Identifying and targeting defective immune surveillance mechanisms in myeloma using multi-parameter single cell profiling by mass cytometry.

PhD ThesisMyeloma is a complex, incurable bone marrow malignancy of plasma cells with a diverse clinical course. Existing data suggests that abnormalities in T cell function and PD1 expression are present in myeloma and that immune subversion may be playing a role in progression of the disease. I hypothesise that characterisation of the cellular immunological landscape in myeloma will identify distinct functional populations which may offer therapeutic targets to restore immunological control of the disease. Mass cytometry is a novel, single cell analysis technique which enables simultaneous assessment of more than 30 cell surface and intracellular antigens by utilising metal tagged antibody probes. Using this technology and an algorithmic based data analysis approach alongside traditional data analysis techniques I explored the bone marrow microenvironment in 9 control, 18 NDMM and 9 RRMM samples. RRMM samples were drawn from patients receiving dual targeting of CD38 and PDL1. In NDMM I demonstrate that immune microenvironment changes include defects in antigen presenting populations, effector and helper lymphocyte populations and NK cells. These changes are present before treatment has been initiated and have prognostic significance. These functional defects are associated with upregulation of PD1 and PDL1 expression across multiple lineages. In the RRMM setting treatment targeting PDL1 and CD38 results in early functional cytotoxicity and cytokine production signals. Defective immunological responses correlate with poor clinical outcome and there is potential to restore immune function, providing a strong argument for considering multi-lineage immunological damage to represent a form of symptomatic myeloma

Copula/Auxiliary Comparisons in African American and Impaired Standard American English

The valid identification and description of language impairment in children who speak African American English (AAE) has been a major clinical challenge for over 30 years. This challenge centers on the issue of deficit versus difference for language features that contrast with Standard American English. The distinction between deficit and difference in identifying language disorders in child African American English speakers is the key to valid language assessment in AAE. Most syntactic targets in SAE are presumably invariable while many syntactic targets in AAE are variable. For example, the SAE target syntactic form for the copula is would be represented by He is bad . Whereas that same production in AAE might yield either He is bad or He_bad . Our research focuses on how one determines if a child AAE speaker who uses He_bad does so as a function of dialect, not impairment

REDD+: Lessons from National and Subnational Implementation : Ending Tropical Deforestation: a stock-take of progress and challenges

REDD+—which stands for reducing emissions from deforestation and forest degradation, and the role of conservation, sustainable management of forests, and enhancement of forest carbon stocks in developing countries—debuted on the global stage more than a decade ago. The idea prompted high expectations that an approach that featured results-based incentives for reducing tropical deforestation and degradation could rapidly succeed where other approaches had failed. Since then, over 50 countries have initiated REDD+ strategies; subnational governments have experimented with jurisdictional REDD+ programs; and more than 350 REDD+ projects have been implemented globally. What are the lessons learned from REDD+ initiatives so far? How can these lessons support future forest-based climate change mitigation

Forest-Based Climate Mitigation : Lessons from REDD+ Implementation

This issue brief is based on a 2018 working paper and summarizes the REDD+ experience over the past decade, taking stock of lessons learned from REDD+ implementation to inform future forest-based climate mitigation activities

Prognostic and predictive effect of KRAS gene copy number and mutation status in early stage non-small cell lung cancer patients

Background: In the current analysis, we characterize the prognostic significance of Methods: Clinical and genomic data from the LACE (Lung Adjuvant Cisplatin Evaluation)-Bio consortium was utilized. CNAs were categorized as Gain (CN ≥2) or Neutral (Neut)/Loss; Results: Of the 946 (399 adenocarcinoma) NSCLC patients, 41 [30] had MUT + Gain, 145 [99] MUT + Neut/Loss, 125 [16] WT + Gain, and 635 [254] WT + Neut/Loss. A non-significant trend towards worse lung cancer-specific survival (LCSS; HR =1.34; 95% CI, 0.83-2.17, P=0.232), DFS (HR =1.34; 95% CI, 0.86-2.09, P=0.202) and OS (HR =1.59; 95% CI, 0.99-2.54, P=0.055) was seen in Conclusions: A small prognostic effect o

Unravelling the complex speciation of halozincate ionic liquids using X-ray spectroscopies and calculations

