Poly(phenylalanine) and poly(3,4-dihydroxy-L-phenylalanine): Promising biomedical materials for building stimuli-responsive nanocarriers.

Cancer is a serious threat to human health because of its high annual mortality rate. It has attracted significant attention in healthcare, and identifying effective strategies for the treatment and relief of cancer pain requires urgency. Drug delivery systems (DDSs) offer the advantages of excellent efficacy, low cost, and low toxicity for targeting drugs to tumor sites. In recent decades, copolymer carriers based on poly(phenylalanine) (PPhe) and poly(3,4-dihydroxy-L-phenylalanine) (PDopa) have been extensively investigated owing to their good biocompatibility, biodegradability, and controllable stimulus responsiveness, which have resulted in DDSs with loading and targeted delivery capabilities. In this review, we introduce the synthesis of PPhe and PDopa, highlighting the latest proposed synthetic routes and comparing the differences in drug delivery between PPhe and PDopa. Subsequently, we summarize the various applications of PPhe and PDopa in nanoscale-targeted DDSs, providing a comprehensive analysis of the drug release behavior based on different stimulus-responsive carriers using these two materials. In the end, we discuss the challenges and prospects of polypeptide-based DDSs in the field of cancer therapy, aiming to promote their further development to meet the growing demands for treatment.

SeeSaw: Learning Soft Tissue Deformation from Laparoscopy Videos with GNNs.

A major challenge in image-guided laparoscopic surgery is that structures of interest often deform and go, even if only momentarily, out of view. Methods which rely on having an up-to-date impression of those structures, such as registration or localisation, are undermined in these circumstances. This is particularly true for soft-tissue structures that continually change shape - in registration, they must often be re-mapped. Furthermore, methods which require 'revisiting' of previously seen areas cannot in principle function reliably in dynamic contexts, drastically weakening their uptake in the operating room. We present a novel approach for learning to estimate the deformed states of previously seen soft tissue surfaces from currently observable regions, using a combined approach that includes a Graph Neural Network (GNN). The training data is based on stereo laparoscopic surgery videos, generated semi-automatically with minimal labelling effort. Trackable segments are first identified using a feature detection algorithm, from which surface meshes are produced using depth estimation and delaunay triangulation. We show the method can predict the displacements of previously visible soft tissue structures connected to currently visible regions with observed displacements, both on our own data and porcine data. Our innovative approach learns to compensate non-rigidity in abdominal endoscopic scenes directly from stereo laparoscopic videos through targeting a new problem formulation, and stands to benefit a variety of target applications in dynamic environments. Project page for this work: https://gitlab.com/nct_tso_public/seesaw-soft-tissue-deformation.

Prognostic assessment of 18F-boronophenylalanine positron emission tomography (BPA-PET) in salvage boron neutron capture therapy for malignant brain tumors.

Background: Boron neutron capture therapy (BNCT) stands out as a propitious anti-cancer modality. 18F-boronophenylalanine positron emission tomography (BPA-PET) holds the potential to ascertain the concentration of BPA within the tumor, enabling meticulous treatment planning and outcome evaluation. However, no studies have been conducted on comparing the outcomes of those treated with BNCT to those who did not undergo this therapy. This study endeavors to analyze the correlation between BPA-PET and BNCT in the context of malignant brain tumors, and assess the survival outcomes following BNCT. Methods: A cohort study was performed on patients who underwent BPA-PET between February 2017 and April 2022 in our hospital. Patients were stratified into two groups: those subjected to BNCT (Group 1) and those not (Group 2). The tumor to normal tissue (T/N) ratio derived from BPA-PET was set at 2.5. The findings were scrutinized based on clinical follow-up. Student's t-test and Chi-squared test were employed to discern differences between the groups. A cumulative survival curve was constructed employing the Kaplan-Meier method. Differences were considered statistically significant at P<0.05. Results: In total, 116 patients with T/N ratios obtained from BPA-PET were enrolled. BNCT was administered to 58 patients, while mortality was observed in 100 patients. The median overall survival (OS) for the two groups was 8.5 and 6.0 months, respectively. The cumulative OS exhibited no significant discrepancy between the two groups, nor in their T/N ratios. Within Group 1, 44 out of 58 (75.9%) patients exhibited T/N ratios exceeding 2.5. Excluding 3 patients who expired within 3 months, 55 out of 58 patients were evaluated for response after BNCT. The objective response rate (ORR) was 30.9%. Patients achieving ORR displayed substantially higher survival rates compared to those without (median OS 13.5 vs. 8.3 months, P=0.0021), particularly when T/N ratio exceeded 2.5 (median OS 14.8 vs. 9.0 months, P=0.0199). Conclusions: BNCT does not appear indispensable for prolonging the survival of patients afflicted with malignant brain tumors. Nevertheless, it proves advantageous when ORR is attained, a condition closely linked to the values of T/N ratio derived from BPA-PET.

