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1.  Call to Action on Use and Reimbursement for Home Blood Pressure Monitoring A Joint Scientific Statement From the American Heart Association, American Society of Hypertension, and the Preventive Cardiovascular Nurses’ Association 
Hypertension  2008;52(1):10-29.
The standard method for the measurement of blood pressure (BP) in clinical practice has traditionally been to use readings taken with the auscultatory technique by a physician or nurse in a clinic or office setting. While such measurements are likely to remain the cornerstone for the diagnosis and management of hypertension for the foreseeable future, it is becoming increasingly clear that they often give inadequate or even misleading information about a patient’s true BP status. All clinical measurements of BP may be regarded as surrogate estimates of the “True” BP, which may regarded as the average level over prolonged periods of time. In the past 30 years there has been an increasing trend to supplement office or clinic readings with out-of-office measurements of BP, taken either by the patient or a relative at home (home or self-monitoring- HBPM) or by an automated recorder for 24 hours (ambulatory blood pressure monitoring- ABPM).
Of the two methods HBPM has the greatest potential for being incorporated into the routine care of hypertensive patients, in the same way that home blood glucose monitoring performed by the patient has become a routine part of the management of diabetes. The currently available monitors are relatively reliable, easy to use, inexpensive, and accurate, and are already being purchased in large numbers by patients. Despite this, their use has only been cursorily endorsed in current guidelines for the management of hypertension, and there have been no detailed recommendations as to how they should be incorporated into routine clinical practice. And despite the fact that there is strong evidence that HBPM can predict clinical outcomes and improve clinical care, the cost of the monitors is not generally reimbursed. It is the purpose of this Call to Action paper to address the issues of the incorporation of HBPM into the routine management of hypertensive patients and its reimbursement.
doi:10.1161/HYPERTENSIONAHA.107.189010
PMCID: PMC2989415  PMID: 18497370
2.  Computer-aided diagnosis of renal obstruction: utility of log-linear modeling versus standard ROC and kappa analysis 
EJNMMI research  2011;1(5):1-8.
Background
The accuracy of computer-aided diagnosis (CAD) software is best evaluated by comparison to a gold standard which represents the true status of disease. In many settings, however, knowledge of the true status of disease is not possible and accuracy is evaluated against the interpretations of an expert panel. Common statistical approaches to evaluate accuracy include receiver operating characteristic (ROC) and kappa analysis but both of these methods have significant limitations and cannot answer the question of equivalence: Is the CAD performance equivalent to that of an expert? The goal of this study is to show the strength of log-linear analysis over standard ROC and kappa statistics in evaluating the accuracy of computer-aided diagnosis of renal obstruction compared to the diagnosis provided by expert readers.
Methods
Log-linear modeling was utilized to analyze a previously published database that used ROC and kappa statistics to compare diuresis renography scan interpretations (non-obstructed, equivocal, or obstructed) generated by a renal expert system (RENEX) in 185 kidneys (95 patients) with the independent and consensus scan interpretations of three experts who were blinded to clinical information and prospectively and independently graded each kidney as obstructed, equivocal, or non-obstructed.
Results
Log-linear modeling showed that RENEX and the expert consensus had beyond-chance agreement in both non-obstructed and obstructed readings (both p < 0.0001). Moreover, pairwise agreement between experts and pairwise agreement between each expert and RENEX were not significantly different (p = 0.41, 0.95, 0.81 for the non-obstructed, equivocal, and obstructed categories, respectively). Similarly, the three-way agreement of the three experts and three-way agreement of two experts and RENEX was not significantly different for non-obstructed (p = 0.79) and obstructed (p = 0.49) categories.
Conclusion
Log-linear modeling showed that RENEX was equivalent to any expert in rating kidneys, particularly in the obstructed and non-obstructed categories. This conclusion, which could not be derived from the original ROC and kappa analysis, emphasizes and illustrates the role and importance of log-linear modeling in the absence of a gold standard. The log-linear analysis also provides additional evidence that RENEX has the potential to assist in the interpretation of diuresis renography studies.
doi:10.1186/2191-219X-1-5
PMCID: PMC3175375  PMID: 21935501
Log-linear modeling; Renal obstruction; Diuresis renography
3.  Computer-aided diagnosis of renal obstruction: utility of log-linear modeling versus standard ROC and kappa analysis 
EJNMMI Research  2011;1:5.
