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Routes for reuse of aged pressure-driven membranes: Current status and future perspectives
No full textDelegation and Agency Deference in Financial Regulation: A Comparative EU-U.S. Perspective
No full textAs the world’s financial system has grown in risk and complexity, major economic systems have gravitated toward binding ex-ante rules or standards of general applicability to regulate financial institutions and markets. Increasingly, such statutes, directives, or regulations bristle with technical detail and can run into the hundreds of pages. The challenges of undertaking such sensitive and complex requirements present economic systems with a choice about which branches of government to entrust to formulate those rules or standards. In constitutional democracies, one broad option is for the legislature and the executive to undertake both the primary law and the technical drafting itself. Another option is for the legislature to enact a statute that sketches the contours of the rule in general language but authorizes an expert agency to flesh out that binding rule in full detail. Between these two poles, there are many possible variations in design. For example, a system that looks to the legislature to do the primary law and to the executive to do the drafting may also look to agencies for an important consultative role. But the basic choice of who holds the pen for the ultimate text of a binding, detailed rule—elected legislators or appointed officials and civil servants—implicates a tension between popular will and agency expertise that is rife in constitutional democracies. This tension has grown, on the one hand, with the rise of scientific knowledge and the technocratic state, and growing public distrust of scientific expert authority, on the other. The balance between independent expertise and accountability is a moving target.In this contribution, we explore different approaches to resolving this tension in the European Union and the United States
Decoding Engagement: Exploring the Influence of Social Communication Cues in Human-Robot Conversational Scenarios
Get PDFEnhancing social human-robot interaction (HRI)
requires a deep understanding of engagement. This paper explores how to capture engagement within conversational HRI by
examining multiple non-verbal communication cues. Specifically,
we analyze the engagement of 16 participants in the context of
a reminiscence task, which establishes a foundational dialogue
between the robot and the user. Head pose and voice activation
were the non-verbal communication cues used in this study. We
developed a methodology that identifies and correlates these cues
with engagement levels during specific epochs of interaction. By
contrasting these cues against video annotations and self-reported
feedback, we refine our understanding of engagement. Our
results demonstrate that a multi-modal approach to analyzing
engagement significantly outperforms unimodal analysis, where
11 out of 16 cases (68%) correlate with engagement, increasing
accuracy compared to using them independently. Critically, the
study reveals that objective and subjective methods to analyse
engagement closely align with users’ perceptions of engagement,
emphasizing the importance of integrated communication strategies in HRI
Medical specialists in LMICs: a systematic review and best-fit framework synthesis of the evidence on their roles and contribution to health systems.
Get PDFBACKGROUND: Medical specialists are integral to the medical workforce and play a pivotal role in referral systems. However, in low-income and middle-income countries (LMICs), there is a perception that specialists often fail to align with local health needs, system capacities and Universal Health Coverage (UHC) objectives. METHODS: A systematic review was conducted in 2024 using a best-fit framework to assess the contributions of specialists to health systems and population health in LMICs. Searches covered eight databases and specialist journals, guided by an expert-validated 'a priori' framework for data extraction and analysis. We used the Johanna Briggs Institute critical appraisal tools to assess the quality of the evidence, and the Preferred Reporting Items for Systematic Review and Meta-Analyses guidelines to report the findings. The study protocol was registered in the PROSPERO database (CRD42024572877). FINDINGS: We found and reviewed 89 studies, focusing on the stock of specialists in LMICs and highlighting a critical shortage of specialists, particularly surgeons, anaesthetists and psychiatrists. Evidence linked specialists' availability to improved health outcomes such as lives saved through expanded surgical capacity, though broader health system contributions were less clear. Specialists were reported to play key roles in referrals, hospital management, mentoring and research. Governance of their professions was found to be rather uneven across LMICs, with wide differences in specialty types, training curricula, accreditation systems and regulation of private-sector involvement. Reports frequently documented specialists' engagement with private health markets, revealing blurred boundaries between public and private care. A dynamic market for specialists was also observed, driven by a sustained global demand for their services. However, few policies were found addressing shortages and improving governance of specialties, with existing strategies focusing on task-shifting, clinical training and sharing responsibilities. CONCLUSIONS: This review offers an evidence-based framework for understanding specialists' roles and health system engagement in LMICs. We discuss the need to reconsider specialists' deployment, prioritise alignment with UHC goals and enhance governance to optimise their contributions to health systems
Developing research resources and minimum data set for care homes' adoption and use (DACHA).
