HBV reactivation in HBsAg-/HBcAb+ rheumatoid arthritis patients receiving biologic/targeted synthetic DMARDs.

BACKGROUND: Rheumatoid arthritis (RA) patients seropositive for hepatitis B core antibody (HBcAb) and negative for hepatitis B surface antigen (HBsAg) are at risk of hepatitis B virus (HBV) reactivation when treated with biologic or targeted synthetic (b/ts) disease-modifying antirheumatic drugs (DMARDs). The study aims to investigate the risk in this population. METHODS: From January 2004 through December 2020, 1068 RA patients undergoing b/tsDMARDs therapy and 416 patients with HBsAg-/HBcAb+ were enrolled. Factors associated with HBV reactivation were analysed. RESULTS: During 2845 person-years of follow-up, 27 of 416 (6.5%,9.5 per 1000 person-years) patients developed HBV reactivation, with a cumulative rate of HBV reactivation of 3.5% at 5 years, 6.1% at 10 years and 24.2% at 17 years. The median interval from beginning b/tsDMARDs to HBV reactivation was 85 months (range: 9-186 months). The risk of HBV reactivation varied by type of b/tsDMARD, with rituximab having the highest risk (incidence rate: 48.3 per 1000 person-years), followed by abatacept (incidence rate: 24.0 per 1000 person-years). In multivariate analysis, rituximab (adjusted hazard ratio [aHR]: 15.77, 95% confidence interval [CI]: 4.12-60.32, p = .001), abatacept (aHR: 9.30, 1.83-47.19, p = .007), adalimumab (aHR: 3.86, 1.05-14.26, p = .04) and negative baseline HBV surface antibody (anti-HBs, <10 mIU/mL) (aHR: 3.89, 1.70-8.92, p < .001) were independent risk factors for HBV reactivation. CONCLUSION: HBsAg-/HBcAb+ RA patients are susceptible to HBV reactivation during b/tsDMARD therapy. Those with negative baseline anti-HBs and those on certain b/tsDMARDs, such as rituximab, abatacept and adalimumab, have high reactivation risks. Risk stratification and management should be based on the patient's baseline anti-HBs titre and type of therapy.

Performance of Prehospital ECG and Impact on Prehospital Service Time: Comparison between EMT-II and EMT-P Teams.

Background: Prehospital electrocardiogram (PHECG) shortens door-to-balloon time in patients with ST-elevation myocardial infarction. However, it may increase the prehospital service time, thus offsetting the benefits gained. The performance of PHECG could be influenced by the proficiency of the emergency medical technicians (EMTs). Objectives: To investigate whether there are differences in the performance of PHECG between EMT-II and EMT-paramedics (EMT-P). Methods: This prospectively designed, retrospectively analyzed study of PHECG was conducted in Taipei from February 2019 to April 2021. Comparisons were made between EMT-II and EMT-P teams. The primary outcomes were the acceptance of PHECG suggestions and prehospital service time. The secondary outcomes were gender disparities in the primary outcomes. Results: A total of 2,991 patients were included, of whom 2,617 received PHECG. For the primary outcomes, the acceptance of PHECG was higher in those approached by EMT-P (99.6% vs. 71.5%, p < 0.001). The scene time and scene-to-hospital time showed no significant differences. For gender disparities, the acceptance of PHECG in female patients was significantly lower in those approached by EMT-II (59.3% vs. 99.2%, p < 0.001). The scene time and scene-to-hospital time were generally longer in the female patients, especially in the younger and middle age groups. Compared to EMT-P, both were significantly longer in the female patients approached by EMT-II. Conclusions: The acceptance of PHECG was lower in those approached by EMT-II, especially in females. Although there were generally no significant differences between EMT-II and EMT-P, the scene time and scene-to-hospital time were significantly longer in female patients, especially in those aged < 75 years approached by EMT-II.

A pervasive phosphorylation cascade modulation of plant transcription factors in response to abiotic stress.

