Bone mineral density optimisation in adults with perinatally acquired HIV infection in routine care

We report on BMD and factors associated with reductions in BMD for all adults with perinatally acquired HIV who attended a London clinic between May 2014 and October 2016. We observed a high prevalence of reductions in BMD and a higher than expected prevalence of factors associated with adverse bone health, namely vitamin D deficiency

Bone mineral density optimisation in adults with perinatally acquired HIV infection in routine care.

We report on BMD and factors associated with reductions in BMD for all adults with perinatally acquired HIV who attended a London clinic between May 2014 and October 2016. We observed a high prevalence of reductions in BMD and a higher than expected prevalence of factors associated with adverse bone health, namely vitamin D deficiency

Diversity of symptom phenotypes in SARS-CoV-2 community infections observed in multiple large datasets

Variability in case severity and in the range of symptoms experienced has been apparent from the earliest months of the COVID-19 pandemic. From a clinical perspective, symptom variability might indicate various routes/mechanisms by which infection leads to disease, with different routes requiring potentially different treatment approaches. For public health and control of transmission, symptoms in community cases were the prompt on which action such as PCR testing and isolation was taken. However, interpreting symptoms presents challenges, for instance in balancing sensitivity and specificity of individual symptoms with the need to maximise case finding, whilst managing demand for limited resources such as testing. For both clinical and transmission control reasons, we require an approach that allows for the possibility of distinct symptom phenotypes, rather than assuming variability along a single dimension. Here we address this problem by bringing together four large and diverse datasets deriving from routine testing, a population-representative household survey and participatory smartphone surveillance in the United Kingdom. Through use of cutting-edge unsupervised classification techniques from statistics and machine learning, we characterise symptom phenotypes among symptomatic SARS-CoV-2 PCR-positive community cases, making comparisons across datasets and by age bands. While we observe separation due to the total number of symptoms experienced by cases, we also see a separation of symptoms into gastrointestinal, respiratory and other types, and different symptom co-occurrence patterns at the extremes of age. In this way, we are able to demonstrate the deep structure of symptoms of COVID-19 without usual biases due to study design.Comment: 52 pages; 25 figure

Validation of a breast cancer assay for radiotherapy omission: an individual participant data meta-analysis

Background: There are currently no molecular tests to identify individual breast cancers where radiotherapy (RT) offers no benefit. Profile for the Omission of Local Adjuvant Radiotherapy (POLAR) is a 16-gene molecular signature developed to identify low risk cancers where RT will not further reduce recurrence rates. Methods: An individual participant data meta-analysis was performed in 623 cases of node-negative ER+/HER2-negative early breast cancer enrolled in three RT randomized trials for whom primary tumor material was available for analysis. A Cox proportional hazards model on time to locoregional recurrence (LRR) was used to test the interaction between POLAR score and RT.Results: 429 (69%) patients’ tumors had a high POLAR score and 194 (31%) had a low score. Patients with high POLAR score had, in the absence of RT, a 10-year cumulative incidence of LRR: 20% (15%-26%) vs 5% (2%-11%) for those with a low score. Patients with a high POLAR score had a large benefit from RT (hazard ratio [HR] for RT vs no RT: 0.37 [0.23-0.60], p&lt;0.001). In contrast, there was no evidence of benefit from RT for patients with a low POLAR score (HR: 0.92 [0.42-2.02], p = 0.832). The test for interaction between RT and POLAR was statistically significant (p = 0.022).Conclusions: POLAR is not only prognostic for locoregional recurrence but also predictive of benefit from radiotherapy in selected patients. Patients ≥ 50 years with ER+/HER2-negative disease and a low POLAR score could consider omitting adjuvant RT. Further validation in contemporary clinical cohorts is required.<br/

FDG uptake, a surrogate of tumour hypoxia?

