bluuebunny/crossref_metadata_2025 huggingface dataset:
Antipsychotic Polypharmacy in Time Course
Authors: Lochmann van Bennekom Marc W.H. , Gijsman Harm J. , IntHout Joanna , Verkes Robbert Jan
Published: October 2024

Purpose/Background

Antipsychotic polypharmacy (APP) is controversial yet applied in 20% of patients with psychotic disorders. We investigated indications for initiating and continuing APP, including the contribution of unfinished cross-titrations.

Methods/Procedures

This 2-month study was part of a prospective study to reduce inappropriate APP in inpatients. With each new prescription resulting in APP, we asked the prescriber for the indication (eg, switching antipsychotics, sedation for agitation/sleep disorders, treatment refractoriness, other) and repeated this at 30 and 60 days. Secondary outcome was unfinished cross-titration at 60 days.

Findings/Results

In a consecutive cohort of 55 patients, 80% diagnosed with schizophrenia, switching antipsychotics was the primary initial indication for APP in 31 of 55 patients (56%), followed by sedation in 12 of 55 patients (22%), and treatment refractoriness in 10 of 55 patients (18%). Overall, APP was discontinued after 30 days in 25 of 55 patients (45%) and after 60 days in 28 of 55 patients (51%). At 60 days, APP initiated for switching antipsychotics was ongoing in 9 of 31 patients (29%), APP initiated for sedation was ongoing in 8 of 12 patients (66%), and APP initiated for refractoriness was ongoing in 9 of 10 patients (90%). The initial indication for APP was maintained at 60 days in 21 of 27 patients (78%). Unfinished cross-titration occurred in 9 of 31 patients (29%) with APP initiated for switching antipsychotics.

Implications/Conclusions

APP was initiated primarily because of cross-titration switching of antipsychotics. The reason for APP was generally maintained consistently over time, particularly when initiated for treatment refractoriness. Of all patients with APP initiated to switch antipsychotics, 29% ended in unfinished cross-titration.
Do People With Stroke Meet Aerobic and Muscle-Strengthening Activity Guidelines? Data From the Canadian Longitudinal Study on Aging
Authors: Noguchi Kenneth S. , Carlesso Lisa C. , Beauchamp Marla K. , Phillips Stuart M. , Thabane Lehana , Tang Ada
Published: October 2024

Background and Purpose:

It is unclear to what extent Canadians with stroke engage in moderate-vigorous physical activity (MVPA) and muscle-strengthening activities (MSA). The purpose of this study was to describe overall physical activity, aerobic MVPA, and MSA participation in Canadians with stroke; determine the functioning, disability, and health classes that best characterize this population; and examine the relationship between-class membership and physical activity participation.

Methods:

Activity levels were quantified using the Physical Activity Scale for the Elderly in 2094 adults with stroke or transient ischemic attack (mean age 67.9 years, 9.5 years poststroke) from the CLSA. Means and percentages were used to characterize participation. Latent class analysis was used to create health and disability classes, and activity levels were compared between classes.

Results:

Only 6.2% (95% confidence interval [CI], 4.8%-8.0%) met both MVPA and MSA guidelines. Most (88.2%, 95% CI, 85.0%-88.9%) engaged in MVPA <3 times/wk and 76.7% (95% CI, 73.7%-79.1%) never engaged in MSA. In latent class analyses, 2 classes for males and females were characterized by high-positive or low-negative levels of intrinsic capacity (eg, grip strength), functional mobility (eg, walking speed), and environment (eg, social support). Those in the low-negative classes had the lowest Physical Activity Scale for the Elderly scores and aerobic MVPA levels compared to the high-positive (healthiest) classes. MSA participation was not different between classes.

Discussion and Conclusions:

Canadians with stroke are not engaging in sufficient physical activity. Clinicians should encourage regular participation in physical activity, especially among those with lower levels of intrinsic capacity, functional mobility, and environmental support.

Video Abstract available for more insights from the authors (see Supplementary Digital Content 3 available at: http://links.lww.com/JNPT/A494).
Measuring Exercise Self-Efficacy After Stroke: Validity and Reliability of Current Measures
Authors: Espernberger Karl , Fini Natalie A. , Ezzat Allison , Peiris Casey L.
Published: October 2024

Background and Purpose:

Many physically capable stroke survivors are insufficiently active, with low self-efficacy considered an important contributor. However, validity and reliability of self-efficacy measures in stroke survivors have not been established. This research aims to evaluate the test-retest reliability and construct validity of 3 self-efficacy measures: Self-Efficacy for Exercise Scale (SEE), Spinal Cord Injury Exercise Self-Efficacy Scale (SCI-ESES), and Participation Strategies Self-Efficacy Scale (PS-SES).

Methods:

A repeated measures study with community-dwelling, independently mobile adult stroke survivors (n = 51, mean age 74 years, 45% female, median 22 months poststroke) was completed. Test-retest reliability was assessed using intraclass correlation coefficients and Bland-Altman analyses. Construct validity was assessed using 8 pre-determined hypotheses concerning physical activity level (subjective and objective), comorbidities, work and volunteering, and measures of function.

Results:

Retest reliability was established for the SEE (intraclass correlation coefficient, ICC = 0.77) and PS-SES (ICC = 0.78) but not for the SCI-ESES (ICC = 0.68). Bland-Altman analysis showed participants consistently scored higher on the second test for all measures. The SEE achieved construct validity by meeting 75% of hypotheses, whereas the PS-SES and SCI-ESES did not. Self-efficacy was positively related to steps/day, functional capacity, self-reported activity levels, and work or volunteering participation.