No full textBACKGROUND: In England, care homes are the primary providers of long-term care for older adults. The increasing recognition of the importance of social care underscores the importance of collaboration between the National Health Service and care homes. The lack of data sharing among stakeholders limits opportunities for co-ordinated care, service development and research. OBJECTIVES: Identify how to support research, service development and innovation in care homes. Combine existing evidence with care home-generated resident data to create a minimum data set that is relevant and usable for stakeholders, including residents, relatives, practitioners, researchers, regulators and commissioners. DESIGN AND METHODS: The study used a mixed-methods approach, structured into five work packages, supported by patient and public involvement and engagement with residents, carers and staff: Work package 1: Conducted two evidence reviews on outcome measures and factors enhancing research productivity in care homes. Work package 2: Created a trial archive for secondary data analysis. Work package 3: Conducted a scoping review, a realist review and a national survey to define minimum data set content and assess implementation challenges in English care homes. Work package 4: Linked residents' data from National Health Service and social care data sets with data from study care homes, deriving useful minimum data set variables and assessing data quality. Work package 5: Piloted the minimum data set at two points in care homes within three integrated care systems, conducted focus groups and interviews with care home and integrated care system staff. Three national consultations explored how stakeholders use resident information, measure quality of life and minimum data set usefulness. Additionally, subprojects examined data availability in domiciliary settings, staff reasoning when assessing resident well-being and completing research during rapid policy changes. FINDINGS: The reviews revealed significant heterogeneity in outcome measurement and questioned the appropriateness of some methods and measures used for care home research. The Virtual International Care Home Trials Archive merged data from 6 United Kingdom randomised controlled trials with 5674 residents across 308 care homes. International minimum data set studies are a valuable resource for international comparative research. The wide range of measures used are mostly clinical with under-representation of measures important to care homes (e.g. quality of life). A national survey of care homes demonstrated the range of information, including clinical measures being routinely collected. The realist review identified motivation, front-line staff monitoring and embedded recording systems as important for minimum data set implementation. The pilot study recruited 996 residents from 45 care homes, with 727 residents' data included in the minimum data set. Residents' digital care records were linked to statutory health and social care data sets, creating a viable minimum data set prototype with metadata as resource. CONCLUSIONS: The study provided an evidence-based critique of care home research and a resource for secondary data analysis for future research. It developed a prototype minimum data set linking National Health Service, social care and care home data, demonstrating its importance as a basis for discussions between health and care staff. LIMITATIONS: The COVID-19 pandemic disrupted relationships and recruitment. Governance challenges prevented linking residents' data to general practitioner records. FUTURE WORK: Future research should assess whether the care home minimum data set improves resident outcomes, service delivery, staff experience, cross-sector collaboration, resource use and digital technology implementation. FUNDING: This synopsis presents independent research funded by the National Institute for Health and Care Research (NIHR) Health and Social Care Delivery Research programme as award number NIHR127234
Human TET2-mutant clonal hematopoiesis expansion is driven by distinct inflammatory signaling responses in stem cells versus myeloid progeny.
No full textClonal hematopoiesis (CH) increases with age and is associated with severe outcome in the course of infections or tumor development. Understanding the environmental conditions that favor mutant clones and the CH-immune system response to such environments is key to designing therapeutic strategies to stall the expansion of mutant clones and the development of CH-associated pathologies. Using human cells, we unravel a cell-specific and opposite impact of TET2 mutations on hematopoietic stem and progenitor cells (HSPC) compared to their myeloid progeny. Multi-omic analyses reveal that TET2-mutant HSPCs exhibit intrinsic epigenetic silencing of AP-1 transcription factors and a blunted transcriptional adaptation to systemic inflammation. Conversely, monocyte-macrophage trajectory derived from TET2Mut HSCs contributes to exacerbated inflammation. Together, these findings reconcile how TET2-mutant CH can simultaneously promote increased stemness within the HSPC compartment and heightened inflammation through its myeloid progeny, providing mechanistic insight into how TET2-CH expands under inflammatory stress
Reducing self-harm in adolescents: the RISA-IPD comprehensive synopsis.
