Treatment Of Chronic Disease Research Articles

Ultra‐Long‐Term Anti‐Inflammatory Polyphenol Capsule to Remodel the Microenvironment for Accelerating Osteoarthritis Healing by Single Dosage

AbstractOsteoarthritis (OA) is a common chronic inflammatory disease that leads to disability and death. Existing therapeutic agents often require frequent use, which can lead to drug resistance and long‐term side effects. Polyphenols have anti‐inflammatory and antioxidant potential. However, they are limited by their short half‐life and low bioavailability. This work presents a novel pure polyphenol capsule for sustained release of polyphenols, which is self‐assembled via hydrophobic and hydrogen bonds. The capsule enhances cellular uptake, scavenges reactive oxygen and nitrogen species, reduces inflammatory markers, and remodels the OA microenvironment by inhibiting the p38 MAPK pathway. The capsule overcomes the limitations of short half‐life and low bioavailability of polyphenols and achieves single‐dose cure in mouse and dog OA models, providing an optimal therapeutic window for OA repair. Taking advantage of simple manufacturing, convenient administration, and pure polyphenol composition, these capsules show great potential for clinical treatment of osteoarthritis and chronic inflammatory diseases.

Mobile App for Patients With Chronic Obstructive Pulmonary Diseases During Home-Based Exercise Care: Usability Study.

Digital health tools have demonstrated promise in the treatment and self-management of chronic diseases while also serving as an important means for reducing the workload of health care professionals (HCPs) and enhancing the quality of care. However, these tools often merely undergo large-scale testing or enter the market without undergoing rigorous user experience analysis in the early stages of their development, leading to frequent instances of low use or failure. This study aims to assess the usability of and satisfaction with a mobile app designed for the clinical monitoring of patients with chronic obstructive pulmonary disease undergoing pulmonary rehabilitation at home. This study used a mixed methods approach involving two key stakeholders-patients with chronic obstructive pulmonary disease and HCPs-across three phases: (1) mobile app mock-up design, (2) usability testing, and (3) satisfaction evaluation. Using convenience sampling, participants were grouped as HCPs (n=12) and patients (n=18). Each received a tablet with mock-ups for usability testing through interviews, with audio recordings transcribed and analyzed anonymously in NVivo12.0, focusing on mock-up features and usability insights. Task difficulty was rated from 1 (very easy) to 5 (very difficult), with noncompletion deemed a critical error. Usability satisfaction was measured on a 5-point Likert scale from 1 (strongly disagree) to 5 (strongly agree). The research indicated a notable difference in app usability perceptions: 66% (8/12) of HCPs found tasks "very easy," compared to only 22% (4/18) of patients. Despite this, no participant made critical errors or withdrew, and satisfaction was high. HCPs completed tasks in about 20 minutes, while patients took 30. Older adults faced challenges with touch screens and scroll menus, suggesting the need for intuitive design aids like auditory support and visual health progress indicators, such as graphs. HCPs noted potential data delays affecting service, while non-native-speaking caregivers faced interpretation challenges. A secure pairing system for privacy in teleconsultations proved difficult for older users; a simpler icon-based system is recommended. This study highlights the need to consider stakeholder abilities in medical app design to enhance function implementation. Most HCPs (11/12, 91%) found the app intuitive, though they recommended adding icons to show patient progress to support clinical decisions. In contrast, 62% (11/18) of patients struggled with tablet navigation, especially with connectivity features. To ensure equitable access, the design should accommodate older users with diverse abilities. Despite challenges, both groups reported high satisfaction, with patients expressing a willingness to learn and recommending the app. These positive usability evaluations suggest that, with design improvements, such apps could see increased use in home-based care.

