Empirical validation of integrated stock assessment models to ensuring risk equivalence: A pathway to resilient fisheries management.

The Precautionary Approach to Fisheries Management requires an assessment of the impact of uncertainty on the risk of achieving management objectives. However, the main quantities, such as spawning stock biomass (SSB) and fish mortality (F), used in management metrics cannot be directly observed. This requires the use of models to provide guidance, for which there are three paradigms: the best assessment, model ensemble, and Management Strategy Evaluation (MSE). It is important to validate the models used to provide advice. In this study, we demonstrate how stock assessment models can be validated using a diagnostic toolbox, with a specific focus on prediction skill. Prediction skill measures the precision of a predicted value, which is unknown to the model, in relation to its observed value. By evaluating the accuracy of model predictions against observed data, prediction skill establishes an objective framework for accepting or rejecting model hypotheses, as well as for assigning weights to models within an ensemble. Our analysis uncovers the limitations of traditional stock assessment methods. Through the quantification of uncertainties and the integration of multiple models, our objective is to improve the reliability of management advice considering the complex interplay of factors that influence the dynamics of fish stocks.

Endoscopic-assisted transorbital extended orbital exenteration: A multi-institutional preclinical study.

BACKGROUND: Sinonasal malignancies with orbital invasion have dismal prognosis even when treated with orbital exenteration (OE). Sugawara et al. developed a surgical strategy called "extended-OE (EOE)," showing encouraging outcomes. We hypothesized that a similar resection is achievable under endoscopic guidance through the exenterated orbit (endoscopic-EOE). METHODS: The study was conducted in three institutions: University of Vienna; Mayo Clinic; University of Insubria; 48 orbital dissections were performed. A questionnaire was developed to evaluate feasibility and safety of each step, scoring from 1 to 10, ("impossible" to "easy," and "high risk" to "low risk," respectively), most likely complication(s) were hypothesized. RESULTS: The step-by-step technique is thoroughly described. The questionnaire was answered by 25 anterior skull base surgeons from six countries. Mean, median, range, and interquartile range of both feasibility and safety scores are reported. CONCLUSIONS: Endoscopic-EOE is a challenging but feasible procedure. Clinical validation is required to assess real-life outcomes.

Discovery of 2-deoxy glucose surfaced mixed layer dendrimer: a smart neuron targeted systemic drug delivery system for brain diseases.

The availability of non-invasive drug delivery systems capable of efficiently transporting bioactive molecules across the blood-brain barrier to specific cells at the injury site in the brain is currently limited. Delivering drugs to neurons presents an even more formidable challenge due to their lower numbers and less phagocytic nature compared to other brain cells. Additionally, the diverse types of neurons, each performing specific functions, necessitate precise targeting of those implicated in the disease. Moreover, the complex synthetic design of drug delivery systems often hinders their clinical translation. The production of nanomaterials at an industrial scale with high reproducibility and purity is particularly challenging. However, overcoming this challenge is possible by designing nanomaterials through a straightforward, facile, and easily reproducible synthetic process. Methods: In this study, we have developed a third-generation 2-deoxy-glucose functionalized mixed layer dendrimer (2DG-D) utilizing biocompatible and cost-effective materials via a highly facile convergent approach, employing copper-catalyzed click chemistry. We further evaluated the systemic neuronal targeting and biodistribution of 2DG-D, and brain delivery of a neuroprotective agent pioglitazone (Pio) in a pediatric traumatic brain injury (TBI) model. Results: The 2DG-D exhibits favorable characteristics including high water solubility, biocompatibility, biological stability, nanoscale size, and a substantial number of end groups suitable for drug conjugation. Upon systemic administration in a pediatric mouse model of traumatic brain injury (TBI), the 2DG-D localizes in neurons at the injured brain site, clears rapidly from off-target locations, effectively delivers Pio, ameliorates neuroinflammation, and improves behavioral outcomes. Conclusions: The promising in vivo results coupled with a convenient synthetic approach for the construction of 2DG-D makes it a potential nanoplatform for addressing brain diseases.

Recent advancements in natural polymers-based self-healing nano-materials for wound dressing.

