Regression based predictor for p53 transactivation

<p>Abstract</p> <p>Background</p> <p>The p53 protein is a master regulator that controls the transcription of many genes in various pathways in response to a variety of stress signals. The extent of this regulation depends in part on the binding affinity of p53 to its response elements (REs). Traditional profile scores for p53 based on position weight matrices (PWM) are only a weak indicator of binding affinity because the level of binding also depends on various other factors such as interaction between the nucleotides and, in case of p53-REs, the extent of the spacer between the dimers.</p> <p>Results</p> <p>In the current study we introduce a novel <it>in-silico </it>predictor for p53-RE transactivation capability based on a combination of multidimensional scaling and multinomial logistic regression. Experimentally validated known p53-REs along with their transactivation capabilities are used for training. Through cross-validation studies we show that our method outperforms other existing methods. To demonstrate the utility of this method we (a) rank putative p53-REs of target genes and target microRNAs based on the predicted transactivation capability and (b) study the implication of polymorphisms overlapping p53-RE on its transactivation capability.</p> <p>Conclusion</p> <p>Taking into account both nucleotide interactions and the spacer length of p53-RE, we have created a novel <it>in-silico </it>regression-based transactivation capability predictor for p53-REs and used it to analyze validated and novel p53-REs and to predict the impact of SNPs overlapping these elements.</p

Capacity management of nursing staff as a vehicle for organizational improvement

<p>Abstract</p> <p>Background</p> <p>Capacity management systems create insight into required resources like staff and equipment. For inpatient hospital care, capacity management requires information on beds and nursing staff capacity, on a daily as well as annual basis. This paper presents a comprehensive capacity model that gives insight into required nursing staff capacity and opportunities to improve capacity utilization on a ward level.</p> <p>Methods</p> <p>A capacity model was developed to calculate required nursing staff capacity. The model used historical bed utilization, nurse-patient ratios, and parameters concerning contract hours to calculate beds and nursing staff needed per shift and the number of nurses needed on an annual basis in a ward. The model was applied to three different capacity management problems on three separate groups of hospital wards. The problems entailed operational, tactical, and strategic management issues: optimizing working processes on pediatric wards, predicting the consequences of reducing length of stay on nursing staff required on a cardiology ward, and calculating the nursing staff consequences of merging two internal medicine wards.</p> <p>Results</p> <p>It was possible to build a model based on easily available data that calculate the nursing staff capacity needed daily and annually and that accommodate organizational improvements. Organizational improvement processes were initiated in three different groups of wards. For two pediatric wards, the most important improvements were found to be improving working processes so that the agreed nurse-patient ratios could be attained. In the second case, for a cardiology ward, what-if analyses with the model showed that workload could be substantially lowered by reducing length of stay. The third case demonstrated the possible savings in capacity that could be achieved by merging two small internal medicine wards.</p> <p>Conclusion</p> <p>A comprehensive capacity model was developed and successfully applied to support capacity decisions on operational, tactical, and strategic levels. It appeared to be a useful tool for supporting discussions between wards and hospital management by giving objective and quantitative insight into staff and bed requirements. Moreover, the model was applied to initiate organizational improvements, which resulted in more efficient capacity utilization.</p

Hospitalisations at the end of life: using a sentinel surveillance network to study hospital use and associated patient, disease and healthcare factors

<p>Abstract</p> <p>Background</p> <p>Hospital deaths following several hospital admissions or long hospital stays may be indicative of a low quality of dying. Although place of death has been extensively investigated at population level, hospital use in the last months of life and its determinants have been studied less often, especially in Europe and with a general end-of-life patient population. In this study we aim to describe hospital use in the last three months of life in Belgium and identify associated patient, disease and healthcare factors.</p> <p>Methods</p> <p>We conducted a retrospective registration study (13 weeks in 2004) with the Belgian Sentinel Network of General Practitioners, an epidemiological surveillance system representative of all GPs in Belgium, covering 1.75% of the total Belgian patient population. All registered non-sudden or expected deaths of patients (aged one year or older) at the GPs' practices were included. Bivariate and regression analyses were performed.</p> <p>Results</p> <p>The response rate was 87%. The GPs registered 319 deaths that met inclusion criteria. Sixty percent had been hospitalised at least once in the last three months of life, for a median of 19 days. The percentage of patients hospitalised increased exponentially in the last weeks before death; one fifth was admitted in the final week of life. Seventy-two percent of patients hospitalised at least once in the final three months died in hospital. A palliative treatment goal, death from cardiovascular diseases, the expression of a wish to die in an elderly home and palliative care delivery by the GP were associated with lower hospitalisation odds.</p> <p>Conclusion</p> <p>Hospital care plays a large role in the end of patients' lives in Belgium, especially in the final weeks of life. The result is a high rate of hospital deaths, showing the institutionalised nature of dying. Patients' clinical conditions, the expression of preferences and also healthcare characteristics such as being treated as a palliative care patient, seem to be associated with hospital transfers. It is recommended that hospitalisation decisions are only made after careful consideration. Short admissions in the final days of life should be prevented in order to make dying at home more feasible.</p

