Development and characterization of nitazoxanide-loaded poly(ε-caprolactone) membrane for GTR/GBR applications.

OBJECTIVE: Guided tissue/guided bone regeneration (GTR/GBR) membranes are widely used for periodontal bone regeneration, but their success depends on a bacteria-free environment. Systemic antibiotic treatment often proves inadequate, moreover, the increasing prevalence of antibiotic resistance in oral infections exacerbates this challenge. This study aimed to fabricate antibacterial membranes using a new class of antibiotics for local drug delivery, to eradicate infections and promote tissue regeneration. METHODS: Membranes loaded with nitazoxanide (NTZ) were fabricated via electrospinning using poly(ε-caprolactone) (PCL) with varying concentrations of NTZ (0 %, 2.5 %, and 5 % w/w) relative to the polymer weight. Morphochemical of NTZ-loaded membranes were assessed using scanning electron microscopy-energy dispersive spectroscopy (SEM-EDS) and Fourier Transform Infrared spectroscopy (FTIR). Mechanical properties were evaluated using universal testing machine and NTZ release profile from membranes was determined by spectrophotometer (λmax = 444) for 14 days. Antimicrobial efficacy against periodontal pathogens, cell compatibility and mineralization were evaluated using periodontal ligament stem cells (PDLSCs). RESULTS: Optimized spinning parameter maintained a uniform fiber diameter and successful loading of NTZ was confirmed by SEM-EDS and FTIR. NTZ incorporation did not significantly affect mechanical properties, whereas the drug release kinetics showed an initial burst, followed by sustained release over 14 days. NTZ-loaded membranes demonstrated antibacterial activity against Aggregatibacter actinomycetemcomitans (Aa) and Fusobacterium nucleatum (Fn). Importantly, the presence of NTZ showed minimal cell toxicity; however, it reduced the mineralization potential compared with that of the pure PCL membrane, which increased over time. SIGNIFICANCE: Taken together, these findings established that NTZ-loaded membranes could be promising barrier membrane to counteract microbial environment and aid periodontal bone regeneration.

SEMA7A-mediated juxtacrine stimulation of IGFBP-3 upregulates IL-17RB at pancreatic cancer invasive front.

Tumor invasion is the hallmark of tumor malignancy. The invasive infiltration pattern of tumor cells located at the leading edge is highly correlated with metastasis and unfavorable patient outcomes. However, the regulatory mechanisms governing tumor malignancy at the invasive margin remain unclear. The IL-17B/IL-17RB pathway is known to promote pancreatic cancer invasion and metastasis, yet the specific mechanisms underlying IL-17RB upregulation during invasion are poorly understood. In this study, we unveiled a multistep process for IL-17RB upregulation at the invasive margin, which occurs through direct communication between tumor cells and fibroblasts. Tumor ATP1A1 facilitates plasma membrane expression of SEMA7A, which binds to and induces IGFBP-3 secretion from fibroblasts. The resulting gradient of IGFBP-3 influences the direction and enhances IL-17RB expression to regulate SNAI2 in invasion. These findings highlight the importance of local tumor-fibroblast interactions in promoting cancer cell invasiveness, potentially leading to the development of new therapeutic strategies targeting this communication.

Precise Control of Intracellular Trafficking and Receptor-Mediated Endocytosis in Living Cells and Behaving Animals.

Intracellular trafficking, an extremely complex network, dynamically orchestrates nearly all cellular activities. A versatile method that enables the manipulation of target transport pathways with high spatiotemporal accuracy in vitro and in vivo is required to study how this network coordinates its functions. Here, a new method called RIVET (Rapid Immobilization of target Vesicles on Engaged Tracks) is presented. Utilizing inducible dimerization between target vesicles and selective cytoskeletons, RIVET can spatiotemporally halt numerous intracellular trafficking pathways within seconds in a reversible manner. Its highly specific perturbations allow for the real-time dissection of the dynamic relationships among different trafficking pathways. Moreover, RIVET is capable of inhibiting receptor-mediated endocytosis. This versatile system can be applied from the cellular level to whole organisms. RIVET opens up new avenues for studying intracellular trafficking under various physiological and pathological conditions and offers potential strategies for treating trafficking-related disorders.

