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1.

Background

Though rare in occurrence, patients with rare bleeding disorders (RBDs) are highly heterogeneous and may manifest with severe bleeding diathesis. Due to the high rate of consanguinity in many caste groups, these autosomal recessive bleeding disorders which are of rare occurrence in populations across the world, may not be as rare in India.

Objectives

To comprehensively analyze the frequency and nature of mutations in Indian patients with RBDs.

Methods

Pubmed search was used (www.pubmed.com) to explore the published literature from India on RBDs using the key words “rare bleeding disorders”, “mutations”, “India”, “fibrinogen”, “afibrinogenemia”, “factor II deficiency”, “prothrombin” “factor VII deficiency”, “factor V deficiency”, “factor X deficiency”, “factor XI deficiency”, “combined factor V and VIII deficiency”, “factor XIII deficiency”, “Bernard Soulier syndrome” and “Glanzmanns thrombasthenia” in different combinations. A total of 60 relevant articles could be retrieved. The distribution of mutations from India was compared with that of the world literature by referring to the Human Gene Mutation Database (HGMD) (www.hgmd.org).

Results

Taken together, 181 mutations in 270 patients with different RBDs have been reported from India. Though the types of mutations reported from India and their percentage distribution with respect to the world data are largely similar, yet much higher percentage of small deletions, duplication mutations, insertions, indels were observed in this analysis. Besides the identification of novel mutations and polymorphisms, several common mutations have also been reported, which will allow to develop a strategy for mutation screening in Indian patients with RBDs.

Conclusion

There is a need for a consortium of Institutions working on the molecular pathology of RBDs in India. This will facilitate a quicker and cheaper diagnosis of RBDs besides its utility in first trimester prenatal diagnosis of the affected families.  相似文献   

2.

Objective

To evaluate the effects of study participation per se at the beginning of a sleep extension trial between screening, randomization, and the run-in visit.

Design

Subjects were screened, returned for randomization (Comparison vs. Intervention) after 81 days (median), and attended run-in visit 121 days later.

Setting

Outpatient.

Patients

Obese (N = 125; M/F, 30/95; Blacks/Whites/Other, N = 73/44/8), mean weight 107.6±19.7 kg, <6.5 h sleep/night.

Intervention

Non-pharmacological sleep extension.

Measurements

Sleep duration (diaries and actigraphy watch), sleep quality (Pittsburgh Sleep Quality Index), daily sleepiness (Epworth Sleepiness Scale), fasting glucose, insulin and lipids.

Results

Prior to any intervention, marked improvements occurred between screening and randomization. Sleep duration increased (diaries: 357.4 ±51.2 vs. 388.1±48.6 min/night; mean±SD; P<0.001 screening vs. randomization; actigraphy: 344.3 ±41.9 vs. 358.6±48.2 min/night; P<0.001) sleep quality improved (9.1±3.2 vs. 8.2±3.0 PSQI score; P<0.001), sleepiness tended to improve (8.9±4.6 vs. 8.3±4.5 ESS score; P = 0.06), insulin resistance decreased (0.327±0.038 vs. 0.351±0.045; Quicki index; P<0.001), and lipids improved, except for HDL-C. Abnormal fasting glucose (25% vs. 11%; P = 0.007), and metabolic syndrome (42% vs. 29%; P = 0.007) both decreased. In absence of intervention, the earlier metabolic improvements disappeared at the run-in visit.

Limitations

Relatively small sample size.

Conclusions

Improvements in biochemical and behavioral parameters between screening and randomization changed the “true” study baseline, thereby potentially affecting outcome. While regression to the mean and placebo effect were considered, these findings are most consistent with the “Hawthorne effect”, according to which behavior measured in the setting of an experimental study changes in response to the attention received from study investigators. This is the first time that biochemical changes were documented with respect to the Hawthorne effect. The findings have implications for the design and conduct of clinical research.

Trial Registration

ClinicalTrials.gov NCT00261898.  相似文献   

3.
4.

Background

We recently described FastTree, a tool for inferring phylogenies for alignments with up to hundreds of thousands of sequences. Here, we describe improvements to FastTree that improve its accuracy without sacrificing scalability.

