Evaluation of Spontaneous Reports of Adverse Reactions to Drugs

An adverse drug-reaction monitoring system based on spontaneous reporting to a central register of adverse reactions has been in operation for eight years. As a test of the validity of the reports and of the probability of causal relationship between drug and reaction a random sample of 82 cases were followed up in detail. The sample included 17 deaths, 26 serious reactions, and 39 reactions of moderate or only minor severity. Altogether 78% of the reactions were considered to be “probably” drug related and 13% “possibly” drug related. It is concluded that the reports are of value in the detection and evaluation of drug safety.     

Adverse Reactions to Daily and Intermittent Rifampicin Regimens for Pulmonary Tuberculosis in Hong Kong

This paper reports the nature, incidence, and severity of adverse reactions to regimens of rifampicin and ethambutol given once weekly, twice weekly, or daily and to a standard reserve regimen in a total of 330 Chinese failure patients who completed at least six months'' chemotherapy in a therapeutic comparison in Hong Kong.The adverse reactions which occurred on the regimens of intermittent rifampicin were termed cutaneous, abdominal, “flu”, and respiratory; in addition, purpura and abnormal liver function tests were encountered. There was an association of adverse reactions with the interval between doses and with the dose size of rifampicin, the highest incidence occurring with once-weekly rifampicin in high dosage. A procedure was developed for managing adverse reactions to intermittent rifampicin. Of 202 patients treated with intermittent rifampicin 60 developed adverse reactions, but in only 7 (3%) was it necessary to terminate the drug, though a further 10 (5%) were changed to daily rifampicin. On daily rifampicin, generalized hypersensitivity, cutaneous reactions, (one with purpura), and impaired liver function were encountered. Adverse reactions on the standard ethionamide, pyrazinamide, and cycloserine regimen were frequent and some were serious.     

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.     

Assessment of the Reporting Quality of Randomized Controlled Trials on the Treatment of Diabetes Mellitus with Traditional Chinese Medicine: A Systematic Review

Background

After the publication of the CONSORT 2010 statement, few studies have been conducted to assess the reporting quality of randomized clinical trials (RCTs) on treatment of diabetes mellitus with Traditional Chinese Medicine (TCM) published in Chinese journals.

Objective

To investigate the current situation of the reporting quality of RCTs in leading medical journals in China with the CONSORT 2010 statement as criteria.

Methods

The China National Knowledge Infrastructure (CNKI) electronic database was searched for RCTs on the treatment of diabetes mellitus with TCM published in the Journal of Traditional Chinese Medicine, Chinese Journal of Integrated Traditional & Western Medicine, and the China Journal of Chinese Materia Medica from January to December 2011. We excluded trials reported as “animal studies”, “in vitro studies”, “case studies”, or “systematic reviews”. The CONSORT checklist was applied by two independent raters to evaluate the reporting quality of all eligible trials after discussing and comprehending the items thoroughly. Each item in the checklist was graded as either “yes” or “no” depending on whether it had been reported by the authors.

Results

We identified 27 RCTs. According to the 37 items in the CONSORT checklist, the average reporting percentage was 45.0%, in which the average reporting percentage for the “title and abstract”, the “introduction”, the “methods”, the “results”, the “discussion” and the “other information” was 33.3%, 88.9%, 36.4%, 54.4%, 71.6% and 14.8%, respectively. In the Journal of Traditional Chinese Medicine, Chinese Journal of Integrated Traditional & Western Medicine, and the China Journal of Chinese Materia Medica the average reporting percentage was 42.2%, 56.8%, and 46.0%, respectively.

Conclusions

The reporting quality of RCTs in these three journals was insufficient to allow readers to assess the validity of the trials. We recommend that editors require authors to use the CONSORT statement when reporting their trial results as a condition of publication.     