Effect of shared decision-making model on the management of diabetes high-risk groups.

OBJECTIVE: A shared decision-making (SDM) model-based intervention programme was implemented for a population at high risk for diabetes to explore its effectiveness in intervening with blood glucose levels in this population. METHODS: One hundred residents were selected according to the principle of voluntary participation and divided into the intervention group (n = 50) and the control group (n = 50) by using multistage cluster sampling. The control group received only brief diabetes knowledge education through a disease brochure issued by the hospital; the intervention group implemented a SDM model based on large classroom and individualised education for 4 months. Univariate analysis and generalised estimating equation fitting model were used to analyse the effect of intervention on blood glucose parameters in the study subjects. RESULTS: Univariate analysis showed that after 4 months of intervention, fasting blood glucose was lower in the intervention group than in the control group (5.57 ± 0.56 vs. 6.07 ± 0.77, F = 45.721, p < 0.001); glycosylated hemoglobin was lower in the intervention group than in the control group (5.91 ± 0.28 vs. 6.02 ± 0.24, F = 25.998, p < 0.001), decreased by 0.26% in the intervention group and increased by 0.01% in the control group. One-way analysis of variance (ANOVA) showed that fasting blood glucose and glycosylated hemoglobin in the intervention group decreased to different extents from baseline. The generalised estimation equation was fitted with the intervention programme, gender, hypertension, smoking, alcohol consumption, physical activity, age, waist circumference, body mass index, baseline fasting blood glucose, and baseline glycosylated hemoglobin as independent variables, and fasting blood glucose and baseline glycosylated hemoglobin as dependent variables. Results showed that compared with the control group, fasting blood glucose and glycosylated hemoglobin levels were significantly different between the two groups (p < 0.001). CONCLUSION: Applying an intervention programme based on SDM model to people at high risk of diabetes can improve patients' adherence to self-management and establish a good lifestyle, thus contributing to their good glycemic control.

Using Deauville Scoring to Guide Consolidative Radiotherapy in Diffuse Large B-Cell Lymphoma.

BACKGROUND: The most common aggressive lymphoma in adults is diffuse large B-cell lymphoma (DLBCL). Consolidative radiotherapy (RT) is often administered to DLBCL patients but guidelines remain unclear, which could lead to unnecessary RT. We aimed to evaluate the value of end-of-treatment PET-CT scans, interpreted using the Deauville score (DV), to guide the utilization of consolidative RT, which may help spare low-risk DLBCL patients from unnecessary RT. METHODS: We included all DLBCL patients diagnosed between 2010 and 2022 at the National Cancer Centre Singapore with DV measured at the end of the first-line chemoimmunotherapy. The outcome measure was time-to-progression (TTP). The predictive value of DV for RT was assessed based on the interaction effect between the receipt of RT and DV in Cox regression models. RESULTS: The data of 349 patients were analyzed. The median follow-up time was 38.1 months (interquartile range 34.0-42.3 months). RT was associated with a significant improvement in TTP amongst the DV4-5 patients (HR 0.33; 95%CI 0.13-0.88; p = 0.027) but not the DV1-3 patients (HR 0.85; 95%CI 0.40-1.81; p = 0.671) (interaction's p = 0.133). Multivariable analysis reported that RT was again significantly associated with improved TTP among the DV4-5 patients (adjusted HR 0.29; 95%CI 0.10-0.80; p = 0.017) but not the DV1-3 group (HR 0.86; 95%CI 0.40-1.86; p = 0.707) (interaction's p = 0.087). CONCLUSION: Our results suggests that DLBCL patients with end-of-treatment PET-CT DV1-3 may not need consolidative RT. Longer follow-up and prospective randomized trials are still necessary to investigate long-term outcomes.