Discussion and Conclusions:

The SEE was found to be the most appropriate tool to measure exercise self-efficacy in independently mobile chronic stroke survivors in terms of retest reliability and validity.

Trial Registration:

N/A

Video Abstract available

for more insights from the authors (see the Video, Supplemental Digital Content 1 “Espernberger-JNPT-Video-Abstract,” available at: http://links.lww.com/JNPT/A489).
The perils of St. John's wort in cancer care
Authors: Boyle Deborah A.
Published: October 2024

Approximately one-third of Americans use healthcare approaches including herbs and botanicals, such as St. John's wort (SJW), to improve overall well-being, gain control over their health, and manage the adverse reactions of conventional therapies. This article examines the use of SJW in cancer care, discussing its pharmacokinetics, toxicity, and potential interactions with cancer treatments while emphasizing the importance of patient education and collaboration between oncology nurses and pharmacists to ensure safe and effective care.
Checkpoint inhibitor therapy
Authors: Davis Lori , Casselbury Mary Beth , Wilson Sharon
Published: October 2024

Treatment with immune checkpoint inhibitors for cancer is associated with a high prevalence of multiple immune-related toxicities. Immune-related adverse events (irAEs) can occur anytime during treatment and up to 3 months after treatment. This article discusses checkpoint inhibitor therapy and describes the implementation of a patient education program focused on recognizing immunotherapy irAEs and their toxicities.
Levator Advancement Surgery with or without Lateral Horn Incision: Effect of Lateral Horn Incision for Severe Involutional Blepharoptosis
Authors: Suga Hirotaka , Fukuju Asako , Murakami Risa
Published: October 2024

Background:

The lateral portion of the levator aponeurosis transforms into fibrous tissue called the lateral horn. Conventional levator advancement surgery for involutional blepharoptosis preserves the integrity of the lateral horn. The impact of incising the lateral horn has not been thoroughly studied.

Methods:

Sixty-nine patients who had undergone levator advancement surgery for involutional blepharoptosis between 2020 and 2023 were included in the study. In cases where the levator aponeurosis could not be well advanced during surgery, we incised the lateral horn to increase the advancement. We then retrospectively reviewed cases with or without the incision. We also measured the effect of the incision intraoperatively using a sheet with a scale grid.

Results:

Lateral horn incisions were performed in 32 of the 69 cases. The preoperative degree of blepharoptosis was significantly more severe in cases that necessitated the incision (margin reflex distance 1; 0.5 vs 1.0 mm, P < 0.05). Patients receiving the incision were significantly older than those without (73.4 vs 61.7 years, P < 0.05). There were no significant differences between the two groups in postoperative margin reflex distance 1 (2.8 vs 3.0 mm, P = 0.20). Intraoperative measurements revealed that the levator aponeurosis was advanced 4.3 mm more caudally and 3.1 mm more medially as a result of the lateral horn incision.

Conclusions:

Lateral horn incision is effective in levator advancement surgery for severe involutional blepharoptosis. This technique aids in preventing undercorrection of palpebral fissures, especially in the medial region.
The Predictors of Patient Safety Culture in Hospital Setting: A Systematic Review
Authors: Vibe Anja , Rasmussen Sara Haurum , Rasmussen Nikolaj Ohm Pranger , Østergaard Doris , Dieckmann Peter
Published: October 2024

Introduction

Patient safety (PS) is a global public health concern. It is estimated that 10% of patients experience preventable harm while hospitalized. Patient safety culture (PSC) has been recognized as essential to improving PS, drawing inspiration from other high-risk industries. In PS research, however, PSC poses conceptual challenges, with inconsistent terminology, a lack of definitions, and limited use of substantiating theory. Despite these challenges, PSC remains widely used in PS research and practice, as it is seen as a potential gateway to understanding sociotechnical complex aspects of the healthcare system and improving safe patient treatment and care.

Objectives

This review explores the concept of PSC in a hospital setting. How PSC is used as an outcome, thus exploring the theoretical position underpinning PSC, which predictors impact PSC, and how these predictors are related to PSC.

Method

Using a search of 3 electronic databases, 23 studies that met the inclusion criteria were selected for review.

Results

The review identified 81 predictors of PSC. Study population, unit of analysis and method varied widely. PSC as an outcome was assessed based on one of 4 surveys. Thus, the underpinning position of the PSC construct is dominated by an organizational/managerial approach.

Conclusions

The large number of predictors explored and the range in outcome measures, units of analysis, and methods make it hard to establish any causal relationship. We argue that studies closer to actual practices in the messy conditions of clinical practice are needed.
Aberrant dynamic functional and effective connectivity changes of the primary visual cortex in patients with retinal detachment via machine learning
Authors: Ji Yu , Wang Yuan-Yuan , Cheng Qi , Fu Wen-Wen , Shu Ben-Liang , Wei Bin , Huang Qin-Yi , Wu Xiao-Rong
Published: October 2024

Objective

Previous neuroimaging studies have identified significant alterations in brain functional activity in retinal detachment (RD) patients, these investigations predominantly concentrated on local functional activity changes. The potential directional alterations in functional connectivity within the primary visual cortex (V1) in RD patients remain to be elucidated.

Methods

In this study, we employed seed-based functional connectivity analysis along with Granger causality analysis to examine the directional alterations in dynamic functional connectivity (dFC) within the V1 region of patients diagnosed with RD. Finally, a support vector machine algorithm was utilized to classify patients with RD and healthy controls (HCs).