Methodology/Principal Findings

Where FastTree 1 used nearest-neighbor interchanges (NNIs) and the minimum-evolution criterion to improve the tree, FastTree 2 adds minimum-evolution subtree-pruning-regrafting (SPRs) and maximum-likelihood NNIs. FastTree 2 uses heuristics to restrict the search for better trees and estimates a rate of evolution for each site (the “CAT” approximation). Nevertheless, for both simulated and genuine alignments, FastTree 2 is slightly more accurate than a standard implementation of maximum-likelihood NNIs (PhyML 3 with default settings). Although FastTree 2 is not quite as accurate as methods that use maximum-likelihood SPRs, most of the splits that disagree are poorly supported, and for large alignments, FastTree 2 is 100–1,000 times faster. FastTree 2 inferred a topology and likelihood-based local support values for 237,882 distinct 16S ribosomal RNAs on a desktop computer in 22 hours and 5.8 gigabytes of memory.

Conclusions/Significance

FastTree 2 allows the inference of maximum-likelihood phylogenies for huge alignments. FastTree 2 is freely available at http://www.microbesonline.org/fasttree.  相似文献   

5.

Background

Preserved Ratio Impaired Spirometry (PRISm), defined as a reduced FEV1 in the setting of a preserved FEV1/FVC ratio, is highly prevalent and is associated with increased respiratory symptoms, systemic inflammation, and mortality. Studies investigating quantitative chest tomographic features, genetic associations, and subtypes in PRISm subjects have not been reported.

Methods

Data from current and former smokers enrolled in COPDGene (n = 10,192), an observational, cross-sectional study which recruited subjects aged 45–80 with ≥10 pack years of smoking, were analyzed. To identify epidemiological and radiographic predictors of PRISm, we performed univariate and multivariate analyses comparing PRISm subjects both to control subjects with normal spirometry and to subjects with COPD. To investigate common genetic predictors of PRISm, we performed a genome-wide association study (GWAS). To explore potential subgroups within PRISm, we performed unsupervised k-means clustering.

Results

The prevalence of PRISm in COPDGene is 12.3%. Increased dyspnea, reduced 6-minute walk distance, increased percent emphysema and decreased total lung capacity, as well as increased segmental bronchial wall area percentage were significant predictors (p-value <0.05) of PRISm status when compared to control subjects in multivariate models. Although no common genetic variants were identified on GWAS testing, a significant association with Klinefelter’s syndrome (47XXY) was observed (p-value < 0.001). Subgroups identified through k-means clustering include a putative “COPD-subtype”, “Restrictive-subtype”, and a highly symptomatic “Metabolic-subtype”.

Conclusions

PRISm subjects are clinically and genetically heterogeneous. Future investigations into the pathophysiological mechanisms behind and potential treatment options for subgroups within PRISm are warranted.

Trial registration

Clinicaltrials.gov Identifier: NCT000608764.

Electronic supplementary material

The online version of this article (doi:10.1186/s12931-014-0089-y) contains supplementary material, which is available to authorized users.  相似文献   

6.

Background

Valproic acid (VPA) has demonstrated potential as a therapeutic candidate for spinal muscular atrophy (SMA) in vitro and in vivo.

Methods

Two cohorts of subjects were enrolled in the SMA CARNIVAL TRIAL, a non-ambulatory group of “sitters” (cohort 1) and an ambulatory group of “walkers” (cohort 2). Here, we present results for cohort 1: a multicenter phase II randomized double-blind intention-to-treat protocol in non-ambulatory SMA subjects 2–8 years of age. Sixty-one subjects were randomized 1∶1 to placebo or treatment for the first six months; all received active treatment the subsequent six months. The primary outcome was change in the modified Hammersmith Functional Motor Scale (MHFMS) score following six months of treatment. Secondary outcomes included safety and adverse event data, and change in MHFMS score for twelve versus six months of active treatment, body composition, quantitative SMN mRNA levels, maximum ulnar CMAP amplitudes, myometry and PFT measures.

