Drug resistant pancreatic cancer cells exhibit altered biophysical interactions with stromal fibroblasts in imaging studies of 3D co-culture models.

Interactions between tumor and stromal cells are well known to play a prominent roles in progression of pancreatic ductal adenocarcinoma (PDAC). As knowledge of stromal crosstalk in PDAC has evolved, it has become clear that cancer associated fibroblasts can play both tumor promoting and tumor suppressive roles through a combination of paracrine crosstalk and juxtacrine interactions involving direct physical contact. Another major contributor to dismal survival statistics for PDAC is development of resistance to chemotherapy drugs. Though less is known about how the acquisition of chemoresistance impacts upon tumor-stromal crosstalk. Here, we use 3D co-culture geometries to recapitulate juxtacrine interactions between epithelial and stromal cells. In particular, extracellular matrix (ECM) overlay cultures in which stromal cells (pancreatic stellate cells, or normal human fibroblasts) are placed adjacent to PDAC cells (PANC1), result in direct heterotypic cell adhesions accompanied by dramatic fibroblast contractility which leads to highly condensed macroscopic multicellular aggregates as detected using particle image velocimetry (PIV) analysis to quantify cell velocities over the course of time lapse movie sequences. To investigate how drug resistance impacts these juxtacrine interactions we contrast cultures in which PANC1 are substituted with a drug resistant subline (PANC1-OR) previously established in our lab. We find that heterotypic cell-cell interactions are highly suppressed in drug-resistant cells relative to the parental PANC1 cells. To investigate further we conduct RNA-seq and bioinformatics analysis to identify differential gene expression in PANC1 and PANC1-OR, which shows that negative regulation of cell adhesion molecules, consistent with increased epithelial mesenchymal transition (EMT), is also consistent with loss of hetrotypic cell-cell contact necessary for the contractile behavior observed in drug naïve cultures. Overall these findings elucidate the role of drug-resistance in inhibiting an avenue of stromal crosstalk which is associated with tumor suppression and also help to establish cell culture conditions useful for further mechanistic investigation.

RNA Sequencing Reveals Candidate Genes and Pathways Associated with Resistance to MDM2 Antagonist Idasanutlin in TP53 Wild-Type Chronic Lymphocytic Leukemia.

Chronic lymphocytic leukemia (CLL) is a genetically and clinically diverse hematological cancer affecting middle-aged and elderly individuals. Novel targeted therapy options are needed for patients who relapse following initial responses or who are intrinsically resistant to current treatments. There is a growing body of investigation currently underway on MDM2 inhibitors in clinical trials, reflecting the increasing interest in including these drugs in cancer treatment regimens. One of the developed compounds, idasanutlin (RG7388), has shown promise in early-stage clinical trials. It is a second-generation MDM2-p53-binding antagonist with enhanced potency, selectivity, and bioavailability. In addition to the TP53 status, which is an important determinant of the response, we have shown in our previous studies that the SF3B1 mutational status is also an independent predictive biomarker of the ex vivo CLL patient sample treatment response to RG7388. The objective of this study was to identify novel biomarkers associated with resistance to RG7388. Gene set enrichment analysis of differentially expressed genes (DEGs) between RG7388-sensitive and -resistant CLL samples showed that the increased p53 activity led to upregulation of pro-apoptosis pathway genes while DNA damage response pathway genes were additionally upregulated in resistant samples. Furthermore, differential expression of certain genes was detected, which could serve as the backbone for novel combination treatment approaches. This research provides preclinical data to guide the exploration of drug combination strategies with MDM2 inhibitors, leading to future clinical trials and associated biomarkers that may improve outcomes for CLL patients.

Odorant transport in a hagfish.

