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Current tissue plasminogen-based therapeutic strategies for stroke suffer from systemic side effects and poor efficacy. Hence, novel drug delivery methods are needed to overcome these shortcomings. Exosome-based drug formulations have been shown to have superior therapeutic outcomes compared to conventional systemic drug delivery approaches. In this paper, we report exosome surface-coated tissue plasminogen activator (tPA)/catalase nanoformulations with improved thrombolytic efficacy compared to free tPA, which also reduce side effects. The results showed that the tPA exosome formulations retained tPA activity, improved tPA stability, exhibited significant fibrinolysis, and showed no significant toxicity effects. Further, when combined with antioxidant enzyme catalase, the formulation was able to inhibit hydrogen peroxide-mediated oxidative stress and toxicity. Hence, exosome-based tPA/catalase nanoformulations could have the potential to offer a safer and effective thrombolytic therapy.

BackgroundAsthma poses a great burden as one of the most common long-term non-communicable diseases. The April 2023 Sudanese war has severely disrupted the healthcare system, greatly affecting asthmatic patients by limiting access to medications and diagnostic services. Therefore, this research aims to investigate asthma control, self-management and healthcare access among asthma patients in Sudan during the ongoing war.MethodsA cross-sectional study was conducted among Sudanese patients with asthma during the ongoing war using a convenience sampling. An online questionnaire was distributed from September 2024 to June 2025. It covered sociodemographic data, the validated Asthma Control Test (ACT), self-management and healthcare access. Data were analysed using SPSS software, employing descriptive statistics, χ2 tests and linear regression, with significance set at p<0.05.ResultsAmong the 229 asthmatic patients surveyed, 60.3% had poorly controlled asthma. Since the onset of the conflict, 43.2% had not attended any follow-up visits, while 48.5% required at least one emergency room visit during the war. Despite these challenges, 86.0% reported having quick access to healthcare during active attacks. However, 17.9% were unable to obtain their medications regularly, forcing many to adopt alternative coping strategies: 6.1% sought medical advice through online consultations, 15.7% increased their prescribed doses on their own and 39.3% used whatever medications were available without prescriptions, which was significantly associated with poor asthma control (χ²=29.29, p<0.01). Regression analysis revealed dose reduction was linked to worse control (β=−3.68, p=0.004), while refugee status and better adherence to medications predicted higher ACT scores (β=2.88, p<0.001; β=0.54, p=0.028).ConclusionsThis study highlights a considerable gap in asthma control during the ongoing war, despite the availability of healthcare services in times of urgent need. Many patients adopted coping strategies such as using whatever medications were available without prescriptions or independently increasing their prescribed doses. Enhancing patient education on proper asthma self-management and improving access to healthcare services, including telemedicine consultations, could play a crucial role in achieving better asthma control.

ObjectivesAllied Health Professionals (AHP) consist of 13 different specialty roles in Wales, sharing the responsibility of promoting and supporting the health and well-being of the population. During the COVID-19 pandemic, there was a shift in care provision, with the increased use of online consultations, such as those using video consultation platforms. However, this shift was associated with uncertainty and hesitancy, and, thus, to understand the usage and reasons for using video consultations, this study aimed to capture the experiences of both AHP and their patients, while investigating each role individually.ParticipantsA survey was distributed to and completed by n=8928 patients and n=4974 clinicians, all AHP were included except for orthoptists and paramedics due to ambiguities in the data. A further 86 clinicians participated in phone interviews.ResultsAll professions had a high prevention of face-to-face with the use of video consultations (68.6% overall and 81.4% of clinicians reported the prevention). However, this was lower for certain professions such as podiatrists, potentially due to the specific patient needs, such as physical assessments. Also, a range of different appointment types were being conducted, and there was a high acceptance of these alternative methods among participants. The interviews with clinicians revealed five important aspects of video consultations: the perceived benefits, the perceived challenges, technology issues and necessary improvements, clinician preference and the future of video consulting. Specifically, the future of video consulting evidenced clinicians’ desire for a blended approach to working, selecting the appropriate modality depending on the situation and patient-specific needs.ConclusionsIntegrating the traditional methods of service delivery (face-to-face), and novel, innovative ways, such as video consultations, can motivate positive transformations for the efficiency and efficacy of health and social care.

