Declaration on Religious Freedom: Three Developmental Aspects

This article considers key aspects of the Vatican II declaration on religious freedom Dignitatis Humanae and John Courtney Murray’s role in its formulation. This will be done with concern for the broader theological context as exemplified in Thomas Aquinas. After a brief outline of the difficulties Murray faced and their resolution, the discussion moves in four stages: a summary of the key ideas in the document on the relationship between truth and freedom from which the following three ideas receive a focus; the person (dignity and conscience); rights and their evolving context; historical consciousness and its role as a mode and locus of theological reflection. Here, a suggestion is offered about the interrelationship of speculative and practical reason in doctrinal development

Enhancing Care Transitions for Older People through Interprofessional Simulation: A Mixed Method Evaluation

Introduction: The educational needs of the health and social care workforce for delivering effective integrated care are important. This paper reports on the development, pilot and evaluation of an interprofessional simulation course, which aimed to support integrated care models for care transitions for older people from hospital to home. Theory and methods: The course development was informed by a literature review and a scoping exercise with the health and social care workforce. The course ran six times and was attended by health and social care professionals from hospital and community (n=49). The evaluation aimed to elicit staff perceptions of their learning about care transfers of older people and to explore application of learning into practice and perceived outcomes. The study used a sequential mixed method design with questionnaires completed pre (n=44) and post (n=47) course and interviews (n=9) 2-5 months later. Results:Participants evaluated interprofessional simulation as a successful strategy. Post-course, participants identified learning points and at the interviews, similar themes with examples of application in practice were: Understanding individual needs and empathy; Communicating with patients and families; Interprofessional working; Working across settings to achieve effective care transitions. Conclusions and discussion:An interprofessional simulation course successfully brought together health and social care professionals across settings to develop integrated care skills and improve care transitions for older people with complex needs from hospital to home

Explaining coronary heart disease trends in Hong Kong: creation of a model for policy and planning.

1. The largest contribution of coronary heart disease (CHD) mortality reductions was from medical treatment. 2. A smaller contribution was estimated to be due to risk factors changes. 3. Improvement of treatment uptake levels can have a substantial effect in reducing CHD mortality.published_or_final_versio

A method for acquiring random range uncertainty probability distributions in proton therapy.

In treatment planning we depend upon accurate knowledge of geometric and range uncertainties. If the uncertainty model is inaccurate then the plan will produce under-dosing of the target and/or overdosing of OAR. We aim to provide a method for which centre and site-specific population range uncertainty due to inter-fraction motion can be quantified to improve the uncertainty model in proton treatment planning. Daily volumetric MVCT data from previously treated radiotherapy patients has been used to investigate inter-fraction changes to water equivalent path-length (WEPL). Daily image-guidance scans were carried out for each patient and corrected for changes in CTV position (using rigid transformations). An effective depth algorithm was used to determine residual range changes, after corrections had been applied, throughout the treatment by comparing WEPL within the CTV at each fraction for several beam angles. As a proof of principle this method was used to quantify uncertainties for inter-fraction range changes for a sample of head and neck patients of [Formula: see text] mm, [Formula: see text] mm and overall [Formula: see text] mm. For prostate [Formula: see text] mm, [Formula: see text] mm and overall [Formula: see text] mm. The choice of beam angle for head and neck did not affect the inter-fraction range error significantly; however this was not the same for prostate. Greater range changes were seen using a lateral beam compared to an anterior beam for prostate due to relative motion of the prostate and femoral heads. A method has been developed to quantify population range changes due to inter-fraction motion that can be adapted for the clinic. The results of this work highlight the importance of robust planning and analysis in proton therapy. Such information could be used in robust optimisation algorithms or treatment plan robustness analysis. Such knowledge will aid in establishing beam start conditions at planning and for establishing adaptive planning protocols.This work was funded by a Medical Research Council Studentship to the University of Cambridge (G1000384). Dr S. Holloway is currently supported by a Cancer Research UK Centres Network Accelerator Award Grant (A21993) to the ART-NET consortium

Epidermal growth factor receptor variant III mediates head and neck cancer cell invasion via STAT3 activation.

Epidermal growth factor receptor (EGFR) is frequently overexpressed in head and neck squamous cell carcinoma (HNSCC) where aberrant signaling downstream of this receptor contributes to tumor growth. EGFR variant III (EGFRvIII) is the most commonly altered form of EGFR and contains a truncated ligand-binding domain. We previously reported that EGFRvIII is expressed in up to 40% of HNSCC tumors where it is associated with increased proliferation, tumor growth and chemoresistance to antitumor drugs including the EGFR-targeting monoclonal antibody cetuximab. Cetuximab was FDA-approved in 2006 for HNSCC but has not been shown to prevent invasion or metastasis. This study was undertaken to evaluate the mechanisms of EGFRvIII-mediated cell motility and invasion in HNSCC. We found that EGFRvIII induced HNSCC cell migration and invasion in conjunction with increased signal transducer and activator of transcription 3 (STAT3) activation, which was not abrogated by cetuximab treatment. Further investigation showed that EGF-induced expression of the STAT3 target gene HIF1-α, was abolished by cetuximab in HNSCC cells expressing wild-type EGFR under hypoxic conditions, but not in EGFRvIII-expressing HNSCC cells. These results suggest that EGFRvIII mediates HNSCC cell migration and invasion by increased STAT3 activation and induction of HIF1-α, which contribute to cetuximab resistance in EGFRvIII-expressing HNSCC tumors

NRF2 Mediates Therapeutic Resistance to Chemoradiation in Colorectal Cancer through a Metabolic Switch