MAIN CONCLUSION: Transcriptional regulation of stress-responsive genes is a crucial step in establishing the mechanisms behind plant abiotic stress tolerance. A sensitive method of regulating transcription factors activity, stability, protein interaction, and subcellular localization is through phosphorylation. This review highlights a widespread regulation mechanism that involves phosphorylation of plant TFs in response to abiotic stress. Abiotic stress is one of the main components limiting crop yield and sustainability on a global scale. It greatly reduces the land area that is planted and lowers crop production globally. In all living organisms, transcription factors (TFs) play a crucial role in regulating gene expression. They participate in cell signaling, cell cycle, development, and plant stress response. Plant resilience to diverse abiotic stressors is largely influenced by TFs. Transcription factors modulate gene expression by binding to their target gene's cis-elements, which are impacted by genomic characteristics, DNA structure, and TF interconnections. In this review, we focus on the six major TFs implicated in abiotic stress tolerance, namely, DREB, bZIP, WRKY, ABF, MYB, and NAC, and the cruciality of phosphorylation of these transcription factors in abiotic stress signaling, as protein phosphorylation has emerged as one of the key post-translational modifications, playing a critical role in cell signaling, DNA amplification, gene expression and differentiation, and modification of other biological configurations. These TFs have been discovered after extensive study as stress-responsive transcription factors which may be major targets for crop development and important contributors to stress tolerance and crop production.

Increased frequency of hospital admissions with active systemic lupus erythematosus disease activity defined by two different disease activity indices: A cohort study.

The objective of this cohort study was to evaluate the association between the frequency of hospital admissions and disease activity, as defined by two different disease activity measurements: the Systemic Lupus Erythematosus Disease Activity Score (SLE-DAS) and the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K), in adult patients with systemic lupus erythematosus (SLEs). Patients with SLE were recruited from the rheumatology outpatient department of a regional hospital in southern Taiwan. SLE-DAS and SLEDAI-2K were used to define SLE disease activity and the cause of hospital admissions was identified by a rheumatologist based on medical records. A generalized linear model (GLM) with gamma distribution and log-linked function was used to analyze variables associated with the frequency of admission. The mean frequency of hospitalization was 0.34 times per year for all-cause and 0.21 times per year for SLE-related admission. Multivariate GLM analysis showed that moderate/severe SLE disease activity defined by SLE-DAS was associated with an increased frequency of all-cause and SLE-related hospital admissions while adjusting for other covariates. Moderate/severe SLE disease activity defined by SLEDAI-2K was only significantly associated with an increased frequency of all-cause hospitalization. When steroid dosage was included in the model, moderate/severe SLE disease activity defined by the SLE-DAS remained significantly associated with SLE-related hospital admissions (p = 0.032). In conclusion, disease activity defined by the SLE-DAS, but not SLEDAI-2K was associated with an increased frequency of SLE-related hospitalization. Steroid dosage, a lower educational level, and smoking were associated with an increased frequency of hospital admissions, whereas underweight and alcohol use were associated with a decreased frequency of hospital admissions. Rheumatologists should promptly control SLE disease activity of their patients, provide them with adequate health education, and maintain steroid doses to as low as possible to reduce the risk of hospital admissions.

Increased risk of hospital admissions in patients with active systemic lupus erythematosus (SLE) classified according to two different SLE disease activity indices: a prospective cohort study.

OBJECTIVES: The aim of this prospective cohort study was to investigate the risk of hospital admissions within one year in patients with active systemic lupus erythematosus (SLE), classified according to the Systemic Lupus Erythematosus Disease Activity Score (SLE-DAS) or the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K). METHODS: This study was conducted in adult patients with SLE recruited from the rheumatology outpatient department in a regional hospital in southern Taiwan. SLE disease activity was measured with SLE-DAS and SLEDAI-2K. The computerised patient record database was accessed to identify patients' hospital admissions. Cox regression analyses were used to estimate the hazard ratio (HR) for all-cause and SLE-related hospital admission in SLE patients classified by SLE-DAS and SLEDAI-2K. RESULTS: A total of 326 adult patients with SLE completed this study. All-cause and SLE-related hospital admissions within one year occurred in 17.5% and 12.6% of the patients, respectively. Results of the Cox regression analysis indicated that SLE patients with moderate/severe disease activity classified by the SLE-DAS (HR=2.43, p=0.005) but not moderate/severe disease activity classified by the SLEDAI-2K (HR=1.84, p=0.057) was significantly associated with the risk of SLE-related admissions. However, only moderate/severe disease activity classified by the SLE-DAS was significantly associated with the risk of all-cause admissions (HR=1.94, p=0.016). When steroid dosage was considered, only the steroid dosage was significantly associated all-cause and SLE-related admissions. CONCLUSIONS: In this study, SLE disease activity classified by SLE-DAS was significantly associated with an increased risk for both all-cause and SLE-related hospital admissions. Rheumatologists should be vigilant for increased risk of hospital admissions in patients with moderate/high SLE disease activity as classified by SLE-DAS.