Introduction Tumour hyperglycolysis is driven by activation of hypoxia-inducible factor-1 (HIF-1) through tumour hypoxia. Accordingly, the degree of 2-fluro-2-deoxy-D-glucose (FDG) uptake by tumours might indirectly reflect the level of hypoxia, obviating the need for more specific radiopharmaceuticals for hypoxia imaging. Discussion In this paper, available data on the relationship between hypoxia and FDG uptake by tumour tissue in vitro and in vivo are reviewed. In pre-clinical in vitro studies, acute hypoxia was consistently shown to increase FDG uptake by normal and tumour cells within a couple of hours after onset with mobilisation or modification of glucose transporters optimising glucose uptake, followed by a delayed response with increased rates of transcription of GLUT mRNA. In pre-clinical imaging studies on chronic hypoxia that compared FDG uptake by tumours grown in rat or mice to uptake by FMISO, the pattern of normoxic and hypoxic regions within the human tumour xenografts, as imaged by FMISO, largely correlated with glucose metabolism although minor locoregional differences could not be excluded. In the clinical setting, data are limited and discordant. Conclusion Further evaluation of FDG uptake by various tumour types in relation to intrinsic and bioreductive markers of hypoxia and response to radiotherapy or hypoxia-dependent drugs is needed to fully assess its application as a marker of hypoxia in the clinical setting

Association between tissue hypoxia and elevated non-protein sulphydryl concentrations in human cervical carcinoma xenografts

A double staining technique was developed for the simultaneous measurement of tissue hypoxia and the concentration of non-protein sulphydryls (NPSH), based on the fluorinated nitroimidazole EF5 and the fluorescent histochemical NPSH stain 1-(4-chloromercuriphenoylazo)-naphthol-2 (mercury orange). Cryostat sections of tumour tissue were examined by fluorescence image analysis, using a computer-controlled microscope stage to generate large tiled field images of the cut tumour surface. This method was applied to the human cervical squamous cell carcinoma lines ME180 and SiHa, grown as xenografts in severe combined immunodeficient (SCID) mice, in order to determine if there is a systematic relationship between tissue hypoxia and NPSH levels. Hypoxic regions of the tumours, defined by EF5 labelling, were found to show greater NPSH concentrations relative to better oxygenated regions. This is probably due to increases in glutathione, since the ME180 and SiHa xenografts contained low levels of cysteine and metallothionein; the other major cellular thiols that can bind to mercury orange. Because the effects of glutathione on radiation and chemotherapy resistance are likely to be greater under hypoxic conditions, these results have potentially important implications for the study of resistance mechanisms in solid tumours. © 1999 Cancer Research Campaig

Adjuvant whole abdominal intensity modulated radiotherapy (IMRT) for high risk stage FIGO III patients with ovarian cancer (OVAR-IMRT-01) – Pilot trial of a phase I/II study: study protocol

<p>Abstract</p> <p>Background</p> <p>The prognosis for patients with advanced epithelial ovarian cancer remains poor despite aggressive surgical resection and platinum-based chemotherapy. More than 60% of patients will develop recurrent disease, principally intraperitoneal, and die within 5 years. The use of whole abdominal irradiation (WAI) as consolidation therapy would appear to be a logical strategy given its ability to sterilize small tumour volumes. Despite the clinically proven efficacy of whole abdominal irradiation, the use of radiotherapy in ovarian cancer has profoundly decreased mainly due to high treatment-related toxicity. Modern intensity-modulated radiation therapy (IMRT) could allow to spare kidneys, liver, and bone marrow while still adequately covering the peritoneal cavity with a homogenous dose.</p> <p>Methods/Design</p> <p>The OVAR-IMRT-01 study is a single center pilot trial of a phase I/II study. Patients with advanced ovarian cancer stage FIGO III (R1 or R2< 1 cm) after surgical resection and platinum-based chemotherapy will be treated with whole abdomen irradiation as consolidation therapy using intensity modulated radiation therapy (IMRT) to a total dose of 30 Gy in 1.5 Gy fractions. A total of 8 patients will be included in this trial. For treatment planning bone marrow, kidneys, liver, spinal cord, vertebral bodies and pelvic bones are defined as organs at risk. The planning target volume includes the entire peritoneal cavity plus pelvic and para-aortic node regions.</p> <p>Discussion</p> <p>The primary endpoint of the study is the evaluation of the feasibility of intensity-modulated WAI and the evaluation of the study protocol. Secondary endpoint is evaluation of the toxicity of intensity modulated WAI before continuing with the phase I/II study. The aim is to explore the potential of IMRT as a new method for WAI to decrease the dose to kidneys, liver, bone marrow while covering the peritoneal cavity with a homogenous dose, and to implement whole abdominal intensity-modulated radiotherapy into the adjuvant multimodal treatment concept of advanced ovarian cancer FIGO stage III.</p

