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• Prostate cancer diagnosis is subject to inter-pathologist variability. • Artificial intelligence can assuage pain points by streamlining diagnosis. • Artificial intelligence is evolving to diagnose, grade, and predict outcomes. • Challenges remain before wide-scale autonomous prostate cancer diagnosis. The diagnosis of prostate cancer (PCa) depends on the evaluation of core needle biopsies by trained pathologists. Artificial intelligence (AI) derived models have been created to address the challenges posed by pathologists' increasing workload, workforce shortages, and variability in histopathology assessment. These models with histopathological parameters integrated into sophisticated neural networks demonstrate remarkable ability to identify, grade, and predict outcomes for PCa. Though the fully autonomous diagnosis of PCa remains elusive, recently published data suggests that AI has begun to serve as an initial screening tool, an assistant in the form of a real-time interactive interface during histological analysis, and as a second read system to detect false negative diagnoses. Our article aims to describe recent advances and future opportunities for AI in PCa histopathology. [ABSTRACT FROM AUTHOR]

Background: Studies in critically ill adults demonstrate associations between serum renin concentrations (a proposed surrogate for renin–angiotensin–aldosterone system dysregulation) and poor outcomes, but data in critically ill children are lacking. We assessed serum renin + prorenin concentrations in children with septic shock to determine their predictive ability for acute kidney injury (AKI) and mortality. Methods: We conducted a secondary analysis of a multicenter observational study of children aged 1 week to 18 years admitted to 14 pediatric intensive care units (PICUs) with septic shock and residual serum available for renin + prorenin measurement. Primary outcomes were development of severe persistent AKI (≥ KDIGO stage 2 for ≥ 48 h) in the first week and 28-day mortality. Results: Among 233 patients, day 1 median renin + prorenin concentration was 3436 pg/ml (IQR 1452–6567). Forty-two (18%) developed severe persistent AKI and 32 (14%) died. Day 1 serum renin + prorenin predicted severe persistent AKI with an AUROC of 0.75 (95% CI 0.66–0.84, p < 0.0001; optimal cutoff 6769 pg/ml) and mortality with an AUROC of 0.79 (95% CI 0.69–0.89, p < 0.0001; optimal cutoff 6521 pg/ml). Day 3/day 1 (D3:D1) renin + prorenin ratio had an AUROC of 0.73 (95% CI 0.63–0.84, p < 0.001) for mortality. On multivariable regression, day 1 renin + prorenin > optimal cutoff retained associations with severe persistent AKI (aOR 6.8, 95% CI 3.0–15.8, p < 0.001) and mortality (aOR 6.9, 95% CI 2.2–20.9, p < 0.001). Similarly, D3:D1 renin + prorenin > optimal cutoff was associated with mortality (aOR 7.6, 95% CI 2.5–23.4, p < 0.001). Conclusions: Children with septic shock have very elevated serum renin + prorenin concentrations on PICU admission, and these concentrations, as well as their trend over the first 72 h, predict severe persistent AKI and mortality. [ABSTRACT FROM AUTHOR]

[Display omitted] The unique properties—such as biocompatibility, biodegradability, bio-absorbability, low cost, easy fabrication, and high versatility—have made polycaprolactone (PCL) the center of attraction for researchers. The derived introduction in this manuscript gives a pretty detailed overview of PCL, so you can first brush up on it. Discussion on the various PCL-based derivatives involves, but is not limited to, poly(ε-caprolactone-co-lactide) (PCL-co-LA), PCL-g-PEG, PCL-g-PMMA, PCL-g-chitosan, PCL-b-PEO, and PCL-g-PU specific properties and their probable applications in biomedicine. This paper has considered examining the differences in the diverse disease subtypes and the therapeutic value of using PCL. Advanced strategies for PCL in delivery systems are also considered. In addition, this review discusses recently patented products to provide a snapshot of recent updates in this field. Furthermore, the text probes into recent advances in PCL-based DDS, for example, nanoparticles, liposomes, hydrogels, and microparticles, while giving special attention to comparing the esters in the delivery of bioactive compounds such as anticancer drugs. Finally, we review future perspectives on using PCL in biomedical applications and the hurdles of PCL-based drug delivery, including fine-tuning mechanical strength/degradation rate, biocompatibility, and long-term effects in living systems. [ABSTRACT FROM AUTHOR]

A critical analysis of the novel sewage treatment concept of anaerobic digestion followed by CO 2 capture by microalgae has been carried out, with particular reference to India. The anaerobic process would convert the sewage COD into methane and CO 2 , the latter being converted into microalgae in a photobioreactor process, using sunlight as an energy source. The microalgae can be used to produce biofuels, co-fired with high yielding fuels (like coke) or just recycled back into the anaerobic digestion cycle as a substrate for methane production. Overall, this process would allow, at least in principle, the conversion of all the carbon in the municipal wastewaters into fuels. This study reports data on municipal wastewater generation and treatment facilities across the globe. The focus is then given to sewage generation and treatment in Indian cities, classified into metropolitan, Class-I and Class-II cities. Aerobic and anaerobic digestion processes for sewage treatment are then compared with a discussion on the advantages of the anaerobic membrane bioreactor (AnMBR). The advantages and limitations of photobioreactors for microalgae growth are discussed. Mass balances are then carried out with reference to sewage flows and concentrations in India, and the potential energy generation from the process is estimated. Overall, the complete process is envisaged to produce about 1.69 × 108 kWhd−1 of energy from biogas and microalgae. This has the potential to replace 3% of the recent total petroleum product consumption in India. The study goes towards "zero discharge" of waste to the environment, thus representing a promising sustainable development. • Integration of AnMBR with PBR is suggested for energy generation from wastewater. • Municipal wastewater generation & treatment facilities in the world is presented. • 1.12 × 107 m3/D of biogas & 7.07 × 106 kg/D of biomass can be produced from wastewater. • 1.69 × 108 kWh/D can be produced, which is ≈ 3% petroleum consumption in India. • The study aims at zero discharge of waste, thus promising a sustainable development. [ABSTRACT FROM AUTHOR]

