face, body, physiological, log data); (2) outcome measures, or operationalizations of collaborative constructs (e.g., group performance, conditions for effective collaboration); (3) the connections found by researchers between sensor-based metrics and outcomes; and (4) how theory was used to inform these connections. An added contribution is an interactive online visualization where researchers can explore collaborative sensor-based metrics, collaborative constructs, and how the two are connected. Based on our review, we highlight gaps in the literature and discuss opportunities for the field of MMCA, concluding with future work for this project.

An integrated multi-omic analysis of iPSC-derived motor neurons from C9ORF72 ALS patients.

Neurodegenerative diseases are challenging for systems biology because of the lack of reliable animal models or patient samples at early disease stages. Induced pluripotent stem cells (iPSCs) could address these challenges. We investigated DNA, RNA, epigenetics, and proteins in iPSC-derived motor neurons from patients with ALS carrying hexanucleotide expansions in C9ORF72. Using integrative computational methods combining all omics datasets, we identified novel and known dysregulated pathways. We used a C9ORF72 Drosophila model to distinguish pathways contributing to disease phenotypes from compensatory ones and confirmed alterations in some pathways in postmortem spinal cord tissue of patients with ALS. A different differentiation protocol was used to derive a separate set of C9ORF72 and control motor neurons. Many individual -omics differed by protocol, but some core dysregulated pathways were consistent. This strategy of analyzing patient-specific neurons provides disease-related outcomes with small numbers of heterogeneous lines and reduces variation from single-omics to elucidate network-based signatures.

The US COVID Atlas: A dynamic cyberinfrastructure surveillance system for interactive exploration of the pandemic.

Distributed spatial infrastructures leveraging cloud computing technologies can tackle issues of disparate data sources and address the need for data-driven knowledge discovery and more sophisticated spatial analysis central to the COVID-19 pandemic. We implement a new, open source spatial middleware component (libgeoda) and system design to scale development quickly to effectively meet the need for surveilling county-level metrics in a rapidly changing pandemic landscape. We incorporate, wrangle, and analyze multiple data streams from volunteered and crowdsourced environments to leverage multiple data perspectives. We integrate explorative spatial data analysis (ESDA) and statistical hotspot standards to detect infectious disease clusters in real time, building on decades of research in GIScience and spatial statistics. We scale the computational infrastructure to provide equitable access to data and insights across the entire USA, demanding a basic but high-quality standard of ESDA techniques. Finally, we engage a research coalition and incorporate principles of user-centered design to ground the direction and design of Atlas application development.

Blood-derived mitochondrial DNA copy number is associated with gene expression across multiple tissues and is predictive for incident neurodegenerative disease.

Mitochondrial DNA copy number (mtDNA-CN) is a proxy for mitochondrial function and is associated with aging-related diseases. However, it is unclear how mtDNA-CN measured in blood can reflect diseases that primarily manifest in other tissues. Using the Genotype-Tissue Expression Project, we interrogated relationships between mtDNA-CN measured in whole blood and gene expression from whole blood and 47 additional tissues in 419 individuals. mtDNA-CN was significantly associated with expression of 700 genes in whole blood, including nuclear genes required for mtDNA replication. Significant enrichment was observed for splicing and ubiquitin-mediated proteolysis pathways, as well as target genes for the mitochondrial transcription factor NRF1. In nonblood tissues, there were more significantly associated genes than expected in 30 tissues, suggesting that global gene expression in those tissues is correlated with blood-derived mtDNA-CN. Neurodegenerative disease pathways were significantly associated in multiple tissues, and in an independent data set, the UK Biobank, we observed that higher mtDNA-CN was significantly associated with lower rates of both prevalent (OR = 0.89, CI = 0.83; 0.96) and incident neurodegenerative disease (HR = 0.95, 95% CI = 0.91;0.98). The observation that mtDNA-CN measured in blood is associated with gene expression in other tissues suggests that blood-derived mtDNA-CN can reflect metabolic health across multiple tissues. Identification of key pathways including splicing, RNA binding, and catalysis reinforces the importance of mitochondria in maintaining cellular homeostasis. Finally, validation of the role of mtDNA CN in neurodegenerative disease in a large independent cohort study solidifies the link between blood-derived mtDNA-CN, altered gene expression in multiple tissues, and aging-related disease.

Student Enrollment and Teacher Statistics Forecasting Based on Time-Series Analysis.

Education competitiveness is a key feature of national competitiveness. It is crucial for nations to develop and enhance student and teacher potential to increase national competitiveness. The decreasing population of children has caused a series of social problems in many developed countries, directly affecting education and com.petitiveness in an international environment. In Taiwan, a low birthrate has had a large impact on schools at every level because of a substantial decrease in enrollment and a surplus of teachers. Therefore, close attention must be paid to these trends. In this study, combining a whale optimization algorithm (WOA) and support vector regression (WOASVR) was proposed to determine trends of student and teacher numbers in Taiwan for higher accuracy in time-series forecasting analysis. To select the most suitable support vector kernel parameters, WOA was applied. Data collected from the Ministry of Education datasets of student and teacher numbers between 1991 and 2018 were used to examine the proposed method. Analysis revealed that the numbers of students and teachers decreased annually except in private primary schools. A comparison of the forecasting results obtained from WOASVR and other common models indicated that WOASVR provided the lowest mean absolute percentage error (MAPE) and root mean square error (RMSE) for all analyzed datasets. Forecasting performed using the WOASVR method can provide accurate data for use in developing education policies and responses.