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Background: Early identification of patients colonized with MDROs can help healthcare facilities improve infection control and treatment. We evaluated whether a model previously validated to predict carbapenem-resistant Enterobacterales (CRE) carriage on hospital admission (area under the curve [AUC]=0.86, Lin et al. OFID 2019) would generalize to predict a patient’s likelihood of CRE and non-CRE MDRO colonization at the time of medical intensive care unit (MICU) admission. Methods: We analyzed data collected previously in a retrospective observational cohort study of patients admitted to Rush University Medical Center’s MICU from 1/2017-1/2018 and screened within the first two days for rectal MDRO colonization. Organisms of interest included CRE, carbapenem-resistant Pseudomonas aeruginosa (CRPA), vancomycin-resistant enterococci (VRE), and third-generation cephalosporin-resistant Enterobacterales (3GCR-E). Methicillin-resistant Staphylococcus aureus (MRSA) nasal colonization at admission was determined by routine clinical screening. Each patient’s first MICU admission during the study period was linked to Illinois’ hospital discharge database and assigned a CRE colonization risk probability using the existing model. Model covariates were age, and during the prior 365 days, number of short-term acute care hospitalizations (STACH) and mean STACH length of stay, number of long-term acute care hospitalizations (LTACH) and mean LTACH length of stay, prior hospital admission with an ICD-10 diagnosis code indicating bacterial infection, and current admission to LTACH. Predictive value of the model was evaluated by receiver operating characteristic (ROC) curves. Results: We analyzed 1237 MICU admissions. MDRO admission prevalence is shown in the Table. The model performed well to predict carriage of healthcare-associated MDROs, including CRE, CRPA, composite CR-MDROs (CRE & CRPA), and VRE. However, the model performed poorly for MDROs with known community reservoirs, including 3GCR-E and MRSA (Table). In general, MDRO admission prevalence increased in parallel with predicted CRE colonization risk (Figure). The number needed to screen (NNS) to detect one healthcare-associated MDRO carrier was inversely related to the CRE colonization risk score. For example, NNS in the total cohort compared to those with CRE risk score of >0.5% was: CRE 111 vs 32 patients, CRPA 333 vs 42 patients, composite CR-MDRO 83 vs 18 patients, and VRE 12 vs 4 patients. However, higher CRE risk score cutoff was inversely related to screening sensitivity. Conclusion: A prediction model using prior healthcare exposure information successfully discriminated patients likely to harbor healthcare-associated MDROs upon MICU admission. Prediction scores generated by a public-health accessible database could be used to target screening/isolation or enact protective measures for high-risk patients.

Purpose: The purpose of this study is to identify clinical and imaging characteristics associated with post-COVID pulmonary function decline. Methods: This study included 22 patients recovering from COVID-19 who underwent serial spirometry pulmonary function testing (PFT) before and after diagnosis. Patients were divided into two cohorts by difference between baseline and post-COVID follow-up PFT: Decline group (>10 % decrease in FEV1), and Stable group (≤10 % decrease or improvement in FEV1). Demographic, clinical, and laboratory data were collected, as well as PFT and chest computed tomography (CT) at the time of COVID diagnosis and follow-up. CTs were semi-quantitatively scored on a five-point severity scale for disease extent in each lobe by two radiologists. Mann-Whitney U-tests, T-tests, and Chi-Squared tests were used for comparison. P-values

Objectives To evaluate if vaginal metronidazole for 5 days before hysterectomy decreases postoperative infections and patient issues.Design This randomized trial compared vaginal metronidazole for 5 days before a scheduled hysterectomy to no intervention. Sample size calculation was based on a 20% difference in issues and infection (30% incidence and 10% in the intervention arm) with 80% power and an alpha error of 0.05 and indicated 62 subjects needed in each arm.Setting Outpatient gynecology clinics at a single academic institution.Participants 154 subjects were screened for eligibility between July 2020 and September 2022. 133 underwent hysterectomy including 68 subjects (51.1%) randomized to the metronidazole and 65 (48.9%) controls. Overall, the population was racially and ethnically diverse. There was no significant difference in characteristics between the two groups.Interventions Vaginal metronidazole for 5 days before hysterectomy.Main outcome measures Postoperative patient issues and documented postoperative infections at 4–8 weeks after surgery.Results There was no difference in the composite rate of patient-reported issues and/or documented postoperative infection (53/133 (39.8%) with no difference between groups (29/68 (42.6%) vs 24/65 (36.9%), p=0.50). There was no difference in patient-reported issues which was 51/133 (38.3%) with no difference between groups (28/68 (41.2%) vs 23/65 (33.8%), p=0.49) or in documented infections with a rate of 25/133 (18.8%) with no significant difference between groups (15/68 (22.0%) vs 10/65 (15.4%), p=0.33). In the intervention arm, the compliance rate was 73.5% for all 5 days of vaginal metronidazole, and a per-protocol analysis was performed which resulted in no significant difference between groups.Conclusions There is insufficient evidence to suggest a significant benefit of preoperative vaginal metronidazole to prevent surgical site infections and postoperative patient issues in patients undergoing hysterectomy.Trial registration number ClinicalTrials.gov, NCT04478617.

Invention education is an emerging field that shows promise for fostering equitable student engagement, especially related to disciplines of science, technology, engineering, arts, and mathematics (STEAM), in both classroom and informal learning. A central concept for practitioners, researchers, and evaluators, student engagement connects with academic, socioemotional, career, and civic success. Nonetheless, more work is needed to ensure more equitable approaches to educational design for student engagement, especially with youth of one or more minoritized identity markers (e.g., Black, Brown, or Indigenous youth; female or non-binary youth; youth from lower socioeconomic statuses; etc.). This Curriculum, Instruction, and Pedagogy article describes six iterations of educational designs for invention education with grades 6–8 classes and camps. Three of the iterations revised the same curriculum for grade 7 classes (N ~ 160 students/year), and the other three iterations involved similar yet distinct curricula for grades 6–8 camps (N ~ 25 students/year). Taking a cultural psychology approach to design-based research, we conducted a phenomenological mixed-methods study for convergence. That is, we iteratively refined educational designs within given microcultures, and we sought to better understand participants’ lived experiences. We share evidence of high affective, behavioral, and cognitive engagement, within and between both individual and social levels, alongside development of self-efficacy with respect to ability beliefs and anxiety management. With a few exceptions, our findings suggest equitable participation of youth. These findings we connect with educational design considerations, including individual vs. social supports, explicit attention to youths’ hobbies and peer-inventors, and formative assessment that broadens response scales and gradations of challenge. Our work supports a more nuanced and socially-situated six-dimensional framework for student engagement, expanding upon commonly-used three-and four-dimensional models. We conclude with local and transferrable implications, towards the main goal of fostering equitable student engagement in science and engineering through invention education.

