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Ivermectin (IVM), a drug originally used for treating parasitic infections, is being explored for its potential applications in cancer therapy. Despite the promising anti-cancer effects of IVM, its low water solubility limits its bioavailability and, consequently, its biological efficacy as an oral formulation. To overcome this challenge, our research focused on developing IVM-loaded lipid polymer hybrid nanoparticles (LPHNPs) designed for potential pulmonary administration. IVM-loaded LPHNPs were developed using the emulsion solvent evaporation method and characterized in terms of particle size, morphology, entrapment efficiency, and release pattern. Solid phase characterization was investigated by Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), and thermogravimetric analysis (TGA). Using a Twin stage impinger (TSI) attached to a device, aerosolization properties of the developed LPHNPs were studied at a flow rate of 60 L/min, and IVM was determined by a validated HPLC method. IVM-loaded LPHNPs demonstrated spherical-shaped particles between 302 and 350 nm. Developed formulations showed an entrapment efficiency between 68 and 80% and a sustained 50 to 60% IVM release pattern within 96 h. Carr’s index (CI), Hausner ratio (HR), and angle of repose (θ) indicated proper flowability of the fabricated LPHNPs. The in vitro aerosolization analysis revealed fine particle fractions (FPFs) ranging from 18.53% to 24.77%. This in vitro study demonstrates the potential of IVM-loaded LPHNPs as a delivery vehicle through the pulmonary route.

Steam methane reforming (SMR) is one of the most widely used hydrogen (H2) production processes. In addition to its extensive utilization in industrial sectors, hydrogen is expanding it share as a clean energy carrier, and more sustainable and efficient H2 production methods are continuously being explored and developed. One method replaces conventional fossil fuel-based heating with electrical heating through the flow of electrons across the reformer. At UCLA, an experimental setup was built of an electrically heated steam methane reforming process. This paper describes the system components, explains the digitalization of the experimental setup and introduces methods for building a first-principles-based dynamic process model using parameters estimated via data-driven methods from process experimental data. The modeling approach uses a lumped parameter approximation and employs algebraic equations to solve for gas-phase variables. The reaction parameters are calculated from steady-state experimental data, and the temperature change is modeled with respect to change in electric current using a first-order dynamic model. The overall dynamic process model is then used in a computational model predictive control (MPC) scheme to drive the process to a new H2 production set-point under unperturbed and steam flowrate disturbance cases. The performance and robustness of the proposed MPC scheme are compared to the ones of a classical proportional–integral (PI) controller and are demonstrated to be superior in terms of closed-loop response, robustness, and constraint handling.

[This corrects the article DOI: 10.1371/journal.pone.0054193.].

Profiling the tumour microenvironment (TME) has been informative in understanding the underlying tumour–immune interactions. Multiplex immunohistochemistry (mIHC) coupled with molecular barcoding technologies have revealed greater insights into the TME. In this study, we utilised the Nanostring GeoMX Digital Spatial Profiler (DSP) platform to profile a non-small-cell lung cancer (NSCLC) tissue microarray for protein markers across immune cell profiling, immuno-oncology (IO) drug targets, immune activation status, immune cell typing, and pan-tumour protein modules. Regions of interest (ROIs) were selected that described tumour, TME, and normal adjacent tissue (NAT) compartments. Our data revealed that paired analysis (n = 18) of matched patient compartments indicate that the TME was significantly enriched in CD27, CD3, CD4, CD44, CD45, CD45RO, CD68, CD163, and VISTA relative to the tumour. Unmatched analysis indicated that the NAT (n = 19) was significantly enriched in CD34, fibronectin, IDO1, LAG3, ARG1, and PTEN when compared to the TME (n = 32). Univariate Cox proportional hazards indicated that the presence of cells expressing CD3 (hazard ratio (HR): 0.5, p = 0.018), CD34 (HR: 0.53, p = 0.004), and ICOS (HR: 0.6, p = 0.047) in tumour compartments were significantly associated with improved overall survival (OS). We implemented both high-plex and high-throughput methodologies to the discovery of protein biomarkers and molecular phenotypes within biopsy samples, and demonstrate the power of such tools for a new generation of pathology research.