Results

RD patients exhibited heightened dynamic functional connectivity (dFC) and dynamic effective connectivity (dEC) between the Visual Network (VN) and default mode network (DMN), as well as within the VN, compared to HCs. Conversely, dFC between VN and auditory network (AN) decreased, and dEC between VN and sensorimotor network (SMN) significantly reduced. In state 4, RD patients had higher frequency. Notably, variations in dFC originating from the left V1 region proved diagnostically effective, achieving an AUC of 0.786.

Conclusion

This study reveals significant alterations in the connectivity between the VN and the default mode network in patients with RD. These changes may disrupt visual information processing and higher cognitive integration in RD patients. Additionally, alterations in the left V1 region and whole-brain dFC show promising potential in aiding the diagnosis of RD. These findings offer valuable insights into the neural mechanisms underlying visual and cognitive impairments associated with RD.
Microhaplotype deep sequencing assays to capturePlasmodium vivaxinfection lineages
Authors: Kleinecke Mariana , Rumaseb Angela , Sutanto Edwin , Trimarsanto Hidayat , Hoon Kian Soon , Osborne Ashley , Manrique Paulo , Peters Trent , Hawkes David , Benavente Ernest Diez , Whitton Georgia , Siegel Sasha V , Pearson Richard D , Amato Roberto , Rai Anjana , Thuy Nhien Nguyen Thanh , Chau Nguyen Hoang , Assefa Ashenafi , Degaga Tamiru S , Abate Dagimawie Tadesse , Rahim Awab Ghulam , Pasaribu Ayodhia Pitaloka , Sutanto Inge , Alam Mohammad Shafiul , Pava Zuleima , Mesa Tatiana Lopera- , Echeverry Diego , William Tim , Anstey Nicholas M , Grigg Matthew J , Day Nicholas , White Nicholas J. , Kwiatkowski Dominic P , Noviyanti Rintis , Neafsey Daniel , Price Ric N , Auburn Sarah
Published: October 2024

The elimination ofPlasmodium vivaxis challenged by dormant liver stages (hypnozoites) that can reactivate months after initial infection resulting in relapses that enhance transmission. Relapsing infections confound antimalarial clinical efficacy trials due to the inability to distinguish between recurrences arising from blood-stage treatment failure (recrudescence), reinfection or relapse. Genetic relatedness of paired parasite isolates, measured by identity-by-descent (IBD), can provide important information on whether individuals have had single or multiple mosquito inoculations, thus informing on recurrence origin. We developed a high-throughput amplicon sequencing assay comprising 93 multi-SNP (microhaplotype)P. vivaxmarkers to determine IBD betweenP. vivaxclinical isolates. The assay was evaluated in 659 independent infections from the Asia-Pacific and Horn of Africa, including 108 pairs of infections from a randomized controlled trial (RCT). A bioinformatics pipeline (vivaxGEN-MicroHaps) was established to support data processing. Simulations usingpaneljudgedemonstrated low error in pairwise IBD estimation in all countries assessed (all RMSE <0.12) and IBD-based networks illustrated strong clustering by geography. IBD analysis in the RCT demonstrated a higher frequency of suspected relapses or recrudescence in patients treated with primaquine regimens (0.84) compared to those without primaquine (0.60). Our results demonstrate the potential to derive information onP. vivaxIBD using amplicon sequencing, that informs policy-relevant treatment and transmission dynamics.
Effect of Compulsory Funding on Post-hospital Neurorehabilitation Outcomes and Length of Stay following Stroke
Authors: Lew Jason T. , Lewis Frank D. , Glenn Mel B. , Horn Gordon J.
Published: October 2024

Background and Purpose

The American Stroke Association recommends post-stroke rehabilitation for those who qualify and have access to this service. Continued services at the post-hospital residential and outpatient rehabilitation levels of care result in further functional gains after acquired brain injury, including stroke, even when provided beyond 6-12 months post onset. Access to care remains a barrier to rehabilitation including third-party limits with funding and coverage restrictions. This study measured outcomes comparing those with state legislated Compulsory Funding (CF) vs. Restricted Funding (RF) for post-hospital neurorehabilitation.

Methods

There were a total of 402 participants across 14 states included in the study. The CF group had 201 and the RF group had 201 participants. The Mayo-Portland Adaptability Inventory (MPAI-4) was selected as the primary dependent measure.

Results

Post-hospital rehabilitation length of stay (LOS) was significantly shorter in the CF group, t(400) = 1.72, p < 0.05 (Cohen’s d = 0.17). A Mixed 2×2 RM-MANCOVA revealed a significant main effect of time of testing, Pillai’s Trace f(1,398) = 402.6, p < 0.001; power to detect = 0.99, partial eta2= 0.50. The analysis also revealed significant between groups main effect f(1,398) = 12.8, p< 0.001, power to detect = 0.94, partial eta2= 0.031. The results of Bonferroni post-hoc pairwise comparisons are presented.