Purpose: A radiation anatomist was trained and integrated into clinical practice at a multi-site academic center. The primary objective of this quality improvement study was to determine whether a radiation anatomist improves the quality of organ-at-risk (OAR) contours, and secondarily to determine the impact on efficiency in the treatment planning process. Methods and Materials: From March to August 2020, all patients undergoing computed tomography–based radiation planning at 2 clinics at Memorial Sloan Kettering Cancer Center were assigned using an “every other” process to either (1) OAR contouring by a radiation anatomist (intervention) or (2) contouring by the treating physician (standard of care). Blinded dosimetrists reported OAR contour quality using a 3-point scoring system based on a common clinical trial protocol deviation scale (1, acceptable; 2, minor deviation; and 3, major deviation). Physicians reported time spent contouring for all cases. Analyses included the Fisher exact test and multivariable ordinal logistic regression. Results: There were 249 cases with data available for the primary endpoint (66% response rate). The mean OAR quality rating was 1.1 ± 0.4 for the intervention group and 1.4 ± 0.7 for the standard of care group (P < .001), with subset analysis showing a significant difference for gastrointestinal cases (n = 49; P

Removal of hydrocarbons from sediments could be achieved using various techniques such as hydraulic flushing aided by surfactants, which works well for sand and gravel but not as effective for finer textured media, such as clay. Electrokinetics (EK) emerged as an effective method to remediate fine-grained soils, especially when combined with the application of surfactants. Here, we analyzed the removal efficiency of EK and a nonionic surfactant (Tween 80) when applied through a fine soil (80% clay) contaminated with n-hexadecane. The study compared the EK results with hydraulic flushing under the same surfactant concentration. After 18 days of treatment, EK removed 80%, which was significantly more efficient than hydraulic flushing which removed 52%. The investigation revealed that EK causes the surfactant to tackle the clayey soil from various directions due to the whole aquifer's electrification. This would be an advantage in field studies as it precludes the need to place numerous electrodes into the soil, as done in hydraulic flushing where multiple wells are placed to direct the surfactant's movement.

Summary: Dravet syndrome (DS) is a severe developmental and epileptic encephalopathy with a high incidence of sudden unexpected death in epilepsy (SUDEP). Most DS patients carry de novo variants in SCN1A, resulting in Nav1.1 haploinsufficiency. Because SCN1A is expressed in heart and in brain, we proposed that cardiac arrhythmia contributes to SUDEP in DS. We generated DS patient and control induced pluripotent stem cell-derived cardiac myocytes (iPSC-CMs). We observed increased sodium current (INa) and spontaneous contraction rates in DS patient iPSC-CMs versus controls. For the subject with the largest increase in INa, cardiac abnormalities were revealed upon clinical evaluation. Generation of a CRISPR gene-edited heterozygous SCN1A deletion in control iPSCs increased INa density in iPSC-CMs similar to that seen in patient cells. Thus, the high risk of SUDEP in DS may result from a predisposition to cardiac arrhythmias in addition to seizures, reflecting expression of SCN1A in heart and brain. : In this article, Isom, Parent, and colleagues show that the high risk of SUDEP in the developmental and epileptic encephalopathy, Dravet syndrome, may result from a predisposition to cardiac arrhythmias in addition to neuronal hyperexcitability, reflecting haploinsufficiency of SCN1A in heart and brain causing potential compensatory overexpression of other sodium-channel genes in those tissues. Keywords: epilepsy, cardiac arrhythmia, sodium channel, SUDEP, induced pluripotent stem cell (iPSC), developmental and epileptic encephalopathy

OBJECTIVES/GOALS: Sudden Unexpected Death in Epilepsy (SUDEP) is a leading cause of death in epilepsy patients. This study aims to determine whether cardiac mechanisms contribute to SUDEP in epilepsy patients with variants in DEPDC5, a gene encoding a member of the mTOR GATOR complex, to identify SUDEP biomarkers. METHODS/STUDY POPULATION: SUDEP has been reported in 10% of epilepsy patients with DEPDC5 loss-of-function variants. We used human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) to measure changes in cellular excitability that are known to be substrates for cardiac arrhythmias. CRISPR-derived isogenic DEPDC5 iPSC-CMs and DEPDC5 patient-derived iPSC-CMs were used in this study. Whole-cell patch-clamp was used to measure voltage-gated sodium current (INa) and calcium current (I>Ca) in single iPSC-CMs in voltage-clamp mode; and to measure action potentials (APs) in 3-dimentional iPSC-CM-derived micro-tissues in current-clamp mode. RESULTS/ANTICIPATED RESULTS: CRISPR generated heterozygous deletion of 1 base-pair in the first coding exon of DEPDC5 gene, resulting in a premature stop codon, simulated the variants identified in DEPDC5 epilepsy patients. In CRISPR generated heterozygousDEPDC5 iPSC-CMs, whole-cell voltage-clamp recordings revealed that INa was increased and ICa was reduced compared with isogenic control iPSC-CMs. Whole-cell current-clamp recordings revealed that AP duration at 80% and 90% of repolarization, APD80 and APD90, respectively, were prolonged compared to isogenic control iPSC-CMs. Similar measurements will be performed for iPSC-CMs derived from DEPDC5 patients. DISCUSSION/SIGNIFICANCE OF IMPACT: This study shows that epilepsy patients with non-ion channel gene variants in DEPDC5 have altered CM excitability, which may serve as a substrate for cardiac arrhythmias in DEPDC5 patients. Importantly, this work may allow us to identify biomarkers for SUDEP risk in these patients in the future. CONFLICT OF INTEREST DESCRIPTION: L.L.I. is the recipient of a collaborative research grant from Stoke Therapeutics.