Background
The accuracy of computer-aided diagnosis (CAD) software is best evaluated by comparison to a gold standard which represents the true status of disease. In many settings, however, knowledge of the true status of disease is not possible and accuracy is evaluated against the interpretations of an expert panel. Common statistical approaches to evaluate accuracy include receiver operating characteristic (ROC) and kappa analysis but both of these methods have significant limitations and cannot answer the question of equivalence: Is the CAD performance equivalent to that of an expert? The goal of this study is to show the strength of log-linear analysis over standard ROC and kappa statistics in evaluating the accuracy of computer-aided diagnosis of renal obstruction compared to the diagnosis provided by expert readers.
Methods
Log-linear modeling was utilized to analyze a previously published database that used ROC and kappa statistics to compare diuresis renography scan interpretations (non-obstructed, equivocal, or obstructed) generated by a renal expert system (RENEX) in 185 kidneys (95 patients) with the independent and consensus scan interpretations of three experts who were blinded to clinical information and prospectively and independently graded each kidney as obstructed, equivocal, or non-obstructed.
Results
Log-linear modeling showed that RENEX and the expert consensus had beyond-chance agreement in both non-obstructed and obstructed readings (both p < 0.0001). Moreover, pairwise agreement between experts and pairwise agreement between each expert and RENEX were not significantly different (p = 0.41, 0.95, 0.81 for the non-obstructed, equivocal, and obstructed categories, respectively). Similarly, the three-way agreement of the three experts and three-way agreement of two experts and RENEX was not significantly different for non-obstructed (p = 0.79) and obstructed (p = 0.49) categories.
Conclusion
Log-linear modeling showed that RENEX was equivalent to any expert in rating kidneys, particularly in the obstructed and non-obstructed categories. This conclusion, which could not be derived from the original ROC and kappa analysis, emphasizes and illustrates the role and importance of log-linear modeling in the absence of a gold standard. The log-linear analysis also provides additional evidence that RENEX has the potential to assist in the interpretation of diuresis renography studies.
doi:10.1186/2191-219X-1-5
PMCID: PMC3175375  PMID: 21935501
Log-linear modeling; Renal obstruction; Diuresis renography
4.  International classification trial of AIA set of 100 radiographs of asbestos workers. 
A series of 100 full size radiographs illustrating the range of asbestos related radiographic changes was collected by the Asbestos International Association to provide a demonstration and teaching supplement to the ILO 1980 International Classification of the Radiographic Appearances of Pneumoconioses. Each film was read by 12 experienced readers from ten countries; the readings have been summarised by a median reading, with the range covered by two thirds of the readers. The occupational histories and some relevant clinical information are also available. It is proposed that, in the use of this set, readers should classify each film using the ILO classification rules, particularly without reference to the summary reading or the additional information. Comparing the individual readings by the 12 readers, most of the variation in reading the profusion of small opacities was ascribable only to random variation, with little consistent bias between readers. By contrast, two readers recorded pleural changes much more frequently than their colleagues. This illustrated a major problem with the ILO 1980 Classification. Several others which occurred in this reading trial are also discussed.
PMCID: PMC1009647  PMID: 3415919
5.  Statistical methods in microbiology. 
Clinical Microbiology Reviews  1990;3(3):219-226.
Statistical methodology is viewed by the average laboratory scientist, or physician, sometimes with fear and trepidation, occasionally with loathing, and seldom with fondness. Statistics may never be loved by the medical community, but it does not have to be hated by them. It is true that statistical science is sometimes highly mathematical, always philosophical, and occasionally obtuse, but for the majority of medical studies it can be made palatable. The goal of this article has been to outline a finite set of methods of analysis that investigators should choose based on the nature of the variable being studied and the design of the experiment. The reader is encouraged to seek the advice of a professional statistician when there is any doubt about the appropriate method of analysis. A statistician can also help the investigator with problems that have nothing to do with statistical tests, such as quality control, choice of response variable and comparison groups, randomization, and blinding of assessment of response variables.
PMCID: PMC358156  PMID: 2200604
6.  Stand-alone performance of a computer-assisted detection prototype for detection of acute pulmonary embolism: a multi-institutional comparison 
The British Journal of Radiology  2012;85(1014):758-764.
Objective
To assess whether the performance of a computer-assisted detection (CAD) algorithm for acute pulmonary embolism (PE) differs in pulmonary CT angiographies acquired at various institutions.