Identifying and targeting specific oncogenic drivers has become standard of care in the routine management of patients with lung cancer. Research is ongoing to expand the number of drug targets that can offer clinically meaningful outcomes. Rearranged during transfection (RET) fusions are the latest oncogenic driver alterations that show potential as a drug target. RET fusions occur in 1−2% of non-small cell lung cancer (NSCLC) cases. They are more commonly associated with younger age, female gender, non-smokers and Asian ethnicity. The RET kinase is abnormally activated through fusion with a partner protein such as KIF5B, CCDC6 or NCOA4. This leads to downstream intracellular signalling and enhancement of gene transcription and cell proliferation. The effectiveness of multi-kinase inhibitors in RET positive NSCLC has been explored in early phase and retrospective studies. From these studies, the most effective agents identified include cabozantanib and vandetanib. Overall response rates (ORR) vary from 18−47% across studies. In general, these agents have a manageable toxicity profile, although there are a number of off-target toxicities. Similar to the increased activity in ALK rearranged disease, pemetrexed has demonstrated superior response rates in this patient group and should be considered. Selective RET inhibitors, including LOXO-292 and BLU-667, are progressing in clinical trials. LOXO-292 has demonstrated an impressive ORR of 77% in RET positive solid tumours. It is anticipated this agent will be an effective targeted therapeutic option for patients with RET positive lung cancer.

Incidental fisheries capture has been identified as having a major effect on shark populations throughout the world. However, factors that contribute to the mortality of shark bycatch during fisheries capture are not fully understood. Here, we investigated the effects of capture duration, sea surface temperature, and shark total length (snout to the tip of the upper caudal lobe) on the physiology and condition of longline-caught bronze whalers, Carcharhinus brachyurus. Plasma lactate and potassium concentration had a positive linear relationship with capture duration, indicating that this species experiences increasing physiological challenges while on fishing gear. Additionally, we used stereotype logistic regression models to determine variables that could predict the capture condition of sharks (categorized as healthy, sluggish, or moribund or dead). In these models, elevated plasma lactate concentration, plasma potassium concentration, and capture duration increased the likelihood of C. brachyurus being captured in a sluggish condition or in a moribund or dead condition. After plasma lactate concentration exceeded 27.4 mmol/L, plasma potassium concentration exceeded 8.3 mmol/L, or capture durations exceeded 293 minutes, the majority of captured sharks (>50%) were predicted to be moribund or dead. We recommend that a reduction in the amount of time longlines are left fishing (soak time) will reduce immediate and post-release mortality in C. brachyurus bycatch and that our methods could be applied to identify causes of fisheries-induced mortality in future studies. The identification of operational, environmental, and biological variables contributing to poor condition will be necessary to implement conservation strategies that reduce mortality during capture.

IntroductionInherent and acquired cisplatin resistance reduces the effectiveness of this agent in the management of non-small cell lung cancer (NSCLC). Understanding the molecular mechanisms underlying this process may result in the development of novel agents to enhance the sensitivity of cisplatin.MethodsAn isogenic model of cisplatin resistance was generated in a panel of NSCLC cell lines (A549, SKMES-1, MOR, H460). Over a period of twelve months, cisplatin resistant (CisR) cell lines were derived from original, age-matched parent cells (PT) and subsequently characterized. Proliferation (MTT) and clonogenic survival assays (crystal violet) were carried out between PT and CisR cells. Cellular response to cisplatin-induced apoptosis and cell cycle distribution were examined by FACS analysis. A panel of cancer stem cell and pluripotent markers was examined in addition to the EMT proteins, c-Met and β-catenin. Cisplatin-DNA adduct formation, DNA damage (γH2AX) and cellular platinum uptake (ICP-MS) was also assessed.ResultsCharacterisation studies demonstrated a decreased proliferative capacity of lung tumour cells in response to cisplatin, increased resistance to cisplatin-induced cell death, accumulation of resistant cells in the G0/G1 phase of the cell cycle and enhanced clonogenic survival ability. Moreover, resistant cells displayed a putative stem-like signature with increased expression of CD133+/CD44+cells and increased ALDH activity relative to their corresponding parental cells. The stem cell markers, Nanog, Oct-4 and SOX-2, were significantly upregulated as were the EMT markers, c-Met and β-catenin. While resistant sublines demonstrated decreased uptake of cisplatin in response to treatment, reduced cisplatin-GpG DNA adduct formation and significantly decreased γH2AX foci were observed compared to parental cell lines.ConclusionOur results identified cisplatin resistant subpopulations of NSCLC cells with a putative stem-like signature, providing a further understanding of the cellular events associated with the cisplatin resistance phenotype in lung cancer.