Vitiligo is a complex dermatological disorder involving the loss of melanocytes, with resultant patches of depigmentation. It affects 1% of the world population, affecting patients' mental health and quality of life. With all the improvement seen, conventional treatment methods-steroids, phototherapy, and immunomodulators-come with the limitations of being less effective, having more side effects, and low compliance. Advances in novel drug delivery systems now provide promising alternatives for better therapy. The general view of the pathophysiology of vitiligo is provided in this manuscript, mainly on oxidative stress, autoimmune mechanisms, and melanocyte apoptosis as chief factors. New approaches towards treatment, especially drug delivery systems based on nanotechnology, such as liposomes, polymeric nanoparticles, and hydrogels are discussed. These systems can facilitate the improvement of stability, penetration, and targeted delivery of drugs, thus reducing systemic exposure to adverse effects. There is also a potential improvement in microneedles, transdermal patches, and gene therapy like CRISPR-Cas9 to correct pigmentation by correcting the underlying factors at the cellular and molecular level. Other novel therapies include Janus Kinase (JAK) inhibitors and cell-based approaches, among them melanocyte-keratinocyte transplantation, which may have the potential to give sustained repigmentation. The article also deals with the role of phytoconstituents, like curcumin, quercetin, and ginkgo biloba, with antioxidant, anti-inflammatory, and immunomodulatory properties, thus it can be a natural adjuvant to conventional treatment. The multidisciplinary approach may be necessary in the incorporation of pharmacological advances along with new delivery systems into an enhancement strategy of treatments of vitiligo. This approach corrects some of the traditional weaknesses and taps emerging technologies for an even better treatment approach, patient oriented. Follow-up studies should then be directed toward clinical trials for the substantiation of such observations and treatment regimens for more universal applications., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Rheumatoid Arthritis (RA) is a chronic autoimmune disorder characterized by inflammation in the joints, leading to pain, swelling, stiffness, and eventual joint damage. This condition occurs when the body's immune system mistakenly attacks the synovium, the lining of the membranes surrounding the joints. Treatment focuses on reducing inflammation, alleviating pain, and preventing joint damage through a combination of medications, physical therapy, and lifestyle modifications. Recently, biological therapies have been introduced, including Tumour Necrosis Factor (TNF) blockers (such as etanercept, infliximab, and adalimumab), IL-6 inhibitors (tocilizumab), and interleukin- 1 inhibitors (anakinra). These treatments can lead to various side effects. The use of herbalbased treatments, such as secondary metabolites, has gained popularity due to their better tolerability, safety, and effectiveness compared to conventional therapies. However, there are also some limitations, like poor bioavailability and permeability and lower stability; to overcome these issues, Novel Drug Delivery Systems (NDDS) have been introduced as better treatment options in recent years. Polymer science advancements and nanotechnology applications have opened new avenues for RA treatment, emphasizing the development of smart drug delivery systems. These systems aim to improve therapeutic outcomes while minimizing adverse effects. Additionally, newly synthesized biocompatible drug delivery systems, combined with anti-inflammatory drugs composed of secondary metabolites, offer potential solutions for RA., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Red blood cells with sickle cell anemia (SCA) have an irregular shape, and it is a genetic blood condition that can cause several problems and shorten life expectancy. Traditional treatments have focused on symptom management, but recent advancements in drug delivery systems offer promising pathways for targeted therapies. This abstract explores novel approaches to combat SCA through innovative drug delivery systems, gene therapy, and new pharmaceutical interventions. One novel pathway for targeting SCA involves utilizing advanced drug delivery systems to enhance the effectiveness of therapeutic agents. Nanotechnology-based delivery systems, such as nanoparticles and liposomes, offer precise drug targeting, controlled release, and improved bioavailability. These systems can encapsulate anti-sickling agents, like hydroxyurea, and enable their specific delivery to affected cells, reducing side effects and enhancing therapeutic outcomes. Additionally, therapy has become a ground-breaking method of treating SCA. CRISPR/Cas9 technology presents a groundbreaking opportunity to correct the genetic mutation responsible for sickle hemoglobin production. By precisely editing the HBB gene, which encodes the abnormal hemoglobin, researchers aim to restore normal hemoglobin expression, potentially offering a curative treatment for SCA. Furthermore, recent advancements in drug development have led to the discovery of promising candidates targeting specific pathways involved in SCA pathophysiology. Experimental drugs, such as voxelotor and crizanlizumab focus on modifying hemoglobin properties or inhibiting cell adhesion, respectively, thereby preventing sickle cell-related complications and reducing vaso-occlusive crisis frequency., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Areca nut (AN) is a substance of abuse consumed by millions worldwide, in spite of established oral and systemic toxicities associated with its use. Previous research demonstrates methyl ester alkaloids in the AN, such as arecoline and guvacoline, exhibit mood-altering and toxicological effects. Nonetheless, their metabolism has not been fully elucidated in humans. In the present study, an HPLC-UV bioanalytical method was developed to evaluate the hydrolytic kinetics and clearance rates of arecoline and guvacoline in human liver microsomes (HLM) and cytosol (HLC). The bioassay was capable of quantifying arecoline and guvacoline (and carboxylate metabolites arecaidine and guvacine, respectively) with good sensitivity, accuracy, and precision. Kinetics of arecoline and guvacoline hydrolysis best followed the Michaelis-Menten model. Apparent intrinsic clearance (Cl int.in vivo ) of arecoline was 57.8 ml/min/kg in HLM and 11.6 mL/min/kg in HLC, a 5-fold difference. Unexpectedly, guvacoline was dramatically less hydrolyzed than arecoline in both HLM and HLC, with Cl int.in vivo estimates of 0.654 ml/min/kg and 0.466 ml/min/kg, respectively. These results demonstrate, for the first time, arecoline undergoes significant hydrolysis with high clearance rates in the liver. Furthermore, differential tissue metabolic rates and utilization of specific esterase inhibitors unequivocally demonstrated arecoline is a substrate for CES1 and not CES2., Competing Interests: Conflict of interest There are no conflicts of interest to disclose., (Copyright © 2024 The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved.)

