Evaluation of Plasma Biomarkers for Causal Association With Peripheral Artery Disease.

BACKGROUND: Hundreds of biomarkers for peripheral artery disease (PAD) have been reported in the literature; however, the observational nature of these studies limits causal inference due to the potential of reverse causality and residual confounding. We sought to evaluate the potential causal impact of putative PAD biomarkers identified in human observational studies through genetic causal inference methods. METHODS: Putative circulating PAD biomarkers were identified from human observational studies through a comprehensive literature search based on terms related to PAD using PubMed, Cochrane, and Embase. Genetic instruments were generated from publicly available genome-wide association studies of circulating biomarkers. Two-sample Mendelian randomization was used to test the association of genetically determined biomarker levels with PAD using summary statistics from a genome-wide association study of 31 307 individuals with and 211 753 individuals without PAD in the Veterans Affairs Million Veteran Program and replicated in data from FinnGen comprised of 11 924 individuals with and 288 638 individuals without PAD. RESULTS: We identified 204 unique circulating biomarkers for PAD from the observational literature, of which 173 were genetically instrumented using genome-wide association study results. After accounting for multiple testing (false discovery rate, <0.05), 10 of 173 (5.8%) biomarkers had significant associations with PAD. These 10 biomarkers represented categories including plasma lipoprotein regulation, lipid homeostasis, and protein-lipid complex remodeling. Observational literature highlighted different pathways including inflammatory response, negative regulation of multicellular organismal processes, and regulation of response to external stimuli. CONCLUSIONS: Integrating human observational studies and genetic causal inference highlights several key pathways in PAD pathophysiology. This work demonstrates that a substantial portion of biomarkers identified in observational studies are not well supported by human genetic evidence and emphasizes the importance of triangulating evidence to understand PAD pathophysiology. Although the identified biomarkers offer insights into atherosclerotic development in the lower limb, their specificity to PAD compared with more widespread atherosclerosis requires further study.

Assessment of Price Variation in Coronary Artery Bypass Surgery at US Hospitals.

BACKGROUND: Little is known about hospital pricing for coronary artery bypass grafting (CABG). Using new price transparency data, we assessed variation in CABG prices across US hospitals and the association between higher prices and hospital characteristics, including quality of care. METHODS AND RESULTS: Prices for diagnosis related group code 236 were obtained from the Turquoise database and linked by Medicare Facility ID to publicly available hospital characteristics. Univariate and multivariable analyses were performed to assess factors predictive of higher prices. Across 544 hospitals, median commercial and self-pay rates were 2.01 and 2.64 times the Medicare rate ($57 240 and $75 047, respectively, versus $28 398). Within hospitals, the 90th percentile insurer-negotiated price was 1.83 times the 10th percentile price. Across hospitals, the 90th percentile commercial rate was 2.91 times the 10th percentile hospital rate. Regional median hospital prices ranged from $35 624 in the East South Central to $84 080 in the Pacific. In univariate analysis, higher inpatient revenue, greater annual discharges, and major teaching status were significantly associated with higher prices. In multivariable analysis, major teaching and investor-owned status were associated with significantly higher prices (+$8653 and +$12 200, respectively). CABG prices were not related to death, readmissions, patient ratings, or overall Centers for Medicare and Medicaid Services hospital rating. CONCLUSIONS: There is significant variation in CABG pricing, with certain characteristics associated with higher rates, including major teaching status and investor ownership. Notably, higher CABG prices were not associated with better-quality care, suggesting a need for further investigation into drivers of pricing variation and the implications for health care spending and access.

Endo-fenchyl acetate rich essential oil of Strobilanthes sessilis Nees inflorescence and its characterisation using GC, GC-MS, and NMR techniques.

Strobilanthes Blume is a genus in the family Acanthaceae, with many species endemic to the Indian subcontinent. Strobilanthes sessilis Nees is endemic to the southern Western Ghats of India. The essential oil of dried inflorescence of S. sessilis was extracted using hydrodistillation method and the chemical composition was determined using GC and GC-MS techniques, which revealed the major compound to be endo-fenchyl acetate (89.33%). Other minor compounds like endo-fenchol (3.74%), (E)-caryophyllene (1.07%), and limonene and ß-phellandrene (0.55%) were also observed. The major diastereomer of fenchyl acetate was determined using 2D-NMR techniques like HSQC, HMBC, and ROESY to confirm the endo configuration. The optical rotation of the oil in different solvents deduced that the laevorotatory enantiomer of endo-fenchyl acetate as the major or single compound. S. sessilis could be further explored as a major source of endo-fenchyl acetate, which has high importance in flavouring and other biological applications.