Guided digital mental health interventions are more effective than unguided interventions. While research often emphasizes the frequency and intensity of guidance, less attention has been paid to the behaviors enacted by the therapists supporting clients using these interventions. A scoping review of the literature was conducted to systematically examine the evidence on therapist behaviors (i.e., the actions and feedback provided by supporters to patients). Applying broad eligibility criteria, a systematic search was conducted in PubMed, PsycInfo, the Cochrane Library, and Embase from their inception to January 1st 2024. Sixteen studies met inclusion criteria and were included in the review. Following data extraction, a descriptive analysis and synthesis of the results was performed. Most studies (n = 12; 75 %) focused on therapist behaviors in the context of internet-delivered Cognitive Behavioral Therapy for anxiety and depression. While earlier studies primarily focused on identifying therapist behaviors, later studies shifted towards examining the associations between therapist behaviors and different outcomes, as well as deriving research and clinical applications for improving guided internet-delivered treatments. Identified gaps and recommendations for clinical practice, research, training, and treatment development are discussed.

Abstract Background In recent years, exponential growth in digital innovations and internet access has provided opportunities to deliver health services at a much greater scale than previously possible. Evidence-based technology-enabled interventions can provide cost-effective, accessible, and resource-efficient solutions for addressing mental health issues. This study evaluated the first year of a supported digital cognitive behavioral therapy (CBT) service provided by the national health service in Ireland, which has been accessible to individuals who receive a referral from one of five referring groups: General Practitioners, Primary Care Psychology, Counselling Primary Care, Community Mental Health, and Jigsaw (a nationwide youth mental health service). Methods A retrospective, observational study examining data from the service between April 2021 to April 2022 was conducted. Descriptive statistics on referrals, account activations, user demographics, program usage, and user satisfaction were extracted, and pre-to-post clinical outcomes for depression measured by the Patient Health Questionnaire-9 and for anxiety measured by the Generalised Anxiety Disorder-7 were analysed using linear mixed effect models. Results There were 5,298 referrals and 3,236 (61%) account activations within the year. Most users were female (72.9%) and aged between 18 and 44 years (75.4%). The CBT programs were associated with significant reductions in both depression (β = 3.34, 95% CI [3.03, 3.65], p 0.8). Time spent using the programs was also found to be a predictor of the variability in these clinical outcomes (p

Abstract Background Citizen science is a way to democratise science by involving groups of citizens in the research process. Clinical guidelines are used to improve practice, but their implementation can be limited. Involving patients and the public can enhance guideline implementation, but there is uncertainty about the best approaches to achieve this. Citizen science is a potential way to involve patients and the public in improving clinical guideline implementation. We aimed to explore the application of citizen science methods to involve patients and the public in the dissemination and implementation of clinical guidelines in oral health and dentistry. Methods We developed GUIDE (GUideline Implementation in oral health and DEntistry), a citizen science online platform, using a participatory approach with researchers, oral health professionals, guideline developers and citizens. Recruitment was conducted exclusively online. The platform focused on prespecified challenges related to oral health assessment guidelines, and asked citizens to generate ideas, as well as vote and comment on other citizens' ideas to improve those challenges. Citizens also shared their views via surveys and two online synchronous group meetings. Data were collected on participant's demographics, platform engagement and experience of taking part. The most promising idea category was identified by an advisory group based on engagement, feasibility and relevance. We presented quantitative data using descriptive statistics and analysed qualitative data using inductive and deductive thematic analysis. Results The platform was open for 6 months and we recruited 189 citizens, from which over 90 citizens actively engaged with the platform. Most citizens were over 34 years (64%), female (58%) and had a university degree (50%). They generated 128 ideas, 146 comments and 248 votes. The challenge that led to most engagement was related to prevention and oral health self‐care. To take this challenge forward, citizens generated a further 36 ideas to improve a pre‐existing National Health Service oral care prevention leaflet. Citizens discussed motivations to take part in the platform (understanding, values, self‐care), reasons to stay engaged (communication and feedback, outputs and impact, and relevance of topics discussed) and suggestions to improve future platforms. Conclusion Citizen science is an effective approach to generate and prioritise ideas from a group of citizens to improve oral health and dental services. Prevention and oral health self‐care were of particular interest to citizens. More research is needed to ensure recruitment of a diverse group of citizens and to improve retention in citizen science projects. Patient or Public Contribution This project was inherently conducted with the input of public partners (citizen scientists) in all key aspects of its conduct and interpretation. In addition, two public partners were part of the research team and contributed to the design of the project, as well as key decisions related to its conduct, analysis, interpretation and dissemination and are co‐authors of this manuscript.