Odorant transport is of fundamental and applied importance. Using computational simulations, we studied odorant transport in an anatomically accurate model of the nasal passage of a hagfish (probably Eptatretus stoutii). We found that ambient water is sampled widely, with a significant ventral element. Additionally, there is a bilateral element to olfactory flow, which enters the single nostril in two narrow, laminar streams that are then split prior to the nasal chamber by the anterior edge of the central olfactory lamella. An appendage on this lamella directs a small portion (10-14%) of the overall nasal flow to the olfactory sensory channels. Much of the remaining flow is diverted away from the sensory channels by two peripheral channels. The anterior edge of the central olfactory lamella, together with a jet-impingement mechanism, disperses flow over the olfactory surfaces. Diffusion of odorant from bulk water to the olfactory surfaces is facilitated by the large surface area:volume ratio of the sensory channels, and by a resistance-based hydrodynamic mechanism that leads to long residence times (up to 4.5 s) in the sensory channels. With increasing volumetric flow rate, the rate of odorant transfer to the olfactory surfaces increases, but the efficiency of odorant uptake decreases, falling in the range 2-6%. Odorant flux decreases caudally across the olfactory surfaces, suggesting in vivo a preponderance of olfactory sensory neurons on the anterior part of each olfactory surface. We conclude that the hagfish has a sophisticated anatomy for locating and capturing odorant molecules.

Peri active site catalysis of proline isomerisation is the molecular basis of allomorphy in ß-phosphoglucomutase.

Metabolic regulation occurs through precise control of enzyme activity. Allomorphy is a post-translational fine control mechanism where the catalytic rate is governed by a conformational switch that shifts the enzyme population between forms with different activities. ß-Phosphoglucomutase (ßPGM) uses allomorphy in the catalysis of isomerisation of ß-glucose 1-phosphate to glucose 6-phosphate via ß-glucose 1,6-bisphosphate. Herein, we describe structural and biophysical approaches to reveal its allomorphic regulatory mechanism. Binding of the full allomorphic activator ß-glucose 1,6-bisphosphate stimulates enzyme closure, progressing through NAC I and NAC III conformers. Prior to phosphoryl transfer, loops positioned on the cap and core domains are brought into close proximity, modulating the environment of a key proline residue. Hence accelerated isomerisation, likely via a twisted anti/C4-endo transition state, leads to the rapid predominance of active cis-P ßPGM. In contrast, binding of the partial allomorphic activator fructose 1,6-bisphosphate arrests ßPGM at a NAC I conformation and phosphoryl transfer to both cis-P ßPGM and trans-P ßPGM occurs slowly. Thus, allomorphy allows a rapid response to changes in food supply while not otherwise impacting substantially on levels of important metabolites.

Validation of Quality Assessment Measures for Inpatient Gastroenterology Consults on Oncologic Patients in Non-teaching Services at a Cancer Center: A Cross-Sectional Study.

OBJECTIVE: To develop and validate tools for measuring inpatient gastroenterology (GI) consultation quality on oncologic patients. METHODS: A total of 145 inpatient GI consults were analyzed using electronic health records in this cross-sectional study. Essential Consult Elements on oncologic-hospitalized patients (EE-COH) and Hospitalized Oncologic Patients Enhanced Quality of Consult Assessment Tool (HOPE-QCAT) were used for grading. Interrater reliability was assessed. RESULTS: Both EE-COH and HOPE-QCAT showed near-perfect interrater reliability across most measures in the validation cohort. On application of these measures for quality assessment, basic evaluation by the requesting hospitalist was partially complete in 24.8%, the request for GI consultation was inappropriate in 18.6%, while the rationale for recommended studies from the GI consultant was provided in 55.7% of cases suggesting key areas for quality improvement. CONCLUSION: We developed highly reliable quality measures for inpatient GI consults on oncology patients. The EE-COH and HOPE-QCAT tools can be utilized in future studies of inpatient GI consult quality and to form the basis for interventions to improve communication between consultants and hospitalists. Such tools could be adapted for inpatient quality assessment across other specialties and settings.

Bioactive alkaloids from Nepalese Corydalis chaerophylla D.C. acting on the regulation of PCSK9 and LDL-R in vitro.

