The Lumpy Breast

“Topics in Primary Care Medicine” presents articles on common diagnostic or therapeutic problems encountered in primary care practice. Physicians interested in contributing to the series are encouraged to contact the series'' editors.     

Diagnostic Value of Run Chart Analysis: Using Likelihood Ratios to Compare Run Chart Rules on Simulated Data Series

Run charts are widely used in healthcare improvement, but there is little consensus on how to interpret them. The primary aim of this study was to evaluate and compare the diagnostic properties of different sets of run chart rules. A run chart is a line graph of a quality measure over time. The main purpose of the run chart is to detect process improvement or process degradation, which will turn up as non-random patterns in the distribution of data points around the median. Non-random variation may be identified by simple statistical tests including the presence of unusually long runs of data points on one side of the median or if the graph crosses the median unusually few times. However, there is no general agreement on what defines “unusually long” or “unusually few”. Other tests of questionable value are frequently used as well. Three sets of run chart rules (Anhoej, Perla, and Carey rules) have been published in peer reviewed healthcare journals, but these sets differ significantly in their sensitivity and specificity to non-random variation. In this study I investigate the diagnostic values expressed by likelihood ratios of three sets of run chart rules for detection of shifts in process performance using random data series. The study concludes that the Anhoej rules have good diagnostic properties and are superior to the Perla and the Carey rules.     

Publication of Original Research in Urologic Journals – A Neglected Orphan?

The pathophysiologic mechanisms behind urologic disease are increasingly being elucidated. The object of this investigation was to evaluate the publication policies of urologic journals during a period of progressively better understanding and management of urologic disease. Based on the ISI Web of Knowledge Journal Citation Reports and the PubMed database, the number and percentage of original experimental, original clinical, review or commentarial articles published between 2002–2010 in six leading urologic journals were analyzed. “British Journal of Urology International”, “European Urology”, “Urologic Oncology-Seminars and Original Investigations” (“Urologic Oncology”), “Urology”, “The Journal of Urology”, and “World Journal of Urology” were chosen, because these journals publish articles in all four categories. The publication policies of the six journals were very heterogeneous during the time period from 2002 to 2010. The percentage of original experimental and original clinical articles, related to all categories, remained the same in “British Journal of Urology International”, “Urologic Oncology”, “Urology” and “The Journal of Urology”. The percentage of experimental reports in “World Journal of Urology” between 2002–2010 significantly increased from 10 to 20%. A distinct elevation in the percentage of commentarial articles accompanied by a reduction of clinical articles became evident in “European Urology” which significantly correlated with a large increase in the journal’s impact factor. No clearly superior policy could be identified with regard to a general increase in the impact factors from all the journals. The publication policy of urologic journals does not expressly reflect the increase in scientific knowledge, which has occurred over the period 2002–2010. One way of increasing the exposure of urologists to research and expand the interface between experimental and clinical research, would be to enlarge the percentage of experimental articles published. There is no indication that such policy would be detrimental to a journal’s impact factor.     

A review of family-based tests for linkage disequilibrium between a quantitative trait and a genetic marker

Quantitative trait transmission/disequilibrium tests (quantitative TDTs) are commonly used in family-based genetic association studies of quantitative traits. Despite the availability of various quantitative TDTs, some users are not aware of the properties of these tests and the relationships between them. This review aims at outlining the broad features of the various quantitative TDT procedures carried out in the frequently used QTDT and FBAT packages. Specifically, we discuss the “Rabinowitz” and the “Monks-Kaplan” procedures, as well as the various “Abecasis” and “Allison” regression-based procedures. We focus on the models assumed in these tests and the relationships between them. Moreover, we discuss what hypotheses are tested by the various quantitative TDTs, what testing procedures are best suited to various forms of data, and whether the regression-based tests overcome population stratification problems. Finally, we comment on power considerations in the choice of the test to be used. We hope this brief review will shed light on the similarities and differences of the various quantitative TDTs.     

Evaluation of Dengue NS1 Antigen Rapid Tests and ELISA Kits Using Clinical Samples

Background

Early diagnosis of dengue virus (DENV) infection can improve clinical outcomes by ensuring close follow-up, initiating appropriate supportive therapies and raising awareness to the potential of hemorrhage or shock. Non-structural glycoprotein-1 (NS1) has proven to be a useful biomarker for early diagnosis of dengue. A number of rapid diagnostic tests (RDTs) and enzyme-linked immunosorbent assays (ELISAs) targeting NS1 antigen (Ag) are now commercially available. Here we evaluated these tests using a well-characterized panel of clinical samples to determine their effectiveness for early diagnosis.