Using a combination of liquid-phase experimental X-ray spectroscopy experiments and small-scale calculations we have gained new insights into the speciation of halozincate anions in ionic liquids (ILs). Both core and valence X-ray photoelectron spectroscopy (XPS) were performed directly on the liquid-phase ILs, supplemented by Zn 1s X-ray absorption near edge structure (XANES) spectroscopy. Density functional theory (DFT) calculations were carried out on both 1- and 2- halozincate anions, in both a generalised solvation model SMD (Solvation Model based on Density) and the gas phase, to give XP spectra and total energy differences; time-dependent DFT was used to calculate XA spectra. Speciation judgements were made using a combination of the shape and width of experimental spectra, and visual matches to calculated spectra. For 2- halozincate anions, excellent matches were found between experimental and calculated XP spectra, clearly showing that only 2- halozincate anions were present at all zinc halide mole fraction, x, studied. At specific x (0.33, 0.50, 0.60) only one halozincate anion was present; equilibria of different halozincate anions at those x were not observed. All findings show that chlorozincate anion and bromozincate anion speciation matched at the same x. Based on the results, predictions are made of the halozincate anion speciation for all x up to 0.67. Caution is advised when using differences in calculated total energies obtained from DFT to judge halozincate anion speciation, even when the SMD was employed, as predictions based on total energy differences did not always match the findings from experimental and calculated spectra. Our findings clearly establish that the combination of high-quality experimental data from multiple spectroscopies and a wide range of calculated structures are essential to have high confidence in halozincate anion speciation identification

Brexucabtagene autoleucel for relapsed or refractory mantle cell lymphoma in the United Kingdom: A real‐world intention‐to‐treat analysis

Brexucabtagene autoleucel (brexu‐cel) is an autologous CD19 CAR T‐cell product, approved for relapsed/refractory (r/r) mantle cell lymphoma (MCL). In ZUMA‐2, brexu‐cel demonstrated impressive responses in patients failing ≥2 lines, including a bruton's tyrosine kinase inhibitor, with an overall and complete response rate of 93% and 67%, respectively. Here, we report our real‐world intention‐to‐treat (ITT) outcomes for brexu‐cel in consecutive, prospectively approved patients, from 12 institutions in the United Kingdom between February 2021 and June 2023, with a focus on feasibility, efficacy, and tolerability. Of 119 approved, 104 underwent leukapheresis and 83 received a brexu‐cel infusion. Progressive disease (PD) and/or manufacturing (MF) were the most common reasons for failure to reach harvest and/or infusion. For infused patients, best overall and complete response rates were 87% and 81%, respectively. At a median follow‐up of 13.3 months, median progression‐free survival (PFS) for infused patients was 21 months (10.1–NA) with a 6‐ and 12‐month PFS of 82% (95% confidence interval [CI], 71–89) and 62% (95% CI, 49–73), respectively. ≥Grade 3 cytokine release syndrome and neurotoxicity occurred in 12% and 22%, respectively. On multivariate analysis, inferior PFS was associated with male sex, bulky disease, ECOG PS > 1 and previous MF. Cumulative incidence of non‐relapse mortality (NRM) was 6%, 15%, and 25% at 6, 12, and 24 months, respectively, and mostly attributable to infection. Outcomes for infused patients in the UK are comparable to ZUMA‐2 and other real‐world reports. However, ITT analysis highlights a significant dropout due to PD and/or MF. NRM events warrant further attention

Implementing a quality improvement programme in palliative care in care homes: a qualitative study

<p>Abstract</p> <p>Background</p> <p>An increasing number of older people reach the end of life in care homes. The aim of this study is to explore the perceived benefits of, and barriers to, implementation of the Gold Standards Framework for Care Homes (GSFCH), a quality improvement programme in palliative care.</p> <p>Methods</p> <p>Nine care homes involved in the GSFCH took part. We conducted semi-structured interviews with nine care home managers, eight nurses, nine care assistants, eleven residents and seven of their family members. We used the Framework approach to qualitative analysis. The analysis was deductive based on the key tasks of the GSFCH, the 7Cs: communication, coordination, control of symptoms, continuity, continued learning, carer support, and care of the dying. This enabled us to consider benefits of, and barriers to, individual components of the programme, as well as of the programme as a whole.</p> <p>Results</p> <p>Perceived benefits of the GSFCH included: improved symptom control and team communication; finding helpful external support and expertise; increasing staff confidence; fostering residents' choice; and boosting the reputation of the home. Perceived barriers included: increased paperwork; lack of knowledge and understanding of end of life care; costs; and gaining the cooperation of GPs. Many of the tools and tasks in the GSFCH focus on improving communication. Participants described effective communication within the homes, and with external providers such as general practitioners and specialists in palliative care. However, many had experienced problems with general practitioners. Although staff described the benefits of supportive care registers, coding predicted stage of illness and advance care planning, which included improved communication, some felt the need for more experience of using these, and there were concerns about discussing death.</p> <p>Conclusions</p> <p>Most of the barriers described by participants are relevant to other interventions to improve end of life care in care homes. There is a need to investigate the impact of quality improvement programmes in care homes, such as the GSFCH, on a wider range of outcomes for residents and their families, and to monitor the sustainability of any resulting improvements. It is also important to explore the impact of the different components of these complex interventions.</p

History, Commemoration, and Belief: Abraham Lincoln in American Memory, 1945-2001

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/91765/1/Schuman-History_Commemoration_Belief.pd