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This project seeks to analyze the complex dynamics of climate change adaptation techniques in agriculture by investigating the synergistic link between diverse agricultural practices and technology intervention s via agent-based modeling. The experimental data, consisting of synthetic datasets, clarifies the iterative adaptation process by illustrating examples such as “Drought Resistant Crop-alpha” and “Water Conservation System-beta,” which demonstrate the effectiveness of swift modifications to evolving climatic circumstances. The revolutionary influence of technology adoption is shown by developments such as “Smart Irrigation-Enhanced,” which underscores its ability to improve resilience and production. The seamless integration of these methods across all agricultural phases, from initial acceptance to extensive application, highlights their interrelated and mutually reinforcing connection. Confronting difficulties, especially those associated with socio-economic dynamics and resource allocation, requires the integration of ethical and policy considerations. This study offers critical insights into the essential comprehension of climate adaptation techniques, which will inform future research and underscore the need for ethical frameworks in enhancing the efficacy of agent-based models for agricultural resilience.

In order to provide light on the relative efficiency of and suitability for different refrigeration technology applications, this study examines the performance of refrigeration cycles using refrigerants 404a and 410a. As part of the research technique, refrigeration systems are tested experimentally under controlled settings. Key performance indicators are then thoroughly analyzed and compared. Test rigs with compressors, condensers, expansion valves, and evaporators—common parts of the refrigeration cycle are used for experimental research. The test rig is outfitted with instruments that can measure critical parameters at various places in the system, such as pressure, temperature, and power consumption. In order to assess the thermodynamic performance of refrigeration cycles utilizing refrigerants 404a and 410a, the study looks at a number of variables, including energy consumption, cooling capacity, and coefficient of performance (COP). The impact of operating parameters on cycle performance, such as system pressure, refrigerant flow rate, and temperatures of the evaporator and condenser, is evaluated by analyzing experimental data. The experimental investigations' results are presented and thoroughly explained, emphasizing the observed trends, correlations, and distinctions between refrigerants 410a and 404a. Analyzing performance metrics comparative provide important information about the relative efficacy and efficiency of each refrigerant in refrigeration applications. The research findings' ramifications are examined in relation to real-world refrigeration technology applications, taking system design, component selection, and refrigerant selection into account. Based on the factors that have been found to influence system reliability and efficiency, recommendations are given for improving the performance of the refrigeration cycle. All things considered, this study advances knowledge of the performance of the refrigeration cycle utilizing refrigerants 404a and 410a, providing insightful information to researchers, engineers, and system designers. The results of this study hold significance for improving the effectiveness and durability of refrigeration systems across multiple sectors, such as cold storage, food processing, and HVAC. The understanding and applications of refrigeration technology are further advanced by identifying future research directions.

This research examines the effectiveness of nanomaterial-based adsorbents in improving water treatment. It specifically looks at their ability to adsorb contaminants, their efficiency in removing pollutants, the speed at which they work, and their ability to be regenerated. Four distinct nanomaterials, labeled as Nanomaterials A, B, C, and D, were produced and analyzed to assess their effectiveness in eliminating contaminants from liquid solutions. The results showed that Nanomaterial D displayed the maximum adsorption capacity, measuring 142 mg/g, which indicates its exceptional capability to adsorb contaminants. In addition, Nanomaterial C had the best removal efficiency of 97.5%, highlighting its efficacy in decreasing pollutant concentrations in water. The analysis of kinetic characteristics revealed that Nanomaterial C had the greatest pseudo-second-order rate constant, indicating fast adsorption kinetics and robust surface contacts. In addition, Nanomaterial C had the greatest regeneration efficiency of 85%, suggesting its suitability for sustainable water treatment purposes. The results emphasize the impressive effectiveness of adsorbents made from nanomaterials in tackling water quality issues and advancing environmental sustainability. Nanomaterial-based adsorbents may have a significant impact on securing clean and secure water supplies for current and future generations by improving synthesis processes, comprehending adsorption mechanisms, and evaluating regeneration features. Additional study is required to investigate other parameters that affect the performance of adsorbents and to assess their long-term stability and cost- effectiveness for practical use in water treatment systems.

In the age of smart grids, fortifying power grids against cyber threats has become of utmost importance. This paper reviews endeavours in the realms of defining, measuring, and scrutinising the resilience of smart grids. An exhaustive overview of both qualitative frameworks and quantitative metrics for resilience study is provided, underscoring the ideal characteristics of a resilience metric. The complexities in formulating and crafting such metrics in practical settings are also broached. Another focal point is the hierarchical outage management scheme, crafted to enhance the robustness of smart distribution systems, particularly those encompassing multi-microgrids. This scheme introduces a two-tiered approach: the preliminary stage revolves around resource scheduling via a model predictive control-based algorithm, whilst the subsequent stage centres on coordinating power transfers amongst microgrids. Moreover, the paper probes into the vulnerabilities of smart grids owing to the incorporation of information technology. A thorough exploration of security prerequisites, accounts of severe cyber-attacks, and a strategic methodology to detect and counteract these threats are elucidated. The paper wraps up by spotlighting future research trajectories, especially in forging a comprehensive framework for resilience and addressing challenges tied to multi-modal cyber/physical attacks and big data concerns.

Unmanned Aerial Vehicles (UAVs), commonly known as drones, have seen significant innovations in recent years. Among these innovations, the integration of solar power and machine learning has opened up new horizons for enhancing UAV capabilities. This review article provides a comprehensive overview of the state-of-the-art in solarpowered UAV design and its synergy with machine learning techniques. We delve into the various aspects of solar-powered UAVs, from their design principles and energy harvesting technologies to their applications across different domains, all while emphasizing the pivotal role that machine learning plays in optimizing their performance and expanding their functionality. By examining recent advancements and challenges, this review aims to shed light on the future prospects of this transformative technology.

This paper offers a comprehensive review of the advancements in the domain of solar energy forecasting models, emphasizing their significance for grid integration and power balancing. The increasing inclusion of renewable resources in global energy portfolios underscores the urgency for precise forecasting of variable resources like solar energy. Solar generation technologies have witnessed remarkable growth, leading to heightened grid penetration rates. However, the ground-level solar resource is characterized by high variability, primarily influenced by factors such as cloud cover changes, atmospheric aerosol levels, and certain atmospheric gases. This variability, especially at elevated grid penetration levels, introduces challenges related to reserve costs, dispatchable generation, and overall grid reliability. To address these challenges, there’s a pressing need for forecast systems with high accuracy across multiple time horizons, catering to regulation, dispatching, scheduling, and unit commitment. Furthermore, the variability of renewable energy stands as a significant barrier to its broader adoption. Energy storage emerges as a potential solution to mitigate power imbalances arising from the disparity between available renewable power and load demands. Through an analytical model, this review explores the potential of storage in reducing power imbalances and the requisite storage capacity to achieve this balance. The paper delves into the theory behind these forecasting methodologies and highlights successful applications in solar forecasting for utility-scale solar plants.

In this paper, the effect of wear parameters on the wear rate of AA5086 alloy reinforced with Alumina (Al2O3) and Titanium boride (TiB2) is investigated. The Al2O3 content is fixed at 5wt%, while the variation in TiB2 content is considered as one of the parameters. The preparation of AA5086/Al2O3/TiB2 hybrid nano composite is carried out using the stir casting technique. To formulate the experimental design, response surface methodology (RSM) is employed, and four factors at three levels are selected using the Box Behnken design. The chosen process parameters include reinforcement wt% (5%, 7.5%, 10%), load (30N, 40N, 50N), sliding speed (500rpm, 600rpm, 700rpm), and sliding distance (400m, 450m, 500m).The results indicate that the highest wear rate of 0.09876 mm3/Nm is observed when using a load of 50N, sliding speed of 500 rpm, sliding distance of 400m, and a reinforcement content of 5%.An analysis of variance (ANOVA) is performed to determine the significance of each factor on the wear rate. According to the ANOVA results, it is found that load is the most critical factor contributing to the increase in wear rate, followed by sliding distance, sliding speed, and reinforcement content.