Four new alkaloids Chaeronepaline-A (1), Chaeronepaline-B (2), Chaeronepaline-C (3), and Chaeronepaline-D (4) were isolated from Corydalis chaerophylla D.C. collected from Nepal and their structures were elucidated by spectroscopic data, 1D, 2D NMR and mass spectrometry. The structures were established as 3,12- Dimethoxy-5,6-dihydroisoquinolino [2,1-b] isoquinolin- 7- ium- 2, 9- diol (1), 7-methyl-5, 6, 7, 8-tetrahydroisoquinoline- 2, 3- methylenedioxy- (8-> 9)- 10, 12- methylenedioxy- benzoic-16-acid (2), 7- methyl-5, 6, 7, 8- tetrahydro- 8H-spiro-9,14-dihydroxy-11,12-methylenedioxy-indane-isoquinoline (3) and 7- methyl-5, 6, 7, 8- tetrahydro- 8H-spiro-9,14-dihydroxy-11,12-methylenedioxy-indane-isoquinoline-N-oxide (4). The new alkaloids were tested in human hepatoma cell line to assess their ability to modulate the expression of low-density lipoprotein receptor (LDL-R), of proprotein convertase subtilisin/kexin 9 (PCSK9) and to affect cellular cholesterol biosynthesis with the aim to evaluate their potential hypocholesterolemic effect. Results indicated that compounds 2 and 3 upregulate the LDLR, and inhibited the cholesterol biosynthesis with compound 2, which also reduced the secretion of PCSK9 by Huh7 cells. These in vitro data indicated a potential hypocholesterolemic effect of compound 2 that requires further in vivo validation.

Phagotrophy in the nitrogen-fixing haptophyte Braarudosphaera bigelowii.

Biological nitrogen fixation provides fixed nitrogen for microbes living in the oligotrophic open ocean. UCYN-A2, the previously known symbiont of Braarudosphaera bigelowii, now believed to be an early-stage B. bigelowii organelle that exchanges fixed nitrogen for fixed carbon, is globally distributed. Indirect evidence suggested that B. bigelowii might be a mixotrophic (phagotrophic) phototrophic flagellate. The goal of this study was to determine if B. bigelowii can graze on bacteria using several independent approaches. The results showed that B. bigelowii grazed on co-occurring bacteria at a rate of 5-7 cells/h/B. bigelowii and that the overall grazing rate was significantly higher at nighttime than at daytime. Bacterial abundance changes, assessed with 16S rRNA gene amplicon sequencing analysis, may have indicated preferential grazing by B. bigelowii on specific bacterial genotypes. In addition, Lysotracker™ staining of B. bigelowii suggested digestive activity inside B. bigelowii. Carbon and nitrogen fixation measurements revealed that the carbon demand of B. bigelowii could not be fulfilled by photosynthesis alone, implying supplementation by heterotrophy. These independent lines of evidence together revealed that B. bigelowii engages in phagotrophy, which, beyond serving as a supplementary source of carbon and energy, may also facilitate the indirect assimilation of inorganic nutrients.

Improving the hemocompatibility of a porohyperelastic layered vascular graft using luminal reversal microflows.

Vascular graft thrombosis is a long-standing clinical problem. A myriad of efforts have been devoted to reducing thrombus formation following bypass surgery. Researchers have primarily taken a chemical approach to engineer and modify surfaces, seeking to make them more suitable for blood contacting applications. Using mechanical forces and surface topology to prevent thrombus formation has recently gained more attention. In this study, we have designed a bilayered porous vascular graft capable of repelling platelets and destabilizing absorbed protein layers from the luminal surface. During systole, fluid penetrates through the graft wall and is subsequently ejected from the wall into the luminal space (Luminal Reversal Flow - LRF), pushing platelets away from the surface during diastole. In-vitro hemocompatibility tests were conducted to compare platelet deposition in high LRF grafts with low LRF grafts. Graft material properties were determined and utilized in a porohyperelastic (PHE) finite element model to computationally predict the LRF generation in each graft type. Hemocompatibility testing showed significantly lower platelet deposition values in high versus low LRF generating grafts (median±IQR = 5,708 ± 987 and 23,039 ± 3,310 platelets per mm2, respectively, p=0.032). SEM imaging of the luminal surface of both graft types confirmed the quantitative blood test results. The computational simulations of high and low LRF generating grafts resulted in LRF values of -10.06 µm/s and -2.87 µm/s, respectively. These analyses show that a 250% increase in LRF is associated with a 75.2% decrease in platelet deposition. PHE vascular grafts with high LRF have the potential to improve anti-thrombogenicity and reduce thrombus-related post-procedure complications. Additional research is required to overcome the limitations of current graft fabrication technologies that further enhance LRF generation.