Objectives: We previously derived the updated Pediatric Sepsis Biomarker Risk for Acute Kidney Injury (PERSEVERE-II AKI) prediction model, which had robust diagnostic test characteristics for severe AKI on day 3 (D3 severe AKI) of septic shock. We now sought to validate this model in an independent cohort of children to the one in which the model was developed., Design: A secondary analysis of a multicenter, prospective, observational study carried out from January 2019 to December 2022., Setting: Ten PICUs in the United States., Patients: Children with septic shock 1 week to 18 years old admitted to the PICU., Interventions: None., Measurements and Main Results: Seventy-nine of 363 patients (22%) had D3 severe AKI, defined as Kidney Disease Improving Global Outcomes stage 2 or higher. Patients were assigned a probability of D3 severe AKI using the PERSEVERE-II AKI model. The model predicted D3 severe AKI with an area under the receiver operating characteristic curve of 0.89 (95% CI, 0.85-0.93), sensitivity of 77% (95% CI, 66-86%), specificity of 88% (95% CI, 84-92%), positive predictive value of 65% (95% CI, 54-74%), and negative predictive value of 93% (95% CI, 89-96%). These data represent an increase in post-test probability of D3 severe AKI with a positive test from 22% to 65%, and a prevalence threshold of 28%. On multivariable regression, the PERSEVERE-II AKI prediction model demonstrated greater adjusted odds ratio (aOR) for D3 severe AKI (aOR, 11.2; 95% CI, 4.9-25.3) and lesser aOR for failure of D3 renal recovery from early AKI (aOR, 0.31; 95% CI, 0.13-0.69)., Conclusions: The PERSEVERE-II AKI model demonstrates consistently robust performance for prediction of new or persistent D3 severe AKI in children with septic shock. A major limitation is that actual D3 severe AKI prevalence is below the prevalence threshold for the test, and thus future work should focus on evaluating use in enriched populations., Competing Interests: Dr. Stanski’s institution received funding from the National Institute of General Medical Sciences (NIGMS); she disclosed that they hold a provisional patent for the Pediatric Sepsis Biomarker Risk for Acute Kidney Injury (AKI) Prediction Model. Drs. Stanski, Cvijanovich, Fitzgerald, Thomas, Weiss, Atreya, Lautz, and Kaplan received support for article research from the National Institutes of Health. Dr. Cvijanovich’s institution received funding from the Cincinnati Children’s Hospital Medical Center, the Nationwide Children’s Hospital, the Boston Children’s Hospital, and the Collaborative Pediatric Critical Care Research Network. Dr. Fitzgerald received funding from the National Institute of Diabetes and Digestive and Kidney Diseases (K23DK119463, P50DK114786) and the Commonwealth of Pennsylvania Department of Health Cure Grant. Dr. Jain received funding from AltaThera Pharmaceuticals. Dr. Lautz received funding from the NIGMS (K08GM148957-01, R21GM150093-01, and L40GM134527-03). Dr. Atreya’s institution received funding from the Cincinnati Children’s Research Foundation; he disclosed that they hold a provisional patent for the integrated PERSEVERE and endothelial biomarker risk model to predict sepsis-associted acute kidney injury (PERSEVEREnce SA-AKI model); and he received funding through the Procter K to R Scholar program awarded by the Cincinnati Children’s Research Foundation and the NIGMS (R21GM151703 and R21GM15009). Dr. Weiss received funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD102396, R01HD101528) and the U.S. Centers for Disease Control and Prevention (75D30123C17693). Dr. Zingarelli’s institution received funding from the NIGMS (R01 GM115973, R21 GM151734, 1R21GM150093, and R01GM145698); she received funding from the National Heart, Lung, and Blood Institute (R01 HL141229); and she disclosed that they are editor of the Shock journal. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2024 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies.)

Cancer is a global health issue that requires ongoing therapeutic advances. This review provides an overview of recent treatment strategies focusing on novel pathways in cancer therapy. Emerging research has unveiled promising targets that go beyond traditional modalities, offering new avenues for precision medicine and improved patient outcomes. One key area of innovation lies in targeted therapies directed at specific molecular pathways implicated in cancer progression. The identification of novel biomarkers has paved the way for the development of precision medicines tailored to individual patient profiles. Immunotherapy has also revolutionised cancer treatment by using the immune system to identify and remove cancer cells. Moreover, advancements in epigenetic therapies and RNA-based interventions demonstrate unprecedented potential in modulating gene expression and disrupting cancer-specific signalling pathways. We have discussed the pathophysiology of cancer, different immune checkpoint inhibitors, and targeted therapies in signalling therapies. The epigenetic modulators, such as Histone deacetylase (HDACs) inhibitors and DNA methyltransferase (DNMT) inhibitors, were studied. Recent breakthroughs in cancer immunotherapy treatment (CAR-T) cell therapy showcase the potential to enhance the immune response against various cancers; thus, related information was incorporated. Further, RNA-based therapies like RNA interference and mRNA-based vaccines and therapies, combination therapies, and novel therapies were discussed in the present article., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: Sepsis poses a grave threat, especially among children, but treatments are limited owing to heterogeneity among patients. We sought to test the clinical and biological relevance of pediatric septic shock subclasses identified using reproducible approaches., Methods: We performed latent profile analyses using clinical, laboratory, and biomarker data from a prospective multi-center pediatric septic shock observational cohort to derive phenotypes and trained a support vector machine model to assign phenotypes in an internal validation set. We established the clinical relevance of phenotypes and tested for their interaction with common sepsis treatments on patient outcomes. We conducted transcriptomic analyses to delineate phenotype-specific biology and inferred underlying cell subpopulations. Finally, we compared whether latent profile phenotypes overlapped with established gene-expression endotypes and compared survival among patients based on an integrated subclassification scheme., Results: Among 1071 pediatric septic shock patients requiring vasoactive support on day 1 included, we identified two phenotypes which we designated as Phenotype 1 (19.5%) and Phenotype 2 (80.5%). Membership in Phenotype 1 was associated with ~ fourfold adjusted odds of complicated course relative to Phenotype 2. Patients belonging to Phenotype 1 were characterized by relatively higher Angiopoietin-2/Tie-2 ratio, Angiopoietin-2, soluble thrombomodulin (sTM), interleukin 8 (IL-8), and intercellular adhesion molecule 1 (ICAM-1) and lower Tie-2 and Angiopoietin-1 concentrations compared to Phenotype 2. We did not identify significant interactions between phenotypes, common treatments, and clinical outcomes. Transcriptomic analysis revealed overexpression of genes implicated in the innate immune response and driven primarily by developing neutrophils among patients designated as Phenotype 1. There was no statistically significant overlap between established gene-expression endotypes, reflective of the host adaptive response, and the newly derived phenotypes, reflective of the host innate response including microvascular endothelial dysfunction. However, an integrated subclassification scheme demonstrated varying survival probabilities when comparing patient endophenotypes., Conclusions: Our research underscores the reproducibility of latent profile analyses to identify pediatric septic shock phenotypes with high prognostic relevance. Pending validation, an integrated subclassification scheme, reflective of the different facets of the host response, holds promise to inform targeted intervention among those critically ill., (© 2024. The Author(s).)

Background: Junctional ectopic tachycardia (JET) is a prevalent life-threatening arrhythmia in children with congenital heart disease. It has a marked resemblance to normal sinus rhythm, often leading to delay in diagnosis and management., Objective: The study sought to develop a novel multimodal automated arrhythmia detection tool that outperforms existing JET detection tools., Methods: This is a cohort study performed on 40 patients with congenital heart disease at Texas Children's Hospital. Electrocardiogram and central venous pressure waveform data produced by bedside monitors are captured by the Sickbay platform. Convolutional neural networks (CNNs) were trained to classify each heartbeat as either normal sinus rhythm or JET based only on raw electrocardiogram signals., Results: Our best model improved the area under the curve from 0.948 to 0.952 and the true positive rate at 5% false positive rate from 71.8% to 80.6%. Using a 3-model ensemble further improved the area under the curve to 0.953 and the true positive rate at 5% false positive rate to 85.2%. Results on a subset of data show that adding central venous pressure can significantly improve area under the receiver-operating characteristic curve from 0.646 to 0.825., Conclusion: This study validates the efficacy of deep neural networks to notably improve JET detection accuracy. We have built a performant and reliable model that can be used to create a bedside alarm that diagnoses JET, allowing for precise diagnosis of this life-threatening postoperative arrhythmia and prompt intervention. Future validation of the model in a larger cohort is needed., (© 2024 Published by Elsevier Inc. on behalf of Heart Rhythm Society.)