Using a mixed-methods approach, we examine the complex link between user happiness and technology adoption in the context of smart homes. Our tests show that user happiness and adoption are highly influenced by the versions of smart home technologies, with Version A producing better user satisfaction (7.2) and adoption rates (68%) than Version B (6.8, 62%). Furthermore, consumers engaging with Features A and C reported the greatest adoption rates (80%) and satisfaction (8.1), indicating that certain features, particularly when paired, have a significant influence on user pleasure. Extended training times resulted in higher user satisfaction and adoption rates of the technology; the 6-hour training group had the greatest adoption rate (84%), and the highest satisfaction (8.3%). Furthermore, user age demographics have a substantial impact on adoption and happiness; young adults have the greatest adoption rate (70%) and contentment (7.6). These results highlight the necessity of developing smart home technologies that are appropriate for various age groups, as well as the significance of feature customization, thorough training, and user-centric design in improving user satisfaction and encouraging technology adoption. Introduction

The popularity and rapid growth of the internet have reemphasized the importance of intrusion detection systems (IDS) significance in the network security. IDS decreases hacking, data theft risk, privacy intrusion, and others. To save the system from external and internal intruders, the primary approaches of IDS are used. Many techniques[13], like genetic algorithms, artificial neural networks, and artificial immune systems, have been applied to IDS. This paper describes an Ensemble Framework of Artificial Immune System (AIS) based on Network Intrusion Detection System. Without placing a significant additional load on networks and monitoring systems, the large volume of data is analysed by a network-based Intrusion Detection System (NIDS). For determining the connection type, data from KDD Cup 99 competitions is utilized. To differentiate between attacks and valid connections, IDS can be utilized. Optimized feature selection is used to speed up the time-consuming rough set. The results obtained from the IDS system indicate that it can effectively identify the attacking connections with a high success rate.

Abstract Background Inflammatory bowel diseases are associated with increased adiponectin (APN) levels, which may exert pro-inflammatory effects in these individuals. Since habitual exercise may increase APN, the aim of this study was to determine how exercise training affects mice with acute colitis. Methods Male adiponectin knock out (APNKO) and wild type (WT) mice (C57BL/6) were randomly assigned to 4 different groups: 1) Sedentary (SED); 2) Exercise trained (ET); 3) Sedentary with dextran sodium sulfate (DSS) treatment (SED + DSS); and 4) Exercise trained with DSS (ET + DSS). Exercise-trained mice ran at 18 m/min for 60 min, 5d/wk for 4 weeks. Subsequently, the ET + DSS and the SED + DSS mice received 2% DSS in their drinking water for 5 days (d), followed by 5d of regular water. Results The clinical symptoms of acute colitis (diarrhea, stool haemoccult, and weight loss) were unaffected by exercise and there was no difference between the APNKO and WT mice (p > 0.05) except on day 39. However, the clinical symptoms of the DSS-treated APNKO mice were worse than WT mice treated with DSS and had increased susceptibility to intestinal inflammation due to increased local STAT3 activation, higher IL-6, TNF-α, IL-1β and IL-10 levels, and as a result had increased intestinal epithelial cell proliferation (p Conclusions Exercise training may contribute in alleviating the symptoms of acute colitis and APN deficiency may exacerbate the intestinal inflammation in DSS-induced colitis.

Background & Aims: Early-onset colorectal cancer (EO-CRC), diagnosed before age 50, is rising in incidence worldwide. Although post-surgical colonoscopy surveillance strategies exist, appropriate intervals in EO-CRC remain elusive, as long-term surveillance outcomes remain scant. We sought to compare findings of surveillance colonoscopies of EO-CRC with patients with average onset colorectal cancer (AO-CRC) to help define surveillance outcomes in these groups., Methods: Single-institution retrospective chart review identified EO-CRC and AO-CRC patients with colonoscopy and no evidence of disease. Surveillance intervals and time to development of advanced neoplasia (CRC and advanced polyps [adenoma/sessile serrated]) were examined. For each group, 3 serial surveillance colonoscopies were evaluated. Statistical analyses were performed utilizing log-ranked Kaplan-Meier method and Cox proportional hazards., Results: A total of 1259 patients with CRC were identified, with 612 and 647 patients in the EO-CRC and AO-CRC groups, respectively. Compared with patients with AO-CRC, patients with EO-CRC had a 29% decreased risk of developing advanced neoplasia from time of initial surgery to first surveillance colonoscopy (hazard ratio, 0.71; 95% confidence interval, 0.52-1.0). Average follow-up time from surgical resection to first surveillance colonoscopy was 12.6 months for both cohorts. Overall surveillance findings differed between cohorts (P = .003), and patients with EO-CRC were found to have less advanced neoplasia compared with their counterparts with AO-CRC (12.4% vs 16.0%, respectively). Subsequent colonoscopies found that, while patients with EO-CRC returned for follow-up surveillance colonoscopy earlier than patients with AO-CRC, the EO-CRC cohort did not have more advanced neoplasia nor non-advanced adenomas., Conclusions: Patients with EO-CRC do not have an increased risk of advanced neoplasia compared with patients with AO-CRC and therefore do not require more frequent colonoscopy surveillance than current guidelines recommend., (Copyright © 2024 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: Cachexia is a common complication of cancer and is associated with an increased risk of death. The level of growth differentiation factor 15 (GDF-15), a circulating cytokine, is elevated in cancer cachexia. In a small, open-label, phase 1b study involving patients with cancer cachexia, ponsegromab, a humanized monoclonal antibody inhibiting GDF-15, was associated with improved weight, appetite, and physical activity, along with suppressed serum GDF-15 levels., Methods: In this phase 2, randomized, double-blind, 12-week trial, we assigned patients with cancer cachexia and an elevated serum GDF-15 level (≥1500 pg per milliliter) in a 1:1:1:1 ratio to receive ponsegromab at a dose of 100 mg, 200 mg, or 400 mg or to receive placebo, administered subcutaneously every 4 weeks for three doses. The primary end point was the change from baseline in body weight at 12 weeks. Key secondary end points were appetite and cachexia symptoms, digital measures of physical activity, and safety., Results: A total of 187 patients underwent randomization. Of these patients, 40% had non-small-cell lung cancer, 32% had pancreatic cancer, and 29% had colorectal cancer. At 12 weeks, patients in the ponsegromab groups had significantly greater weight gain than those in the placebo group, with a median between-group difference of 1.22 kg (95% credible interval, 0.37 to 2.25) in the 100-mg group, 1.92 (95% credible interval, 0.92 to 2.97) in the 200-mg group, and 2.81 (95% credible interval, 1.55 to 4.08) in the 400-mg group. Improvements were observed across measures of appetite and cachexia symptoms, along with physical activity, in the 400-mg ponsegromab group relative to placebo. Adverse events of any cause were reported in 70% of the patients in the ponsegromab group and in 80% of those in the placebo group., Conclusions: Among patients with cancer cachexia and elevated GDF-15 levels, the inhibition of GDF-15 with ponsegromab resulted in increased weight gain and overall activity level and reduced cachexia symptoms, findings that confirmed the role of GDF-15 as a driver of cachexia. (Funded by Pfizer; ClinicalTrials.gov number, NCT05546476.)., (Copyright © 2024 Massachusetts Medical Society.)