Chronic Administration of Red Yeast Rice Mitigates Endothelial Dysfunction in Spontaneously Hypertensive Rats by Inhibiting Oxidative Stress and Endothelial Nitric Oxide Synthase Uncoupling.

BACKGROUND: Hypertension is associated with endothelial dysfunction. An imbalance in the production of Nitric Oxide (NO) and Reactive Oxygen Species (ROS), leading to impaired NO-cyclic Guanosine Monophosphate (cGMP) pathway, contributes to this disorder. Red Yeast Rice (RYR), produced from the fermentation of rice with Monascus purpureus, is a traditional functional food originating from China. Although recognized for its anti-dyslipidemia properties, there has been growing evidence regarding the anti-hypertensive effects of RYR. However, these studies only focused on its direct and short-term effects. AIM: This study aims to investigate the vasoprotective effects of chronic oral RYR administration using Spontaneously Hypertensive Rats (SHR). MATERIALS AND METHODS: SHR were randomly divided into 3 groups: SHR - Control; SHR - RYR extract (100 mg/kg/day); SHR - lovastatin (10 mg/kg/day). Wistar-Kyoto Rats (WKY) were used as normotensive controls. All animals were treated for 12 weeks by oral gavage. Systolic Blood Pressure (SBP) was measured weekly (tail-cuff method). Vascular reactivity was determined using isolated rat aortic rings in an organ bath. Aortic ROS, NO, tetrahydrobiopterin (BH4 ), and cGMP levels were evaluated. RESULTS: Administration of RYR attenuated SBP elevation and enhanced endothelium-dependent vasodilation in aortic rings. In addition, RYR decreased ROS production and significantly improved the level of vascular NO, BH4, and cGMP. CONCLUSION: In an SHR model, treatment with RYR for 12 weeks exerts an SBP lowering effect that can be attributed to improved vascular function via reduction of oxidative stress, decreased endothelial NO Synthase (eNOS) uncoupling and enhanced NO-cGMP pathway.

Scoping review: Exploring the relationship between chrononutrition and glycemic responses in the adult population.

Chrononutrition, an emerging body of evidence on the relationship between biological rhythms and metabolism, has been established to be associated with glycemic responses. However, the available evidence is inconsistent, due to protocol variations. Therefore, this review aims to summarize the findings on chrononutrition characteristics and their association with glycemic responses among adults. Systematic searches were conducted across six databases (PubMed, EBSCO Host, ProQuest Central, MEDLINE & Ovid, Scopus and Web of Science) to identify all relevant studies published from January 2012. Two reviewers independently screened the abstracts and full-text articles based on the inclusion and exclusion criteria. Details about population characteristics, study methods and key findings were extracted following the PRISMA-ScR guideline. The quality of selected studies was evaluated using the mixed methods appraisal tool. The searchers identified 49 studies eligible for analysis. The results showed that meal timing, particularly night-time eating and snacking were associated with glycemic responses. Regarding meal regularity, skipping breakfast may affect glycemic responses, but no clear conclusion was drawn about its effect on insulin. The association between meal frequency and glycemic responses was inconclusive. Night fasting duration and restricted eating window are potentially associated with glycemic responses. The current review extensively investigates the association between chrononutrition factors and glycemic responses in adults. However, more prospective cohort and interventional studies are needed to better understand this causal-effect relationship.