The field of wound healing has witnessed remarkable progress in recent years, driven by the pursuit of advanced wound dressings. Traditional dressing materials have limitations like poor biocompatibility, nonbiodegradability, inadequate moisture management, poor breathability, lack of inherent therapeutic properties, and environmental impacts. There is a compelling demand for innovative solutions to transcend the constraints of conventional dressing materials for optimal wound care. In this extensive review, the therapeutic potential of natural polymers as the foundation for the development of self-healing nano-materials, specifically for wound dressing applications, has been elucidated. Natural polymers offer a multitude of advantages, possessing exceptional biocompatibility, biodegradability, and bioactivity. The intricate engineering strategies employed to fabricate these polymers into nanostructures, thereby imparting enhanced mechanical robustness, flexibility, critical for efficacious wound management has been expounded. By harnessing the inherent properties of natural polymers, including chitosan, alginate, collagen, hyaluronic acid, and so on, and integrating the concept of self-healing materials, a comprehensive overview of the cutting-edge research in this emerging field is presented in the review. Furthermore, the inherent self-healing attributes of these materials, wherein they exhibit innate capabilities to autonomously rectify any damage or disruption upon exposure to moisture or body fluids, reducing frequent dressing replacements have also been explored. This review consolidates the existing knowledge landscape, accentuating the benefits and challenges associated with these pioneering materials while concurrently paving the way for future investigations and translational applications in the realm of wound healing.

Recent treatment and novel imaging studies evaluating treatment of internet gaming disorder: a narrative review.

Internet Gaming Disorder (IGD) is an emerging public health concern; effective treatments are still under development. This mini-review focuses on summarizing the main scientific evidence from psychological, pharmacological, brain imaging, and emerging treatment approaches for IGD. We searched PubMed and Scopus databases using keywords related to IGD and treatment. Cognitive behavioral therapy (CBT) is the most extensively researched psychological treatment for IGD, supported by several randomized controlled trials (RCTs). Other promising approaches include mindfulness, relapse prevention, abstinence protocols, and family therapy. Pharmacological treatments like bupropion and escitalopram have shown benefits, especially when IGD is comorbid with conditions like major depressive disorder. However, the quality of evidence is moderate for psychological interventions but low to moderate for pharmacological approaches. Emerging treatments such as transcranial direct current stimulation (tDCS), repetitive transcranial magnetic stimulation (rTMS), and electro-acupuncture have demonstrated efficacy in reducing IGD symptoms and modulating brain activity. Brain imaging techniques like functional magnetic resonance imaging (fMRI) have provided insights into the neural mechanisms underlying IGD and treatment effects, although these studies lack randomized controlled designs. While multimodal approaches show promise, larger, well-designed RCTs are needed to establish effective IGD treatments.

Surgical fixation of traumatic sternal manubrium dislocation and right-sided rib fractures following a motorcycle accident.

This brief report discusses the diagnosis, management and surgical intervention of a man in his 30s presenting with a rare traumatic sternal manubrium dislocation following a motorcycle crash, accompanied by multiple concomitant rib fractures. The severity and complexity of the patient's injuries necessitated an operative approach for his sternomanubrial dislocation, emphasising the importance of multidisciplinary coordination, accurate diagnosis and prompt surgical intervention. The report provides valuable insights into the successful application of open reduction and internal fixation with plating in a real-world setting, which resulted in positive patient outcomes, despite the rarity and severity of this type of trauma. It further underscores the need for additional research to advance best practices for managing traumatic sternal manubrium dislocations in the context of high-impact injuries.

Selective targeting and modulation of plaque associated microglia via systemic hydroxyl dendrimer administration in an Alzheimer's disease mouse model.

BACKGROUND: In Alzheimer's disease (AD), microglia surround extracellular plaques and mount a sustained inflammatory response, contributing to the pathogenesis of the disease. Identifying approaches to specifically target plaque-associated microglia (PAMs) without interfering in the homeostatic functions of non-plaque associated microglia would afford a powerful tool and potential therapeutic avenue. METHODS: Here, we demonstrated that a systemically administered nanomedicine, hydroxyl dendrimers (HDs), can cross the blood brain barrier and are preferentially taken up by PAMs in a mouse model of AD. As proof of principle, to demonstrate biological effects in PAM function, we treated the 5xFAD mouse model of amyloidosis for 4 weeks via systemic administration (ip, 2x weekly) of HDs conjugated to a colony stimulating factor-1 receptor (CSF1R) inhibitor (D-45113). RESULTS: Treatment resulted in significant reductions in amyloid-beta (Aß) and a stark reduction in the number of microglia and microglia-plaque association in the subiculum and somatosensory cortex, as well as a downregulation in microglial, inflammatory, and synaptic gene expression compared to vehicle treated 5xFAD mice. CONCLUSIONS: This study demonstrates that systemic administration of a dendranib may be utilized to target and modulate PAMs.

