Evaluation of the implementation and routine clinical effectiveness of the Newcastle Model for behaviours that challenge in dementia

Background Dementia is a syndrome caused by various diseases or injuries that affect the brain. It causes progressive decline in cognitive function resulting in impaired memory, understanding, learning, language and judgement. This is usually accompanied by increasing decline in the individual’s ability to regulate their emotions and behaviour. Systematic review: Current generations of Lesbian, Gay, Bisexual, Transgender and Queer (LGBTQ+) people have lived through marked pathologisation of their minority status. LGBTQ+ people report poorer health outcomes and experience social inequalities that increase modifiable risk factors for developing dementia. They are more likely to require residential care than heterosexual peers as they age. This review sought to identify the experiences and care needs of LGBTQ+ people affected by dementia, and those who care for them, and critically appraise the quality of the current evidence base. Empirical: Behaviours that challenge (BtC) such as physical and verbal aggression are displayed by most people living with dementia (PLwD) to some extent. They are associated with poorer quality of life, caregiver burden, institutionalisation, and distress. The Newcastle Model (TNM) is an intensive formulation driven intervention conceptualising BtC as attempts to meet unmet needs. It posits BtC and distress throughout the system reduce when the PLwD’s unmet needs are identified, understood and addressed. There is an emerging evidence base demonstrating the effectiveness of this approach. This study aimed to a) evaluate the effectiveness of the routine clinical implementation of TNM in two behaviour support services (BSS-A and BSS-B) and b) compare the effectiveness of standard and shortened delivery versions of TNM. Methods: Systematic review: A systematic search of electronic databases was conducted to identify papers that explored the experiences and care needs of LGBTQ+ people affected by dementia. All designs were included. The methodological quality of papers was assessed. Findings were synthesised using narrative synthesis. Empirical paper: Retrospective analysis of routinely collected clinical data from two specialist behaviour support services (BSS-A and BSS-B) that use TNM was conducted. The Cohen Mansfield Agitation Inventory (CMAI), a measure of BtC, was administered at baseline and post-intervention. Mixed two-way ANOVAs were used to analyse the difference within participants CMAI scores pre and post intervention, between behaviour support services, and shortened and standard delivery formats of TNM. Results Systematic review: 24 papers were included. The sources were heterogeneous, and quality of the included papers varied considerably. The evidence synthesis was informed by the highest quality qualitative papers (n=8) and cross checked against other evidence sources. Three themes were identified: ‘Impact of gender and sexual identity on experiences of dementia’; ‘Experiences of navigating health and social care systems’ and ‘Characteristics of culturally competent dementia care’. Empirical Paper: 210 participants were included: 143 in BSS-A and 67 in BSS-B. There was a significant reduction in CMAI scores post intervention (p< .05) in both services, across shortened and standard delivery formats. There was no difference in patient outcome (p>.05) when BSS-A was following the standard TNM protocol (mean delivery duration 23.2 weeks) or the condensed version (mean delivery duration 11.7 weeks). Conclusion Systematic Review: The current evidence base is small and of varying methodological quality. LGBTQ+ people affected by dementia experience unique challenges and have specific care needs that vary within the LGBTQ+ population. Further research is warranted. Empirical Paper: TNM is an effective intervention for reducing BtC in PLwD. The model has ecological validity, demonstrated by two different behaviour support teams outwith that of the TNM developers. A condensed model protocol may promote fidelity to the model and reduce intervention duration whilst maintaining clinical effectiveness

Procalcitonin increase is associated with the development of critical care-acquired infections in COVID-19 ARDS