Reservoir-computing based associative memory and itinerancy for complex dynamical attractors.

Traditional neural network models of associative memories were used to store and retrieve static patterns. We develop reservoir-computing based memories for complex dynamical attractors, under two common recalling scenarios in neuropsychology: location-addressable with an index channel and content-addressable without such a channel. We demonstrate that, for location-addressable retrieval, a single reservoir computing machine can memorize a large number of periodic and chaotic attractors, each retrievable with a specific index value. We articulate control strategies to achieve successful switching among the attractors, unveil the mechanism behind failed switching, and uncover various scaling behaviors between the number of stored attractors and the reservoir network size. For content-addressable retrieval, we exploit multistability with cue signals, where the stored attractors coexist in the high-dimensional phase space of the reservoir network. As the length of the cue signal increases through a critical value, a high success rate can be achieved. The work provides foundational insights into developing long-term memories and itinerancy for complex dynamical patterns.

In Situ Growth of Amorphous MnO2 on Graphite Felt via Mild Etching Engineering as a Powerful Catalyst for Advanced Vanadium Redox Flow Batteries.

Owing to the advantages of low cost, high safety, and a desirable cycling lifetime, vanadium redox flow batteries (VRFBs) have attracted great attention in the large-scale energy storage field. However, graphite felts (GFs), widely used as electrode materials, usually possess an inferior catalytic activity for the redox reaction of vanadium ions, largely limiting the energy efficiency and rate performance of VRFBs. Here, an in situ growth of amorphous MnO2 on graphite felt (AMO@GF) was designed for application in VRFBs via mild and rapid etching engineering (5 min). After the etching process, the graphite felt fibers showed a porous and defective surface, contributing to abundant active sites toward the redox reaction. In addition, formed amorphous MnO2 can also serve as a powerful catalyst to facilitate the redox couples of VO2+/VO2+ based on density functional theoretical (DFT) calculations. As a result, the VRFB using AMO@GF displayed an elevated energy efficiency and superior stability after 2400 cycles at 200 mA cm-2, and the maximum current density can reach 300 mA cm-2. Such a high-efficiency and convenient design strategy for the electrode material will drive the further development and industrial application of VRFBs and other flow battery systems.

Evaluating the clinical impact of resuscitative endovascular balloon occlusion of the aorta in patients with blunt trauma with hemorrhagic shock and coexisting traumatic brain injuries: a retrospective cohort study.

BACKGROUND: The impact of resuscitative endovascular balloon occlusion of the aorta (REBOA) on traumatic brain injuries remains uncertain, with potential outcomes ranging from neuroprotection to exacerbation of the injury. The study aimed to evaluate consciousness recovery in patients with blunt trauma with shock and traumatic brain injuries. MATERIAL AND METHODS: Data were obtained from the American College of Surgeons Trauma Quality Improvement Program from 2017-2019. During the study period, 3,138,896 trauma registries were examined, and 16,016 adult patients with blunt trauma, shock, and traumatic brain injuries were included. Among these, 172 (1.1%) underwent REBOA. Comparisons were conducted between patients with and without REBOA after implementing 1:3 propensity score matching to mitigate disparities. The primary outcome was the highest Glasgow Coma Scale score during admission. The secondary outcomes encompassed the volume of blood transfusion, the necessity for hemostatic interventions and therapeutic neurosurgery, and mortality rate. RESULTS: Through well-balanced propensity score matching, a notable difference in mortality rate was observed, with 59.7% in the REBOA group and 48.7% in the non-REBOA group (P=0.015). In the REBOA group, the median 4-hour red blood cell transfusion was significantly higher (2800 mL [1500, 4908] vs. 1300 mL [600, 2500], P<0.001). The REBOA group required lesser hemorrhagic control surgeries (31.8% vs. 47.7%, P<0.001) but needed more transarterial embolization interventions (22.2% vs 15.9%, P=0.076). The incidence of therapeutic neurosurgery was 5.1% in the REBOA group and 8.7% in the non-REBOA group (P=0.168). Among survivors in the REBOA group, the median highest Glasgow Coma Scale score during admission was significantly greater for both total (11 [8, 14] vs. 9 [6, 12], P=0.036) and motor components (6 [4, 6] vs. 5 [3, 6], P=0.037). The highest GCS score among the survivors with predominant pelvic injuries was not different between the two groups (11 [8, 13] vs. 11 [7, 14], P=0.750). CONCLUSIONS: Patients experiencing shock and traumatic brain injury have high mortality rates, necessitating swift resuscitation and prompt hemorrhagic control. The use of REBOA as an adjunct for bridging definitive hemorrhagic control may correlate with enhanced consciousness recovery.