Methods
In this retrospective study, we included 40 consecutive scans with and 40 without PE from 3 institutions (n=240) using 64-slice scanners made by different manufacturers (General Electric; Philips; Siemens). CAD markers were classified as true or false positive (FP) using independent evaluation by two readers and consultation of a third chest radiologist in discordant cases. Image quality parameters were subjectively scored using 4/5-point scales. Image noise and vascular enhancement were measured. Statistical analysis was done to correlate image quality of the three institutions with CAD stand-alone performance.
Results
Patient groups were comparable with respect to age (p=0.22), accompanying lung disease (p=0.12) and inpatient/outpatient ratio (p=0.67). The sensitivity was 100% (34/34), 97% (37/38) and 92% (33/36), and the specificity was 18% (8/44), 15% (6/41) and 13% (5/39). Neither significantly differed between the institutions (p=0.21 and p=0.820, respectively). The mean number of FP findings (4.5, 6.2 and 3.7) significantly varied (p=0.02 and p=0.03), but median numbers (2, 3 and 3) were comparable. Image quality parameters were significantly associated with the number of FP findings (p<0.05) but not with sensitivity. After correcting for noise and vascular enhancement, the number of FPs did not significantly differ between the three institutions (p=0.43).
Conclusions
CAD stand-alone performance is independent of scanner type but strongly related to image quality and thus scanning protocols.
doi:10.1259/bjr/26769569
PMCID: PMC3474087  PMID: 22167514
7.  The impact of free access to the scientific literature: a review of recent research 
Objectives:
The paper reviews recent studies that evaluate the impact of free access (open access) on the behavior of scientists as authors, readers, and citers in developed and developing nations. It also examines the extent to which the biomedical literature is used by the general public.
Method:
The paper is a critical review of the literature, with systematic description of key studies.
Results:
Researchers report that their access to the scientific literature is generally good and improving. For authors, the access status of a journal is not an important consideration when deciding where to publish. There is clear evidence that free access increases the number of article downloads, although its impact on article citations is not clear. Recent studies indicate that large citation advantages are simply artifacts of the failure to adequately control for confounding variables. The effect of free access on the general public's use of the primary medical literature has not been thoroughly evaluated.
Conclusions:
Recent studies provide little evidence to support the idea that there is a crisis in access to the scholarly literature. Further research is needed to investigate whether free access is making a difference in non-research contexts and to better understand the dissemination of scientific literature through peer-to-peer networks and other informal mechanisms.
doi:10.3163/1536-5050.99.3.008
PMCID: PMC3133904  PMID: 21753913
8.  Breast cancer detection: radiologists’ performance using mammography with and without automated whole-breast ultrasound 
European Radiology  2010;20(11):2557-2564.
Objective
Radiologist reader performance for breast cancer detection using mammography plus automated whole-breast ultrasound (AWBU) was compared with mammography alone.
Methods
Screenings for non-palpable breast malignancies in women with radiographically dense breasts with contemporaneous mammograms and AWBU were reviewed by 12 radiologists blinded to the diagnoses; half the studies were abnormal. Readers first reviewed the 102 mammograms. The American College of Radiology (ACR) Breast Imaging Reporting and Data System (BIRADS) and Digital Mammographic Imaging Screening Trial (DMIST) likelihood ratings were recorded with location information for identified abnormalities. Readers then reviewed the mammograms and AWBU with knowledge of previous mammogram-only evaluation. We compared reader performance across screening techniques using absolute callback, areas under the curve (AUC), and figure of merit (FOM).
Results
True positivity of cancer detection increased 63%, with only a 4% decrease in true negativity. Reader-averaged AUC was higher for mammography plus AWBU compared with mammography alone by BIRADS (0.808 versus 0.701) and likelihood scores (0.810 versus 0.703). Similarly, FOM was higher for mammography plus AWBU compared with mammography alone by BIRADS (0.786 versus 0.613) and likelihood scores (0.791 versus 0.614).
Conclusion
Adding AWBU to mammography improved callback rates, accuracy of breast cancer detection, and confidence in callbacks for dense-breasted women.
doi:10.1007/s00330-010-1844-1
PMCID: PMC2948156  PMID: 20632009
Multi-reader multi-case (MRMC) study; Diagnostic accuracy; JAFROC analysis; Breast screening; Breast ultrasound
9.  Emerging Bcl-2 inhibitors for the treatment of cancer 
Importance of the field
Bcl-2 family proteins are a component of the anti-apoptotic machinery and are overexpressed in different malignancies. Accordingly, their enhanced expression has been attributed to the observed chemoresistance in most of the cancers. Therefore, targeting Bcl-2 family members becomes an important and attractive approach towards cancer therapy and is currently a very rapidly evolving area of research. This article highlights the numerous advancements that have been made in the design and synthesis of small molecule inhibitors (SMI) of pro-survival Bcl-2 proteins.
