206 research outputs found

    Stratification of PD-1 blockade response in melanoma using pre- and post-treatment immunophenotyping of peripheral blood

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    Efficacy of checkpoint inhibitor therapies in cancer varies greatly, with some patients showing complete responses while others do not respond and experience progressive disease. We aimed to identify correlates of response and progression following PD-1-directed therapy by immunophenotyping peripheral blood samples from 20 patients with advanced malignant melanoma before and after treatment with the PD-1 blocking antibody pembrolizumab. Our data reveal that individuals responding to PD-1 blockade were characterised by increased CD8 T cell proliferation following treatment, while progression was associated with an increase in CTLA-4-expressing Treg. Remarkably, unsupervised clustering analysis of pre-treatment T cell subsets revealed differences in individuals that went on to respond to PD-1 blockade compared to individuals that did not. These differences mapped to expression of the proliferation marker Ki67 and the costimulatory receptor CD28 as well as the inhibitory molecules 2B4 and KLRG1. While these results require validation in larger patient cohorts, they suggest that flow cytometric analysis of a relatively small number of T cell markers in peripheral blood could potentially allow stratification of PD-1 blockade treatment response prior to therapy initiation

    Gene Co-Expression Network Analysis Identifies Vitamin D-Associated Gene Modules in Adult Normal Rectal Epithelium Following Supplementation

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    Colorectal cancer (CRC) is a common, multifactorial disease. While observational studies have identified an association between lower vitamin D and higher CRC risk, supplementation trials have been inconclusive and the mechanisms by which vitamin D may modulate CRC risk are not well understood. We sought to perform a weighted gene co-expression network analysis (WGCNA) to identify modules present after vitamin D supplementation (when plasma vitamin D level was sufficient) which were absent before supplementation, and then to identify influential genes in those modules. The transcriptome from normal rectal mucosa biopsies of 49 individuals free from CRC were assessed before and after 12 weeks of 3200IU/day vitamin D (Fultium-D3) supplementation using paired-end total RNAseq. While the effects on expression patterns following vitamin D supplementation were subtle, WGCNA identified highly correlated genes forming gene modules. Four of the 17 modules identified in the post-vitamin D network were not preserved in the pre-vitamin D network, shedding new light on the biochemical impact of supplementation. These modules were enriched for GO terms related to the immune system, hormone metabolism, cell growth and RNA metabolism. Across the four treatment-associated modules, 51 hub genes were identified, with enrichment of 40 different transcription factor motifs in promoter regions of those genes, including VDR:RXR. Six of the hub genes were nominally differentially expressed in studies of vitamin D effects on adult normal mucosa organoids: LCN2, HLA-C, AIF1L, PTPRU, PDE4B and IFI6. By taking a gene-correlation network approach, we have described vitamin D induced changes to gene modules in normal human rectal epithelium in vivo, the target tissue from which CRC develops

    The burden of co-existing dermatological disorders and their tendency of being overlooked among patients admitted to muhimbili national hospital in Dar es Salaam, Tanzania