Public perceptions and interactions with UK COVID-19 Test, Trace and Isolate policies, and implications for pandemic infectious disease modelling.

BACKGROUND: The efforts to contain SARS-CoV-2 and reduce the impact of the COVID-19 pandemic have been supported by Test, Trace and Isolate (TTI) systems in many settings, including the United Kingdom. Mathematical models of transmission and TTI interventions, used to inform design and policy choices, make assumptions about the public’s behaviour in the context of a rapidly unfolding and changeable emergency. This study investigates public perceptions and interactions with UK TTI policy in July 2021, assesses them against how TTI processes are conceptualised and represented in models, and then interprets the findings with modellers who have been contributing evidence to TTI policy. METHODS: 20 members of the public recruited via social media were interviewed for one hour about their perceptions and interactions with the UK TTI system. Thematic analysis identified key themes, which were then presented back to a workshop of pandemic infectious disease modellers who assessed these findings against assumptions made in TTI intervention modelling. Workshop members co-drafted this report. RESULTS: Themes included education about SARS-CoV-2, perceived risks, trust, mental health and practical concerns. Findings covered testing practices, including the uses of and trust in different types of testing, and the challenges of testing and isolating faced by different demographic groups. This information was judged as consequential to the modelling process, from guiding the selection of research questions, influencing choice of model structure, informing parameter ranges and validating or challenging assumptions, to highlighting where model assumptions are reasonable or where their poor reflection of practice might lead to uninformative results. CONCLUSIONS: We conclude that deeper engagement with members of the public should be integrated at regular stages of public health intervention modelling

Public perceptions and interactions with UK COVID-19 Test, Trace and Isolate policies, and implications for pandemic infectious disease modelling

Background The efforts to contain SARS-CoV-2 and reduce the impact of the COVID-19 pandemic have been supported by Test, Trace and Isolate (TTI) systems in many settings, including the United Kingdom. Mathematical models of transmission and TTI interventions, used to inform design and policy choices, make assumptions about the public’s behaviour in the context of a rapidly unfolding and changeable emergency. This study investigates public perceptions and interactions with UK TTI policy in July 2021, assesses them against how TTI processes are conceptualised and represented in models, and then interprets the findings with modellers who have been contributing evidence to TTI policy. Methods 20 members of the public recruited via social media were interviewed for one hour about their perceptions and interactions with the UK TTI system. Thematic analysis identified key themes, which were then presented back to a workshop of pandemic infectious disease modellers who assessed these findings against assumptions made in TTI intervention modelling. Workshop members co-drafted this report. Results Themes included education about SARS-CoV-2, perceived risks, trust, mental health and practical concerns. Findings covered testing practices, including the uses of and trust in different types of testing, and the challenges of testing and isolating faced by different demographic groups. This information was judged as consequential to the modelling process, from guiding the selection of research questions, influencing choice of model structure, informing parameter ranges and validating or challenging assumptions, to highlighting where model assumptions are reasonable or where their poor reflection of practice might lead to uninformative results. Conclusions We conclude that deeper engagement with members of the public should be integrated at regular stages of public health intervention modelling.</ns4:p