Enhancing optical characteristics of mediator-assisted wafer-scale MoS2and WS2on h-BN.

Two-dimensional (2D) materials and their heterostructures exhibit intriguing optoelectronic properties; thus, they are good platforms for exploring fundamental research and further facilitating real device applications. The key is to preserve the high quality and intrinsic properties of 2D materials and their heterojunction interface even in production scale during the transfer and assembly process so as to apply in semiconductor manufacturing field. In this study, we successfully adopted a wet transfer existing method to separate mediator-assisted wafer-scale from SiO2/Si growing wafer for the first time with intermediate annealing to fabricate wafer-scale MoS2/h-BN and WS2/h-BN heterostructures on a SiO2/Si wafer. Interestingly, the high-quality wafer-scale 2D material heterostructure optical properties were enhanced and confirmed by Raman and photoluminescence spectroscopy. Our approach can be applied to other 2D materials and expedite mass production for industrial applications.

PREDICTING VISUAL OUTCOME AFTER SURGERY IN PATIENTS WITH IDIOPATHIC EPIRETINAL MEMBRANE USING A NOVEL CONVOLUTIONAL NEURAL NETWORK.

PURPOSE: To develop a deep convolutional neural network that enables the prediction of postoperative visual outcomes after epiretinal membrane surgery based on preoperative optical coherence tomography images and clinical parameters to refine surgical decision making. METHODS: A total of 529 patients with idiopathic epiretinal membrane who underwent standard vitrectomy with epiretinal membrane peeling surgery by two surgeons between January 1, 2014, and June 1, 2020, were enrolled. The newly developed Heterogeneous Data Fusion Net was introduced to predict postoperative visual acuity outcomes (improvement ≥2 lines in Snellen chart) 12 months after surgery based on preoperative cross-sectional optical coherence tomography images and clinical factors, including age, sex, and preoperative visual acuity. The predictive accuracy, sensitivity, specificity, and area under the receiver operating characteristic curve of the convolutional neural network model were evaluated. RESULTS: The developed model demonstrated an overall accuracy for visual outcome prediction of 88.68% (95% CI, 79.0%-95.7%) with an area under the receiver operating characteristic curve of 97.8% (95% CI, 86.8%-98.0%), sensitivity of 87.0% (95% CI, 67.9%-95.5%), specificity of 92.9% (95% CI, 77.4%-98.0%), precision of 0.909, recall of 0.870, and F1 score of 0.889. The heatmaps identified the critical area for prediction as the ellipsoid zone of photoreceptors and the superficial retina, which was subjected to tangential traction of the proliferative membrane. CONCLUSION: The novel Heterogeneous Data Fusion Net demonstrated high accuracy in the automated prediction of visual outcomes after weighing and leveraging multiple clinical parameters, including optical coherence tomography images. This approach may be helpful in establishing personalized therapeutic strategies for epiretinal membrane management.

Increased Expression of Long Noncoding RNA LOC100506314 in T cells from Patients with Nonsegmental Vitiligo and Its Contribution to Vitiligo Pathogenesis.