How Humans Run Faster: The Neuromechanical Contributions of Functional Muscle Groups to Running at Different Speeds.

How the neuromechanics of the lower limb functional muscle groups change with running speed remains to be fully elucidated, with implications for our understanding of human locomotion, conditioning, and injury prevention. This study compared the neuromechanics (ground reaction and joint kinetics, kinematics and muscle activity) of middle-distance athletes running on an instrumented treadmill at six wide-ranging speeds (2.78-8.33 m·s-1). Ground reaction forces and kinematics were analyzed using inverse dynamics to calculate flexor and extensor joint torques, and positive and negative work done by these torques. Contributions of each functional muscle group to the total positive and negative work done by the limb during stance, swing, and the whole stride were quantified. During stance, the ankle plantar flexors were the major energy generator and absorber (>60%) at all speeds, but their contribution to whole stride energy generation and absorption declined with speed. Positive work by the hip extensors rose superlinearly with speed during stance (3-fold) and especially during swing (12-fold), becoming the biggest energy generator across the whole stride at >5 m·s-1. Knee flexor and extensor negative work also rose superlinearly with speed during swing, with the knee flexors becoming the greatest energy absorber over the whole stride at >7.22 m·s-1. Across speeds, plantar flexor peak moment and positive work accounted for 97% and 96% of the variance in step length, and swing hip extension peak moment and positive work accounted for 98% and 99% of the variance in step frequency. There were pronounced speed, phase (stance/swing), and work (positive/negative) dependent contributions of the different functional muscle groups during running, with extensive implications for conditioning and injury prevention.

Variations in candidalysin amino acid sequence influence toxicity and host responses.

Candida albicans causes millions of mucosal infections in humans annually. Hyphal overgrowth on mucosal surfaces is frequently associated with tissue damage caused by candidalysin, a secreted peptide toxin that destabilizes the plasma membrane of host cells thereby promoting disease and immunopathology. Candidalysin was first identified in C. albicans strain SC5314, but recent investigations have revealed candidalysin "variants" of differing amino acid sequence in isolates of C. albicans, and the related species C. dubliniensis, and C tropicalis, suggesting that sequence variation among candidalysins may be widespread in natural populations of these Candida species. Here, we analyzed ECE1 gene sequences from 182 C. albicans isolates, 10 C. dubliniensis isolates, and 78 C. tropicalis isolates and identified 10, 3, and 2 candidalysin variants in these species, respectively. Application of candidalysin variants to epithelial cells revealed differences in the ability to cause cellular damage, changes in metabolic activity, calcium influx, MAPK signalling, and cytokine secretion, while biophysical analyses indicated that variants exhibited differences in their ability to interact with and permeabilize a membrane. This study identifies candidalysin variants with differences in biological activity that are present in medically relevant Candida species. IMPORTANCE: Fungal infections are a significant burden to health. Candidalysin is a toxin produced by Candida albicans that damages host tissues, facilitating infection. Previously, we demonstrated that candidalysins exist in the related species C. dubliniensis and C. tropicalis, thereby identifying these molecules as a toxin family. Recent genomic analyses have highlighted the presence of a small number of candidalysin "variant" toxins, which have different amino acid sequences to those originally identified. Here, we screened genome sequences of isolates of C. albicans, C. dubliniensis, and C. tropicalis and identified candidalysin variants in all three species. When applied to epithelial cells, candidalysin variants differed in their ability to cause damage, activate intracellular signaling pathways, and induce innate immune responses, while biophysical analysis revealed differences in the ability of candidalysin variants to interact with lipid bilayers. These findings suggest that intraspecies variation in candidalysin amino acid sequence may influence fungal pathogenicity.

Management and Outcomes of Hepatoblastoma in Patients With Trisomy 18: A Systematic Review and Pooled Analysis of 70 Patients.