Clinico-histopathological characteristics and management outcome of rare chronic infective granulomatous diseases: A case series study

Granulomatous skin diseases are common cutaneous dermatoses commonly encountered by practicing dermatologist. Granulomatous skin lesions are distinctive pattern of chronic inflammatory response of skin due to reaction against various organic and inorganic antigens. Granulomas are characterized by focal collection of epithelioid cells or histiocytes, admixed with variable number of leucocytes (especially mononuclear cells) and multinucleated giant cells. Granulomatous reaction is a type IV hypersensitivity reaction evoked by poorly soluble reactive substances. Incidence and prevalence of different types of granulomatous dermatitis depend on geographic location. Granulomatous skin lesions are common in the eastern parts of India. Many granulomatous skin lesions have identical histomorphology and conversely a single pathology can produce varied histological features. Some rare suppurative chronic granulomatous skin diseases include Botryomycosis, Actinomycosis, Rhinosporoidosis, Nocardiosis, and Cutaneous Tuberculosis. To describe clinical, histopathological features and treatment outcome of rare chronic infective granulomatous diseases. In this observational case series study, we retrospectively analysed six biopsy proven cases of rare chronic infective granulomatous diseases presented to our department (OPD) of Dermatology, Venereology and Leprosy (DVL) over a period of six months between June 2023 to November 2023 at Great Eastern Medical School and Hospital (GEMS), Srikakulam, Andhra Pradesh, India. The patient’s full clinical history, morphology of lesions, histopathological findings and treatment outcome were analysed. Along with histopathology, other necessary laboratory investigations were performed if required. A total of six patients were involved in the study, of whom four were males and two were females. The male to female ratio was 2:1, with a slight male majority. The most common age group was 31-40 years for both males and females. Painful raised lesion for long duration was the predominant complaint among those patients. Out of these six rare chronic granulomatous diseases, bacterial infections were common than fungal infection. All the cases showed clinical improvement after one month of starting treatment.: Most of the patients had a chronic history with improper treatment. So, it is imperative that the clinical diagnosis has to be confirmed with histopathology for the definitive diagnosis and appropriate treatment of these rare chronic infective granulomatous diseases. All these rare cases showed excellent progress after starting the right treatment.

Mechanism of action of Nrf2 and its related natural regulators in rheumatoid arthritis.

Rheumatoid arthritis (RA) is an autoimmune disease characterized by synovitis that can lead to joint deformities. To date, more than 18 million individuals worldwide have been diagnosed with RA, making it one of the most prevalent autoimmune diseases globally and posing a significant threat to public health and safety. Due to the complex pathogenesis of the disease, which involves autoimmunity, genetics, inflammation and oxidative stress in the body's tissues, the current drug therapy generally targets a single molecule, and effective and efficient drugs involving multiple levels and targets are lacking; thus, there is an urgent need for high-quality research and treatment in this field. Nuclear transcription factor erythroid 2-associated factor 2 (Nrf2) plays a crucial role in cellular resistance to oxidative stress and electrophilic attacks and is a potential pharmacological target for chronic disease treatment. While currently no drugs that target Nrf2 have been approved specifically for RA treatment, such an approach holds great significance. In recent years, the use of natural products to treat RA and other chronic conditions has become increasingly widespread because of their superior efficacy and minimal side effects. Therefore, this article provides a review of the mechanism of Nrf2 in RA and summarizes natural products that target Nrf2 and its associated pathways in the treatment of RA, aiming to offer new insights and strategies for the prevention and management of RA.

PDE4 Inhibitors and their Potential Combinations for the Treatment of Chronic Obstructive Pulmonary Disease: A Narrative Review

Chronic Obstructive Pulmonary Disease (COPD) is associated with cough, sputum production, and a reduction in lung function, quality of life, and life expectancy. Currently, bronchodilator combinations (β2-agonists and muscarinic receptor antagonists, dual therapy) and bronchodilators combined with inhaled corticosteroids (ICS), triple therapy, are the mainstays for the management of COPD. However, the use of ICS in triple therapy has been shown to increase the risk of pneumonia in some patients. These findings have laid the foundation for developing new therapies that possess both anti-inflammatory and/or bronchodilation properties. Phosphodiesterase-4 (PDE4) inhibitors have been reported as an effective therapeutic strategy for inflammatory conditions, such as asthma and COPD, but their use is limited because of class-related side effects. Efforts have been made to mitigate these side effects by targeting the PDE4B subtype of PDE4, which plays a pivotal role in the anti-inflammatory effects. Unfortunately, no selective oral PDE4B inhibitors have progressed to clinical trials. This has led to the development of inhaled PDE4 inhibitors to minimize systemic exposure and maximize the therapeutic effect. Another approach, the bronchodilation property of PDE3 inhibitors, is combined with anti-inflammatory PDE4 inhibitors to develop dual inhaled PDE4/PDE3 inhibitors. A few of these dual inhibitors have shown positive effects and are in phase 3 studies. The current review provides an overview of various PDE4 inhibitors in the treatment of COPD. The possibility of studying different selective PDE4 inhibitors and dual PDE3/4 inhibitors in combination with currently available treatments as a way forward to increase their therapeutic effectiveness is also emphasized.