Aim: To investigate the effects of lotiglipron (PF-07081532), a once-daily, oral small-molecule glucagon-like peptide-1 receptor agonist, in participants with type 2 diabetes (T2D) and/or obesity., Materials and Methods: Two Phase 1 randomized, double-blind, placebo-controlled, multiple-ascending-dose studies were conducted to investigate the safety, tolerability, pharmacokinetics and pharmacodynamics of lotiglipron., Results: Across the studies, 74 participants with T2D were treated for 28 or 42 days, and 26 participants with obesity without diabetes were treated for 42 days, following randomization to placebo or lotiglipron (target doses 10-180 mg/day, with dose titration to higher target doses). Most adverse events were mild (89.6%), with nausea the most frequently reported in both studies. There were no clinically meaningful adverse trends noted in safety laboratory tests, vital signs, or electrocardiogram parameters. In participants with T2D, lotiglipron resulted in dose-dependent reductions in mean daily glucose. The 180-mg dose was associated with least squares mean decreases from baseline in glycated haemoglobin (-1.61% [90% confidence interval {CI} -2.08, -1.14] vs. -0.61% [-1.56, 0.34] for placebo) and body weight (-5.10 kg [90% CI -6.62, -3.58] vs. -2.06 kg [90% CI -4.47, 0.36] for placebo) after 42 days; a similar magnitude of weight loss was seen in participants with obesity. The observed pharmacokinetic profile supported once-daily dosing., Conclusions: The profile of once-daily lotiglipron with doses up to 180 mg, as observed in these two Phase 1 studies, indicated a safety and tolerability profile consistent with the mechanism of action, with dose-dependent reductions in glycaemic indices (T2D) and body weight (both populations) after multiple doses., Clinicaltrials: gov identifier: NCT04305587, NCT05158244., (© 2024 Pfizer Inc. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Background: Cancer cachexia is a multifactorial metabolic wasting syndrome characterized by anorexia, unintentional loss of weight involving both skeletal muscle and adipose tissues, progressive functional impairment and reduced survival. Therapeutic strategies for this serious condition are very limited. Growth differentiation factor 15 (GDF-15) is a cytokine that is implicated in cancer cachexia and may represent both a biomarker of cancer cachexia and a potential therapeutic target. Ponsegromab is a potent and selective humanized monoclonal antibody that inhibits GDF-15-mediated signalling. Preclinical and preliminary phase 1 data suggest that ponsegromab-mediated inactivation of circulating GDF-15 may lead to improvement in key characteristics of cachexia. The primary objective of this phase 2 study is to assess the effect of ponsegromab on body weight in patients with cancer, cachexia and elevated GDF-15 concentrations. Secondary objectives include assessing physical activity, physical function, actigraphy, appetite, nausea and vomiting, fatigue and safety. Exploratory objectives include evaluating pharmacokinetics, pharmacodynamics, immunogenicity, lumbar skeletal muscle index and Response Evaluation Criteria in Solid Tumors., Methods: Approximately 168 adults with non-small-cell lung, pancreatic or colorectal cancers who have cachexia and elevated GDF-15 concentrations will be randomized in a double-blind, placebo-controlled study (NCT05546476). Participants meeting eligibility criteria will be randomized 1:1:1:1 to one of three dose groups of ponsegromab (100, 200 or 400 mg) or matching placebo administered subcutaneously every 4 weeks for an initial 12-week treatment period. This is followed by optional open-label treatment with ponsegromab of 400 mg administered every 4 weeks for up to 1 year. The primary endpoint is mean change from baseline in body weight at Week 12. A mixed model for repeated measures followed by a Bayesian E max model will be used for the primary analysis. Secondary endpoints include physical activity, physical function and actigraphy measured by remote digital sensors; patient-reported appetite-related symptoms assessed by Functional Assessment of Anorexia-Cachexia Therapy subscale scores; anorexia/appetite, nausea and vomiting, and fatigue evaluated according to questions from the Cancer-Related Cachexia Symptom Diary; and incidence of adverse events, safety laboratory tests, vital signs and electrocardiogram abnormalities., Perspective: Cancer-related cachexia is an area of significant unmet medical need. This study will support the clinical development of ponsegromab as a novel inhibitor of GDF-15, which may ameliorate key pathologies of cancer cachexia to improve patient symptoms, functionality and quality of life., Trial Registration: ClinicalTrials.gov ID: NCT05546476., (© 2024 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by Wiley Periodicals LLC.)

Danuglipron (PF-06882961) is an oral, small-molecule glucagon-like peptide-1 receptor agonist in development for the treatment of type 2 diabetes (T2D) and obesity. Impaired renal function is prevalent in patients with T2D. This Phase 1, open-label study evaluated the effect of renal impairment on the pharmacokinetics, safety, and tolerability of danuglipron (20 mg) in healthy participants with normal renal function (estimated glomerular filtration rate [eGFR] unnormalized for body surface area: ≥90 mL/min), in participants with T2D and normal renal function (eGFR ≥90 mL/min), and in participants with T2D and mild (eGFR 60-89 mL/min), moderate (eGFR 30-59 mL/min), or severe (eGFR <30 mL/min) renal impairment (N = 39). Log-linear regression analyses and analyses of variance showed no evidence of a clinically significant effect of reduced renal function on danuglipron pharmacokinetics. Renal clearance of unchanged danuglipron was minimal (<1% across all renal function groups). Danuglipron pharmacokinetics were similar between healthy participants and participants with T2D and normal renal function. A single 20-mg oral dose of danuglipron was generally safe and well tolerated in all participant groups. In participants with T2D, renal impairment had no clinically meaningful effect on the pharmacokinetic, safety, and tolerability profiles of danuglipron, indicating that dose adjustment of danuglipron will not be required when administered to patients with T2D and reduced renal function., (© 2023 Pfizer Inc. The Journal of Clinical Pharmacology published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.)

Aim: To evaluate the tolerability, safety and pharmacodynamics of different dose-escalation schemes of the oral small-molecule glucagon-like peptide-1 receptor (GLP-1R) agonist danuglipron., Materials and Methods: This Phase 2a, double-blind, placebo-controlled, parallel-group study randomly assigned adults with type 2 diabetes (T2D) treated with metformin to placebo or danuglipron (low [5-mg] or high [10-mg] starting dose, with 1- or 2-week dose-escalation steps, to target doses of 80, 120 or 200 mg twice daily [BID]) and adults with obesity without diabetes to placebo or danuglipron 200 mg BID., Results: Participants with T2D (n = 123, mean glycated haemoglobin [HbA1c] 8.19%) or obesity without diabetes (n = 28, mean body mass index 37.3 kg/m 2 ) were randomly assigned and treated. Discontinuation from study medication occurred in 27.3% to 72.7% of participants across danuglipron groups versus 16.7% to 18.8% for placebo, most often due to adverse events. Nausea (20.0%-47.6% of participants across danuglipron groups vs. 12.5% for placebo) and vomiting (18.2%-40.9% danuglipron vs. 12.5% placebo, respectively) were most commonly reported in participants with T2D. Gastrointestinal adverse events were generally related to danuglipron target dose and were not substantially affected by starting dose. In participants with T2D, least squares mean changes from baseline in HbA1c (-1.04% to -1.57% across danuglipron groups vs. -0.32% for placebo), fasting plasma glucose (-23.34 mg/dL to -53.94 mg/dL danuglipron vs. -13.09 mg/dL placebo) and body weight (-1.93 to -5.38 kg danuglipron vs. -0.42 kg placebo) at Week 12 were generally statistically significant for danuglipron compared with placebo (P < 0.05)., Conclusions: Danuglipron resulted in statistically significant reductions in HbA1c, FPG and body weight over 12 weeks, in the setting of higher discontinuation rates and incidence of gastrointestinal adverse events with higher target doses., Clinicaltrials: gov identifier: NCT04617275., (© 2023 John Wiley & Sons Ltd.)

Introduction: Dexmedetomidine is one of the anesthetics of choice for drug induced sleep endoscopy (DISE), with advantages including limited respiratory depression, analgesia, and decreased incidence of emergence delirium. However, challenges with determining sedation levels and prolonged recovery have limited its usage. An improved understanding of the effect of dexmedetomidine on the level of sedation and the corresponding electroencephalographic (EEG) changes could help overcome these barriers., Methods: Fifty-one patients received dexmedetomidine sedation with Richmond Agitation-Sedation Scale (RASS) score assessment and continuous EEG monitoring via SedLine for DISE. We constructed a pharmacokinetic model to determine continuous dexmedetomidine blood concentration. From the SedLine, we extracted the patient state index (PSI), and from the EEG we calculated the spectral edge frequency 95% (SEF95) and the correlation dimension (CD), a type of fractal dimension used to assess the complexity of a system. These metrics were subsequently compared against one another and with the dexmedetomidine concentration., Results: Our pharmacokinetic model yielded a two-compartment model with volumes of 51.8 L and 106.2 L, with clearances of 69.5 and 168.9 L/h, respectively, and a time to effect of 9 min, similar to prior studies. Based on this model, decreasing RASS score, SEF95, CD, and PSI were all significantly associated with increasing dexmedetomidine concentration ( p  < 0.001, p  = 0.006, p  < 0.001 respectively). The CD, SEF95, and PSI better captured the effects of increasing dexmedetomidine concentration as compared to the RASS score. Simulating dexmedetomidine concentration based on titration to target levels derived from CD and PSI confirmed commonly used dexmedetomidine infusion dosages., Conclusion: Dexmedetomidine use for DISE confirmed previous pharmacokinetic models seen with dexmedetomidine. Complex EEG metrics such as PSI and CD, as compared to RASS score and SEF95, better captured changes in brain state from dexmedetomidine and have potential to improve the monitoring of dexmedetomidine sedation., Competing Interests: DD was a consultant for Masimo Inc. RC was a consultant for SAB – Bryte LLC and Invicta Medical. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Han, Drover, Chen, Saxena, Eagleman, Nekhendzy, Pritchard and Capasso.)