Secondary bacterial infection in COVID-19 patients is associated with increased mortality and disproportionately affects critically ill patients. This single-centre retrospective observational study investigates the comparative efficacy of change in procalcitonin (PCT) and other commonly available biomarkers in revealing or predicting microbiologically proven secondary infection in critical COVID-19 patients. Adult patients admitted to an intensive care unit (ICU) with confirmed SARS-CoV-2 infection between 9 March 2020 and 5 June 2020 were recruited to the study. For daily biomarker and secondary infection, laboratory-confirmed bloodstream infection (LCBI) and ventilator-associated pneumonia/tracheobronchitis (VAP/VAT) data were collected. We observed a PCT rise in 53 (81.5%) of the patients, a C-reactive protein (CRP) rise in 55 (84.6%) and a white blood cell count (WBC) rise in 61 (93.8%). Secondary infection was confirmed in 33 (50.8%) of the patients. A PCT rise was present in 97.0% of patients with at least one confirmed VAP/VAT and/or LCBI event. CRP and WBC rises occurred in 93.9% and 97.0% of patients with confirmed VAP/VAT and/or LCBI, respectively. Logistic regression analysis found that, when including all biomarkers in the same model, there was a significant association between PCT rise and the occurrence of LCBI and/or VAP/VAT (OR = 14.86 95%CI: 2.20, 342.53; p = 0.021). Conversely, no statistically significant relationship was found between either a CRP rise (p = 0.167) or a WBC rise (p = 0.855) and the occurrence of VAP/VAT and/or LCBI. These findings provide a promising insight into the usefulness of PCT measurement in predicting the emergence of secondary bacterial infection in ICU

Telomere Length Shows No Association with BRCA1 and BRCA2 Mutation Status

This study aimed to determine whether telomere length (TL) is a marker of cancer risk or genetic status amongst two cohorts of BRCA1 and BRCA2 mutation carriers and controls. The first group was a prospective set of 665 male BRCA1/2 mutation carriers and controls (mean age 53 years), all healthy at time of enrolment and blood donation, 21 of whom have developed prostate cancer whilst on study. The second group consisted of 283 female BRCA1/2 mutation carriers and controls (mean age 48 years), half of whom had been diagnosed with breast cancer prior to enrolment. TL was quantified by qPCR from DNA extracted from peripheral blood lymphocytes. Weighted and unweighted Cox regressions and linear regression analyses were used to assess whether TL was associated with BRCA1/2 mutation status or cancer risk. We found no evidence for association between developing cancer or being a BRCA1 or BRCA2 mutation carrier and telomere length. It is the first study investigating TL in a cohort of genetically predisposed males and although TL and BRCA status was previously studied in females our results don't support the previous finding of association between hereditary breast cancer and shorter TL

Childhood brain tumors: A review of strategies to translate CNS drug delivery to clinical trials

Brain tumors account for over 20% of childhood cancers and are the biggest cancer killer in children and young adults. Several initiatives over the past 40 years have tried to identify more effective drug treatments, but with very limited success. This is largely due to the bloodâ brain barrier, which restricts the entry of many drugs into the brain. In this review, we describe the main techniques that are being developed to enhance brain tumor drug delivery and explore the preclinical brain tumor models that are essential for translational development of these techniques. We also identify existing approved drugs that, if coupled with an efficient delivery method, could have potential as brain tumor treatments. Bringing this information together is part of a funded initiative to highlight drug delivery as a research strategy to overcome the current challenges for children diagnosed with brain tumors

Role of Engrailed-2 (EN2) as a prostate cancer detection biomarker in genetically high risk men

Controversy surrounds the use of PSA as a biomarker for prostate cancer detection, leaving an unmet need for a novel biomarker in this setting; urinary EN2 may identify individuals with clinically relevant prostate cancer. Male BRCA1 and BRCA2 mutation carriers are at increased risk of clinically significant prostate cancer and may benefit from screening. Urine samples from 413 BRCA1 and BRCA2 mutation carriers and controls were evaluated. Subjects underwent annual PSA screening with diagnostic biopsy triggered by PSA > 3.0 ng/ml; 21 men were diagnosed with prostate cancer. Urinary EN2 levels were measured by ELISA and had a sensitivity of 66.7% and specificity of 89.3% for cancer detection. There was no statistically significant difference in EN2 levels according to genetic status or Gleason score. Urinary EN2 may be useful as a non-invasive early biomarker for prostate cancer detection in genetically high-risk individuals

An updated assessment of near-surface temperature change from 1850: the HadCRUT5 dataset