Health Monitoring and Prediction Using Non-invasive Sensors in IoT Environment

Introduction: IoT's blend with non-invasive sensors has made health state prediction possible and constant real-time monitoring transformed healthcare. Using photoplethysmography (PPG) and electrocardiograms (ECG), this device evaluates important parameters including heart rate, blood oxygen saturation, and blood pressure. As healthcare systems face increasing demands, this technology provides a patient-centered and efficient method for long-term health tracking—needed for early intervention and management of chronic diseases. Objectives: The main goal is to evaluate using time-series data from PPG and ECG sensors the efficiency of an IoT-enabled health monitoring system coupled with machine learning models in predicting health conditions including arrhythmias and hypoxia. Methods: This system detects events based on temporal pattern recognition by use of Long Short-Term Memory (LSTM) networks and Random Forest classifiers. Noise reduction is preprocessed and wearable device data is labeled for training of machine learning models. The design combines wearable sensors, a smartphone app, and cloud-based analysis for continuous monitoring and real-time input. Results: Experimental data shows that the LSTM model attained a 95% accuracy while the Random Forest classifier attained a 92.5% accuracy. Both models displayed remarkable accuracy and recall even while the LSTM model excels in identifying anomalies in time-series data and the Random Forest classifier skillfully detects health events depending on certain criteria. Conclusions: This study demonstrates the capability of IoT-based health monitoring systems to enhance patient outcomes through continuous, non-invasive monitoring and predictive analytics. Despite its potential, difficulties persist, including data security, sensor reliability, and energy efficiency, necessitating additional research for broad use and clinical integration.

A molecular toolkit for heterologous protein secretion across Bacteroides species.

Bacteroides species are abundant, prevalent, and stable members of the human gut microbiota, making them a promising chassis for developing long-term interventions for chronic diseases. Engineering Bacteroides as in situ bio-factories, however, requires efficient protein secretion tools, which are currently lacking. Here, we systematically investigate methods to enable heterologous protein secretion in Bacteroides. We identify a collection of secretion carriers that can export functional proteins across multiple Bacteroides species at high titers. To understand the mechanistic drivers of Bacteroides secretion, we characterize signal peptide sequence features, post-secretion extracellular fate, and the size limit of protein cargo. To increase titers and enable flexible control of protein secretion, we develop a strong, self-contained, inducible expression circuit. Finally, we validate the functionality of our secretion carriers in vivo in a mouse model. This toolkit promises to enable expanded development of long-term living therapeutic interventions for chronic gastrointestinal disease.

Systematic review and meta-analysis of combined cognitive-behavioral therapy and physical activity and exercise interventions for pediatric chronic disease.

Cognitive-behavioral (CBT) interventions combined with either a physical activity (CBT+PA) or exercise intervention (CBT+Ex) are becoming more common in pediatric populations. Considering the independent effects of PA and exercise on health and psychological outcomes, it is unclear whether CBT alone differs from CBT+PA or CBT+Ex in efficacy. The main objective of this systematic review and meta-analysis of randomized clinical trials (RCTs) was to assess the efficacy of CBT+PA and CBT+Ex interventions in pediatric chronic disease. This review included RCTs in children (≤18 years) with a chronic condition, a CBT+Ex or CBT+PA intervention, and an objective measure of PA&Ex. Seven databases were searched using MeSH terms and key terms and included studies published before July 1, 2023. Abstracts were reviewed for inclusion by two independent reviewers, data was extracted by three independent reviewers. Risk of bias (RoB 2) and study quality were coded. Random effect meta-analyses of differences in between-group change in PA&Ex were conducted. Eligible studies (k = 5) reported outcomes for a combined 446 children. A small, nonsignificant overall effect was found (d = 0.10, 95% CI -0.16, 0.35) indicating intervention groups (CBT+PA or CBT+Ex) increased engagement in PA&Ex more than comparator groups (CBT). Additional analyses were inconclusive due to the small number of eligible studies. Additional RCTs are needed with integrated PA&Ex interventions targeting pediatric chronic disease. Future trials should report more detailed PA&Ex data. The full protocol for this analysis was prospectively registered in Open Science Framework (project ID: osf.io/m4wtc).