Multiple electroencephalographic (EEG) monitors and their associated EEG markers have been developed to aid in assessing the level of sedation in the operating room. While many studies have assessed the response of these markers to propofol sedation and anesthetic gases, few studies have compared these markers when using dexmedetomidine, an alpha-2 agonist. Fifty-one patients underwent drug induced sleep endoscopy with dexmedetomidine sedation. Continuous EEG was captured using SedLine (Masimo, Inc), and a playback system was used to extract the bispectral index (BIS) (Medtronic Inc), the patient state index (PSI) (Masimo, Inc), the state and response Entropy (GE Healthcare), and calculate the spectral edge frequency 95% (SEF95). Richmond Agitation-Sedation Scale (RASS) scores were assessed continually throughout the procedure and in recovery. We assessed the correlation between EEG markers and constructed ordinal logistic regression models to predict the RASS score and compare EEG markers. All three commercial EEG metrics were significantly associated with the RASS score (p < 0.001 for all metrics) whereas SEF95 alone was insufficient at characterizing dexmedetomidine sedation. PSI and Entropy achieved higher accuracy at predicing deeper levels of sedation as compared to BIS (PSI: 58.3%, Entropy: 58.3%, BIS: 44.4%). Lightening secondary to RASS score assessment is significantly captured by all three commercial EEG metrics (p < 0.001). Commercial EEG monitors can capture changes in the brain state associated with the RASS score during dexmedetomidine sedation. PSI and Entropy were highly correlated and may be better suited for assessing deeper levels of sedation., (© 2022. The Author(s), under exclusive licence to Springer Nature B.V.)

Importance: Currently available glucagon-like peptide 1 receptor (GLP-1R) agonists for treating type 2 diabetes (T2D) are peptide agonists that require subcutaneous administration or strict fasting requirements before and after oral administration., Objective: To investigate the efficacy, safety, and tolerability of multiple dose levels of the novel, oral, small molecule GLP-1R agonist danuglipron over 16 weeks., Design, Setting, and Participants: A phase 2b, double-blind, placebo-controlled, parallel-group, 6-group randomized clinical trial with 16-week double-blind treatment period and 4-week follow-up was conducted from July 7, 2020, to July 7, 2021. Adults with T2D inadequately controlled by diet and exercise, with or without metformin treatment, were enrolled from 97 clinical research sites in 8 countries or regions., Interventions: Participants received placebo or danuglipron, 2.5, 10, 40, 80, or 120 mg, all orally administered twice daily with food for 16 weeks. Weekly dose escalation steps were incorporated to achieve danuglipron doses of 40 mg or more twice daily., Main Outcomes and Measures: Change from baseline in glycated hemoglobin (HbA1c, primary end point), fasting plasma glucose (FPG), and body weight were assessed at week 16. Safety was monitored throughout the study period, including a 4-week follow-up period., Results: Of 411 participants randomized and treated (mean [SD] age, 58.6 [9.3] years; 209 [51%] male), 316 (77%) completed treatment. For all danuglipron doses, HbA1c and FPG were statistically significantly reduced at week 16 vs placebo, with HbA1c reductions up to a least squares mean difference vs placebo of -1.16% (90% CI, -1.47% to -0.86%) for the 120-mg twice daily group and FPG reductions up to a least squares mean difference vs placebo of -33.24 mg/dL (90% CI, -45.63 to -20.84 mg/dL). Body weight was statistically significantly reduced at week 16 compared with placebo in the 80-mg twice daily and 120-mg twice daily groups only, with a least squares mean difference vs placebo of -2.04 kg (90% CI, -3.01 to -1.07 kg) for the 80-mg twice daily group and -4.17 kg (90% CI, -5.15 to -3.18 kg) for the 120-mg twice daily group. The most commonly reported adverse events were nausea, diarrhea, and vomiting., Conclusions and Relevance: In adults with T2D, danuglipron reduced HbA1c, FPG, and body weight at week 16 compared with placebo, with a tolerability profile consistent with the mechanism of action., Trial Registration: ClinicalTrials.gov Identifier: NCT03985293.