Where does the gadolinium go? A review into the excretion and retention of intravenous gadolinium.

Gadolinium-based contrast agents (GBCAs) are commonly used in medical imaging. Most intravenously (IV) administered gadolinium is excreted via the kidneys, and pathological retention in renal failure leading to nephrogenic systemic fibrosis (NSF) is well described. More recently, retention of gadolinium in the body in the absence of renal disease has been identified, with unknown clinical consequences. Many patients are aware of this, either through the media or via comprehensive consent documentation. Some internet sites, without hard evidence, have suggested a constellation of possible symptoms associated with GBCA retention. Recent experience with patients ascribing symptoms to a contrast-enhanced MRI examination prompted this review of the fate of injected GBCA after MRI study, and of information available to patients online regarding gadolinium retention.

Contemporary Patients Have Better Perioperative Outcomes Following Cytoreductive Nephrectomy: A Multi-institutional Analysis of 1272 Consecutive Patients.

OBJECTIVE: To evaluate factors associated with perioperative outcomes in a multi-institutional cohort of patients treated with cytoreductive nephrectomy (CN). METHODS: Data were analyzed for metastatic renal cell carcinoma patients treated with CN at 6 tertiary academic centers from 2005 to 2019. Outcomes included: Clavien-Dindo complications, mortality, length of hospitalization, 30-day readmission rate, and time to systemic therapy. Univariate and multivariable models evaluated associations between outcomes and prognostic variables including the year of surgery. RESULTS: A total of 1272 consecutive patients were treated with CN. Patients treated in 2015-2019 vs 2005-2009 had better performance status (P<.001), higher pathologic N stage (P = .04), more frequent lymph node dissections (P<.001), and less frequent presurgical therapy (P = .02). Patients treated in 2015-2019 vs 2005-2009 had lower overall and major complications from surgery, 22% vs 39%, P<.001% and 10% vs 16%, P = .03. Mortality at 90days was higher for patients treated 2005-2009 vs 2015-2019; 10% vs 5%, P = .02. After multivariable analysis, surgical time period was an independent predictor of major complications and 90-day mortality following cytoreductive surgery. CONCLUSION: Postoperative major complications and mortality rates following CN are significantly lower in patients treated within the most recent time period.

The Additional Cost of Perioperative Medication Errors.

ABSTRACT: The purpose of this report was to estimate the additional annual cost to the U.S. healthcare system attributable to preventable medication errors (MEs) in the operating room. The ME types were iteratively grouped by their associated harm (or potential harm) into 13 categories, and we determined the incidence of operations involving each ME category (number of operations involving each category/total number of operations): (1) delayed or missed required perioperative antibiotic (1.4% of operations); (2) prolonged hemodynamic swings (7.6% of operations); (3) untreated postoperative pain >4/10 (18.9% of operations); (4) residual neuromuscular blockade (2.9% of operations); (5) oxygen saturation <90% due to ME (1.8% of operations); (6) delayed emergence (1.1% of operations); (7) untreated new onset intraoperative cardiac arrhythmia (0.72% of operations); (8) medication documentation errors (7.6% of operations); (9) syringe swaps (5.8% of operations); (10) presumed hypotension with inability to obtain a blood pressure reading (2.2% of operations); (11) potential for bacterial contamination due to expired medication syringes (8.3% of operations); (12) untreated bradycardia <40 beats/min (1.1% of operations); and (13) other (13.0% of operations). Through a PubMed search, we determined the likelihood that the ME category would result in downstream patient harm such as surgical site infection or acute kidney injury, and the additional fully allocated cost of care (in 2021 U.S. dollars) for each potential downstream patient harm event. We then estimated the cost of the MEs across the U.S. healthcare system by scaling the number of MEs to the total number of annual operations in the United States (N = 19,800,000). The total estimated additional fully allocated annual cost of care due to perioperative MEs was $5.33 billion U.S. dollars.