INTRODUCTION: Predicted 1-year survival of children with trisomy 18 (T18) has increased to 59.3%. We aimed to systematically review the characteristics, management, and outcomes of children with T18 and hepatoblastoma. METHODS: A systematic literature review of the PubMed, Embase, Scopus, Web of Science, and Cochrane Library databases was performed according to the PRISMA 2020 statement (end-of-search date: 03/03/2024). RESULTS: Fifty studies reporting on 70 patients were included. The median age at diagnosis was 11.5 months, 85.9% were female (n = 55/64), and 15.0% had mosaic T18 (n = 6/40). Diagnosis was made during symptom evaluation (most commonly hepatomegaly or abdominal mass) in 45.5% (n = 15/33), incidentally in 24.2% (n = 8/33), during surveillance with abdominal ultrasound in 18.2% (n = 6/33), and at autopsy in 12.1% (n = 4/33). The median tumor size was 6.4 cm, 33.3% had multiple tumors (n = 14/42), and metastasis was present in one patient (3.8%; n = 1/26). Neoadjuvant chemotherapy was administered in 42.6% (n = 26/61) and adjuvant chemotherapy in 31.6% (n = 18/57). Surgical treatment was performed in 64.2% (n = 43/67). Of the patients not diagnosed on autopsy, overall mortality was 35.5% (n = 22/62) over a median follow-up of 11.0 months. Among the 26 deceased patients (including those diagnosed on autopsy), the most common causes of death were cardiopulmonary disease (38.5%, n = 10/26) and tumor progression (30.8%, n = 8/26). CONCLUSIONS: T18 does not preclude resection with curative intent for hepatoblastoma. Combination of surgery and chemotherapy should be considered in children on an individualized basis depending on tumor characteristics and underlying cardiopulmonary comorbidities. Locoregional modalities may have a role in the setting of severe comorbidities. LEVEL OF EVIDENCE: Level IV evidence.

Rapid mode switching facilitates the growth of Trichodesmium: A model analysis.

Trichodesmium is one of the dominant dinitrogen (N2) fixers in the ocean, influencing global carbon and nitrogen cycles through biochemical reactions. Although its photosynthetic activity fluctuates rapidly, the physiological or ecological advantage of this fluctuation is unclear. We develop a metabolic model of Trichodesmium that can perform daytime N2 fixation. We examined (1) the effect of the duration of switches between photosynthetic and non-photosynthetic cellular states and (2) the effect of the presence and absence of N2 fixation in photosynthetic states. Results show that a rapid switch between photosynthetic and non-photosynthetic states increases Trichodesmium growth rates by improving metabolic efficiencies due to an improved balance of C and N metabolism. This provides a strategy for previous paradoxical observations that all Trichodesmium cells can contain nitrogenase. This study reveals the importance of fluctuating photosynthetic activity and provides a mechanism for daytime N2 fixation that allows Trichodesmium to fix N2 aerobically in the global ocean.

Mommy's microbes: Gestational diabetes mellitus shapes the maternal and infant gut microbiome.

Gestational diabetes mellitus (GDM) is associated with increased risk of metabolic and neurodevelopmental disorders in offspring. In this issue of Cell Host & Microbe, Wang et al. provide evidence that changes in the gut microbiome of mothers with GDM may lead to dysbiosis in their infants and altered development in a sex-dependent manner.

Uses of infrared thermography in acute illness: a systematic review.

Introduction: Infrared thermography (IRT) is a non-contact, non-ionising imaging modality, providing a visual representation of temperature distribution across a surface. Methods: We conducted a systematic search of indexed and grey literature for studies investigating IRT applications involving patients in acute care settings. Studies were categorised and described along themes identified iteratively using narrative synthesis. Quality appraisal of included studies was performed using the Quality Assessment tool for Diagnostic Accuracy Studies. Results: Of 1,060 unique records, 30 studies were included. These were conducted in emergency departments and intensive care units involving adult, paediatric and neonatal patients. IRT was studied for the diagnosis, monitoring or risk stratification of a wide range of individual conditions. IRT was predominantly used to display thermal change associated with localised inflammation or microcirculatory dysfunction. Existing research is largely at an early developmental stage. Discussion: We recommend that high quality diagnostic validation studies are now required for some clinical applications. IRT has the potential to be a valuable tool in the acute care setting and represents an important area for future research particularly when combined with advances in machine learning technology. Systematic review registration: CRD 42022327619 (https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=327619).

