Plant-based hydrolysates as building blocks for cellular agriculture.

Cellular agriculture, an emerging technology, aims to produce animal-based products such as meat through scalable tissue culture methods. Traditional techniques rely on chemically undefined media using fetal bovine serum (FBS) or chemically defined media utilizing specific growth factors. To be a viable alternative to conventional meat production, cellular agriculture requires cost-effective materials with established supply chains for growth media. Here, we investigate hydrolysates from Kikuyu grass, Alfalfa grass, and cattle rearing pellets. We identified conditions that promote C2C12 myoblast cell growth in media containing 0.1% and 0% serum. These effects are more pronounced in combination with existing growth promoters such as insulin, transferrin, and selenium. Overall, the rearing pellet hydrolysates were most effective in promoting growth particularly when in combination with the growth promoters. Our findings suggest that leveraging these materials, along with known growth factors, can facilitate the development of improved, scalable, and commercially viable media for cellular agriculture.

Protocol for measuring the effects of an inhibitory signal associated with danger on honey bee dopamine levels.

The stop signal is produced in response to negative experiences at the food source and inhibits honey bee (Apis mellifera) waggle dancing. Here, we present a protocol for measuring the effects of an inhibitory signal associated with danger on honey bee dopamine levels. We describe steps for observing honey bee colonies, training them with artificial nectar, and simulating hornet attacks. We then detail procedures for recording waggle dancing and stop signals and measuring brain dopamine levels during different treatments. For complete details on the use and execution of this protocol, please refer to Dong et al.1.

Identification and Characterization of a Blood-Brain Barrier Penetrant Inositol Hexakisphosphate Kinase (IP6K) Inhibitor.

Inositol hexakisphosphate kinases (IP6Ks) have been studied for their role in glucose homeostasis, metabolic disease, fatty liver disease, chronic kidney disease, neurological development, and psychiatric disease. IP6Ks phosphorylate inositol hexakisphosphate (IP6) to the pyrophosphate, 5-diphosphoinositol-1,2,3,4,6-pentakisphosphate (5-IP7). Most of the currently known potent IP6K inhibitors contain a critical carboxylic acid which limits blood-brain barrier (BBB) penetration. In this work, the synthesis and testing of a variety of carboxylic acid isosteres resulted in several new compounds with improved BBB penetration. The most promising compound has an IP6K1 IC50 of 16 nM with an improved brain/plasma ratio and a favorable pharmacokinetic profile. This series of brain penetrant compounds may be used to investigate the role of IP6Ks in CNS disorders.

Primaquine-5,6-orthoquinone is directly hemolytic to older G6PD deficient RBCs in a humanized mouse model.

Primaquine and tafenoquine are the only approved drugs that can achieve a radical cure for Plasmodium vivax malaria but are contraindicated in patients who are deficient in glucose 6-phosphate dehydrogenase (G6PDd) due to risk of severe hemolysis from reactive oxygen species (ROS) generated by redox cycling of drug metabolites. 5-hydroxyprimaquine and its quinone-imine cause robust redox cycling in red blood cells (RBCs), but are so labile as to not be detected in blood or urine. Rather, the 5,8-quinoneimine is rapidly converted into primaquine-5,6-orthoquinone (5,6-POQ) that is then excreted in the urine. The extent to which 5,6-POQ contributes to hemolysis remains unclear, although some have suggested that it is a minor toxin that should be used predominantly as a surrogate to infer levels of 5-hydroxyprimaquine. In this report, we describe a novel humanized mouse model of the G6PD Mediterranean variant (hG6PDMed-) that recapitulates the human biology of RBC age dependent enzyme decay, as well as an isogenic matched control mouse with human non-deficient G6PD hG6PDND In vitro challenge of RBCs with 5,6-POQ causes increased generation of superoxide and methemoglobin. Infusion of treated RBCs shows that 5,6-POQ selectively causes in vivo clearance of older hG6PDMed- RBCs. These findings support the hypothesis that 5,6-POQ directly induces hemolysis and challenges the notion that 5,6-POQ is an inactive metabolic waste product. Indeed, given the extreme lability of 5-hydroxyprimaquine and the relative stability of 5,6-POQ, these data raise the possibility that 5,6-POQ is a major hemolytic primaquine metabolite in vivo. Significance Statement These findings demonstrate that 5,6-POQ, which has been suggested to be an inert waste product of active primaquine metabolites, directly induces ROS that lead specifically to removal of older G6PDd RBCs from circulation. As 5,6-POQ is relatively stable compared to other active primaquine metabolites, these data support the hypothesis that 5,6-POQ is a major toxin in primaquine induced hemolysis. In addition, a new model of G6PDd is used to show that young G6PDd RBCs are resistant to primaquine induced hemolysis.

