The Responsibility to Protect: Answering Civil Conflict in the 21st Century – A RAMSI Case Study

This thesis will attempted to analyse the Responsibility to Protect, whether the doctrine has a future in the workings of the international system as an effective mechanism for conflict resolution and for consensus on issues that surround violations of life, liberty and security of person. The R2P is acknowledged as a very new doctrine, the that has its fair share of warranted criticism and a long way to go before it becomes customary law in the international system. Through an in-depth analysis of the Regional Assistance Mission to Solomon Islands, the thesis aimed to highlight the potential of the R2P in addressing modern conflict situations and providing long standing stability through committed assistance in capacity development. Despite failures in the RAMSI intervention, and the relatively small scale nature, it stands as a significant success in implementation of the R2P and exemplifies the doctrine‟s potential in application. At its base the R2P demonstrates a powerful normative shift towards the protection of the fundamental human rights of all people, and a shift away from traditional understandings of sovereignty as absolute

The Responsibility to Protect: Answering Civil Conflict in the 21st Century – A RAMSI Case Study

This thesis will attempted to analyse the Responsibility to Protect, whether the doctrine has a future in the workings of the international system as an effective mechanism for conflict resolution and for consensus on issues that surround violations of life, liberty and security of person. The R2P is acknowledged as a very new doctrine, the that has its fair share of warranted criticism and a long way to go before it becomes customary law in the international system. Through an in-depth analysis of the Regional Assistance Mission to Solomon Islands, the thesis aimed to highlight the potential of the R2P in addressing modern conflict situations and providing long standing stability through committed assistance in capacity development. Despite failures in the RAMSI intervention, and the relatively small scale nature, it stands as a significant success in implementation of the R2P and exemplifies the doctrine‟s potential in application. At its base the R2P demonstrates a powerful normative shift towards the protection of the fundamental human rights of all people, and a shift away from traditional understandings of sovereignty as absolute

100 years post-insulin: immunotherapy as the next frontier in type 1 diabetes.

Type 1 diabetes (T1D) is an autoimmune disease characterised by T cell-mediated destruction of the insulin-producing β cells in the pancreas. Similar to other autoimmune diseases, the incidence of T1D is increasing globally. The discovery of insulin 100 years ago dramatically changed the outlook for people with T1D, preventing this from being a fatal condition. As we celebrate the centenary of this milestone, therapeutic options for T1D are once more at a turning point. Years of effort directed at developing immunotherapies are finally starting to pay off, with signs of progress in new onset and even preventative settings. Here, we review a selection of immunotherapies that have shown promise in preserving β cell function and highlight future considerations for immunotherapy in the T1D setting

100 years post-insulin: immunotherapy as the next frontier in type 1 diabetes.

Type 1 diabetes (T1D) is an autoimmune disease characterised by T cell-mediated destruction of the insulin-producing β cells in the pancreas. Similar to other autoimmune diseases, the incidence of T1D is increasing globally. The discovery of insulin 100 years ago dramatically changed the outlook for people with T1D, preventing this from being a fatal condition. As we celebrate the centenary of this milestone, therapeutic options for T1D are once more at a turning point. Years of effort directed at developing immunotherapies are finally starting to pay off, with signs of progress in new onset and even preventative settings. Here, we review a selection of immunotherapies that have shown promise in preserving β cell function and highlight future considerations for immunotherapy in the T1D setting

Transforming undergraduate education in geriatric medicine:an innovative curriculum at Bristol Medical School

The World Health Organization (WHO) advocates investment in high-quality undergraduate education in geriatric medicine as a means of meeting the future needs of the aging population. However, there is a lack of evidence for the optimal delivery of training in this area. Rigorous pedagogical research is required to determine the most effective way to equip tomorrow’s doctors with the skills and knowledge to care for older adults with complex health and social care needs. The transition between two undergraduate medical curricula meant that Bristol Medical School (BMS) was uniquely positioned to innovate and evaluate undergraduate education in geriatric medicine. This transition marked BMS’ departure from a ‘traditional’ curriculum to case-based learning. The outgoing curriculum included a 4-week unit in geriatrics, whilst the new programme includes an 18-week clerkship titled ‘Complex Medicine in Older People’ (CMOP). CMOP is a clinical clerkship with 18 cases at its core, covering the fundamental aspects of geriatric medicine. The core cases and clinical learning are enhanced with five expert lectures, six tutorials and three journal clubs. Reflective practice is modelled and promoted with Balint groups and a book club. Consolidative workplace-based assessments and clinical portfolio mirror those used in postgraduate training, preparing students for professional practice. CMOP is iteratively improved in real-time using staff and student feedback. This marked shift in mode and duration of teaching affords the opportunity to evaluate the impact of differing education in geriatrics, providing an evidence-based model for teaching on aging. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s41999-022-00690-w

