The prognostic effect of mechanical, ultrastructural, and ECM signatures in glioblastoma core and rim.

Glioblastoma (GBM) is a highly invasive, aggressive brain cancer that carries a median survival of 15 months and is resistant to standard therapeutics. Recent studies have demonstrated that intratumoral heterogeneity plays a critical role in promoting resistance by mediating tumor adaptation through microenvironmental cues. GBM can be separated into two distinct regions-a core and a rim, which are thought to drive specific aspects of tumor evolution. These differences in tumor progression are regulated by the diverse biomolecular and biophysical signals in these regions, but the acellular biophysical characteristics remain poorly described. This study investigates the mechanical and ultrastructural characteristics of the tumor extracellular matrix (ECM) in patient-matched GBM core and rim tissues. Seven patient-matched tumor core and rim samples and one non-neoplastic control were analyzed using atomic force microscopy, scanning electron microscopy, and immunofluorescence imaging to quantify mechanical, ultrastructural, and ECM composition changes. The results reveal significant differences in biophysical parameters between GBM core, rim, and non-neoplastic tissues. The GBM core is stiffer, denser, and is rich in ECM proteins hyaluronic acid and tenascin-C when compared to tumor rim and non-neoplastic tissues. These alterations are intimately related and have prognostic effect with stiff, dense tissue correlating with longer progression-free survival. These findings reveal new insights into the spatial heterogeneity of biophysical parameters in the GBM tumor microenvironment and identify a set of characteristics that may correlate with patient prognosis. In the long term, these characteristics may aid in the development of strategies to combat therapeutic resistance.

Unanticipated loss of inflammasomes in birds.

Inflammasomes are multiprotein complexes that form in response to ligands originating from pathogens as well as alterations of normal cell physiology caused by infection or tissue damage. These structures engage a robust inflammatory immune response that eradicates environmental microbes before they cause disease, and slow the growth of bona fide pathogens. Despite their undeniable utility in immunity, inflammasomes are radically reduced in birds. Perhaps most surprising is that, within all birds, NLRP3 is retained, while its signaling adapter ASC is lost, suggesting that NLRP3 signals via a novel unknown adapter. Crocodilian reptiles and turtles, which share a more recent common ancestor with birds, retain many of the lost inflammasome components, indicating that the deletion of inflammasomes occurred after birds diverged from crocodiles. Some bird lineages have even more extensive inflammasome loss, with songbirds continuing to pare down their inflammasomes until only NLRP3 and CARD8 remain. Remarkably, songbirds have lost caspase-1 but retain the downstream targets of caspase-1: IL-1ß, IL-18, and the YVAD-linker encoding gasdermin A. This suggests that inflammasomes can signal through alternative proteases to activate cytokine maturation and pyroptosis in songbirds. These observations may reveal new contexts of activation that may be relevant to mammalian inflammasomes, and may suggest new avenues of research to uncover the enigmatic nature of the poorly understood NLRP3 inflammasome.

Phase I clinical trial of the feasibility and safety of direct peritoneal resuscitation in liver transplantation.

BACKGROUND: Direct peritoneal resuscitation (DPR) is associated with improved outcomes in trauma. Animal models suggest DPR has favorable effects on the liver. We sought to evaluate its safety and assess for improved outcomes in liver transplantation (LT). METHODS: LT patients with renal dysfunction and/or obesity were enrolled in a phase-I clinical trial. DPR lasted 8-24 â€‹h depending on postoperative disposition. Primary outcome was percent of patients completing DPR. Secondary outcomes evaluated complications. Controls with either obesity (control-1) or both risk factors (obesity â€‹+ â€‹renal dysfunction, control-2) were analyzed. RESULTS: Fifteen patients were enrolled (seven with both criteria and eight with obesity alone). DPR was completed in 87 â€‹% of patients, with one meeting stopping criteria. Controls included 45 (control-1) and 24 (control-2) patients. Return to operating room, graft loss, and late infections were lower with DPR. CONCLUSION: DPR appears to be safe in closed abdomens following LT, warranting a follow-up phase-II trial to assess efficacy.