Molecular docking and dynamics simulation study of quinones and pyrones from Alternaria solani and Alternaria alternata with HSP90: an important therapeutic target of cancer.

Although cancer continues to be one of the world's major causes of death, current cancer drugs have many serious side effects. There remains a need for new anticancer agents to overcome these shortcomings. Alternaria is one of the most widespread fungal genera, many species of which produce several classes of metabolites with potential polypharmacological activities. A few quinones and pyrones from Alternaria spp. have proven to exert cytotoxic effects against certain cancer cell lines, but their molecular mode of action is not known. The current study aimed to investigate the potential mechanisms that underlie the anticancer activity of a few selected quinones and pyrones from Alternaria solani and Alternaria alternata by molecular docking and dynamic simulation approaches. The selected metabolites were screened for their binding affinity to Heat shock protein 90 (HSP90), which is a known anticancer drug target. Molecular docking studies have revealed that Macrosporin, Altersolanol B, Fonsecin, and Neoaltenuene have good binding affinities with the target protein and the stabilities of the formed complexes were evaluated through molecular dynamics simulations. By analyzing the Root Mean Square Distance (RMSD), Root Mean Square Fluctuation (RMSF), and Principal Component Analysis (PCA) plots obtained from molecular dynamics simulations, this study shows that the complexes of all 4 lead molecules with target protein are stable over a 100 ns period. Molecular Mechanics Poisson-Boltzmann Surface Area (MM-PBSA) calculations were used to compute the binding free energies. The lead molecules were studied using in-silico analysis to determine their drug-likeness based on their Absorption, Distribution, Metabolism, Excretion and Toxicity (ADMET) and physicochemical properties. The results demonstrate that Macrosporin, Fonsecin, and Neoaltenuene could become promising anticancer molecules that target HSP90.Communicated by Ramaswamy H. Sarma.

Supplementary Posteromedial Plating for the Fixation of Complex Tibial Plateau Fractures: A Prospective Study.

Introduction The management of complex tibial plateau fractures (CTPF) involving the posterior tibial plateau remains challenging and achieving maintenance of an axially stable construct with a single lateral locked plate is uncertain. Dual plating for such fractures via separate incisions can provide better fixation with superior clinical and radiological outcomes. This prospective study aimed to evaluate the results of the management of Schatzker type V and VI complex tibial plateau fractures using a conventional anterolateral plate along with a posteromedial buttress plate via two separate approaches and the potential complications associated with it. Methods Fifty-six patients presenting with tibial plateau fractures to the Department of Orthopaedics at a tertiary care center in the northern part of the state of Uttar Pradesh, India, between January 2018 and July 2022 were screened. Subsequently, 28 patients with CTPFs (AO/OTA types 41C1, 41C2, AND 41C3) were included in the study, managed with dual plating, and followed up for a duration of 12 months. The clinico-radiological outcome was assessed using Rasmussen's Functional Grading System (RFS), Oxford Knee Score (OKS), knee range of motion achieved, and Rasmussen's Radiological Scoring System (RRS), and statistical analysis of the data was performed. Results A total of 24 (85.71%) patients had excellent OKS and good to excellent RFS at the final follow-up. The average knee range of motion was 3.21° to 122°, with only two patients reporting an extensor lag of more than 10°. The final follow-up radiographs showed a mean medial proximal tibial angle (MPTA) of 83.98° ± 6.89 (75.44-89.21) and a mean posterior tibial plateau angle (PTPA) of 12.31 ± 4.69 (5.12 to 16.49) with the RRS showing excellent or good radiographic results with a mean score of 14.1 ± 1.7 (range 8-16). None of the patients showed signs of deep infection, whereas superficial infection was reported in two patients. A single case of secondary loss of particular reduction was seen. Conclusion Supplementary posterior buttress plating, along with the conventional anterolateral plate for the management of CTPF, achieves rigid fixation with superior articular reduction, a high knee score, a good range of motion, lower complication rates, and limited deformities with a good radiological outcome, with a few demerits of prolonged operative time, technically demanding procedure, increased blood loss, and a protracted hospital stay which can be minimized in most instances using minimally open reduction techniques and careful soft-tissue handling.