MicroRNA cluster mirn23a has previously been shown to promote myeloid development at the expense of lymphoid development in overexpression and knockout mouse models. This polarization is observed early in hematopoietic development, with an increase in common lymphoid progenitors (CLPs) and a decrease in all myeloid progenitor subsets in adult bone marrow. The pool size of multipotential progenitors (MPPs) is unchanged; however, in this report we observe by flow cytometry that polarized subsets of MPPs are changed in the absence of mirn23a. Additionally, in vitro culture of MPPs and sorted MPP transplants showed that these cells have decreased myeloid and increased lymphoid potential in vitro and in vivo. We investigated the mechanism by which mirn23a regulates hematopoietic differentiation and observed that mirn23a promotes myeloid development of hematopoietic progenitors through regulation of hematopoietic transcription factors and signaling pathways. Early transcription factors that direct the commitment of MPPs to CLPs (Ikzf1, Runx1, Satb1, Bach1 and Bach2) are increased in the absence of mirn23a miRNAs as well as factors that commit the CLP to the B cell lineage (FoxO1, Ebf1, and Pax5). Mirn23a appears to buffer transcription factor levels so that they do not stochastically reach a threshold level to direct differentiation. Intriguingly, mirn23a also inversely regulates the PI3 kinase (PI3K)/Akt and BMP/Smad signaling pathways. Pharmacological inhibitor studies, coupled with dominant active/dominant negative biochemical experiments, show that both signaling pathways are critical to mirn23a's regulation of hematopoietic differentiation. Lastly, consistent with mirn23a being a physiological inhibitor of B cell development, we observed that the essential B cell transcription factor EBF1 represses expression of mirn23a. In summary, our data demonstrates that mirn23a regulates a complex array of transcription and signaling pathways to modulate adult hematopoiesis.

Background5'-deoxy-5'-methylthioadenosine (MTA) is an endogenous compound produced through the metabolism of polyamines. The therapeutic potential of MTA has been assayed mainly in liver diseases and, more recently, in animal models of multiple sclerosis. The aim of this study was to determine the neuroprotective effect of this molecule in vitro and to assess whether MTA can cross the blood brain barrier (BBB) in order to also analyze its potential neuroprotective efficacy in vivo.MethodsNeuroprotection was assessed in vitro using models of excitotoxicity in primary neurons, mixed astrocyte-neuron and primary oligodendrocyte cultures. The capacity of MTA to cross the BBB was measured in an artificial membrane assay and using an in vitro cell model. Finally, in vivo tests were performed in models of hypoxic brain damage, Parkinson's disease and epilepsy.ResultsMTA displays a wide array of neuroprotective activities against different insults in vitro. While the data from the two complementary approaches adopted indicate that MTA is likely to cross the BBB, the in vivo data showed that MTA may provide therapeutic benefits in specific circumstances. Whereas MTA reduced the neuronal cell death in pilocarpine-induced status epilepticus and the size of the lesion in global but not focal ischemic brain damage, it was ineffective in preserving dopaminergic neurons of the substantia nigra in the 1-methyl-4-phenyl-1,2,3,6-tetrahydro-pyridine (MPTP)-mice model. However, in this model of Parkinson's disease the combined administration of MTA and an A2A adenosine receptor antagonist did produce significant neuroprotection in this brain region.ConclusionMTA may potentially offer therapeutic neuroprotection.

We examine the impact of transparency on the convenience yield of AAA-rated asset-backed security (ABS) tranches. AAA tranches of ABS are commonly held by investors to manage financial liquidity and therefore enjoy a price premium beyond what is determined solely by the expected monetary payoff (i.e., convenience yield). The Securities and Exchange Commission (SEC) requires ABS issuers to provide monthly disclosures about the performance of the underlying individual loans for ABS issued after November 23, 2016 to improve transparency. We document that AAA tranches of ABS experience a significant increase in price volatility after the loan-level disclosure mandate. As a result, the use of these tranches as collateral for short-term funding and their convenience yield decrease significantly after the increased disclosure. Our collective evidence highlights an important unintended consequence of increased transparency in the ABS market; it diminishes the pledgeability of long-term safe assets. [ABSTRACT FROM AUTHOR]

BACKGROUND: This study aimed to review bicycle-related injuries during the COVID-19 pandemic to assist with reinforcement or implementation of new policies for injury prevention. METHODS: This is a retrospective descriptive analysis of injuries sustained during cycling for patients 18 years old and above who presented to Singapore General Hospital from January to June 2021. Medical records were reviewed and consolidated. Descriptive analyses were used to summarize patient characteristics, and differences in characteristics sub grouped by triage acuity and discharge status were analyzed. RESULTS: The study included 272 patients with a mean age of 43 years and a male predominance (71.7%). Most presented without referrals (88.2%) and were not conveyed by ambulances (70.6%). Based on acuity category, there were 24 (8.8%) Priority 1 (P1) patients with 7 trauma activations, 174 (64.0%) and 74 (27.2%) P2 and P3 patients respectively. The most common injuries were fractures (34.2%), followed by superficial abrasion/contusion (29.4%) and laceration/wound (19.1%). Thirteen (4.8%) patients experienced head injury and 85 patients (31.3%) were documented to be wearing a helmet. The majority occurred on the roads as traffic accidents (32.7%). Forty-two patients (15.4%) were admitted with a mean length of stay of 4.1 d and 17 (6.3%) undergone surgical procedures. Out of 214 (78.7%) discharged patients, no re-attendances or mortality were observed. In the subgroup analysis, higher acuity patients were generally older, with higher proportions of head injuries leading to admission. CONCLUSION: Our study highlights significant morbidities in bicycle-related injuries. There is also a high proportion of fractures in the young healthy male population. Injury prevention is paramount and we propose emphasizing helmet use and road user safety. [ABSTRACT FROM AUTHOR]

