The Reporting of a Disproportionality Analysis for Drug Safety Signal Detection Using Individual Case Safety Reports in PharmacoVigilance (READUS-PV): Development and Statement.

BACKGROUND AND AIM: Disproportionality analyses using reports of suspected adverse drug reactions are the most commonly used quantitative methods for detecting safety signals in pharmacovigilance. However, their methods and results are generally poorly reported in published articles and existing guidelines do not capture the specific features of disproportionality analyses. We here describe the development of a guideline (REporting of A Disproportionality analysis for drUg Safety signal detection using individual case safety reports in PharmacoVigilance [READUS-PV]) for reporting the results of disproportionality analyses in articles and abstracts. METHODS: We established a group of 34 international experts from universities, the pharmaceutical industry, and regulatory agencies, with expertise in pharmacovigilance, disproportionality analyses, and assessment of safety signals. We followed a three-step process to develop the checklist: (1) an open-text survey to generate a first list of items; (2) an online Delphi method to select and rephrase the most important items; (3) a final online consensus meeting. RESULTS: Among the panel members, 33 experts responded to round 1 and 30 to round 2 of the Delphi and 25 participated to the consensus meeting. Overall, 60 recommendations for the main body of the manuscript and 13 recommendations for the abstracts were retained by participants after the Delphi method. After merging of some items together and the online consensus meeting, the READUS-PV guidelines comprise a checklist of 32 recommendations, in 14 items, for the reporting of disproportionality analyses in the main body text and four items, comprising 12 recommendations, for abstracts. CONCLUSIONS: The READUS-PV guidelines will support authors, editors, peer-reviewers, and users of disproportionality analyses using individual case safety report databases. Adopting these guidelines will lead to more transparent, comprehensive, and accurate reporting and interpretation of disproportionality analyses, facilitating the integration with other sources of evidence.

The REporting of A Disproportionality Analysis for DrUg Safety Signal Detection Using Individual Case Safety Reports in PharmacoVigilance (READUS-PV): Explanation and Elaboration.

In pharmacovigilance, disproportionality analyses based on individual case safety reports are widely used to detect safety signals. Unfortunately, publishing disproportionality analyses lacks specific guidelines, often leading to incomplete and ambiguous reporting, and carries the risk of incorrect conclusions when data are not placed in the correct context. The REporting of A Disproportionality analysis for drUg Safety signal detection using individual case safety reports in PharmacoVigilance (READUS-PV) statement was developed to address this issue by promoting transparent and comprehensive reporting of disproportionality studies. While the statement paper explains in greater detail the procedure followed to develop these guidelines, with this explanation paper we present the 14 items retained for READUS-PV guidelines, together with an in-depth explanation of their rationale and bullet points to illustrate their practical implementation. Our primary objective is to foster the adoption of the READUS-PV guidelines among authors, editors, peer reviewers, and readers of disproportionality analyses. Enhancing transparency, completeness, and accuracy of reporting, as well as proper interpretation of their results, READUS-PV guidelines will ultimately facilitate evidence-based decision making in pharmacovigilance.

Data-Driven Identification of Factors That Influence the Quality of Adverse Event Reports: 15-Year Interpretable Machine Learning and Time-Series Analyses of VigiBase and QUEST.