Combined dapagliflozin and roxadustat effectively protected heart and kidney against cardiorenal syndrome-induced damage in rodent through activation of cell stress-Nfr2/ARE signalings and stabilizing HIF-1α.

BACKGROUND: This study tested whether combined dapagliflozin (DAPA) and roxadustat (ROX) therapy was superior to a singular therapy in protecting heart and kidney functions in rats with cardiorenal syndrome (CRS). METHODS AND RESULTS: An in vitro study demonstrated that the cell survival (PI3K/Akt/mTOR)/cell stress (ERK1/2, JNK/p-38) signaling was significantly activated by combination therapy with ROX-DAPA (all p<0.001). Additionally, these two signaling pathways further significantly upregulated the hypoxia-induced factor (HIF)-1α which, in turn, significantly upregulated Nrf2/ARE (HO-1/NQO-1) and angiogenesis/cell-growth factors (EPO/SDF-1α/VEGF/FGF/IGF-2) and downregulated hypoxia-inducible factor prolyl-4-hydroxylase-1 (all p<0.001). Adult-male SD rats were categorized into Groups 1 (sham-operated control)/2 (CRS)/3 (CRS+ROX)/4 (CRS+DAPA)/5 (CRS+ROX+DAPA). By Day 60 after rodent CRS induction, the levels of BUN/creatinine and the ratio of urine protein to creatinine were lowest in Group 1, highest in Group 2, and significantly lower in Group 5 than in Groups 3 and 4; however, they were similar in the latter two groups, whereas the left-ventricular-ejection-fraction exhibited the opposite trend of creatinine among the groups (all p<0.0001). The protein expression levels of cell-survival (p-PI3K/p-Akt-p-mTOR)/cell-stress (p-JNK/p-p38/p-ERK1/2)/Nrf2-ARE (HO-1/NQO-1/SIRT1/SIRT3) signaling factors and angiogenesis factors (HIF-1α/VEGF/SDF-1α/FGF/IGF-2/EPO) significantly and progressively increased from Groups 1-5 (all p<0.0001). CONCLUSION: Combined DAPA-ROX therapy has a synergistic effect on protecting heart and kidney functions against CRS-induced damage in rodents.

Positive vaccine beliefs linked to reduced mental stress in healthcare professionals during COVID-19: a retrospective study.

Background and aim: The COVID-19 pandemic has led to a significant adverse effect on the mental health of healthcare professionals. This study aims to assess the effects of the prolonged pandemic on burnout and mood disorders and to evaluate the influence of positive vaccination beliefs on these factors at a medical center during the extended COVID-19 pandemic. Methods: This retrospective study analyzed the results of an online questionnaire survey including burnout status and mood disorders from 2020 to 2022. The factors related to mood moderate/severe disorders and the impact of the positive vaccine belief were also explored. Results: The initial analysis revealed that healthcare professionals continued to experience significant levels of personal and work-related burnout, along with mood disorders. However, the scores and the percentage of moderate to severe burnout gradually decreased. Notably, the percentage of individuals with moderate to severe mood disorders also gradually declined (2020: 13.4%, 2021: 12.3%, 2022: 11.1%). The number of participants who need professional interventions decreased from 56.2% in 2020 to 45.9% in 2021, and 46% in 2022. Multivariate analysis revealed a positive vaccine belief was associated with a lower risk of moderate/severe mood disorders, with odd ratios (OR) and 95% confidence intervals (95% CI) of 0.38 (0.28 - 0.52) and 0.41 (0.30 - 0.52) in the 2021 and 2022 cohorts, respectively. Further investigation revealed that age over 50 was linked to a positive vaccine belief in 2021 and 2022. Within the 2022 cohort, working as nurses was identified as the independent factor associated with a less positive belief, with the OR and 95% CI of 0.49 (0.27 - 0.90). Conclusion: The findings of the present study suggest burnout and mood disorders are still significant during the pandemic. A positive vaccine belief may mitigate pandemic-related mental distress. Further interventions to enhance the belief combined with other supporting measures are important in a long fight against the pandemic.

