Are survival and mortality rates associated with recruitment to clinical trials in teenage and young adult patients with acute lymphoblastic leukaemia? A retrospective observational analysis in England

Objective: Participation rates in clinical trials are low in teenagers and young adults (TYA) with cancer. Whilst the importance of clinical trials in informing best practice is well established, data regarding individual patient benefit are scarce. We have investigated the association between overall survival and trial recruitment in TYA patients with acute lymphoblastic leukaemia (ALL). Design: Retrospective. Setting: National (England) TYA patients treated for ALL. Participants: 511 patients aged 15–24 years diagnosed with ALL between 2004 and 2010 inclusive, of whom 239 (46.7%) participated in the UKALL2003 trial. Outcome measures: Patients were identified using National Clinical Trial (UKALL2003) and Cancer Registry (National Cancer Data Repository, English National Cancer Online Registration Environment) Databases. Relative survival rates were calculated for trial and non-trial patients and observed differences were modelled using a multiple regression approach. The numbers and percentages of deaths in those patients included in the survival analysis were determined for each 3-month period, p values were calculated using the two-tailed z-test for difference between proportions and 95% CIs for percentage deaths were derived using the binomial distribution based on the Wilson Score method. Results: Patients treated on the trial had a 17.9% better 2-year survival (85.4% vs 67.5%, p<0.001) and 8.9% better 1-year survival (90.8% vs 81.9%, p=0.004) than those not on the trial. 35 (14.6%) patients recruited to the trial died in the 2 years following diagnosis compared with 86 (32.6%) of those not recruited (p<0.001). Conclusions: TYA patients recruited to the clinical trial UKALL 2003 in England had a lower risk of mortality and a higher overall survival than contemporaneous non-trial patients. These data underline the potential for individual patient benefit in participating in a clinical trial and the importance of international efforts to increase trial participation in the TYA age group. Trial registration number: ISRCTN07355119

Reduction of circulating cholesterol and apolipoprotein levels during sepsis

Sepsis with multiple organ failure is frequently associated with a substantial decrease of cholesterol levels. This decrease of cholesterol is strongly associated with mortality suggesting a direct relation between inflammatory conditions and altered cholesterol homeostasis. The host response during sepsis is mediated by cytokines and growth factors, which are capable of influencing lipid metabolism. Conversely lipoproteins are also capable of modulating cytokine production during the inflammatory response. Therefore the decrease in circulating cholesterol levels seems to play a crucial role in the pathophysiology of sepsis. In this review the interaction between cytokines and lipid metabolism and its clinical consequences will be discussed

Things change: Women’s and men’s marital disruption dynamics in Italy during a time of social transformations, 1970-2003

We study women’s and men’s marital disruption in Italy between 1970 and 2003. By applying an event-history analysis to the 2003 Italian variant of the Generations and Gender Survey we found that the spread of marital disruption started among middle-highly educated women. Then in recent years it appears that less educated women have also been able to dissolve their unhappy unions. Overall we can see the beginning of a reversed educational gradient from positive to negative. In contrast the trend in men’s marital disruption risk appears as a change over time common to all educational groups, although with persisting educational differentials.determinants, educational differences, event history analysis, gender difference, Italy, marital disruption

Association between free testosterone levels and anal human papillomavirus Types 16/18 infections in a cohort of men who have sex with men

Background Human papillomavirus (HPV) types 16 and 18 cause invasive cervical cancer and most invasive anal cancers (IACs). Overall, IAC rates are highest among men who have sex with men (MSM), especially MSM with HIV infection. Testosterone is prescribed for men showing hypogonadism and HIV-related wasting. While there are direct and indirect physiological effects of testosterone in males, its role in anal HPV16/18 infections in men is unknown. Methods Free testosterone (FT) was measured in serum from 340 Multicenter AIDS Cohort Study (MACS) participants who were tested for anal HPV16/18-DNA approximately 36 months later. The effect of log10-transformed current FT level on anal HPV16/18 prevalence was modeled using Poisson regression with robust error variance. Multivariate models controlled for other HPV types, cumulative years of exogenous testosterone use, race, age, lifetime number of receptive anal intercourse partnerships, body mass index, tobacco smoking, HIV-infection and CD4+ T-cell counts among HIV-infected, and blood draw timing. Results Participants were, on average, 60 (+5.4) years of age, White (86%), and HIV-uninfected (56%); Twenty-four percent tested positive for anal HPV16 and/or 18-DNA (HPV16 prevalence= 17.1%, HPV18=9.1%). In adjusted analysis, each half-log10 increase of FT was associated with a 1.9-fold (95% Confidence Interval: 1.11, 3.24) higher HPV16/18 prevalence. Additionally, other Group 1 high-risk HPVs were associated with a 1.56-fold (1.03, 2.37) higher HPV16/18 prevalence. Traditional risk factors for HPV16/18 infection (age, tobacco smoking; lifetime number of sexual partners, including the number of receptive anal intercourse partnerships within 24 months preceding HPV testing) were poorly correlated with one another and not statistically significantly associated with higher prevalence of HPV16/ 18 infection in unadjusted and adjusted analyses. Conclusions Higher free testosterone was associated with increased HPV16/18 prevalence measured approximately three years later, independent of sexual behavior and other potential confounders. The mechanisms underlying this association remain unclear and warrant further study