Aim: To assess the safety, tolerability and pharmacodynamics (PD) of the ketohexokinase inhibitor PF-06835919 in participants with non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes (T2D)., Materials and Methods: This double-blind, placebo-controlled, parallel-group study enrolled adults with NAFLD (≥ 8% whole liver fat [WLF] using MRI proton density fat fraction [MRI-PDFF]) and T2D on stable doses of metformin (≥ 500 mg/day). Participants received once-daily placebo, PF-06835919 150 or 300 mg for 16 weeks. Randomization (1:1:1) was via an interactive response technology system. Endpoints included percentage change from baseline (CFB) in WLF using MRI-PDFF (primary endpoint) and CFB in HbA1c (co-primary endpoint) at 16 weeks, PD, safety and tolerability., Results: Among 164 participants randomized and treated, 145 completed the treatment (placebo, n = 50; PF-06835919 150 mg, n = 46; PF-06835919 300 mg, n = 49). At week 16, least squares mean (90% confidence interval) percentage CFB in WLF was -5.26% (-12.86%, 2.99%), -17.05% (-24.01%, -9.46%) and -19.13% (-25.51%, -12.20%) in the placebo, PF-06835919 150-mg and 300-mg groups, respectively (PF-06835919 300-mg group vs. placebo, P = .0288). Modest numerical reductions in HbA1c were observed in all groups that did not reach statistical significance. Treatment-emergent adverse event incidence was similar across groups (40.7%, 45.5% and 32.7% in the placebo, PF-06835919 150-mg and 300-mg groups, respectively), with no apparent dose-related trend., Conclusions: PF-06835919 administration over 16 weeks was generally safe and well tolerated and resulted in reductions in WLF in participants with NAFLD and T2D., (© 2022 Pfizer, Inc. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Aims: This study investigated the safety, tolerability, pharmacokinetics and pharmacodynamics of danuglipron (PF-06882961), which is a novel, oral small-molecule glucagon-like peptide-1 receptor agonist, in Japanese participants with type 2 diabetes mellitus (T2DM)., Materials and Methods: This phase 1, randomized, double-blind, placebo-controlled, parallel-group study enrolled adult Japanese participants with T2DM inadequately controlled on diet and exercise. Participants received twice-daily oral doses of placebo or multiple ascending doses of danuglipron titrated to 40, 80 or 120 mg twice daily over 8 weeks. The primary outcome was the safety and tolerability of danuglipron. Secondary and exploratory outcomes included plasma pharmacokinetics, glycaemic parameters and body weight., Results: In the 37 participants randomized, the most common treatment-emergent adverse events were nausea, vomiting, abdominal discomfort, diarrhoea and headache. Most treatment-emergent adverse events were of mild or moderate intensity. Dose-proportional increases in danuglipron exposure parameters were observed at steady state (Day 56). Significant reductions from baseline were observed with danuglipron on Day 56 for mean daily glucose [least squares mean (90% confidence interval) placebo-adjusted difference of up to -67.89 (-88.98, -46.79) mg/dl] and on Day 57 for fasting plasma glucose [up to -40.87 (-53.77, -27.98) mg/dl], glycated haemoglobin [up to -1.41% (-2.01%, -0.82%)] and body weight [up to -1.87 (-3.58, -0.17) kg]., Conclusions: In Japanese adults with T2DM, danuglipron exhibited dose-proportional increases in plasma exposure at steady state and robustly reduced glycaemic parameters and body weight after 8 weeks of dosing, with a safety profile consistent with the mechanism of action., (© 2022 Pfizer Inc. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Purpose: Hepatic steatosis due to altered lipid metabolism and accumulation of hepatic triglycerides is a hallmark of nonalcoholic fatty liver disease (NAFLD). Diacylglycerol acyltransferase (DGAT) enzymes, DGAT1 and DGAT2, catalyze the terminal reaction in triglyceride synthesis, making them attractive targets for pharmacologic intervention. There is a common misconception that these enzymes are related; however, despite their similar names, DGAT1 and DGAT2 differ significantly on multiple levels. As we look ahead to future clinical studies of DGAT2 inhibitors in patients with NAFLD and nonalcoholic steatohepatitis (NASH), we review key differences and include evidence to highlight and support DGAT2 inhibitor (DGAT2i) pharmacology., Methods: Three Phase I, randomized, double-blind, placebo-controlled trials assessed the safety, tolerability, and pharmacokinetic properties of the DGAT2i ervogastat (PF-06865571) in healthy adult participants (Single Dose Study to Assess the Safety, Tolerability and Pharmacokinetics of PF-06865571 [study C2541001] and Study to Assess the Safety, Tolerability, and Pharmacokinetics of Multiple Doses of PF-06865571 in Healthy, Including Overweight and Obese, Adult Subjects [study C2541002]) or participants with NAFLD (2-Week Study in People With Nonalcoholic Fatty Liver Disease [study C2541005]). Data from 2 Phase I, randomized, double-blind, placebo-controlled trials of the DGAT1i PF-04620110 in healthy participants (A Single Dose Study of PF-04620110 in Overweight and Obese, Otherwise Healthy Volunteers [study B0961001] and A Multiple Dose Study of PF-04620110 in Overweight and Obese, Otherwise Healthy Volunteers [study B0961002]) were included for comparison. Safety outcomes were the primary end point in all studies, except in study C2541005, in which safety was the secondary end point, with relative change from baseline in whole liver fat at day 15 assessed as the primary end point. Safety data were analyzed across studies by total daily dose of ervogastat (5, 15, 50, 100, 150, 500, 600, 1000, and 1500 mg) or PF-04620110 (0.3, 1, 3, 5, 7, 10, 14, and 21 mg), with placebo data pooled separately across ervogastat and PF-04620110 studies., Findings: Published data indicate that DGAT1 and DGAT2 differ in multiple dimensions, including gene family, subcellular localization, substrate preference, and specificity, with unrelated pharmacologic inhibition properties and differing safety profiles. Although initial nonclinical studies suggested a potentially attractive therapeutic profile with DGAT1 inhibition, genetic and pharmacologic data suggest otherwise, with common gastrointestinal adverse events, including nausea, vomiting, and diarrhea, limiting further clinical development. Conversely, DGAT2 inhibition, although initially not pursued as aggressively as a potential target for pharmacologic intervention, has consistent efficacy in nonclinical studies, with reduced triglyceride synthesis accompanied by reduced expression of genes essential for de novo lipogenesis. In addition, early clinical data indicate antisteatotic effects with DGAT2i ervogastat, in participants with NAFLD, accompanied by a well-tolerated safety profile., Implications: Although pharmacologic DGAT1is are limited by an adverse safety profile, data support use of DGAT2i as an effective and well-tolerated therapeutic strategy for patients with NAFLD, NASH, and NASH with liver fibrosis., Clinicaltrials: gov identifiers: NCT03092232, NCT03230383, NCT03513588, NCT00799006, and NCT00959426., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Peptide agonists of the glucagon-like peptide-1 receptor (GLP-1R) have revolutionized diabetes therapy, but their use has been limited because they require injection. Herein, we describe the discovery of the orally bioavailable, small-molecule, GLP-1R agonist PF-06882961 (danuglipron). A sensitized high-throughput screen was used to identify 5-fluoropyrimidine-based GLP-1R agonists that were optimized to promote endogenous GLP-1R signaling with nanomolar potency. Incorporation of a carboxylic acid moiety provided considerable GLP-1R potency gains with improved off-target pharmacology and reduced metabolic clearance, ultimately resulting in the identification of danuglipron. Danuglipron increased insulin levels in primates but not rodents, which was explained by receptor mutagensis studies and a cryogenic electron microscope structure that revealed a binding pocket requiring a primate-specific tryptophan 33 residue. Oral administration of danuglipron to healthy humans produced dose-proportional increases in systemic exposure (NCT03309241). This opens an opportunity for oral small-molecule therapies that target the well-validated GLP-1R for metabolic health.

Worldwide, there are nearly 10 million new cases of dementia annually, of which Alzheimer's disease (AD) is the most common. New measures are needed to improve the diagnosis of individuals with cognitive impairment due to various etiologies. Here, we report a deep learning framework that accomplishes multiple diagnostic steps in successive fashion to identify persons with normal cognition (NC), mild cognitive impairment (MCI), AD, and non-AD dementias (nADD). We demonstrate a range of models capable of accepting flexible combinations of routinely collected clinical information, including demographics, medical history, neuropsychological testing, neuroimaging, and functional assessments. We then show that these frameworks compare favorably with the diagnostic accuracy of practicing neurologists and neuroradiologists. Lastly, we apply interpretability methods in computer vision to show that disease-specific patterns detected by our models track distinct patterns of degenerative changes throughout the brain and correspond closely with the presence of neuropathological lesions on autopsy. Our work demonstrates methodologies for validating computational predictions with established standards of medical diagnosis., (© 2022. The Author(s).)

Patients often recognize unmet needs that can improve patient-provider experiences in disease treatment management. These needs are rarely captured and may be hard to quantify in difficult-to-treat disease states such as drug-resistant epilepsy (DRE). To further understand challenges living with and managing DRE, a team of medical anthropologists conducted ethnographic field assessments with patients to qualitatively understand their experience with DRE across the United States. In addition, healthcare provider assessments were conducted in community clinics and Comprehensive Epilepsy Centers to further uncover patient-provider treatment gaps. We identified four distinct stages of the treatment and management journey defined by patients' perceived control over their epilepsy: Gripped in the Panic Zone, Diligently Tracking to Plan, Riding a Rollercoaster in the Dark, and Reframing Priorities to Redefine Treatment Success. We found that patients sought resources to streamline communication with their care team, enhanced education on treatment options beyond medications, and long-term resources to protect against a decline in control over managing their epilepsy once drug-resistant. Likewise, treatment management optimization strategies are provided to improve current DRE standard of care with respect to identified patient-provider gaps. These include the use of digital disease management tools, standardizing neuropsychiatrists into patients' initial care team, and introducing surgical and non-pharmacological treatment options upon epilepsy and DRE diagnoses, respectively. This ethnographic study uncovers numerous patient-provider gaps, thereby presenting a conceptual framework to advance DRE treatment. Further Incentivization from professional societies and healthcare systems to support standardization of the treatment optimization strategies provided herein into clinical practice is needed., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Agonism of the glucagon-like peptide-1 receptor (GLP-1R) results in glycemic lowering and body weight loss and is a therapeutic strategy to treat type 2 diabetes (T2D) and obesity. We developed danuglipron (PF-06882961), an oral small-molecule GLP-1R agonist and found it had comparable efficacy to injectable peptidic GLP-1R agonists in a humanized mouse model. We then completed a placebo-controlled, randomized, double-blind, multiple ascending-dose phase 1 study ( NCT03538743 ), in which we enrolled 98 patients with T2D on background metformin and randomized them to receive multiple ascending doses of danuglipron or placebo for 28 d, across eight cohorts. The primary outcomes were assessment of adverse events (AEs), safety laboratory tests, vital signs and 12-lead electrocardiograms. Most AEs were mild, with nausea, dyspepsia and vomiting most commonly reported. There were no clinically meaningful AEs in laboratory values across groups. Heart rate generally increased with danuglipron treatment at day 28, but no heart-rate AEs were reported. Systolic blood pressure was slightly decreased and changes in diastolic blood pressure were similar with danuglipron treatment at day 28, compared with placebo. There were no clinically meaningful electrocardiogram findings. In this study in T2D, danuglipron was generally well tolerated, with a safety profile consistent with the mechanism of action of GLP-1R agonism.