This study aimed to identify the abnormal expression of long noncoding RNAs (lncRNAs) in T cells from patients with vitiligo and to investigate their functional roles in the immune system. Using microarray analysis, the expression levels of RNA transcripts in T cells from patients with vitiligo and controls were compared. We identified several genes and validated their expression levels in T cells from 41 vitiligo patients and 41 controls. The biological functions of the lncRNAs were studied in a transfection study using an RNA pull-down assay, followed by proteomic analysis and western blotting. The expression levels of 134 genes were significantly increased, and those of 142 genes were significantly decreased in T cells from vitiligo patients. After validation, six genes had increased expression, and three genes had decreased expression in T cells from patients with vitiligo. T-cell expression of LOC100506314 was increased in vitiligo, especially CD4+, but not CD8+ T cells. The expression levels of LOC100506314 in CD4+ T cells was positively and significantly associated with the severity of vitiligo. LOC100506314 was bound to the signal transducer and activator of transcription 3 (STAT3) and macrophage migration inhibitory factor (MIF). Enhanced expression of LOC100506314 inhibited the phosphorylation of STAT3, protein kinase B (AKT), and extracellular signal-regulated protein kinases (ERK), as well as the levels of nuclear protein of p65 and the expression of IL-6 and IL-17 in Jurkat cells and T cells from patients with vitiligo. In conclusion, this study showed that the expression of LOC100506314 was elevated in CD4+ T cells from patients with vitiligo and associated the severity of vitiligo. LOC100506314 interacted with STAT3 and MIF and inhibited IL-6 and IL-17 expression by suppressing the STAT3, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), AKT, and ERK pathways. Enhanced expression of LOC100506314 in T cells may be a potential treatment strategy for vitiligo.

Revealing the Structural Organization of Gamma-irradiated Starch Granules Using Polarization-resolved Second Harmonic Generation Microscopy.

Starch is a semi-crystalline macromolecule with the presence of amorphous and crystalline components. The amorphous amylose and crystalline amylopectin regions in starch granules are susceptible to certain physical modifications, such as gamma irradiation. Polarization-resolved second harmonic generation (P-SHG) microscopy in conjunction with SHG-circular dichroism (CD) was used to assess the three-dimensional molecular order and inherent chirality of starch granules and their reaction to different dosages of gamma irradiation. For the first time, the relationship between starch achirality (χ21/χ16 and χ22/χ16) and chirality (χ14/χ16) determining susceptibility tensor ratios has been elucidated. The results showed that changes in the structure and orientation of long-chain amylopectin were supported by the decrease in the SHG anisotropy factor and the χ22/χ16 ratio. Furthermore, SHG-CD illustrated the molecular tilt angle by revealing the arrangement of amylopectin molecules pointing either upward or downward owing to molecular polarity.

Neuroimaging of Dopamine Transporter Density in the Striatum of Disordered Gamblers.

The aim of the present research was to add to the growing literature on dopamine and gambling disorder (GD) by assessing whether GD is associated with dopamine transporter (DAT) density in the ventral striatum compared to healthy controls and whether DAT density was associated with key characteristics of GD (e.g., abstinence, craving). In a cross-sectional investigation using single-photon emission computed tomography with a technetium-99m-labeled tropane derivative as a radiotracer with SPECT imaging, fifteen participants with GD and 15 controls (non-gambling individuals, matched for age, gender, handedness, and smoking status) were measured. The GD group completed self-reported questionnaires regarding gambling. Striatal DAT density did not differ between the two groups. Conversely, striatal DAT density correlated significantly with various measures of recent gambling, but not with measures of chronic gambling. Multivariate analysis, adjusted for age and smoking status, showed that DAT density in the left striatum correlated positively with time spent gambling and gambling craving in the last month, whereas DAT density in the right striatum correlated negatively with abstinence self-efficacy. The results suggests that DAT density in the striatum is associated with recent gambling activity and gambling expectation.

A Near-Optimal Energy Management Mechanism Considering QoS and Fairness Requirements in Tree Structure Wireless Sensor Networks.

The rapid development of AIOT-related technologies has revolutionized various industries. The advantage of such real-time sensing, low costs, small sizes, and easy deployment makes extensive use of wireless sensor networks in various fields. However, due to the wireless transmission of data, and limited built-in power supply, controlling energy consumption and making the application of the sensor network more efficient is still an urgent problem to be solved in practice. In this study, we construct this problem as a tree structure wireless sensor network mathematical model, which mainly considers the QoS and fairness requirements. This study determines the probability of sensor activity, transmission distance, and transmission of the packet size, and thereby minimizes energy consumption. The Lagrangian Relaxation method is used to find the optimal solution with the lowest energy consumption while maintaining the network's transmission efficiency. The experimental results confirm that the decision-making speed and energy consumption can be effectively improved.