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    \ud Skin diseases are underestimated and overlooked by most clinicians despite being common in clinical practice. Many patients are hospitalized with co-existing dermatological conditions which may not be detected and managed by the attending physicians. The objective of this study was to determine the burden of co-existing and overlooked dermatological disorders among patients admitted to medical wards of Muhimbili National hospital in Dar es Salaam. A hospital-based descriptive cross-sectional study conducted at Muhimbili National hospital in Dar es Salaam, Tanzania. Patients were consecutively recruited from the medical wards. Detailed interview to obtain clinico-demographic characteristics was followed by a complete physical examination. Dermatological diagnoses were made mainly clinically. Appropriate confirmatory laboratory investigations were performed where necessary. Data was analyzed using the 'Statistical Package for Social Sciences' (SPSS) program version 10.0. A p-value of < 0.5 was statistically significant. Three hundred and ninety patients admitted to medical wards were enrolled into the study of whom, 221(56.7%) were females. The mean age was 36.7 ± 17.9 (range 7-84 years). Overall, 232/390 patients (59.5%) had co-existing dermatological disorders with 49% (191/390) having one, 9% (36/390) two and 5 patients (1%) three. A wide range of co-existing skin diseases was encountered, the most diverse being non-infectious conditions which together accounted for 36.4% (142/390) while infectious dermatoses accounted for 31.5% (123/390). The leading infectious skin diseases were superficial fungal infections accounting for 18%. Pruritic papular eruption of HIV/AIDS (PPE) and seborrheic eczema were the most common non-infectious conditions, each accounting for 4.3%. Of the 232/390 patients with dermatological disorders, 191/232 (82.3%) and 154/232 (66.3%) had been overlooked by their referring and admitting doctors respectively. Dermatological disorders are common among patients admitted to medical wards and many are not detected by their referring or admitting physicians. Basic dermatological education should be emphasized to improve knowledge and awareness among clinicians.\u

    Talking really does matter : lay perspectives from older people on talking about suicide in later life

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    Background. The cumulative body of research on suicidality in later life describes its unique and complex features when compared to other population groups. Yet significant gaps exist in how research informs the further development of suitable interventions. The perspectives of older people are also limited in research findings. Aims: This exploratory study aimed to (1) identify potential barriers and enablers in discussing suicide thought and its expression in later life from the perspectives of lay older people, (2) explore where opportunities might occur in approach, place, relationships and, language with older people to discuss suicide thought and its expression Method: We conducted in-depth qualitative individual interviews with 15 people aged 70-89 years. This method helped to explore older peoples own lay perspectives on suicide thought in later life, how it is expressed, their understanding of where and how people might seek support. Results. Three themes emerged: 1) intergenerational and socio-cultural differences in suicide expression; 2) The normalization of suicide thoughts in later life, and 3) the importance and difficulties of everyday discussion and opportunities to express suicide thought. Conclusion. Suicide thought and its expression appear common and normalized in later life yet remain taboo and hidden. Participants revealed how such thoughts and behaviours are typically expressed through colloquial or ‘off-hand’ remarks and comments and the importance of authentic listening. The findings highlight the importance of more informal discussions around these topics and how care professionals, practitioners and providers might frame opportunities for dialogue with people who may want to access support. Further engagement with community informed participatory research methods in which older people provide their own perspectives and experiences is important in addressing these gaps. There is a need for co-design in developing screening, assessment and signposting outside of clinical settings that can be used in everyday caring relationships with people in later life

    A mechanistic hydro-epidemiological model of liver fluke risk

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    The majority of existing models for predicting disease risk in response to climate change are empirical. These models exploit correlations between historical data, rather than explicitly describing relationships between cause and response variables. Therefore, they are unsuitable for capturing impacts beyond historically observed variability and have limited ability to guide interventions. In this study, we integrate environmental and epidemiological processes into a new mechanistic model, taking the widespread parasitic disease of fasciolosis as an example. The model simulates environmental suitability for disease transmission at a daily time step and 25 m resolution, explicitly linking the parasite life cycle to key weather–water–environment conditions. Using epidemiological data, we show that the model can reproduce observed infection levels in time and space for two case studies in the UK. To overcome data limitations, we propose a calibration approach combining Monte Carlo sampling and expert opinion, which allows constraint of the model in a process-based way, including a quantification of uncertainty. The simulated disease dynamics agree with information from the literature, and comparison with a widely used empirical risk index shows that the new model provides better insight into the time–space patterns of infection, which will be valuable for decision support

    Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

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    Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