Exploring the use of deep learning models for accurate tracking of 3D zebrafish trajectories.

Zebrafish are ideal model organisms for various fields of biological research, including genetics, neural transmission patterns, disease and drug testing, and heart disease studies, because of their unique ability to regenerate cardiac muscle. Tracking zebrafish trajectories is essential for understanding their behavior, physiological states, and disease associations. While 2D tracking methods are limited, 3D tracking provides more accurate descriptions of their movements, leading to a comprehensive understanding of their behavior. In this study, we used deep learning models to track the 3D movements of zebrafish. Videos were captured by two custom-made cameras, and 21,360 images were labeled for the dataset. The YOLOv7 model was trained using hyperparameter tuning, with the top- and side-view camera models trained using the v7x.pt and v7.pt weights, respectively, over 300 iterations with 10,680 data points each. The models achieved impressive results, with an accuracy of 98.7% and a recall of 98.1% based on the test set. The collected data were also used to generate dynamic 3D trajectories. Based on a test set with 3,632 3D coordinates, the final model detected 173.11% more coordinates than the initial model. Compared to the ground truth, the maximum and minimum errors decreased by 97.39% and 86.36%, respectively, and the average error decreased by 90.5%.This study presents a feasible 3D tracking method for zebrafish trajectories. The results can be used for further analysis of movement-related behavioral data, contributing to experimental research utilizing zebrafish.

CD8+ T cells infiltrating into tumors were controlled by immune status of pulmonary lymph nodes and correlated with non-small cell lung cancer (NSCLC) patients' prognosis treated with chemoimmunotherapy.

PURPOSE: Neoadjuvant chemoimmunotherapy has the potential to reduce tumor burden, improve the pathological complete response (pCR) rate, and significantly prolong patients' disease-free survival (DFS). However, the treatment's effectiveness varies among NSCLC patients. The immunological mechanisms contributing to tumor regression still require further exploration and elucidation. METHODS: The immune status of patients' local tumor microenvironment (TME) before and after neoadjuvant chemoimmunotherapy, their paired pulmonary lymph nodes (11th LNs) after therapy, including infiltrating immune cell densities and their correlations, were analyzed using multiplex immunofluorescence. RESULTS: Fifty-six NSCLC patients undergoing neoadjuvant chemoimmunotherapy were enrolled and subsequently underwent surgical resection and pathological evaluation. Among these, 19 patients achieved a pCR, 6 patients exhibited a major pathological response (MPR), and 31 patients did not achieve MPR. There were no significant difference in the densities of CD8+ T cell, Treg and Dendritic cell (DC) in patients' TME before neoadjuvant therapy (n = 26, P = 0.091, P = 0.753, P = 0.905, respectively), but after treament, these immune cells' dynamics were significantly different between different response group. CD8+ T cell densities were increased in pCR gourp (P = 0.006), but not in non-pCR group (P = 0.389); the densities of Treg were increased in non-pCR gourp (P = 0.0004), but DC were significantly decreased in non-pCR gourp (P = 0.005). After surgery, the TME were also significantly different: patients achieving pCR typically demonstrated high densities of CD8+ T cell, DC and low densities of Tregs (P = 0.0001, P < 0.0001 and P = 0.0004). The immune status of 11th LNs also exhibited significant differences. DC densities were much higher in pCR patients, whereas Treg in the pCR group were significantly lower than those in the non-pCR group (P = 0.0008 and P = 0.003). Furthermore, the densities of DC in the TME showed a moderate positive correlation with DC in 11th LNs (P = 0.0002), while the densities of Tregs in the TME exhibited a moderate negative correlation with DC densities in 11th LNs (P = 0.03). Patients who had high densities of CD8+ T cell in the resection tissues and DC in the LNs, experienced longer DFS (P = 0.048 and P = 0.024). CONCLUSION: Immune cells in both pulmonary LNs and the TME collectively influence the remodeling of the NSCLC patient's TME, thus impacting treatment response and prognosis.