Nephroprotective effect of SGLT2 inhibitors in elderly patients with type 2 diabetes mellitus and hypertension: a real-world population-based cohort study

ABSTRACT Objectives This study aimed to investigate the nephroprotective effect of sodium-glucose cotransporter 2 inhibitors (SGLT2i) in elderly patients with type 2 diabetes mellitus (T2DM) and hypertension based on real-world clinical data. The study aimed to provide a theoretical basis for evidence-based pharmacological treatment of chronic kidney disease in this population. Methods The ‘Health Cloud’ platform of the Shanghai Municipal Health Commission was employed to identify and screen elderly patients with T2DM and hypertension. The propensity score matching cohort was further constructed to estimate the effect of SGLT2i on the risk of rapid decline in renal function (∆eGFR≤-5 ml/min/1.73 m2 or ∆eGFR%≤-5%). Multiple sensitivity analyses were conducted to assess the robustness of the results. Results After propensity score matching, no significant differences of covariates were identified between the SGLT2i and non-SGLT2i groups. The results of multivariate logistic models demonstrated a consistent and inverse correlation between SGLT2i use and the risk of rapid eGFR decline, whether defined as ∆eGFR≤-5 ml/min/1.73 m2 (OR = 0.60, 95% CI:0.38-0.96) or ∆eGFR%≤-5%（OR = 0.57, 95% CI:0.37-0.89). In the stratification of renin-angiotensin system inhibitor (RASi) treatment, SGLT2i was associated with a lower risk of rapid eGFR decline in the RASi group (all ORs < 1, p < 0.05), with no interaction between SGLT2i and RASi (all P for interaction > 0.05) detected. Conclusions SGLT2i significantly reduced the risk of rapid eGFR decline in elderly patients with T2DM and hypertension, but the synergistic effect with RASi remains unclear.

The peri-operative implications of sodium-glucose co-transporter 2 inhibitors: a narrative review.

Sodium-glucose co-transporter 2 inhibitors are a novel class of antihyperglycaemic drugs used in the management of type 2 diabetes, that improve glycaemic control, cardiovascular outcomes and promote weight loss. They are also approved for the treatment of heart failure and chronic kidney disease in patients with or without diabetes. This narrative review discusses the peri-operative effects and implications of sodium-glucose co-transporter 2 inhibitors and gives an overview of current evidence and existing peri-operative guidelines. We conducted a literature review to identify peer-reviewed English language articles published since 2000, with further articles identified by reviewing the references of key papers. Peri-operative sodium-glucose cotransporter 2 inhibitor use carries a risk of euglycaemic ketoacidosis. Although clinically significant diabetic ketoacidosis remains a rare event, sodium-glucose co-transporter 2 inhibitors inhibitor-associated diabetic ketoacidosis has been observed across almost all surgical specialities. Ketoacidosis may present with any blood glucose level. Existing guidelines are inconsistent and may be a source of clinical confusion. Based on the half-life of sodium-glucose cotransporter 2 inhibitors, we recommend withholding treatment for 72 h before elective surgery (5 half-lives), with additional multidisciplinary input for specific procedures with dietary alterations and in patients with poorly controlled diabetes of cardiac/renal disease. In the event of emergency surgery or any surgery within 72 h of sodium-glucose cotransporter 2 inhibitor administration, we recommend pre-, intra- and postoperative blood ketone monitoring (6 hourly for 24 h post-surgery and until full oral diet is resumed). Sodium-glucose cotransporter 2 inhibitor treatment should only be resumed after resumption of full oral diet in the absence of ketosis.

A Survey on Machine Learning, Its Approaches and Challenges in Health Care

The area of machine learning research is constantly growing, offering several opportunities for investigation and application. ML is widely utilized in various applications like finance, life science, health care, transportation, education, security etc. The health care sector has long been an early adopter of and benefited greatly from technological advances. These days, machine learning plays a key role in many health related realms, including the development of new medical procedures, the handling of patient data and records, the treatment of chronic diseases, the findings of effects of various medicines, to discover patterns from medical data sources and provide excellent capabilities to predict diseases etc. An overview of machine learning-based approaches, learning algorithms, and applications in several healthcare domains is given in this study.