Results

At 6 months, there was no difference in change from the baseline MHFMS score between treatment and placebo groups (difference = 0.643, 95% CI = −1.22–2.51). Adverse events occurred in >80% of subjects and were more common in the treatment group. Excessive weight gain was the most frequent drug-related adverse event, and increased fat mass was negatively related to change in MHFMS values (p = 0.0409). Post-hoc analysis found that children ages two to three years that received 12 months treatment, when adjusted for baseline weight, had significantly improved MHFMS scores (p = 0.03) compared to those who received placebo the first six months. A linear regression analysis limited to the influence of age demonstrates young age as a significant factor in improved MHFMS scores (p = 0.007).

Conclusions

This study demonstrated no benefit from six months treatment with VPA and L-carnitine in a young non-ambulatory cohort of subjects with SMA. Weight gain, age and treatment duration were significant confounding variables that should be considered in the design of future trials.

Trial Registry

Clinicaltrials.gov NCT00227266  相似文献   

7.

Objectives

Metabolic disturbances are well-known risk factors for atherosclerosis, but it remains unclear which cardiometabolic components are the predominant determinants. This study aimed to compare and identify the key determinants of carotid atherosclerosis in asymptomatic middle-aged and elderly Chinese.

Methods

A community-based cross-sectional study including 3,162 apparently healthy residents aged 37–75 years was performed from July 2008 to June 2010 in Guangzhou, China. Carotid artery intima-media thickness (IMT) was assessed by B-mode ultrasound, and increased IMT was defined as IMT>1.00 mm. Obesity indices, blood pressure, fasting blood lipids, glucose and uric acid levels were determined. Principal components factor analysis was used to extract common factors underlying 11 metabolic factors.

Results

Four common factors, defined as “adiposity,” “blood lipids,” “triglycerides/uric acid (TG/UA)” (in men) or “triglycerides/uric acid/glucose (TG/UA/Glu)” (in women), and “blood pressure,” were retained for both sexes. After adjustment for potential covariates, the “adiposity” factor showed the strongest positive association with increased IMT in men. Comparing the extreme quartiles, ORs (95% CI) of increased IMT were 4.64 (2.04–10.59) at the CCA and 2.37 (1.54–3.64) at the BIF), followed by “blood pressure”, the corresponding OR (95% CI) was 2.85 (1.37–5.90) at the CCA. Whereas, the four common factors showed comparable and weak relationship with increased IMTs, the ORs for quartile 4 vs. quartile 1 varied from 0.89 to 3.59 in women.

Conclusions

Among the metabolic factors, “adiposity” and “blood pressure” play predominant roles in the presence of carotid atherosclerosis in men, but no key factor is identified in women.  相似文献   

8.

Background

In psychiatry, hospital stays and transitions to the ambulatory sector are susceptible to major changes in drug therapy that lead to complex medication regimens and common non-adherence among psychiatric patients. A multi-dimensional and inter-sectoral intervention is hypothesized to improve the adherence of psychiatric patients to their pharmacotherapy.

Methods

269 patients from a German university hospital were included in a prospective, open, clinical trial with consecutive control and intervention groups. Control patients (09/2012-03/2013) received usual care, whereas intervention patients (05/2013-12/2013) underwent a program to enhance adherence during their stay and up to three months after discharge. The program consisted of therapy simplification and individualized patient education (multi-dimensional component) during the stay and at discharge, as well as subsequent phone calls after discharge (inter-sectoral component). Adherence was measured by the “Medication Adherence Report Scale” (MARS) and the “Drug Attitude Inventory” (DAI).

Results

The improvement in the MARS score between admission and three months after discharge was 1.33 points (95% CI: 0.73–1.93) higher in the intervention group compared to controls. In addition, the DAI score improved 1.93 points (95% CI: 1.15–2.72) more for intervention patients.

Conclusion

These two findings indicate significantly higher medication adherence following the investigated multi-dimensional and inter-sectoral program.

Trial Registration

German Clinical Trials Register DRKS00006358  相似文献   

9.

Background

Graphical representation of data is one of the most easily comprehended forms of explanation. The current study describes a simple visualization tool which may allow greater understanding of medical and epidemiological data.

Method

We propose a simple tool for visualization of data, known as a “quilt plot”, that provides an alternative to presenting large volumes of data as frequency tables. Data from the Australian Needle and Syringe Program survey are used to illustrate “quilt plots”.