Identification of New Antiseizure Medication Candidates in Preclinical Animal Studies.

Epilepsy is a multifactorial neurologic disease that often leads to many devastating disabilities and an enormous burden on the healthcare system. Until now, drug-resistant epilepsy has presented a major challenge for approximately 30% of the epileptic population. The present article summarizes the validated rodent models of seizures employed in pharmacological researches and comprehensively reviews updated advances of novel antiseizure candidates in the preclinical phase. Newly discovered compounds that demonstrate antiseizure efficacy in preclinical trials will be discussed in the review. It is inspiring that several candidates exert promising antiseizure activities in drug-resistant seizure models. The representative compounds consist of derivatives of hybrid compounds that integrate multiple approved antiseizure medications, novel positive allosteric modulators targeting subtype-selective γ-Aminobutyric acid type A receptors, and a derivative of cinnamamide. Although the precise molecular mechanism, pharmacokinetic properties, and safety are not yet fully clear in every novel antiseizure candidate, the adapted approaches to design novel antiseizure medications provide new insights to overcome drug-resistant epilepsy.

Opioid-Modulated Receptor Localization and Erk1/2 Phosphorylation in Cells Coexpressing µ-Opioid and Nociceptin Receptors.

We attempted to examine the alterations elicited by opioids via coexpressed µ-opioid (MOP) and nociceptin/orphanin FQ (NOP) receptors for receptor localization and Erk1/2 (p44/42 MAPK) in human embryonic kidney (HEK) 293 cells. Through two-photon microscopy, the proximity of MOP and NOP receptors was verified by fluorescence resonance energy transfer (FRET), and morphine but not buprenorphine facilitated the process of MOP-NOP heterodimerization. Single-particle tracking (SPT) further revealed that morphine or buprenorphine hindered the movement of the MOP-NOP heterodimers. After exposure to morphine or buprenorphine, receptor localization on lipid rafts was detected by immunocytochemistry, and phosphorylation of Erk1/2 was determined by immunoblotting in HEK 293 cells expressing MOP, NOP, or MOP+NOP receptors. Colocalization of MOP and NOP on lipid rafts was enhanced by morphine but not buprenorphine. Morphine stimulated the phosphorylation of Erk1/2 with a similar potency in HEK 293 cells expressing MOP and MOP+NOP receptors, but buprenorphine appeared to activate Erk1/2 solely through NOP receptors. Our results suggest that opioids can fine-tune the cellular localization of opioid receptors and phosphorylation of Erk1/2 in MOP+NOP-expressing cells.

Effects of a walking exercise programme on disease activity, sleep quality, and quality of life in systemic lupus erythematosus patients.

AIM: This quasi-experimental study aimed to explore effects of walking exercise on disease activity, sleep quality, and quality of life among individuals with systemic lupus erythematosus. METHODS: After recruiting people with systemic lupus erythematosus from a hospital in Taiwan between October 2020 and June 2021, participants were free to opt to receive one walking exercise programme plus standard care for 3 months or to membership of a control group receiving routine care. Primary outcomes included Systemic Lupus Erythematosus Disease Activity Score, the Pittsburgh Sleep Quality Scale, and a quality-of-life scale for patients with systemic lupus erythematosus, namely, LupusQoL. These scales were administered first, at baseline and later, within 1 week following completion of the intervention. Between-group effects were compared using generalized estimating equations with adjustment for baseline variables. RESULTS: The experimental and control groups each included 40 participants. Multivariate analysis indicated that adding the walking exercise programme into routine care elevated sleep quality and LupusQoL (the latter in the subscales of physical health, planning, and intimate relationships), except for disease activity. CONCLUSION: Findings of this study supported the addition of walking exercise as part of routine care for people with systemic lupus erythematosus and may be a reference in the provision of adequate care for these patients.

Rheumatic Diseases: New Progress in Clinical Research and Pathogenesis.

Rheumatic diseases encompass a group of disorders that primarily target the musculoskeletal system, including joints, bones, muscles, and connective tissue [...].