Enhanced liver fibrosis (ELF) score predicts hepatic decompensation and mortality

BACKGROUND &amp; AIMS: In community pathways for detection of liver disease the most common reason for referral is fibrosis assessment. We investigated the impact of adding the Enhanced Liver Fibrosis (ELF) score as a second-line test (subsequent to an indeterminate or high Fibrosis-4 index [FIB-4] and/or non-alcoholic fatty liver disease fibrosis score) to guide referral and prognostication in our multi-aetiology pathway.METHODS: Patients with ELF results from the intelligent Liver Function Testing (iLFT) pathway were recruited. Case note review was undertaken to compare ELF with endpoints of cirrhosis, hepatic decompensation, and mortality (liver-related and all-cause death).RESULTS: In total, 1,327 individuals were included with a median follow-up of 859 days and median ELF score of 10.2. Overall sensitivity for cirrhosis at the 9.8 threshold was 94% (100% for metabolic-associated steatotic liver disease, 89% for alcohol-related liver disease). Determination of the ELF score as a second-line test reduced the referral rate by 34%. ELF scores predicted hepatic outcomes; each unit change was associated with increased decompensation (adjusted Hazard Ratio [aHR] 2.215, 95% CI: 1.934-2.537) and liver-related mortality (aHR 2.024, 95% CI: 1.674-2.446). ELF outperformed FIB-4 for risk of liver-related mortality, particularly in the short-term (area under the curve [AUC] 94.3% vs. 82.8% at six months). Where FIB-4 was indeterminate, ELF had higher AUC for all outcomes within at least 2 years. ELF ≥13 was associated with particularly high rates of decompensation (26% within 90 days) and all-cause mortality (38% at 1 year). CONCLUSIONS: The addition of ELF reduced the number of individuals referred for fibrosis assessment following iLFT pathway testing and provided useful prognostic information. Individuals with ELF scores ≥13 were considered at high-risk of negative outcomes warranting urgent clinical assessment.IMPACT AND IMPLICATIONS: Primary care pathways for suspected liver disease are increasingly common and often lead to increased specialist hepatology referrals for fibrosis assessment. This study, using clinical follow-up for liver-related outcomes, provides further evidence supporting ELF testing to safely reduce referrals in a two-step approach when combined with other simple fibrosis markers. Additionally, ELF scores predict liver-related morbidity and mortality, with ELF scores ≥13 indicating particularly high-risk patients. This study may help inform the implementation of diagnostic pathways for early detection of liver disease and highlights the need for urgent review of individuals with very high ELF scores.</p

Highway deicing salt dynamic runoff to surface water and subsequent infiltration to groundwater during severe UK winters

Dynamic impact to the water environment of deicing salt application at a major highway (motorway) interchange in the UK is quantitatively evaluated for two recent severe UK winters. The contaminant transport pathway studied allowed controls on dynamic highway runoff and storm-sewer discharge to a receiving stream and its subsequent leakage to an underlying sandstone aquifer, including possible contribution to long-term chloride increases in supply wells, to be evaluated. Logged stream electrical-conductivity (EC) to estimate chloride concentrations, stream flow, climate and motorway salt application data were used to assess salt fate. Stream loading was responsive to salt applications and climate variability influencing salt release. Chloride (via EC) was predicted to exceed the stream Environmental Quality Standard (250 mg/l) for 33% and 18% of the two winters. Maximum stream concentrations (3500 mg/l, 15% sea water salinity) were ascribed to salt-induced melting and drainage of highway snowfall without dilution from, still frozen, catchment water. Salt persistance on the highway under dry-cold conditions was inferred from stream observations of delayed salt removal. Streambed and stream-loss data demonstrated chloride infiltration could occur to the underlying aquifer with mild and severe winter stream leakage estimated to account for 21 to 54% respectively of the 70 t of increased chloride (over baseline) annually abstracted by supply wells. Deicing salt infiltration lateral to the highway alongside other urban/natural sources were inferred to contribute the shortfall. Challenges in quantifying chloride mass/fluxes (flow gauge accuracy at high flows, salt loading from other roads, weaker chloride-EC correlation at low concentrations), may be largely overcome by modest investment in enhanced data acquisition or minor approach modification. The increased understanding of deicing salt dynamic loading to the water environment obtained is relevant to improved groundwater resource management, highway salt application practice, surface-water - ecosystem management, and decision making on highway drainage to ground