Conclusion

Visualization of large volumes of data using “quilt plots” enhances interpretation of medical and epidemiological data. Such intuitive presentations are particularly useful for the rapid assessment of problems in the data which cannot be readily identified by manual review. We recommend that, where possible, “quilt plots” be used along with traditional quantitative assessments of the data as an explanatory data analysis tool.  相似文献   

10.
11.

Objective

Oncostatin M (OSM) is produced by activated T cells, monocytes, and dendritic cells and signals through two distinct receptor complexes consisting of gp130 and LIFR (I) or OSMR-β and gp130 (II), respectively. Aim of this study was to analyze the role of OSM in intestinal epithelial cells (IEC) and intestinal inflammation.

Methods

OSM expression and OSM receptor distribution was analyzed by PCR and immunohistochemistry experiments, signal transduction by immunoblotting. Gene expression studies were performed by microarray analysis and RT-PCR. Apoptosis was measured by caspases-3/7 activity. IEC migration and proliferation was studied in wounding and water soluble tetrazolium assays.

Results

The IEC lines Caco-2, DLD-1, SW480, HCT116 and HT-29 express mRNA for the OSM receptor subunits gp130 and OSMR-β, while only HCT116, HT-29 and DLD-1 cells express LIFR mRNA. OSM binding to its receptor complex activates STAT1, STAT3, ERK-1/2, SAPK/JNK-1/2, and Akt. Microarray analysis revealed 79 genes that were significantly up-regulated (adj.-p≤0.05) by OSM in IEC. Most up-regulated genes belong to the functional categories “immunity and defense” (p = 2.1×10−7), “apoptosis” (p = 3.7×10−4) and “JAK/STAT cascade” (p = 3.4×10−6). Members of the SERPIN gene family were among the most strongly up-regulated genes. OSM significantly increased STAT3- and MEK1-dependent IEC cell proliferation (p<0.05) and wound healing (p = 3.9×10−5). OSM protein expression was increased in colonic biopsies of patients with active inflammatory bowel disease (IBD).

Conclusions

OSM promotes STAT3-dependent intestinal epithelial cell proliferation and wound healing in vitro. Considering the increased OSM expression in colonic biopsy specimens of patients with active IBD, OSM upregulation may modulate a barrier-protective host response in intestinal inflammation. Further in vivo studies are warranted to elucidate the exact role of OSM in intestinal inflammation and the potential of OSM as a drug target in IBD.  相似文献   

12.

Background

This cluster-randomised controlled trial determined the effectiveness of an evidence-based, pamphlet intervention in improving low back pain (LBP)-related beliefs among pharmacy consumers.

Methods

Thirty five community pharmacies were randomised to three groups: pamphlet+education intervention [n = 11]; pamphlet only intervention [n = 11]; control: usual care [n = 13]. Eligibility requirements for clusters included: community-based pharmacies and proprietor participation consent. Pharmacy consumers (N = 317) aged 18–65 years currently experiencing LBP participated. Intervention group allocation depended on the pharmacy attended. Individual-level outcomes were measured at pre-intervention (T0), at two (T1) and eight (T2) weeks post-intervention and included beliefs about LBP [Back Pain Beliefs Questionnaire (BBQ); Fear Avoidance Beliefs Questionnaire (FABQ)]. Secondary outcomes included pain severity, activity impairment and pamphlet perceived usefulness. Blinding to group allocation included primary investigators, outcome assessors and the statistician. Pharmacy staff and consumers were un-blinded.

Results

Of 35 pharmacies recruited (317 consumers), no clusters were lost to follow-up. Follow-up was available for n = 24 at 2 weeks only; n = 38 at 8 weeks only; n = 148 at both time points, with n = 148+24+38 = 210 analysed (107 excluded: no follow up). Adjusting for baseline scores demonstrated no significant differences in beliefs (2 or at 8 weeks) between pamphlet (with or without education) versus control, or between ‘pamphlet with’ versus ‘without’ education. Work-related fear (FABQ) was significantly lower in consumers receiving pamphlet (with or without education) versus control (difference −2.3, 95%CI: −4.4 to −0.2). There was no significant difference between “pamphlet with” versus “pamphlet without” groups. Consumers receiving the “pamphlet with” reported greater perceived usefulness than consumers receiving the “pamphlet without” (difference 0.9 (95%CI: 0.0 to 1.8)).