Выявление понятий и их взаимосвязей в рамках технологии контент-мониторинга

Приведены подходы к решению проблемы выявления фактографической информации из неструктурированных текстовых потоков. Описаны технологические решения, позволяющие извлекать из полнотекстовых документов такие понятия как фирмы, фамилии, географические названия и т.п., а также выявлять силу их взаимосвязей на основе применения двух алгоритмов. Первый из этих алгоритмов основывается на учете совместного вхождения понятий в одни и те же документы, а второй на учете общего для рассматриваемых понятий контекста.Наведено підходи до вирішення проблеми виявлення фактографічної інформації з неструктурованих текстових потоків. Описано технологічні рішення, що дозволяють добути з повнотекстових документів такі поняття як фірми, прізвища, географічні назви тощо, а також виявляти силу їхніх взаємозв’язків на базі застосування двох алгоритмів. Перший з цих алгоритмів базується на врахуванні спільного входження понять до одних і тих самих документів, а другий — на врахуванні загального для понять, що розглядаються, контексту.Approaches to the solution of a problem of revealing factual information from unstructured text flows are given. The technological solutions, allowing to take from text-through documents such concepts as a firm, a surname, place names, etc., and also to reveal force of their interrelations on the basis of application of two algorithms are described. The first of these algorithms is based on the account of joint concepts occurrence in the same documents, and the second one on the account of the context common for considered concepts

A New Model of Delirium Care in the Acute Geriatric Setting: Geriatric Monitoring Unit

<p>Abstract</p> <p>Background</p> <p>Delirium is a common and serious condition, which affects many of our older hospitalised patients. It is an indicator of severe underlying illness and requires early diagnosis and prompt treatment, associated with poor survival, functional outcomes with increased risk of institutionalisation following the delirium episode in the acute care setting. We describe a new model of delirium care in the acute care setting, titled Geriatric Monitoring Unit (GMU) where the important concepts of delirium prevention and management are integrated. We hypothesize that patients with delirium admitted to the GMU would have better clinical outcomes with less need for physical and psychotropic restraints compared to usual care.</p> <p>Methods/Design</p> <p>GMU models after the Delirium Room with adoption of core interventions from Hospital Elder Life Program and use of evening bright light therapy to consolidate circadian rhythm and improve sleep in the elderly patients. The novelty of this approach lies in the amalgamation of these interventions in a multi-faceted approach in acute delirium management. GMU development thus consists of key considerations for room design and resource planning, program specific interventions and daily core interventions. Assessments undertaken include baseline demographics, comorbidity scoring, duration and severity of delirium, cognitive, functional measures at baseline, 6 months and 12 months later. Additionally we also analysed the pre and post-GMU implementation knowledge and attitude on delirium care among staff members in the geriatric wards (nurses, doctors) and undertook satisfaction surveys for caregivers of patients treated in GMU.</p> <p>Discussion</p> <p>This study protocol describes the conceptualization and implementation of a specialized unit for delirium management. We hypothesize that such a model of care will not only result in better clinical outcomes for the elderly patient with delirium compared to usual geriatric care, but also improved staff knowledge and satisfaction. The model may then be transposed across various locations and disciplines in the acute hospital where delirious patients could be sited.</p> <p>Trial Registration</p> <p>Current Controlled Trials <a href="http://www.controlled-trials.com/ISRCTN52323811">ISRCTN52323811</a></p

imPlatelet classifier: image-converted RNA biomarker profiles enable blood-based cancer diagnostics

Liquid biopsies offer a minimally invasive sample collection, outperforming traditional biopsies employed for cancer evaluation. The widely used material is blood, which is the source of tumor-educated platelets. Here, we developed the imPlatelet classifier, which converts RNA-sequenced platelet data into images in which each pixel corresponds to the expression level of a certain gene. Biological knowledge from the Kyoto Encyclopedia of Genes and Genomes was also implemented to improve accuracy. Images obtained from samples can then be compared against standard images for specific cancers to determine a diagnosis. We tested imPlatelet on a cohort of 401 non-small cell lung cancer patients, 62 sarcoma patients, and 28 ovarian cancer patients. imPlatelet provided excellent discrimination between lung cancer cases and healthy controls, with accuracy equal to 1 in the independent dataset. When discriminating between noncancer cases and sarcoma or ovarian cancer patients, accuracy equaled 0.91 or 0.95, respectively, in the independent datasets. According to our knowledge, this is the first study implementing an image-based deep-learning approach combined with biological knowledge to classify human samples. The performance of imPlatelet considerably exceeds previously published methods and our own alternative attempts of sample discrimination. We show that the deep-learning image-based classifier accurately identifies cancer, even when a limited number of samples are available.publishedVersio