Molecular communication between red blood cells of different phenotypes during blood storage in mice.

BACKGROUND: The cellular and molecular changes during red blood cell (RBC) storage that affect posttransfusion recovery (PTR) remain incompletely understood. We have previously reported that RBCs of different storage biology cross-regulate each other when stored together (co-storage cross-regulation [CSCR]). However, the mechanism of CSCR is unclear. In the current study, we tested the hypothesis that CSCR involves acquisition of molecular signatures associated with PTR. STUDY DESIGN AND METHODS: The whole blood compartment of either B6 or FVB mice was biotinylated in vivo prior to blood collection and storage. Bio-B6 or Bio.FVB were stored with RBCs from B6 mice transgenic for green florescent protein (GFP) (B6.GFP). After storage, avidin-magnetic beads were used to simultaneous purify Bio-RBCs (positive selection) and B6.GFPs (negative selection). Isolated populations were analyzed by transfusion to establish PTR, and subjected to metabolomic and proteomic analysis. RESULTS: B6 RBCs acquired molecular signatures associated with stored FVB RBCs at both the metabolomic and proteomic level including metabolites associated with energy metabolism, oxidative stress regulation, and oxidative damage. Mitochondrial signatures were also acquired by B6 RBCs. Protein signatures acquired by B6 RBCs include proteins associated with vesiculation. CONCLUSION: The data presented herein demonstrate the appearance of multiple molecular changes from poor-storing RBCs in good-storing RBCs during co-storage. Whether this is a result of damage causing intrinsic molecular changes in B6 RBCs or if molecules of FVB RBC origin are transferred to B6 RBCs remains unclear. These studies broaden our mechanistic understanding of RBC storage (in particular) and potentially RBC biology (in general).

Self-Reported Sodium Intake and Sodium Vulnerability in Heart Failure With Preserved Ejection Fraction.

OBJECTIVE: To determine the pathophysiologic and prognostic meaning of patient self-reported sodium intake in heart failure (HF) with preserved ejection fraction (HFpEF). METHODS: This cohort analysis used data from the Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist (TOPCAT) trial of patients enrolled in the Americas. Tertiles of baseline self-reported sodium intake were used to assess the relationship between self-reported sodium intake and clinical presentation/outcome and interactions with treatment effect of spironolactone. RESULTS: Self-reported sodium intake of 1748 patients with HFpEF included in TOPCAT were divided according to tertiles of sodium intake (47% low, 35% moderate, and 18% high sodium intake). After covariate adjustment, lower self-reported sodium intake was associated with higher risk of HF hospital admission (P=.009). Patients with lower sodium intake had higher E-wave velocity, left ventricular end diastolic volume, and estimated plasma volume (P<.001). Lower sodium intake was associated with a larger treatment effect of spironolactone on HF hospitalizations (hazard ratio, 0.69; 95% CI, 0.53 to 0.91) vs the highest tertile (hazard ratio, 1.37; 95% CI, 0.79 to 2.38; interaction P=.030). In addition, linear mixed models indicated larger reductions in blood pressure, dyspnea, and edema (all interaction P<.001) in patients with lower sodium intake receiving spironolactone. CONCLUSION: Low self-reported sodium level in HFpEF is associated with higher risk of HF hospital admissions and may indicate a sodium-vulnerable state; patients should not be falsely reassured that they are in a lower risk category despite greater adherence to medical recommendations.