No full textBACKGROUND: Self-harm is common in adolescents and a major public health concern. Evidence for effective interventions is lacking. An individual participant data meta-analysis has potential to provide more reliable estimates of the effects of therapeutic interventions than conventional meta-analyses and to explore which treatments are best suited to certain groups. METHODS: A systematic review and individual participant data meta-analysis of randomised controlled trials of therapeutic interventions to reduce repeat self-harm in adolescents with a history of self-harm and who had presented to clinical services. We searched Cochrane Library, EMBASE, trial registers and other databases for randomised controlled trials published in January 2022. Eligible randomised controlled trials compared any therapeutic intervention against a control, aimed to reduce self-harm in adolescents (11-18 years old), with past self-harm presenting to clinical services, and collected outcome data on self-harm or suicide attempts. Interventions reviewed were grouped into nine categories: cognitive-behavioural therapy; dialectical behaviour therapy; family therapy; group therapy; mentalisation based, psychodynamic, cognitive analytic therapy; multisystemic therapy; problem-solving, psychoeducation, support; postcards, tokens, documents (postcards/tokens); and other single session, brief interventions. Control interventions were all either treatment as usual or enhanced treatment as usual and were not usually well described. There were no 'no treatment' controls except in the postcard/document/token studies. Primary outcome was repetition of self-harm at 12 months. Other outcomes included repetition of self-harm at other time points, overall mental health, depressive symptoms, thoughts of suicide, quality of life and death. Two-stage random-effects individual participant data meta-analyses were conducted overall and by intervention, and to examine interaction between treatment received and participant characteristics. Secondary analyses incorporated aggregate data from randomised controlled trials without individual participant data. Metaregression explored moderating study effects. RESULTS: We identified 39 eligible studies, from 10 countries, where we sought individual participant data (18 studies with full sample eligibility, 21 with partial sample eligibility). We obtained individual participant data from 26 studies of 3448 eligible participants. We used published data from a further seven studies where individual participant data were not available for a combined individual participant data aggregate data meta-analysis (698 participants). For our primary outcome, repetition of self-harm, only six studies were rated as low risk of bias. There was no evidence that intervention/s were more or less effective than controls at preventing repeat self-harm by 12 months using individual participant data (odds ratios 1.06, 95% confidence interval 0.86 to 1.31) or individual participant data + aggregate data (odds ratios 1.02, 95% confidence interval 0.82 to 1.27) and no evidence of heterogeneity of treatment effects on study and treatment factors. We found no evidence that intervention was more or less effective than control for secondary outcomes, except general psychopathology and suicidal ideation at 12 and 6 months, respectively. Across all interventions, participants with multiple prior self-harm episodes showed evidence of improved treatment effect on self-harm repetition 6-12 months after randomisation [odds ratios 0.33 (95% confidence interval 0.12 to 0.94), studies = 9, n = 1771]. Modest evidence suggesting differential treatment effects based on participants' age, gender, self-harm method, and anxiety levels are noted. LIMITATIONS: A significant limitation was missing individual participant data where authors were unable to share data; we offset this by including published data in secondary individual participant data plus aggregate meta-analysis. A wide range of interventions were evaluated and lacked replication. There was variability in the definitions and timings of outcomes, measures used for data collection, and available moderator data, with little consistency across studies. CONCLUSIONS: More attention needs to be paid to seeking appropriate consent from study participants for data-sharing. We found no evidence that any therapeutic intervention (overall or by intervention) was more or less effective than control for reducing repeat self-harm. We are therefore unable to recommend any specific intervention to prevent repetition of self-harm in adolescents. We observed evidence and trends indicating more effective interventions within specific subgroups. Analysis was constrained due to scarcity of data concerning common baseline characteristics, outcomes, and follow-up lengths. We recommend efficient, adaptive platform trial designs to tackle research questions and ascertain the most effective interventions for different groups, covering available treatments. FUNDING: This synopsis presents independent research funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme as award number 17/117/11
Diazoxide Choline Extended-release Tablets in Prader-Willi Syndrome: A Randomized, Double-blind, Withdrawal Period Study