Induction chemotherapy followed by transoral laser microsurgery with or without adjuvant therapy for advanced hypopharyngeal cancer patients: A preliminary result.

BACKGROUND: Hypopharyngeal squamous cell carcinoma (HPSCC) has the poorest prognosis among head and neck cancers. Its treatment may significantly affect breathing, speaking, and swallowing. Induction chemotherapy (ICT) followed by transoral laser microsurgery (TLM) could reduce these adverse effects and achieve good outcomes. METHODS: This was a retrospective study of 11 patients with advanced HPSCC. All patients underwent ICT and TLM alongside tailor-made adjuvant therapy based on the pathological features. RESULTS: Adjuvant therapy was done in 7 out of 11 patients (64%). The 3-year disease-free survival and laryngeal preservation rates were 78% and 91%, respectively. At the last follow-up, 10 out of 11 patients (91%) had no tracheostomy or feeding tube. CONCLUSION: ICT followed by TLM is an appropriate treatment for good tumor control in select patients with advanced HPSCC while preserving laryngeal function.

The impact of ZTE-based MR attenuation correction compared to CT-AC in 18F-FBPA PET before boron neutron capture therapy.

Tumor-to-normal ratio (T/N) measurement of 18F-FBPA is crucial for patient eligibility to receive boron neutron capture therapy. This study aims to compare the difference in standard uptake value ratios on brain tumors and normal brains using PET/MR ZTE and atlas-based attenuation correction with the current standard PET/CT attenuation correction. Regarding the normal brain uptake, the difference was not significant between PET/CT and PET/MR attenuation correction methods. The T/N ratio of PET/CT-AC, PET/MR ZTE-AC and PET/MR AB-AC were 2.34 ± 0.95, 2.29 ± 0.88, and 2.19 ± 0.80, respectively. The T/N ratio comparison showed no significance using PET/CT-AC and PET/MR ZTE-AC. As for the PET/MRI AB-AC, significantly lower T/N ratio was observed (- 5.18 ± 9.52%; p < 0.05). The T/N difference between ZTE-AC and AB-AC was also significant (4.71 ± 5.80%; p < 0.01). Our findings suggested PET/MRI imaging using ZTE-AC provided superior quantification on 18F-FBPA-PET compared to atlas-based AC. Using ZTE-AC on 18F-FBPA-PET /MRI might be crucial for BNCT pre-treatment planning.

Development and evaluation of a deep learning-based model for simultaneous detection and localization of rib and clavicle fractures in trauma patients' chest radiographs.

Purpose: To develop a rib and clavicle fracture detection model for chest radiographs in trauma patients using a deep learning (DL) algorithm. Materials and methods: We retrospectively collected 56 145 chest X-rays (CXRs) from trauma patients in a trauma center between August 2008 and December 2016. A rib/clavicle fracture detection DL algorithm was trained using this data set with 991 (1.8%) images labeled by experts with fracture site locations. The algorithm was tested on independently collected 300 CXRs in 2017. An external test set was also collected from hospitalized trauma patients in a regional hospital for evaluation. The receiver operating characteristic curve with area under the curve (AUC), accuracy, sensitivity, specificity, precision, and negative predictive value of the model on each test set was evaluated. The prediction probability on the images was visualized as heatmaps. Results: The trained DL model achieved an AUC of 0.912 (95% CI 87.8 to 94.7) on the independent test set. The accuracy, sensitivity, and specificity on the given cut-off value are 83.7, 86.8, and 80.4, respectively. On the external test set, the model had a sensitivity of 88.0 and an accuracy of 72.5. While the model exhibited a slight decrease in accuracy on the external test set, it maintained its sensitivity in detecting fractures. Conclusion: The algorithm detects rib and clavicle fractures concomitantly in the CXR of trauma patients with high accuracy in locating lesions through heatmap visualization.