Objectives: Post-ICU admission cumulative positive fluid balance (PFB) is associated with increased mortality among critically ill patients. We sought to test whether this risk varied across biomarker-based risk strata upon adjusting for illness severity, presence of severe acute kidney injury (acute kidney injury), and use of continuous renal replacement therapy (CRRT) in pediatric septic shock., Design: Ongoing multicenter prospective observational cohort., Setting: Thirteen PICUs in the United States (2003-2023)., Patients: Six hundred and eighty-one children with septic shock., Interventions: None., Measurements and Main Results: Cumulative percent PFB between days 1 and 7 (days 1-7 %PFB) was determined. Primary outcome of interest was complicated course defined as death or persistence of greater than or equal to two organ dysfunctions by day 7. Pediatric Sepsis Biomarker Risk Model (PERSEVERE)-II biomarkers were used to assign mortality probability and categorize patients into high mortality ( n = 91), intermediate mortality ( n = 134), and low mortality ( n = 456) risk strata. Cox proportional hazard regression models with adjustment for PERSEVERE-II mortality probability, presence of sepsis-associated acute kidney injury on day 3, and use of CRRT, demonstrated that time-dependent variable days 1-7%PFB was independently associated with an increased hazard of complicated course. Risk-stratified analyses revealed that each 10% increase in days 1-7 %PFB was associated with increased hazard of complicated course only among patients with high mortality risk strata (adjusted hazard ratio 1.24 (95% CI, 1.08-1.43), p = 0.003). However, this association was not causally mediated by PERSEVERE-II biomarkers., Conclusions: Our data demonstrate the influence of cumulative %PFB on the risk of complicated course in pediatric septic shock. Contrary to our previous report, this risk was largely driven by patients categorized as having a high mortality risk based on PERSEVERE-II biomarkers. Incorporation of such prognostic enrichment tools in randomized trials of restrictive fluid management or early initiation of de-escalation strategies may inform targeted application of such interventions among at-risk patients., Competing Interests: Dr. Atreya and Cincinnati Children’s Hospital (CCHMC) hold a provisional patent for a unified biomarker model—PERSEVERENCE that incorporates Pediatric Sepsis Biomarker Risk Model (PERSEVERE) and endothelial dysfunction markers to predict the risk of multiple organ dysfunctions in sepsis. Dr. Atreya received funding through the Cincinnati Children’s Research Foundation (CCRF) Procter-Scholar Award. Dr. Stanski and CCHMC hold a provisional patent for the use of PERSEVERE biomarkers in sepsis-associated acute kidney injury. Dr. Stanski is supported by the National Center for Advancing Translational Sciences of the National Institutes of Health (NIH) (KL2TR001426). Dr. Atreya, Dr. Stanski, and CCHMC hold a provisional patent for PERSEVERENCE sepsis-associated acute kidney injury model to identify high-risk patients for microvascular modulating therapies. Dr. Fitzgerald, Dr. Weiss, Dr. Haileselassie, Dr. Quasney, and Dr. Alder received funding from the NIH., (Copyright © 2024 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine.)

Cancer is a broad term for a set of disorders marked by the development of physically and functionally changed cells that proliferate uncontrollably, infect neighboring tissues, and result in malignant tumours, 'neoplasm'. Cancer remains a difficult disease to treat because of the significant adverse effects and poor pharmacokinetic profile of antineoplastic drugs, despite advancements in our understanding of the features and behavior of tumor cells in recent decades. In this series, the role of natural polymers is prominent as a component of a novel delivery system of anticancer drugs. These natural polymeric drug delivery systems (NPDDS) have many advantages over synthetic polymers like controlled delivery, biodegradability, inexpensive, low toxicity profile, and easily obtainable. These polymers further modify for the targeting of tumour cells. This review discusses and critically analyses the different natural polymers, such as chitosan, cellulose, starch, albumin, dextran, fucoidan, gelatin, etc., in terms of natural ingredient-based polymeric nanocarriers specifically for cancer therapy. It also describes benefits, drawbacks, and opinions and provides insights about the efficacy of NPDDS as well as its future perspectives and tabulated recent patents and cases under clinical trials exploited for cancer treatment., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Abstract: Background: Multiple-organ dysfunction syndrome disproportionately contributes to pediatric sepsis morbidity. Humanin (HN) is a small peptide encoded by mitochondrial DNA and thought to exert cytoprotective effects in endothelial cells and platelets. We sought to test the association between serum HN (sHN) concentrations and multiple-organ dysfunction syndrome in a prospectively enrolled cohort of pediatric septic shock. Methods: Human MT-RNR2 ELISA was used to determine sHN concentrations on days 1 and 3. The primary outcome was thrombocytopenia-associated multiorgan failure (TAMOF). Secondary outcomes included individual organ dysfunctions on day 7. Associations across pediatric sepsis biomarker (PERSEVERE)-based mortality risk strata and correlation with platelet and markers of endothelial activation were tested. Results: One hundred forty subjects were included in this cohort, of whom 39 had TAMOF. The concentration of sHN was higher on day 1 relative to day 3 and among those with TAMOF phenotype in comparison to those without. However, the association between sHN and TAMOF phenotype was not significant after adjusting for age and illness severity in multivariate models. In secondary analyses, sHN was associated with presence of day 7 sepsis-associated acute kidney injury ( P = 0.049). Furthermore, sHN was higher among those with high PERSEVERE-mortality risk strata and correlated with platelet counts and several markers of endothelial activation. Conclusion: Future investigation is necessary to validate the association between sHN and sepsis-associated acute kidney injury among children with septic shock. Furthermore, mechanistic studies that elucidate the role of HN may lead to therapies that promote organ recovery through restoration of mitochondrial homeostasis among those critically ill., Competing Interests: B.Z. and Cincinnati Children's Hospital Medical Center hold a provisional patent for serum humanin as a biomarker in trauma and sepsis. The remaining authors report no conflicts of interest., (Copyright © 2023 by the Shock Society.)