Background and Objective: Obesity is a chronic disease associated with many serious comorbidities. Pharmacologic therapies are approved for the treatment of obesity; however, short-term biomarkers to predict weight loss are not well understood. This study aimed to determine the ability of single-meal energy intake (EI) to predict weight loss in participants with obesity treated with liraglutide., Methods: In this randomized, double-blind, placebo-controlled study, participants received subcutaneous liraglutide (titrated to 3.0 mg/day) or placebo once daily, with inpatient assessments at baseline and weeks 3 and 6. The primary endpoint was change from baseline (CFB) in EI during consecutive ad libitum lunch meals at weeks 3 and 6. Secondary endpoints included CFB in 24- and 48-h EI, weight, appetite scores, and gastric emptying measures., Results: Sixty-one participants were randomized ( n  = 32, liraglutide; n  = 29, placebo). The least squares mean (LSM) difference (95% CI; p -value) in CFB in EI during ad libitum lunch meals between the liraglutide and placebo groups was -236 (-322, -149; p  < 0.0001) kcal at week 3 and -244 (-339, -148, p  < 0.0001) kcal at week 6. The liraglutide group experienced significant weight loss at weeks 3 and 6, compared with placebo. Weight loss was significantly correlated with EI, but not with appetite score or gastric emptying., Conclusions: EI during a single meal is a robust clinical predictor of weight changes in participants with obesity. Future clinical trials can utilize EI at a single meal as a predictor of weight loss., Competing Interests: Aditi R. Saxena and Anindita Banerjee are full‐time employees and stockholders of Pfizer Inc. Karen D. Corbin and Stephanie A. Parsons have no conflicts of interest to report. Steven R. Smith reports personal fees from Eisai outside of the submitted work., (© 2021 The Authors. Obesity Science & Practice published by World Obesity and The Obesity Society and John Wiley & Sons Ltd.)

Lymph nodal metastasis is one of the most important prognostic factors determining survival in patients with carcinoma esophagus. Radical esophagectomy, with the resection of surrounding lymph nodes, is considered the prime treatment of carcinoma esophagus. An extensive lymphadenectomy improves the accuracy of staging and betters locoregional control, but its effect on survival is still not apparent and carries the disadvantage of increased morbidity. The extent of lymphadenectomy during esophagectomy also remains debatable, with many studies revealing contradictory results, especially in the era of neoadjuvant therapy . The pattern of distribution and the number of nodal metastasis are modified by neoadjuvant therapy. The paper reviews the existing evidence to determine whether increased lymph node yield improves oncological outcomes in patients undergoing esophagectomy with particular attention to those patients receiving neoadjuvant therapy., Competing Interests: Conflict of InterestThe authors declare no conflicts of interest., (© Indian Association of Surgical Oncology 2020.)

Her2-dependent breast cancer is treated with pharmacological drugs (eg, Herceptin, lapatinib) that target Her2 signaling. Curcumin has emerged as a potential co-treatment for this and other cancers, but prior studies have focused on non-attainable concentrations. Here we test the hypothesis that attainable in vivo levels of dietary curcumin can reduce Her2 signaling. Consistent with previous studies, higher dose curcumin (18 μmol/L) inhibits Her2-Akt pathway signaling (pHer2, total Her2 and pAkt levels) and cell growth using AU565 human breast cancer cells. We then examined lower, more physiologically relevant concentrations of curcumin, alone and in combination with other dietary botanicals (quercetin and OptiBerry fruit extract). At 4 μmol/L, curcumin reduced Her2 signaling, and even more when combined with quercetin or OptiBerry. At 1.5 μmol/L curcumin, pHer2 and Her2 (but not pAkt) were reduced, with all three pathway markers reduced more in the presence of quercetin. We also found that 1.5 μmol/L curcumin strongly potentiated lapatinib inhibition of Her2-Akt pathway signaling, and more so for pAkt, when combined with quercetin plus OptiBerry (CQO). Parallel analyses revealed cell growth inhibition at 18 and 4 μmol/L but not 1.5 μmol/L curcumin, and potentiation of 1.5 μmol/L curcumin growth arrest with other botanicals +/- lapatinib. These studies demonstrate that a physiological attainable level of curcumin (1.5 μmol/L) can reduce some components of the critical Her2-Akt pathway; that even more complete inhibition can be achieved by combination with other dietary botanicals; and that curcumin and other botanicals can potentiate the action of the Her2-cancer metastatic drug lapatinib, in turn suggesting the potential anti-cancer clinical use of these botanicals., (Copyright © 2020 Elsevier Inc. All rights reserved.)

PF-05221304 is a liver-targeted inhibitor of acetyl-CoA carboxylase, an enzyme that catalyzes the first committed step in de novo lipogenesis (DNL). This first-in-human study investigated safety/tolerability and pharmacokinetics of single and multiple ascending oral PF-05221304 doses, and fructose-stimulated DNL inhibition with repeated oral doses. Healthy subjects (n = 96) received single (1-240 mg) or repeated (2-200 mg daily) doses for 14 days or single 100-mg doses with and without food. PF-05221304 was well tolerated at all doses. Repeated PF-05221304 doses inhibited hepatic DNL in a dose-dependent manner, with near-complete inhibition seen at higher doses. With doses yielding ≥90% DNL inhibition, asymptomatic increases in fasting/postprandial serum triglyceride levels (≥40 mg/day) and declines in platelet count (≥60 mg/day) occurred; these were not observed at ≤80% DNL inhibition. Steady-state pharmacokinetics generally increased dose-proportionally, with a half-life of 14-18 hours and a minimal food effect on plasma exposure. The observed safety and tolerability, pharmacokinetics, and pharmacodynamics support the continued evaluation of PF-05221304 for the treatment of nonalcoholic steatohepatitis., (© 2020 Pfizer Inc. Clinical Pharmacology in Drug Development published by Wiley Periodicals, Inc. on behalf of American College of Clinical Pharmacology.)

Inflammation is implicated in a wide range of disorders, and thought to be involved in most leading causes of death today in the United States with high associated costs. New insights into better understanding its etiology, detection and prevention are thus of major importance in health care. One emerging field providing such insights has been the identification of DAMPs, or damage-associated molecular patterns. We have studied DAMPs within the context of degraded and oxidized mitochondrial DNA and RNA ("DeMP"), most recently demonstrating potent mitochondrial RNA (mtRNA) immunogenic response in mouse macrophages. Here, we extend these studies to assess the proinflammatory role of mitochondrial control (native) and oxidized RNA using human RNA and cells. THP-1 macrophage mtRNA triggered a proinflammatory response (induction of IL-6 and TNFα) when transfected into the same cells. Modestly oxidized mtRNA (DeMP RNA) but not cytoplasmic RNA induced a similar response, in contrast to attenuated immunogenicity previously observed with more oxidized DeMP RNA. This DeMP RNA may also cause a mild prooxidant stress. The proinflammatory effects of mtRNA was significantly reduced following pretreatment with RNases specific for single and double stranded RNA, implicating these forms of mtRNA in proinflammatory response. The natural nucleic acid-encapsulating peptide LL-37 also triggered a proinflammatory effect in the presence of control mtRNA and DeMP RNA. Finally, human blood plasma RNA exhibits proinflammatory activity. These results provide new insights into the immunostimulation of mitochondrial RNA including its activity in human cells; identify human plasma RNA as proinflammatory; and provide further evidence that oxidized DeMP mtRNA acts as a sensitive and broad-spectrum sensor and regulator of mitochondrial oxidative stress., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Context: Hypertension in young women is uncommon compared with young men and older women. Estrogen appears to protect most women against hypertension, with incidence increasing after menopause. Because some premenopausal women develop hypertension, estrogen may play a different role in these women. Genetic variations in the estrogen receptor (ER) are associated with cardiovascular disease. ER-β, encoded by ESR2, is the ER predominantly expressed in vascular smooth muscle., Objective: To determine an association of single nucleotide polymorphisms in ESR2 with salt sensitivity of blood pressure (SSBP) and estrogen status in women., Methods: Candidate gene association study with ESR2 and SSBP conducted in normotensive and hypertensive women and men in two cohorts: International Hypertensive Pathotype (HyperPATH) (n = 584) (discovery) and Mexican American Hypertension-Insulin Resistance Study (n = 662) (validation). Single nucleotide polymorphisms in ESR1 (ER-α) were also analyzed. Analysis conducted in younger (<51 years, premenopausal, "estrogen-replete") and older women (≥51 years, postmenopausal, "estrogen-deplete"). Men were analyzed to control for aging., Results: Multivariate analyses of HyperPATH data between variants of ESR2 and SSBP documented that ESR2 rs10144225 minor (risk) allele carriers had a significantly positive association with SSBP driven by estrogen-replete women (β = +4.4 mm Hg per risk allele, P = 0.004). Findings were confirmed in Hypertension Insulin-Resistance Study premenopausal women. HyperPATH cohort analyses revealed risk allele carriers vs noncarriers had increased aldosterone/renin ratios. No associations were detected with ESR1., Conclusions: The variation at rs10144225 in ESR2 was associated with SSBP in premenopausal women (estrogen-replete) and not in men or postmenopausal women (estrogen-deplete). Inappropriate aldosterone levels on a liberal salt diet may mediate the SSBP., (Copyright © 2017 Endocrine Society)