Impact of female age and male infertility on ovarian reserve markers to predict outcome of assisted reproduction technology cycles

<p>Abstract</p> <p>Background</p> <p>This study was designed to assess the capability of ovarian reserve markers, including baseline FSH levels, baseline anti-Müllerian hormone (AMH) levels, and antral follicle count (AFC), as predictors of live births during IVF cycles, especially for infertile couples with advanced maternal age and/or male factors.</p> <p>Methods</p> <p>A prospective cohort of 336 first IVF/ICSI cycles undergoing a long protocol with GnRH agonist was investigated. Patients with endocrine disorders or unilateral ovaries were excluded.</p> <p>Results</p> <p>Among the ovarian reserve tests, AMH and age had a greater area under the receiving operating characteristic curve than FSH in predicting live births. Furthermore, AMH and age were the sole predictive factors of live births for women greater than or equal to 35 years of age; while AMH was the major determinant of live births for infertile couples with absence of male factors by multivariate logistic regression analysis. However, all the studied ovarain reserve tests were not preditive of live births for women < 35 years of age or infertile couples with male factors.</p> <p>Conclusion</p> <p>The serum AMH levels were prognostic for pregnancy outcome for infertile couples with advanced female age or absence of male factors. The predictive capability of ovarian reserve tests is clearly influenced by the etiology of infertility.</p

Randomised controlled trial of a new palliative care service: Compliance, recruitment and completeness of follow-up

<p>Abstract</p> <p>Background</p> <p>Palliative care has been proposed for progressive non-cancer conditions but there have been few evaluations of service developments. We analysed recruitment, compliance and follow-up data of a fast track (or wait list control) randomised controlled trial of a new palliative care service – a design not previously used to assess palliative care.</p> <p>Methods/Design</p> <p>An innovative palliative care service (comprising a consultant in palliative medicine, a clinical nurse specialist, an administrator and a psychosocial worker) was delivered to people severely affected by multiple sclerosis (MS), and their carers, in southeast London. Our design followed the MRC Framework for the Evaluation of Complex Interventions. In phase II we conducted randomised controlled trial, of immediate referral to the service (fast-track) versus a 12-week wait (standard best practice). Main outcome measures were: compliance (the extent the trial protocol was adhered to), recruitment (target 50 patients), attrition and missing data rates; trial outcomes were Palliative Care Outcome Scale and MS Impact Scale.</p> <p>Results</p> <p>69 patients were referred, 52 entered the trial (26 randomised to each arm), 5 refused consent and 12 were excluded from the trial for other reasons, usually illness or urgent needs, achieving our target numbers. 25/26 fast track and 21/26 standard best practice patients completed the trial, resulting in 217/225 (96%) of possible interviews completed, 87% of which took place in the patient's home. Main reasons for failure to interview and/or attrition were death or illness. There were three deaths in the standard best practice group and one in the fast-track group during the trial. At baseline there were no differences between groups. Missing data for individual questionnaire items were small (median 0, mean 1–5 items out of 56+ items per interview), not associated with any patient or carer characteristics or with individual questionnaires, but were associated with interviewer.</p> <p>Conclusion</p> <p>This is the first time a fast track (or wait list) randomised trial has been reported in palliative care. We found it achieved good recruitment and is a feasible method to evaluate palliative care services when patients are expected to live longer than 3–6 months. Home interviews are needed for a trial of this kind; interviewers need careful recruitment, training and supervision; and there should be careful separation from the clinical service of the control patients to prevent accidental contamination.</p> <p>Trial Registration</p> <p>Clinical Trials.Gov NCT00364963</p

Study protocol: optimization of complex palliative care at home via telemedicine. A cluster randomized controlled trial