The temperature-triggered in situ gelling system has been revolutionized by introducing an intelligent polymeric system. Temperature-triggered polymer solutions are initially in a sol state and then undergo a phase transition to form a gel at body temperature due to various parameters like pH, temperature, and so on. These smart polymers offer a number of advantages, including ease of administration, long duration of release of the drug, low administration frequency with good patient compliance, and targeted drug delivery with fewer adverse effects. Polymers such as poly(N-isopropylacrylamide) (PNIPAAm), polyethylene glycol (PEG), poly (N, N'-diethyl acrylamide), and polyoxypropylene (PPO) have been briefly discussed. In addition to various novel Drug Delivery Systems (DDS), the smart temperature-triggered polymeric system has various applications in cancer therapy and many other disease conditions. This review focuses on the principals involved in situ gelling systems using various temperature-triggered polymers for chemotherapeutic purposes, using smart DDS, and their advanced application in cancer therapy, as well as available marketed formulations and recent advances in these thermoresponsive sol-gel transforming systems., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: Sepsis poses a grave threat, especially among children, but treatments are limited due to clinical and biological heterogeneity among patients. Thus, there is an urgent need for precise subclassification of patients to guide therapeutic interventions., Methods: We used clinical, laboratory, and biomarker data from a prospective multi-center pediatric septic shock cohort to derive phenotypes using latent profile analyses. Thereafter, we trained a support vector machine model to assign phenotypes in a hold-out validation set. We tested interactions between phenotypes and common sepsis therapies on clinical outcomes and conducted transcriptomic analyses to better understand the phenotype-specific biology. Finally, we compared whether newly identified phenotypes overlapped with established gene-expression endotypes and tested the utility of an integrated subclassification scheme., Findings: Among 1,071 patients included, we identified two phenotypes which we named 'inflamed' (19.5%) and an 'uninflamed' phenotype (80.5%). The 'inflamed' phenotype had an over 4-fold risk of 28-day mortality relative to those 'uninflamed'. Transcriptomic analysis revealed overexpression of genes implicated in the innate immune response and suggested an overabundance of developing neutrophils, pro-T/NK cells, and NK cells among those 'inflamed'. There was no significant overlap between endotypes and phenotypes. However, an integrated subclassification scheme demonstrated varying survival probabilities when comparing endophenotypes., Interpretation: Our research underscores the reproducibility of latent profile analyses to identify clinical and biologically informative pediatric septic shock phenotypes with high prognostic relevance. Pending validation, an integrated subclassification scheme, reflective of the different facets of the host response, holds promise to inform targeted intervention among those critically ill., Competing Interests: The authors declare the following competing interests: Cincinnati Children’s Hospital Medical Center (CCHMC) and the estate of the late Dr. Hector R. Wong hold patents for gene-expression-based pediatric septic shock endotypes, reflective of the host adaptive immune system. M.R.A and R.K hold a provisional patent for gene-expression-based multiple organ dysfunction syndrome (MODS) subclass identification, reflective of the innate immune response. Inflammatix is a for-profit company focusing on the development and commercialization of best-in-class host-response diagnostic tests. Y.H.B and T.E.S are employees and/or stockholders of Inflammatix Inc. P.K is a stockholder of Inflammatix Inc. The remaining authors have no conflicts of interest to disclose.

Background: Acute kidney injury (AKI) occurs commonly in pediatric septic shock and increases morbidity and mortality. Early identification of high-risk patients can facilitate targeted intervention to improve outcomes. We previously modified the renal angina index (RAI), a validated AKI prediction tool, to improve specificity in this population (sRAI). Here, we prospectively assess sRAI performance in a separate cohort., Methods: A secondary analysis of a prospective, multicenter, observational study of children with septic shock admitted to the pediatric intensive care unit from 1/2019 to 12/2022. The primary outcome was severe AKI (≥ KDIGO Stage 2) on Day 3 (D3 severe AKI), and we compared predictive performance of the sRAI (calculated on Day 1) to the original RAI and serum creatinine elevation above baseline (D1 SCr > Baseline +). Original renal angina fulfillment (RAI +) was defined as RAI ≥ 8; sepsis renal angina fulfillment (sRAI +) was defined as RAI ≥ 20 or RAI 8 to < 20 with platelets < 150 × 10 3 /µL., Results: Among 363 patients, 79 (22%) developed D3 severe AKI. One hundred forty (39%) were sRAI + , 195 (54%) RAI + , and 253 (70%) D1 SCr > Baseline + . Compared to sRAI-, sRAI + had higher risk of D3 severe AKI (RR 8.9, 95%CI 5-16, p < 0.001), kidney replacement therapy (KRT) (RR 18, 95%CI 6.6-49, p < 0.001), and mortality (RR 2.5, 95%CI 1.2-5.5, p = 0.013). sRAI predicted D3 severe AKI with an AUROC of 0.86 (95%CI 0.82-0.90), with greater specificity (74%) than D1 SCr > Baseline (36%) and RAI + (58%). On multivariable regression, sRAI + retained associations with D3 severe AKI (aOR 4.5, 95%CI 2.0-10.2, p < 0.001) and need for KRT (aOR 5.6, 95%CI 1.5-21.5, p = 0.01)., Conclusions: Prediction of severe AKI in pediatric septic shock is important to improve outcomes, allocate resources, and inform enrollment in clinical trials examining potential disease-modifying therapies. The sRAI affords more accurate and specific prediction than context-free SCr elevation or the original RAI in this population., (© 2023. The Author(s).)

Abstract: Background: Endothelial activation is a key driver of multiple organ dysfunction syndrome (MODS). Soluble endoglin (sENG) is expressed by mature and progenitor endothelial cells and thought to have angiogenic properties. We sought to determine the association between sENG and pediatric sepsis-associated MODS. Methods: Prospective observational study of pediatric septic shock. Primary outcome of interest was complicated course-a composite of death by (or) MODS on day 7 of illness. Secondary outcomes included individual organ dysfunctions. Endothelial biomarkers including sENG were measured using multiplex Luminex assays among patients with existing data on the Pediatric Sepsis Biomarker Risk Model (PERSEVERE-II) data. Multivariable regression was used to test the independent association between sENG and clinical outcomes. Serum sENG concentrations across PERSEVERE-II mortality risk strata and correlations with established markers of endothelial dysfunction were determined. Results: Three hundred six critically ill children with septic shock were included. Serum sENG concentrations were higher among those with primary and secondary outcomes of interest, with the exception of acute neurological dysfunction. Soluble endoglin was independently associated with increased odds of complicated course (adjusted odds ratio, 1.53; 95% confidence interval, 1.02-2.27; P = 0.038) and acute renal dysfunction (adjusted odds ratio, 1.84; 95% confidence interval, 1.18-2.876; P = 0.006). Soluble endoglin demonstrated graded responses across PERSEVERE-II risk strata and was positively correlated with endothelial biomarkers, except angiopoietin-1. Conclusions: Serum sENG is independently associated with complicated course and acute renal dysfunction in pediatric septic shock. Future studies are required to validate our observational data, and mechanistic studies are necessary to elucidate whether endoglin plays an organ-specific role in the development or resolution of acute renal dysfunction in sepsis., Competing Interests: The author reports no conflicts of interest., (Copyright © 2023 by the Shock Society.)