Objectives: This study aims at identifying associations between therapeutics used during labor and the occurrence of postpartum preeclampsia (PPPE), a poorly understood entity., Study Design and Main Outcome Measures: This is a case-control study of women who received an ICD-9 code for PPPE (cases) during the years 2009-2011, compared to women with a normotensive term pregnancy, delivery and postpartum period until discharge (controls), matched on age (±1year) and delivery date (±3months). Cases were defined as women having a normotensive term pregnancy, delivery and initial postpartum period (48h post-delivery) but developing hypertension between 48h and 6weeks postpartum. Single variable and multiple variable models were used to determine significant risk factors., Results: Forty-three women with PPPE were compared to 86 controls. Use of vasopressors and oxytocin did not differ between cases and controls, but rate of fluids administered during labor (OR=1.68 per 100cc/h; 95% CI: 1.09-2.59, p=0.02) and an elevated pre-pregnancy/first trimester BMI (OR=1.18 per kg/m 2 , 95% CI: 1.07-1.3, p=0.001) were identified as significant risk factors in multivariate analysis., Conclusions: We identified two potentially modifiable risk factors for PPPE; further studies are needed to better define the role of these two variables in the development of PPPE., (Copyright © 2017 International Society for the Study of Hypertension in Pregnancy. Published by Elsevier B.V. All rights reserved.)

Certain mitochondrial components can act as damage-associated molecular patterns (DAMPs) or danger signals, triggering a proinflammatory response in target (usually immune) cells. We previously reported the selective degradation of mitochondrial DNA and RNA in response to cellular oxidative stress, and the immunogenic effect of this DNA in primary mouse astrocytes. Here, we extend these studies to assess the immunogenic role of both mitochondrial DNA and RNA isolated from hydrogen peroxide (HP) treated HA1 cells (designated "DeMPs" for degraded mitochondrial polynucleotides) using mouse bone marrow derived macrophages (BMDMs), a conventional immune cell type. DeMPs and control mitochondrial DNA (cont mtDNA) and RNA (cont mtRNA) were transfected into BMDMs and cell-free media analyzed for the presence of proinflammatory cytokines (IL-6, MCP-1, and TNFα) and Type I interferon (IFN-α and IFN-β). Cont mtDNA induced IL-6 and MCP-1 production, and this effect was even greater with DeMP DNA. A similar response was observed for Type I interferons. An even stronger induction of proinflammatory cytokine and type 1 interferons was observed for cont mtRNA. However, contrary to DeMP DNA, DeMP RNA attenuated rather than potentiated the cont mtRNA cytokine inductions. This attenuation effect was not accompanied by an IL-10 or TGFβ anti-inflammatory response. All DeMP effects were observed at multiple oxidant concentrations. Finally, DeMP production and immunogenicity overlaps with cellular adaptive response and so may contribute to cellular oxidant protection. These results provide new insight into the immunogenicity of mitochondrial polynucleotides, and identify new roles and selective consequences of cellular oxidation., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Higher exposure to certain phthalates is associated with a diabetes and insulin resistance, with sex differences seen. Yet, little is known about the association between phthalates and metabolic syndrome (MetS), particularly with consideration for differences by sex and menopausal status., Methods: We analyzed data from 2719 participants in the National Health and Nutrition Examination Survey (NHANES) 2001-2010 aged 20-80 years. Five urinary phthalate metabolites (MEP, MnBP, MiBP, MBzP, and MCPP) and DEHP metabolites were analyzed by the Centers for Disease Control and Prevention and were evaluated as population-specific quartiles. MetS was defined by National Cholesterol Education Program's Adult Treatment Panel III report criteria. Prevalence odds ratios (POR) and 95 % confidence intervals (CI) were calculated using multivariable logistic regression, adjusting for potential confounders and stratifying by sex and menopausal status., Results: Participants with MetS (32 % of the study population) had higher concentrations for all urinary phthalate metabolites. After full adjustment, higher DEHP metabolite concentrations were associated with an increased odds of MetS in men, but not women (adj. POR for men Q4 versus Q1: 2.20; 95 % CI: 1.32, 3.68 and adj. POR for women Q4 versus Q1: 1.50; 95 % CI: 0.89, 2.52). When evaluating by menopausal status, pre-menopausal women with higher concentrations of MBzP had close to a 4-fold increased odds of MetS compared to pre-menopausal women with the lowest concentrations of MBzP (adj POR: Q4 versus Q1: 3.88; 95 % CI: 1.59, 9.49)., Conclusions: Higher concentrations of certain phthalate metabolites were associated with an increased odds of MetS. Higher DEHP metabolite concentrations were associated with an increased odds of MetS for men. In women, the strongest association was between higher concentrations of MBzP and MetS, but only among pre-menopausal women.

We have considered a novel gene targeting approach for treating pathologies and conditions whose genetic bases are defined using diet and nutrition. One such condition is Down syndrome, which is linked to overexpression of RCAN1 on human chromosome 21 for some phenotypes. We hypothesize that a decrease in RCAN1 expression with dietary supplements in individuals with Down syndrome represents a potential treatment. Toward this, we used in vivo studies and bioinformatic analysis to identify potential healthy dietary RCAN1 expression modulators. We observed Rcan1 isoform 1 (Rcan1-1) protein reduction in mice pup hippocampus after a 4-week curcumin and fish oil supplementation, with only fish oil reduction being statistically significant. Focusing on fish oil, we observed a 17% Rcan1-1 messenger RNA (mRNA) and 19% Rcan1-1 protein reduction in BALB/c mice after 5 weeks of fish oil supplementation. Fish oil supplementation starting at conception and in a different mouse strain (C57BL) led to a 27% reduction in hippocampal Rcan1-1 mRNA and a 34% reduction in spleen Rcan1-1 mRNA at 6 weeks of age. Hippocampal protein results revealed a modest 11% reduction in RCAN1-1, suggesting translational compensation. Bioinformatic mining of human fish oil studies also revealed reduced RCAN1 mRNA expression, consistent with the above studies. These results suggest the potential use of fish oil in treating Down syndrome and support our strategy of using select healthy dietary agents to treat genetically defined pathologies, an approach that we believe is simple, healthy, and cost-effective., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Age, sex, hypertension and dietary sodium are proposed to affect plasma and urinary catecholamines. Yet no prior study has examined the simultaneous effects of these factors within the same study population. So results may have been confounded by factors not determined. We investigate, for the first time, the impact of simultaneously determined predictors of plasma and urinary catecholamines and the relationship of catecholamines with the diagnosis of hypertension. Hypertensive and normotensive subjects (n=308) were studied off antihypertensives in liberal and low sodium balance. 24 h urinary catecholamines (norepinephrine and epinephrine) were measured. Plasma catecholamines were measured supine after overnight fast. Repeated measures multivariate linear regression models examined the effect of sex, race, age, body mass index (BMI), dietary salt (liberal salt vs low salt), hypertension status and mean arterial pressure (MAP) on plasma and urinary catecholamines. Logistic regression determined the relationship of catecholamines with diagnosis of hypertension. Dietary sodium restriction and increasing age predicted increased plasma and urinary norepinephrine, with sodium restriction having the greatest effect. Female sex predicted lower urinary and plasma epinephrine. Neither plasma nor urinary catecholamines predicted the diagnosis of hypertension. In summary, specific demographic factors variably impact catecholamines and should be considered when assessing catecholamines in research and clinical settings.