Impact and effect of imaging referral guidelines on patients and radiology services: a systematic review.

OBJECTIVES: The objective of this systematic review was to offer a comprehensive overview and explore the associated outcomes from imaging referral guidelines on various key stakeholders, such as patients and radiologists. MATERIALS AND METHODS: An electronic database search was conducted in Medline, Embase and Web of Science to retrieve citations published between 2013 and 2023. The search was constructed using medical subject headings and keywords. Only full-text articles and reviews written in English were included. The quality of the included papers was assessed using the mixed methods appraisal tool. A narrative synthesis was undertaken for the selected articles. RESULTS: The search yielded 4384 records. Following the abstract, full-text screening, and removal of duplication, 31 studies of varying levels of quality were included in the final analysis. Imaging referral guidelines from the American College of Radiology were most commonly used. Clinical decision support systems were the most evaluated mode of intervention, either integrated or standalone. Interventions showed reduced patient radiation doses and waiting times for imaging. There was a general reduction in radiology workload and utilisation of diagnostic imaging. Low-value imaging utilisation decreased with an increase in the appropriateness of imaging referrals and ratings and cost savings. Clinical effectiveness was maintained during the intervention period without notable adverse consequences. CONCLUSION: Using evidence-based imaging referral guidelines improves the quality of healthcare and outcomes while reducing healthcare costs. Imaging referral guidelines are one essential component of improving the value of radiology in the healthcare system. CLINICAL RELEVANCE STATEMENT: There is a need for broader dissemination of imaging referral guidelines to healthcare providers globally in tandem with the harmonisation of the application of these guidelines to improve the overall value of radiology within the healthcare system. KEY POINTS: The application of imaging referral guidelines has an impact and effect on patients, radiologists, and health policymakers. The adoption of imaging referral guidelines in clinical practice can impact healthcare costs and improve healthcare quality and outcomes. Implementing imaging referral guidelines contributes to the attainment of value-based radiology.

Immune aging: biological mechanisms, clinical symptoms, and management in lung transplant recipients.

While chronologic age can be precisely defined, clinical manifestations of advanced age occur in different ways and at different rates across individuals. The observed phenotype of advanced age likely reflects a superposition of several biological aging mechanisms which have gained increasing attention as the world contends with an aging population. Even within the immune system, there are multiple age-associated biological mechanisms at play, including telomere dysfunction, epigenetic dysregulation, immune senescence programs, and mitochondrial dysfunction. These biological mechanisms have associated clinical syndromes, such as telomere dysfunction leading to short telomere syndrome (STS), and optimal patient management may require recognition of biologically based aging syndromes. Within the clinical context of lung transplantation, select immune aging mechanisms are particularly pronounced. Indeed, STS is increasingly recognized as an indication for lung transplantation. At the same time, common aging phenotypes may be evoked by the stress of transplantation because lung allografts face a potent immune response, necessitating higher levels of immune suppression and associated toxicities, relative to other solid organs. Age-associated conditions exacerbated by lung transplant include bone marrow suppression, herpes viral infections, liver cirrhosis, hypogammaglobulinemia, frailty, and cancer risk. This review aims to dissect the molecular mechanisms of immune aging and describe their clinical manifestations in the context of lung transplantation. While these mechanisms are more likely to manifest in the context of lung transplantation, this mechanism-based approach to clinical syndromes of immune aging has broad relevance to geriatric medicine.

The mind wanders to dark places: Mind-wandering catalyzes rumination in the context of negative affect and impulsivity.