Improving postsurgical fall detection for older Americans using LLM-driven analysis of clinical narratives.

Postsurgical falls have significant patient and societal implications but remain challenging to identify and track. Detecting postsurgical falls is crucial to improve patient care for older adults and reduce healthcare costs. Large language models (LLMs) offer a promising solution for reliable and automated fall detection using unstructured data in clinical notes. We tested several LLM prompting approaches to postsurgical fall detection in two different healthcare systems with three open-source LLMs. The Mixtral-8×7B zero-shot had the best performance at Stanford Health Care (PPV = 0.81, recall = 0.67) and the Veterans Health Administration (PPV = 0.93, recall = 0.94). These results demonstrate that LLMs can detect falls with little to no guidance and lay groundwork for applications of LLMs in fall prediction and prevention across many different settings.

Potentiation of BKCa channels by cystic fibrosis transmembrane conductance regulator (CFTR) correctors VX-445 and VX-121.

Cystic fibrosis (CF) results from mutations in the CFTR anion channel, ultimately leading to diminished transepithelial anion secretion and mucociliary clearance. CFTR correctors are therapeutics that restore the folding/trafficking of mutated CFTR to the plasma membrane. The BKCa potassium channel is also critical for maintaining lung ASL volume. Here, we show the CFTR corrector, VX-445 (Elexacaftor), a component of Trikafta, induces K+ secretion across WT and F508del CFTR primary human bronchial epithelial cells (HBEs), which was entirely inhibited by the BKCa antagonist paxilline. Similar results were observed with VX-121 - a corrector under clinical evaluation. Whole-cell patch-clamp recordings confirmed potentiated channel activity from CFTR correctors on the BKCa α-subunit, and excised patch-clamp recordings demonstrated a significant increase in open probability. In mesenteric artery, VX-445 induced a paxilline-sensitive vasorelaxation of preconstricted arteries. VX-445 also reduced action potential firing frequency in primary hippocampal and cortical neurons. VX-445 effects were observed at low micomolar concentrations (1-10 µM) - within the range reported in plasma and tissues from CF patients. We raise the possibilities that CFTR correctors gain additional clinical benefit by activation of BKCa in the lung, yet may lead to adverse events through BKCa activation, elsewhere.

Firearm Injury, It's Not Just Physical: The Adverse Impact on Patient-Reported Socioeconomic, Mental Health, and Quality-of-Life Outcomes.

Background: The burden of firearm injury (FI) extends beyond hospitalization; however, literature focuses mostly on short-term physical outcomes. This study aimed to assess changes in patient-reported outcomes following firearm-related trauma. We hypothesized long-term patient-reported socioeconomic, mental health, and quality-of-life (QoL) outcomes are worse post-FI compared to pre-FI.Methods: This was a retrospective study where a phone survey was conducted with FI survivors admitted between January 2017 and August 2022 at a level 1 trauma center. Survey questions assessed demographics, socioeconomics, and mental and physical health pre-FI vs ≥ 6 months post-FI; the McNemar test was used for comparisons. The PROMIS-29 + 2v2.1 NIH validated instrument was used to assess long-term QoL. Standardized NIH PROMIS T-scores were calculated using the HealthMeasures Scoring Service.Results: Of 204 eligible FI survivors, 71 were successfully contacted and 38 surveyed. Respondents were male (86.8%), Black (76%), and aged 18-29 (55.3%), and 68.4% had high school level education. Post-FI, patients were more likely to be unemployed (55.2% vs 13.2%, P < .001) and report increased mental health needs (84.2% vs 21%, P < .001) compared to pre-FI. Most (73.7%) also reported lasting physical disability. Similarly, the PROMIS instrument demonstrated largely worse health-related QoL scores post-FI, particularly high anxiety/fear (T-score 60.2, SE 3.1, CI 54.6-66.3, Table 2), pain resulting in life interference (T-score 60.0, SE 2.3, CI 55.7-63.9), and worse physical function (T-score 42.5, SE 3.0, CI 38.2-46.9).Conclusions: Firearm injury survivors had more unemployment and worse mental health post-FI compared to pre-FI. Firearm injury survivors also reported significantly worse health-related QoL metrics including pain, anxiety, and physical function 6 months following their trauma. These long-term patient-reported outcomes are a framework to build future outpatient resources.Level of Evidence: IV.