Multiclass probability estimation is the problem of estimating conditional probabilities of a data point belonging to a class given its covariate information. It has broad applications in statistical analysis and data science. Recently a class of weighted Support Vector Machines (wSVMs) has been developed to estimate class probabilities through ensemble learning for K-class problems (Wu et al., 2010; Wang et al., 2019), where K is the number of classes. The estimators are robust and achieve high accuracy for probability estimation, but their learning is implemented through pairwise coupling, which demands polynomial time in K. In this paper, we propose two new learning schemes, the baseline learning and the One-vs-All (OVA) learning, to further improve wSVMs in terms of computational efficiency and estimation accuracy. In particular, the baseline learning has optimal computational complexity in the sense that it is linear in K. Though not the most efficient in computation, the OVA is found to have the best estimation accuracy among all the procedures under comparison. The resulting estimators are distribution-free and shown to be consistent. We further conduct extensive numerical experiments to demonstrate their finite sample performance. [ABSTRACT FROM AUTHOR]

A study proposes the multiclass proximal support vector machine (MPSVM) classifier, which extends the binary PSVM to the multiclass case. The effectiveness of MPSVM is demonstrated by both simulation studies and applications to cancer classifications using microarray data.

If the student does not feel the hot and cold difference between the two sides after two seconds, the teacher should ask the student to first disconnect the Peltier tile from the batteries and then check if there is any incorrect connection in the circuitry. To prevent students from taking the criticism personally, the teacher can ask students to present their classmates' work. The teacher needs to be cautious as it may get too hot for students to hold and should explicitly instruct students not to continuously hold the tile for more than five seconds while it is connected to the batteries. The teacher can ask students to think about how to improve the cell phone or iPad stands they have seen before and help students realize that small improvements can be inventions, too. [Extracted from the article]

Following two O121 Shiga toxin–producing Escherichia coli (STEC) outbreaks linked to wheat flour, this study was conducted to gain baseline information on the occurrence of bacterial pathogens and levels of indicator organisms in wheat flour in Canada. A total of 347 prepackaged wheat flour samples were analyzed for Salmonella species, STEC, Listeria monocytogenes, aerobic colony count (ACC), total coliforms, and Escherichia coli. Salmonella spp. and O157 STEC were not detected in any of the samples. L. monocytogenes was identified in two samples (0.6%) at levels below the limit of detection (,0.7 log CFU/g). Non-O157 STEC were isolated from six samples (1.7%) and were characterized for the presence of STEC virulence genes: stx1, stx2, and their subtypes, eae, hlyA, and aggR. One O103:H25 STEC isolate carried virulence genes (stx1a+eae) that are known to be capable of causing diarrhea and/or bloody diarrhea in humans. Of the five remaining non-O157 STEC isolates, four carried single stx2a or stx2c genes and were considered to have the potential of causing diarrhea. The remaining non-O157 STEC isolate (stx2), while not a priority non-O157 STEC, was not available for sequencing; thus, its potential to cause illness is unknown. ACC, total coliforms, and E. coli were detected (0.48 log CFU/g) in 98.8, 72.6, and 0.6% of the flour samples. The mean counts of ACC were greater in whole wheat flour compared with the other flour types tested (P , 0.001). The results of this study suggest that the occurrence of O157 STEC and Salmonella is low but that the occurrence of non-O157 STEC in wheat flour with the potential to cause human illness of diarrhea is relatively common. Therefore, the consumption of raw flour could increase the likelihood of STEC infections. Further research is merited for potential risk mitigation strategies within the food production system and with consumers. [ABSTRACT FROM AUTHOR]

The reactivation of quiescent cells to proliferate is fundamental to tissue repair and homeostasis in the body. Often referred to as the G0 state, quiescence is, however, not a uniform state but with graded depth. Shallow quiescent cells exhibit a higher tendency to revert to proliferation than deep quiescent cells, while deep quiescent cells are still fully reversible under physiological conditions, distinct from senescent cells. Cellular mechanisms underlying the control of quiescence depth and the connection between quiescence and senescence are poorly characterized, representing a missing link in our understanding of tissue homeostasis and regeneration. Here we measured transcriptome changes as rat embryonic fibroblasts moved from shallow to deep quiescence over time in the absence of growth signals. We found that lysosomal gene expression was significantly up-regulated in deep quiescence, and partially compensated for gradually reduced autophagy flux. Reducing lysosomal function drove cells progressively deeper into quiescence and eventually into a senescence-like irreversibly arrested state; increasing lysosomal function, by lowering oxidative stress, progressively pushed cells into shallower quiescence. That is, lysosomal function modulates graded quiescence depth between proliferation and senescence as a dimmer switch. Finally,we found that a gene-expression signature developed by comparing deep and shallow quiescence in fibroblasts can correctly classify a wide array of senescent and aging cell types in vitro and in vivo, suggesting that while quiescence is generally considered to protect cells from irreversible arrest of senescence, quiescence deepening likely represents a common transition path from cell proliferation to senescence, related to aging. [ABSTRACT FROM AUTHOR]

Dysregulated adult hippocampal neurogenesis occurs in many temporal lobe epilepsy (TLE) models. Most dentate granule cells (DGCs) generated in response to an epileptic insult develop features that promote increased excitability, including ectopic location, persistent hilar basal dendrites (HBDs), and mossy fiber sprouting. However, some appear to integrate normally and even exhibit reduced excitability compared to other DGCs. To examine the relationship between DGC birthdate, morphology, and network integration in a model of TLE, we retrovirally birthdated either early-born [EB; postnatal day (P)7] or adult-born (AB; P60) DGCs. Male rats underwent pilocarpine-induced status epilepticus (SE) or sham treatment at P56. Three to six months after SE or sham treatment, we used whole-cell patch-clamp and fluorescence microscopy to record spontaneous excitatory and inhibitory currents from birthdated DGCs. We found that both AB and EB populations of DGCs recorded from epileptic rats received increased excitatory input compared with age-matched controls. Interestingly, when AB populations were separated into normally integrated (normotopic) and aberrant (ectopic or HBDcontaining) subpopulations, only the aberrant populations exhibited a relative increase in excitatory input (amplitude, frequency, and charge transfer). The ratio of excitatory-to-inhibitory input was most dramatically upregulated for ectopically localized DGCs. These data provide definitive physiological evidence that aberrant integration of post-SE, AB DGCs contributes to increased synaptic drive and support the idea that ectopic DGCs serve as putative hub cells to promote seizures. [ABSTRACT FROM AUTHOR]