Validation of the Early Warning and Response System (EWARS) for dengue outbreaks: Evidence from the national vector control program in Mexico

BackgroundDuring 2017, twenty health districts (locations) implemented a dengue outbreak Early Warning and Response System (EWARS) in Mexico, which processes epidemiological, meteorological and entomological alarm indicators to predict dengue outbreaks and triggers early response activities.Out of the 20 priority districts where more than one fifth of all national disease transmission in Mexico occur, eleven districts were purposely selected and analyzed. Nine districts presented outbreak alarms by EWARS but without subsequent outbreaks (“non-outbreak districts”) and two presented alarms with subsequent dengue outbreaks (“outbreak districts”). This evaluation study assesses and compares the impact of alarm-informed response activities and the consequences of failing a timely and adequate response across the outbreak groups.MethodsFive indicators of dengue outbreak response (larval control, entomological studies with water container interventions, focal spraying and indoor residual spraying) were quantitatively analyzed across two groups (”outbreak districts” and “non-outbreak districts”). However, for quality control purposes, only qualitative concluding remarks were derived from the fifth response indicator (fogging).ResultsThe average coverage of vector control responses was significantly higher in non-outbreak districts and across all four indicators. In the “outbreak districts” the response activities started late and were of much lower intensity compared to “non-outbreak districts”. Vector control teams at districts-level demonstrated diverse levels of compliance with local guidelines for ‘initial’, ‘early’ and ‘late’ responses to outbreak alarms, which could potentially explain the different outcomes observed following the outbreak alarms.ConclusionFailing timely and adequate response of alarm signals generated by EWARS showed to negatively impact the disease outbreak control process. On the other hand, districts with adequate and timely response guided by alarm signals demonstrated successful records of outbreak prevention. This study presents important operational scenarios when failing or successding EWARS but warrants investigating the effectiveness and cost-effectiveness of EWARS using a more robust designs.     

A Controlled Study of Disturbances Recorded Following the Use of Oral Poliomyelitis Vaccine

A double-blind study of disturbances recorded following the administration of a live trivalent oral poliomyelitis vaccine and an identical-appearing placebo was undertaken. Seven hundred and forty-one persons, 81% of the entire population of a small town, constituted the trial group. The two feedings, with a varied feeding sequence, were eight days apart, and at the second feeding and again eight days later, the participants were investigated under controlled conditions. There were no statistically significant differences in the number, nature or timing of the disturbances reported following the administration of the two vaccines. With both vaccines, significantly fewer reactions were reported among males, among the under-5 year group, among Occupational Class I, and after the first feeding as compared with the second. The Salk vaccine immunization status of the participants made no significant difference. With both active vaccine and placebo “vaccine” 14 to 15% of the participants reported some “reaction”.     

Assessing Website Pharmacy Drug Quality: Safer Than You Think?

Background

Internet-sourced drugs are often considered suspect. The World Health Organization reports that drugs from websites that conceal their physical address are counterfeit in over 50 percent of cases; the U.S. Food and Drug Administration (FDA) works with the National Association of Boards of Pharmacy (NABP) to regularly update a list of websites likely to sell drugs that are illegal or of questionable quality.

Methods and Findings

This study examines drug purchasing over the Internet, by comparing the sales of five popular drugs from a selection of websites stratified by NABP or other ratings. The drugs were assessed for price, conditions of purchase, and basic quality. Prices and conditions of purchase varied widely. Some websites advertised single pills while others only permitted the purchase of large quantities. Not all websites delivered the exact drugs ordered, some delivered no drugs at all; many websites shipped from multiple international locations, and from locations that were different from those advertised on the websites. All drug samples were tested against approved U.S. brand formulations using Raman spectrometry. Many (17) websites substituted drugs, often in different formulations from the brands requested. These drugs, some of which were probably generics or perhaps non-bioequivalent copy versions, could not be assessed accurately. Of those drugs that could be assessed, none failed from “approved”, “legally compliant” or “not recommended” websites (0 out of 86), whereas 8.6% (3 out of 35) failed from “highly not recommended” and unidentifiable websites.

Conclusions

Of those drugs that could be assessed, all except Viagra® passed spectrometry testing. Of those that failed, few could be identified either by a country of manufacture listed on the packaging, or by the physical location of the website pharmacy. If confirmed by future studies on other drug samples, then U.S. consumers should be able to reduce their risk by relying on credentialing agencies recommended lists and by using common sense when examining packaging and pills.     