Analysis of folylpoly-γ-glutamate synthetase gene expression in human B-precursor ALL and T-lineage ALL cells

BACKGROUND: Expression of folylpoly-γ-glutamate synthetase (FPGS) gene is two- to three-fold higher in B-precursor ALL (Bp- ALL) than in T-lineage ALL (T-ALL) and correlates with intracellular accumulation of methotrexate (MTX) polyglutamates and lymphoblast sensitivity to MTX. In this report, we investigated the molecular regulatory mechanisms directing FPGS gene expression in Bp-ALL and T-ALL cells. METHODS: To determine FPGS transcription rate in Bp-ALL and T-ALL we used nuclear run-on assays. 5'-RACE was used to uncover potential regulatory regions involved in the lineage differences. We developed a luciferase reporter gene assay to investigate FPGS promoter/enhancer activity. To further characterize the FPGS proximal promoter, we determined the role of the putative transcription binding sites NFY and E-box on FPGS expression using luciferase reporter gene assays with substitution mutants and EMSA. RESULTS: FPGS transcription initiation rate was 1.6-fold higher in NALM6 vs. CCRF-CEM cells indicating that differences in transcription rate led to the observed lineage differences in FPGS expression between Bp-ALL and T-ALL blasts. Two major transcripts encoding the mitochondrial/cytosolic and cytosolic isoforms were detected in Bp-ALL (NALM6 and REH) whereas in T-ALL (CCRF-CEM) cells only the mitochondrial/cytosolic transcript was detected. In all DNA fragments examined for promoter/enhancer activity, we measured significantly lower luciferase activity in NALM6 vs. CCRF-CEM cells, suggesting the need for additional yet unidentified regulatory elements in Bp-ALL. Finally, we determined that the putative transcription factor binding site NFY, but not E-box, plays a role in FPGS transcription in both Bp- and T-lineage. CONCLUSION: We demonstrated that the minimal FPGS promoter region previously described in CCRF-CEM is not sufficient to effectively drive FPGS transcription in NALM6 cells, suggesting that different regulatory elements are required for FPGS gene expression in Bp-cells. Our data indicate that the control of FPGS expression in human hematopoietic cells is complex and involves lineage-specific differences in regulatory elements, transcription initiation rates, and mRNA processing. Understanding the lineage-specific mechanisms of FPGS expression should lead to improved therapeutic strategies aimed at overcoming MTX resistance or inducing apoptosis in leukemic cells

A Research Agenda for Helminth Diseases of Humans: Health Research and Capacity Building in Disease-Endemic Countries for Helminthiases Control

Capacity building in health research generally, and helminthiasis research particularly, is pivotal to the implementation of the research and development agenda for the control and elimination of human helminthiases that has been proposed thematically in the preceding reviews of this collection. Since helminth infections affect human populations particularly in marginalised and low-income regions of the world, they belong to the group of poverty-related infectious diseases, and their alleviation through research, policy, and practice is a sine qua non condition for the achievement of the United Nations Millennium Development Goals. Current efforts supporting research capacity building specifically for the control of helminthiases have been devised and funded, almost in their entirety, by international donor agencies, major funding bodies, and academic institutions from the developed world, contributing to the creation of (not always equitable) North–South “partnerships”. There is an urgent need to shift this paradigm in disease-endemic countries (DECs) by refocusing political will, and harnessing unshakeable commitment by the countries' governments, towards health research and capacity building policies to ensure long-term investment in combating and sustaining the control and eventual elimination of infectious diseases of poverty. The Disease Reference Group on Helminth Infections (DRG4), established in 2009 by the Special Programme for Research and Training in Tropical Diseases (TDR), was given the mandate to review helminthiases research and identify research priorities and gaps. This paper discusses the challenges confronting capacity building for parasitic disease research in DECs, describes current capacity building strategies with particular reference to neglected tropical diseases and human helminthiases, and outlines recommendations to redress the balance of alliances and partnerships for health research between the developed countries of the “North” and the developing countries of the “South”. We argue that investing in South–South collaborative research policies and capacity is as important as their North–South counterparts and is essential for scaled-up and improved control of helminthic diseases and ultimately for regional elimination