Prospective Comparative Study Between Proximal Femoral Nail vs. Screw Augmented Proximal Femoral Nail in Unstable Intertrochanteric Fractures of Femur.

Introduction The proximal femoral nail (PFN) is a widely accepted fixation method for the management of unstable intertrochanteric fractures. Reconstructing the lateral trochanteric wall and ensuring the stability of the trochanteric fragments are considered to be essential for enhancing the prognosis of unstable intertrochanteric fractures. The aim of this study is to evaluate and compare the results of the management of unstable intertrochanteric fracture of the femur using PFN and the screw-augmented PFN (aPFN). Methods This prospective comparative study was undertaken from January 2020 to July 2021 and included 60 patients presenting with unstable intertrochanteric fractures (AO/OTA type 31-A2.2 and 31-A2.3) at a tertiary care teaching institute in northern India. The enrolled patients were randomly divided into two groups (group 1 and group 2) and were managed with screw-augmented PFN and PFN, respectively. Functional outcome was evaluated using the Salvati and Wilson score at the 12-month follow-up. SPSS version 24.0 (IBM Corp., Armonk, NY, USA) was used for statistical analysis. A p-value less than 0.05 was regarded as significant. Results The average time to union of the fractures in group 1 was 12.66 ± 1.68 weeks, while it was 13.47 ± 1.47 weeks in group 2 (p = 0.055). At the 12-month follow-up, the average functional outcome, as evaluated by Salvati and Wilson score, was 34 ± 2.40 in group 1, whereas it was 31.58 ± 4.4 in group 2; and the difference was observed to be statistically significant (p = 0.011). Group 1 had 28 patients (93.33%) with excellent to good results, while group 2 had 25 patients (83.33%) with excellent to good results. One patient in group 1 and five patients in group 2 had poor outcomes at the 12-month follow-up. Conclusion Screw-augmented PFN has better functional outcomes as compared to PFN alone for the management of unstable intertrochanteric fractures. Hence, in our opinion, screw augmentation of PFN may be the better fixation technique for most unstable intertrochanteric femur fractures.

A bistable and reconfigurable molecular system with encodable bonds.

Molecular systems with ability to controllably transform between different conformations play pivotal roles in regulating biochemical functions. Here, we report the design of a bistable DNA origami four-way junction (DOJ) molecular system that adopts two distinct stable conformations with controllable reconfigurability by using conformation-controlled base stacking. Exquisite control over DOJ's conformation and transformation is realized by programming the stacking bonds (quasi-blunt-ends) within the junction to induce prescribed coaxial stacking of neighboring junction arms. A specific DOJ conformation may be achieved by encoding the stacking bonds with binary stacking sequences based on thermodynamic calculations. Dynamic transformations of DOJ between various conformations are achieved by using specific environmental and molecular stimulations to reprogram the stacking codes. This work provides a useful platform for constructing self-assembled DNA nanostructures and nanomachines and insights for future design of artificial molecular systems with increasing complexity and reconfigurability.

Activity-Induced Cortical Glutamatergic Neuron Nascent Proteins.