Areas covered in this review
This review comprehensively describes the progress made over the last 2 decades on this subject including the clinical status of SMIs of Bcl-2 family proteins.
What the reader will gain
Newer insights will be gained on the status of our knowledge on SMIs of Bcl-2 family proteins, their most beneficial application as well as current and future directions in this field.
Take home message
Targeting Bcl-2 family proteins using SMI strategies is gaining momentum with emergence of certain new classes of inhibitors in Phase I and II clinical setting. In view of the tremendous progress toward the development of such inhibitors, this innovative approach certainly holds promise and has the potential to become a future mainstay for cancer therapy.
doi:10.1517/14728214.2010.515210
PMCID: PMC3084453  PMID: 20812891
apoptosis; Bcl-2; cancer therapy; small molecule inhibitor
10.  Statistical analysis of the effects of trial, reader, and replicates on MIC determination for cefoxitin. 
Antimicrobial Agents and Chemotherapy  1990;34(11):2246-2249.
A pilot study was designed to estimate the variance components in the determination of the MIC of cefoxitin for isolates of the Bacteroides fragilis group. Twenty different organisms were tested, and replicate, trial, and reader variabilities were examined. When the total-variance component was used, if the true MIC was 16 micrograms/ml, then the chance that the observed MIC was between 8 and 32 micrograms/ml, inclusive, was 95%. For all analyses, the isolate (P = 0.0001) and reader (P less than 0.03) effects were significant. The probability of specific MIC observations for various true MICs (over the range of 16 to 32 micrograms/ml at 4-micrograms/ml increments) was calculated. For true MICs of 20, 24, and 28 micrograms/ml, the probabilities of observing an MIC of 16 or 32 micrograms/ml (inclusive) were 86, 75, and 62%, respectively. An upward bias was shown to exist in addition to sources of sizeable variation. The recommendation stemming from recognition of this inherent variability is that ranges of percent susceptibility at various concentrations be included in reports of in vitro susceptibility studies.
PMCID: PMC172030  PMID: 2073115
11.  Austere Librarians— Volte-Face! * 
Medical Libraries are too concerned with their customers and not interested enough in their wares. The number, nature, behavior, and satisfaction of readers and the book use by readers are extensively analyzed. Though important for library operation, such studies tend to make library staff regard and treat readers as impersonal members of a study population.
As opposed to critical analysis of readers, little effort is made in this direction with respect to journals. It is, therefore, proposed that medical libraries take a hard look at the journals they offer and classify and display them in A, B, C, and D categories. The following benefits might be envisioned: the reader would be helped in looking up a subject that is not in his immediate field of specialization, the occupancy of valuable space by poor journals would be prevented, medium quality journals would strive to improve themselves, and it is even possible that poor and superfluous journals would be put out of business.
PMCID: PMC198485  PMID: 6016364
12.  Modifying the Brain Activation of Poor Readers during Sentence Comprehension with Extended Remedial Instruction: A Longitudinal Study of Neuroplasticity 
Neuropsychologia  2008;46(10):2580-2592.
This study used fMRI to longitudinally assess the impact of intensive remedial instruction on cortical activation among 5th grade poor readers during a sentence comprehension task. The children were tested at 3 time points: prior to remediation, after 100 hours of intensive instruction, and 1 year after the instruction had ended. Changes in brain activation were also measured among 5th grade good readers at the same time points for comparison. The central finding was that prior to instruction, the poor readers had significantly less activation than good readers bilaterally in the parietal cortex. Immediately after instruction, poor readers made substantial gains in reading ability, and demonstrated significantly increased activation in the left angular gyrus and the left superior parietal lobule. Activation in these regions continued to increase among poor readers 1 year post-remediation, resulting in a normalization of the activation. These results are interpreted as reflecting changes in the processes involved in word-level and sentence-level assembly. Areas of overactivation were also found among poor readers in the medial frontal cortex, possibly indicating a more effortful and attentionally-guided reading strategy.