No full textAbstract Context The hallmark condition of Prader-Willi syndrome, a rare, genetic neurobehavioral/metabolic disorder, is life-threatening hyperphagia. Objective We assessed the efficacy and safety of diazoxide choline extended-release (DCCR) tablets for the treatment of hyperphagia in adults and children four years of age and older with Prader-Willi syndrome. Methods We conducted a 16-week, randomized withdrawal study in children and adults with Prader-Willi syndrome and hyperphagia. Participants who previously completed randomized (13-week DCCR or placebo) and open-label (2.5-4.5 years DCCR) studies were randomized 1:1 to receive once-daily DCCR or placebo. The primary endpoint was Hyperphagia Questionnaire for Clinical Trials (HQ-CT) total score change from baseline to 16 weeks. Secondary endpoints included Clinical Global Impression of Severity (CGI-S) and Improvement (CGI-I); exploratory endpoints included weight and body mass index (BMI) z-score. Results Seventy-seven participants were randomized (DCCR:38; placebo:39). Statistically significant increases in HQ-CT from baseline to week 16 were observed with placebo vs DCCR [least square (LS) mean (standard error) change 7.6 (1.09)] with placebo and 2.6 (1.12) with DCCR; P = .0022. CGI scores favored DCCR but were not significantly changed. Consistent with the hyperphagia response, the placebo cohort gained more weight and increased their BMI z-score more than the DCCR cohort [LS mean weight difference (95% confidence interval) −1.6 kg (−3.1, −0.1)]; LS mean z-score difference was −0.09 (−0.17, −0.01). Adverse events were similar with both treatments, with no serious adverse events in the DCCR arm. Conclusion Continued DCCR treatment was superior to placebo for hyperphagia. DCCR appears to offer meaningful therapeutic benefits for people with Prader-Willi syndrome. </jats:sec
Distinct Event-Related-Potential Biomarkers of Broad Versus Specific Dimensions of the Hierarchical Taxonomy of Psychopathology Externalizing Spectrum
No full textThe Hierarchical Taxonomy of Psychopathology (HiTOP) provides a dimensional framework for connecting psychological disorders to neural systems/processes. We examined how neurophysiological measures of cognitive-attentional (oddball P300) and perceptual-emotional processing (fear-face N170/P200) relate to dimensions of the HiTOP externalizing spectrum. Employing 666 community participants, we fit a model in which antagonistic externalizing and substance-problems subfactors, defined via symptom and questionnaire-scale measures, loaded with a disinhibitory trait scale onto a higher-order externalizing factor. Hierarchical regression was used to evaluate how much observed relations of each neural measure with the two subfactors reflected their unique variance versus their covariance (reflected in the general factor). P300’s relations were fully accounted for by the general factor, suggesting that impaired cognitive processing characterizes broad risk for externalizing problems. Neural indicators of sensitivity to others’ distress (N170, P200) were uniquely related to antagonistic externalizing. Findings highlight the HiTOP framework’s potential to advance biobehavioral understanding of psychopathology
The Src inhibitor peptide TAT-Cx43266-283 improves survival in an intracranial murine model of lung cancer brain metastasis.
No full textBACKGROUND: TAT-Cx43266-283 is a novel Src inhibitor, which has shown noteworthy antitumor effects in preclinical models of glioblastoma. Because Src plays a pivotal role in several tumor types, including lung cancer brain metastasis derived from non-small cell lung cancer (NSCLC) cells, we investigated the effect of TAT-Cx43266-283 in NSCLC-derived brain metastasis, a disease of unmet clinical need. METHODS: The effect of TAT-Cx43266-283 was studied in Lewis Lung Carcinoma (LLC), LSZ4, A549, and H441 NSCLC cells. The non-adherent stem-like LLC cells (LLC-CSCs) were intracranially implanted in immunocompetent mice to study the effect of TAT-Cx43266-283 in vivo. Phosphoproteomic analysis was employed to identify signaling pathways affected by TAT-Cx43266-283, and the most prominent were validated by Western blot and immunohistochemistry. Datasets of human NSCLC adenocarcinoma were also analyzed. RESULTS: TAT-Cx43266-283 significantly reduced LLC-CSCs viability and increased the survival of mice bearing brain tumors derived from these cells. Phosphoproteomic analysis identified MEK and ERK as key effectors of this treatment. TAT-Cx43266-283 induced apoptosis, impaired cytoskeletal dynamics and disrupted tumor vascularization. Patient datasets revealed that the targets of TAT-Cx43266-283 were significantly enriched in KRAS-altered lung tumors. Functional validation in several human and mouse KRAS-mutated non-adherent NSCLC cells confirmed that TAT-Cx43266-283 reduced their growth and invasiveness. CONCLUSIONS: Our results suggest that TAT-Cx43266-283 is a promising antitumor drug for lung cancer brain metastasis, as judged by the dual inhibition of Src and the MEK-ERK pathway in KRAS-mutated NSCLC. This study opens new avenues for exploring TAT-Cx43266-283 in other tumor types driven by these molecular alterations