Cholinergic Interneurons in the Accumbal Shell Region Regulate Binge Alcohol Self-Administration in Mice: An In Vivo Calcium Imaging Study.

Recently, we and others have shown that manipulating the activity of cholinergic interneurons (CIN) present in the NAc can modulate binge alcohol consumption. The present study is designed to examine the relationship between binge alcohol consumption and the activity of the CIN in real time by using an in vivo microendoscopic technique. We hypothesized that mice exposed to Drinking in the Dark (DID)-a recognized mouse model for binge drinking-would exhibit increased activity in the accumbal shell region (NAcSh). To test this hypothesis, male mice expressing Cre-recombinase in the cholinergic neurons were exposed to binge alcohol consumption (alcohol group), employing the DID method, and utilized in vivo calcium imaging to observe CIN activity in real time during alcohol consumption. The control (sucrose) group was exposed to 10% (w/v) sucrose. As compared to sucrose, mice in the alcohol group displayed a significant increase in the frequency and amplitude of discharge activity, which was measured using calcium transients in the CIN present in the NAcSh. In summary, our findings suggest that the activity of CIN in the NAcSh plays a crucial role in alcohol self-administration. These results emphasize the potential significance of targeting CIN activity as a therapeutic approach for addressing AUD.

Sophorin mitigates flutamide-induced hepatotoxicity in wistar rats.

Flutamide is frequently used in the management of prostate cancer, hirsutism, and acne. It is a non-steroidal anti-androgenic drug and causes hepatotoxicity. The current study's objective is to evaluate sophorin's hepatoprotective effectiveness against flutamide-induced hepatotoxicity in Wistar rats. Sophorin is a citrus flavonoid glycoside, also known as rutin, which is a low molecular weight polyphenolic compound with natural antioxidant properties and reported to have promising hepatoprotective efficacy. In this study, sophorin was used at a dose of 100 mg/kg body weight in purified water via oral route for 4 week daily whereas, flutamide was used at a dose of 100 mg kg/b.wt for 4 weeks daily in 0.5% carboxy methyl cellulose (CMC) through the oral route for the induction of hepatotoxicity. Flutamide administration leads to enhanced reactive oxygen species (ROS) generation, an imbalance in redox homeostasis and peroxidation of lipid resulted in reduced natural antioxidant level in liver tissue. Our result demonstrated that sophorin significantly abrogate flutamide induced lipid peroxidation, protein carbonyl (PC), and also significantly increasesed in enzymatic activity/level of tissue natural antioxidant such as reduced glutathione(GSH), glutathione reductase(GR), catalase, and superoxide dismutase(SOD). Additionally, sophorin reduced the activity of cytochrome P450 3A1 in liver tissue which was elevated due to flutamide treatment. Furthermore, sophorin treatment significantly decreased the pro-inflammatory cytokines (TNF-α and IL-6) level. Immunohistochemical analysis for the expression of inflammatory proteins (iNOS and COX-2) in hepatic tissue was decreased after sophorin treatment against flutamide-induced hepatotoxicity. Moreover, sophorin suppressed the infiltration of mast cells in liver tissue which further showed anti-inflammatory potential of sophorin. Our histological investigation further demonstrated sophorin's hepatoprotective function by restoring the typical histology of the liver. Based on the aforementioned information, we are able to come to the conclusion that sophorin supplementation might benefit wistar rats with flutamide-induced hepatic damage by reducing oxidative stress and hepatocellular inflammation.

Cholinergic interneurons in the shell region of the nucleus accumbens regulate binge alcohol consumption: A chemogenetic and genetic lesion study.