Physical Activity and Cognition: Longitudinal findings from the Thinking and Living with Cancer Study.

BACKGROUND: Physical activity can improve cognition; however, little is known regarding the relationships between longitudinal objectively-measured physical activity, cognition, and inflammation in older breast cancer survivors. METHODS: Older (≥60 yrs) breast cancer survivors (n = 216) and frequency-matched non-cancer controls (n = 216) were assessed at baseline (pre-systemic therapy for survivors) and annually for up to five years. Assessments included hip-worn ActiGraphs worn for seven days, neuropsychological tests, the Functional Assessment of Cancer Therapy-Cognitive Function Perceived Cognitive Impairment (FACT-Cog PCI) subscale, and circulating levels of C-reactive protein (CRP) and interleukin-6 (IL-6). Data were analyzed using linear mixed-effect, random-effect contemporaneous fluctuation, and multi-level mediation models, considering covariates; p < .05 (two-sided) was considered significant. RESULTS: Survivors had fewer minutes of moderate-to-vigorous physical activity (MVPA) than controls at 36-, 48-, and 60-month time points (p < .03). Fewer survivors met Aerobic Physical Activity Guidelines at 36 months than controls (17.7% vs 33.0%, p = .030). When Guidelines were met (vs not), FACT-Cog PCI scores were 2.1 ± 1.0 (p = .034) points higher. Higher MVPA and meeting Aerobic Guidelines were not related to objective neuropsychological performance. MVPA was inversely associated with CRP and IL-6 (p < .001), but inflammation did not mediate physical activity effects on perceived cognition. CONCLUSIONS: Older breast cancer survivors were less physically active than older non-cancer controls, especially farther from baseline. Meeting Aerobic Guidelines was associated with better perceived cognition in survivors. Survivorship care should consider physical activity monitoring and referral to rehabilitation and supervised exercise programs to promote physical activity and improve recovery in older survivors.

Human in vivo baseline intrarenal pressure, peristaltic activity and response to ureteric stenting.

OBJECTIVES: To assess human in vivo intrarenal pressure (IRP) and peristaltic activity at baseline and after ureteric stent placement, using a narrow calibre pressure guidewire placed retrogradely in the renal pelvis. PATIENTS AND METHODS: A prospective, multi-institutional study recruiting consenting patients undergoing ureteroscopy was designed with ethical approval. Prior to ureteroscopy, the urinary bladder was emptied and the COMET™ II pressure guidewire (Boston Scientific) was advanced retrogradely via the ureteric orifice to the renal pelvis. Baseline IRPs were recorded for 1-2 min. At procedure completion, following ureteric stent insertion, IRPs were recorded for another 1-2 min. Statistical analysis of mean baseline IRP, peristaltic waveforms and frequency of peristaltic contractions was performed, thereby analysing the influence of patient variables and ureteric stenting. RESULTS: A total of 100 patients were included. Baseline mean (±SD) IRP was 16.76 (6.4) mmHg in the renal pelvis, with maximum peristaltic IRP peaks reaching a mean (SD) of 25.75 (17.9) mmHg. Peristaltic activity generally occurred in a rhythmic, coordinated fashion, with a mean (SD) interval of 5.63 (3.08) s between peaks. On univariate analysis, higher baseline IRP was observed with male sex, preoperative hydronephrosis, and preoperative ureteric stenting. On linear regression, male sex was no longer statistically significant, whilst the latter two variables remained significant (P = 0.004; P < 0.001). The mean (SD) baseline IRP in the non-hydronephrotic, unstented cohort was 14.19 (4.39) mmHg. Age, α-blockers and calcium channel blockers did not significantly influence IRP, and no measured variables influenced peristaltic activity. Immediately after ureteric stent insertion, IRP decreased (mean [SD] 15.18 [5.28] vs 16.76 [6.4] mmHg, P = 0.004), whilst peristaltic activity was maintained. CONCLUSIONS: Human in vivo mean (SD) baseline IRP is 14.19 (4.39) mmHg in normal kidneys and increases with both hydronephrosis and preoperative ureteric stenting. Mean (SD) peristaltic peak IRP values of 25.75 (17.9) mmHg are reached in the renal pelvis every 3-7 s and maintained in the early post-stent period.