Nursing and Chaplain Partnership for Pain Management: A Survey of Nurses.

PURPOSE: Pain is a universal experience for hospitalized patients, with physical, psychological, spiritual, and cognitive implications. As hospitals seek to identify nonpharmaceutical options for managing acute pain, the role of chaplains has been overlooked. The purpose of this study was to evaluate the perceptions of nurses regarding chaplain involvement in pain management. METHODS: A survey was distributed to nurses to determine if they would request spiritual care services in various patient and family scenarios. Respondents were dichotomized into two groups based on self-report of whether they would contact a chaplain for patients with uncontrolled pain. Differences between groups were calculated using chi-square tests. RESULTS: Of 45 nurse respondents, 27 (60%) reported they would not contact a chaplain for patients with uncontrolled pain. Nurses who would consult the chaplain for pain management did not differ from nurses who would not consult the chaplain in terms of their own religious identification, knowledge of patient religious documentation in the medical record, or past experience with chaplain services. CONCLUSIONS: Study findings suggest that nurses' perceptions of chaplain involvement in pain management must be addressed prior to implementing a new hospital pain management protocol. CLINICAL IMPLICATIONS: When developing and implementing new pain protocols based on holistic care of patients, hospitals should ensure that nursing staff are educated on when and how to incorporate chaplains as part of a holistic approach to managing acute pain.

Ribosome-Associated Vesicles promote activity-dependent local translation.

Local protein synthesis in axons and dendrites underpins synaptic plasticity. However, the composition of the protein synthesis machinery in distal neuronal processes and the mechanisms for its activity-driven deployment to local translation sites remain unclear. Here, we employed cryo-electron tomography, volume electron microscopy, and live-cell imaging to identify Ribosome-Associated Vesicles (RAVs) as a dynamic platform for moving ribosomes to distal processes. Stimulation via chemically-induced long-term potentiation causes RAV accumulation in distal sites to drive local translation. We also demonstrate activity-driven changes in RAV generation and dynamics in vivo, identifying tubular ER shaping proteins in RAV biogenesis. Together, our work identifies a mechanism for ribosomal delivery to distal sites in neurons to promote activity-dependent local translation.

Nematode-resistance loci in Upland cotton genomes are associated with structural differences.

Reniform and root-knot nematode are two of the most destructive pests of conventional upland cotton, Gossypium hirsutum, L. and continue to be a major threat to cotton fiber production in semi-arid regions of the southern United States and Central America. Fortunately, naturally occurring tolerance to these nematodes has been identified in the Pima cotton species (G. barbadense) and several upland cotton varieties (G. hirsutum), which has led to a robust breeding program that has successfully introgressed and stacked these independent resistant traits into several upland cotton lineages with superior agronomic traits, e.g. BAR 32-30 and BARBREN-713. This work identifies the genomic variations of these nematode tolerant accessions by comparing their respective genomes to the susceptible, high-quality fiber producing parental line of this lineage: Phytogen 355 (PSC355). We discover several large genomic differences within marker regions that harbor putative resistance genes as well as expression mechanisms shared by the two resistant lines, with respect to the susceptible PSC355 parental line. This work emphasizes the utility of whole genome comparisons as a means of elucidating large and small nuclear differences by lineage and phenotype.  .

Role of Occupational Therapy Cognitive Assessment in Mild Traumatic Brain Injury: Is Universal Consultation Required?