doi:10.1016/j.neuropsychologia.2008.03.012
PMCID: PMC2598765  PMID: 18495180
Dyslexia; Phonology; Reading ability; Neuroimaging; Treatment
13.  The influence of print exposure on the body-object interaction effect in visual word recognition 
We examined the influence of print exposure on the body-object interaction (BOI) effect in visual word recognition. High print exposure readers and low print exposure readers either made semantic categorizations (“Is the word easily imageable?”; Experiment 1) or phonological lexical decisions (“Does the item sound like a real English word?”; Experiment 2). The results from Experiment 1 showed that there was a larger BOI effect for the low print exposure readers than for the high print exposure readers in semantic categorization, though an effect was observed for both print exposure groups. However, the results from Experiment 2 showed that the BOI effect was observed only for the high print exposure readers in phonological lexical decision. The results of the present study suggest that print exposure does influence the BOI effect, and that this influence varies as a function of task demands.
doi:10.3389/fnhum.2012.00113
PMCID: PMC3342677  PMID: 22563312
embodied cognition; perceptual symbol systems; motor simulation; print exposure; lexical conceptual processing
14.  The Effect of Film Quality on Reading Radiographs of Simple Pneumoconiosis in a trial of X-ray sets 
Four chest radiographs (14 in. × 14 in. postero-anterior) for each of 86 coal-miners were taken (in a trial to compare ϰ-ray sets) and assessed by a number of experienced readers for both quality and pneumoconiosis. All films were developed by one technician under standard conditions so that variations in the quality of the films produced for one subject arose because of differences in the sets and in the way they were used by the radiographers taking the films. The data thus obtained allowed a study of film quality to be made (a) in relation to the subject and (b) as it affected the reading of simple pneumoconiosis.
The subjects were selected to include a high proportion whose earlier radiographs showed pneumoconiosis; they were thus substantially older than a normal colliery population.
The assessments of quality were found to be reasonably consistent both between observers and on different occasions for the same observer.
A clear tendency was found for the quality of a film to depend on the subject. Men with no radiological evidence of pneumoconiosis tended to produce films which were assessed as of better quality than those of men with pneumoconiosis, however slight. Among the latter, chest thickness had an important effect on film quality; men with thicker chests produced poorer films. The subject's age did not appear to have any effect on the quality of his film.
Film quality was found to introduce only slight biases into the reading of pneumoconiosis. Individual readers varied considerably so that, although on average the readers tended to overcorrect for technical faults, i.e. to read more abnormality in black films than in good ones, and less in grey, some readers undercorrected slightly.
What little evidence was available did not suggest that poor quality of films introduced any excess variability into film reading.
PMCID: PMC1038146  PMID: 13761945
15.  Rate theories for biologists 
Quarterly reviews of biophysics  2010;43(2):219-293.
Some of the rate theories that are most useful for modeling biological processes are reviewed. By delving into some of the details and subtleties in the development of the theories, the review will hopefully help the reader gain a more than superficial perspective. Examples are presented to illustrate how rate theories can be used to generate insight at the microscopic level into biomolecular behaviors. Attempt is made to clear up a number of misconceptions in the literature regarding popular rate theories, including the appearance of Planck’s constant in the transition-state theory and the Smoluchowski result as an upper limit for protein-protein and protein-DNA association rate constants. Future work in combining the implementation of rate theories through computer simulations with experimental probes of rate processes, and in modeling effects of intracellular environments so theories can be used for generating rate constants for systems biology studies is particularly exciting.
doi:10.1017/S0033583510000120
PMCID: PMC3540998  PMID: 20691138
16.  On the processing of canonical word order during eye fixations in reading: Do readers process transposed word previews? 
Visual cognition  2013;21(3):353-381.
Whether readers always identify words in the order they are printed is subject to considerable debate. In the present study, we used the gaze-contingent boundary paradigm (Rayner, 1975) to manipulate the preview for a two-word target region (e.g. white walls in My neighbor painted the white walls black). Readers received an identical (white walls), transposed (walls white), or unrelated preview (vodka clubs). We found that there was a clear cost of having a transposed preview compared to an identical preview, indicating that readers cannot or do not identify words out of order. However, on some measures, the transposed preview condition did lead to faster processing than the unrelated preview condition, suggesting that readers may be able to obtain some useful information from a transposed preview. Implications of the results for models of eye movement control in reading are discussed.
doi:10.1080/13506285.2013.791739
PMCID: PMC3758745  PMID: 24003322
Eye movements; reading; parafoveal processing; preview benefit; word order
17.  Effect of nutritional supplementation of breastfeeding HIV positive mothers on maternal and child health: findings from a randomized controlled clinical trial 
BMC Public Health  2011;11:946.