Background: Phthalates are ubiquitous endocrine disrupting chemicals associated with diabetes. Although women and minorities are more likely to be exposed to phthalates, no prior studies have examined phthalate exposure and markers of diabetes risk evaluating effect modification by gender and race/ethnicity., Methods: We analyzed CDC data for 8 urinary phthalate metabolites from 3,083 non-diabetic, non-pregnant participants aged 12- < 80 years in the National Health and Nutrition Examination Survey (NHANES) 2001-2008. We used median regression to assess the associations between urinary phthalate metabolites and fasting blood glucose (FBG), fasting insulin and Homeostatic Model Assessment of insulin resistance (HOMA-IR), controlling for urinary creatinine as well as several sociodemographic and behavioral factors. Stratified analyses were conducted to compare the gender- and race/ethnicity-specific patterns for the associations., Results: Urinary levels of several phthalate metabolites, including MBzP, MnBP, MiBP, MCPP and ∑DEHP showed significant positive associations with FBG, fasting insulin and HOMA-IR. No clear difference was noted between men and women. Mexican-Americans and non-Hispanic blacks had stronger dose-response relationships for MnBP, MiBP, MCPP and ∑DEHP compared to non-Hispanic whites. For example, the highest quartile of MiBP relative to its lowest quartile showed a median FBG increase of 5.82 mg/dL (95% CI: 3.77, 7.87) in Mexican-Americans, 3.63 mg/dL (95% CI: 1.23, 6.03) in blacks and 1.79 mg/dL (95% CI: -0.29, 3.87) in whites., Conclusions: The findings suggest that certain populations may be more vulnerable to phthalates with respect to disturbances in glucose homeostasis. Whether endocrine disrupting chemicals contribute to gender and racial/ethnic differences in diabetes risk will be an important area for further study.

Background: First trimester Pregnancy Associated Plasma Protein A (PAPP-A) levels, routinely measured for aneuploidy screening, may predict development of preeclampsia. This study tests the hypothesis that first trimester PAPP-A levels correlate with soluble fms-like tyrosine kinase-1 (sFlt-1) levels, an angiogenic marker associated with preeclampsia, throughout pregnancy., Methods: sFlt-1 levels were measured longitudinally in 427 women with singleton pregnancies in all three trimesters. First trimester PAPP-A and PAPP-A Multiples of Median (MOM) were measured. Student's T and Wilcoxon tests compared preeclamptic and normal pregnancies. A linear mixed model assessed the relationship between log PAPP-A and serial log sFlt-1 levels., Results: PAPP-A and PAPP-A MOM levels were significantly lower in preeclamptic (n = 19), versus normal pregnancies (p = 0.02). Although mean third trimester sFlt-1 levels were significantly higher in preeclampsia (p = 0.002), first trimester sFlt-1 levels were lower in women who developed preeclampsia, compared with normal pregnancies (p = 0.03). PAPP-A levels correlated significantly with serial sFlt-1 levels. Importantly, low first trimester PAPP-A MOM predicted decreased odds of normal pregnancy (OR 0.2, p = 0.002)., Conclusions: Low first trimester PAPP-A levels suggests increased future risk of preeclampsia and correlate with serial sFlt-1 levels throughout pregnancy. Furthermore, low first trimester PAPP-A status significantly predicted decreased odds of normal pregnancy.

Background: Exogenous estrogens have been shown to affect markers of cardiovascular risk in women., Aim: The objective of this study was to determine the effect of menstrual cycle phase on markers of cardiovascular risk in young, healthy women with regular menstrual cycles., Subjects and Methods: This prospective cohort study examined 20 healthy pre-menopausal women at 2 time-points in the menstrual cycle, in early follicular phase and early luteal phase., Results: In the early luteal phase, levels of estrogen, progesterone, LH, total cholesterol, and HDL were significantly higher, compared with the early follicular phase. In contrast, there were no significant differences in LDL or triglyceride levels between the 2 phases. Furthermore, there were no significant effects of menstrual cycle phase on glycemic indices (fasting blood glucose, glycohemoglobin or homeostatic model assessment of insulin resistance), markers of inflammation (C-reactive protein, soluble CD40 ligand, intercellular adhesion molecule-1, vascular cell adhesion molecule-1, or adiponectin), or vascular function, as measured by brachial artery reactivity., Conclusions: Although menstrual cycle phase affects total cholesterol and HDL levels, it does not affect other markers of cardiovascular risk in young women with regular menstrual cycles.

Objective: To test utility of cystatin-C as a marker of glomerular filtration rate during pregnancy, we performed serial correlations with inulin clearance during pregnancy and postpartum., Methods: Twelve subjects received inulin infusions and serum cystatin-C at three time points. Pearson's correlation coefficient was calculated., Results: Cystatin-C levels ranged 0.66-1.48 mg/L during pregnancy, and 0.72-1.26 mg/L postpartum. Inulin clearance ranged 130-188 mL/min during pregnancy, and 110-167 mL/min postpartum. Cystatin-C did not correlate with inulin clearance at any time point., Conclusion: Serum cystatin-C did not correlate with inulin clearance during pregnancy or postpartum.

Pregnancies complicated by new-onset hypertension are associated with increased sensitivity to angiotensin II, but it is unclear whether this sensitivity persists postpartum. We studied pressor response to infused angiotensin II in 25 normotensive postpartum women in both high- and low-sodium balance. Ten women had a history of hypertensive pregnancy (5 with preeclampsia; 5 with transient hypertension of pregnancy), and 15 women had a history of uncomplicated, normotensive pregnancy. Systolic and diastolic blood pressures, aldosterone, and soluble fms-like tyrosine kinase 1 levels were measured before and after angiotensin II infusion in both dietary phases. In high sodium balance, women with a history of hypertensive pregnancy were normotensive but had significantly higher systolic and diastolic blood pressures than controls (115 versus 104 mm Hg and 73 versus 65 mm Hg, respectively; P<0.05). Women with a history of hypertensive pregnancy had a pressor response to salt loading, demonstrated by an increase in systolic blood pressure on a high-salt diet. They also had greater systolic pressor response (10 versus 2 mm Hg; P=0.03), greater increase in aldosterone (56.8 versus 30.8 ng/dL; P=0.03), and increase in soluble fms-like tyrosine kinase 1 levels (11.0 versus -18.9 pg/mL; P=0.02) after infusion of angiotensin II in low-sodium balance compared with controls. Thus, women with a history of hypertensive pregnancy demonstrated salt sensitivity of blood pressure and had increased pressor, adrenal, and soluble fms-like tyrosine kinase 1 responses to infused angiotensin II in low-sodium balance. Increased sensitivity to angiotensin II observed during pregnancy in women with hypertensive pregnancy is present postpartum; this feature may contribute to future cardiovascular risk in these women.

The present investigation was aimed at developing and exploring the use of mannosylated gelatin nanoparticles for the selective delivery of an anti-HIV drug, didanosine, to the target organs. The mannosylated gelatin nanoparticles (MN-G-NPs) were prepared using a two-step desolvation technique and coupled with mannose using the amino group of gelatin present on the surface of nanoparticles. The mannosylation was confirmed using infrared and nuclear magnetic resonance spectroscopy. MN-G-NPs were characterized for shape, particle size, zeta potential, and percentage drug entrapment. The size of nanoparticles was found to be in range of 248-325 nm, and maximum drug payload was found to be 40.2% to 48.5%. Average size was found to be more, but drug payload was less in the case of MN-G-NPs as compared with unconjugated nanoparticles (G-NPs). The results of the in vitro release profile demonstrated that G-NPs release a comparatively higher percentage of drug than MN-G-NPs. Cellular uptake by MN-G-NPs was 2.7 times more as compared with G-NPs. Fluorescence studies revealed the enhanced uptake of MN-G-NPs in the macrophage tissues when compared with unmodified G-NPs. Intravenous administration of free-drug solution resulted in a high concentration of drug in serum, whereas it was much less in the case of G-NPs. Coupling of the nanoparticles with mannose significantly enhanced the lung, liver, and lymph nodes uptake of drug, which is reflected in the recovery of a higher percentage of the dose from these organs following administration of MN-G-NPs in comparison to noncoupled G-NPs or free drug.

A report of our experience with a new self-retaining aortic cannula is presented. We have used this cannula in more than 30 patients and found it to be very secure and convenient for rapid cannulation since no pursestring sutures are required for initial placement.