Neuronal activity initiates signaling cascades that culminate in diverse outcomes including structural and functional neuronal plasticity, and metabolic changes. While studies have revealed activity-dependent neuronal cell type-specific transcriptional changes, unbiased quantitative analysis of cell-specific activity-induced dynamics in newly synthesized proteins (NSPs) synthesis in vivo has been complicated by cellular heterogeneity and a relatively low abundance of NSPs within the proteome in the brain. Here we combined targeted expression of mutant MetRS (methionine tRNA synthetase) in genetically defined cortical glutamatergic neurons with tight temporal control of treatment with the noncanonical amino acid, azidonorleucine, to biotinylate NSPs within a short period after pharmacologically induced seizure in male and female mice. By purifying peptides tagged with heavy or light biotin-alkynes and using direct tandem mass spectrometry detection of biotinylated peptides, we quantified activity-induced changes in cortical glutamatergic neuron NSPs. Seizure triggered significant changes in ∼300 NSPs, 33% of which were decreased by seizure. Proteins mediating excitatory and inhibitory synaptic plasticity, including SynGAP1, Pak3, GEPH1, Copine-6, and collybistin, and DNA and chromatin remodeling proteins, including Rad21, Smarca2, and Ddb1, are differentially synthesized in response to activity. Proteins likely to play homeostatic roles in response to activity, such as regulators of proteastasis, intracellular ion control, and cytoskeleton remodeling proteins, are activity induced. Conversely, seizure decreased newly synthetized NCAM, among others, suggesting that seizure induced degradation. Overall, we identified quantitative changes in the activity-induced nascent proteome from genetically defined cortical glutamatergic neurons as a strategy to discover downstream mediators of neuronal plasticity and generate hypotheses regarding their function.SIGNIFICANCE STATEMENT Activity-induced neuronal and synaptic plasticity are mediated by changes in the protein landscape, including changes in the activity-induced newly synthesized proteins; however, identifying neuronal cell type-specific nascent proteome dynamics in the intact brain has been technically challenging. We conducted an unbiased proteomic screen from which we identified significant activity-induced changes in ∼300 newly synthesized proteins in genetically defined cortical glutamatergic neurons within 20 h after pharmacologically induced seizure. Bioinformatic analysis of the dynamic nascent proteome indicates that the newly synthesized proteins play diverse roles in excitatory and inhibitory synaptic plasticity, chromatin remodeling, homeostatic mechanisms, and proteasomal and metabolic functions, extending our understanding of the diversity of plasticity mechanisms.

MRI determined prostate volume and the incidence of prostate cancer on MRI-fusion biopsy: a systemic review of reported data for the last 20 years.

PURPOSE: Magnetic resonance imaging (MRI) is a precise, systemic and advantageous imaging technique when compared to transrectal ultrasound (TRUS) which is very operator dependent. The negative correlation between prostate volume and the incidence of prostate cancer (PCa) obtained by TRUS biopsy has been well documented in the literature. The purpose of this systemic review is analyzing the reported MRI-fusion study results on prostate biopsies regarding any correlation between prostate volume and the incidence of PCa. METHODS: After defining the inclusion and exclusion criteria an in-depth review were performed between 01.01.2000 and 02.08.2022 using the PubMed database and applying the "PRISMA" guidelines. RESULTS: Twelve studies qualified, and all showed an inverse/negative relationship between prostate volume and incidence of PCa. Sample sizes ranged from 33 to 2767 patients in single and multi-institutional studies. All studies showed a statistically significant inverse relationship with a p value < 0.05. The graph summarizing all of studies and using Fisher's method revealed a highly significant combined p level of 0.00001. Additionally, not one single study was found showing the contrary (a positive correlation between prostate size and the incidence of PCa). CONCLUSION: To our knowledge, this is the first systemic review of reported MRI-Fusion data on the incidence of PCa in correlation with prostate volume. This MRI review confirms previous TRUS-biopsy studies which demonstrated an inverse relationship between prostate volume and the incidence of PCa, and thus further supports the hypothesis that large prostates size may be protective against PCa when compared to smaller prostates.

Binding kinetics of harmonically confined random walkers.

Diffusion-mediated binding of molecules under the influence of discrete spatially confining potentials is a commonly encountered scenario in systems subjected to explicit fields or implicit fields arising from tethering restraints. Here, we derive analytical expressions for the mean binding time of two random walkers geometrically confined by means of two harmonic potentials in one- and two-dimensional systems, which show excellent agreement with Brownian dynamics simulations. As a demonstration of its utility, we use this theory to maximize the communication speed in existing DNA walkers, obtaining quantitative agreement with previously reported experimental findings. The analytical expressions derived in this paper are broadly applicable to diverse systems, providing ways to characterize communication processes and optimize the rate of signal propagation for sensing and computing applications at the nanoscale.

Evolution of Androgen Deprivation Therapy (ADT) and Its New Emerging Modalities in Prostate Cancer: An Update for Practicing Urologists, Clinicians and Medical Providers.

Androgen deprivation therapy (ADT) has been the main management strategy for prostate cancer for more than eight decades, nowadays achieved commonly by administration of luteinizing hormone-releasing hormone agonists. ADT markedly suppresses androgen hormones with the long-term risks of adverse events such as muscle weakness, impairment of glucose and lipid metabolism, impotence, osteoporosis, and secondary fractures. Extensive research has provided significantly better insight into the dynamics of ADT including identification of the benefits of sequential and combination therapies. This has led to the development of new pharmaceutical ADT modalities. This review provides a general overview of the evolution of ADT in the context of the new emerging pharmaceutical ADT modalities so that clinicians and medical providers have a better understanding of personalizing the available ADT options with their different risk-benefit profiles.