Methodology/Principal Findings

Retrospective samples from South America were used to evaluate the following tests: (i) “Dengue NS1 Ag STRIP” and (ii) “Platelia Dengue NS1 Ag ELISA” (Bio-Rad, France), (iii) “Dengue NS1 Detect Rapid Test (1^st Generation)” and (iv) “DENV Detect NS1 ELISA” (InBios International, United States), (v) “Panbio Dengue Early Rapid (1^st generation)” (vi) “Panbio Dengue Early ELISA (2^nd generation)” and (vii) “SD Bioline Dengue NS1 Ag Rapid Test” (Alere, United States). Overall, the sensitivity of the RDTs ranged from 71.9%–79.1% while the sensitivity of the ELISAs varied between 85.6–95.9%, using virus isolation as the reference method. Most tests had lower sensitivity for DENV-4 relative to the other three serotypes, were less sensitive in detecting secondary infections, and appeared to be most sensitive on Day 3–4 post symptom onset. The specificity of all evaluated tests ranged from 95%–100%.

Conclusions

ELISAs had greater overall sensitivity than RDTs. In conjunction with other parameters, the performance data can help determine which dengue diagnostics should be used during the first few days of illness, when the patients are most likely to present to a clinic seeking care.     

Evaluation of four slide test kits for the detection of human chorionic gonadotropin in urine

Three “indirect-type” slide tests utilizing the principle of hemagglutination inhibition and one new “direct-type” slide test employing direct agglutination were evaluated for their sensitivity in detecting human chorionic gonadotropin (HCG) in urine. The results of positive tests in a group of woman in very early pregnancy were correlated with the “days after last menses”. In this series the direct slide test was the most accurate. A control must be used with each direct test to indicate interfering substances and when such are present a different test must be used. All tests were found to be of the relative sensitivity stated by the manufacturer.     

Portrayal of the Human Resource Crisis and Accountability in Healthcare: A Qualitative Analysis of Ugandan Newspapers

Background

Uganda is one of the 57 countries with a critical shortage of health workers. The aim of this study was to determine how the human resources and health service crisis was covered in Ugandan newspapers and, in particular, how the newspapers attributed accountability for problems in the health services.

Methods

We collected all articles related to health workers and health services for the calendar year 2012 in the two largest national newspapers in Uganda (collection on daily basis) and in one local newspaper (collection on weekly basis). These articles were analysed qualitatively regarding the main themes covered and attribution of accountability.

Results

The two more urban national newspapers published 229 articles on human resources and health services in Uganda (on average over two articles per week), whereas the local more rural newspaper published only a single article on this issue in the 12 month period. The majority of articles described problems in the health service without discussing accountability. The question of accountability is raised in only 46% of articles (106 articles). The responsibility of the government was discussed in 50 articles (21%), and negligence, corruption and misbehaviour by individual health workers was reported in 56 articles (25%). In the articles about corruption (n=35), 60% (21 articles) mention corruption by health workers and 40% (14 articles) mention corruption by government officials. Six articles defended the situation of health workers in Uganda.

Conclusions

The coverage of accountability in the Ugandan newspapers surveyed is insufficient to generate informed debate on what political actions need to be taken to improve the crisis in health care and services. There exists not only an “inverse care law” but also an “inverse information law”: those sections of society with the greatest health needs and problems in accessing quality health care receive the least information about health services.     

How Often Are Antibiotic-Resistant Bacteria Said to “Evolve” in the News?