BACKGROUND: The completeness of adverse event (AE) reports, crucial for assessing putative causal relationships, is measured using the vigiGrade completeness score in VigiBase, the World Health Organization global database of reported potential AEs. Malaysian reports have surpassed the global average score (approximately 0.44), achieving a 5-year average of 0.79 (SD 0.23) as of 2019 and approaching the benchmark for well-documented reports (0.80). However, the contributing factors to this relatively high report completeness score remain unexplored. OBJECTIVE: This study aims to explore the main drivers influencing the completeness of Malaysian AE reports in VigiBase over a 15-year period using vigiGrade. A secondary objective was to understand the strategic measures taken by the Malaysian authorities leading to enhanced report completeness across different time frames. METHODS: We analyzed 132,738 Malaysian reports (2005-2019) recorded in VigiBase up to February 2021 split into historical International Drug Information System (INTDIS; n=63,943, 48.17% in 2005-2016) and newer E2B (n=68,795, 51.83% in 2015-2019) format subsets. For machine learning analyses, we performed a 2-stage feature selection followed by a random forest classifier to identify the top features predicting well-documented reports. We subsequently applied tree Shapley additive explanations to examine the magnitude, prevalence, and direction of feature effects. In addition, we conducted time-series analyses to evaluate chronological trends and potential influences of key interventions on reporting quality. RESULTS: Among the analyzed reports, 42.84% (56,877/132,738) were well documented, with an increase of 65.37% (53,929/82,497) since 2015. Over two-thirds (46,186/68,795, 67.14%) of the Malaysian E2B reports were well documented compared to INTDIS reports at 16.72% (10,691/63,943). For INTDIS reports, higher pharmacovigilance center staffing was the primary feature positively associated with being well documented. In recent E2B reports, the top positive features included reaction abated upon drug dechallenge, reaction onset or drug use duration of <1 week, dosing interval of <1 day, reports from public specialist hospitals, reports by pharmacists, and reaction duration between 1 and 6 days. In contrast, reports from product registration holders and other health care professionals and reactions involving product substitution issues negatively affected the quality of E2B reports. Multifaceted strategies and interventions comprising policy changes, continuity of education, and human resource development laid the groundwork for AE reporting in Malaysia, whereas advancements in technological infrastructure, pharmacovigilance databases, and reporting tools concurred with increases in both the quantity and quality of AE reports. CONCLUSIONS: Through interpretable machine learning and time-series analyses, this study identified key features that positively or negatively influence the completeness of Malaysian AE reports and unveiled how Malaysia has developed its pharmacovigilance capacity via multifaceted strategies and interventions. These findings will guide future work in enhancing pharmacovigilance and public health.

A Comparison of Signals of Designated Medical Events and Non-designated Medical Events: Results from a Scoping Review.

INTRODUCTION AND OBJECTIVE: The European Medicines Agency (EMA) maintains a list of designated medical events (DMEs), events that are inherently serious and are prioritized for signal detection, irrespective of statistical criteria. We have analysed the results of our previously published scoping review to determine whether DME signals differ from those of other adverse events in terms of time to communication and characteristics of supporting reports of suspected adverse drug reactions. METHODS: For all signals, we obtained the launch year of medicinal products from textbooks or regulatory agencies, extracted the year of the first report in VigiBase and calculated the interval between the first report and communication (time to communication, TTC). We further retrieved the average completeness (via vigiGrade) of the reports in each case series in the years before the communication. We categorised as DME signals those concerning an event in the EMA's list. We described the two groups of signals using medians and interquartile ranges (IQR) and compared them using the Brunner-Munzel test, calculating 95% confidence intervals (95% CI) and P values. RESULTS: Of 4520 signals, 919 concerned DMEs and 3601 concerned non-DMEs. Signals of DMEs were supported by a median of 15 reports (IQR 6-38 reports) with a completeness score of 0.52 (IQR 0.43-0.62) and signals of non-DMEs by 20 reports (IQR 6-84 reports) with a completeness score of 0.46 (IQR 0.38-0.56). The probability that a random DME signal was supported by fewer reports than non-DME signals was 0.56 (95% CI 0.54-0.58, P < 0.001) and that of one having lower average completeness was 0.39 (95% CI 0.36-0.41, P < 0.001). The median TTCs of DME and non-DME signals did not differ (10 years), but the TTC was as low as 2 years when signals (irrespective of classification) were supported by reports whose average completeness was > 0.80. CONCLUSIONS: Signals of designated medical events were supported by fewer reports and higher completeness scores than signals of other adverse events. Although statistically significant, the differences in effect sizes between the two groups were small. This suggests that listing certain adverse events as DMEs is not having the expected effect of encouraging a focus on reports of the types of suspected adverse reactions that deserve special attention. Further enhancing the completeness of the reports of suspected adverse drug reactions supporting signals of designated medical events might shorten their time to communication and reduce the number of reports required to support them.

Aspergillus ochraceus biocontrol by Hanseniaspora opuntiae in vitro and on coffee fruits.

