Dielectric molding apparatus Patent

Dielectric apparatus for heating, fusing, and hardening of organic matrix to form plastic material into shaped produc

The Political Mentoring Toolkit

ESRC Impact Report, to be disseminated to all UK local authorities by Local Government Group

Patient Preference Studies for Advanced Prostate Cancer Treatment Along the Medical Product Life Cycle: Systematic Literature Review

Background: Patient preference studies can inform decision-making across all stages of the medical product life cycle (MPLC). The treatment landscape for advanced prostate cancer (APC) treatment has substantially changed in recent years. However, the most patient-relevant aspects of APC treatment remain unclear. This systematic review of patient preference studies in APC aimed to summarize the evidence on patient preferences and patient-relevant aspects of APC treatments, and to evaluate the potential contribution of existing studies to decision-making within the respective stages of the MPLC. Methods: We searched MEDLINE and EMBASE for studies evaluating patient preferences related to APC treatment up to October 2020. Two reviewers independently performed screening, data extraction and quality assessment in duplicate. We descriptively summarized the findings and analyzed the studies regarding their contribution within the MPLC using an analytical framework. Results: Seven quantitative preference studies were included. One study each was conducted in the marketing approval and the health technology assessment (HTA) and reimbursement stage, and five were conducted in the post-marketing stage of the MPLC. While almost all stated to inform clinical practice, the specific contributions to clinical decision-making remained unclear for almost all studies. Evaluated attributes related to benefits, harms, and other treatment-related aspects and their relative importance varied relevantly between studies. All studies were judged of high quality overall, but some methodological issues regarding sample selection and the definition of patient-relevant treatment attributes were identified. Conclusion: The most patient-relevant aspects regarding the benefits and harms of APC treatment are not yet established, and it remains unclear which APC treatments are preferred by patients. Findings from this study highlight the importance of transparent reporting and discussion of study findings according to their aims and with respect to their stage within the MPLC. Future research may benefit from using the MPLC framework for analyzing or determining the aims and design of patient preference studies. Keywords: benefit-harm assessment; medical product life cycle; patient preferences; patient-centered care; preference research; prostate cancer; systematic revie

Influence of water availability in the distributions of branched glycerol dialkyl glycerol tetraether in soils of the Iberian Peninsula

The combined application of the MBT (degree of methylation) and CBT (degree of cyclization) indices, based on the distribution of branched glycerol dialkyl glycerol tetraethers (brGDGTs) in soils, has been proposed as a paleoproxy to estimate mean annual temperature (MAT). CBT quantifies the degree of cyclization of brGDGTs and relates to soil pH. MBT and the simplified version MBT' quantify the degree of methylation of brGDGTs and relate to MAT and soil pH. However, other factors such as soil water availability have also been suggested to influence MBT' and possibly restrict the combined application of the MBT' and CBT indices as a paleotemperature proxy. To assess the effect of hydrological conditions on MBT' and CBT, a set of 23 Iberian Peninsula soil samples, covering a MAT range from 10 to 18 °C and a mean annual precipitation (MAP) range of 405 mm to 1455 mm, was analyzed. We found that the CBT was indeed significantly correlated with soil pH in our sample set. In contrast, MBT' was not correlated with MAT but had a significant correlation with the aridity index (AI), a parameter related to water availability in soils. The AI can explain 50% of the variation of the MBT', and 70% of the residuals of MAT estimated with the MBT/CBT proxy as compared to instrumentally measured MAT. We propose that, in arid settings, where water may be an ecologically limiting factor, MBT' is influenced by hydrological conditions rather than temperature. Thus, our results suggest that the combination of MBT' and CBT indices should be applied with caution in paleotemperature reconstructions in soils from dry subhumid to hyperarid environments

Electrical and Thermal Transport at the Planckian Bound of Dissipation in the Hydrodynamic Electron Fluid of WP2

Materials with strongly-correlated electrons exhibit interesting phenomena such as metal-insulator transitions and high-temperature superconductivity. In stark contrast to ordinary metals, electron transport in these materials is thought to resemble the flow of viscous fluids. Despite their differences, it is predicted that transport in both, conventional and correlated materials, is fundamentally limited by the uncertainty principle applied to energy dissipation. Here we discover hydrodynamic electron flow in the Weyl-semimetal tungsten phosphide (WP2). Using thermal and magneto-electric transport experiments, we observe the transition from a conventional metallic state, at higher temperatures, to a hydrodynamic electron fluid below 20 K. The hydrodynamic regime is characterized by a viscosity-induced dependence of the electrical resistivity on the square of the channel width, and by the observation of a strong violation of the Wiedemann-Franz law. From magneto-hydrodynamic experiments and complementary Hall measurements, the relaxation times for momentum and thermal energy dissipating processes are extracted. Following the uncertainty principle, both are limited by the Planckian bound of dissipation, independent of the underlying transport regime

Survival modelling and cost-effectiveness analysis of treatments for newly diagnosed metastatic hormone-sensitive prostate cancer