Background
It has been well established that breastfeeding is beneficial for child health, however there has been debate regarding the effect of lactation on maternal health in the presence of HIV infection and the need for nutritional supplementation in HIV positive lactating mothers.
Aims
To assess the effect of nutritional supplementation to HIV infected lactating mothers on nutritional and health status of mothers and their infants.
Methods
A randomized controlled clinical trial to study the impact of nutritional supplementation on breastfeeding mothers. Measurements included anthropometry; body composition indicators; CD4 count, haemoglobin and albumin; as well as incidence rates of opportunistic infections; depression and quality of life scores. Infant measurements included anthropometry, development and rates of infections.
Results
The supplement made no significant impact on any maternal or infant outcomes. However in the small group of mothers with low BMI, the intake of supplement was significantly associated with preventing loss of lean body mass (1.32 kg vs. 3.17 kg; p = 0.026). There was no significant impact of supplementation on the infants.
Conclusions
A 50 g daily nutritional supplement to breastfeeding mothers had no or limited effect on mother and child health outcomes.
Clinical trial registration
ISRCTN68128332 (http://www.controlled-trials.com/ISRCTN68128332)
doi:10.1186/1471-2458-11-946
PMCID: PMC3268126  PMID: 22192583
HIV positive mothers; HIV exposed infants; breastfeeding; nutrition supplement; body composition; anthropometry; SRQ 20; RCT
18.  Expert agreement confirms that negative changes in hand and foot radiographs are a surrogate for repair in patients with rheumatoid arthritis 
The objective of the present study was to test the hypothesis that experts recognize repair of erosions and, if so, to determine which, if any, morphologic features permitted them to recognize the repair. We also tested whether scoring by a standard method detected repair. Seven experienced readers of radiographs in rheumatoid arthritis were presented with 64 sets of single joints-of-interest at two time points, randomized and blinded for the correct sequence. The readers assessed which joint was better, and recorded whether any of six specific features were seen. Two independent readers, experienced in scoring by the van der Heijde-modified Sharp method who were not on the expert panel, then scored the complete films that included the joint-of-interest. The panel agreed very well on which of two joints was better, and, even though they did not know the true sequence, the panel accurately assigned a sequence slightly better than chance alone (58%) but worse than their agreement on which image was 'better or worse' (78%). The readers therefore indirectly assigned repair by choosing the second film as the best. Putative repair features were seen in cases of both repair and progression, and were not discriminatory. Similar results were obtained when the experts were presented with the entire hand or foot containing the joint-of-interest. In the third repair exercise, two independent readers who scored whole hands and feet using a standard method found a mean negative score in 22/60 joints-of-interest. All 22 joints were also scored as repair by the panel. Repair was detected reliably by a majority of the panel on viewing paired images based on a better/worse decision and assigning sequence in a set of images that were blinded for sequence by an independent project manager. In this test set of images, repair was manifested by a reduction in the size of erosion in many cases. Size was one feature that aided the experts to detect repair but cannot be the only one; the experts had to find other features to determine whether a smaller erosion was the first in a sequence of radiographs in a patient with progressive damage or was the second film in a patient exhibiting repair. The change in size of erosion was also picked up by independent readers applying the van der Heijde-modified Sharp scoring method and was reflected in their scores.
doi:10.1186/ar2220
PMCID: PMC2206368  PMID: 17605816
19.  Is gastric cancer part of the tumour spectrum of hereditary non‐polyposis colorectal cancer? A molecular genetic study 
Gut  2007;56(7):926-933.
Background
Gastric cancer is the second most common extracolonic malignancy in individuals with hereditary non‐polyposis colorectal cancer (HNPCC)/Lynch syndrome. As gastric cancer is relatively common in the general population as well, it is not clear whether or not gastric cancer is a true HNPCC spectrum malignancy.
Aim
To determine whether or not gastric cancer is a true HNPCC spectrum malignancy.
Subjects and methods
The molecular and clinicopathological profiles of gastric cancers (n = 13) from HNPCC mutation carriers were evaluated and compared with the profiles of sporadic gastric cancers (n = 46) stratified by histology and microsatellite instability (MSI) status.