Contains fulltext : 97378.pdf (publisher's version ) (Open Access)ABSTRACT: BACKGROUND: Due to the growing number of elderly with advanced chronic conditions, healthcare services will come under increasing pressure. Teleconsultation is an innovative approach to deliver quality of care for palliative patients at home. Quantitative studies assessing the effect of teleconsultation on clinical outcomes are scarce. The aim of this present study is to investigate the effectiveness of teleconsultation in complex palliative homecare. METHODS/DESIGN: During a 2-year recruitment period, GPs are invited to participate in this cluster randomized controlled trial. When a GP refers an eligible patient for the study, the GP is randomized to the intervention group or the control group. Patients in the intervention group have a weekly teleconsultation with a nurse practitioner and/or a physician of the palliative consultation team. The nurse practitioner, in cooperation with the palliative care specialist of the palliative consultation team, advises the GP on treatment policy of the patient. The primary outcome of patient symptom burden is assessed at baseline and weekly using the Edmonton Symptom Assessment Scale (ESAS) and at baseline and every four weeks using the Hospital Anxiety and Depression Scale (HADS). Secondary outcomes are self-perceived burden from informal care (EDIZ), patient experienced continuity of medical care (NCQ), patient and caregiver satisfaction with the teleconsultation (PSQ), the experienced problems and needs in palliative care (PNPC-sv) and the number of hospital admissions. DISCUSSION: This is one of the first randomized controlled trials in palliative telecare. Our data will verify whether telemedicine positively affects palliative homecare. TRIAL REGISTRATION: The Netherlands National Trial Register NTR2817

Stress-Induced PARP Activation Mediates Recruitment of Drosophila Mi-2 to Promote Heat Shock Gene Expression

Eukaryotic cells respond to genomic and environmental stresses, such as DNA damage and heat shock (HS), with the synthesis of poly-[ADP-ribose] (PAR) at specific chromatin regions, such as DNA breaks or HS genes, by PAR polymerases (PARP). Little is known about the role of this modification during cellular stress responses. We show here that the nucleosome remodeler dMi-2 is recruited to active HS genes in a PARP–dependent manner. dMi-2 binds PAR suggesting that this physical interaction is important for recruitment. Indeed, a dMi-2 mutant unable to bind PAR does not localise to active HS loci in vivo. We have identified several dMi-2 regions which bind PAR independently in vitro, including the chromodomains and regions near the N-terminus containing motifs rich in K and R residues. Moreover, upon HS gene activation, dMi-2 associates with nascent HS gene transcripts, and its catalytic activity is required for efficient transcription and co-transcriptional RNA processing. RNA and PAR compete for dMi-2 binding in vitro, suggesting a two step process for dMi-2 association with active HS genes: initial recruitment to the locus via PAR interaction, followed by binding to nascent RNA transcripts. We suggest that stress-induced chromatin PARylation serves to rapidly attract factors that are required for an efficient and timely transcriptional response

The OPTIMIST study: optimisation of cost effectiveness through individualised FSH stimulation dosages for IVF treatment. A randomised controlled trial

Contains fulltext : 109739.pdf (publisher's version ) (Open Access)ABSTRACT: BACKGROUND: Costs of in vitro fertilisation (IVF) are high, which is partly due to the use of follicle stimulating hormone (FSH). FSH is usually administered in a standard dose. However, due to differences in ovarian reserve between women, ovarian response also differs with potential negative consequences on pregnancy rates. A Markov decision-analytic model showed that FSH dose individualisation according to ovarian reserve is likely to be cost-effective in women who are eligible for IVF. However, this has never been confirmed in a large randomised controlled trial (RCT). The aim of the present study is to assess whether an individualised FSH dose regime based on an ovarian reserve test (ORT) is more cost-effective than a standard dose regime. METHODS/DESIGN: Multicentre RCT in subfertile women indicated for a first IVF or intracytoplasmic sperm injection cycle, who are aged < 44 years, have a regular menstrual cycle and no major abnormalities at transvaginal sonography. Women with polycystic ovary syndrome, endocrine or metabolic abnormalities and women undergoing IVF with oocyte donation, will not be included. Ovarian reserve will be assessed by measuring the antral follicle count. Women with a predicted poor response or hyperresponse will be randomised for a standard versus an individualised FSH regime (150 IU/day, 225-450 IU/day and 100 IU/day, respectively). Participants will undergo a maximum of three stimulation cycles during maximally 18 months. The primary study outcome is the cumulative ongoing pregnancy rate resulting in live birth achieved within 18 months after randomisation. Secondary outcomes are parameters for ovarian response, multiple pregnancies, number of cycles needed per live birth, total IU of FSH per stimulation cycle, and costs. All data will be analysed according to the intention-to-treat principle. Cost-effectiveness analysis will be performed to assess whether the health and associated economic benefits of individualised treatment of subfertile women outweigh the additional costs of an ORT. DISCUSSION: The results of this study will be integrated into a decision model that compares cost-effectiveness of the three dose-adjustment strategies to a standard dose strategy. The study outcomes will provide scientific foundation for national and international guidelines. TRIAL REGISTRATION: NTR2657