BACKGROUND: Binge drinking, characterized by heavy episodic alcohol consumption, poses significant health hazards and increases the likelihood of developing an alcohol use disorder (AUD). Given the growing prevalence of this behavior and its negative consequences, there is a need to explore novel therapeutic targets. Accumulating evidence suggests that cholinergic interneurons (CIN) within the shell region of the nucleus accumbens (NAcSh) play a critical role in reward and addiction. However, their specific involvement in binge alcohol administration remains unclear. We hypothesized that CIN in the NAcSh regulates binge alcohol consumption. METHODS: To test this hypothesis, we used male ChAT-cre mice expressing Cre-recombinase in cholinergic neurons. We performed chemogenetic manipulation using Designer Receptor Exclusively Activated by Designer Drugs (DREADD) to examine the activity, and genetic ablation of CIN in the NAcSh to examine the amount of alcohol consumed in mice exposed to binge alcohol consumption using the 4-Days Drinking-in-Dark (DID) paradigm. The impact of CIN manipulations in the NAcSh on sucrose self-administration was used to control for taste and caloric effects. Additionally, in a separate group of mice, c-Fos immunofluorescence was employed to verify chemogenetic activation or inhibition. Histological and immunohistochemical techniques were used to verify microinfusion sites, DREADD expression in CINs, and genetic ablation. RESULTS: We found that, while chemogenetic activation of CIN in the NAcSh caused a significant increase in alcohol consumption, chemogenetic inhibition or genetic ablation of CIN significantly reduced the amount of alcohol consumed without affecting sucrose self-administration. The chemogenetic inhibition caused a significant reduction, whereas activation caused a significant increase, in the number of c-Fos-labeled CIN in the NAcSh. CONCLUSIONS: Our findings highlight the crucial involvement of CIN in the NAcSh in modulating binge alcohol consumption, suggesting that targeting these neurons could serve to modify alcohol-related behaviors.

PSMA-targeted dendrimer as an efficient anticancer drug delivery vehicle for prostate cancer.

Prostate cancer (PCa) is the second leading cause of cancer-related deaths among men in the United States. Although early-stage treatments exhibit promising 5-year survival rates, the treatment options for advanced stage disease are constrained, with short survival benefits due to the challenges associated with effective and selective drug delivery to PCa cells. Even though targeting Prostate Specific Membrane Antigen (PSMA) has been extensively explored and is clinically employed for imaging and radio-ligand therapy, the clinical success of PSMA-based approaches for targeted delivery of chemotherapies remains elusive. In this study, we combine a generation 4 hydroxy polyamidoamine dendrimer (PD) with irreversible PSMA ligand (CTT1298) to develop a PSMA-targeted nanoplatform (PD-CTT1298) for selective intracellular delivery of potent chemotherapeutics to PCa. PD-CTT1298-Cy5 exhibits a PSMA IC50 in the nanomolar range and demonstrates selective uptake in PSMA (+) PCa cells via PSMA mediated internalization. When systemically administered in a prostate tumor xenograft mouse model, PD-CTT1298-Cy5 selectively targets PSMA (+) tumors with significantly less accumulation in PSMA (-) tumors or upon blocking of the PSMA receptors. Moreover, the dendrimer clears rapidly from the off-target organs limiting systemic side-effects. Further, the conjugation of an anti-cancer agent, cabozantinib to the PSMA-targeted dendrimer translates to a significantly enhanced anti-proliferative activity in vitro compared to the free drug. These findings highlight the potential of PD-CTT1298 nanoplatform as a versatile approach for selective delivery of high payloads of potent chemotherapeutics to PCa, where dose related systemic side-effects are a major concern.

Cardiac calcified amorphous tumour: an unusual aetiology for recurrent cardioembolic strokes.

We report an elderly woman with vascular risk factors and recurrent cardioembolic strokes in whom the stroke aetiology was finally ascertained to be a calcified amorphous tumour of the heart after repeated negative investigations for embolic aetiology over 2 years. This report discusses the clinical and imaging characteristics of calcified amorphous tumours of the heart with emphasis of recent advances in cardiac imaging.

Online health information on sinonasal inverted papillomas: An assessment on readability and quality.