Background In metastatic hormone-sensitive prostate cancer (mHSPC) treatment, survival benefits have been shown by adding docetaxel or recent androgen receptor axis-targeted therapies (ARATs) abiraterone, apalutamide, or enzalutamide to androgen deprivation therapy (ADT). However, the optimal treatment strategy in terms of costs and effects is unclear, not least due to high ARAT costs. Methods To assess treatment cost-effectiveness, we developed a Markov cohort model with health states of progression-free disease, progressive disease and death for men with newly diagnosed mHSPC, with a 30-year time horizon. Survival data, adverse events and utilities were informed by randomized controlled trial results, our meta-analysis of re-created individual patient survival data, and publicly available sources of unit costs. We applied a Swiss healthcare payer perspective and discounted costs and effects by 3%. Results We found a significant overall survival benefit for ADT+abiraterone versus ADT+docetaxel. The corresponding incremental cost-effectiveness ratio (ICER) was predicted to be EUR 39,814 per quality-adjusted life-year (QALY) gained. ADT+apalutamide and ADT+enzalutamide incurred higher costs and lower QALYs compared to ADT+abiraterone. For all ARATs, drug costs constituted the most substantial cost component. Results were stable except for a large univariable reduction in the pre-progression utility under ADT+abiraterone and very large variations in drug prices. Conclusions Our model projected ADT+abiraterone to be cost-effective compared to ADT+docetaxel at a willingness-to-pay threshold of EUR 70,400/QALY (CHF 100,000 applying purchasing power parities). Given lower estimated QALYs for ADT+apalutamide and ADT+enzalutamide compared to ADT+abiraterone, the former only became cost-effective (the preferred) treatment option(s) at substantial 75–80% (80–90%) price reductions

Treatments for Metastatic Hormone-sensitive Prostate Cancer: Systematic Review, Network Meta-analysis, and Benefit-harm assessment

Context: Multiple treatments for metastatic, hormone-sensitive prostate cancer (mHSPC) are available, but their effects on health-related quality of life (HRQoL) and benefit-harm balance remain unclear. Objective: To assess clinical effectiveness regarding survival and HRQoL, safety, and benefit-harm balance of mHSPC treatments. Evidence acquisition: We searched MEDLINE, EMBASE, CENTRAL, and ClinicalTrials.gov until March 1, 2022. Randomized controlled trials (RCTs) comparing docetaxel, abiraterone, enzalutamide, apalutamide, darolutamide, and radiotherapy combined with androgen deprivation therapy (ADT) mutually or with ADT alone were eligible. Three reviewers independently performed screening, data extraction, and risk of bias assessment in duplicate. Evidence synthesis: Across ten RCTs, we found relevant survival benefits for ADT + docetaxel (high certainty according to the Grading of Recommendations, Assessment, Development and Evaluation [GRADE]), ADT + abiraterone (moderate certainty), ADT + enzalutamide (low certainty), ADT + apalutamide (high certainty), and ADT + docetaxel + darolutamide (high certainty) compared with ADT alone. ADT + radiotherapy appeared effective only in low-volume de novo mHSPC. We found a short-term HRQoL decrease lasting 3-6 mo for ADT + docetaxel (moderate certainty) and a potential HRQoL benefit for ADT + abiraterone up to 24 mo of follow-up (moderate certainty) compared with ADT alone. There was no difference in HRQoL for ADT + enzalutamide, ADT + apalutamide, or ADT + radiotherapy over ADT alone (low-high certainty). Grade 3-5 adverse effect rates were increased with all systemic combination treatments. A benefit-harm assessment showed high probabilities (>60%) for a net clinical benefit with ADT + abiraterone, ADT + enzalutamide, and ADT + apalutamide, while ADT + docetaxel and ADT + docetaxel + darolutamide appeared unlikely (<40%) to be beneficial. Conclusions: Despite substantial survival benefits, no systemic combination treatment showed a clear HRQoL improvement compared with ADT alone. We found evidence for a short-term HRQoL decline with ADT + docetaxel and a higher net clinical benefit with ADT + abiraterone, ADT + apalutamide and ADT + enzalutamide. While individualized decision-making remains important and economic factors need to be considered, the evidence may support a general preference for the combination of ADT with androgen receptor axis-targeted therapies over docetaxel-containing strategies. Patient summary: We assessed different combination treatments for metastatic hormone-sensitive prostate cancer. While survival was better with all systemic combination treatments, there was no clear improvement in health-related quality of life compared with androgen deprivation therapy alone. Novel hormonal combination treatments had a more favorable benefit-harm balance than combination treatments that include chemotherapy. Keywords: Adverse effects; Benefit-harm assessment; Benefit-harm balance; Health-related quality of life; Network meta-analysis; Overall survival; Prostate cancer; Systematic revie

Surgical Trauma and Postoperative Immune Dysfunction

Background: In postoperative sepsis, mortality is increased due to the surgically induced immune dysfunction. Further causes of this traumatic effect on the immune system include burn injuries and polytrauma, as well as endogenous traumata like stroke. Several animal models have been defined to analyse the characteristics of trauma-induced immune suppression. This article will correlate our results from animal studies and clinical observations with the recent literature on postoperative immune suppression. Methods: The previously described model of surgically induced immune dysfunction (SID) was performed in mice by laparotomy and manipulation of the small intestine in the antegrade direction. Blood samples were collected 6 and 72 h following SID to analyse the white blood cell count and corticosterone levels. To assess the postoperative immune status in humans, we analysed expression of HLA-DR on monocytes of 118 patients by flow cytometry prior to and 24, 48 and 72 h after surgery. Results: The postoperative immune suppression in our SID model is characterised by lymphocytopenia and significantly increased corticosterone levels in mice dependent on the degree of surgical trauma. This is comparable to the postoperative situation in humans: major and especially long-lasting surgery results in a significantly reduced expression of HLA-DR on circulating monocytes. Previous studies describe a similar situation following burn injury and endogenous trauma, i.e. stroke. Conclusions: We suggest the completion of our previously published sepsis classification due to the immune status at the onset of sepsis: type A as the spontaneously acquired sepsis and type B as sepsis in trauma-induced pre-existing immune suppression