Background and Objective Pancreatic cancer (PC) is a significant cause of cancer-related mortality, with limited curative options and high rates of cachexia, a debilitating syndrome associated with poor prognosis. While previous research has linked sarcopenia to poor outcomes in PC, the correlation between cachexia and treatment outcomes remains underexplored. This meta-analysis aims to investigate the association between cachexia and overall survival and time to treatment failure in advanced PC patients undergoing first-line chemotherapy. Method A systematic search of electronic databases was conducted following PRISMA guidelines. Eligible studies compared cachexic and non-cachexic PC patients, reporting outcomes of observed survival or time to treatment failure. Data extraction and analysis were performed using Comprehensive Meta-Analysis Version 3.3, employing random-effects models and sensitivity analyses to assess heterogeneity and bias. Results Seven observational studies involving 2834 PC patients were included. The incidence of cachexia was 45% (95% CI: 0.27-0.65), with a higher prevalence in East Asian populations. Cachexic patients experienced significantly earlier treatment failure (SDM: −2.22, 95% CI: −2.6 to −1.7, P = 0.0001) and higher mortality risk (HR: 2.02, 95% CI: 1.17-3.48, P = 0.011) compared to non-cachexic patients. Overall survival was lower in cachexic patients (SDM: −2.34, 95% CI: −3.7 to −0.90, P = 0.001), with considerable heterogeneity across studies. Meta-regression analysis revealed significant differences between countries but insignificant correlations with age. Conclusion Cachexia is associated with reduced overall survival, early chemotherapy failure, and elevated mortality in advanced PC patients undergoing first-line chemotherapy. Recognition and management of cachexia are crucial for optimizing treatment outcomes and improving patient survival. Future research should focus on prospective studies to better understand the impact of cachexia on treatment response and develop tailored interventions to mitigate its adverse effects. Plain language summary Pancreatic cancer (PC) presents a formidable challenge due to its limited treatment options and association with cachexia, a debilitating condition linked to poor prognosis. This meta-analysis investigates the relationship between cachexia and treatment outcomes in advanced PC patients undergoing first-line chemotherapy. Seven observational studies encompassing 2834 patients were analyzed, revealing a 45% incidence of cachexia, notably higher in East Asian populations. Cachexic patients exhibited earlier treatment failure and higher mortality risk compared to non-cachexic counterparts. Their overall survival was significantly reduced, although with notable heterogeneity across studies. Meta-regression analysis highlighted variations between countries but found no significant correlation with age. The findings underscore the importance of recognizing and addressing cachexia to optimize treatment outcomes and enhance patient survival. Future research should emphasize prospective studies to further elucidate cachexia’s impact on treatment response and develop tailored interventions to alleviate its adverse effects.

IntroductionThe use of video consulting (VC) in Wales UK has expanded rapidly. Previous VC evidence has been the subject of small-scale projects and evaluations. Technology Enabled Care Cymru is an all-Wales digital service and rolls out digital interventions and evaluates on large scales, thus capturing representative data sets across Wales, and therefore a wide range of National Health Service (NHS) specialties.ObjectiveTo extract and analyse narrative feedback from patients and clinicians using the NHS Wales VC Service for 6 months (September 2020 to March 2021).DesignA coding reliability approach of a cross-sectional study was conducted.SettingFrom all health boards across Wales.ParticipantsNHS patients and clinicians across primary, secondary and community care settings in Wales.ResultsData were captured on benefits, challenges and sustainability of VC. A coding reliability analysis was used with six domain summaries materialising to include: ‘The Ease of VC’; ‘The Personal Touches’; ‘The Benefits of VC’; ‘The Challenges of VC’; ‘Technical Quality’; and ‘Recommendations & Future Use’. An additional 17 subdomains are included. Direct quotations from patients and clinicians are provided for context.ConclusionsA total of 22 978 participants were included. These data help demonstrate that NHS remote service delivery, via the method of VC, can be highly satisfactory, well accepted and clinically suitable yielding many benefits. Despite this, the data are not without its challenges surrounding engagement and suitability for VC. The NHS Wales VC Service rolled out and evaluated at scale and demonstrates that VC has potential for long-term sustainability. For the future, use a ‘blended approach’ for NHS appointments that are clinically judged and centred on patient choice.

Cancer management has traditionally depended on chemotherapy as the mainstay of treatment; however, recent advancements in targeted therapies and immunotherapies have offered new options. Ubiquitin-specific proteases (USPs) have emerged as promising therapeutic targets in cancer treatment due to their crucial roles in regulating protein homeostasis and various essential cellular processes. This review covers the following: (1) the structural and functional characteristics of USPs, highlighting their involvement in key cancer-related pathways, and (2) the discovery, chemical structures, mechanisms of action, and potential clinical implications of USP inhibitors in cancer therapy. Particular attention is given to the role of USP inhibitors in enhancing cancer immunotherapy, e.g., modulation of the tumor microenvironment, effect on regulatory T cell function, and influence on immune checkpoint pathways. Furthermore, this review summarizes the current progress and challenges of clinical trials involving USP inhibitors as cancer therapy. We also discuss the complexities of achieving target selectivity, the ongoing efforts to develop more specific and potent USP inhibitors, and the potential of USP inhibitors to overcome drug resistance and synergize with existing cancer treatments. We finally provide a perspective on future directions in targeting USPs, including the potential for personalized medicine based on specific gene mutations, underscoring their significant potential for enhancing cancer treatment. By elucidating their mechanisms of action, clinical progress, and potential future applications, we hope that this review could serve as a useful resource for both basic scientists and clinicians in the field of cancer therapeutics.