Performance of a New Instrument for the Measurement of Systemic Lupus Erythematosus Disease Activity: The SLE-DAS.

Systemic lupus erythematosus (SLE) is a chronic systemic autoimmune disease that affects multiple organ systems and manifests in a relapsing-remitting pattern. Consequently, it is paramount for rheumatologists to assess disease activity, identify flare-ups, and establish treatment goals for patients with SLE. In 2019, the Systemic Lupus Erythematosus Disease Activity Score (SLE-DAS) was introduced as a novel tool for measuring disease activity. This tool refines the parameters of the established SLE Disease Activity Index 2000 (SLEDAI-2K) to enhance the assessment process. This review aims to provide an introduction to the Systemic Lupus Erythematosus Disease Activity Score (SLE-DAS) and summarizes research on its development, its comparison with existing disease activity measures, and its performance in clinical settings. Literature searches on PubMed using the keyword "SLE-DAS" were conducted, covering publications from March 2019 to September 2023. Studies that compared SLE-DAS with other SLE disease activity measurement tools were reviewed. Findings indicated that SLE-DAS consistently performs on par with, and sometimes better than, traditional measures in assessing clinically meaningful changes, patient improvement, disease activity, health-related quality of life, hospitalization rates, and disease flare-ups. The association between SLE-DAS and mortality rates among patients with SLE, however, remains to be further explored. Although SLE-DAS is a promising and potentially effective tool for measuring SLE disease activity, additional research is needed to confirm its effectiveness and broaden its clinical use.

Relationship between Chinese Herbal Medicine Use and Risk of Sjögren's Syndrome in Patients with Rheumatoid Arthritis: A Retrospective, Population-Based, Nested Case-Control Study.

Background and Objectives: Sjögren's Syndrome (SS) is a common extra-articular feature among subjects with rheumatoid arthritis (RA). While Chinese herbal medicine (CHM) has been used to treat symptoms of RA for many years, few studies have examined its efficacy in guarding against the SS onset. This study aimed to compare risk of SS for RA patients with and without use of CHM. Materials and Methods: Data obtained for this nested case-control study were retrieved from Taiwanese nationwide insurance database from 2000-2013. Cases with SS claims were defined and matched to two randomly selected controls without SS from the recruited RA cohorts. Risk of SS in relation to CHM use was estimated by fitting multiple conditional logistic regression. Results: Patients aged between 20 and 80 years were included and 916 patients with incident SS were matched to 1832 non-SS controls by age, sex and index year. Among them, 28.1% and 48.4% cases ever received CHM therapy, respectively. After adjusting for baseline characteristics, CHM use was found to be related to a lower risk of SS among them (adjusted odds ratio = 0.40, 95% confidence interval: 0.34-0.47). A dose-dependent, reverse association, was further detected between the cumulative duration of CHM use and SS risk. Those receiving CHM therapy for more than 730 days showed a significantly reduced risk of SS by 83%. Conclusions: Findings of this study indicated that the add-on CHM formula, as part of RA care, may be a beneficial treatment for prevention against the incident SS.

Underestimated Subsequent Sensorineural Hearing Loss after Septicemia.

Background and Objectives: Hearing loss after septicemia has been found in mice; the long-term risk increased 50-fold in young adults in a previous study. Hearing loss after septicemia has not received much attention. The aim of this study was to assess the relationship between septicemia and subsequent hearing loss. Materials and Methods: Inpatient data were obtained from the Taiwan Insurance Database. We defined patients with sensorineural hearing loss and excluded patients under 18 years of age. Patients without hearing loss were selected as controls at a frequency of 1:5. The date of admission was defined as the date of diagnosis. Comorbidities in the 3 years preceding the date of diagnosis were retrieved retrospectively. Associations with hearing loss were established by multiple logistic regression and forward stepwise selection. Results: The odds ratio (OR) for the association between sepsis and hearing loss was 3.052 (95% CI: 1.583-5.884). Autoimmune disease (OR: 5.828 (95% CI: 1.906-17.816)), brain injury (OR: 2.264 (95% CI: 1.212-4.229)) and ischemic stroke (OR: 1.47 (95% CI: 1.087-1.988)) were associated with hearing loss. Conclusions: Our study shows that hearing loss occurred after septicemia. Apoptosis caused by sepsis and ischemia can lead to hair cell damage, leading to hearing loss. Clinicians should be aware of possible subsequent complications of septicemia and provide appropriate treatment and prevention strategies for complications.