Reactivating quiescent cells to proliferate is critical to tissue repair and homoeostasis. Quiescence exit is highly noisy even for genetically identical cells under the same environmental conditions. Deregulation of quiescence exit is associated with many diseases, but cellular mechanisms underlying the noisy process of exiting quiescence are poorly understood. Here we show that the heterogeneity of quiescence exit reflects a memory of preceding cell growth at quiescence induction and immediate division history before quiescence entry, and that such a memory is reflected in cell size at a coarse scale. The deterministic memory effects of preceding cell cycle, coupled with the stochastic dynamics of an Rb-E2F bistable switch, jointly and quantitatively explain quiescence-exit heterogeneity. As such, quiescence can be defined as a distinct state outside of the cell cycle while displaying a sequential cell order reflecting preceding cell growth and division variations. [ABSTRACT FROM AUTHOR]

Background: Transcriptome analytic tools are commonly used across patient cohorts to develop drugs and predict clinical outcomes. However, as precision medicine pursues more accurate and individualized treatment decisions, these methods are not designed to address single-patient transcriptome analyses. We previously developed and validated the N-of-1-pathways framework using two methods, Wilcoxon and Mahalanobis Distance (MD), for personal transcriptome analysis derived from a pair of samples of a single patient. Although, both methods uncover concordantly dysregulated pathways, they are not designed to detect dysregulated pathways with up- and downregulated genes (bidirectional dysregulation) that are ubiquitous in biological systems. Results: We developed N-of-1-pathways MixEnrich, a mixture model followed by a gene set enrichment test, to uncover bidirectional and concordantly dysregulated pathways one patient at a time. We assess its accuracy in a comprehensive simulation study and in a RNA-Seq data analysis of head and neck squamous cell carcinomas (HNSCCs). In presence of bidirectionally dysregulated genes in the pathway or in presence of high background noise, MixEnrich substantially outperforms previous single-subject transcriptome analysis methods, both in the simulation study and the HNSCCs data analysis (ROC Curves; higher true positive rates; lower false positive rates). Bidirectional and concordant dysregulated pathways uncovered by MixEnrich in each patient largely overlapped with the quasi-gold standard compared to other single-subject and cohort-based transcriptome analyses. Conclusion: The greater performance of MixEnrich presents an advantage over previous methods to meet the promise of providing accurate personal transcriptome analysis to support precision medicine at point of care. [ABSTRACT FROM AUTHOR]

Sufficient dimension reduction is popular for reducing data dimensionality without stringent model assumptions. However, most existing methods may work poorly for binary classification. For example, sliced inverse regression (Li, 1991) can estimate at most one direction if the response is binary. In this paper we propose principal weighted support vector machines, a unified framework for linear and nonlinear sufficient dimension reduction in binary classification. Its asymptotic properties are studied, and an efficient computing algorithm is proposed. Numerical examples demonstrate its performance in binary classification. [ABSTRACT FROM AUTHOR]

Motivation: Understanding dynamic, patient-level transcriptomic response to therapy is an important step forward for precision medicine. However, conventional transcriptome analysis aims to discover cohort-level change, lacking the capacity to unveil patient-specific response to therapy. To address this gap, we previously developed two N-of-1-pathways methods, Wilcoxon and Mahalanobis distance, to detect unidirectionally responsive transcripts within a pathway using a pair of samples from a single subject. Yet, these methods cannot recognize bidirectionally (up and down) responsive pathways. Further, our previous approaches have not been assessed in presence of background noise and are not designed to identify differentially expressed mRNAs between two samples of a patient taken in different contexts (e.g. cancer vs non cancer), which we termed responsive transcripts (RTs).Methods: We propose a new N-of-1-pathways method, k-Means Enrichment (kMEn), that detects bidirectionally responsive pathways, despite background noise, using a pair of transcriptomes from a single patient. kMEn identifies transcripts responsive to the stimulus through k-means clustering and then tests for an over-representation of the responsive genes within each pathway. The pathways identified by kMEn are mechanistically interpretable pathways significantly responding to a stimulus.Results: In ∼9000 simulations varying six parameters, superior performance of kMEn over previous single-subject methods is evident by: (i) improved precision-recall at various levels of bidirectional response and (ii) lower rates of false positives (1-specificity) when more than 10% of genes in the genome are differentially expressed (background noise). In a clinical proof-of-concept, personal treatment-specific pathways identified by kMEn correlate with therapeutic response (p-value<0.01).Conclusion: Through improved single-subject transcriptome dynamics of bidirectionally-regulated signals, kMEn provides a novel approach to identify mechanism-level biomarkers. [ABSTRACT FROM AUTHOR]

Meta-analysis plays an important role in summarizing and synthesizing scientific evidence derived from multiple studies. With high-dimensional data, the incorporation of variable selection into meta-analysis improves model interpretation and prediction. Existing variable selection methods require direct access to raw data, which may not be available in practical situations. We propose a new approach, sparse meta-analysis (SMA), in which variable selection for meta-analysis is based solely on summary statistics and the effect sizes of each covariate are allowed to vary among studies. We show that the SMA enjoys the oracle property if the estimated covariance matrix of the parameter estimators from each study is available. We also show that our approach achieves selection consistency and estimation consistency even when summary statistics include only the variance estimators or no variance/covariance information at all. Simulation studies and applications to high-throughput genomics studies demonstrate the usefulness of our approach. [ABSTRACT FROM AUTHOR]