Background: Sepsis-associated acute kidney injury (SA-AKI) is associated with high morbidity, with no current therapies available beyond continuous renal replacement therapy (CRRT). Systemic inflammation and endothelial dysfunction are key drivers of SA-AKI. We sought to measure differences between endothelial dysfunction markers among children with and without SA-AKI, test whether this association varied across inflammatory biomarker-based risk strata, and develop prediction models to identify those at highest risk of SA-AKI., Methods: Secondary analyses of prospective observational cohort of pediatric septic shock. Primary outcome of interest was the presence of ≥ Stage II KDIGO SA-AKI on day 3 based on serum creatinine (D3 SA-AKI SCr). Biomarkers including those prospectively validated to predict pediatric sepsis mortality (PERSEVERE-II) were measured in Day 1 (D1) serum. Multivariable regression was used to test the independent association between endothelial markers and D3 SA-AKI SCr. We conducted risk-stratified analyses and developed prediction models using Classification and Regression Tree (CART), to estimate risk of D3 SA-AKI among prespecified subgroups based on PERSEVERE-II risk., Results: A total of 414 patients were included in the derivation cohort. Patients with D3 SA-AKI SCr had worse clinical outcomes including 28-day mortality and need for CRRT. Serum soluble thrombomodulin (sTM), Angiopoietin-2 (Angpt-2), and Tie-2 were independently associated with D3 SA-AKI SCr. Further, Tie-2 and Angpt-2/Tie-2 ratios were influenced by the interaction between D3 SA-AKI SCr and risk strata. Logistic regression demonstrated models predictive of D3 SA-AKI risk performed optimally among patients with high- or intermediate-PERSEVERE-II risk strata. A 6 terminal node CART model restricted to this subgroup of patients had an area under the receiver operating characteristic curve (AUROC) 0.90 and 0.77 upon tenfold cross-validation in the derivation cohort to distinguish those with and without D3 SA-AKI SCr and high specificity. The newly derived model performed modestly in a unique set of patients (n = 224), 84 of whom were deemed high- or intermediate-PERSEVERE-II risk, to distinguish those patients with high versus low risk of D3 SA-AKI SCr., Conclusions: Endothelial dysfunction biomarkers are independently associated with risk of severe SA-AKI. Pending validation, incorporation of endothelial biomarkers may facilitate prognostic and predictive enrichment for selection of therapeutics in future clinical trials among critically ill children., (© 2023. The Author(s).)

Introduction: Post-ICU admission cumulative positive fluid balance (PFB) is associated with increased mortality among critically ill patients. We sought to test whether this risk varied across biomarker-based risk strata upon adjusting for illness severity, presence of severe acute kidney injury (AKI), and use of renal replacement therapy (CRRT) in pediatric septic shock., Design: Ongoing multi-center prospective observational cohort., Setting: Thirteen pediatric ICUs in the United States (2003-2023)., Patients: Six hundred and eighty-one children with septic shock., Interventions: None., Measurements and Main Results: Cumulative percent positive fluid balance between day 1-7 (Day 1-7%PFB) was determined. Primary outcome of interest was complicated course defined as death or persistence of ≥ 2 organ dysfunctions by day 7. PERSEVERE-II biomarkers were used to assign mortality probability and categorize patients into high (n = 91), intermediate (n = 134), and low (n = 456) mortality risk strata. Cox proportional hazard regression models with adjustment for PERSEVERE-II mortality probability, presence of sepsis associated acute kidney injury (SA-AKI) on Day 3, and any use of CRRT, demonstrated that time-dependent variable Day 1-7%PFB was independently associated with increased hazard of complicated course in the cohort. Risk stratified analyses revealed that each 10% increase in Day 1-7%PFB was independently associated with increased hazard of complicated course among patients with high mortality risk strata (adj HR of 1.24 (95%CI: 1.08-1.42), p = 0.002), but not among those categorized as intermediate- or low- mortality risk., Conclusions: Our data demonstrate the independent influence of cumulative %PFB on the risk of complicated course. Contrary to our previous report, this risk was largely driven by patients categorized as having a high-mortality risk based on PERSEVERE-II biomarkers. Further research is necessary to determine whether this subset of patients may benefit from targeted deployment of restrictive fluid management or early initiation of de-escalation therapies upon resolution of shock., Competing Interests: Conflicts of interest: N.L.S and CCHMC hold a provisional patent for the use of PERSEVERE biomarkers in sepsis associated acute kidney injury. M.R.A and Cincinnati Children’s Hospital (CCHMC) hold a provisional patent for a unified biomarker model – PERSEVERENCE that incorporates PERSEVERE and endothelial dysfunction markers to predict risk of multiple organ dysfunctions in sepsis. M.R.A, N.L.S, and Cincinnati Children’s Hospital Medical Center (CCHMC) hold a provisional patent for PERSEVERENCE-SA-AKI model to identify high-risk patients for microvascular modulating therapies.

Background: Sepsis is associated with significant mortality. Yet, there are no efficacious therapies beyond antibiotics. PCSK9 loss-of-function (LOF) and inhibition, through enhanced low-density lipoprotein receptor (LDLR) mediated endotoxin clearance, holds promise as a potential therapeutic approach among adults. In contrast, we have previously demonstrated higher mortality in the juvenile host. Given the potential pleiotropic effects of PCSK9 on the endothelium, beyond canonical effects on serum lipoproteins, both of which may influence sepsis outcomes, we sought to test the influence of PCSK9 LOF genotype on endothelial dysfunction., Methods: Secondary analyses of a prospective observational cohort of pediatric septic shock. Genetic variants of PCSK9 and LDLR genes, serum PCSK9, and lipoprotein concentrations were determined previously. Endothelial dysfunction markers were measured in day 1 serum. We conducted multivariable linear regression to test the influence of PCSK9 LOF genotype on endothelial markers, adjusted for age, complicated course, and low- and high-density lipoproteins (LDL and HDL). Causal mediation analyses to test impact of select endothelial markers on the association between PCSK9 LOF genotype and mortality. Juvenile Pcsk9 null and wildtype mice were subject to cecal slurry sepsis and endothelial markers were quantified., Results: A total of 474 patients were included. PCSK9 LOF was associated with several markers of endothelial dysfunction, with strengthening of associations after exclusion of those homozygous for the rs688 LDLR variant that renders it insensitive to PCSK9. Serum PCSK9 was not correlated with endothelial dysfunction. PCSK9 LOF influenced concentrations of Angiopoietin-1 (Angpt-1) upon adjusting for potential confounders including lipoprotein concentrations, with false discovery adjusted p value of 0.042 and 0.013 for models that included LDL and HDL, respectively. Causal mediation analysis demonstrated that the effect of PCSK9 LOF on mortality was mediated by Angpt-1 (p = 0.0008). Murine data corroborated these results with lower Angpt-1 and higher soluble thrombomodulin among knockout mice with sepsis relative to the wildtype., Conclusions: We present genetic and biomarker association data that suggest a potential direct role of the PCSK9-LDLR pathway on Angpt-1 in the developing host with septic shock and warrant external validation. Further, mechanistic studies on the role of PCSK9-LDLR pathway on vascular homeostasis may lead to the development of pediatric-specific sepsis therapies., (© 2023. The Author(s).)