Media plays an important role in informing the general public about scientific ideas. We examine whether the word “evolve,” sometimes considered controversial by the general public, is frequently used in the popular press. Specifically, we ask how often articles discussing antibiotic resistance use the word “evolve” (or its lexemes) as opposed to alternative terms such as “emerge” or “develop.” We chose the topic of antibiotic resistance because it is a medically important issue; bacterial evolution is a central player in human morbidity and mortality. We focused on the most widely-distributed newspapers written in English in the United States, United Kingdom, Canada, India, and Australia. We examined all articles that focused primarily on the evolution of antibiotic resistance, were published in 2014 or earlier, and were accessible in online archives, for a total of 1639 articles. The total years examined per newspaper ranged from 5 to 37 years with a median of 27 years, and the overall range was 1978–2014. We quantified how many articles included the term “evolve” and analyzed how this varied with newspaper, country, and time. We found that an overall rate of 18% of articles used the term “evolve” but with significant variation among countries. Newspapers in the United Kingdom had the highest rate (24%), more than double of those in India (9%), the country with the lowest rate. These frequencies were lower than those found in scientific papers from both evolutionary journals and biomedical journals. There were no statistically significant changes in frequency and no trends when “evolve” usage was compared against variables such as newspaper circulation, liberal/conservative bias, time, and state evolution acceptance in U.S. newspapers. This study highlights the globally low usage of the word “evolve” in the popular press. We suggest this low usage may affect public understanding and acceptance of evolutionary concepts.     

Blood Pressure: A Consideration of Terminology

Concepts of hypertension have changed and changes in terminology to reflect this state of affairs are suggested. Statistically, the best mortality experience is associated with blood pressure commonly regarded as subnormal, and increments of blood pressure above this level are associated with progressive increases in mortality. The terms “normal”, “benign” and “essential” in relation to blood pressure should be abandoned. “Optimal”, “acceptable” and “hypertensive” ranges of blood pressure are suggested. Hypertension is regarded as a symptom of disease, rather than as a disease in itself, and “hypertension”, when used as a diagnostic label, should be qualified always by the primary disease, if known, or by the modifying phrase, “of unknown cause”, if not known.     

SCREENING TESTS FOR DIABETES DETECTION—Combined with a Chest X-Ray Survey

A program was carried out to test the value and feasibility of performing blood sugar screening tests in conjunction with a community-wide chest x-ray survey. A simple, rapid and inexpensive blood sugar screening test requiring only about two drops of blood from the finger tip was used. Among 14,681 persons who stated that they did not have diabetes, 191 or 1.3 per cent had “positive” results in screening tests. The number of persons referred to their physicians for diagnostic study because of the possibility of diabetes was reduced from 191 to 127 by means of a more specific secondary screening test.Diagnostic information with regard to 102 of the 127 persons referred to their physicians was supplied by the physicians. In 58 (0.40 per cent of the 14,681 participants) the diagnosis was diabetes—newly discovered as a result of referral by the survey.Some of the persons referred to their physicians because of suspicion of diabetes, while not then diabetic, might be considered prediabetic. The appearance of diabetes in this group during the year following the survey was therefore investigated. Glucose tolerance tests were performed for 32 of the diabetes suspects whose diagnosis immediately following the survey was either “not diabetic” or unknown. In 15 cases the glucose tolerance curves were indicative of diabetes, in seven cases questionable and in ten cases normal.The 58 persons diagnosed immediately after the survey plus the 15 found to have “diabetic” glucose tolerance curves a year later made a total of 73 newly discovered diabetics. This is a discovery rate of 0.50 per cent among the 14,681 participants in the survey.The success of this combined diabetes detection and chest x-ray survey suggests that other screening procedures should be studied to determine the desirability of adding them to similar community-wide case-finding programs.     

THE CYTOLOGICAL DIAGNOSIS OF GASTRIC CANCER

Established centers find that cytological study of gastric washings with saline or chymotrypsin, adequately performed, is a valuable diagnostic tool in the detection of early and curable gastric carcinoma.Our experience with a small series of 150 patients, studied by saline gastric washing, has emphasized the difficulties of collection and the particular importance of obtaining, by repeated washings if necessary, an adequate specimen of gastric epithelial cells for diagnosis, before an opinion is given.It seems likely that the cytological method will be of future value in study of the natural history of gastric malignant disease and in detection of its surface lesions in their earliest form in asymptomatic, known-susceptible persons. Further, it should become a complementary part of the “stomach profile” in gastric diagnostic problems, where roentgenologic and gastroscopic studies may be expected to reveal the older, necrotic, or infiltrative lesions; cytological study, the earlier and more superficial stages of disease.     