Results
This study on sporadic and HNPCC gastric cancers revealed several important universal associations. Loss of heterozygosity in the adenomatous polyposis coli (APC) region was associated with intestinal histology regardless of the MSI (p = 0.007). KRAS‐mutations (p = 0.019) and frameshift mutations in repeat tracts of growth‐regulatory genes (p<0.001) were associated with MSI tumours being absent in microsatellite stable (MSS) tumours. The average number of methylated tumour suppressor gene loci among the 24 genes studied (methylation index) was higher in MSI than in MSS tumours regardless of histology (p<0.001). Gastric cancers from HNPCC mutation carriers resembled sporadic intestinal MSI gastric cancers, except that MLH1 promoter methylation was absent (p<0.001) and the general methylation index was lower (p = 0.038), suggesting similar, but not identical, developmental pathways. All these lacked the mismatch repair protein corresponding to the germline mutation and displayed high MSI.
Conclusion
The present molecular evidence, combined with the previous demonstration of an increased incidence relative to the general population, justify considering gastric cancers as true HNPCC spectrum malignancies.
doi:10.1136/gut.2006.114876
PMCID: PMC1994336  PMID: 17267619
20.  Suspected poisoning in children. Study of the incidence of true poisoning and poisoning scare in a defined population in North East Bristol. 
Archives of Disease in Childhood  1976;51(3):180-185.
The distinction between true and suspected poisoning in children has not been made clear in previous work on childhood poisoning. A study of suspected poisoning in children under 15 years of age in a defined population of North East Bristol from November 1970 to July 1973 carried out by the Health Education Council Medical Research Division included 53,000 child-years at risk. The number of suspected poisonings was 3-4/1000 population aged under 15 years per year, with a higher incidence in younger age groups. Detailed investigation of the circumstances of the accidents carried out by a multidisciplinary team showed that at least 65%, and possibly as many as 78% were poisoning scares and not true poisoning. The evidence used by the casualty doctor and by the parents to diagnose poisoning was explored, and in many cases was circumstantial. Children with fathers in nonmanual occupations were over-represented. This may reflect differences in patterns of utilization behaviour rather than true differences in incidence.
PMCID: PMC1545931  PMID: 952551
21.  QOI6/416: The Health On the Net Code of Conduct for Medical and Health-related Web sites: Three years on 
Introduction
The explosive growth of the World Wide Web has made it more and more urgent to monitor and improve the quality of the information circulating through the Internet. But assessing medical and health information on the Web is a difficult challenge. In recent years, some organisations have been working on this issue. The Health On the Net Foundation (HON), for its part, administers an eight-point Code of Conduct called the HONcode, initiated in 1996. This solution is different from the others. The HONcode does not intend to rate or assess the quality of information provided by a Web site. This article gives a general presentation of the HONcode and its status in 1999, three years after it was launched.
Methods
It defines a set of voluntary rules designed to help a Web developer site practice responsible and to make sure a reader always knows the source and the purpose of the information he or she is reading. These guidelines encourage the authority, complimentarity, confidentiality, proper attribution, justifiability and validity of the medical advice and information provided. Furthermore, sites that subscribe to the HONcode commit themselves to providing transparent information on site sponsorship and clearly separating advertising and editorial content.
Results
In 1998, the number of external links to the HONcode principles page grew by about 250% (e.g., from 2 to 5) . The rate of increase from January through April, 1999, suggests 300% this year. The growth in the number of links to the HONcode matches that of links to of the entire Web site, and is slightly higher than growth in links to HON's MedHunt search engine. Statistical analysis shows that approximately 50% of Web sites linked to the HONcode principles have a commercial domain name, 16% are from European countries, 15% are from non-profit organisations, and 7% are educational sites.
Discussion
This evolution shows a real need of guidelines for the developers of medical and health Web sites and their users. This conclusion is reinforced by the result of an international survey which HON conducted on the Internet in March and April 1999. The HONcode's scope of application is currently limited to publishing policy and ethical aspects. The HONcode does not address issues of quality and the relevance of the health and medical content of a Web page -- and this is a crucial issue for the further healthy development of the Internet in the medical domain. One way to assess and provide reliable medical and health content could be to review medical and health-related Web content by peers. Building on the system adopted by the scientific community decades ago for the paper medium, this Electronic peer review method could cover content as well as ethical and publishing aspects while retaining use of the HONcode display icon on registered sites as an additional reference.
doi:10.2196/jmir.1.suppl1.e99
PMCID: PMC1761776
Quality Assurance; Quality Health Care; Peer Review; Ethics
22.  A survey of parent training manuals 
Twenty-six commercially available parent training manuals were surveyed with the goal of providing helpful information to the professional for selection of manuals. Included were manuals for parents as well as manuals for professionals for use in conducting individual or group treatment. The following information was given for all manuals: the characteristics of the target populations for whom the manuals were intended, readability levels, use made of technical language, provision of glossary, organization and format of the book, availability of supplementary materials such as leaders' guides, and references to reviews by other authors. In an additional section, the research literature dealing with evaluation of these manuals was reviewed and summarized as a means of acquainting the reader with the available scientific information on their effectiveness. A report on the status of each manual in terms of evaluation was provided in tabular form. The evaluation of manuals by conduct of empirical research to determine their usefulness to the consumer was emphasized.