Precision Cut Lung Slices: Emerging Tools for Preclinical and Translational Lung Research. An Official American Thoracic Society Workshop Report.

The urgent need for effective treatments for acute and chronic lung diseases underscores the significance of developing innovative preclinical human research tools. The 2023 ATS Workshop on Precision Cut Lung Slices (PCLS) brought together 35 experts to discuss and address the role of human tissue-derived PCLS as a unique tool for target and drug discovery and validation in pulmonary medicine. With increasing interest and usage, along with advancements in methods and technology, there is a growing need for consensus on PCLS methodology and readouts. The current document recommends standard reporting criteria and emphasizes the requirement for careful collection and integration of clinical metadata. We further discuss current clinically relevant readouts that can be applied to PCLS and highlight recent developments and future steps for implementing novel technologies for PCLS modeling and analysis. The collection and correlation of clinical metadata and multiomic analysis will further advent the integration of this preclinical platform into patient endotyping and the development of tailored therapies for lung disease patients.

Evaluation of the Total Antioxidant Capacity of Three Selected Plants in Guyana

Aims: This study aimed to evaluate the leaf extracts of three commonly used medicinal plants in Guyana, namely Brassica juncea (mustard), Struchium sparganophora (antsbush), and Psidium guajava (guava), for their total antioxidant capacity. Study Design: Experimental-based study. Place and Duration of Study: The experiments were performed at the chemistry laboratory in the Faculty of Natural Sciences and the main laboratory in the College of Medical Sciences at the University of Guyana from September 2022 to August 2023. Methodology: The leaves of these plants were collected, washed, and air-dried at 280C for approximately one month, then pulverised in a sterilised food processor. Leaf extracts were then obtained by maceration with various solvents such as hexane, ethyl acetate, chloroform, and methanol; followed by filtration and rotary evaporation. The extracts obtained were then subjected to total antioxidant quantification via the phosphomolybdate method using a spectrophotometer. The total antioxidant capacity of the extracts was expressed as ascorbic acid equivalents. Results: Antioxidant activity was seen for all the extracts but in varying quantities. The highest antioxidant capacity was observed for the P. guajava extracts with a mean of 5.2 mg/mL. The least activity was observed for the S. sparganophora extracts, with a mean of 0.9 mg/mL. The ethanolic extracts showed the highest antioxidant capacity (10.6 mg/mL for P. guajava; 2.5 mg/mL for B. juncea). The hexane extracts had the least (0.33 mg/mL for P. guajava; 0.24 mg/mL for B. juncea). Conclusion: The leaves of B. juncea, S. sparganophora, and P. guajava have antioxidant capacity but those of P. guajava have greater potential for use as complementary and alternative treatments for chronic diseases.

Sonogenetics in the Treatment of Chronic Diseases: A New Method for Cell Regulation.

Sonogenetics is an innovative technology that integrates ultrasound with genetic editing to precisely modulate cellular activities in a non-invasive manner. This method entails introducing and activating mechanosensitive channels on the cell membrane of specific cells using gene delivery vectors. When exposed to ultrasound, these channels can be manipulated to open or close, thereby impacting cellular functions. Sonogenetics is currently being used extensively in the treatment of various chronic diseases, including Parkinson's disease, vision restoration, and cancer therapy. This paper provides a comprehensive review of key components of sonogenetics and focuses on evaluating its prospects and potential challenges in the treatment of chronic disease.

Finerenone: A Novel Drug Discovery for the Treatment of Chronic Kidney Disease.