Miniaturized Implantable Fluorescence Probes Integrated with Metal-Organic Frameworks for Deep Brain Dopamine Sensing.

Continuously monitoring neurotransmitter dynamics can offer profound insights into neural mechanisms and the etiology of neurological diseases. Here, we present a miniaturized implantable fluorescence probe integrated with metal-organic frameworks (MOFs) for deep brain dopamine sensing. The probe is assembled from physically thinned light-emitting diodes (LEDs) and phototransistors, along with functional surface coatings, resulting in a total thickness of 120 µm. A fluorescent MOF that specifically binds dopamine is introduced, enabling a highly sensitive dopamine measurement with a detection limit of 79.9 nM. A compact wireless circuit weighing only 0.85 g is also developed and interfaced with the probe, which was later applied to continuously monitor real-time dopamine levels during deep brain stimulation in rats, providing critical information on neurotransmitter dynamics. Cytotoxicity tests and immunofluorescence analysis further suggest a favorable biocompatibility of the probe for implantable applications. This work presents fundamental principles and techniques for integrating fluorescent MOFs and flexible electronics for brain-computer interfaces and may provide more customized platforms for applications in neuroscience, disease tracing, and smart diagnostics.

CD177 drives the transendothelial migration of Treg cells enriched in human colorectal cancer.

Objectives: Regulatory T (Treg) cells regulate immunity in autoimmune diseases and cancers. However, immunotherapies that target tumor-infiltrating Treg cells often induce unwanted immune responses and tissue inflammation. Our research focussed on exploring the expression pattern of CD177 in tumor-infiltrating Treg cells with the aim of identifying a potential target that can enhance immunotherapy effectiveness. Methods: Single-cell RNA sequencing (scRNA-seq) data and survival data were obtained from public databases. Twenty-one colorectal cancer patient samples, including fresh tumor tissues, peritumoral tissues and peripheral blood mononuclear cells (PBMCs), were analysed using flow cytometry. The transendothelial activity of CD177+ Treg cells was substantiated using in vitro experiments. Results: ScRNA-seq and flow cytometry results indicated that CD177 was exclusively expressed in intratumoral Treg cells. CD177+ Treg cells exhibited greater activation status and expressed elevated Treg cell canonical markers and immune checkpoint molecules than CD177- Treg cells. We further discovered that both intratumoral CD177+ Treg cells and CD177-overexpressing induced Treg (iTreg) cells had lower levels of PD-1 than their CD177- counterparts. Moreover, CD177 overexpression significantly enhanced the transendothelial migration of Treg cells in vitro. Conclusions: These results demonstrated that Treg cells with higher CD177 levels exhibited an enhanced activation status and transendothelial migration capacity. Our findings suggest that CD177 may serve as an immunotherapeutic target and that overexpression of CD177 may improve the efficacy of chimeric antigen receptor T (CAR-T) cell therapy.

Deep-learning reconstruction of complex dynamical networks from incomplete data.

Reconstructing complex networks and predicting the dynamics are particularly challenging in real-world applications because the available information and data are incomplete. We develop a unified collaborative deep-learning framework consisting of three modules: network inference, state estimation, and dynamical learning. The complete network structure is first inferred and the states of the unobserved nodes are estimated, based on which the dynamical learning module is activated to determine the dynamical evolution rules. An alternating parameter updating strategy is deployed to improve the inference and prediction accuracy. Our framework outperforms baseline methods for synthetic and empirical networks hosting a variety of dynamical processes. A reciprocity emerges between network inference and dynamical prediction: better inference of network structure improves the accuracy of dynamical prediction, and vice versa. We demonstrate the superior performance of our framework on an influenza dataset consisting of 37 US States and a PM2.5 dataset covering 184 cities in China.