Risk of chronic fatigue syndrome after COVID-19: A retrospective cohort study of 3227281 patients.

BACKGROUND: Many patients who recovered from COVID-19 still suffer from chronic fatigue syndrome (CFS). It was observed that patients with comorbidities were more prone to developing CFS. This research investigates the risk of post-COVID-19 CFS to assist healthcare professionals in reducing the risk of CFS. METHODS: A retrospective cohort study is conducted to investigate the risk of post-COVID-19 CFS based on the TriNetX-sourced electronic health records. Factors including age, sex, race, vaccination, and severity of COVID-19 are analysed. Propensity score matching was applied to balance COVID-19 and non-COVID-19 cohorts. Kaplan-Meier analysis and Cox proportional hazard model were used to perform the relationship between COVID-19 and CFS risk. RESULTS: This research involved 3227281 patients with COVID-19 and 3227281 with non-COVID-19 between 1st January 2020 and 31st December 2023. The incidence of CFS was higher in the COVID-19 group compared to the non-COVID-19 group at 1 follow-up intervals (HR 1.59, 95 % CI = 1.54-1.63). Subgroup analysis revealed increased CFS risk across different age groups (>18), sexes, races, and comorbid conditions, with notable variations. CONCLUSIONS: COVID-19 patients have a higher risk of developing CFS compared to individuals without COVID-19. The increased risk is particularly significant in adults aged 18 years and older.

Sustainability of health outcomes of patients with type-2 diabetes mellitus after completing 6 months of remote tele-monitoring: Two-year results from a randomised controlled trial (OPTIMUM).

INTRODUCTION: Meta-analysis shows that home tele-monitoring (HTM) improves glycaemic control in patients with type-2 diabetes mellitus (T2DM) up to 12 months, but their health outcomes after HTM cessation remains unclear. This study aimed to determine the health outcomes of these patients 18 months after completing 6 months of HTM, compared to standard care. METHODS: Patients with T2DM were enrolled in an open-labelled randomised controlled trial, aged 26 to 65 years, and suboptimal glycaemic control (HbA1c = 7.5%-10%). Patients in the intervention group (n = 165) undertook HTM using the OPTIMUM (Optimising care of Patients via Telemedicine In Monitoring and aUgmenting their control of diabetes Mellitus) HTM system for 6 months followed by usual care for another 18 months, while control group (n = 165) had usual care for 24 months. The OPTIMUM HTM system includes in-app video-based tele-education, tele-monitoring of the blood pressure (BP), capillary glucose and weight via Bluetooth devices and mobile applications, followed by algorithm-based telecare by the investigators. They were assessed using the Self-Care Inventory Scale (SCIR) and medication adherence (Medication Adherence Report Scale 5) at baseline, 6-month and 24-month time-points. RESULTS: The data from 146 (intervention) and 152 (control) patients, with comparable baseline demographic profiles were eventually analysed. The decrease in HbA1c over 24 months was comparable between intervention and control group. Those in the intervention group were more likely to maintain their glycemic control (HbA1c ≤ 8%) (adjusted odds ratio (AOR) = 1.9, 95%confidence interval (CI) = 1.1-3.2; p = 0.028), had higher SCIR score (p = 0.004), and less likely to "never forget" (p = 0.022), or "stop medications" (p = 0.048), at 24-month time-point as compared to subjects in the control group. CONCLUSION: The glycaemic control of patients with T2DM continued to be maintained for another 18 months after 6 months of HTM, which were attributed to sustained self-care behaviour and medication adherence.