Pediatric Critical Care Illness Severity Toolkit: Stata Commands for Calculation of Pediatric Index of Mortality and Pediatric Logistic Organ Dysfunction Scores.

Introduction: Illness severity scoring tools, such as PRISM III/IV, PIM-3, and PELOD-2, are widely used in pediatric critical care research. However, their application is hindered by complex calculation processes, privacy concerns with third-party online calculators, and challenges in accurate implementation within statistical packages. Methods: We have developed a comprehensive, open-source toolkit for implementing the PIM-3, Simplified PIM-3, and PELOD-2 scores. The toolkit includes the pim3 and pelod2 commands and is compatible with Stata versions 12 and above. It features robust data validation, error messaging, a graphical interface, and support for SI and Imperial units. The toolkit's accuracy was validated through unit testing and synthetic data, comparing results with existing implementations. Results: In performance tests, the toolkit exhibited a median processing time of 21.82 seconds for PELOD-2, 14.06 seconds for PIM-3, and 9.74 seconds for Simplified PIM-3, when applied to datasets of 10,000,000 records. It consistently achieved 100% accuracy in both synthetic data tests and manual spot checks. Conclusion: The toolkit decreases processing time and improves accuracy in calculating pediatric critical care severity scores such as PELOD-2, PIM-3, and Simplified PIM-3. Its application in large datasets and validation highlights its utility as a tool for streamlining pediatric critical care research.

Discovery of a Myeloid Cell Leukemia 1 (Mcl-1) Inhibitor That Demonstrates Potent In Vivo Activities in Mouse Models of Hematological and Solid Tumors.

Myeloid cell leukemia 1 (Mcl-1) is a key regulator of the intrinsic apoptosis pathway. Overexpression of Mcl-1 is correlated with high tumor grade, poor survival, and both intrinsic and acquired resistance to cancer therapies. Herein, we disclose the structure-guided design of a small molecule Mcl-1 inhibitor, compound 26, that binds to Mcl-1 with subnanomolar affinity, inhibits growth in cell culture assays, and possesses low clearance in mouse and dog pharmacokinetic (PK) experiments. Evaluation of 26 as a single agent in Mcl-1 sensitive hematological and solid tumor xenograft models resulted in regressions. Co-treatment of Mcl-1-sensitive and Mcl-1 insensitive lung cancer derived xenografts with 26 and docetaxel or topotecan, respectively, resulted in an enhanced tumor response. These findings support the premise that pro-apoptotic priming of tumor cells by other therapies in combination with Mcl-1 inhibition may significantly expand the subset of cancers in which Mcl-1 inhibitors may prove beneficial.

Microinterventional system for robot-assisted gonioscopic surgery- technical feasibility and preclinical evaluation in synthetic eye models.

BACKGROUND: Preclinical technical feasibility study of robot-assisted microinvasive glaucoma surgery using a novel ophthalmic robot-assisted surgery system. METHODS: Feasibility was assessed in synthetic eye models in two stages: Stage I, nonimplantable robot-assisted goniotomy; and Stage II, robot-assisted stent implantation using a trabecular bypass stent. Robot-assisted interventions were subsequently compared to the manual approach. RESULTS: Stage I: Two surgeons completed 10 trials each of ab-interno sectoral goniotomy with and without robotic assistance for at least 3 clock hours using a standard goniotomy knife and more than 10 clock hours of extended goniotomy using a flexible, guided goniotomy instrument. Stage II: Trabecular bypass stent deployment was successfully achieved in 100% of the attempts with and without robotic assistance. Surgical time was recorded and compared between the robotic-assisted and the manual approach. CONCLUSIONS: A system for robot-assisted microinvasive glaucoma surgery can successfully achieve implantable and nonimplantable interventions in the anterior segment. This is the first known demonstration of the feasibility of robot-assisted glaucoma surgery.

Perioperative Gastrointestinal Myoelectric Activity Measurement Using Wireless External Patches.

