Drug-resistant genotypes and multi-clonality in Plasmodium falciparum analysed by direct genome sequencing from peripheral blood of malaria patients.

Naturally acquired blood-stage infections of the malaria parasite Plasmodium falciparum typically harbour multiple haploid clones. The apparent number of clones observed in any single infection depends on the diversity of the polymorphic markers used for the analysis, and the relative abundance of rare clones, which frequently fail to be detected among PCR products derived from numerically dominant clones. However, minority clones are of clinical interest as they may harbour genes conferring drug resistance, leading to enhanced survival after treatment and the possibility of subsequent therapeutic failure. We deployed new generation sequencing to derive genome data for five non-propagated parasite isolates taken directly from 4 different patients treated for clinical malaria in a UK hospital. Analysis of depth of coverage and length of sequence intervals between paired reads identified both previously described and novel gene deletions and amplifications. Full-length sequence data was extracted for 6 loci considered to be under selection by antimalarial drugs, and both known and previously unknown amino acid substitutions were identified. Full mitochondrial genomes were extracted from the sequencing data for each isolate, and these are compared against a panel of polymorphic sites derived from published or unpublished but publicly available data. Finally, genome-wide analysis of clone multiplicity was performed, and the number of infecting parasite clones estimated for each isolate. Each patient harboured at least 3 clones of P. falciparum by this analysis, consistent with results obtained with conventional PCR analysis of polymorphic merozoite antigen loci. We conclude that genome sequencing of peripheral blood P. falciparum taken directly from malaria patients provides high quality data useful for drug resistance studies, genomic structural analyses and population genetics, and also robustly represents clonal multiplicity

A novel locus for Meckel-Gruber syndrome, MKS3, maps to chromosome 8q24

Meckel-Gruber syndrome (MKS), the most common monogenic cause of neural tube defects, is an autosomal recessive disorder characterised by a combination of renal cysts and variably associated features, including developmental anomalies of the central nervous system (typically encephalcoele), hepatic ductal dysplasia and cysts, and polydactyly. Locus heterogeneity has been demonstrated by the mapping of the MKS1 locus to 17q21-24 in Finnish kindreds, and of MKS2 to 11q13 in North African-Middle Eastern cohorts. In the present study, we have investigated the genetic basis of MKS in eight consanguineous kindreds, originating from the Indian sub-continent, that do not show linkage to either MKS1 or MKS2. We report the localisation of a third MKS locus (MKS3) to chromosome 8q24 in this cohort by a genome-wide linkage search using autozygosity mapping. We identified a 26-cM region of autozygosity between D8S586 and D8S1108 with a maximum cumulative two-point LOD score at D8S1179 (Z(max)=3.04 at theta=0.06). A heterogeneity test provided evidence of one unlinked family. Exclusion of this family from multipoint analysis maximised the cumulative multipoint LOD score at locus D8S1128 (Z(max)=5.65). Furthermore, a heterozygous SNP in DDEF1, a putative candidate gene, suggested that MKS3 mapped within a 15-cM interval. Comparison of the clinical features of MKS3-linked cases with reports of MKS1- and MKS2-linked kindreds suggests that polydactyly (and possibly encephalocele) appear less common in MKS3-linked families

Patient satisfaction in neurological second opinions and tertiary referrals

Although the number of neurological second opinions (SOs) and tertiary referrals (TRs) is increasing, only little is known about expectations and patient satisfaction in this group of patients. Therefore, the purpose of this study was to explore expectations of patients who get a neurological SO or TR and to assess patient satisfaction in these groups of patients. All new patients attending an academic neurological day-care clinic in a 6-month period were investigated. Demographic characteristics, duration of symptoms, expectations and motivation, new diagnoses and treatment consequences were studied, and patient satisfaction with the previous physician and the day-care clinic physician was assessed. Three hundred consecutive patients (183 SOs and 117 TRs) were evaluated. SO patients were younger (47 years vs. 51 years), and their duration of symptoms was longer (24 vs. 13 months) than TR patients. Most patients expected a new diagnosis or treatment (60%). SO patients were equally as satisfied with the day-care clinic consultation as TR patients (overall satisfaction using a VAS-score ranging 0–10: 7.4 vs. 7.5; p = 0.81), and significantly less satisfied with the referring physician (overall satisfaction: 5.6 vs. 7.0; p < 0.001). SO patients, in particular, were more satisfied with the degree of information and emotional support provided by the consulting neurologist as compared to the referring physician. Receiving a new diagnosis and/or treatment advice did not influence satisfaction. A day-care admission for neurological SO and TR leads to an increase of patient satisfaction, irrespective of making a new diagnosis or initiation of a new treatment

A retrospective study on the use of post-operative colonoscopy following potentially curative surgery for colorectal cancer in a Canadian province

BACKGROUND: Surveillance colonoscopy is commonly recommended following potentially curative surgery for colorectal cancer. We determined factors associated with patients undergoing a least one colonoscopy within five years of surgery. METHODS: In this historical cohort study, data on 3918 patients age 30 years or older residing in Alberta, Canada, who had undergone a potentially curative surgical resection for local or regional stage colorectal cancer between 1983 and 1995 were obtained from the provincial cancer registry, ministry of health and cancer clinic charts. Kaplan-Meier estimates of the probability of undergoing a post-operative colonoscopy were calculated for patient, tumor and treatment-related variables of interest. RESULTS: A colonoscopy was performed within five years of surgery in 1979 patients. The probability of undergoing a colonoscopy for those diagnosed in the 1990s was greater than for those diagnosed earlier (0.65 vs 0.55, P < 0.0001). The majority of the difference was seen at one-year following surgery, consistent with changes in surveillance practices. Those most likely to undergo a colonoscopy were those under age 70 (0.74 vs 0.50 for those age 70 – 79, P < 0.0001), who underwent a pre-operative colonoscopy (0.69 vs 0.54, P < 0.0001), and who underwent a resection with reanastomosis (0.62 vs 0.47 for abdominoperineal resection, P < 0.0001) by a surgeon who performs colonoscopies (0.68 vs 0.54, P < 0.0001). CONCLUSIONS: The majority of patients undergo colonoscopy following colorectal cancer surgery. However, there are important variations in surveillance practices across different patient and treatment characteristics

The pseudogap: friend or foe of high Tc?