We present a new version of the Met Office Hadley Centre/Climatic Research Unit global surface temperature dataset, HadCRUT5. HadCRUT5 presents monthly average near-surface temperature anomalies, relative to the 1961-1990 period, on a regular 5° latitude by 5° longitude grid from 1850 to 2018. HadCRUT5 is a combination of sea-surface temperature measurements over the ocean from ships and buoys and near-surface air temperature measurements from weather stations over the land surface. These data have been sourced from updated compilations and the adjustments applied to mitigate the impact of changes in sea-surface temperature measurement methods have been revised. Two variants of HadCRUT5 have been produced for use in different applications. The first represents temperature anomaly data on a grid for locations where measurement data are available. The second, more spatially complete, variant uses a Gaussian process based statistical method to make better use of the available observations, extending temperature anomaly estimates into regions for which the underlying measurements are informative. Each is provided as a 200-member ensemble accompanied by additional uncertainty information. The combination of revised input datasets and statistical analysis results in greater warming of the global average over the course of the whole record. In recent years, increased warming results from an improved representation of Arctic warming and a better understanding of evolving biases sea-surface temperature measurements from ships. These updates result in greater consistency with other independent global surface temperature datasets, despite their different approaches to dataset construction, and further increase confidence in our understanding of changes seen

Clinical assessment of depth sensor based pose estimation algorithms for technology supervised rehabilitation applications

Encouraging rehabilitation by the use of technology in the home can be a cost-effective strategy, particularly if consumer-level equipment can be used. We present a clinical qualitative and quantitative analysis of the pose estimation algorithms of a typical consumer unit (Xbox One Kinect), to assess its suitability for technology supervised rehabilitation and guide development of future pose estimation algorithms for rehabilitation applciations. We focused the analysis on upper-body stroke rehabilitation as a challenging use case. We found that the algorithms require improved joint tracking, especially for the shoulder, elbow and wrist joints, and exploiting temporal information for tracking when there is full or partial occlusion in the depth data

Childhood Brain Tumors: A Review of Strategies to Translate CNS Drug Delivery to Clinical Trials

Brain and spinal tumors affect 1 in 1000 people by 25 years of age, and have diverse histological, biological, anatomical and dissemination characteristics. A mortality of 30–40% means the majority are cured, although two-thirds have life-long disability, linked to accumulated brain injury that is acquired prior to diagnosis, and after surgery or chemo-radiotherapy. Only four drugs have been licensed globally for brain tumors in 40 years and only one for children. Most new cancer drugs in clinical trials do not cross the blood–brain barrier (BBB). Techniques to enhance brain tumor drug delivery are explored in this review, and cover those that augment penetration of the BBB, and those that bypass the BBB. Developing appropriate delivery techniques could improve patient outcomes by ensuring efficacious drug exposure to tumors (including those that are drug-resistant), reducing systemic toxicities and targeting leptomeningeal metastases. Together, this drug delivery strategy seeks to enhance the efficacy of new drugs and enable re-evaluation of existing drugs that might have previously failed because of inadequate delivery. A literature review of repurposed drugs is reported, and a range of preclinical brain tumor models available for translational development are explored

Identification of a BRCA2-Specific modifier locus at 6p24 related to breast cancer risk

Common genetic variants contribute to the observed variation in breast cancer risk for BRCA2 mutation carriers; those known to date have all been found through population-based genome-wide association studies (GWAS). To comprehensively identify breast cancer risk modifying loci for BRCA2 mutation carriers, we conducted a deep replication of an ongoing GWAS discovery study. Using the ranked P-values of the breast cancer associations with the imputed genotype of 1.4 M SNPs, 19,029 SNPs were selected and designed for inclusion on a custom Illumina array that included a total of 211,155 SNPs as part of a multi-consortial project. DNA samples from 3,881 breast cancer affected and 4,330 unaffected BRCA2 mutation carriers from 47 studies belonging to the Consortium of Investigators of Modifiers of BRCA1/2 were genotyped and available for analysis. We replicated previously reported breast cancer susceptibility alleles in these BRCA2 mutation carriers and for several regions (including FGFR2, MAP3K1, CDKN2A/B, and PTHLH) identified SNPs that have stronger evidence of association than those previously published. We also identified a novel susceptibility allele at 6p24 that was inversely associated with risk in BRCA2 mutation carriers (rs9348512; per allele HR = 0.85, 95% CI 0.80-0.90, P = 3.9×10−8). This SNP was not associated with breast cancer risk either in the general population or in BRCA1 mutation carriers. The locus lies within a region containing TFAP2A, which encodes a transcriptional activation protein that interacts with several tumor suppressor genes. This report identifies the first breast cancer risk locus specific to a BRCA2 mutation background. This comprehensive update of novel and previously reported breast cancer susceptibility loci contributes to the establishment of a panel of SNPs that modify breast cancer risk in BRCA2 mutation carriers. This panel may have clinical utility for women with BRCA2 mutations weighing options for medical prevention of breast cancer