BACKGROUND: Stomach, small intestine, and colon have distinct patterns of contraction related to their function to mix and propel enteric contents. In this study, we aim to measure gut myoelectric activity in the perioperative course using external patches in an animal model. METHODS: Four external patches were placed on the abdominal skin of female Yucatan pigs to record gastrointestinal myoelectric signals for 3 to 5 d. Pigs subsequently underwent anesthesia and placement of internal electrodes on stomach, small intestine, and colon. Signals were collected by a wireless transmitter. Frequencies associated with peristalsis were analyzed for both systems for 6 d postoperatively. RESULTS: In awake pigs, we found frequency peaks in several ranges, from 4 to 6.5 cycles per minute (CPM), 8 to 11 CPM, and 14 to 18 CPM, which were comparable between subjects and concordant between internal and external recordings. The possible effect of anesthesia during the 1 or 2 h before surgical manipulation was observed as a 59% (±36%) decrease in overall myoelectric activity compared to the immediate time before anesthesia. The myoelectrical activity recovered quickly postoperatively. Comparing the absolute postsurgery activity levels to the baseline for each pig revealed higher overall activity after surgery by a factor of 1.69 ± 0.3. CONCLUSIONS: External patch measurements correlated with internal electrode recordings. Anesthesia and surgery impacted gastrointestinal myoelectric activity. Recordings demonstrated a rebound phenomenon in myoelectric activity in the postoperative period. The ability to monitor gastrointestinal tract myoelectric activity noninvasively over multiple days could be a useful tool in diagnosing gastrointestinal motility disorders.

Enolase inhibitors as therapeutic leads for Naegleria fowleri infection.

Infections with the pathogenic free-living amoebae Naegleria fowleri can lead to life-threatening illnesses including catastrophic primary amoebic meningoencephalitis (PAM). Efficacious treatment options for these infections are lacking and the mortality rate remains >95% in the US. Glycolysis is very important for the infectious trophozoite lifecycle stage and inhibitors of glucose metabolism have been found to be toxic to the pathogen. Recently, human enolase 2 (ENO2) phosphonate inhibitors have been developed as lead agents to treat glioblastoma multiforme (GBM). These compounds, which cure GBM in a rodent model, are well-tolerated in mammals because enolase 1 (ENO1) is the predominant isoform used systemically. Here, we describe findings that demonstrate these agents are potent inhibitors of N. fowleri ENO (NfENO) and are lethal to amoebae. In particular, (1-hydroxy-2-oxopiperidin-3-yl) phosphonic acid (HEX) was a potent enzyme inhibitor (IC50 = 0.14 ± 0.04 µM) that was toxic to trophozoites (EC50 = 0.21 ± 0.02 µM) while the reported CC50 was >300 µM. Molecular docking simulation revealed that HEX binds strongly to the active site of NfENO with a binding affinity of -8.6 kcal/mol. Metabolomic studies of parasites treated with HEX revealed a 4.5 to 78-fold accumulation of glycolytic intermediates upstream of NfENO. Last, nasal instillation of HEX increased longevity of amoebae-infected rodents. Two days after infection, animals were treated for 10 days with 3 mg/kg HEX, followed by one week of observation. At the end of the one-week observation, eight of 12 HEX-treated animals remained alive (resulting in an indeterminable median survival time) while one of 12 vehicle-treated rodents remained, yielding a median survival time of 10.9 days. However, intranasal HEX delivery was not curative as brains of six of the eight survivors were positive for amoebae. These findings suggest that HEX requires further evaluation to develop as a lead for treatment of PAM.

Coupling Microdroplet-Based Sample Preparation, Multiplexed Isobaric Labeling, and Nanoflow Peptide Fractionation for Deep Proteome Profiling of the Tissue Microenvironment.