BACKGROUND/OBJECTIVES: Sinonasal inverted papilloma (IP) is a rare but serious diagnosis, with a paucity of patient-centred information regarding this condition. As more patients are seeking healthcare information online, the quality and comprehensibility of this information becomes ever more important. The aim of the study was to investigate the readability and quality of websites on inverted papilloma. METHODS: The term IP and seven of its synonyms were inputted into the three of the most commonly used search engines in the English-speaking world (Google, Yahoo and Bing). The first 20 results returned for each search term were then screened with our exclusion criteria. The remaining websites were assessed for their readability using the using the Flesch Reading Ease Score (FRES) and average grade level (AGL). Quality was assessed using the DISCERN questionnaire. RESULTS: Of the 480 websites returned using our search strategy, 410 were excluded using our screening criteria. Removal of duplicates from the remaining 70 websites left 14 for inclusion in the final analysis. The mean FRES score of the remaining websites was 30.5 ± 10 and the mean AGL was 15.2 ± 1.1, corresponding to a reading age of a 21-year-old. The median DISCERN score was 33.5 (30.5-36.5), a score which falls within the 'poor quality' range. CONCLUSION: The readability and quality of online patient information on IP is far below the expected standard. Healthcare providers have a responsibility to direct patients to appropriate sources of information or consider producing new material should a lack of appropriate sources exist.

Racial Impact on Inpatient Stroke Quality of Care in Two Community Hospitals.

INTRODUCTION: This analysis was conducted as a part of a quality improvement project aiming at identifying racial disparity in inpatient stroke quality of care. METHODS: The Get With The Guidelines (GWTG) database was used to identify all patients discharged with any stroke diagnosis between January and December 2021. An additional chart review was conducted to ensure the accuracy of racial/ethnic categorization. The sample was dichotomized into white vs. non-white groups and compared with univariate analysis. RESULTS: The study sample comprised 1408 encounters (1347 patients) with Mean age of 71 ± 15 years, 51% women, 82% white patients, 15% non-white patients, 72% acute ischemic stroke (AIS); 15% transient ischemic attack (TIA), 9% intracerebral hemorrhage (ICH), 3% subarachnoid hemorrhage (SAH), and 1% stroke not otherwise specified. Non-white patients were younger and had fewer concomitant diagnoses, a lower proportion of TIA, and a higher proportion of ICH (p = 0.004). In the AIS cohort, compared to white patients, non-white patients had less frequent ambulance (p = 0.009), arrived at the hospital later than white patients (7.7 h longer; p < 0.001), had more severe strokes, and had less frequent IV thrombolysis utilization (7% vs. 13%; p = 0.042). Similarly, in the TIA cohort, non-white patients' utilization of EMS was lower than that of white patients, and their hospital arrival was delayed. In the ICH cohort, non-white patients were younger and had a lower frequency of atrial fibrillation and a non-significant trend toward higher disease severity. The SAH cohort had only eight non-white patients, six of whom were transferred to a higher level of hospital care within a few hours of arrival. Importantly, the hospital-based quality metrics, such as door-to-CT time, door-to-needle time, and the Joint Commission stroke quality metrics, were similar between the two groups. CONCLUSIONS: There is a racial disparity in the pre-hospital phase of the stroke chain of survival of non-white patients, impacting IV thrombolysis utilization. The younger age and worse lipid profile and hemoglobin A1c of non-white patients suggest the need for better preventative care starting at a young age.

Development and Initial Assessment of [18F]OP-801: a Novel Hydroxyl Dendrimer PET Tracer for Preclinical Imaging of Innate Immune Activation in the Whole Body and Brain.

PURPOSE: Innate immune activation plays a critical role in the onset and progression of many diseases. While positron emission tomography (PET) imaging provides a non-invasive means to visualize and quantify such immune responses, most available tracers are not specific for innate immune cells. To address this need, we developed [18F]OP-801 by radiolabeling a novel hydroxyl dendrimer that is selectively taken up by reactive macrophages/microglia and evaluated its ability to detect innate immune activation in mice following lipopolysaccharide (LPS) challenge. PROCEDURES: OP-801 was radiolabeled in two steps: [18F]fluorination of a tosyl precursor to yield [18F]3-fluoropropylazide, followed by a copper-catalyzed click reaction. After purification and stability testing, [18F]OP-801 (150-250 µCi) was intravenously injected into female C57BL/6 mice 24 h after intraperitoneal administration of LPS (10 mg/kg, n=14) or saline (n=6). Upon completing dynamic PET/CT imaging, mice were perfused, and radioactivity was measured in tissues of interest via gamma counting or autoradiography. RESULTS: [18F]OP-801 was produced with >95% radiochemical purity, 12-52 µCi/µg specific activity, and 4.3±1.5% decay-corrected yield. Ex vivo metabolite analysis of plasma samples (n=4) demonstrated high stability in mice (97±3% intact tracer >120 min post-injection). PET/CT images of mice following LPS challenge revealed higher signal in organs known to be inflamed in this context, including the liver, lung, and spleen. Gamma counting confirmed PET findings, showing significantly elevated signal in the same tissues compared to saline-injected mice: the liver (p=0.009), lung (p=0.030), and spleen (p=0.004). Brain PET/CT images (summed 50-60 min) revealed linearly increasing [18F]OP-801 uptake in the whole brain that significantly correlated with murine sepsis score (r=0.85, p<0.0001). Specifically, tracer uptake was significantly higher in the brain stem, cortex, olfactory bulb, white matter, and ventricles of LPS-treated mice compared to saline-treated mice (p<0.05). CONCLUSION: [18F]OP-801 is a promising new PET tracer for sensitive and specific detection of activated macrophages and microglia that warrants further investigation.