Enhancing regional control in p16-negative oropharyngeal cancer: A propensity score-matched analysis of upfront neck dissection and definitive chemoradiotherapy.

BACKGROUND: The presence of p16 and neck disease is important predictors of prognosis for oropharyngeal squamous cell carcinoma (OPSCC). Patients who are p16-negative and have clinically node-positive (cN+) disease generally have worse oncologic outcomes. This study aimed to investigate whether upfront neck dissection (UFND) could provide potential benefits for patients with cN+ p16-negative OPSCC. METHODS: Through this retrospective study, 76 patients with cN+ p16-negative OPSCC were analyzed, those who received either definite concurrent chemoradiotherapy (CCRT group) or UFND followed by chemoradiotherapy (UFND group). The primary endpoints were regional recurrence-free survival (RRFS), disease-specific survival (DSS), and overall survival (OS). Factors associated with survival were evaluated by univariate and multivariate analysis. Survival between the two groups was compared by propensity score-matched analysis. RESULTS: Matched 23 patients in each group through propensity analysis, the UFND group showed a significantly better 5-year RRFS (94.1% vs 61.0%, p = 0.011) compared to the CCRT group. Univariate analysis revealed that UFND was the sole factor associated with regional control (hazard ratio [HR] = 0.110; 95% CI, 0.014-0.879; p = 0.037). Furthermore, the study found that the CCRT group was associated with a higher dose of radiotherapy and exhibited a significantly higher risk of mortality due to pneumonia. CONCLUSION: The study indicated that UFND followed by CCRT may be a potential treatment option for patients with cN+ p16-negative OPSCC, as it can reduce the risk of regional recurrence. Additionally, the study highlights that definite CCRT is connected to a larger dose of radiotherapy and a higher risk of fatal pneumonia. These findings could be beneficial in informing clinical decision-making and improving treatment outcomes for patients with OPSCC.

Sirt6 promotes DNA damage repair in osteoarthritis chondrocytes by activating the Keap1/Nrf2/HO-1 signaling pathway.

The aim of this study was to explore the effect and mechanism of Sirt6 on DNA damage repair in OA chondrocytes. Cartilage tissues were collected from OA patients with knee arthroplasty and traumatic amputation patients without OA. Besides, 7-week-old male C57BL/6 mice were randomly divided into Control and OA groups; CHON-001 cells of corresponding groups were treated with 10 ng/ml interleukin (IL)-1ß, respectively. Subsequently, Sirt6 or siNrf2 was over-expressed in CHON-001 cells to observe the effect of Sirt6 on DNA damage and senescence of chondrocytes by IL-1ß through the nuclear factor E2-related factor 2 (Nrf2) signaling pathway. The expression level of Sirt6 in human and mouse OA cartilage tissues was significantly decreased. However, 24 h of treatment with IL-1ß significantly decreased the expression of Sirt6 in chondrocytes, induced DNA damage, and promoted cellular senescence. In addition, over-expression of Sirt6 promoted DNA damage repair and inhibited cellular senescence in IL-1ß-induced chondrocytes. Moreover, the overexpression of Sirt6 activated the Keap1/Nrf2/HO-1 signaling pathway in chondrocytes, while knockdown of Nrf2 expression inhibited the DNA damage repair and anti-senescence effects of Sirt6 on IL-1ß-treated chondrocytes. Sirt6 may reduce DNA damage and cellular senescence in OA chondrocytes induced by IL-1ß through activating the Keap1/Nrf2/HO-1 signaling pathway.

Effect of phosphoric acid additive on the electrolyte of all-vanadium flow batteries.

A phosphoric acid additive with an optimal concentration of 0.1 M can vastly promote the diffusion kinetics of the redox reaction between V(IV) and V(V) without a significant decline in energy efficiency for 300 cycles, and maintain the high-temperature stability (55 °C) of an electrolyte at a high state of charge (SOC) of 70% over the course of 30 days.