Cancer-linked targets modulated by curcumin

In spite of major advances in oncology, the World Health Organization predicts that cancer incidence will double within the next two decades. Although it is well understood that cancer is a hyperproliferative disorder mediated through dysregulation of multiple cell signaling pathways, most cancer drug development remains focused on modulation of specific targets, mostly one at a time, with agents referred to as “targeted therapies,” “smart drugs,” or “magic bullets.” How many cancer targets there are is not known, and how many targets must be attacked to control cancer growth is not well understood. Although more than 90% of cancer-linked deaths are due to metastasis of the tumor to vital organs, most drug targeting is focused on killing the primary tumor. Besides lacking specificity, the targeted drugs induce toxicity and side effects that sometimes are greater problems than the disease itself. Furthermore, the cost of some of these drugs is so high that most people cannot afford them. The present report describes the potential anticancer properties of curcumin, a component of the Indian spice turmeric (Curcuma longa), known for its safety and low cost. Curcumin can selectively modulate multiple cell signaling pathways linked to inflammation and to survival, growth, invasion, angiogenesis, and metastasis of cancer cells. More clinical trials of curcumin are needed to prove its usefulness in the cancer setting.     

The Role of Androgen Receptor Mutations in Prostate Cancer Progression

Prostate tumour growth is almost always dependent upon the androgen receptor pathway and hence therapies aimed at blocking this signalling axis are useful tools in the management of this disease. Unfortunately such therapies invariably fail; and the tumour progresses to an “androgen-independent” stage. In such cases androgen receptor expression is almost always maintained and much evidence exists to suggest that it may still be driving growth. One mechanism by which the receptor is thought to remain active is mutation. This review summarises the present data on androgen receptor mutations in prostate cancer, and how such substitutions offer a growth advantage by affecting cofactor interactions or by reducing ligand specificity. Such alterations appear to have a subsequent effect upon gene expression suggesting that tumours may “behave” differently dependent upon the ligand promoting growth and if a mutation is present.     

The new role of the hospital emergency department

The volume of medical services delivered within hospital emergency departments in the City of Saskatoon is increasing rapidly. These probably are not “new” medical services but rather represent a transfer of “old” services to the emergency departments from other sites where they were previously rendered. The visit to the emergency department is initiated more often by the patient than the doctor and once there the patient is treated in a relatively short period of time. The illnesses so managed do not have a diagnostic, therapeutic or prognostic uniformity but rather are characterized by their acute and totally unexpected onset. This acute and non-programmable nature of the illness makes it difficult to deliver the service in a physician''s office where the appointment system prevails and efficiently deals with the great majority of his patients. Data to determine whether or not this is a desirable development have not yet been obtained but it is clear that in its present usage the emergency department must be thought of as a facility which not only provides exceptional diagnostic and therapeutic equipment but as one which also provides a treatment facility without prior appointment available at any hour of the day or night.     

Surgery in Management of Patients with Leukaemia

Though leukaemia is not a “surgical” disease, the need for surgery in patients with leukaemia is increasing. Acute surgical problems in such patients present diagnostic difficulties, and accepted surgical principles do not necessarily apply in patients with very abnormal haematological and immunological features. The improved prognosis in some types of leukaemia means that elective surgical procedures, which formerly would not have been considered, may now be applicable just as they would be in patients with non-malignant conditions.Recent advances in the management of the leukaemias include several surgical procedures—for example, to facilitate intravenous or intrathecal therapy. Splenectomy is of value in chronic lymphocytic leukaemia when the correct indications are present, while early elective splenectomy, when no classical indications are present, may have a useful role in the management of patients with chronic granulocytic leukaemia.     

The Effect of Disease Modifying Therapies on Disease Progression in Patients with Relapsing-Remitting Multiple Sclerosis: A Systematic Review and Meta-Analysis

Importance

A number of officially approved disease-modifying drugs (DMD) are currently available for the early intervention in patients with relapsing-remitting multiple sclerosis (RRMS). The aim of the present study was to systematically evaluate the effect of DMDs on disability progression in RRMS

Methods

We performed a systematic review on MEDLINE and SCOPUS databases to include all available placebo-controlled randomized clinical trials (RCTs) of RRMS patients that reported absolute numbers or percentages of disability progression during each study period. Observational studies, case series, case reports, RCTs without placebo subgroups and studies reporting the use of RRMS therapies that are not still officially approved were excluded. Risk ratios (RRs) were calculated in each study protocol to express the comparison of disability progression in RRMS patients treated with a DMD and those RRMS patients receiving placebo. The mixed-effects model was used to calculate both the pooled point estimate in each subgroup and the overall estimates.