Adult hippocampal neurogenesis is thought to be essential for learning and memory, and has been implicated in the pathogenesis of several disorders. Although recent studies have identified key factors regulating neuroprogenitor proliferation in the adult hippocampus, the mechanisms that control the migration and integration of adult-born neurons into circuits are largely unknown. Reelin is an extracellular matrix protein that is vital for neuronal development. Activation of the Reelin cascade leads to phosphorylation of Disabled-1, an adaptor protein required for Reelin signaling. Here we used transgenic mouse and retroviral reporters along with Reelin signaling gain-of-function and loss-of-function studies to show that the Reelin pathway regulates migration and dendritic development of adult-generated hippocampal neurons. Whereas overexpression of Reelin accelerated dendritic maturation, inactivation of the Reelin signaling pathway specifically in adult neuroprogenitor cells resulted in aberrant migration, decreased dendrite development, formation of ectopic dendrites in the hilus, and the establishment of aberrant circuits. Our findings support a cell-autonomous and critical role for the Reelin pathway in regulating dendritic development and the integration of adult-generated granule cells and point to this pathway as a key regulator of adult neurogenesis. Moreover, our data reveal a novel role of the Reelin cascade in adult brain function with potential implications for the pathogenesis of several neurological and psychiatric disorders. [ABSTRACT FROM AUTHOR]

We propose a double-penalized likelihood approach for simultaneous model selection and estimation in semiparametric mixed models for longitudinal data. Two types of penalties are jointly imposed on the ordinary log-likelihood: the roughness penalty on the nonparametric baseline function and a nonconcave shrinkage penalty on linear coefficients to achieve model sparsity. Compared to existing estimation equation based approaches, our procedure provides valid inference for data with missing at random, and will be more efficient if the specified model is correct. Another advantage of the new procedure is its easy computation for both regression components and variance parameters. We show that the double-penalized problem can be conveniently reformulated into a linear mixed model framework, so that existing software can be directly used to implement our method. For the purpose of model inference, we derive both frequentist and Bayesian variance estimation for estimated parametric and nonparametric components. Simulation is used to evaluate and compare the performance of our method to the existing ones. We then apply the new method to a real data set from a lactation study. [ABSTRACT FROM AUTHOR]

We propose a novel model selection method for a nonparametric extension of the Cox proportional hazard model, in the framework of smoothing splines ANOVA models. The method automates the model building and model selection processes simultaneously by penalizing the reproducing kernel Hilbert space norms. On the basis of a reformulation of the penalized partial likelihood, we propose an efficient algorithm to compute the estimate. The solution demonstrates great flexibility and easy interpretability in modeling relative risk functions for censored data. Adaptive choice of the smoothing parameter is discussed. Both simulations and a real example suggest that our proposal is a useful tool for multivariate function estimation and model selection in survival analysis. [ABSTRACT FROM AUTHOR]

Abstract We leverage machine learning approaches to adapt nanopore sequencing basecallers for nucleotide modification detection. We first apply the incremental learning (IL) technique to improve the basecalling of modification-rich sequences, which are usually of high biological interest. With sequence backbones resolved, we further run anomaly detection (AD) on individual nucleotides to determine their modification status. By this means, our pipeline promises the single-molecule, single-nucleotide, and sequence context-free detection of modifications. We benchmark the pipeline using control oligos, further apply it in the basecalling of densely-modified yeast tRNAs and E.coli genomic DNAs, the cross-species detection of N6-methyladenosine (m6A) in mammalian mRNAs, and the simultaneous detection of N1-methyladenosine (m1A) and m6A in human mRNAs. Our IL-AD workflow is available at: https://github.com/wangziyuan66/IL-AD .

The secreted phospholipase A 2 (sPLA 2 ) isoform, sPLA 2 -IIA, has been implicated in a variety of diseases and conditions, including bacteremia, cardiovascular disease, COVID-19, sepsis, adult respiratory distress syndrome, and certain cancers. Given its significant role in these conditions, understanding the regulatory mechanisms impacting its levels is crucial. Genome-wide association studies (GWAS) have identified several single nucleotide polymorphisms (SNPs), including rs11573156, that are associated with circulating levels of sPLA 2 -IIA. The work in the manuscript leveraged 4 publicly available datasets to investigate the mechanism by which rs11573156 influences sPLA 2 -IIA levels via bioinformatics and modeling analysis. Through genotype-tissue expression (GTEx), 234 expression quantitative trait loci (eQTLs) were identified for the gene that encodes for sPLA 2 -IIA, PLA2G2A . SNP2TFBS was used to ascertain the binding affinities between transcription factors (TFs) to both the reference and alternative alleles of identified eQTL SNPs. Subsequently, candidate TF-SNP interactions were cross-referenced with the ChIP-seq results in matched tissues from ENCODE. SP1-rs11573156 emerged as the significant TF-SNP pair in the liver. Further analysis revealed that the upregulation of PLA2G2A transcript levels through the rs11573156 variant was likely affected by tissue SP1 protein levels. Using an ordinary differential equation based on Michaelis-Menten kinetic assumptions, we modeled the dependence of PLA2G2A transcription on SP1 protein levels, incorporating the SNP influence. Collectively, our analysis strongly suggests that the difference in the binding dynamics of SP1 to different rs11573156 alleles may underlie the allele-specific PLA2G2A expression in different tissues, a mechanistic model that awaits future direct experimental validation. This mechanism likely contributes to the variation in circulating sPLA 2 -IIA protein levels in the human population, with implications for a wide range of human diseases.

Cytopathologists have assumed a progressively pivotal role in diagnosing lymphoproliferative disorders. This review outlines a concise approach to the work-up of suspected lymphoma in cytopathology practice, emphasizing the integration of cytomorphologic evaluation with ancillary studies. These include the application of rapid onsite evaluation (ROSE) for proper specimen triage, immunophenotyping through flow cytometry (FC) and immunohistochemistry (IHC), and molecular studies on cytology/small biopsy specimens. Furthermore, the review provides a brief introduction to the forthcoming WHO Reporting System in Lymph Node Cytopathology.

The upcoming World Health Organization (WHO) Reporting System in Liver Cytopathology marks the first internationally applicable system for diverse medical infrastructure settings. This system categorizes cases into five groups: Insufficient/Inadequate/Nondiagnostic, Benign, Atypical, Suspicious for Malignancy, and Malignant. Each category is associated with a risk of malignancy (ROM), guiding recommendations for further diagnostic testing to achieve specific diagnoses or refine differential diagnoses and follow-up management. The primary goal is to enhance and standardize cytopathology reporting, improve communication between cytopathologists and clinicians, and ultimately elevate patient care. The online WHO System provides direct access to the WHO Classification for Tumours 5th Edition. This review delves into the latest classification guidelines, addresses terminology standardization, navigates diagnostic complexities, and aligns patient management options with cytopathological interpretations, contributing to an overall enhancement of patient care.