Conclusions

This study examined the differences in rehabilitation outcomes and LOS for persons receiving CF post-acute neurorehabilitation with individuals receiving services in other states with RF. While both groups improved, the state legislated access to care CF group started post-hospital neurorehabilitation without delay, discharged more quickly thereby reducing cost, with a lower level of disability (MPAI-4 Indices) at discharge compared to the RF group.
SFSWAP is a negative regulator of OGT intron detention and global pre-mRNA splicing
Authors: Govindan Ashwin , Conrad Nicholas K.
Published: October 2024

O-GlcNAcylation is the reversible post-translational addition of β-N-acetylglucosamine to serine and threonine residues of nuclear and cytoplasmic proteins. It plays an important role in several cellular processes through the modification of thousands of protein substrates. O-GlcNAcylation in humans is mediated by a single essential enzyme, O-GlcNAc transferase (OGT). OGT, together with the sole O-GlcNAcase OGA, form an intricate feedback loop to maintain O-GlcNAc homeostasis in response to changes in cellular O-GlcNAc using a dynamic mechanism involving nuclear retention of its fourth intron. However, the molecular mechanism of this dynamic regulation remains unclear. Using an O-GlcNAc responsive GFP reporter cell line, we identify SFSWAP, a poorly characterized splicing factor, as a trans-acting factor regulating OGT intron detention. We show that SFSWAP is a global regulator of retained intron splicing and exon skipping that primarily acts as a negative regulator of splicing. In contrast, knockdown of SFSWAP leads to reduced inclusion of a ‘decoy exon’ present in the OGT retained intron which may mediate its role in OGT intron detention. Global analysis of decoy exon inclusion in SFSWAP and UPF1 double knockdown cells indicate altered patterns of decoy exon usage. Together, these data indicate a role for SFSWAP as a global negative regulator of pre-mRNA splicing and positive regulator of intron retention.
Spillover rate is not a predictor of host jump risk
Authors: Simony Brandon J. , Kennedy David A.
Published: October 2024

1

Abstract

Spillover of infectious diseases is a significant issue for human, animal, and plant health, in part due to their potential to host jump. Current approaches to predict and prevent host jumps are structured around discovering new viruses, drawing associations between pathogen characteristics and host jump risk, and managing spillover, but prediction and prevention are still elusive. Spillover is a critical step in the process of completing a host jump, so it is often assumed that a pathogen’s spillover rate is predictive of host jump risk. However, this may not necessarily be the case. While a pathogen that spills over into a novel host frequently will indeed have many opportunities to establish itself, the lack of success establishing itself in previous spillovers demonstrates a poor ability to do so. In comparison, a pathogen that rarely spills over will have few opportunities to establish itself, but may be well suited to do so, and could, in theory, be more likely to host jump despite these limited opportunities. Here we address the question of which of these poses the greater risk. Using a Bayesian framework, we create a model to quantify the probability that a host jump occurs in some future time interval. This model only depends on the number of spillover events in the past and future, and our uncertainty regarding the probability that a single spillover will result in a host jump. We derive an analytical solution to this model, which shows that when past and future spillover rates are linearly correlated, a pathogen’s inherent rate of spillover is a poor predictor of host jump risk owing to two complementary factors. First, the pathogens that pose the greatest host jump risk may be either those that spillover extremely rarely or extremely commonly, with the result depending on our prior uncertainly in the probability that a spillover will result in a host jump. Second, as spillover rate becomes large, the increase in the number of opportunities for a host jump to occur conferred by the increase in the number of spillover events is exactly balanced by a decrease in the probability of success for each individual spillover event. Therefore, we show that spillover rate is not a useful metric for evaluating host jump risk.
An 8-Week Oral Therapy with Ashwagandha (Withania Somnifera) Root Extract (600 mg/day) Improves Frailty and Quality of Life in Elderly: A Prospective, Randomized, Placebo-Controlled, Efficacy and Safety Study
Authors: Naik K. Sunil , Muralidhar Gudla , Rao Bade Srinivas , Wankhade Kalpana
Published: October 2024

Frailty is a state of increased vulnerability resulting from aging due to cumulative decline in physiological system over a lifespan. Few pharmacological agents have been investigated for the treatment of frailty. In Ayurveda, Ashwagandha (Withania Somnifera) is a popular botanical medicine used for improvement in physical strength and mental stress and has a potential for treatment of frailty. This placebo-controlled study assessed the efficacy and safety of a capsule containing 300mg of Ashwagandha Root Extract (ARE) administered twice daily orally for 8 weeks. Fifty elderly subjects with a frailty score ≥7 based on Frailty Assessment and Screening Tool (FAST) were randomized in a 1:1 ratio to receive either Ashwagandha (ARE, n=25) or placebo (PL, n=25). Improvement in frailty after 8 weeks was assessed by FAST, 6-minute Walk Test (6MWT), Pittsburgh Sleep Quality Index (PSQI), Mini-Mental State Examination (MMSE) and Short Form Survey (SF-12) scores. Blood samples were collected at baseline and week 8 for estimation of C-Reactive Protein (CRP), cortisol and Creatinine Kinase (CK). Significant improvement (p<0.01) in scores for FAST, 6MWTs, PSQI, MMSE, and SF-12 were seen with ARE after 8 weeks. Also, significant improvements (p<0.05) were observed in CK and in CRP with ARE. These improvements were greater (p<0.05) with ARE as compared to placebo. ARE was well tolerated with no adverse effects, and no changes in hepatic and renal parameters. Thus, Ashwagandha root extract can be a valuable therapeutic option for improvement of health condition in frailty.
Circulating Adenoid Cystic Carcinoma associated MYB transcripts enable rapid and sensitive detection of metastatic disease in blood liquid biopsies
Authors: Moeyersoms Acadia H.M. , Knechtel Kendall W. , Rong Andrew J. , Gallo Ryan A. , Zhang Michelle , Marsh Harper M. , Sargi Zoukaa B. , Leibowitz Jason M. , Civantos Francisco J. , Weed Donald T. , Dubovy Sander R. , Tse David T. , Pelaez Daniel
Published: October 2024

