The multiple sclerosis risk sharing scheme monitoring study - early results and lessons for the future

Background: Risk sharing schemes represent an innovative and important approach to the problems of rationing and achieving cost-effectiveness in high cost or controversial health interventions. This study aimed to assess the feasibility of risk sharing schemes, looking at long term clinical outcomes, to determine the price at which high cost treatments would be acceptable to the NHS. Methods: This case study of the first NHS risk sharing scheme, a long term prospective cohort study of beta interferon and glatiramer acetate in multiple sclerosis ( MS) patients in 71 specialist MS centres in UK NHS hospitals, recruited adults with relapsing forms of MS, meeting Association of British Neurologists (ABN) criteria for disease modifying therapy. Outcome measures were: success of recruitment and follow up over the first three years, analysis of baseline and initial follow up data and the prospect of estimating the long term cost-effectiveness of these treatments. Results: Centres consented 5560 patients. Of the 4240 patients who had been in the study for a least one year, annual review data were available for 3730 (88.0%). Of the patients who had been in the study for at least two years and three years, subsequent annual review data were available for 2055 (78.5%) and 265 (71.8%) patients respectively. Baseline characteristics and a small but statistically significant progression of disease were similar to those reported in previous pivotal studies. Conclusion: Successful recruitment, follow up and early data analysis suggest that risk sharing schemes should be able to deliver their objectives. However, important issues of analysis, and political and commercial conflicts of interest still need to be addressed

Mice with targeted disruptions in the paralogous genes hoxa-3 and hoxd-3 reveal synergistic interactions.

Journal ArticleThe Hox genes encode transcription factors which mediate the formation of the mammalian body plan along the anteroposterior and appendicular axes. Paralogous Hox genes within the separate linkage groups are closely related with respect to DNA sequence and expression, suggesting that they could have at least partially redundant functions. We showed previously that mice homozygous for independent targeted disruptions in the paralogous genes hoxa-3 and hoxd-3 had no defects in common. But our current analysis of double mutants has revealed strong, dosage-dependent interactions between these genes. We report here that in hoxd-3- homozygotes the first cervical vertebra, the atlas, is homeotically transformed to the adjacent anterior structure. Unexpectedly, in double mutants, rather than observing a more extensive homeotic transformation, the entire atlas is deleted. These observations are interpreted in terms of a model in which these Hox genes differentially regulate the proliferation rates of the appropriate sets of precursor cells

Underutilization of information and knowledge in everyday medical practice: Evaluation of a computer-based solution

<p>Abstract</p> <p>Background</p> <p>The medical history is acknowledged as the <it>sine qua non </it>for quality medical care because recognizing problems is pre-requisite for managing them. Medical histories typically are incomplete and inaccurate, however. We show here that computers are a solution to this issue of information gathering about patients. Computers can be programmed to acquire more complete medical histories with greater detail across a range of acute and chronic issues than physician histories.</p> <p>Methods</p> <p>Histories were acquired by physicians in the usual way and by a computer program interacting directly with patients. Decision-making of what medical issues were queried by computer were made internally by the software, including determination of the chief complaint. The selection of patients was from admissions to the Robert-Bosch-Hospital, Stuttgart, Germany by convenience sampling. Physician-acquired and computer-acquired histories were compared on a patient-by-patient basis for 45 patients.</p> <p>Results</p> <p>The computer histories reported 160 problems not recorded in physician histories or slightly more than 3.5 problems per patient. However, physicians but not the computer reported 13 problems. The data show that computer histories reported problems across a range of organ systems, that the problems detected by computer but not physician histories were both acute and chronic and that the computer histories detected a significant number of issues important for preventing further morbidity.</p> <p>Conclusion</p> <p>A combination of physician and computer-acquired histories, in non-emergent situations, with the latter available to the physician at the time he or she sees the patient, is a far superior method for collecting historical data than the physician interview alone.</p

Chemical combinations elucidate pathway interactions and regulation relevant to Hepatitis C replication

SREBP-2, oxidosqualene cyclase (OSC) or lanosterol demethylase were identified as novel sterol pathway-associated targets that, when probed with chemical agents, can inhibit hepatitis C virus (HCV) replication.Using a combination chemical genetics approach, combinations of chemicals targeting sterol pathway enzymes downstream of and including OSC or protein geranylgeranyl transferase I (PGGT) produce robust and selective synergistic inhibition of HCV replication. Inhibition of enzymes upstream of OSC elicit proviral responses that are dominant to the effects of inhibiting all downstream targets.Inhibition of the sterol pathway without inhibition of regulatory feedback mechanisms ultimately results in an increase in HCV replication because of a compensatory upregulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) expression. Increases in HMGCR expression without inhibition of HMGCR enzymatic activity ultimately stimulate HCV replication through increasing the cellular pool of geranylgeranyl pyrophosphate (GGPP).Chemical inhibitors that ultimately prevent SREBP-2 activation, inhibit PGGT or encourage the production of polar sterols have great potential as HCV therapeutics if associated toxicities can be reduced