This article compares the transreading of Chinese texts in German by Sinologist Richard Wilhelm and novelist Alfred Döblin. Wilhelm, a spiritual intermediary between China and Europe, worked with eminent Chinese scholars to write accessible translations for German readers of Confucian and Daoist classics. Döblin relied on Wilhelm’s translation of the Liezi for his artistic breakthrough, The Three Leaps of Wang-lun: Chinese Novel. Over two decades later, while exiled in France, he crafted an idiosyncratic presentation of Confucius. Although he used excerpts from James Legge’s English translation, Döblin’s perspective on Confucius is grounded in his exposure to Chinese texts in Wilhelm’s German translation. Both Wilhelm and Döblin reinterpreted Chinese philosophy to provide lessons for 20th-century Western readers. Our analysis recognizes the social environment that shaped both writers’ interest in Chinese philosophy. We examine selected passages from these two representatives of the German literary tradition in order to indicate their convergent positions on Sino-Western cultural contact. Their shared stances toward the Chinese tradition, their own marginal positioning, physical migration, and intellectual alienation culminated in a unifying, outsider’s view. Both Wilhelm and Döblin initiated and promoted significant interactions on a basis of equality between Chinese and Western cultures.

Conflicting clinical trial results on omega-3 highly unsaturated fatty acids (n-3 HUFA) have prompted uncertainty about their cardioprotective effects. While the VITAL trial found no overall cardiovascular benefit from n-3 HUFA supplementation, its substantial African American (AfAm) enrollment provided a unique opportunity to explore racial differences in response to n-3 HUFA supplementation. The current observational study aimed to simulate randomized clinical trial (RCT) conditions by matching 3766 AfAm and 15,553 non-Hispanic White (NHW) individuals from the VITAL trial utilizing propensity score matching to address the limitations related to differences in confounding variables between the two groups. Within matched groups (3766 AfAm and 3766 NHW), n-3 HUFA supplementation’s impact on myocardial infarction (MI), stroke, and cardiovascular disease (CVD) mortality was assessed. A weighted decision tree analysis revealed belonging to the n-3 supplementation group as the most significant predictor of MI among AfAm but not NHW. Further logistic regression using the LASSO method and bootstrap estimation of standard errors indicated n-3 supplementation significantly lowered MI risk in AfAm (OR 0.17, 95% CI [0.048, 0.60]), with no such effect in NHW. This study underscores the critical need for future RCT to explore racial disparities in MI risk associated with n-3 HUFA supplementation and highlights potential causal differences between supplementation health outcomes in AfAm versus NHW populations.

This review discusses the occurrence, impact, analysis and treatment of metformin and guanylurea in coastal aquatic environments of Canada, USA and Europe. Metformin, a biguanide in chemical classification, is widely used as one of the most effective first-line oral drugs for type 2 diabetes. It is difficult to be metabolized by the human body and exists in both urine and faeces samples in these regions. Guanylurea is metformin's biotransformation product. Consequently, significant concentrations of metformin and guanylurea have been reported in wastewater treatment plants (WWTPs) and coastal aquatic environments. The maximum concentrations of metformin and guanylurea in surface water samples were as high as 59,000 and 4502 ng L-1, respectively. Metformin can be absorbed in non-target organisms by plants and in Atlantic salmon (Salmo salar). Guanylurea has a confirmed mitotic activity in plant cells. Analysis methods of metformin are currently developed based on high-performance liquid chromatography (HPLC) and gas chromatography-mass spectrometry (GC-MS). The removal of metformin from aquatic environments in the target regions is summarized. The review helps to fill a knowledge gap and provides insights for regulatory considerations. The potential options for managing these emerging pollutants are outlined too. [ABSTRACT FROM AUTHOR]

Metformin-associated lactic acidosis (MALA) and euglycaemic diabetic ketoacidosis (EKA) are both life-threatening endocrine emergencies. MALA is a well-documented complication of anti-glycaemic therapy in diabetics while EKA is an increasingly recognized disease entity with the advent of use of sodium-glucose co-transporter-2 (SGLT-2) inhibitors. However, the occurrence of concurrent metformin-associated lactic acidosis and euglycaemic ketoacidosis (MALKA) is uncommon and rarely reported in the literature. We report an unusual case of MALKA, in a 74-year-old gentleman with no previous history of chronic kidney disease and SGLT-2 inhibitor use, who presented with altered mental status, acute renal failure and profound high anion-gap metabolic acidosis (HAGMA) with lactaemia, ketonaemia and normoglycaemia (pH 6.965, bicarbonate 3.1, creatinine 522, glucose 6.6, lactate 17.5, ketones >8). The patient was initiated on intravenous insulin infusion with dextrose-containing drip and continuous renal replacement therapy (CRRT) in the intensive care unit (ICU). The patient had a prolonged hospital stay but was eventually discharged with a normalised renal function without need for long-term dialysis. The parallel occurrence of MALA and EKA suggest a metformin-associated inhibition of gluconeogenesis. This case highlights the importance of early recognition and investigation of concurrent diabetic ketoacidosis in the presence of MALA and vice versa as MALKA benefits from both prompt institution of parenteral glucose therapy and insulin infusion and consideration of initiation of haemodialysis.