INTRODUCTION: Mild traumatic brain injury (mTBI) or concussion is prevalent among trauma patients, but symptoms vary. Assessing discharge safety is not standardized. At our institution, occupational therapy (OT) performs cognitive assessments for mTBI to determine discharge readiness, potentially increasing resource utilization. We aimed to describe characteristics and outcomes in mTBI trauma patients and hypothesized that OT consultation was associated with increased length of stay (LOS). METHODS: This is a retrospective study at a level 1 trauma center over 17 mo. All patients with mTBI, without significant concomitant injuries, were included. We collected data regarding OT assessment, LOS, mechanism of injury, Glasgow coma score, injury severity score (ISS), concussion symptoms, and patient disposition. Statistical analysis was performed, and significance was determined when P < 0.05. RESULTS: Two hundred thirty three patients were included. Median LOS was 1 d and ISS 5. Ninety percent were discharged home. The most common presenting symptom was loss of consciousness (85%). No symptoms were associated with differences in LOS or discharge disposition (P > 0.05). OT consult (n = 114, 49%) was associated with longer LOS and higher ISS (P < 0.01). Representation with concussive symptoms, discharge disposition, mechanism of injury, and patient demographics were no different regardless of OT consultation (P > 0.05). CONCLUSIONS: mTBI is common and assessment for discharge safety is not standardized. OT cognitive assessment was associated with longer LOS and higher injury severity. Despite institutional culture, OT consultation was variable and not associated with improved concussion-related outcomes. Our data suggest that OT is not required for mTBI discharge readiness assessment. To improve resource utilization, more selective OT consultation should be considered. Further prospective data are needed to identify which patients would most benefit.

Catalysis of the Oxygen-Evolution Reaction in 1.0 M Sulfuric Acid by Manganese Antimonate Films Synthesized via Chemical Vapor Deposition.

Manganese antimonate (MnySb1-yOx) electrocatalysts for the oxygen-evolution reaction (OER) were synthesized via chemical vapor deposition. Mn-rich rutile Mn0.63Sb0.37Ox catalysts on fluorine-doped tin oxide (FTO) supports drove the OER for 168 h (7 days) at 10 mA cm-2 with a time-averaged overpotential of 687 ± 9 mV and with >97% Faradaic efficiency. Time-dependent anolyte composition analysis revealed the steady dissolution of Mn and Sb. Extended durability analysis confirmed that Mn-rich MnySb1-yOx materials are more active but dissolve at a faster rate than previously reported Sb-rich MnySb1-yOx alloys.

Does the Subtalar or Tibiotalar Joint Need Fused in Primary Retrograde Tibiotalocalcaneal Nailing for Fragility Ankle Fractures?

BACKGROUND: As an alternative to traditional open reduction internal fixation of ankle fragility fractures, primary retrograde tibiotalocalcaneal (TTC) nailing has been investigated as a treatment option. These results suggest that this treatment is an acceptable alternative treatment option for these injuries. There are still questions about the need for formal joint preparation at the subtalar or tibiotalar joint when performing primary TTC nailing for fragility fractures. METHODS: In this study, we retrospectively evaluated 32 patients treated with primary retrograde TTC nail without subtalar or tibiotalar joint preparation for a mean of 2.4 years postoperatively. We specifically reviewed the charts for nail breakages at either joint, patients developing subtalar or tibiotalar joint pathology requiring additional treatment, including return to the operating room for formal joint preparation. RESULTS: Fracture union occurred in 100% of patients. There were 3 cases (10.0%) of hardware failure, and 2 of these cases were asymptomatic and did not require any treatment. One patient (3.3%) developed hardware failure with nail breakage at the subtalar joint. This patient developed progressive pain and symptoms requiring revision surgery with formal arthrodesis of the subtalar and tibiotalar joint. CONCLUSIONS: This study shows that retrograde hindfoot nailing without formal subtalar or tibiotalar joint preparation is an acceptable potential treatment option in ankle fragility fractures. Mid-term follow-up demonstrates favorable outcomes without the need for formal joint preparation in this high-risk population. Comparative studies with higher patient numbers and long-term follow-up are needed to confirm the results of this study.Levels of Evidence: Level IV.

Left hemisphere lateralization of the limbic system and frontoparietal network (FPN) correlates with positive and negative symptom improvement following cannabidiol (CBD) administration in psychosis and ultra-high risk (UHR) populations: A voxel-wise meta-analysis.