There is increasing interest in developing in-depth proteomic approaches for mapping tissue heterogeneity in a cell-type-specific manner to better understand and predict the function of complex biological systems such as human organs. Existing spatially resolved proteomics technologies cannot provide deep proteome coverage due to limited sensitivity and poor sample recovery. Herein, we seamlessly combined laser capture microdissection with a low-volume sample processing technology that includes a microfluidic device named microPOTS (microdroplet processing in one pot for trace samples), multiplexed isobaric labeling, and a nanoflow peptide fractionation approach. The integrated workflow allowed us to maximize proteome coverage of laser-isolated tissue samples containing nanogram levels of proteins. We demonstrated that the deep spatial proteomics platform can quantify more than 5000 unique proteins from a small-sized human pancreatic tissue pixel (∼60,000 µm2) and differentiate unique protein abundance patterns in pancreas. Furthermore, the use of the microPOTS chip eliminated the requirement for advanced microfabrication capabilities and specialized nanoliter liquid handling equipment, making it more accessible to proteomic laboratories.

Associations between COVID-19 therapies and outcomes in rural and urban America: A multisite, temporal analysis from the Alpha to Omicron SARS-CoV-2 variants.

PURPOSE: To investigate the enduring disparities in adverse COVID-19 events between urban and rural communities in the United States, focusing on the effects of SARS-CoV-2 vaccination and therapeutic advances on patient outcomes. METHODS: Using National COVID Cohort Collaborative (N3C) data from 2021 to 2023, this retrospective cohort study examined COVID-19 hospitalization, inpatient death, and other adverse events. Populations were categorized into urban, urban-adjacent rural (UAR), and nonurban-adjacent rural (NAR). Adjustments included demographics, variant-dominant waves, comorbidities, region, and SARS-CoV-2 treatment and vaccination. Statistical methods included Kaplan-Meier survival estimates, multivariable logistic, and Cox regression. FINDINGS: The study included 3,018,646 patients, with rural residents constituting 506,204. These rural dwellers were older, had more comorbidities, and were less vaccinated than their urban counterparts. Adjusted analyses revealed higher hospitalization odds in UAR and NAR (aOR 1.07 [1.05-1.08] and 1.06 [1.03-1.08]), greater inpatient death hazard (aHR 1.30 [1.26-1.35] UAR and 1.37 [1.30-1.45] NAR), and greater risk of other adverse events compared to urban dwellers. Delta increased, while Omicron decreased, inpatient adverse events relative to pre-Delta, with rural disparities persisting throughout. Treatment effectiveness and vaccination were similarly protective across all cohorts, but dexamethasone post-ventilation was effective only in urban areas. Nirmatrelvir/ritonavir and molnupiravir better protected rural residents against hospitalization. CONCLUSIONS: Despite advancements in treatment and vaccinations, disparities in adverse COVID-19 outcomes persist between urban and rural communities. The effectiveness of some therapeutic agents appears to vary based on rurality, suggesting a nuanced relationship between treatment and geographic location while highlighting the need for targeted rural health care strategies.

In situ via Contact to hBN-Encapsulated Air-Sensitive Atomically Thin Semiconductors.

Establishing reliable electrical contacts to atomically thin materials is a prerequisite for both fundamental studies and applications yet remains a challenge. In particular, the development of contact techniques for air-sensitive monolayers has lagged behind, despite their unique properties and significant potential for applications. Here, we present a robust method to create contacts to device layers encapsulated within hexagonal boron nitride (hBN). This method uses plasma etching and metal deposition to create 'vias' in the hBN with graphene forming an atomically thin etch-stop. The resulting partially fluorinated graphene (PFG) protects the underlying device layer from air-induced degradation and damage during metal deposition. PFG is resistive in-plane but maintains high out-of-plane conductivity. The work function of the PFG/metal contact is tunable through the degree of fluorination, offering opportunities for contact engineering. Using the in situ via technique, we achieve ambipolar contact to air-sensitive monolayer 2H-molybdenum ditelluride (MoTe2) with more than 1 order of magnitude improvement in on-current density compared to previous literature. The complete encapsulation provides high reproducibility and long-term stability. The technique can be extended to other air-sensitive materials as well as air-stable materials, offering highly competitive device performance.

TNFR1-mediated senescence and lack of TNFR2-signaling limit human intervertebral disc cell repair in back pain conditions.