Higher early pregnancy plasma myo-inositol associates with increased postprandial glycaemia later in pregnancy: Secondary analyses of the NiPPeR randomized controlled trial.

AIM: Myo-inositol supplementation from ~13 weeks' gestation reportedly improves glycaemia regulation in metabolically at-risk women, with speculation that earlier supplementation might bring further improvement. However, the NiPPeR trial of a myo-inositol-containing supplement starting preconception did not lower gestational glycaemia in generally healthy women. We postulated that the earlier timing of supplementation influences the maternal metabolic adaptation for gestational glycaemia regulation. METHODS: In total, 585 women were recruited from Singapore, UK and New Zealand for the NiPPeR study. We examined associations of plasma myo-inositol concentrations at 7 and 28 weeks' gestation with 28 weeks plasma glucose (PG; fasting, and 1 h and 2 h in 75 g oral glucose tolerance test) and insulin indices using linear regression adjusting for covariates. RESULTS: Higher 7-week myo-inositol, but not 28-week myo-inositol, associated with higher 1 h PG [ßadj (95% confidence intervals) 0.05 (0.01, 0.09) loge mmol/L per loge µmol/L, p = .022] and 2 h PG [0.08 (0.03, 0.12), p = .001]; equivalent to 0.39 mmol/L increase in 2 h PG for an average 7-week myo-inositol increase of 23.4 µmol/L with myo-inositol supplementation. Higher 7-week myo-inositol associated with a lower 28-week Stumvoll index (first phase), an approximation of insulin secretion [-0.08 (-0.15, -0.01), p = .020] but not with 28-week Matsuda insulin sensitivity index. However, the clinical significance of a 7-week myo-inositol-related increase in glycaemia was limited as there was no association with gestational diabetes risk, birthweight and cord C-peptide levels. In-silico modelling found higher 28-week myo-inositol was associated with lower gestational glycaemia in White, but not Asian, women after controlling for 7-week myo-inositol effects. CONCLUSION: To our knowledge, our study provides the first evidence that increasing first trimester plasma myo-inositol may slightly exacerbate later pregnancy post-challenge glycaemia, indicating that the optimal timing for starting prenatal myo-inositol supplementation needs further investigation.

A phase 4 multicentre, 2×2 factorial randomised, double-blind, placebo-controlled trial to investigate the efficacy and safety of tobramycin inhalation solution for Pseudomonas aeruginosa eradication in bronchiectasis: ERASE.

Chronic Pseudomonas aeruginosa (PA) infection significantly contributes to morbidity and mortality in bronchiectasis patients. Initiating antibiotics early may lead to the eradication of PA. Here we outline the design of a trial (ERASE; NCT06093191) assessing the efficacy and safety of inhaled tobramycin, alone or with oral ciprofloxacin, in bronchiectasis patients with a new isolation of PA. This multicentre, 2×2 factorial randomised, double-blind, placebo-controlled, parallel-group trial includes a 2-week screening period, a 12-week treatment phase (with a combination of ciprofloxacin or a placebo at initial 2 weeks) and a 24-week follow-up. 364 adults with bronchiectasis and a new PA isolation will be randomly assigned to one of four groups: placebo (inhaled saline and ciprofloxacin placebo twice daily), ciprofloxacin alone (750 mg ciprofloxacin and inhaled saline twice daily), inhaled tobramycin alone (inhaled 300 mg tobramycin and ciprofloxacin placebo twice daily) or a combination of both drugs (inhaled 300 mg tobramycin and 750 mg ciprofloxacin twice daily). The primary objective of this study is to assess the proportion of patients successfully eradicating PA in each group by the end of the study. Efficacy will be evaluated based on the eradication rate of PA at other time points (12, 24 and 36 weeks), the occurrence of exacerbations and hospitalisations, time to first pulmonary exacerbations, patient-reported outcomes, symptom measures, pulmonary function tests and the cost of hospitalisations. To date no randomised trial has evaluated the benefit of different PA eradication strategies in bronchiectasis patients. The ERASE trial will therefore generate crucial data to inform future clinical guidelines.