Optimal timing for video assisted thoracic surgery decortication for improved survival in chronic empyema.

BACKGROUND: Video-assisted thoracic surgery decortication for phase 3 thoracic empyema is widely accepted, but its optimal timing has not been established. We aim to investigate and assess this timing, in terms of overall survival, for chronic empyema. METHODS: Two hundred four patients with pneumonia-caused phase 3 empyema were treated with video-assisted thoracic surgery decortication over 10-years at Changhua Christian Hospital. The 90-day post-operative survival status was analyzed, and we compared the survivor group versus the non-survivor group. A receiver operating characteristic curve was used to identify the optimal decortication timing. RESULTS: A comparison between survivors and non-survivors showed statistical differences among age (p=0.004), presence of cardiovascular disease (p=0.018), presence of end-stage renal disease (p=0.002), duration to surgery (p=0.013), length of intensive care unit stay (p=0.010), and overall length of hospital stay (p=0.015). ROC curve analysis determined the cut-off for video-assisted thoracic surgery decortication, based on optimal 90-day post-operative survival, to be 7.5 days after hospitalization; mortality increases threefold thereafter (14.2% vs 44.6%, p<0.001). Multivariate analysis revealed that age, end-stage renal disease, pleural effusion pH≦7.2 and duration to surgery >7.5 days negatively impacted 90-day post-operative survival. CONCLUSIONS: Patients receiving decortication surgery within 7.5 days of hospital admission had better overall survival.

Comparisons of Intradialytic Exercise Versus Home-Based Exercise in Hemodialysis Patients: A Narrative Review.

With the increasing prevalence of end-stage kidney disease, the number of patients requiring hemodialysis (HD) continues to rise. While life-sustaining, HD is often associated with adverse effects such as muscle loss, physical deconditioning, fatigue, and compromised health-related quality of life (HRQoL). Recent research suggests that intradialytic exercise (IDE) and home-based exercise (HBE) may mitigate these adverse effects and improve patient outcomes. However, the existing literature mainly focuses on the outcomes of both exercises, whereas the comparison of types is often omitted. Hence, this review consolidates findings from studies investigating the effectiveness, implementation, safety, feasibility, and adherence of different types of IDE and HBE in HD patients. Overall, the current literature bolsters the significance of IDE and HBE for improving health in HD patients. IDE and HBE enhance physical function, cardiopulmonary capacity, HRQoL, and cognitive well-being. Some research proposed an indirect link between IDE and survival rates. Despite these benefits, challenges remain in implementing these exercise modalities, including patient adherence and the feasibility of routine exercise during HD sessions. Integrating these exercises into routine care allows healthcare providers to enhance outcomes for HD patients. Further research is suggested to optimize exercise protocols and explore long-term effects and cost-effectiveness.

Feasibility of a Home-Based Developmental Behavioral Intervention for Children With Autism Spectrum Disorder in Underserved Taiwanese Families.

PURPOSE: This study aims to investigate the feasibility of the home-based parent- mediated intervention Naturalistic developmental behavioral intervention (HB-NDBI) in underserved Taiwanese families of children with Autism spectrum disorder (ASD) and explore its effects on children's developmental skills and parents' parenting stress. METHOD: 24 underserved Taiwanese families of children with ASD (mean age = 46.5 months) received 12-week HB-NDBI programs. Social Responsiveness Scale, Second Edition (SRS-2), Mullen Scales of Early Learning (MSEL), Child Behavior Checklist (CBCL/1.5-5), and Parenting Stress Index (PSI) were administered before and after the HB-NDBI programs. RESULTS: Following the HB-NDBI programs, significant improvements in social cognition, social communication subscales, receptive language subscale, internalizing, externalizing, and total behavioral problems scales of children, and release of parenting stress were observed. CONCLUSION: This study demonstrated the feasibility of home-based parent-mediated intervention for underserved families in Taiwan. These promising results might facilitate the development of such interventions for underserved families.