Adenoid cystic carcinoma (ACC) is a rare and lethal malignancy that originates in secretory glands of the head and neck. A prominent molecular feature of ACC is the overexpression of the proto-oncogene MYB. ACC has a poor long-term survival due to its high propensity for recurrence and protracted metastasis. Currently, clinical technologies lack the efficiency to distinguish patient prognosis prior to its redevelopment. We hypothesize that metastatic ACC can be detected by monitoring tumor-specific MYB expression in patients’ blood. We developed a quantitative polymerase chain reaction (qPCR) assay for MYB transcripts and screened blood samples from four patient cohorts: no history or evidence of ACC (n=23), past history of ACC and no evidence of disease (NED) for greater than three years (n=15), local ACC (n=6), and metastatic ACC (n=5). Our assay detected significantly elevated levels of MYB transcripts in the metastatic ACC cohort (p < 0.01). Receiver operating characteristic (ROC) curves comparing metastatic to NED and metastatic to local disease were significant, with p values < 0.0001 and 0.0008, respectively. Single-cell RNA sequencing (scRNA-seq) of blood from metastatic ACC identified a cluster of circulating tumor cells (CTCs) expressing MYB. Here, we report a sensitive, cost-effective, and minimally invasive diagnostic test that leverages tumor-specific signatures to screen for metastatic ACC disease, potentially enhancing detection earlier than the current clinical standard.
The Role of Predictive Processing and Perceptual Load in Selective Visual Attention: An Examination with Semantically Salient and Less Salient Distractors
Authors: Ozsu Ataol Burak , Urgen Burcu A.
Published: October 2024

Our attentional resources are allocated to the various aspects of the environment based on the context, and predictive coding has been used as a model to explain the interaction between sensory-based information and top-down expectations in visual attention (Spratling, 2008; Rauss et al., 2011). On the other hand, the saliency of the environmental stimuli is also hypothesized to be capturing the attentional resources of the individuals involuntarily, and thus, it is thought to be playing a crucial role in attentional resource allocation. The current study investigates the role of predictive processing of task difficulty in selective visual attention in the presence of various distractors. Utilizing a letter search task, we provided brief cues about the upcoming task’s difficulty, and participants were asked to detect the target letters. We investigated whether predictive processing about task demands may cause a difference in behavioral measures in the presence of semantically less salient distractors in Experiment 1 (Gabor patches) and semantically more salient distractors in Experiment 2 (faces). Results showed that unmet expectations about the task demands caused longer reaction times in both studies. We observed that all independent variables, which are task difficulty, cue congruency, and distractor presence, affected reaction times in both experiments, but cue congruency interacted with distractor presence only in Experiment 2. Here, we argue that though predictive processing plays a role in attentional resource allocation and, distractors’ characteristics are also crucial as the saliency level interacts with the cue congruency.
Targeted, high-resolution sensing of volatile organic compounds by covalent nanopore detection
Authors: McGivern Lauren E , Lim Zhong Hui , Yuan Yizhi , Bo Zonghua , Bayley Hagan , Qing Yujia
Published: October 2024

Volatile organic compounds are choice analytes in a variety of contexts. For example, humans release over 4000 volatile organic compounds, many of which are diagnostic of life-threatening medical conditions. A combination of a large number of potential analytes requires the application of costly, cumbersome technology. Here, we show that covalent nanopore sensing can be used for the targeted detection of a reduced set of analytes in a mixture: in this case aldehydes, which constitute ∼5% of human volatiles. Further, nanopore engineering permits high-resolution detection, which allows closely related aldehydes including isomers to be distinguished. Differential sensing of other chemical classes, such as alcohols, is demonstrated by leveraging their enzymatic conversion to aldehydes. Our approach is compatible with the use of cheap, portable, user-friendly diagnostic devices applicable to a wide variety of objectives, including pollutant monitoring, food and beverage testing and the quality control of pharmaceuticals, as well as disease diagnostics.
A lineage-specific nascent RNA assay unveils principles of gene regulation in tissue biology
Authors: Chovatiya Gopal , Wang Alex B , Versluis Philip , Bai Chris K , Huang Sean Y , DeBerardine Michael , Ray Judhajeet , Ozer Abdullah , Lis John T , Tumbar Tudorita
Published: October 2024

Gene regulatory mechanisms that modulate RNA Polymerase II activity are difficult to access in mammalian tissues composed of multiple cell lineages. Here, we develop a nascent RNA assay (PReCIS-seq) that measures lineage-specific transcriptionally-engaged Pol II on genes and DNA enhancer elements in intact mouse tissue. By employing keratinocytes as a prototype lineage, we unearth Pol II promoter-recruitment versus pause-release mechanisms operating in adult skin homeostasis. Moreover, we relate active enhancer proximity and transcription factor binding motifs on promoters to Pol II activity and promoter-proximal pausing level. Finally, we find Pol II firing rapidly into elongation on lineage identity genes and highly paused on cellular safeguarding genes in a context-dependent manner. Our work provides a basic platform to investigate mechanistic principles of gene regulation in individual lineages of complex mammalian tissues.
Fast Single-Cell MALDI Imaging of Low-Mass Metabolites Reveals Cellular Activation Markers
Authors: Cairns James L. , Huber Johanna , Lewen Andrea , Jung Jessica , Maurer Stefan J. , Bausbacher Tobias , Schmidt Stefan , Levkin Pavel A. , Sevin Daniel , Göpfrich Kerstin , Koch Philipp , Kann Oliver , Hopf Carsten
Published: October 2024