The most common cause of chronic kidney disease (CKD) is diabetic nephropathy (DN). Primarilymineralocorticoid receptor antagonists (MRAs) (spironolactone and eplerenone), angiotensin-converting enzyme inhibitors or angiotensin receptor blockers were used for the treatment of CKD, but due to the high risk of hyperkalaemia, the combination was infrequently used. Currently after approval by FDA in 2021, finerenone was found to be effective in the treatment of CKD. Finerenone slowdowns the progression of diabetic nephropathy and lessens the cardiovascular morbidity in DN patients. The main objective of this review article is to provide a comprehensive and insightful overview of the role of finerenone by mainly focusing on its pharmacological properties, toxicity, uses, bioanalytical technique used for determination, and treatment options. Finerenone works by inhibiting the action of the mineralocorticoid receptor. Finerenone is quickly absorbed from the digestive tract after oral treatment and achieves peak plasma concentrations in 1-2 hours. Finerenone is actively metabolized through oxidation, epoxidation substitution, and direct hydroxylation. Elimination of finerenone is done through urine and feces. Determination of finerenone can be done through HPLC-MS and LSC. The present review covers the complete picture of ADME properties, bioanalytical techniques, clinical trials, toxicity, and possible avenues in this arena. Finerenone is effective compared to other mineralocorticoid receptor-like spironolactone and eplerenone, for the treatment of chronic kidney disease.

Fenbendazole and Diisopropylamine Dichloroacetate Exert Synergistic Anti-cancer Effects by Inducing Apoptosis and Arresting the Cell Cycle in A549 Lung Cancer Cells.

Lung cancer is the leading cause of cancer-related mortality worldwide, accounting for approximately 2 million new cases and 1.8 million deaths annually. Standard treatment options include surgery, radiation therapy, chemotherapy, and targeted therapies. Despite advancements over the past 25 years, the prognosis of patients with lung cancer remains poor. This study evaluated the synergistic anticancer effects of fenbendazole (FZ) and diisopropylamine dichloroacetate (DADA) on A549 lung cancer cells. Fenbendazole (methyl N-(6-phenylsulfanyl-1H-benzimidazol-2-yl) carbamate) is a broad-spectrum benzimidazole anthelmintic commonly used in veterinary medicine. Diisopropylamine Dichloroacetate (DADA), an over-the-counter treatment for chronic liver disease, has demonstrated anti-tumor properties as an inhibitor of pyruvate dehydrogenase kinase. The combination of FZ and DADA exhibited a synergistic effect on inhibiting the proliferation of A549 lung cancer cells. After 48 h of treatment, the FZ-DADA combination produced reactive oxygen species (ROS) and promoted apoptosis by down-regulating Bcl2 and up-regulating BAX protein expression. The combination activated caspase-3, caspase-7, and PARP, further driving apoptosis in A549 cells. The FZ-DADA treatment also induced cell cycle arrest, as evidenced by the inhibition of Cyclin A and Cyclin E proteins. The synergistic anticancer effects of the FZ-DADA combination were confirmed at both cellular and protein levels in A549 lung cancer cells. The combination modulates key apoptotic proteins, induces cell cycle arrest, and increases mitochondrial ROS production, suggesting a promising approach for lung cancer treatment that warrants further investigation and development.

Efficient extraction of interstitial fluid using an ultrasonic-powered replaceable hexagram-shaped hydrogel microneedle patch for monitoring of dermal pharmacokinetics and psoriatic biomarkers

Monitoring biomarkers and pharmacokinetics is crucial for the precise diagnosis and treatment of chronic skin diseases. Dermal interstitial fluid (ISF) presents an attractive alternative source of biomarkers and drugs to blood; however, a simple, efficient, and comfortable extraction method is lacking. Here, we combine high-precision 3D printing and micromolding to develop an ultrasonic-powered, replaceable hexagram-shaped hydrogel microneedle (HMN) patch. Hexagram-shaped HMNs exhibit superior mechanical strength and faster ISF extraction rates compared to cone, pyramid, and octagram shapes. The patch, attached to a holder and integrated with a commercial ultrasonic device via a customized connector, allows easy replacement after use. With ultrasound assistance, the patch extracts over 15 μL, 6 μL, and 4 μL of ISF from porcine skin ex vivo, healthy mouse skin, and psoriatic mouse skin in vivo, respectively, within 1 min. The recovered ISF, obtained via centrifugation from HMNs, is used to monitor the dermal pharmacokinetics of drugs (e.g., methotrexate) and psoriasis-related biomarkers (e.g., interleukin-17 and –22) in mouse models, showing trends comparable to those detected via skin biopsy and blood draw. This ultrasonic-powered, replaceable hexagram-shaped HMN patch holds great promise for advancing the diagnosis, treatment, and research of skin diseases.