Olaparib and Ceralasertib (AZD6738) in Patients with Triple-Negative Advanced Breast Cancer: Results from Cohort E of the plasmaMATCH Trial (CRUK/15/010)

Olaparib; Ceralasertib; Triple-negative advanced breast cancerOlaparib; Ceralasertib; Càncer de mama avançat triple negatiuOlaparib; Ceralasertib; Cáncer de mama avanzado triple negativoPurpose: Approximately 10% to 15% of triple-negative breast cancers (TNBC) have deleterious mutations in BRCA1 and BRCA2 and may benefit from PARP inhibitor treatment. PARP inhibitors may also increase exogenous replication stress and thereby increase sensitivity to inhibitors of ataxia telangiectasia and Rad3-related (ATR) protein. This phase II study examined the activity of the combination of PARP inhibitor, olaparib, and ATR inhibitor, ceralasertib (AZD6738), in patients with advanced TNBC. Patients and Methods: Patients with TNBC on most recent biopsy who had received 1 or 2 lines of chemotherapy for advanced disease or had relapsed within 12 months of (neo)adjuvant chemotherapy were eligible. Treatment was olaparib 300 mg twice a day continuously and celarasertib 160 mg on days 1–7 on a 28-day cycle until disease progression. The primary endpoint was confirmed objective response rate (ORR). Tissue and plasma biomarker analyses were preplanned to identify predictors of response. Results: 70 evaluable patients were enrolled. Germline BRCA1/2 mutations were present in 10 (14%) patients and 3 (4%) patients had somatic BRCA mutations. The confirmed ORR was 12/70; 17.1% (95% confidence interval, 10.4–25.5). Responses were observed in patients without germline or somatic BRCA1/2 mutations, including patients with mutations in other homologous recombination repair genes and tumors with functional homologous recombination deficiency by RAD51 foci. Conclusions: The response rate to olaparib and ceralasertib did not meet prespecified criteria for activity in the overall evaluable population, but responses were observed in patients who would not be expected to respond to olaparib monotherapy.This research was funded by the Stand Up to Cancer Campaign for Cancer Research UK (CRUK/15/010, C30746/A19505; to S. Martin, H. Johnson, L. Moretti) with additional support from AstraZeneca, Guardant Health, Bio-Rad and Asociación Española Contra el Cáncer (AECC, INVES20095LLOP; to A. Llop-Guevara). The ICR Clinical Trials and Statistics Unit is supported by the Cancer Research UK core programme grant (C1491/A25351; to L.S. Kilburn). This study represents independent research supported by the National Institute for Health Research (NIHR) Biomedical Research Centre at the Royal Marsden National Health Service Foundation Trust and the Institute of Cancer Research, London, UK. In addition, plasmaMATCH is supported by the NIHR Manchester Clinical Research Facility at the Christie Hospital, Manchester, UK, the NIHR UCLH Clinical Research Facility at University College London Hospitals NHS Foundation Trust, London, UK, the Cancer Research UK Cambridge Centre, Cambridge Biomedical Research Centre (BRC-1215–20014) and Cambridge Experimental Cancer Medicine Centre, Cambridge, UK. The RAD51 analysis was supported with grants from the Spanish Association of Cancer Research and Instituto de Salud Carlos III (ERAPERMED2019–215, CPII19/00033, and INVES20095LLOP). plasmaMATCH is supported at participating sites in England by the NIHR Clinical Research Network, in Scotland by the Chief Scientist Office, and in Wales by Health and Care Research Wales

Reward-related attentional capture is associated with severity of addictive and obsessive-compulsive behaviors

A cue that signals reward can capture attention and elicit approach behaviors in people and animals. The current study examined whether attentional capture by reward-related cues is associated with severity of addiction-related and obsessive-compulsive behaviors. Participants were recruited via Mechanical Turk and included 143 adults [mean age 34 years (SD = 8.5), 43% female] who had endorsed at least one addiction-related or obsessive-compulsive behavior in the past month. All assessment components were delivered via the internet, and included questionnaires to assess severity of compulsivity-related problems across addiction-related and obsessive-compulsive behaviors, as well as a visual search task to measure reward-related attentional capture. Reward-related attentional capture was associated with severity of compulsivity, transdiagnostically. These findings have implications for understanding the mechanisms that underlie compulsive behaviors and suggest that reward-related attentional capture is a promising transdiagnostic cognitive risk marker for compulsivity