Conserving the Stage: Climate Change and the Geophysical Underpinnings of Species Diversity

Conservationists have proposed methods for adapting to climate change that assume species distributions are primarily explained by climate variables. The key idea is to use the understanding of species-climate relationships to map corridors and to identify regions of faunal stability or high species turnover. An alternative approach is to adopt an evolutionary timescale and ask ultimately what factors control total diversity, so that over the long run the major drivers of total species richness can be protected. Within a single climatic region, the temperate area encompassing all of the Northeastern U.S. and Maritime Canada, we hypothesized that geologic factors may take precedence over climate in explaining diversity patterns. If geophysical diversity does drive regional diversity, then conserving geophysical settings may offer an approach to conservation that protects diversity under both current and future climates. Here we tested how well geology predicts the species diversity of 14 US states and three Canadian provinces, using a comprehensive new spatial dataset. Results of linear regressions of species diversity on all possible combinations of 23 geophysical and climatic variables indicated that four geophysical factors; the number of geological classes, latitude, elevation range and the amount of calcareous bedrock, predicted species diversity with certainty (adj. R2 = 0.94). To confirm the species-geology relationships we ran an independent test using 18,700 location points for 885 rare species and found that 40% of the species were restricted to a single geology. Moreover, each geology class supported 5–95 endemic species and chi-square tests confirmed that calcareous bedrock and extreme elevations had significantly more rare species than expected by chance (P<0.0001), strongly corroborating the regression model. Our results suggest that protecting geophysical settings will conserve the stage for current and future biodiversity and may be a robust alternative to species-level predictions

Reptilian Heart Development And The Molecular Basis Of Cardiac Chamber Evolution

The emergence of terrestrial life witnessed the need for more sophisticated circulatory systems. This has evolved in birds, mammals and crocodilians into complete septation of the heart into left and right sides, allowing separate pulmonary and systemic circulatory systems, a key requirement for the evolution of endothermy(1-3). However, the evolution of the amniote heart is poorly understood. Reptilian hearts have been the subject of debate in the context of the evolution of cardiac septation: do they possess a single ventricular chamber or two incompletely septated ventricles(4-7)? Here we examine heart development in the red-eared slider turtle, Trachemys scripta elegans (a chelonian), and the green anole, Anolis carolinensis (a squamate), focusing on gene expression in the developing ventricles. Both reptiles initially form a ventricular chamber that homogenously expresses the T-box transcription factor gene Tbx5. In contrast, in birds and mammals, Tbx5 is restricted to left ventricle precursors(8,9). In later stages, Tbx5 expression in the turtle (but not anole) heart is gradually restricted to a distinct left ventricle, forming a left-right gradient. This suggests that Tbx5 expression was refined during evolution to pattern the ventricles. In support of this hypothesis, we show that loss of Tbx5 in the mouse ventricle results in a single chamber lacking distinct identity, indicating a requirement for Tbx5 in septation. Importantly, misexpression of Tbx5 throughout the developing myocardium to mimic the reptilian expression pattern also results in a single mispatterned ventricular chamber lacking septation. Thus ventricular septation is established by a steep and correctly positioned Tbx5 gradient. Our findings provide a molecular mechanism for the evolution of the amniote ventricle, and support the concept that altered expression of developmental regulators is a key mechanism of vertebrate evolution

Differences in genotype and virulence among four multidrug-resistant <i>Streptococcus pneumoniae</i> isolates belonging to the PMEN1 clone

We report on the comparative genomics and characterization of the virulence phenotypes of four &lt;i&gt;S. pneumoniae&lt;/i&gt; strains that belong to the multidrug resistant clone PMEN1 (Spain&lt;sup&gt;23F&lt;/sup&gt; ST81). Strains SV35-T23 and SV36-T3 were recovered in 1996 from the nasopharynx of patients at an AIDS hospice in New York. Strain SV36-T3 expressed capsule type 3 which is unusual for this clone and represents the product of an in vivo capsular switch event. A third PMEN1 isolate - PN4595-T23 - was recovered in 1996 from the nasopharynx of a child attending day care in Portugal, and a fourth strain - ATCC700669 - was originally isolated from a patient with pneumococcal disease in Spain in 1984. We compared the genomes among four PMEN1 strains and 47 previously sequenced pneumococcal isolates for gene possession differences and allelic variations within core genes. In contrast to the 47 strains - representing a variety of clonal types - the four PMEN1 strains grouped closely together, demonstrating high genomic conservation within this lineage relative to the rest of the species. In the four PMEN1 strains allelic and gene possession differences were clustered into 18 genomic regions including the capsule, the blp bacteriocins, erythromycin resistance, the MM1-2008 prophage and multiple cell wall anchored proteins. In spite of their genomic similarity, the high resolution chinchilla model was able to detect variations in virulence properties of the PMEN1 strains highlighting how small genic or allelic variation can lead to significant changes in pathogenicity and making this set of strains ideal for the identification of novel virulence determinant

Psychometric Properties of an Arabic Pain Anxiety Symptoms Scale-20 (PASS-20) in Healthy Volunteers and Patients Attending a Physiotherapy Clinic.