Mast cell-mediated immune regulation in health and disease.

Mast cells are important components of the immune system, and they perform pro-inflammatory as well as anti-inflammatory roles in the complex process of immune regulation in health and disease. Because of their strategic perivascular localization, sensitivity and adaptability to the microenvironment, and ability to release a variety of preformed and newly synthesized effector molecules, mast cells perform unique functions in almost all organs. Additionally, Mast cells express a wide range of surface and cytoplasmic receptors which enable them to respond to a variety of cytokines, chemicals, and pathogens. The mast cell's role as a cellular interface between external and internal environments as well as between vasculature and tissues is critical for protection and repair. Mast cell interactions with different immune and nonimmune cells through secreted inflammatory mediators may also turn in favor of disease promoting agents. First and forefront, mast cells are well recognized for their multifaceted functions in allergic diseases. Reciprocal communication between mast cells and endothelial cells in the presence of bacterial toxins in chronic/sub-clinical infections induce persistent vascular inflammation. We have shown that mast cell proteases and histamine induce endothelial inflammatory responses that are synergistically amplified by bacterial toxins. Mast cells have been shown to exacerbate vascular changes in normal states as well as in chronic or subclinical infections, particularly among cigarette smokers. Furthermore, a potential role of mast cells in SARS-CoV-2-induced dysfunction of the capillary-alveolar interface adds to the growing understanding of mast cells in viral infections. The interaction between mast cells and microglial cells in the brain further highlights their significance in neuroinflammation. This review highlights the significant role of mast cells as the interface that acts as sensor and early responder through interactions with cells in systemic organs and the nervous system.

Effects of Angiotensin Receptor-Neprilysin Inhibitors Versus Enalapril or Valsartan on Patients With Heart Failure: A Systematic Review and Meta-Analysis.

Recent studies have focused on treating heart failure, primarily mitigating symptoms and reducing the risk of mortality and other cardiovascular complications. A promising new treatment approach involves using LCZ696, an angiotensin receptor-neprilysin inhibitor (ARNI) comprising sacubitril and valsartan. This treatment is superior to the conventional drugs enalapril or valsartan in patients diagnosed with heart failure. A systematic search was conducted on PubMed, the Cochrane Library, and Elsevier's ScienceDirect databases to identify studies comparing sacubitril/valsartan with other drugs in heart failure patients with reduced ejection fraction (HFrEF) and preserved ejection fraction (HFpEF). The analyses were conducted using the random-effects model. The study's primary outcomes included all-cause mortality, death from cardiovascular causes, first hospitalization for heart failure, congestive heart failure, and changes in the Kansas City Cardiomyopathy Questionnaire (KCCQ) clinical score. The pooled analysis showed that treatment with the sacubitril/valsartan combination was associated with a significantly decreased rate of first hospitalization for heart failure (RR: 0.86; 95% CI: 0.79, 0.98, p: 0.03; I2: 57%) and significantly increased KCCQ clinical score (WMD: 2.20; 95% CI: 0.33, 4.06, p: 0.02; I2: 100%). However, the two groups had no significant difference in all-cause mortality (RR: 0.90; 95% CI: 0.80, 1.01, p: 0.08; I2: 20%), death from cardiovascular causes (RR: 0.96; 95% CI: 0.87, 1.05, p: 0.34; I2: 0%), or congestive heart failure (RR: 0.97; 95% CI: 0.75, 1.25, p: 0.19; I2: 38%). The research findings suggest that sacubitril/valsartan (LCZ696) reduces hospitalizations due to heart failure and improves KCCQ clinical scores. This treatment also reduces the decline in renal function and side effects associated with enalapril or valsartan. Nonetheless, further high-quality randomized controlled trials with large sample sizes are needed to assess other impacts of this therapy on heart failure patients. Overall, the use of LCZ696 represents a promising new approach to the treatment of heart failure.