Results

DMDs for RRMS were found to have a significantly lower risk of disability progression compared to placebo (RR = 0.72, 95%CI: 0.66–0.79; p<0.001), with no evidence of heterogeneity or publication bias. In subsequent subgroup analyses, neither dichotomization of DMDs as “first” and “second” line RRMS therapies [(RR = 0.72, 95% CI = 0.65–0.80) vs. (RR = 0.72, 95% = 0.57–0.91); p = 0.96] nor the route of administration (injectable or oral) [RR = 0.75 (95% CI = 0.64–0.87) vs. RR = 0.74 (95% CI = 0.66–0.83); p = 0.92] had a differential effect on the risk of disability progression. Either considerable (5–20%) or significant (>20%) rates of loss to follow-up were reported in many study protocols, while financial and/or other support from pharmaceutical industries with a clear conflict of interest on the study outcomes was documented in all included studies.

Conclusions

Available DMD are effective in reducing disability progression in patients with RRMS, independently of the route of administration and their classification as “first” or “second” line therapies. Attrition bias needs to be taken into account in the interpretation of these findings.     

The Extended Statistical Analysis of Toxicity Tests Using Standardised Effect Sizes (SESs): A Comparison of Nine Published Papers

The safety of chemicals, drugs, novel foods and genetically modified crops is often tested using repeat-dose sub-acute toxicity tests in rats or mice. It is important to avoid misinterpretations of the results as these tests are used to help determine safe exposure levels in humans. Treated and control groups are compared for a range of haematological, biochemical and other biomarkers which may indicate tissue damage or other adverse effects. However, the statistical analysis and presentation of such data poses problems due to the large number of statistical tests which are involved. Often, it is not clear whether a “statistically significant” effect is real or a false positive (type I error) due to sampling variation. The author''s conclusions appear to be reached somewhat subjectively by the pattern of statistical significances, discounting those which they judge to be type I errors and ignoring any biomarker where the p-value is greater than p = 0.05. However, by using standardised effect sizes (SESs) a range of graphical methods and an over-all assessment of the mean absolute response can be made. The approach is an extension, not a replacement of existing methods. It is intended to assist toxicologists and regulators in the interpretation of the results. Here, the SES analysis has been applied to data from nine published sub-acute toxicity tests in order to compare the findings with those of the author''s. Line plots, box plots and bar plots show the pattern of response. Dose-response relationships are easily seen. A “bootstrap” test compares the mean absolute differences across dose groups. In four out of seven papers where the no observed adverse effect level (NOAEL) was estimated by the authors, it was set too high according to the bootstrap test, suggesting that possible toxicity is under-estimated.     

Profiling Critical Cancer Gene Mutations in Clinical Tumor Samples

Background

Detection of critical cancer gene mutations in clinical tumor specimens may predict patient outcomes and inform treatment options; however, high-throughput mutation profiling remains underdeveloped as a diagnostic approach. We report the implementation of a genotyping and validation algorithm that enables robust tumor mutation profiling in the clinical setting.

Methodology

We developed and implemented an optimized mutation profiling platform (“OncoMap”) to interrogate ∼400 mutations in 33 known oncogenes and tumor suppressors, many of which are known to predict response or resistance to targeted therapies. The performance of OncoMap was analyzed using DNA derived from both frozen and FFPE clinical material in a diverse set of cancer types. A subsequent in-depth analysis was conducted on histologically and clinically annotated pediatric gliomas. The sensitivity and specificity of OncoMap were 93.8% and 100% in fresh frozen tissue; and 89.3% and 99.4% in FFPE-derived DNA. We detected known mutations at the expected frequencies in common cancers, as well as novel mutations in adult and pediatric cancers that are likely to predict heightened response or resistance to existing or developmental cancer therapies. OncoMap profiles also support a new molecular stratification of pediatric low-grade gliomas based on BRAF mutations that may have immediate clinical impact.

Conclusions

Our results demonstrate the clinical feasibility of high-throughput mutation profiling to query a large panel of “actionable” cancer gene mutations. In the future, this type of approach may be incorporated into both cancer epidemiologic studies and clinical decision making to specify the use of many targeted anticancer agents.