    The phase diagram of NiSi under the conditions of small planetary interiors

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    The phase diagram of NiSi has been determined using in situ synchrotron X-ray powder diffraction multi-anvil experiments to 19 GPa, with further preliminary results in the laser-heated diamond cell reported to 60 GPa. The low-pressure MnP-structured phase transforms to two different high-pressure phases depending on the temperature: the Δ-FeSi structure is stable at temperatures above ∌1100 K and a previously reported distorted-CuTi structure (with Pmmn symmetry) is stable at lower temperature. The invariant point is located at 12.8 ± 0.2 GPa and 1100 ± 20 K. At higher pressures, Δ -FeSi-structured NiSi transforms to the CsCl structure with CsCl-NiSi as the liquidus phase above 30 GPa. The Clapeyron slope of this transition is -67 MPa/K. The phase boundary between the Δ -FeSi and Pmmn structured phases is nearly pressure independent implying there will be a second sub-solidus invariant point between CsCl, Δ -FeSi and Pmmn structures at higher pressure than attained in this study. In addition to these stable phases, the MnP structure was observed to spontaneously transform at room temperature to a new orthorhombic structure (also with Pnma symmetry) which had been detailed in previous ab initio simulations. This new phase of NiSi is shown here to be metastable

    A qualitative study of professional and client perspectives on information flows and decision aid use

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    <p>Abstract</p> <p>Background</p> <p>This paper explores the meanings given by a diverse range of stakeholders to a decision aid aimed at helping carers of people in early to moderate stages of dementia (PWD) to select community based respite services. Decision aids aim to empower clients to share decision making with health professionals. However, the match between health professionals' perspectives on decision support needs and their clients' perspective is an important and often unstudied aspect of decision aid use.</p> <p>Methods</p> <p>A secondary analysis was undertaken of qualitative data collected as part of a larger study. The data included twelve interviews with carers of people with dementia, three interviews with expert advisors, and three focus groups with health professionals. A theoretical analysis was conducted, drawing on theories of 'positioning' and professional identity.</p> <p>Results</p> <p>Health professionals are seen to hold varying attitudes and beliefs about carers' decision support needs, and these appeared to be grounded in the professional identity of each group. These attitudes and beliefs shaped their attitudes towards decision aids, the information they believed should be offered to dementia carers, and the timing of its offering. Some groups understood carers as needing to be protected from realistic information and consequently saw a need to filter information to carer clients.</p> <p>Conclusion</p> <p>Health professionals' beliefs may cause them to restrict information flows, which can limit carers' ability to make decisions, and limit health services' ability to improve partnering and shared decision making. In an era where information is freely available to those with the resources to access it, we question whether health professionals should filter information.</p

    The clinical utility of pain classification in non-specific arm pain

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    Mechanisms-based pain classification has received considerable attention recently for its potential use in clinical decision making. A number of algorithms for pain classification have been proposed. Non-specific arm pain (NSAP) is a poorly defined condition, which could benefit from classification according to pain mechanisms to improve treatment selection. This study used three published classification algorithms (hereafter called NeuPSIG, Smart, Schafer) to investigate the frequency of different pain classifications in NSAP and the clinical utility of these systems in assessing NSAP. Forty people with NSAP underwent a clinical examination and quantitative sensory testing. Findings were used to classify participants according to three classification algorithms. Frequency of pain classification including number unclassified was analysed using descriptive statistics. Inter-rater agreement was analysed using kappa coefficients. NSAP was primarily classified as ‘unlikely neuropathic pain’ using NeuPSIG criteria, ‘peripheral neuropathic pain’ using the Smart classification and ‘peripheral nerve sensitisation’ using the Schafer algorithm. Two of the three algorithms allowed classification of all but one participant; up to 45% of participants (n = 18) were categorised as mixed by the Smart classification. Inter-rater agreement was good for the Schafer algorithm (Đș = 0.78) and moderate for the Smart classification (Đș = 0.40). A kappa value was unattainable for the NeuPSIG algorithm but agreement was high. Pain classification was achievable with high inter-rater agreement for two of the three algorithms assessed. The Smart classification may be useful but requires further direction regarding the use of clinical criteria included. The impact of adding a pain classification to clinical assessment on patient outcomes needs to be evaluated
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