This voxel-wise meta-analysis assesses current findings about the neural correlates of cannabidiol on the positive and negative symptoms among individuals with psychosis or ultra-high risk (UHR) for psychosis. We used PubMed, EMBASE, and ScienceDirect as primary databases and initially retrieved 157 studies. After applying our eligibility criteria, 13 studies remained for inclusion. Ten studies focused on psychosis. Three studies focused on UHR. Quality assessment was performed for included articles using the RoB2 instrument. Statistical analysis implicated a voxel-wise meta-analysis of different task paradigms (emotion recognition, verbal memory recall, and inhibitory control) with a jackknife sensitivity measure, Egger's test of random effects, and a meta-regression with relevant covariates. Article quality was determined to be primarily low risk of bias, with some elements of unclear bias figuring across studies. Our results showed robust, convergent correlations between CBD administration and left hemisphere lateralization of limbic system and frontoparietal network (FPN) subregions across task paradigms in psychosis and UHR populations. Our meta-regression revealed that decreased limbic system activity correlated with positive symptom improvements, and decreased FPN activity correlated with negative symptom improvements. Lastly, sensitivity analyses determined that there was minimal risk bias or risk of confounding variables unduly influencing our meta-analyses (p > 0.05).

Illustrating the importance of edge constraints in backbones of bipartite projections.

Bipartite projections (e.g., event co-attendance) are often used to measure unipartite networks of interest (e.g., social interaction). Backbone extraction models can be useful for reducing the noise inherent in bipartite projections. However, these models typically assume that the bipartite edges (e.g., who attended which event) are unconstrained, which may not be true in practice (e.g., a person cannot attend an event held prior to their birth). We illustrate the importance of correctly modeling such edge constraints when extracting backbones, using both synthetic data that varies the number and type of constraints, and empirical data on children's play groups. We find that failing to impose relevant constraints when the data contain constrained edges can result in the extraction of an inaccurate backbone. Therefore, we recommend that when bipartite data contain constrained edges, backbones be extracted using a model such as the Stochastic Degree Sequence Model with Edge Constraints (SDSM-EC).

New Estimates on the Cost of a Delay Day in Drug Development.

Two frequently cited figures by clinical research insiders and observers - the cost of missing a day to generate prescription drug sales and the cost of a day to conduct a clinical trial - are outdated and based on anecdotal evidence. In late 2023, the Tufts Center for the Study of Drug Development conducted empirical research to gather more accurate and granular estimates and to test whether average sales per day have changed over time. 645 drugs launched since 2000, and 409 clinical trial budgets were drawn from commercially available and proprietary data sets and analyzed. The results indicate that a single day equals approximately $500,000 in lost prescription drug or biologic sales, with daily prescription sales for infectious, hematologic, cardiovascular, and gastrointestinal diseases among the highest. The results also show that each year, the average sales per day of prescription drugs and biologics has decreased by approximately $80,000-$100,000. The estimated direct daily cost to conduct a clinical trial is approximately $40,000 per day for phase II and III clinical trials, with those in respiratory, rheumatology, and dermatology having the highest relative daily direct costs.

Multipolar Electrograms: A New Configuration That Increases the Measurement Accuracy of Intracardiac Signals.

BACKGROUND: Accurate measurements of intracardiac electrograms (EGMs) remain a clinical challenge because of the suboptimal attenuation of far-field potentials. Multielectrode mapping catheters provide an opportunity to construct multipolar instead of bipolar EGMs for rejecting common far-field potentials recorded from a multivectorial space. OBJECTIVES: The purpose of this study was to develop a multipolar EGM and compare its characteristics to those of bipolar EGMs METHODS: Using a 36-electrode array catheter (Optrell-36; Biosense Webster), a far-field component was mathematically constructed from clusters of electrodes surrounding each inspected electrode. This component was subtracted from the unipolar waveform to produce a local unipolar, referred to as a "multipolar EGM." The performance of multipolar EGMs was evaluated in 7 swine with healed anteroseptal infarction. RESULTS: Multipolar EGMs proved superior in attenuating far-field potentials in infarct border zones, increasing the near-field to far-field ratio from 0.92 ± 0.2 to 2.25 ± 0.3 (P < 0.001). Removal of far-field components reduced the voltage amplitude (P < 0.001) and enlarged the infarct surface area (P = 0.02), aligning more closely with histological findings. Of 379 EGMs with ≥20 ms activation time difference between bipolar and multipolar EGMs, 95.3% (361 of 379) were accurately annotated using multipolar EGMs, while annotation based on bipolar EGM was predominantly made on far-field components. CONCLUSIONS: Multielectrode array catheters provide a unique platform for constructing multipolar EGMs. This new EGM may be beneficial for "purifying" local potentials within a complex electrical field, resulting in more accurate voltage and activation maps.