Single-cell MALDI mass spectrometry imaging (MSI) of lipids and metabolites >200 Da has recently come to the forefront of biomedical research and chemical biology, but fast metabolome-preserving methods without paraformaldehyde fixation for analysis of low mass, hydrophilic metabolites (<200 Da) in large cell populations are lacking. Introducing giant unilamellar vesicles (GUVs) as MSI ground truth for cell-sized objects and Monte Carlo reference-based consensus clustering for data-dependent identification of cell subpopulations. The PRISM-MS (PRescanImaging forSmallMolecule -MassSpectrometry) dual-scan MSI workflow is presented, enabling space-efficient and therefore faster lipid analysis in single GUVs and cells. Beyond lipids, PRISM-MS enables MSI and on-cell MS2-based identification of low-mass metabolites like amino acids or Krebs cycle intermediates involved in stimulus-dependent cell activation. The utility of PRISM-MS is demonstrated through the characterization of complex metabolome changes in lipopolysaccharide (LPS)-stimulated microglial cells and human-induced pluripotent stem cell-derived microglia. Translation of single cell results to endogenous microglia in organotypic hippocampal slice cultures indicates that LPS-activation involves changes of the itaconate-to-taurine ratio and alterations in neuron-to-glia glutamine-glutamate shuttling. The data suggests that PRISM-MS could serve as a standard method in single cell metabolomics, given its capability to characterize larger cell populations and low-mass metabolites.
Replacing Normalizations with Interval Assumptions Improves the Rigor and Robustness of Differential Expression and Differential Abundance Analyses
Authors: McGovern Kyle C. , Silverman Justin D.
Published: October 2024

Standard methods for differential expression and differential abundance analysis rely on normalization to address sample-to-sample variation in sequencing depth. However, normalizations imply strict, unrealistic assumptions about the unmeasured scale of biological systems (e.g., microbial load or total cellular transcription). This introduces bias that can lead to false positives and false negatives. To overcome these limitations, we suggest replacing normalizations with interval assumptions. This approach allows researchers to explicitly define plausible lower and upper bounds on the unmeasured biological system’s scale, making these assumptions more realistic, transparent, and flexible than those imposed by traditional normalizations. Compared to recent alternatives like scale models and sensitivity analyses, interval assumptions are easier to use, resulting in potentially reduced false positives and false negatives, and have stronger guarantees of Type-I error control. We make interval assumptions accessible by introducing a modified version of ALDEx2 as a publicly available software package. Through simulations and real data studies, we show these methods can reduce false positives and false negatives compared to normalization-based tools.
Subtractive proteomics unravel the potency of D-Alanine-D-Alanine Ligase as the drug target forBurkholderia pseudomallei
Authors: Rahman Shakilur , Bhattacharya Ayush , Jana Prerona , Ganguly Manisha , Das Amit Kumar , Hazra Ditipriya , Roychowdhury Amlan
Published: October 2024

Melioidosis, also known as Whitmore’s disease, is caused by the deadly pathogenBurkholderia pseudomalleiand remains a significant global health concern, particularly in South Asia. The disease is contracted through exposure to contaminated soil, water, air, and food. Infected individuals often present with abscesses in internal organs such as the lungs, spleen, and liver, and in soft tissues, with severe cases leading to septic shock and acute pneumonia. The rising incidence and mortality rates, coupled withB. pseudomallei’sability to form biofilms and develop resistance to antibiotics like cephalosporins, make treatment increasingly challenging. This highlights the urgent need for novel therapeutic approaches.

D-Alanine-D-Alanine ligase (Ddl), a crucial enzyme involved in the final stage of bacterial cell wall synthesis, which protects the pathogen from the hostile cellular environment of the host. While many bacteria have two isoforms of this enzyme,B. pseudomalleipossesses only the DdlB isoform, presenting a significant vulnerability. Our study represents the first successful attempt to target DdlB through a combination of molecular docking and molecular dynamics simulations. These investigations provide strong evidence that Conivaptan acts as an effective inhibitor of DdlB, offering a novel therapeutic approach for combating melioidosis.
Micro-RNA 7975 directly regulates MDTH expression and mediates endothelial cell proliferation and migration in the development of early atherosclerosis
Authors: Wagner Nathan , Karere Genesio
Published: October 2024

Cardiovascular disease (CVD) is commonly due to the development of atherosclerosis. Endothelial integrity is critical in the prevention of pathogenesis of atherosclerosis. The key to prevention of CVD is understanding the molecular mechanisms responsible for initiation of early atherosclerosis. MiRNAs are mediators of endothelial homeostasis, and their dysregulation could lead to early atherosclerotic disorder. We previously revealed the expression of miR-7975 in early atherosclerotic lesions. The aim of this study was to investigate the novel roles of miR-7975 on endothelial cell proliferation and migration, and in the regulation of metadherin (MTDH) expression. We performed proliferation and migration assays coupled with luciferase assay. We show that miR-7975 promotes proliferation and migration of endothelial cells and that miR-7976 directly regulates (MTDH), previously associated with cancer pathogenesis. In conclusion our results show miR-7975 could be a potential mediator of endothelial homeostasis and that MTDH is a novel target of miR-7975.
Dynamic multi-omics and mechanistic modeling approach uncovers novel mechanisms of kidney fibrosis progression
Authors: Tuechler Nadine , Burtscher Mira Lea , Garrido-Rodriguez Martin , Khan Muzamil Majid , Turei Denes , Tischer Christian , Kaspar Sarah , Schwarz Jennifer Jasmin , Stein Frank , Rettel Mandy , Kramann Rafael , Savitski Mikhail M , Saez-Rodriguez Julio , Pepperkok Rainer
Published: October 2024