PURPOSE: The aim of this study was to cross-culturally adapt the PASS-20 questionnaire for use in Libya. METHODS: Participants were 71 patients (42 women) attending the physiotherapy clinic, Ibn Sina Hospital, Sirt, Libya for management of persistent pain and 137 healthy unpaid undergraduate students (52 women) from the University of Sirt, Libya. The English PASS-20 was translated into Arabic. Patients completed the Arabic PASS-20 and the Arabic Pain Rating Scales on two occasions separated by a 14-day interval. Healthy participants completed the Arabic PASS-20 on one occasion. RESULTS: The internal consistency (ICC) for pain patient and healthy participant samples yielded a good reliability for the total score, cognitive anxiety, fear of pain, and physiological anxiety. The test-retest reliability of the Arabic PASS-20 score showed high reliability for the total score (ICC = 0.93, p < 0.001), escape/avoidance (ICC = 0.93, p < 0.001), fear of pain (ICC = 0.94, p < 0.001), and physiological anxiety subscales (ICC = 0.96, p < 0.001) and good reliability for the cognitive anxiety (ICC = 0.85, p < 0.001). Inspection of the Promax rotation showed that each factor comprised of five items were consistent with the theoretical constructs of the original PASS-20 subscales. CONCLUSION: The Arabic PASS-20 retained internal consistency and reliability with the original English version and can be used to measure pain anxiety symptoms in both pain and healthy individual samples in Libya

The Effect of Interocular Phase Difference on Perceived Contrast

Binocular vision is traditionally treated as two processes: the fusion of similar images, and the interocular suppression of dissimilar images (e.g. binocular rivalry). Recent work has demonstrated that interocular suppression is phase-insensitive, whereas binocular summation occurs only when stimuli are in phase. But how do these processes affect our perception of binocular contrast? We measured perceived contrast using a matching paradigm for a wide range of interocular phase offsets (0–180°) and matching contrasts (2–32%). Our results revealed a complex interaction between contrast and interocular phase. At low contrasts, perceived contrast reduced monotonically with increasing phase offset, by up to a factor of 1.6. At higher contrasts the pattern was non-monotonic: perceived contrast was veridical for in-phase and antiphase conditions, and monocular presentation, but increased a little at intermediate phase angles. These findings challenge a recent model in which contrast perception is phase-invariant. The results were predicted by a binocular contrast gain control model. The model involves monocular gain controls with interocular suppression from positive and negative phase channels, followed by summation across eyes and then across space. Importantly, this model—applied to conditions with vertical disparity—has only a single (zero) disparity channel and embodies both fusion and suppression processes within a single framework

Household possession, use and non-use of treated or untreated mosquito nets in two ecologically diverse regions of Nigeria – Niger Delta and Sahel Savannah

<p>Abstract</p> <p>Background</p> <p>Current use of treated mosquito nets for the prevention of malaria falls short of what is expected in sub-Saharan Africa (SSA), though research within the continent has indicated that the use of these commodities can reduce malaria morbidity by 50% and malaria mortality by 20%. Governments in sub-Sahara Africa are investing substantially in scaling-up treated mosquito net coverage for impact. However, certain significant factors still prevent the use of the treated mosquito nets, even among those who possess them. This survey examines household ownership as well as use and non-use of treated mosquito nets in Sahel Savannah and Niger Delta regions of Nigeria.</p> <p>Methodology</p> <p>This survey employed cross-sectional survey to collect data from households on coverage and use of mosquito nets, whether treated or not. Fever episodes in previous two weeks among children under the age of five were also recorded. The study took place in August 1 – 14 2007, just five months after the March distribution of treated mosquito nets, coinciding with the second raining period of the year and a time of high malaria transmission during the wet season. EPI INFO version 2003 was used in data analysis.</p> <p>Results</p> <p>The survey covered 439 households with 2,521 persons including 739 under-fives, 585 women in reproductive age and 78 pregnant women in Niger Delta Region and Sahel Savannah Region. Of the 439 HHs, 232 had any mosquito nets. Significantly higher proportion of households in the Niger Delta Region had any treated or untreated mosquito nets than those in the Sahel Savannah Region. In the Niger Delta Region, the proportion of under-fives that had slept under treated nets the night before the survey exceeded those that slept under treated nets in the Sahel Savannah Region. Children under the age of five years in the Niger Delta Region were four times more likely to sleep under treated nets than those in the Sahel Savannah Region.</p> <p>Conclusion</p> <p>This study found that despite the fact that treated nets were distributed widely across Nigeria, the use of this commodity was still very low in the Sahel Savannah region. Future campaigns should include more purposeful social and health education on the importance and advantages of the use of treated nets to save lives in the Sahel Savannah region of Nigeria.</p