We investigate the variable selection problem for Coxs proportional hazards model, and propose a unified model selection and estimation procedure with desired theoretical properties and computational convenience. The new method is based on a penalized log partial likelihood with the adaptively weighted L1 penalty on regression coefficients, providing what we call the adaptive Lasso estimator. The method incorporates different penalties for different coefficients: unimportant variables receive larger penalties than important ones, so that important variables tend to be retained in the selection process, whereas unimportant variables are more likely to be dropped. Theoretical properties, such as consistency and rate of convergence of the estimator, are studied. We also show that, with proper choice of regularization parameters, the proposed estimator has the oracle properties. The convex optimization nature of the method leads to an efficient algorithm. Both simulated and real examples show that the method performs competitively. [ABSTRACT FROM AUTHOR]

Introduction: End-of-life (EOL) conditions are commonly encountered by emergency physicians (EP). We aim to explore EPs' experience and perspectives toward EOL discussions in acute settings. Methods: A qualitative survey was conducted among EPs in three tertiary institutions. Data on demographics, EOL knowledge, conflict management strategies, comfort level, and perceived barriers to EOL discussions were collected. Data analysis was performed using SPSS and SAS. Results: Of 63 respondents, 40 (63.5%) were male. Respondents comprised 22 senior residents/registrars, 9 associate consultants, 22 consultants, and 10 senior consultants. The median duration of emergency department practice was 8 (interquartile range: 6–10) years. A majority (79.3%) reported conducting EOL discussions daily to weekly, with most (90.5%) able to obtain general agreement with families and patients regarding goals of care. Top barriers were communications with family/clinicians, lack of understanding of palliative care, and lack of rapport with patients. 38 (60.3%) deferred discussions to other colleagues (e.g., intensivists), 10 (15.9%) involved more family members, and 13 (20.6%) employed a combination of approaches. Physician's comfort level in discussing EOL issues also differed with physician seniority and patient type. There was a positive correlation between the mean general comfort level when discussing EOL and the seniority of the EPs up till consultancy. However, the comfort level dropped among senior consultants as compared to consultants. EPs were most comfortable discussing EOL of patients with a known terminal illness and least comfortable in cases of sudden death. Conclusions: Formal training and standardized framework would be useful to enhance the competency of EPs in conducting EOL discussions.

Purpose: : Guidelines for early-stage breast cancer allow for radiation therapy (RT) omission after breast conserving surgery among older women, though high utilization of RT persists. This study explored surgeon referral and the effect of a productivity-based bonus metric for radiation oncologists in an academic institution with centralized quality assurance review. Methods and materials: : We evaluated patients ≥70 years of age treated with breast conserving surgery for estrogen receptor (ER)+ pT1N0 breast cancer at a single tertiary cancer network between 2015 and 2018. The primary outcomes were radiation oncology referral and RT receipt. Covariables included patient and physician characteristics and treatment decisions before versus after productivity metric implementation. Univariable generalized linear effects models explored associations between these outcomes and covariables. Results: : Of 703 patients included, 483 (69%) were referred to radiation oncology and 273 (39%) received RT (among those referred, 57% received RT). No difference in RT receipt pre- versus post-productivity metric implementation was observed (P = .57). RT receipt was associated with younger patient age (70-74 years; odds ratio [OR], 2.66; 95% confidence interval [CI], 1.54-4.57) and higher grade (grade 3; OR, 7.75; 95% CI, 3.33-18.07). Initial referral was associated with younger age (70-74; OR, 5.64; 95% CI, 3.37-0.45) and higher performance status (Karnofsky performance status ≥90; OR, 5.34; 95% CI, 2.63-10.83). Conclusions: : Nonreferral to radiation oncology accounted for half of RT omission but was based on age and Karnofsky performance status, in accordance with guidelines. Lack of radiation oncologist practice change in response to misaligned financial incentives is reassuring, potentially reflecting incentive design and/or centralized quality assurance review. Multi-institutional studies are needed to confirm these findings.

We conducted and analyzed several internet surveys in order to understand the profile of global research integrity and ethical awareness, encompassing global population distribution. These were (1) the global distribution of Committee of Publishing Ethics (COPE) membership; (2) the global distribution of “Integrity” or “Ethics” journals; (3) the level of academic integrity awareness in European higher education institutions and (4) awareness of academic integrity in the top universities of Asia and Africa. The results of this survey series highlight seriously imbalanced awareness of research integrity and publishing ethics across the world, especially in developing areas with the highest population density. We therefore propose a new index, the “Academic Integrity Awareness Index” for future discussions across the linked spheres of publishing and research.

Abstract Background In this era of data science-driven bioinformatics, machine learning research has focused on feature selection as users want more interpretation and post-hoc analyses for biomarker detection. However, when there are more features (i.e., transcripts) than samples (i.e., mice or human samples) in a study, it poses major statistical challenges in biomarker detection tasks as traditional statistical techniques are underpowered in high dimension. Second and third order interactions of these features pose a substantial combinatoric dimensional challenge. In computational biology, random forest (RF) classifiers are widely used due to their flexibility, powerful performance, their ability to rank features, and their robustness to the “P > > N” high-dimensional limitation that many matrix regression algorithms face. We propose binomialRF, a feature selection technique in RFs that provides an alternative interpretation for features using a correlated binomial distribution and scales efficiently to analyze multiway interactions. Results In both simulations and validation studies using datasets from the TCGA and UCI repositories, binomialRF showed computational gains (up to 5 to 300 times faster) while maintaining competitive variable precision and recall in identifying biomarkers’ main effects and interactions. In two clinical studies, the binomialRF algorithm prioritizes previously-published relevant pathological molecular mechanisms (features) with high classification precision and recall using features alone, as well as with their statistical interactions alone. Conclusion binomialRF extends upon previous methods for identifying interpretable features in RFs and brings them together under a correlated binomial distribution to create an efficient hypothesis testing algorithm that identifies biomarkers’ main effects and interactions. Preliminary results in simulations demonstrate computational gains while retaining competitive model selection and classification accuracies. Future work will extend this framework to incorporate ontologies that provide pathway-level feature selection from gene expression input data.

Recent years have witnessed the tendency of measuring a biological sample on multiple omics scales for a comprehensive understanding of how biological activities on varying levels are perturbed by genetic variants, environments, and their interactions. This new trend raises substantial challenges to data integration and fusion, of which the latter is a specific type of integration that applies a uniform method in a scalable manner, to solve biological problems which the multi-omics measurements target. Fusion-based analysis has advanced rapidly in the past decade, thanks to application drivers and theoretical breakthroughs in mathematics, statistics, and computer science. We will briefly address these methods from methodological and mathematical perspectives and categorize them into three types of approaches: data fusion (a narrowed definition as compared to the general data fusion concept), model fusion, and mixed fusion. We will demonstrate at least one typical example in each specific category to exemplify the characteristics, principles, and applications of the methods in general, as well as discuss the gaps and potential issues for future studies.