Kidney fibrosis, characterized by excessive extracellular matrix deposition, is a progressive disease that, despite affecting 10% of the population, lacks specific treatments and suitable biomarkers. This study presents a comprehensive, time-resolved multi-omics analysis of kidney fibrosis using an in vitro model system based on human kidney PDGFRβ+ mesenchymal cells aimed at unraveling disease mechanisms. Using transcriptomics, proteomics, phosphoproteomics, and secretomics we quantified over 14,000 biomolecules across seven time points following TGF-β stimulation. This revealed distinct temporal patterns in the expression and activity of known and potential kidney fibrosis markers and modulators. Data integration resulted in time-resolved multi-omic network models which allowed us to propose mechanisms related to fibrosis progression through early transcriptional reprogramming. Using siRNA knockdowns and phenotypic assays, we validated predictions and regulatory mechanisms underlying kidney fibrosis. In particular, we show that several early-activated transcription factors, including FLI1 and E2F1, act as negative regulators of collagen deposition and propose underlying molecular mechanisms. This work advances our understanding of the pathogenesis of kidney fibrosis and provides a resource to be further leveraged by the community.
Co-delivery of Paclitaxel and Cannabidiol in Lipid Nanoparticles Enhances Cytotoxicity Against Melanoma Cells
Authors: de Carvalho Fabíola V. , Geronimo Gabriela , de Moura Ludmilla D. , Mendonça Talita C. , Breitkreitz Márcia Cristina , de Paula Eneida , da Silva Gustavo H. Rodrigues
Published: October 2024

Although chemotherapy regimens are well-established in clinical practice, chemoresistance and adverse side effects pose significant obstacles in cancer treatment. Paclitaxel (PTX), a widely used chemotherapeutic agent, faces formulation challenges due to its poor solubility and permeability. Research suggests that the phytochemical Cannabidiol (CBD) holds potential not only in targeting cancer cells but also in alleviating pain and nausea, thereby improving the quality of life for cancer patients. However, CBD’s clinical application is also limited by its poor solubility, low bioavailability, and susceptibility to oxidation. Nanostructured lipid carriers (NLCs) represent a promising drug delivery system for hydrophobic compounds like PTX and CBD and allows their co-encapsulation. Nonetheless, achieving a stable formulation requires identifying suitable preparation methods and excipients. The aim of this study was to develop and optimize an NLC formulation for the co-encapsulation of PTX and CBD. Using factorial design, an optimized formulation was obtained with homogeneous particle sizes (200 nm), negative zeta potentials (−17 mV), particle concentration of 1013particles/mL, spherical morphology (TEM images), and a lipid core with low crystallinity (as confirmed by XRD). To evaluate the therapeutic potential of the drug combination, cell viability assays were conducted on murine melanoma cells (B16-F10) at different exposure times (24 and 48 hours). The NLC-CBD-PTX formulation significantly reduced cell viability in a time- and concentration-dependent manner, demonstrating at least 75% greater activity at 24 hours compared to each drug individually whether free (PTX, CBD) or encapsulated (NLC-PTX, NLC-CBD). This indicates a synergistic effect of the encapsulated drugs on cytotoxicity. In conclusion, an innovative pharmaceutical formulation co-encapsulating PTX and CBD was validated, showing potential to enhance antitumor efficacy, overcome chemoresistance, reduce side effects, and broaden therapeutic applications. The resulting NLCs exhibited favorable physicochemical properties, supporting their suitability for various routes of administration.
Regulator of G-Protein Signaling 2 Knockout in CD4+ T Cells Promotes Anti-Inflammatory T Cells, Enhancing Ovulation, and Oocyte Yield
Authors: Raff Marika , Benton Trinity , Brummond Daniel , Kovach Denali , Bunton Olivia , Janky Ella , Duran Eyup Hakan , Scroggins Douglas G. , Gray Gabrielle , Scroggins Sabrina Marie
Published: October 2024

Structured Abstract

Objective

To determine the downstream effects on ovarian function and immune cell differentiation in the ovary and uterus using a model in which RGS2 was knocked out specifically in CD4+ T cells.

Design

Laboratory based experiments with female mice.

Animals

Female congenic (fully backcrossed) and non-congenic (mixed strain) mice with CD4 T cell-specific RGS2 knockout.

Exposure

Four-week-old female CD4 RGS2 knockout (CD4 RGS2KO) mice and their littermate controls (CD4 RGS2CTL) were subjected to superovulation using pregnant mare serum gonadotropins.

Main Outcome Measures

Oocyte numbers, lymphocyte populations in the ovary and uterus, and serum estradiol and progesterone concentrations.

Result

In non-congenic (mixed strain) mice, CD4 RGS2 knockout (KO) promoted higher oocyte ovulation and increased uterine total leukocyte numbers. Similarly, congenic (fully backcrossed strain) mice showed higher oocyte numbers and increased uterine total leukocytes in the CD4 RGS2KOmice compared to CD4 RGS2CTLmice. Pro-inflammatory CD4+ T helper (TH) 1 and TH17 cell frequencies in the ovary and uterus were unchanged, while Treg and TH2 cell frequencies were elevated, along with increased concentrations of estradiol and progesterone in the serum of CD4 RGS2KOmice.