Genetic susceptibility to caffeine intake and metabolism: a systematic review.

BACKGROUND: Coffee and tea consumption account for most caffeine intake and 2-3 billion cups are taken daily around the world. Caffeine dependence is a widespread but under recognized problem. OBJECTIVES: To conduct a systematic review on the genetic susceptibility factors affecting caffeine metabolism and caffeine reward and their association with caffeine intake. METHODOLOGY: We conducted PubMed and Embase searches using the terms "caffeine", "reward", "gene", "polymorphism", "addiction", "dependence" and "habit" from inception till 2024. The demographics, genetic and clinical data from included studies were extracted and analyzed. Only case-control studies on habitual caffeine drinkers with at least 100 in each arm were included. RESULTS: A total of 2552 studies were screened and 26 studies involving 1,851,428 individuals were included. Several genes that were involved with caffeine metabolism such as CYP1A2, ADORA2A, AHR, POR, ABCG2, CYP2A6, PDSS2 and HECTD4 rs2074356 (A allele specific to East Asians and monomorphic in Europeans, Africans and Americans) were associated with habitual caffeine consumption with effect size difference of 3% to 32% in number of cups of caffeinated drink per day per effect allele. In addition, ALDH2 was linked to the Japanese population. Genes associated with caffeine reward included BDNF, SLC6A4, GCKR, MLXIPL and dopaminergic genes such as DRD2 and DAT1 which had around 2-5% effect size difference in number of cups of caffeinated drink for each allele per day. CONCLUSION: Several genes that were involved in caffeine metabolism and reward were associated with up to 30% effect size difference in number of cups of caffeinated drink per day, and some associations were specific to certain ethnicities. Identification of at-risk caffeine dependence individuals can lead to early diagnosis and stratification of at-risk vulnerable individuals such as pregnant women and children, and can potentially lead to development of drug targets for dependence to caffeine.

Candida tropicalis-derived vitamin B3 exerts protective effects against intestinal inflammation by promoting IL-17A/IL-22-dependent epithelial barrier function.

Candida tropicalis-a prevalent gut commensal fungus in healthy individuals - contributes to intestinal health and disease. However, how commensal C. tropicalis influences intestinal homeostasis and barrier function is poorly understood. Here, we demonstrated that the reference strain of C. tropicalis (MYA-3404) ameliorated intestinal inflammation in murine models of chemically induced colitis and bacterial infection. Intestinal colonization of C. tropicalis robustly upregulated the expression of IL-17A and IL-22 to increase barrier function and promote proliferation of intestinal epithelial cells in the mouse colon. Metabolomics analysis of fecal samples from mice colonized with C. tropicalis revealed alterations in vitamin B3 metabolism, promoting conversion of nicotinamide to nicotinic acid. Although nicotinamide worsened colitis, treatment with nicotinic acid alleviated disease symptoms and enhanced epithelial proliferation and Th17 cell differentiation. Oral gavage of C. tropicalis mitigated nicotinamide-induced intestinal dysfunction in experimental colitis. Blockade of nicotinic acid production with nicotinamidase inhibitors lowered the protective effects against colitis in mice treated with C. tropicalis. Notably, a clinical C. tropicalis strain isolated from patients with candidemia lacked the protective effects against murine colitis observed with the reference strain. Together, our results highlight a novel role for C. tropicalis in resolving intestinal inflammation through the modulation of vitamin B3 metabolism.

• Protection against colitis conferred by intestinal colonization of Candida tropicalis depends on metabolic activity and strain• C. tropicalis MYA-3404 supplementation promotes intestinal epithelial barrier function through IL-17A and IL-22 expressed by Th17 cells, γδ T cells, and ILC3• MYA-3404 strain uses its enzymatic activity to modulate vitamin B3 metabolism for protective benefits.