Differences between Drug-Induced and Contrast Media-Induced Adverse Reactions Based on Spontaneously Reported Adverse Drug Reactions

Objective

We analyzed differences between spontaneously reported drug-induced (not including contrast media) and contrast media-induced adverse reactions.

Methods

Adverse drug reactions reported by an in-hospital pharmacovigilance center (St. Mary’s teaching hospital, Daejeon, Korea) from 2010–2012 were classified as drug-induced or contrast media-induced. Clinical patterns, frequency, causality, severity, Schumock and Thornton’s preventability, and type A/B reactions were recorded. The trends among causality tools measuring drug and contrast-induced adverse reactions were analyzed.

Results

Of 1,335 reports, 636 drug-induced and contrast media-induced adverse reactions were identified. The prevalence of spontaneously reported adverse drug reaction-related admissions revealed a suspected adverse drug reaction-reporting rate of 20.9/100,000 (inpatient, 0.021%) and 3.9/100,000 (outpatients, 0.004%). The most common adverse drug reaction-associated drug classes included nervous system agents and anti-infectives. Dermatological and gastrointestinal adverse drug reactions were most frequently and similarly reported between drug and contrast media-induced adverse reactions. Compared to contrast media-induced adverse reactions, drug-induced adverse reactions were milder, more likely to be preventable (9.8% vs. 1.1%, p < 0.001), and more likely to be type A reactions (73.5% vs. 18.8%, p < 0.001). Females were over-represented among drug-induced adverse reactions (68.1%, p < 0.001) but not among contrast media-induced adverse reactions (56.6%, p = 0.066). Causality patterns differed between the two adverse reaction classes. The World Health Organization–Uppsala Monitoring Centre causality evaluation and Naranjo algorithm results significantly differed from those of the Korean algorithm version II (p < 0.001).

Conclusions

We found differences in sex, preventability, severity, and type A/B reactions between spontaneously reported drug and contrast media-induced adverse reactions. The World Health Organization–Uppsala Monitoring Centre and Naranjo algorithm causality evaluation afforded similar results.     

Simulating the effect of evaluation unit size on eligibility to stop mass drug administration for lymphatic filariasis in Haiti

BackgroundThe Transmission Assessment Survey (TAS) is a decision-making tool to determine when transmission of lymphatic filariasis is presumed to have reached a level low enough that it cannot be sustained even in the absence of mass drug administration. The survey is applied over geographic areas, called evaluation units (EUs); existing World Health Organization guidelines limit EU size to a population of no more than 2 million people.Methodology/Principal findingsIn 2015, TASs were conducted in 14 small EUs in Haiti. Simulations, using the observed TAS results, were performed to understand the potential programmatic impact had Haiti chosen to form larger EUs. Nine “combination-EUs” were formed by grouping adjacent EUs, and bootstrapping was used to simulate the expected TAS results.When the combination-EUs were comprised of at least one “passing” and one “failing” EU, the majority of these combination-EU would pass the TAS 79% - 100% of the time. Even in the case when both component EUs had failed, the combination-EU was expected to “pass” 11% of the time.Simulations of mini-TAS, a strategy with smaller power and hence smaller sample size than TAS, resulted in more conservative “passing” and “failing” when implemented in original EUs.Conclusions/SignificanceOur results demonstrate the high potential for misclassification when the average prevalence of lymphatic filariasis in the combined areas differs with regards to the TAS threshold. Of particular concern is the risk of “passing” larger EUs that include focal areas where prevalence is high enough to be potentially self-sustaining. Our results reaffirm the approach that Haiti took in forming smaller EUs. Where baseline or monitoring data show a high or heterogeneous prevalence, programs should leverage alternative strategies like mini-TAS in smaller EUs, or consider gathering additional data through spot check sites to advise EU formation.     