Conclusion

Community pharmacies provided a feasible primary care portal for implementing evidence-based information. The associated improvement in work-related LBP-beliefs for consumers receiving the pamphlet suggests this simple intervention may be a useful component of care.

Trial Registration

ACTR.org.au ACTRN12611000053921  相似文献   

13.

Objective

Studies from the USA have identified medical students as a major source of stigmatizing attitudes towards overweight and obese individuals. As data from Europe is scarce, medical students’ attitudes were investigated at the University of Leipzig in Leipzig, Germany.

Design

Cross-sectional survey containing an experimental manipulation consisting of a pair of vignettes depicting an obese and a normal weight 42-year-old woman, respectively. Vignettes were followed by the Fat Phobia Scale (FPS), a semantic differential assessing weight related attitudes. In case of the overweight vignette a panel of questions on causal attribution for the overweight preceded administration of the FPS.

Subjects

671 medical students were enrolled at the University of Leipzig from May to June 2011.

Results

The overweight vignette was rated significantly more negative than the normal weight vignette (mean FPS score 3.65±0.45 versus 2.54±0.38, p<0.001). A higher proportion of students had negative attitudes towards the overweight as compared to the normal weight individual (98.9% versus 53.7%, p<0.001). A “positive energy balance” was perceived as the most relevant cause for the overweight, followed by “negligent personality trait”, “societal and social environment” and “biomedical causes”. Attributing a “positive energy balance” or “negligent personality trait” as relevant cause for the overweight was positively associated with negative attitudes.

Conclusion

The results of this study confirm and complement findings from other countries, mainly the USA, and indicate that weight bias in the health care setting may be a global issue. Stigmatizing attitudes towards overweight and obesity are prevalent among a sample of medical students at the University of Leipzig. Negative attitudes arise on the basis of holding the individual accountable for the excess weight. They call for bringing the topic of overweight and obesity more into the focus of the medical curriculum and for enhancing medical students’ awareness of the complex aetiology of this health condition.  相似文献   

14.

Objective

To assess the validity of CRB-65 (Confusion, Respiratory rate >30 breaths/min, BP<90/60 mmHg, age >65 years) as a pneumonia severity index in a Malawian hospital population, and determine whether an alternative score has greater accuracy in this setting.

Design

Forty three variables were prospectively recorded during the first 48 hours of admission in all patients admitted to Queen Elizabeth Central Hospital, Malawi, for management of lower respiratory tract infection over a two month period (N = 240). Calculation of sensitivity and specificity for CRB-65 in predicting mortality was followed by multivariate modeling to create a score with superior performance in this population.

Results

Median age 37, HIV prevalence 79.9%, overall mortality 18.3%. CRB-65 predicted mortality poorly, indicated by the area under the ROC curve of 0.649. Independent predictors of death were: Male sex, “S” (AOR 2.6); Wasting, “W” (AOR 6.6); non-ambulatory, “A” (AOR 2.5); Temp >38°C or <35°C, “T” (AOR 3.2); BP<100/60, “Bp” (AOR 3.7). Combining these factors to form a severity index (SWAT-Bp) predicted mortality with high sensitivity and specificity (AUC: 0.867). Mortality for scores 0–5 was 0%, 3.3%, 7.4%, 29.2%, 61.5% and 87.5% respectively. A score ≥3 was 84% sensitive and 77% specific for mortality prediction, with a negative predictive value of 95.8%.

Conclusion

CRB-65 performs poorly in this population. The SWAT-Bp score can accurately stratify patients; ≤2 indicates non-severe infection (mortality 4.4%) and ≥3 severe illness (mortality 45%).  相似文献   

15.

Background

Tree nut consumption has been associated with reduced diabetes risk, however, results from randomized trials on glycemic control have been inconsistent.

Objective

To provide better evidence for diabetes guidelines development, we conducted a systematic review and meta-analysis of randomized controlled trials to assess the effects of tree nuts on markers of glycemic control in individuals with diabetes.

Data Sources

MEDLINE, EMBASE, CINAHL, and Cochrane databases through 6 April 2014.