IntroductionDigital healthcare in the UK was adopted out of necessity rather than choice during the COVID-19 pandemic. However, as we move forward, UK governments and healthcare services have acknowledged its evident benefits for patients, staff and the National Health Service (NHS), and are keen to sustain its improvements in the long term.ObjectiveTo understand the benefits, challenges and sustainability of a future-proof digital healthcare.DesignA semi-structured interview study was conducted.SettingIn NHS services in Wales, UK.ParticipantsWith clinical and non-clinical staff across a mix of clinical specialties.Outcome measuresSemi-structured interviews were conducted to address benefits, challenges and sustainability of a national video consulting (VC) service, and thematically coded using a quantification method of qualitative work.ResultsA total of 203 interviews were conducted and 3 dominant domains emerged, with 7 themes and 26 categories.LimitationsIt is important to acknowledge that these findings were captured during a pandemic.ConclusionsNHS Wales has demonstrated that currently there are an equal measure of benefits and challenges to a national digital healthcare. However, with ongoing government and service support, improvement and evaluation, it has potential for a sustainable digital future, in which the benefits can outweigh the challenges.

Social distancing laws during the first year of the pandemic, and its unprecedented changes to the National Health Service (NHS) forced a large majority of services, especially mental health teams to deliver patient care remotely. For many, this approach was adopted out of necessity, rather than choice, thus presenting a true ‘testing ground’ for remote healthcare and a robust evaluation on a national and representative level.ObjectiveTo extract and analyse mental health specific data from a national dataset for 1 year (March 2020–March 2021).DesignA mixed-methods study using surveys and interviews.SettingIn NHS mental health services in Wales, UK.ParticipantsWith NHS patients and clinicians across child and adolescent, adult and older adult mental health services.Outcome measuresMixed methods data captured measures on use, value, benefits and challenges of video consulting (VC).ResultsA total of 3561 participants provided mental health specific data. These data and its findings demonstrate that remote mental health service delivery, via the method of VC is highly satisfactory, well-accepted and clinically suitable for many patients, and provides a range of benefits to NHS patients and clinicians. Interestingly, clinicians working from ‘home’ rated VC more positively compared with those at their ‘clinical base’.ConclusionsPost 1-year adoption, remote mental health services in Wales UK have demonstrated that VC is possible from both a technical and behavioural standpoint. Moving forward, we suggest clinical leaders and government support to sustain this approach ‘by default’ as an option for NHS appointments.

Wnt/ß-catenin signaling is strongly implicated in neoplasia, but the role of this pathway in human breast cancer has been controversial. Here, we examined Wnt/ß-catenin pathway activation as a function of breast cancer progression, and tested for a relationship with HER2/neu expression, using a human tissue microarray comprising benign breast tissues, ductal carcinoma in situ (DCIS), and invasive carcinomas. Cores were scored for membranous ß-catenin, a key functional component of adherens junctions, and for nucleocytoplasmic ß-catenin, a hallmark of Wnt/ß-catenin pathway activation. Only 82% of benign samples exhibited membrane-associated ß-catenin, indicating a finite frequency of false-negative staining. The frequency of membrane positivity was similar in DCIS samples, but was significantly reduced in carcinomas (45%, P<0.001), consistent with loss of adherens junctions during acquisition of invasiveness. Negative membrane status in cancers correlated with higher grade (P = 0.04) and estrogen receptor-negative status (P = 0.03), both indices of poor prognosis. Unexpectedly, a substantial frequency of nucleocytoplasmic ß-catenin was observed in benign breast tissues (36%), similar to that in carcinomas (35%). Positive-staining basal nuclei observed in benign breast may identify putative stem cells. An increased frequency of nucleocytoplasmic ß-catenin was observed in DCIS tumors (56%), suggesting that pathway activation may be an early event in human breast neoplasia. A correlation was observed between HER2/neu expression and nucleocytoplasmic ß-catenin in node-positive carcinomas (P = 0.02). Furthermore, cytoplasmic ß-catenin was detected in HER2/neu-induced mouse mammary tumors. The Axin2(NLSlacZ) mouse strain, a previously validated reporter of mammary Wnt/ß-catenin signaling, was utilized to define in vivo transcriptional consequences of HER2/neu-induced ß-catenin accumulation. Discrete hyperplastic foci observed in mammary glands from bigenic MMTV/neu, Axin2(NLSlacZ) mice, highlighted by robust ß-catenin/TCF signaling, likely represent the earliest stage of mammary intraepithelial neoplasia in MMTV/neu mice. Our study thus provides provocative evidence for Wnt/ß-catenin signaling as an early, HER2/neu-inducible event in breast neoplasia.