CYTOLOGIC DETECTION OF CERVICAL CANCER—Four Years' Experience with Routine Smear Examination in Private Practice

Simplified Papanicolaou smear techniques appear to be adaptable to private clinical practice when experienced cytodetection laboratory facilities are available. A private physician''s office seems potentially an efficient, economical and practical place for detection of cervical cancer by use of the smear technique as a routine part of examination of patients.In a series here reported upon, examination of 11,207 cervical smears taken at the first examination of patients of all ages led to diagnosis of unsuspected malignant disease in 80 cases—in all instances at a stage when it should be easily curable. Cancer was not detected in examination of 6,060 smears taken later from women who had had a “negative” smear at the time of first examination, which seems to indicate that the first screening was reasonably accurate.In a few cases, early cancer was detected when smears were reported as “atypical” or “suspicious.” Such reports demand as careful follow-up as do “positive” reports.There are dangers and limitations in wide-spread clinical application of screening by this method. Care must be observed in the development of programs for its use lest the potential benefits in early detection be outweighed by the dangers from misuse.     

Thematic Minireview Series: New Directions in G Protein-coupled Receptor Pharmacology

Over the past half-century, The Journal of Biological Chemistry has been the venue for many landmark publications on the topic of G protein-coupled receptors (GPCRs, also known as seven-transmembrane receptors). The GPCR superfamily in humans is composed of about 800 members, and is the target of about one-third of all pharmaceuticals. Most of these drugs target a very small subset of GPCRs, and do so by mimicking or competing with endogenous hormones and neurotransmitters. This thematic minireview series examines some emerging trends in GPCR drug discovery. The first article describes efforts to systematically interrogate the human “GPCR-ome,” including more than 150 uncharacterized “orphan” receptors. The second article describes recent efforts to target alternative receptor binding sites with drugs that act as allosteric modulators of orthosteric ligands. The third article describes how the recent expansion of GPCR structures is providing new opportunities for computer-guided drug discovery. Collectively, these three articles provide a roadmap for the most important emerging trends in GPCR pharmacology.     

High-throughput framework for genetic analyses of adverse drug reactions using electronic health records

Understanding the contribution of genetic variation to drug response can improve the delivery of precision medicine. However, genome-wide association studies (GWAS) for drug response are uncommon and are often hindered by small sample sizes. We present a high-throughput framework to efficiently identify eligible patients for genetic studies of adverse drug reactions (ADRs) using “drug allergy” labels from electronic health records (EHRs). As a proof-of-concept, we conducted GWAS for ADRs to 14 common drug/drug groups with 81,739 individuals from Vanderbilt University Medical Center’s BioVU DNA Biobank. We identified 7 genetic loci associated with ADRs at P < 5 × 10⁻⁸, including known genetic associations such as CYP2D6 and OPRM1 for CYP2D6-metabolized opioid ADR. Additional expression quantitative trait loci and phenome-wide association analyses added evidence to the observed associations. Our high-throughput framework is both scalable and portable, enabling impactful pharmacogenomic research to improve precision medicine.     

Idiopathic Hypercalciuria and Hyperparathyroidism

With provocative tests of parathyroid activity based on phosphate deprivation and the administration of chlorothiazide 8 out of 19 patients with idiopathic hypercalciuria developed hypercalcaemia. Five of the eight underwent exploration of the neck and four of them had parathyroid adenomas; the fifth patient had “normal” glands but responded satisfactorily to subtotal parathyroidectomy. One patient who failed to develop hypercalcaemia had primary chief cell hyperplasia of the parathyroids.     

Accuracy and Completeness of Drug Information in Wikipedia: A Comparison with Standard Textbooks of Pharmacology

The online resource Wikipedia is increasingly used by students for knowledge acquisition and learning. However, the lack of a formal editorial review and the heterogeneous expertise of contributors often results in skepticism by educators whether Wikipedia should be recommended to students as an information source. In this study we systematically analyzed the accuracy and completeness of drug information in the German and English language versions of Wikipedia in comparison to standard textbooks of pharmacology. In addition, references, revision history and readability were evaluated. Analysis of readability was performed using the Amstad readability index and the Erste Wiener Sachtextformel. The data on indication, mechanism of action, pharmacokinetics, adverse effects and contraindications for 100 curricular drugs were retrieved from standard German textbooks of general pharmacology and compared with the corresponding articles in the German language version of Wikipedia. Quantitative analysis revealed that accuracy of drug information in Wikipedia was 99.7%±0.2% when compared to the textbook data. The overall completeness of drug information in Wikipedia was 83.8±1.5% (p<0.001). Completeness varied in-between categories, and was lowest in the category “pharmacokinetics” (68.0%±4.2%; p<0.001) and highest in the category “indication” (91.3%±2.0%) when compared to the textbook data overlap. Similar results were obtained for the English language version of Wikipedia. Of the drug information missing in Wikipedia, 62.5% was rated as didactically non-relevant in a qualitative re-evaluation study. Drug articles in Wikipedia had an average of 14.6±1.6 references and 262.8±37.4 edits performed by 142.7±17.6 editors. Both Wikipedia and textbooks samples had comparable, low readability. Our study suggests that Wikipedia is an accurate and comprehensive source of drug-related information for undergraduate medical education.     