Aspergillus ochraceus is an ochratoxin-producing fungus which contaminates coffee. In this study the antifungal effect of the yeast Hanseniaspora opuntiae on three Aspergillus ochraceus strains (IOC 4417, IOC 4462, Ao 14) was evaluated in vitro and on coffee fruits. H. opuntiae (106 and 107 cells mL-1) reduced in vitro fungal growth from 82% to 87%, when co-cultivated with A. ochraceus. The yeast cell free supernatant (CFS) inhibited conidial germination from 76.5% to 92.5%, and hyphal growth from 54% to 78%. The yeast (107 and 109 cells mL-1) applied on coffee fruits delayed fruit decay by A. ochraceus (IOC 4417 and Ao 14) until the 9th day, and was significantly different (p < 0.05) from the controls. Furthermore, the ultrastructure of the yeast-fungus interaction on the coffee fruit surface showed yeast attachment to A. ochraceus hyphae, and morphological alterations in fungal structures, with hyphal abnormalities, such as tortuous hyphae with irregular, non-uniform surface compared to the control without yeast. H. opuntiae showed efficacy as biocontrol agent and, to the best of our knowledge, this is the first study on the antifungal activity of H. opuntiae against A. ochraceus on coffee fruits Nevertheless, application of H. opuntiae to the crop in the field requires further studies.

Supporting Pharmacovigilance Signal Validation and Prioritization with Analyses of Routinely Collected Health Data: Lessons Learned from an EHDEN Network Study.

INTRODUCTION: Individual case reports are the main asset in pharmacovigilance signal management. Signal validation is the first stage after signal detection and aims to determine if there is sufficient evidence to justify further assessment. Throughout signal management, a prioritization of signals is continually made. Routinely collected health data can provide relevant contextual information but are primarily used at a later stage in pharmacoepidemiological studies to assess communicated signals. OBJECTIVE: The aim of this study was to examine the feasibility and utility of analysing routine health data from a multinational distributed network to support signal validation and prioritization and to reflect on key user requirements for these analyses to become an integral part of this process. METHODS: Statistical signal detection was performed in VigiBase, the WHO global database of individual case safety reports, targeting generic manufacturer drugs and 16 prespecified adverse events. During a 5-day study-a-thon, signal validation and prioritization were performed using information from VigiBase, regulatory documents and the scientific literature alongside descriptive analyses of routine health data from 10 partners of the European Health Data and Evidence Network (EHDEN). Databases included in the study were from the UK, Spain, Norway, the Netherlands and Serbia, capturing records from primary care and/or hospitals. RESULTS: Ninety-five statistical signals were subjected to signal validation, of which eight were considered for descriptive analyses in the routine health data. Design, execution and interpretation of results from these analyses took up to a few hours for each signal (of which 15-60 minutes were for execution) and informed decisions for five out of eight signals. The impact of insights from the routine health data varied and included possible alternative explanations, potential public health and clinical impact and feasibility of follow-up pharmacoepidemiological studies. Three signals were selected for signal assessment, two of these decisions were supported by insights from the routine health data. Standardization of analytical code, availability of adverse event phenotypes including bridges between different source vocabularies, and governance around the access and use of routine health data were identified as important aspects for future development. CONCLUSIONS: Analyses of routine health data from a distributed network to support signal validation and prioritization are feasible in the given time limits and can inform decision making. The cost-benefit of integrating these analyses at this stage of signal management requires further research.

Yeasts as sustainable biocontrol agents against ochratoxigenic Aspergillus species and in vitro optimization of ochratoxin A detoxification.