Spontaneous mind-wandering has been theorized to increase susceptibility for rumination, contributing to risk for major depressive disorder (MDD). Clarifying whether-and under what circumstances-mind-wandering leads to rumination could inform the development of targeted interventions to reduce risk for ruminative sequelae. Using intensively sampled data in 44 young adults with remitted MDD and 38 healthy volunteers with 1,558 total observations collected from 2018 to 2022, we conducted multilevel models to investigate temporal relationships between mind-wandering and rumination. Contextual factors (e.g., intensity of negative affect; momentary impulsivity) and individual factors (e.g., MDD history) were examined as moderators of these relationships. Mind-wandering predicted increased rumination, whereas rumination did not predict increased mind-wandering. When individuals experienced greater negative affect or acted more impulsively compared to their usual levels, they showed a stronger relationship between mind-wandering and subsequent rumination. Depression history did not significantly moderate temporal relationships between mind-wandering and rumination. Spontaneous mind-wandering may transition into rumination, particularly during moments when people experience more negative affect or impulsivity compared to usual. Delivering interventions in these moments could reduce risk for ruminative sequelae. The tendency to ruminate in response to mind-wandering is suggested to be consistent regardless of depression history, suggesting the transdiagnostic and dimensional nature of rumination as a possible consequence of mind-wandering. Future work is needed to determine whether these associations are generalizable across the lifespan. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Time from admission to randomization and the effect of empagliflozin in acute heart failure: A post-hoc analysis from EMPULSE.

AIMS: Patients hospitalized for acute heart failure (HF) could be enrolled in EMPULSE (NCT04157751) upon haemodynamic stabilization and between 24 h and 5 days after hospital admission. The timing of treatment initiation may influence the efficacy and safety of drugs such as empagliflozin. The aim of this study was to evaluate patient characteristics, clinical events, and treatment effects according to time from admission to randomization. METHODS AND RESULTS: The EMPULSE population was dichotomized by median time from hospital admission to randomization (1-2 days vs. 3-5 days). The primary outcome was a hierarchical composite endpoint of time to all-cause death, number of HF events, time to first HF event, and a ≥5-point difference in Kansas City Cardiomyopathy Questionnaire total symptom score change from baseline after 90 days, analysed using the win ratio (WR) method. Patients randomized later (3-5 days, average time 3.9 days; n = 312) had a higher risk of experiencing clinical events than patients randomized earlier (1-2 days, average time 1.7 days; n = 215). The treatment effect favoured empagliflozin versus placebo in patients randomized later (3-5 days: WR 1.69, 95% confidence interval [CI] 1.26-2.25) but was attenuated in patients randomized earlier (1-2 days: WR 1.04, 95% CI 0.74-1.44) (interaction p = 0.029). A similar pattern was observed for the composite of HF hospitalization or cardiovascular death and all-cause hospitalizations (interaction p < 0.1 for both). The reduction of N-terminal pro-B-type natriuretic peptide levels was more pronounced with empagliflozin among patients randomized later than in patients randomized earlier (interaction p = 0.004). CONCLUSIONS: Among patients hospitalized for acute HF enrolled in EMPULSE, those randomized later after hospital admission (3-5 days) experienced greater clinical benefit with empagliflozin than those randomized earlier (1-2 days). These findings should be confirmed in future studies before clinical application.

A comparison of techniques to determine active motor threshold for transcranial magnetic stimulation research.

The determination of active motor threshold (AMT) is a critical step in transcranial magnetic stimulation (TMS) research. As AMT is frequently determined using an absolute electromyographic (EMG) threshold (e.g., 200 µV peak-to-peak amplitude), wide variation in EMG recordings across participants has given reason to consider relative thresholds (e.g., = 2 × background sEMG) for AMT determination. However, these approaches have not been systemically compared. Our purpose was to compare AMT estimations derived from absolute and relative criteria commonly used in the quadriceps, and assess the test-retest reliability of each approach. We used a repeated measures design to assess AMT estimations in the vastus lateralis (VL) from eighteen young adults (9 males and 9 females; mean ± SD age = 23 ± 2 years) across two laboratory visits. AMT was determined for each criterion, at each lab visit. A paired samples t-test was used to compare mean differences in AMT estimations during the second laboratory visit. Paired samples t-tests and intraclass correlation coefficients (ICC2,1) were calculated to assess test-retest reliability of each criterion. Differences between the criteria were small and not statistically significant (p = 0.309). The absolute criterion demonstrated moderate to excellent reliability (ICC2,1 = 0.866 [0.648-0.950]), but higher AMTs were observed in the second visit (p = 0.043). The relative criteria demonstrated good-to-excellent test-retest reliability (ICC2,1 = 0.894 [0.746-0.959]) and AMTs were not different between visits (p = 0.420). TMS researchers aiming to track corticospinal characteristics across visits should consider implementing relative criterion approaches during their AMT determination protocol.