From emergence to endemicity of highly pathogenic H5 avian influenza viruses in Taiwan.

A/goose/Guangdong/1/96-like (GsGd) highly pathogenic avian influenza (HPAI) H5 viruses cause severe outbreaks in poultry when introduced. Since emergence in 1996, control measures in most countries have suppressed local GsGd transmission following introductions, making persistent transmission in domestic birds rare. However, geographical expansion of clade 2.3.4.4 sublineages has raised concern about establishment of endemic circulation, while mechanistic drivers leading to endemicity remain unknown. We reconstructed the evolutionary history of GsGd sublineage, clade 2.3.4.4c, in Taiwan using a time-heterogeneous rate phylogeographic model. During Taiwan's initial epidemic wave (January 2015 - August 2016), we inferred that localised outbreaks had multiple origins from rapid spread between counties/cities nationwide. Subsequently, outbreaks predominantly originated from a single county, Yunlin, where persistent transmission harbours the trunk viruses of the sublineage. Endemic hotspots determined by phylogeographic reconstruction largely predicted the locations of re-emerging outbreaks in Yunlin. The transition to endemicity involved a shift to chicken-dominant circulation, following the initial bidirectional spread between chicken and domestic waterfowl. Our results suggest that following their emergence in Taiwan, source-sink dynamics from a single county have maintained GsGd endemicity up until 2023, pointing to where control efforts should be targeted to eliminate the disease.

Respiratory insufficiency in an infant with osteogenesis imperfecta.

Osteogenesis imperfecta (OI) is a rare presentation in the pediatric population. Whilst orthopedic manifestations are well-publicised, the multiple respiratory complications and mechanisms of respiratory failure in more severe cases are less well described. We report the clinical, radiological and histopathological details of the case of an infant with genetically-confirmed OI (Type 2) and associated respiratory insufficiency, as well as summarise the relevant existing literature. This case highlights the importance of the recognition of clinical challenges associated with the management of respiratory complications in a patient with OI.

A digital health-supported and community pharmacy-based lifestyle intervention program for adults with pre-diabetes: a study protocol for a cluster randomised controlled trial.

INTRODUCTION: Pre-diabetes indicates an elevated risk of developing type-2 diabetes and presents a window for preventive actions. The Pre-diabetes Intervention, Management and Evaluation (PRIME) programme is a community pharmacy-based pre-diabetes management programme that uses a mobile application for self-monitoring and pre-diabetes education, aiming to promote lifestyle changes among participants with pre-diabetes. METHODS AND ANALYSIS: This is a protocol for a cluster randomised controlled trial that aims to evaluate the impact of the PRIME programme on participants' clinical outcomes and explore participants' and pharmacists' views towards its implementation. This protocol describes the development of the PRIME programme and mobile app, its feasibility and implementation in community pharmacy settings. 16 pharmacies from two states in Malaysia will be randomised to the intervention arm or standard care. The study will include overweight or obese adults with pre-diabetes. During each follow-up visit at the pharmacy, intervention participants will receive in-depth counselling from pharmacists after reviewing their self-monitoring data recorded in the PRIME app. They will also receive pre-diabetes education through the app and join a peer support chatgroup. The primary clinical outcome includes changes in body weight at 6 months, while the secondary clinical outcomes include changes in blood glucose profile, lipid profile, blood pressure and adiposity measures. The sustainability of the PRIME programme will be accessed using a follow-up questionnaire, while participants' engagement with the intervention will be evaluated using attendance rate and the app data. Focus group discussions and one-to-one interviews will be conducted for process evaluation. This study will inform the impact of community pharmacists-led digital health intervention in pre-diabetes management. ETHICS AND DISSEMINATION: This study has been registered with clinicaltrials.gov (NCT04832984) and approved by the Monash University Human Research Ethics Committee (Project ID: 27512). TRIAL REGISTRATION NUMBER: clinicaltrials.gov (NCT04832984).