Prior studies have found metacognitive biases are linked to a transdiagnostic dimension of anxious-depression, manifesting as reduced confidence in performance. However, previous work has been cross-sectional and so it is unclear if under-confidence is a trait-like marker of anxious-depression vulnerability, or if it resolves when anxious-depression improves. Data were collected as part of a large-scale transdiagnostic, four-week observational study of individuals initiating internet-based cognitive behavioural therapy (iCBT) or antidepressant medication. Self-reported clinical questionnaires and perceptual task performance were gathered to assess anxious-depression and metacognitive bias at baseline and 4-week follow-up. Primary analyses were conducted for individuals who received iCBT (n=649), with comparisons between smaller samples that received antidepressant medication (n=82) and a control group receiving no intervention (n=88). Prior to receiving treatment, anxious-depression severity was associated with under-confidence in performance in the iCBT arm, replicating previous work. From baseline to follow-up, levels of anxious-depression were significantly reduced, and this was accompanied by a significant increase in metacognitive confidence in the iCBT arm (β=0.17, SE=0.02, p

Abstract Background Evidence-based treatments for depression exist but not all patients benefit from them. Efforts to develop predictive models that can assist clinicians in allocating treatments are ongoing, but there are major issues with acquiring the volume and breadth of data needed to train these models. We examined the feasibility, tolerability, patient characteristics, and data quality of a novel protocol for internet-based treatment research in psychiatry that may help advance this field. Methods A fully internet-based protocol was used to gather repeated observational data from patient cohorts receiving internet-based cognitive behavioural therapy (iCBT) (N = 600) or antidepressant medication treatment (N = 110). At baseline, participants provided > 600 data points of self-report data, spanning socio-demographics, lifestyle, physical health, clinical and other psychological variables and completed 4 cognitive tests. They were followed weekly and completed another detailed clinical and cognitive assessment at week 4. In this paper, we describe our study design, the demographic and clinical characteristics of participants, their treatment adherence, study retention and compliance, the quality of the data gathered, and qualitative feedback from patients on study design and implementation. Results Participant retention was 92% at week 3 and 84% for the final assessment. The relatively short study duration of 4 weeks was sufficient to reveal early treatment effects; there were significant reductions in 11 transdiagnostic psychiatric symptoms assessed, with the largest improvement seen for depression. Most participants (66%) reported being distracted at some point during the study, 11% failed 1 or more attention checks and 3% consumed an intoxicating substance. Data quality was nonetheless high, with near perfect 4-week test retest reliability for self-reported height (ICC = 0.97). Conclusions An internet-based methodology can be used efficiently to gather large amounts of detailed patient data during iCBT and antidepressant treatment. Recruitment was rapid, retention was relatively high and data quality was good. This paper provides a template methodology for future internet-based treatment studies, showing that such an approach facilitates data collection at a scale required for machine learning and other data-intensive methods that hope to deliver algorithmic tools that can aid clinical decision-making in psychiatry.