Midgut Volvulus on an Octogenarian Male: A Case Report.

Midgut volvulus is a rare incidence in adults, especially in octogenarians. More unlikely is to find a midgut volvulus without necrosis or the need to do bowel resection when the volvulus is found within an internal hernia due to a mesenteric defect. No case has been reported with our unusual presentation, making it a rare and challenging discovery. We describe the case of an 83-year-old male who presented with nonspecific symptoms and was found to have a midgut volvulus with an internal hernia through a mesenteric defect, which had a successful recovery at the end.

Clinical Radiosynthesis and Translation of [18F]OP-801: A Novel Radiotracer for Imaging Reactive Microglia and Macrophages.

Positron emission tomography (PET) is a powerful tool for studying neuroinflammatory diseases; however, current PET biomarkers of neuroinflammation possess significant limitations. We recently reported a promising dendrimer PET tracer ([18F]OP-801), which is selectively taken up by reactive microglia and macrophages. Here, we describe further important characterization of [18F]OP-801 in addition to optimization and validation of a two-step clinical radiosynthesis. [18F]OP-801 was found to be stable in human plasma for 90 min post incubation, and human dose estimates were calculated for 24 organs of interest; kidneys and urinary bladder wall without bladder voiding were identified as receiving the highest absorbed dose. Following optimization detailed herein, automated radiosynthesis and quality control (QC) analyses of [18F]OP-801 were performed in triplicate in suitable radiochemical yield (6.89 ± 2.23% decay corrected), specific activity (37.49 ± 15.49 GBq/mg), and radiochemical purity for clinical imaging. Importantly, imaging mice with tracer (prepared using optimized methods) 24 h following the intraperitoneal injection of liposaccharide resulted in the robust brain PET signal. Cumulatively, these data enable clinical translation of [18F]OP-801 for imaging reactive microglia and macrophages in humans. Data from three validation runs of the clinical manufacturing and QC were submitted to the Food and Drug Administration (FDA) as part of a Drug Master File (DMF). Subsequent FDA approval to proceed was obtained, and a phase 1/2 clinical trial (NCT05395624) for first-in-human imaging in healthy controls and patients with amyotrophic lateral sclerosis is underway.

Galactosylated hydroxyl-polyamidoamine dendrimer targets hepatocytes and improves therapeutic outcomes in a severe model of acetaminophen poisoning-induced liver failure.

Toxicity to hepatocytes caused by various insults including drugs is a common cause of chronic liver failure requiring transplantation. Targeting therapeutics specifically to hepatocytes is often a challenge since they are relatively nonendocytosing unlike the highly phagocytic Kupffer cells in the liver. Approaches that enable targeted intracellular delivery of therapeutics to hepatocytes have significant promise in addressing liver disorders. We synthesized a galactose-conjugated hydroxyl polyamidoamine dendrimer (D4-Gal) that targets hepatocytes efficiently through the asialoglycoprotein receptors in healthy mice and in a mouse model of acetaminophen (APAP)-induced liver failure. D4-Gal localized specifically in hepatocytes and showed significantly better targeting when compared with the non-Gal functionalized hydroxyl dendrimer. The therapeutic potential of D4-Gal conjugated to N-acetyl cysteine (NAC) was tested in a mouse model of APAP-induced liver failure. A single intravenous dose of a conjugate of D4-Gal and NAC (Gal-d-NAC) improved survival in APAP mice, decreased cellular oxidative injury and areas of necrosis in the liver, even when administered at the delayed time point of 8 h after APAP exposure. Overdose of APAP is the most common cause of acute hepatic injury and liver transplant need in the United States, and is treated with large doses of NAC administered rapidly within 8 h of overdose leading to systemic side effects and poor tolerance. NAC is not effective when treatment is delayed. Our results suggest that D4-Gal is effective in targeting and delivering therapies to hepatocytes and Gal-D-NAC has the potential to salvage and treat liver injury with a broader therapeutic window.