An Overview of Self-Administered Health Literacy Instruments

With the increasing recognition of health literacy as a worldwide research priority, the development and refinement of indices to measure the construct is an important area of inquiry. Furthermore, the proliferation of online resources and research means that there is a growing need for self-administered instruments. We undertook a systematic overview to identify all published self-administered health literacy assessment indices to report their content and considerations associated with their administration. A primary aim of this study was to assist those seeking to employ a self-reported health literacy index to select one that has been developed and validated for an appropriate context, as well as with desired administration characteristics. Systematic searches were carried out in four electronic databases, and studies were included if they reported the development and/or validation of a novel health literacy assessment measure. Data were systematically extracted on key characteristics of the instruments: breadth of construct (“generic” vs. “content- or context- specific” health literacy), whether it was an original instrument or a derivative, country of origin, administration characteristics, age of target population (adult vs. pediatric), and evidence for validity. 35 articles met the inclusion criteria. There were 27 original instruments (27/35; 77.1%) and 8 derivative instruments (8/35; 22.9%). 22 indices measured “general” health literacy (22/35; 62.9%) while the remainder measured condition- or context- specific health literacy (13/35; 37.1%). Most health literacy measures were developed in the United States (22/35; 62.9%), and about half had adequate face, content, and construct validity (16/35; 45.7%). Given the number of measures available for many specific conditions and contexts, and that several have acceptable validity, our findings suggest that the research agenda should shift towards the investigation and elaboration of health literacy as a construct itself, in order for research in health literacy measurement to progress.     

Prevalence and Correlates of HIV Testing among Young People Enrolled in Non-Formal Education Centers in Urban Chiang Mai,Thailand: A Cross-Sectional Study

BackgroundHIV testing is the gateway to HIV prevention, treatment, and care. Despite the established vulnerability of young Thai people to HIV infection, studies examining the prevalence and correlates of HIV testing among the general population of Thai youth are still very limited. This study investigates socio-demographic, behavioral, and psychosocial factors associated with HIV testing among young Thai people enrolled in Non-formal Education Centers (NFEC) in urban Chiang Mai, Northern Thailand.MethodsThis was a cross-sectional quantitative study conducted among young unmarried Thai youth—between the ages of 15 and 24—who were enrolled in NFEC in urban Chiang Mai. Multiple logistic regressions were used to identify correlates of “ever tested for HIV” among the sexually active participants.FindingsOf the 295 sexually active participants, 27.3% reported “ever tested for HIV;” 65.4% “did not consistently use condom;” and 61.7% “had at least 2 lifetime partners.” We found that “self-efficacy” (AOR, 4.92; CI, 1.22–19.73); “perception that it is easy to find a location nearby to test for HIV” (AOR, 4.67; CI, 1.21–18.06); “having at least 2 lifetime sexual partners” (AOR, 2.05; CI, 1.09–3.85); and “ever been pregnant or made someone pregnant” (AOR, 4.06; CI, 2.69–9.15); were associated with increased odds of having ever been tested. On the other hand, “fear of HIV test results” (AOR, 0.21; CI, 0.08–0.57) was associated with lower odds of ever having been tested for HIV.ConclusionThe main finding is that a substantially high proportion of Thai youth is engaged in risky sexual behaviors—yet reports low rates of ever having been tested for HIV. This highlights an urgent need to develop appropriate interventions—based on the identified correlates of HIV testing. There is also an urgent need to enhance HIV testing and to promote safer sexual behaviors among young Thai people—particularly those who are out-of-school.