Abstract Background Many refugees suffer from mental health problems due to stressful and traumatic events before, during, and after migration. However, refugees are facing a wide variety of barriers, limiting their access to mental health care. Internet-based tools, available in several languages, could be one way to increase the availability of mental health services for refugees. The present study aimed to develop and test a screening tool to screen for clinically relevant symptoms of psychiatric disorders common among refugees (i.e. Depression, Anxiety, Post-traumatic stress disorder, and Insomnia). We, designed, translated, and adapted an internet-based tiered screening procedure suitable for use with the largest refugee populations residing in Sweden. The tool aims to accurately identify symptoms of mental distress (Tier 1), differentiate between symptoms of specific psychiatric disorders (Tier 2), and assess symptom severity (Tier 3). We tested the overall efficiency of using a tiered screening procedure. Methods Seven hundred fifty-seven refugees residing in Sweden, speaking any of the languages Arabic, Dari, Farsi, English, or Swedish, completed an online questionnaire following a three-tiered procedure with screening instruments for each tier. In this study, the Tier 3 scales were used as reference standards for clinically relevant symptoms, to evaluate screening efficiency in terms of accuracy and reduction of item burden in previous tiers. Results The results show that the tiered procedure could reduce the item burden while maintaining high accuracy, with up to 86% correctly assessed symptoms and few false negatives with moderate symptoms and above (at most 9%), and very few with severe symptoms (at most 1.3%). Discussion This study generated an accurate screening tool that efficiently identifies clinically relevant symptoms of common psychiatric disorders among refugees. Using an adapted online tiered procedure to screen for multiple mental health issues among refugees has the potential to facilitate screening and increase access to mental health services for refugees. We discuss the utility of the screening tool and the necessity of further evaluation.

BackgroundThis study consisted of a qualitative exploration of stakeholder experience regarding the implementation of internet-delivered cognitive behavioral therapy (iCBT) as part of routine service provision within the UK's Improving Access to Psychological Therapies program.MethodsStakeholder groups included service providers (n = 6), commercial iCBT representatives (n = 6) and patients who received a course of iCBT as part of treatment at the service (n = 7). Participants took part in a semi-structured interview over the telephone, and subsequent data were qualitatively analyzed using the descriptive-interpretive approach.ResultsService providers highlighted the importance of effective leadership and management, training initiatives, the provision of feedback to commercial iCBT representatives and creating work structures around iCBT to facilitate iCBT supporting staff in their use of it. Commercial iCBT representatives similarly reported the importance of training clinicians in iCBT use, identifying the appropriate individuals at all levels of the service to drive iCBT implementation, and the importance of being responsive to any problems or needs that arise from the service. Patients reported an overall positive experience of receiving iCBT but highlighted a need for more information from their supporter and the intervention to better structure their usage. Contextual factors, in terms of barriers and facilitators, were also highlighted by service provider and commercial participants; citing negative clinician attitudes and technological issues/bugs as barriers to implementation, and the exposure to iCBT created by COVID-19 and perseverance in using iCBT over time as facilitators.DiscussionThe findings contribute to a growing field of literature that seeks to understand the experience of relevant stakeholders who are involved with and contribute to iCBT implementation, including commercial iCBT representatives who, to our knowledge, have not been accounted for as part of published research to date.

BackgroundResearch suggests there is heterogeneity in treatment response for internet-delivered cognitive behavioral therapy (iCBT) users, but few studies have investigated the trajectory of individual symptom change across iCBT treatment. Large patient data sets using routine outcome measures allows the investigation of treatment effects over time as well as the relationship between outcomes and platform use. Understanding trajectories of symptom change, as well as associated characteristics, may prove important for tailoring interventions or identifying patients who may not benefit from the intervention. ObjectiveWe aimed to identify latent trajectories of symptom change during the iCBT treatment course for depression and anxiety and to investigate the patients’ characteristics and platform use for each of these classes. MethodsThis is a secondary analysis of data from a randomized controlled trial designed to examine the effectiveness of guided iCBT for anxiety and depression in the UK Improving Access to Psychological Therapies (IAPT) program. This study included patients from the intervention group (N=256) and followed a longitudinal retrospective design. As part of the IAPT’s routine outcome monitoring system, patients were prompted to complete the Patient Health Questionnaire-9 (PHQ-9) and Generalized Anxiety Disorder-7 (GAD-7) after each supporter review during the treatment period. Latent class growth analysis was used to identify the underlying trajectories of symptom change across the treatment period for both depression and anxiety. Differences in patient characteristics were then evaluated between these trajectory classes, and the presence of a time-varying relationship between platform use and trajectory classes was investigated. ResultsFive-class models were identified as optimal for both PHQ-9 and GAD-7. Around two-thirds (PHQ-9: 155/221, 70.1%; GAD-7: 156/221, 70.6%) of the sample formed various trajectories of improvement classes that differed in baseline score, the pace of symptom change, and final clinical outcome score. The remaining patients were in 2 smaller groups: one that saw minimal to no gains and another with consistently high scores across the treatment journey. Baseline severity, medication status, and program assigned were significantly associated (P