Background: Cancer is a deadly disease responsible for worldwide mortality; usually, middle- and low-income countries have been more affected by cancer and are responsible for 70% of deaths. The present study was performed with the aim to design silver nanoparticles using three species of Curcuma, i.e., Curcuma longa, Curcuma aromatica, and Curcuma caesia., Methods: The rhizomes of different plants were extracted with ethanol. The rhizome extracts were used to prepare silver nanoparticles. It was optimized at different pH, silver ion concentrations, and concentrations of plant extracts. The anticancer activity of prepared nanoparticles of C. longa, C. aromatica, and C. caesia was evaluated on a human colon cancer cell line (HT-29) using sulforhodamine B (SRB) assay., Results: The percentage yield of C. longa, C. aromatica, and C. caesia was 11.34 g, 15.45 g, and 12.67 g, respectively. The results exhibited that the prepared nanoparticles were smooth and spherical. All the nanoparticles of rhizome extracts rescued the viability of HT-29 cells in a different extent. HT-29 cells were sensitive to prepared nanoparticles that induce more cytotoxicity towards cancer cells., Conclusion: Thus, the prepared silver nanoparticle of Curcuma species through green synthesis may help treat cancer with low toxicity., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Monkeypox is an orthopoxvirus-based zoonotic illness that causes symptoms similar to smallpox in humans. Health care workers around the world are making it a priority to educate themselves on the many clinical manifestations and treatment options for this virus as public health agencies strive to stop the current outbreak. The infected do not have access to any treatment at this time. However, information obtained from the smallpox pandemic has led researchers to examine vaccinia immune globulin (IVG), tecovirimat, and cidofovir as viable treatments for monkeypox. Moreover, medication like tecovirimat may be given in extreme circumstances, and supportive therapy can help with symptom relief. The European Medicines Agency (EMA) certified tecovirimat as safe and effective against monkeypox in 2022, per the World Health Organization (WHO). As there are now no established guidelines for alleviating these symptoms, the efficacy of these treatments is highly questionable. Some high-profile cases in recent years have cast doubt on the long-held belief that this illness is rare and always resolves itself without treatment. We aimed to conduct this review to get a deeper comprehension of the evolving epidemiology of monkeypox by analysing such factors as the number of confirmed, probable, and potential cases, the median age at presentation, the mortality rate, and the geographic distribution of the disease. This study offers an updated review of monkeypox and the clinical treatments that are currently available as a result of the worldwide epidemics., Competing Interests: The authors declared no conflict of interest., (© 2022 The Authors. Published by Elsevier Ltd.)

Background: Multiple organ dysfunction syndrome (MODS) is a critical driver of sepsis morbidity and mortality in children. Early identification of those at risk of death and persistent organ dysfunctions is necessary to enrich patients for future trials of sepsis therapeutics. Here, we sought to integrate endothelial and PERSEVERE biomarkers to estimate the composite risk of death or organ dysfunctions on day 7 of septic shock., Methods: We measured endothelial dysfunction markers from day 1 serum among those with existing PERSEVERE data. TreeNet® classification model was derived incorporating 22 clinical and biological variables to estimate risk. Based on relative variable importance, a simplified 6-biomarker model was developed thereafter., Results: Among 502 patients, 49 patients died before day 7 and 124 patients had persistence of MODS on day 7 of septic shock. Area under the receiver operator characteristic curve (AUROC) for the newly derived PERSEVEREnce model to predict death or day 7 MODS was 0.93 (0.91-0.95) with a summary AUROC of 0.80 (0.76-0.84) upon tenfold cross-validation. The simplified model, based on IL-8, HSP70, ICAM-1, Angpt2/Tie2, Angpt2/Angpt1, and Thrombomodulin, performed similarly. Interaction between variables-ICAM-1 with IL-8 and Thrombomodulin with Angpt2/Angpt1-contributed to the models' predictive capabilities. Model performance varied when estimating risk of individual organ dysfunctions with AUROCS ranging from 0.91 to 0.97 and 0.68 to 0.89 in training and test sets, respectively., Conclusions: The newly derived PERSEVEREnce biomarker model reliably estimates risk of death or persistent organ dysfunctions on day 7 of septic shock. If validated, this tool can be used for prognostic enrichment in future pediatric trials of sepsis therapeutics., (© 2022. The Author(s).)

Background: Increasing numbers of adults with congenital heart disease (ACHD) undergo cardiac surgical procedures in children's hospitals, yet surgical outcomes data are limited. We sought to better understand the impact of preoperative risk factors on postoperative complications and cardiac intensive care unit (CICU) length of stay (LOS)., Methods: Surgical CICU admissions for patients aged 18 years and older in the Pediatric Cardiac Critical Care Consortium registry from August 2014 to January 2019 in 34 hospitals were included. Primary outcomes included prolonged LOS (defined as LOS ≥90th percentile) and major complications (cardiac arrest, extracorporeal membrane oxygenation, arrhythmia requiring intervention, stroke, renal replacement therapy, infection, and reoperation/reintervention)., Results: We analyzed 1764 surgical CICU admissions. Prolonged LOS was 7 days or longer. Eighteen patients (1.0%) died, of whom 9 (0.5%) died before the LOS cutoff and were excluded from analysis. Of 1755 CICU admissions, 8.8% (n = 156) had prolonged LOS, and 23.3% (n = 413) had 1 or more major complications. Several variables, including The Society of Thoracic Surgeons-European Association for Cardio-Thoracic Surgery 4/5 operation, 3 or more previous sternotomies, and preoperative renal dysfunction/dialysis were independent risk factors for both prolonged LOS and major complications (P < .05). Preoperative ventilation was associated with increased odds of prolonged LOS and preoperative arrhythmia with major complications., Conclusions: This analysis of postoperative ACHD care in pediatric CICUs found high complexity operations, 3 or more previous sternotomies, preoperative arrhythmias, renal dysfunction, and respiratory failure are associated with prolonged LOS and/or major complications. Future quality improvement initiatives focused on preoperative optimization and implementation of adult-specific perioperative protocols may mitigate morbidity in these patients undergoing cardiac surgical procedures at children's hospitals., (Copyright © 2022 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Central venous pressure (CVP) is the blood pressure in the venae cavae, near the right atrium of the heart. This signal waveform is commonly collected in clinical settings, and yet there has been limited discussion of using this data for detecting arrhythmia and other cardiac events. In this paper, we develop a signal processing and feature engineering pipeline for CVP waveform analysis. Through a case study on pediatric junctional ectopic tachycardia (JET), we show that our extracted CVP features reliably detect JET with comparable results to the more commonly used electrocardiogram (ECG) features. This machine learning pipeline can thus improve the clinical diagnosis and ICU monitoring of arrhythmia. It also corroborates and complements the ECG-based diagnosis, especially when the ECG measurements are unavailable or corrupted.