Conclusion

Our study highlights the important role of RGS2 in CD4+ T cells within the context of reproduction. The dysregulation of immune responses due to RGS2 knockout in CD4+ T cells appears to enhance oocyte production. Further research is warranted to elucidate the precise mechanisms by which RGS2 influences reproductive outcomes, including its impact on fecundability, endometrial receptivity, and successful implantation.
A simple model of population dynamics with beneficial and harmful interaction networks for empirical applications
Authors: Bimler Malyon D. , Pascal Luz Valerie , Adams Matthew P. , Baker Chris
Published: October 2024

Population dynamic models can forecast changes in the abundances of multiple interconnected species, which makes them potentially powerful tools for managing ecological communities, yet they remain largely under-utilised in applied settings. High data requirements and the ability to only model a narrow range of ecological interactions and/or trophic levels together limits their usefulness when faced with complex and data-poor systems, where beneficial (e.g. mutualism) and harmful (e.g. competition) interactions may operate simultaneously within and between species.

We present a model of population dynamics that can describe a wide range of ecological interaction outcomes with a simple, unified structure. Species growth rates are constrained by a maximum growth rate parameter which prevents the risk of population explosions even in the case of mutualism. Species interactions are defined by two, not mutually-exclusive interactions matrices that describe the effects of beneficial and harmful interactions respectively, together providing the potential for the net effect of interactions between one species and another to switch from beneficial to harmful as population density increases.

This model recreates classic dynamics in two-species mutualistic, competitive, and predator-prey scenarios, allowing us to model a wide range of trophic levels and interaction types together within the same equation. The maximum growth rate parameter, theoretically based in intrinsic constraints on reproduction, can be parameterised from a wide range of sources including natural history, historical data, and breeding programs. We illustrate the potential of this model with a data-poor case study of a threatened species and two interacting predators.

This new model is generaliseable to a wide range of natural ecological communities. Its model structure lowers data requirements whilst remaining intuitive and biologically realistic, making it an accessible option for predicting community-wide population changes in applied contexts where data is sparse and/or uncertain.
Design, rationale, and baseline characteristics of the SONIC-HF multicenter registry
Authors: Kagiyama Nobuyuki , Kamiya Kentaro , Toki Misako , Saito Hiroshi , Iwata Kentaro , Matsue Yuya , Yoshioka Kenji , Saito Kazuya , Murata Azusa , Hayashida Akihiro , Ako Junya , Kitai Takeshi , Maekawa Emi
Published: October 2024

Background

Skeletal muscle mass and function are crucial for assessing physical frailty, sarcopenia, and cachexia, which significantly impact the prognosis of geriatric patients with heart failure (HF). Ultrasound-based assessment of skeletal muscles offers a non-invasive, real-time alternative to traditional methods. ThecompariSON of various methods In evaluatIon of sarCopenia in patients with Heart Failurestudy (SONIC-HF) aimed to evaluate the feasibility and prognostic impact of ultrasound-based muscle assessment in geriatric patients with HF.

Methods

This multicenter, prospective cohort study enrolled HF patients aged ≥65 years who could ambulate independently at discharge. Certified observers assessed muscle thickness (biceps, quadriceps, rectus femoris, and diaphragm) using ultrasound at rest and during contraction. The primary endpoint was all-cause mortality. Secondary endpoints included HF hospitalization, unplanned hospital visits, and cardiovascular and non-cardiovascular mortality.

Results

Of the 692 enrolled patients (median age 81 (IQR 74–86) years, 57.6% female, left ventricular ejection fraction 45% (32%–60%)), ultrasound-based muscle assessments were completed in 606 patients. Interobserver reliability was excellent (intraclass correlation coefficient 0.84–0.99). Median muscle thicknesses at rest and during contraction were: diaphragm 1.9 (1.6–2.3) mm and 2.9 (2.3–3.8) mm; biceps 19.6 (15.9–23.1) mm and 25.3 (21.3–29.5) mm; quadriceps 19.0 (15.0–23.5) mm and 24.8 (19.9–29.5) mm; rectus femoris 9.7 (7.1–12.3) mm and 12.1 (9.6–15.0) mm. The median follow-up time was 733.5 (438–882) days.

Conclusions

The SONIC-HF registry will provide valuable insights into the feasibility and prognostic implications of ultrasound-based muscle assessment in geriatric patients with HF.
Imaging, Pulmonary Function, and Histopathologic Findings of Persistent Fibrosis in a Longitudinal Cohort Three Years after Severe COVID-19 Infection
Authors: Murphy Scarlett O. , McGroder Claire F. , Salvatore Mary M. , D’Souza Belinda M. , Capaccione Kathleen M. , Saqi Anjali , Shaikh Faisal , Benesh Shannon , Zhang David , Baldwin Matthew R. , Garcia Christine Kim
Published: October 2024

Fibrotic-like abnormalities are present in 60% of a single-center, longitudinal, multi-ethnic cohort 3-years after severe COVID-19. They are independently associated with male sex, low BMI, shorter telomere length, increased severity of illness, and mechanical ventilation; Black race and asthma are protective. Participants with fibrotic-like abnormalities are more likely to have reduced diffusion capacity and 6-minute walk distance. Fibrotic-like abnormalities persist but modestly improve over time. Transbronchial biopsies show small airways histopathology, consistent with high prevalence of air trapping in expiration, and infrequent interstitial thickening. This study highlights the need for continued monitoring of patients with persistent fibrosis after severe COVID-19.