Study Selection

Randomized controlled trials ≥3 weeks conducted in individuals with diabetes that compare the effect of diets emphasizing tree nuts to isocaloric diets without tree nuts on HbA1c, fasting glucose, fasting insulin, and HOMA-IR.

Data Extraction and Synthesis

Two independent reviewer’s extracted relevant data and assessed study quality and risk of bias. Data were pooled by the generic inverse variance method and expressed as mean differences (MD) with 95% CI’s. Heterogeneity was assessed (Cochran Q-statistic) and quantified (I2).

Results

Twelve trials (n = 450) were included. Diets emphasizing tree nuts at a median dose of 56 g/d significantly lowered HbA1c (MD = −0.07% [95% CI:−0.10, −0.03%]; P = 0.0003) and fasting glucose (MD = −0.15 mmol/L [95% CI: −0.27, −0.02 mmol/L]; P = 0.03) compared with control diets. No significant treatment effects were observed for fasting insulin and HOMA-IR, however the direction of effect favoured tree nuts.

Limitations

Majority of trials were of short duration and poor quality.

Conclusions

Pooled analyses show that tree nuts improve glycemic control in individuals with type 2 diabetes, supporting their inclusion in a healthy diet. Owing to the uncertainties in our analyses there is a need for longer, higher quality trials with a focus on using nuts to displace high-glycemic index carbohydrates.

Trial Registration

ClinicalTrials.gov NCT01630980  相似文献   

16.
17.

Motivation

Biomedical entities, their identifiers and names, are essential in the representation of biomedical facts and knowledge. In the same way, the complete set of biomedical and chemical terms, i.e. the biomedical “term space” (the “Lexeome”), forms a key resource to achieve the full integration of the scientific literature with biomedical data resources: any identified named entity can immediately be normalized to the correct database entry. This goal does not only require that we are aware of all existing terms, but would also profit from knowing all their senses and their semantic interpretation (ambiguities, nestedness).

Result

This study compiles a resource for lexical terms of biomedical interest in a standard format (called “LexEBI”), determines the overall number of terms, their reuse in different resources and the nestedness of terms. LexEBI comprises references for protein and gene entries and their term variants and chemical entities amongst other terms. In addition, disease terms have been identified from Medline and PubmedCentral and added to LexEBI. Our analysis demonstrates that the baseforms of terms from the different semantic types show only little polysemous use. Nonetheless, the term variants of protein and gene names (PGNs) frequently contain species mentions, which should have been avoided according to protein annotation guidelines. Furthermore, the protein and gene entities as well as the chemical entities, both do comprise enzymes leading to hierarchical polysemy, and a large portion of PGNs make reference to a chemical entity. Altogether, according to our analysis based on the Medline distribution, 401,869 unique PGNs in the documents contain a reference to 25,022 chemical entities, 3,125 disease terms or 1,576 species mentions.

Conclusion

LexEBI delivers the complete biomedical and chemical Lexeome in a standardized representation (http://www.ebi.ac.uk/Rebholz-srv/LexEBI/). The resource provides the disease terms as open source content, and fully interlinks terms across resources.  相似文献   

18.

Background

The “Just-in-time Information” (JIT) librarian consultation service was designed to provide rapid information to answer primary care clinical questions during patient hours. This study evaluated whether information provided by librarians to answer clinical questions positively impacted time, decision-making, cost savings and satisfaction.

Methods and Finding

A randomized controlled trial (RCT) was conducted between October 2005 and April 2006. A total of 1,889 questions were sent to the service by 88 participants. The object of the randomization was a clinical question. Each participant had clinical questions randomly allocated to both intervention (librarian information) and control (no librarian information) groups. Participants were trained to send clinical questions via a hand-held device. The impact of the information provided by the service (or not provided by the service), additional resources and time required for both groups was assessed using a survey sent 24 hours after a question was submitted. The average time for JIT librarians to respond to all questions was 13.68 minutes/question (95% CI, 13.38 to 13.98). The average time for participants to respond their control questions was 20.29 minutes/question (95% CI, 18.72 to 21.86). Using an impact assessment scale rating cognitive impact, participants rated 62.9% of information provided to intervention group questions as having a highly positive cognitive impact. They rated 14.8% of their own answers to control question as having a highly positive cognitive impact, 44.9% has having a negative cognitive impact, and 24.8% with no cognitive impact at all. In an exit survey measuring satisfaction, 86% (62/72 responses) of participants scored the service as having a positive impact on care and 72% (52/72) indicated that they would use the service frequently if it were continued.