ULK1-regulated AMP sensing by AMPK and its application for the treatment of chronic kidney disease

Adenosine monophosphate (AMP)-activated protein kinase (AMPK) is a central kinase involved in energy homeostasis. Increased intracellular AMP levels result in AMPK activation through the binding of AMP to the γ-subunit of AMPK. Recently, we reported that AMP-induced AMPK activation is impaired in the kidneys in chronic kidney disease (CKD) despite an increase in the AMP/ATP ratio. However, the mechanisms by which AMP sensing is disrupted in CKD are unclear. Here, we identified mechanisms of energy homeostasis in which Unc-51-like kinase 1 (ULK1)-dependent phosphorylation of AMPKγ1 at Ser260/Thr262 promoting AMP sensitivity of AMPK. AMPK activation by AMP was impaired in Ulk1 knockout mice despite an increased AMP/ATP ratio. ULK1 expression is markedly downregulated in CKD kidneys, leading to AMP sensing failure. Additionally, MK8722, an allosteric AMPK activator, stimulated AMPK in the kidneys of a CKD mouse model (5/6th nephrectomy) via a pathway that is independent of AMP sensing. Thus, our study shows that MK8722 treatment significantly attenuates the deterioration of kidney function in CKD and may be a potential therapeutic option in CKD therapeutics.

Golden Breath: Feasibility and acceptability of a biofeedback-based virtual reality game on reducing children's needle-related pain and fear

BackgroundNeedle procedures can cause pain and fear in children. Current literature reports that biofeedback-based virtual reality applications may help alleviate children's pain and fear. This study aims to evaluate the feasibility, acceptability, and safety of the newly developed game Golden Breath, which uses biofeedback-based virtual reality to reduce children's needle-related pain and fear. MethodsThe development of Golden Breath includes; (1) development of the application's features based on needs assessment, (2) gamification of the application content based on literature, (3) development of the prototype, (4) expert evaluation and feedback on the application content, (5) usability testing by 11 children (4–12 years). ResultsRegarding acceptability, the expert evaluation showed a high usability of the system. All children provided positive feedback and reported high satisfaction with Golden Breath. The game was feasible and effective for reducing children's pain and fear levels during needle procedures. Golden Breath was deemed safe for children because it did not cause symptoms such as dizziness, vomiting, or nausea. ConclusionThe expert evaluation, children's feedback, and pilot study results showed that the Golden Breath game is feasible, acceptable, and safe for children during the needle-related procedure. The pilot study revealed that the Golden Breath game effectively reduced pain and fear during blood sampling in children. Practice to implicationsIt is recommended that healthcare professionals use Golden Breath to optimize the well-being of children receiving treatment for chronic and acute diseases.

Dry powder inhaler deposition in the larynx and the risk of steroid inhaler laryngitis: a computational fluid dynamics study

Dry Powder Inhalers (DPIs) are a mainstay in the treatment of obstructive respiratory diseases, including asthma and chronic obstructive pulmonary disease (COPD). Deposition of inhaled corticosteroids in the larynx elicits local side effects, potentially leading to steroid inhaler laryngitis. The objective of this study was to estimate the dose of DPIs that are deposited in the larynx relative to other regions of the respiratory tract using computational fluid dynamics (CFD). An anatomically accurate model of the airways (mouth to main bronchi) was constructed based on medical imaging of a healthy adult. Respiratory airflow and particle transport were simulated for constant inhalation rates of 30, 45, and 60 L/min. Two turbulence models were compared, namely the large eddy simulation (LES) and the models. DPIs were assumed to generate an aerosol cloud with a log-normal particle size distribution characterized by the mass median aerodynamic diameter () and geometric standard deviation (). We compared two commercial DPIs, namely DPI 1 had a large particle size ( = 50 μm, ) and DPI 2 had a small particle size ( = 2 μm, ). The laryngeal dose was 1.6-to-3.8-fold higher than the bronchial dose for DPI 1, while the laryngeal and bronchial doses (units of mass per unit surface area) were similar for DPI 2 for both turbulence models and all inhalation rates. The choice of turbulence model had little impact on the total extrathoracic deposition, but a significant impact on regional doses, with the LES model predicting higher larynx-to-bronchi relative doses than the model. Our prediction that the larynx is a hotspot for DPI deposition is consistent with the observation of laryngeal side effects in DPI users. Importantly, our simulations suggest that DPIs with larger particles ( = 50 μm) may increase the risk of steroid inhaler laryngitis.