Poor intervertebral disc (IVD) healing causes IVD degeneration (IVDD) and progression to herniation and back pain. This study identified distinct roles of TNFα-receptors (TNFRs) in contributing to poor healing in painful IVDD. We first isolated IVDD tissue of back pain subjects and determined the complex pro-inflammatory mixture contained many chemokines for recruiting inflammatory cells. Single-cell RNA-sequencing of human IVDD tissues revealed these pro-inflammatory cytokines were dominantly expressed by a small macrophage-population. Human annulus fibrosus (hAF) cells treated with IVDD-conditioned media (CM) underwent senescence with greatly reduced metabolic rates and limited inflammatory responses. TNFR1 inhibition partially restored hAF cell metabolism sufficiently to enable a robust chemokine and cytokine response to CM. We showed that the pro-reparative TNFR2 was very limited on hIVD cell membranes so that TNFR2 inhibition with blocking antibodies or activation using Atsttrin had no effect on hAF cells with CM challenge. However, TNFR2 was expressed in high levels on macrophages identified in scRNA-seq analyses, suggesting their role in repair responses. Results therefore point to therapeutic strategies for painful IVDD involving immunomodulation of TNFR1 signaling in IVD cells to enhance metabolism and enable a more robust inflammatory response including recruitment or delivery of TNFR2 expressing immune cells to enhance IVD repair.

Reducing Cardiovascular Disease-An Alternative Approach.

PURPOSE: Statin drugs are effective at reducing cardiovascular events, but adherence to statin therapy remains a problem for patients and their physicians. We review a paper estimating the economic costs of poor adherence to statin drugs. METHODS: The authors examined two large databases (Medicare and Market Scan databases) including 230,000 patients with hospitalization for myocardial infarction between 2018 and 2019 to determine how many patients were not adhering to guideline-recommended anti-hyperlipidemic medications. They have also calculated the potential consequences of patients who are not adhering to the recommended therapy. RESULTS: The authors estimate that if all patients were receiving guideline-directed medical therapy, then a 22% relative risk reduction would occur in the 3-year period following discharge from the initial cardiovascular event. These findings are consistent with prior reports. This editorial discusses rationale and strategies clinicians can use to improve patients' compliance with recommendations for lipid-lowering therapy. CONCLUSION: The authors conclude that better compliance with guideline-directed lipid therapy after a cardiovascular event would lead to a large reduction in second events. Increased efforts by clinicians to improve adherence to statin therapy are warranted.

Parsing evoked and induced gamma response differences in Autism: A visual evoked potential study.

OBJECTIVE: Electroencephalography (EEG) measures of visual evoked potentials (VEPs) provide a targeted approach for investigating neural circuit dynamics. This study separately analyses phase-locked (evoked) and non-phase-locked (induced) gamma responses within the VEP to comprehensively investigate circuit differences in autism. METHODS: We analyzed VEP data from 237 autistic and 114 typically developing (TD) children aged 6-11, collected through the Autism Biomarkers Consortium for Clinical Trials (ABC-CT). Evoked and induced gamma (30-90 Hz) responses were separately quantified using a wavelet-based time-frequency analysis, and group differences were evaluated using a permutation-based clustering procedure. RESULTS: Autistic children exhibited reduced evoked gamma power but increased induced gamma power compared to TD peers. Group differences in induced responses showed the most prominent effect size and remained statistically significant after excluding outliers. CONCLUSIONS: Our study corroborates recent research indicating diminished evoked gamma responses in children with autism. Additionally, we observed a pronounced increase in induced power. Building upon existing ABC-CT findings, these results highlight the potential to detect variations in gamma-related neural activity, despite the absence of significant group differences in time-domain VEP components. SIGNIFICANCE: The contrasting patterns of decreased evoked and increased induced gamma activity in autistic children suggest that a combination of different EEG metrics may provide a clearer characterization of autism-related circuitry than individual markers alone.

Ophthalmic drop waste due to self-imposed use cessation dates.

Self-imposed use cessation dates for multi-use eye drop bottles lead to significant drug waste and increased costs. We quantified the residual medication in eye drop bottles across three clinics in an academic ambulatory setting.