Although nineteen years have passed since the discovery of high temperature superconductivity, there is still no consensus on its physical origin. This is in large part because of a lack of understanding of the state of matter out of which the superconductivity arises. In optimally and underdoped materials, this state exhibits a pseudogap at temperatures large compared to the superconducting transition temperature. Although discovered only three years after the pioneering work of Bednorz and Muller, the physical origin of this pseudogap behavior and whether it constitutes a distinct phase of matter is still shrouded in mystery. In the summer of 2004, a band of physicists gathered for five weeks at the Aspen Center for Physics to discuss the pseudogap. In this perspective, we would like to summarize some of the results presented there and discuss its importance in the context of strongly correlated electron systems.Comment: expanded version, 20 pages, 11 figures, to be published, Advances in Physic

Multi-centre parallel arm randomised controlled trial to assess the effectiveness and cost-effectiveness of a group-based cognitive behavioural approach to managing fatigue in people with multiple sclerosis

Abstract (provisional) Background Fatigue is one of the most commonly reported and debilitating symptoms of multiple sclerosis (MS); approximately two-thirds of people with MS consider it to be one of their three most troubling symptoms. It may limit or prevent participation in everyday activities, work, leisure, and social pursuits, reduce psychological well-being and is one of the key precipitants of early retirement. Energy effectiveness approaches have been shown to be effective in reducing MS-fatigue, increasing self-efficacy and improving quality of life. Cognitive behavioural approaches have been found to be effective for managing fatigue in other conditions, such as chronic fatigue syndrome, and more recently, in MS. The aim of this pragmatic trial is to evaluate the clinical and cost-effectiveness of a recently developed group-based fatigue management intervention (that blends cognitive behavioural and energy effectiveness approaches) compared with current local practice. Methods This is a multi-centre parallel arm block-randomised controlled trial (RCT) of a six session group-based fatigue management intervention, delivered by health professionals, compared with current local practice. 180 consenting adults with a confirmed diagnosis of MS and significant fatigue levels, recruited via secondary/primary care or newsletters/websites, will be randomised to receive the fatigue management intervention or current local practice. An economic evaluation will be undertaken alongside the trial. Primary outcomes are fatigue severity, self-efficacy and disease-specific quality of life. Secondary outcomes include fatigue impact, general quality of life, mood, activity patterns, and cost-effectiveness. Outcomes in those receiving the fatigue management intervention will be measured 1 week prior to, and 1, 4, and 12 months after the intervention (and at equivalent times in those receiving current local practice). A qualitative component will examine what aspects of the fatigue management intervention participants found helpful/unhelpful and barriers to change. Discussion This trial is the fourth stage of a research programme that has followed the Medical Research Council guidance for developing and evaluating complex interventions. What makes the intervention unique is that it blends cognitive behavioural and energy effectiveness approaches. A potential strength of the intervention is that it could be integrated into existing service delivery models as it has been designed to be delivered by staff already working with people with MS. Service users will be involved throughout this research. Trial registration: Current Controlled Trials ISRCTN7651747

Palliative chemotherapy or best supportive care? A prospective study explaining patients' treatment preference and choice

Item does not contain fulltextIn palliative cancer treatment, the choice between palliative chemotherapy and best supportive care may be difficult. In the decision-making process, giving information as well as patients' values and preferences become important issues. Patients, however, may have a treatment preference before they even meet their medical oncologist. An insight into the patient's decision-making process can support clinicians having to inform their patients. Patients (n=207) with metastatic cancer, aged 18 years or older, able to speak Dutch, for whom palliative chemotherapy was a treatment option, were eligible for the study. We assessed the following before they consulted their medical oncologist: (1) socio-demographic characteristics, (2) disease-related variables, (3) quality-of-life indices, (4) attitudes and (5) preferences for treatment, information and participation in decision-making. The actual treatment decision, assessed after it had been made, was the main study outcome. Of 207 eligible patients, 140 patients (68%) participated in the study. At baseline, 68% preferred to undergo chemotherapy rather than wait watchfully. Eventually, 78% chose chemotherapy. Treatment preference (odds ratio (OR)=10.3, confidence interval (CI) 2.8-38.0) and a deferring style of decision-making (OR=4.9, CI 1.4-17.2) best predicted the actual treatment choice. Treatment preference (total explained variance=38.2%) was predicted, in turn, by patients' striving for length of life (29.5%), less striving for quality of life (6.1%) and experienced control over the cause of disease (2.6%). Patients' actual treatment choice was most strongly predicted by their preconsultation treatment preference. Since treatment preference is positively explained by striving for length of life, and negatively by striving for quality of life, it is questionable whether the purpose of palliative treatment is made clear. This, paradoxically, emphasises the need for further attention to the process of information giving and shared decision-making