Efficacy and safety of inhaled ENaC inhibitor BI 1265162 in patients with cystic fibrosis: BALANCE-CF 1, a randomised, phase II study.

BACKGROUND: Inhibition of the epithelial sodium channel (ENaC) in cystic fibrosis (CF) airways provides a mutation-agnostic approach that could improve mucociliary clearance in all CF patients. BI 1265162 is an ENaC inhibitor with demonstrated pre-clinical efficacy and safety already demonstrated in humans. OBJECTIVE: We present results from BALANCE-CFTM 1, a phase II, placebo-controlled, randomised, double-blind study of four dose levels of BI 1265162 versus placebo for 4 weeks on top of standard of care in adults and adolescents with CF. RESULTS: Initially, 28 randomised subjects (BI 1265162 200 µg twice daily n=14, placebo twice daily n=14) were assessed at an interim futility analysis. Compared with placebo, numerical changes of -0.8% (95% CI -6.6 to 4.9%) in percentage predicted forced expiratory volume in 1s (ppFEV1) and +2.1 units (95% CI -2.4 to 6.5 units) in lung clearance index (LCI) were observed in the active group, meeting a pre-defined stopping rule; accordingly, the study was terminated. Recruitment had continued during the interim analysis and pending results; 24 patients were added across three dose levels and placebo. The final results including these patients (+1.5% ppFEV1, 200 µg twice-daily dose versus placebo) were not supportive of relevant clinical effect. Furthermore, LCI change was not supportive, although interpretation was limited due to insufficient traces meeting quality criteria. A 9.4-point improvement in the Cystic Fibrosis Questionnaire - Revised Respiratory Domain was observed in the 200 µg twice daily dose group versus placebo. BI 1265162 up to 200 µg twice daily was safe and well-tolerated. Pharmacokinetics were similar to those in healthy volunteers. CONCLUSION: BI 1265162 was safe, but did not demonstrate a potential for clinical benefit. Development has been terminated.

Machine Learning-Based Text Analysis to Predict Severely Injured Patients in Emergency Medical Dispatch: Model Development and Validation.

BACKGROUND: Early recognition of severely injured patients in prehospital settings is of paramount importance for timely treatment and transportation of patients to further treatment facilities. The dispatching accuracy has seldom been addressed in previous studies. OBJECTIVE: In this study, we aimed to build a machine learning-based model through text mining of emergency calls for the automated identification of severely injured patients after a road accident. METHODS: Audio recordings of road accidents in Taipei City, Taiwan, in 2018 were obtained and randomly sampled. Data on call transfers or non-Mandarin speeches were excluded. To predict cases of severe trauma identified on-site by emergency medical technicians, all included cases were evaluated by both humans (6 dispatchers) and a machine learning model, that is, a prehospital-activated major trauma (PAMT) model. The PAMT model was developed using term frequency-inverse document frequency, rule-based classification, and a Bernoulli naïve Bayes classifier. Repeated random subsampling cross-validation was applied to evaluate the robustness of the model. The prediction performance of dispatchers and the PAMT model, in severe cases, was compared. Performance was indicated by sensitivity, specificity, positive predictive value, negative predictive value, and accuracy. RESULTS: Although the mean sensitivity and negative predictive value obtained by the PAMT model were higher than those of dispatchers, they obtained higher mean specificity, positive predictive value, and accuracy. The mean accuracy of the PAMT model, from certainty level 0 (lowest certainty) to level 6 (highest certainty), was higher except for levels 5 and 6. The overall performances of the dispatchers and the PAMT model were similar; however, the PAMT model had higher accuracy in cases where the dispatchers were less certain of their judgments. CONCLUSIONS: A machine learning-based model, called the PAMT model, was developed to predict severe road accident trauma. The results of our study suggest that the accuracy of the PAMT model is not superior to that of the participating dispatchers; however, it may assist dispatchers when they lack confidence while making a judgment.