Radiation resistance is a significant clinical problem in rectal cancer treatment, the mechanisms of which are poorly understood. NRF2 signalling is known to contribute to chemo/radioresistance in some cancers, but its role in therapeutic resistance in colorectal cancer (CRC) is unexplored. Using siRNA and CRiSPR/Cas9 isogenic CRC cell lines, we investigated the effect of the knockdown and upregulation of the NRF2 pathway on chemo-radiosensitivity. Poly (A) enriched RNA sequencing and geneset enrichment analysis (GSEA) were carried out on both sensitive and resistant cell models for mechanistic insights. Finally, a cohort of rectal patient samples was profiled to understand the clinical relevance of NRF2 signalling. Radioresistant cell lines were significantly radiosensitised by siRNA knockdown (SW1463, SER10 1.22, ANOVA p < 0.0001; HT55, SER10 1.17, ANOVA p < 0.01), but not the (already) radiosensitive HCT116. The constitutive activation of NRF2 via a CRISPR Cas9 NFE2L2 mutation, E79K, induced radioresistance in HCT116 (SER10 0.71, ANOVA, p < 0.0001). GSEA demonstrated significant opposing metabolic dependencies in NRF2 signalling, specifically, the downregulation of amino acid and protein synthesis with low levels of NRF2 and upregulation with over expression. In a clinical cohort of 127 rectal patients, using a validated mRNA signature, higher baseline NRF2 signalling was associated with incomplete responses to radiation higher final neoadjuvant rectal (NAR) score (OR 1.34, 95% C.I. 1.01–1.80, LRT p-value = 0.023), where high NAR indicates poor radiation response and poor long-term prognosis. This is the first demonstration of NRF2-mediated radiation resistance in colorectal cancer. NRF2 appears to regulate crucial metabolic pathways, which could be exploited for therapeutic interventions

La filogenética molecular revela múltiples orígenes de vicariancia terciaria de los árboles africanos de la selva tropical

Background Tropical rain forests are the most diverse terrestrial ecosystems on the planet. How this diversity evolved remains largely unexplained. In Africa, rain forests are situated in two geographically isolated regions: the West-Central Guineo-Congolian region and the coastal and montane regions of East Africa. These regions have strong floristic affinities with each other, suggesting a former connection via an Eocene pan-African rain forest. High levels of endemism observed in both regions have been hypothesized to be the result of either 1) a single break-up followed by a long isolation or 2) multiple fragmentation and reconnection since the Oligocene. To test these hypotheses the evolutionary history of endemic taxa within a rain forest restricted African lineage of the plant family Annonaceae was studied. Molecular phylogenies and divergence dates were estimated using a Bayesian relaxed uncorrelated molecular clock assumption accounting for both calibration and phylogenetic uncertainties. Results Our results provide strong evidence that East African endemic lineages of Annonaceae have multiple origins dated to significantly different times spanning the Oligocene and Miocene epochs. Moreover, these successive origins (c. 33, 16 and 8 million years – Myr) coincide with known periods of aridification and geological activity in Africa that would have recurrently isolated the Guineo-Congolian rain forest from the East African one. All East African taxa were found to have diversified prior to Pleistocene times. Conclusion Molecular phylogenetic dating analyses of this large pan-African clade of Annonaceae unravels an interesting pattern of diversification for rain forest restricted trees co-occurring in West/Central and East African rain forests. Our results suggest that repeated reconnections between the West/Central and East African rain forest blocks allowed for biotic exchange while the break-ups induced speciation via vicariance, enhancing the levels of endemicity. These results provide an explanation for present day distribution patterns and origins of endemicity for African rain forest trees. Moreover, given the pre-Pleistocene origins of all the studied endemic East African genera and species, these results also offer important insights for setting conservation priorities in these highly diversified but threatened ecosystems

Why and how the work of Motor Neurone Disease Associations matters before and during bereavement: a consumer perspective

Background: Studies on the experiences of consumers with Motor Neurone Disease Associations at end of life and bereavement are lacking, and their role and capability within the broader sectors of health and disability are unknown. Objectives: To ascertain the experiences and views of bereaved motor neurone disease caregivers with Motor Neurone Disease Associations about service gaps and needed improvements before and during bereavement and to propose a model of care that fits with consumer preferences and where Motor Neurone Disease Associations are effective enablers of care. Methods: A national bereavement survey was facilitated in 2019 by all Motor Neurone Disease Associations in Australia. A total of 363 respondents completed the section on support provided by Motor Neurone Disease Associations. A mixed-method design was used. Results: Respondents were generally positive about support received before bereavement (73-76%), except for emotional support (55%). Positive experiences related to the following: information, equipment advice/provision, advocacy/linking to services, showing empathy/understanding, personal contact and peer social support. Negative experiences included lack of continuity in case management and contact, perceived lack of competence or training, lack of emotional support and a lack of access to motor neurone disease services in rural areas. Suggested improvements were as follows: more contact and compassion at end of life and postdeath; better preparation for end of life; option of discussing euthanasia; providing referrals and links for counseling; access to caregiver support groups and peer interaction; provision of a genuine continuum of care rather than postdeath abandonment; guidance regarding postdeath practicalities; and more access to bereavement support in rural areas. Conclusion: This study provides consumer perspectives on driving new or improved initiatives by Motor Neurone Disease Associations and the need for a national standardised approach to training and service delivery, based on research evidence. A public health approach to motor neurone disease end-of-life care, of international applicability, is proposed to address the needs and preferences of motor neurone disease consumers, while supporting the capability of Motor Neurone Disease Associations within a multidisciplinary workforce to deliver that care