Introduction: Sepsis-associated acute kidney injury (AKI) is a common diagnosis in children that is associated with poor outcomes. The lack of therapeutic options once present makes early identification of at-risk patients essential. The renal angina index (RAI) has been previously validated to predict severe AKI in heterogeneous populations of critically ill children. The performance of this score specifically in children with septic shock is unknown., Methods: A secondary analysis of a multicenter, prospective, observational study of 379 children with septic shock to determine the ability of the RAI to predict severe AKI at day 3, and to assess for the potential need for recalibration of the RAI in this unique subset of patients., Results: At the original cutoff of ≥8, the RAI predicted day 3 severe AKI with an area under the receiving operating characteristic (AUROC) curve 0.90 (95% confidence interval [CI]: 0.86 to 93), 95% sensitivity, and 54% specificity. A Youden's index identified a higher optimal cutoff of ≥20 (sensitivity 83%, specificity 80%), and day 1 platelet count <150 × 10 3 /μl was an independent predictor of severe AKI (adjusted odds ratio: 3.2; 95% CI: 1.7 to 6.3; P  < 0.001). Recalibration of the RAI to include platelet count and this new threshold restored the sensitivity of the original ≥8 threshold (95%), while improving its specificity (69%)., Conclusions: The RAI appears to be a sensitive and reliable tool for prediction of severe AKI in children with septic shock, although the use of a recalibrated sepsis-specific RAI using a higher cutoff and platelet count may be beneficial., (© 2021 International Society of Nephrology. Published by Elsevier Inc.)

The study examines the whole blood transcriptome profile before and after cardiopulmonary bypass (CPB) in neonates with hypoplastic left heart syndrome (HLHS), a severe form of congenital heart disease, that can develop low cardiac output syndrome (LCOS). Whole blood mRNA transcriptome profiles of 13 neonates with HLHS before and after their first palliative surgery were analyzed to determine differentially expressed genes and pathways. The median age and weight at surgery were 4 days and 3.2 kg, respectively. Of the 13 patients, 8 developed LCOS. There was no significant difference between CPB, aortic cross clamp, deep hypothermic cardiac arrest times between patients that develop LCOS and those that do not. Upon comparing differential gene expression profiles between patients that develop LCOS and those that do not in pre-operative samples, 1 gene was up-regulated and 13 were down regulated. In the post-operative samples, 4 genes were up-regulated, and 4 genes were down regulated when patients that develop LCOS were compared to those that do not. When comparing post-operative samples to pre-operative samples in the patients that do not develop LCOS, 1484 genes were up-regulated, and 1388 genes were down regulated; while patients that developed LCOS had 2423 up-regulated genes, and 2414 down regulated genes for the same pre to post-operative comparison. Pathway analysis revealed differential regulation of inflammatory pathways (IL signaling, PDGF, NOTCH1, NGF, GPCR) and metabolic pathways (heme metabolism, oxidative phosphorylation, protein metabolism including amino acid and derivatives, fatty acid metabolism, TCA cycle and respiratory electron transport chain). By identifying altered transcriptome profiles related to inflammation and metabolism in neonates with HLHS who develop LCOS after CPB, this study opens for exploration novel pathways and potential therapeutic targets to improve outcomes in this high-risk population.

The roles played by nurse practitioners and physician assistants have expanded exponentially during the last decade. Although existing professional advancement models for nurse practitioners/physician assistants have led to enhanced integration in different patient care units, the development of a distinctive professional identity formation is lacking. This perspective proposes a new framework to guide the planning of an educational program that provides not only clinical knowledge and technical skills but also opportunities for enhancing leadership and research skills, along with strong career mentorship. Such a program will lead to formation of a distinctive identity for critical care nurse practitioners and physician assistants, which in turn can improve job satisfaction and employee retention.

Objectives: The goals of this research were to evaluate acute (single-dose) and sub-acute (repeated-dose) toxicity profiles of methanolic extract of Pistacia integerrima J. L. Stewart ex Brandis (PI) for Wistar rats and to assess the safety profile of PI by observing physiological changes, mortality, changes in body weight, the histopathology of body organs, the hematology and the biochemistry of the animals., Methods: The toxicity profile of PI was evaluated using Wistar rats of both sexes. Animals were divided into four groups: Group 1; control group (normal saline), Group 2; PI-1 (250 mg/kg), Group 3; PI-2 (500 mg/kg), Group 4; PL-3 (1,000 mg/kg). An acute-toxicity study in which animals received a single dose of PI extract (2,000 mg/ kg) and were then observed for 14 days for changes in skin, fur, eye color, mucous membrane secretions and excretions, gait, posture, and tonic or clonic movements was performed according to guideline 425 of the Organization of Economic and Corporation Development (OECD). In the repeated-dose toxicity study (OECD - 407) animals received a daily dose of PI extract for 28 days (4 weeks). The parameters observed in this study include body weight, hematology and biochemistry of the animals., Results: In the acute toxicity study, no mortalities or changes in behavior were noted in the animals. The repeated-dose toxicity study was also devoid of any toxicity in the animals during the 28 days of testing with PI extract. The extract did not alter- the body weight, hematology or biochemistry of the animals. The methanolic extract of PI was to be found safe to the no-observed-adverse-effect-level (NOAEL) for the single- dose and repeated-dose toxicity tests in rats., Conclusion: The methanolic extract of PI was devoid of toxicity; hence, it can be used for various ayurvedic preparations and treatments of diseases., Competing Interests: The authors declare that there are no conflict of interest.