doi:10.1901/jaba.1978.11-533
PMCID: PMC1311340  PMID: 16795601
training manuals; parents; children
23.  A Review of Sudden Cardiac Death in Young Athletes and Strategies for Preparticipation Cardiovascular Screening 
Journal of Athletic Training  2001;36(2):197-204.
Objectives:
To provide the reader with an overview of the many causes of sudden cardiac death in young athletes and to present various strategies for preparticipation cardiovascular screening.
Data Source:
A MEDLINE search using the phrase sudden cardiac death and the key word athlete for the years 1980 to 2000.
Data Synthesis:
Sudden cardiac death is a rare event in athletics. More than 20 different causes have been described, but most cases result from a few distinct entities. Most afflicted athletes have no symptoms before death. Many attempts have been made to detect those at risk for sudden cardiac death before athletic participation. At this time, a thorough history and physical examination are the most efficient screening methods for detecting cardiovascular abnormalities. Studies show that the current status of preparticipation cardiovascular screening of high school and college athletes nationwide is poor.
Conclusions and Recommendations:
The use of diagnostic tests to screen for cardiovascular abnormalities is ineffective and inefficient. The most prudent and effective methods of preparticipation screening for cardiovascular abnormalities at this time are a history and physical examination in accordance with the American Heart Association guidelines. Athletic trainers must ensure that their institutions comply with these minimum standards.
PMCID: PMC155532  PMID: 12937463
sudden cardiac death; hypertrophic cardiomyopathy; preparticipation athletic evaluation; coronary artery anomalies
24.  Brain Activation during Sentence Comprehension among Good and Poor Readers 
This study sought to increase current understanding of the neuro-psychological basis of poor reading ability by using fMRI to examine brain activation during a visual sentence comprehension task among good and poor readers in the third (n = 32) and fifth (n = 35) grades. Reading ability, age, and the combination of both factors made unique contributions to cortical activation. The main finding was of parietotemporal underactivation (less activation than controls) among poor readers at the 2 grade levels. A positive linear relationship (spanning both the poor and good readers) was found between reading ability and activation in the left posterior middle temporal and postcentral gyri and in the right inferior parietal lobule such that activation increased with reading ability. Different developmental trajectories characterized good and poor readers in the left angular gyrus: activation increased with age among good readers, a change that failed to occur among poor readers. The parietotemporal cortex is discussed in terms of its role in reading acquisition, with the left angular gyrus playing a key role. It is proposed that the functioning of the cortical network underlying reading is dependent on a combination of interacting factors, including physiological maturation, neural integrity, skill level, and the nature of the task.
doi:10.1093/cercor/bhm006
PMCID: PMC2599909  PMID: 17317678
dyslexia; fMRI; maturation; reading ability
25.  Demonstration of LanthaScreen™ TR-FRET-based nuclear receptor coactivator recruitment assay using PHERAstar, a multi-detection HTS microplate reader 
Indian Journal of Pharmacology  2008;40(2):89-90.
An attempt was made to demonstrate the possibility of performing LanthaScreen™ TR-FRET based nuclear receptor coactivator recruitment assay using PHERAstar, a multi-detection HTS microplate reader. LanthaScreen™ nuclear receptor coactivator recruitment assay (M/s Invitrogen corporation, USA) was performed using PPAR-gamma receptor preparation in the agonist mode. TR-FRET measurements were done on PHERAstar, a multimode microplate reader (BMG LABTECH, Germany). The Lanthascreen PPAR gamma coactivator recruitment assay was successfully performed in the PHERAstar, multimode microplate reader. This was evidenced by an assay robustness score (Z') of 0.71. The current work demonstrates the suitability of using PHERAstar, a multi-detection HTS microplate reader.for performing LanthaScreen™ TR-FRET based nuclear receptor coactivator recruitment assays.
doi:10.4103/0253-7613.41046
PMCID: PMC3025134  PMID: 21279174
HTS; LanthaScreen™ nuclear receptor coregulator assays; nuclear receptors; PHERAstar; time resolved-fluorescence resonance energy transfer

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