Inflammatory Scores: Correlation with Clinical Outcomes in Hepatocellular Carcinoma Patients Undergoing Transarterial Radioembolization.

PURPOSE: To evaluate the ability of neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), aspartate aminotransferase-to-lymphocyte ratio (ALRI) and systemic-inflammation index (SII) to predict clinical outcomes in hepatocellular carcinoma (HCC) patients undergoing transarterial radioembolization (TARE). MATERIALS AND METHODS: One hundred forty-five patients who underwent treatment of 167 HCCs had their pretreatment and 1 month post treatment laboratory values evaluated. Overall survival (OS), progression-free survival (PFS) and local PFS models were performed with patients separated by median inflammatory scores. RESULTS: The median pretreatment NLR, PLR, ALRI and SII were 3.0 (range: 0.5-176), 104.4 (range: 25-830), 55.7 (range: 7.5-2090) and 360.2 (range: 51.1-7207.8), respectively. While the median post treatment NLR, PLR, ALRI and SII were 6.2 (range: 0.4-176), 180 (range: 35-2100), 125 (range: 15.9-5710) and 596.8 (range: 28.9-19,320), respectively. OS models showed significant differences when separating the groups by median post treatment NLR (p = 0.003) and SII (p = 0.003). Multivariate Cox regression models for OS with all pre and post treatment inflammatory markers (log-scale) as well as tumor size, AFP and Child-Pugh score showed significant pretreatment NLR [HR: 0.22 (95% CI:0.06-0.75), p = 0.016] and SII [3.52 (95% CI: 1.01-12.3), p = 0.048], as well as post treatment NLR [6.54 (95% CI: 1.57-27.2), p = 0.010] and SII [0.20 (95% CI: 0.05-0.82), p = 0.025] association. The post treatment ALRI (p = 0.010) correlated with PFS while, post treatment NLR (p < 0.001), ALRI (p = 0.024) and SII (p = 0.005) correlated with local PFS. CONCLUSION: Pretreatment and post treatment NLR and SII may be associated with OS and post treatment ALRI may be associated with both PFS and local PFS in HCC patients undergoing TARE.

Proteomic screen reveals diverse protein transport between connected neurons in the visual system.

Intercellular transfer of toxic proteins between neurons is thought to contribute to neurodegenerative disease, but whether direct interneuronal protein transfer occurs in the healthy brain is not clear. To assess the prevalence and identity of transferred proteins and the cellular specificity of transfer, we biotinylated retinal ganglion cell proteins in vivo and examined biotinylated proteins transported through the rodent visual circuit using microscopy, biochemistry, and mass spectrometry. Electron microscopy demonstrated preferential transfer of biotinylated proteins from retinogeniculate inputs to excitatory lateral geniculate nucleus (LGN) neurons compared with GABAergic neurons. An unbiased mass spectrometry-based screen identified ∼200 transneuronally transported proteins (TNTPs) isolated from the visual cortex. The majority of TNTPs are present in neuronal exosomes, and virally expressed TNTPs, including tau and ß-synuclein, were detected in isolated exosomes and postsynaptic neurons. Our data demonstrate transfer of diverse endogenous proteins between neurons in the healthy intact brain and suggest that TNTP transport may be mediated by exosomes.

An Atypical Presentation of Hemosuccus Pancreaticus Manifesting as Hematochezia.

Hemosuccus pancreaticus is a rare cause of upper gastrointestinal bleeding that is often associated with chronic pancreatitis. The bleeding usually manifests as melena because the source originates superior to the ligament of Treitz. We present a patient who was admitted for acute-on-chronic pancreatitis and ultimately developed hematochezia. Endoscopy revealed active oozing at the minor duodenal papilla. Computed tomography angiography identified active contrast extravasation at the gastroduodenal artery, and it was managed successfully with angioembolization. Our case emphasizes clinicians to consider hemosuccus pancreaticus as an alternative differential in a patient with a history of chronic pancreatitis manifesting with hematochezia.