Conclusions

In this study, providing timely information to clinical questions had a highly positive impact on decision-making and a high approval rating from participants. Using a librarian to respond to clinical questions may allow primary care professionals to have more time in their day, thus potentially increasing patient access to care. Such services may reduce costs through decreasing the need for referrals, further tests, and other courses of action.

Trial Registration

Controlled-Trials.com ISRCTN96823810  相似文献   

19.

Objective

Clinical trial outcomes often involve an ordinal scale of subjective functional assessments but the optimal way to quantify results is not clear. In stroke, the most commonly used scale, the modified Rankin Score (mRS), a range of scores (“Shift”) is proposed as superior to dichotomization because of greater information transfer. The influence of known uncertainties in mRS assessment has not been quantified. We hypothesized that errors caused by uncertainties could be quantified by applying information theory. Using Shannon’s model, we quantified errors of the “Shift” compared to dichotomized outcomes using published distributions of mRS uncertainties and applied this model to clinical trials.

Methods

We identified 35 randomized stroke trials that met inclusion criteria. Each trial’s mRS distribution was multiplied with the noise distribution from published mRS inter-rater variability to generate an error percentage for “shift” and dichotomized cut-points. For the SAINT I neuroprotectant trial, considered positive by “shift” mRS while the larger follow-up SAINT II trial was negative, we recalculated sample size required if classification uncertainty was taken into account.

Results

Considering the full mRS range, error rate was 26.1%±5.31 (Mean±SD). Error rates were lower for all dichotomizations tested using cut-points (e.g. mRS 1; 6.8%±2.89; overall p<0.001). Taking errors into account, SAINT I would have required 24% more subjects than were randomized.

Conclusion

We show when uncertainty in assessments is considered, the lowest error rates are with dichotomization. While using the full range of mRS is conceptually appealing, a gain of information is counter-balanced by a decrease in reliability. The resultant errors need to be considered since sample size may otherwise be underestimated. In principle, we have outlined an approach to error estimation for any condition in which there are uncertainties in outcome assessment. We provide the user with programs to calculate and incorporate errors into sample size estimation.  相似文献   

20.

Background

Previous trials have often defined genotype 2 and 3 patients as an “easy to treat” group and guidelines recommend similar management.

Aims

The present study looks for differences between the two genotypes and analyzes predictive factors for SVR.

Methods

Prospective, community-based cohort study involving 421 physicians throughout Germany. The analysis includes 2,347 patients with untreated chronic HCV genotype 2 (n = 391) and 3 (n = 1,956) infection treated with PEG-IFN α-2a plus ribavirin between August 2007 and July 2012.

Results

When compared with genotype 2 patients, those with genotype 3 were younger, had a shorter duration of infection, lower values of total cholesterol, LDL cholesterol and BMI, a higher frequency of drug use as infection mode and male gender (p<0.0001, respectively), and a higher APRI score (p<0.005). SVR was higher in genotype 2 when compared with genotype 3 (64.7% vs. 56.9%, p = 0.004). By multivariate analysis of genotype 2 patients, low baseline γ -GT and RVR predicted SVR. In genotype 3 age ≤45 years, cholesterol>130 mg/dl, a low APRI score, and a γ-GT ≥3-times ULN, RVR, and RBV starting dose were associated with SVR by multivariate analysis.

Conclusions

The present study corroborates that liver fibrosis is more pronounced in genotype 3 vs. 2. SVR is higher in genotype 2 versus genotype 3 partly because of follow-up problems in genotype 3 patients, in particular in those infected by drug use. Thus, subgroups of genotype 3 patients have adherence problems and need special attention also because they often have significant liver fibrosis.

Trial Registration

Verband Forschender Arzneimittelhersteller e.V., Berlin, Germany ML21645 ClinicalTrials.gov NCT02106156  相似文献   

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