Dynamic Multiplexed Control and Modeling of Optogenetic Systems Using the High-Throughput Optogenetic Platform, Lustro.

The ability to control cellular processes using optogenetics is inducer-limited, with most optogenetic systems responding to blue light. To address this limitation, we leverage an integrated framework combining Lustro, a powerful high-throughput optogenetics platform, and machine learning tools to enable multiplexed control over blue light-sensitive optogenetic systems. Specifically, we identify light induction conditions for sequential activation as well as preferential activation and switching between pairs of light-sensitive split transcription factors in the budding yeast, Saccharomyces cerevisiae. We use the high-throughput data generated from Lustro to build a Bayesian optimization framework that incorporates data-driven learning, uncertainty quantification, and experimental design to enable the prediction of system behavior and the identification of optimal conditions for multiplexed control. This work lays the foundation for designing more advanced synthetic biological circuits incorporating optogenetics, where multiple circuit components can be controlled using designer light induction programs, with broad implications for biotechnology and bioengineering.

Single Layer Silk and Cotton Woven Fabrics for Acoustic Emission and Active Sound Suppression.

Whether intentionally generating acoustic waves or attempting to mitigate unwanted noise, sound control is an area of challenge and opportunity. This study investigates traditional fabrics as emitters and suppressors of sound. When attached to a single strand of a piezoelectric fiber actuator, a silk fabric emits up to 70 dB of sound. Despite the complex fabric structure, vibrometer measurements reveal behavior reminiscent of a classical thin plate. Fabric pore size relative to the viscous boundary layer thickness is found-through comparative fabric analysis-to influence acoustic-emission efficiency. Sound suppression is demonstrated using two distinct mechanisms. In the first, direct acoustic interference is shown to reduce sound by up to 37 dB. The second relies on pacifying the fabric vibrations by the piezoelectric fiber, reducing the amplitude of vibration waves by 95% and attenuating the transmitted sound by up to 75%. Interestingly, this vibration-mediated suppression in principle reduces sound in an unlimited volume. It also allows the acoustic reflectivity of the fabric to be dynamically controlled, increasing by up to 68%. The sound emission and suppression efficiency of a 130 µm silk fabric presents opportunities for sound control in a variety of applications ranging from apparel to transportation to architecture.

Agricultural insect pests as models for studying stress-induced evolutionary processes.

Agricultural insect pests (AIPs) are widely successful in adapting to natural and anthropogenic stressors, repeatedly overcoming population bottlenecks and acquiring resistance to intensive management practices. Although they have been largely overlooked in evolutionary studies, AIPs are ideal systems for understanding rapid adaptation under novel environmental conditions. Researchers have identified several genomic mechanisms that likely contribute to adaptive stress responses, including positive selection on de novo mutations, polygenic selection on standing allelic variation and phenotypic plasticity (e.g., hormesis). However, new theory suggests that stress itself may induce epigenetic modifications, which may confer heritable physiological changes (i.e., stress-resistant phenotypes). In this perspective, we discuss how environmental stress from agricultural management generates the epigenetic and genetic modifications that are associated with rapid adaptation in AIPs. We summarise existing evidence for stress-induced evolutionary processes in the context of insecticide resistance. Ultimately, we propose that studying AIPs offers new opportunities and resources for advancing our knowledge of stress-induced evolution.