AIMS: The aims of this study were to evaluate the potential of Hanseniaspora opuntiae, Meyerozyma caribbica, and Kluyveromyces marxianus for in vitro biocontrol of Aspergillus ochraceus, A. westerdijkiae, and A. carbonarius growth, the ochratoxin A (OTA) effect on yeast growth, and yeast in vitro OTA detoxification ability using an experimental design to predict the combined effects of inoculum size, incubation time, and OTA concentration. METHODS AND RESULTS: Predictive models were developed using an incomplete Box-Behnken experimental design to predict the combined effects of inoculum size, incubation time, and OTA concentration on OTA detoxification by the yeasts. The yeasts were able to inhibit fungal growth from 13% to 86%. Kluyveromyces marxianus was the most efficient in inhibiting the three Aspergillus species. Furthermore, high OTA levels (100 ng ml-1) did not affect yeast growth over 72 h incubation. The models showed that the maximum OTA detoxification under optimum conditions was 86.8% (H. opuntiae), 79.3% (M. caribbica), and 73.7% (K. marxianus), with no significant difference (P > 0.05) between the values predicted and the results obtained experimentally. CONCLUSION: The yeasts showed potential for biocontrol of ochratoxigenic fungi and OTA detoxification, and the models developed are important tools for predicting the best conditions for the application of these yeasts as detoxification agents.

Role of Acetic Acid Bacteria in Food and Beverages.

Acetic acid bacteria (AAB) are microorganisms widely distributed in nature. Although this group is involved in the spoilage of some foods, AAB are of great industrial interest, and their functionality is still poorly understood. AAB convert ethanol, sugars and polyols into various organic acids, aldehydes and ketones via oxidative fermentation. These metabolites are produced during a succession of biochemical reactions in various fermented foods and beverages, such as vinegar, kombucha, water kefir, lambic and cocoa. Furthermore, important products such as gluconic acid and ascorbic acid precursors can be produced industrially from their metabolism. The development of new AAB-fermented fruit drinks with healthy and functional properties is an interesting niche for research and the food industry to explore, as it can meet the needs of a wide range of consumers. Exopolysaccharides such as levan and bacterial cellulose have unique properties, but they need to be produced on a larger scale to expand their applications in this area. This work emphasizes the importance and applications of AAB during the fermentation of various foods, their role in the development of new beverages as well as numerous applications of levan and bacterial cellulose.

Perspectives on the Use of Biopolymeric Matrices as Carriers for Plant-Growth Promoting Bacteria in Agricultural Systems.

The subject of this review is to discuss some aspects related to the use of biopolymeric matrices as carriers for plant-growth promoting bacteria (PGPB) in agricultural systems as a possible technological solution for the establishment of agricultural production practices that result in fewer adverse impacts on the environment, reporting some promising and interesting results on the topic. Results from the encapsulation of different PGPB on alginate, starch, chitosan, and gelatin matrices are discussed, systematizing some advances made in this area of knowledge in recent years. Encapsulation of these bacteria has been shown to be an effective method for protecting them from unsuitable environments, and these new products that can act as biofertilizers and biopesticides play an important role in the establishment of a sustainable and modern agriculture. These new products are technological solutions for replacing deleterious chemical fertilizers and pesticides, maintaining soil fertility and stability, and improving crop productivity and food security. Finally, in the near future, scale-up studies will have to provide new information about the large-scale production of these materials as well as their application in the field under different biotic and abiotic stress conditions.

Signals of Adverse Drug Reactions Communicated by Pharmacovigilance Stakeholders: A Scoping Review of the Global Literature.

INTRODUCTION AND OBJECTIVE: Signals of adverse drug reactions (ADRs) can be supported by reports of ADRs and by interventional and non-interventional studies. The evidence base and features of ADR reports that are used to support signals remain to be comprehensively described. To this end, we have undertaken a scoping review. METHODS: We searched the following databases: PubMed, EMBASE, PsycINFO, Web of Science, and Google Scholar, without language or time restrictions. We also hand searched the bibliographies of relevant studies. We included studies of any design if the results were described as signals. We assessed the levels of evidence using the Oxford Centre for Evidence-Based Medicine (OCEBM) criteria and coded features of reports of ADRs using the Bradford Hill guidelines. RESULTS: Overall, 1974 publications reported 2421 studies of signals; 1683/2421 were clinical assessments of anecdotal reports of ADRs, but only 225 (13%) of these included explicit judgments on which features of the ADR reports were supportive of a signal. These 225 studies yielded 228 signals; these were supported by features, which were: 'experimental evidence' (i.e., positive dechallenge or rechallenge, 154 instances [68%]), 'temporality' (i.e., time to onset, 130 [57%]), 'exclusion of competing causes' (49 [21%]), and others (40 [17%]). Positive dechallenge/rechallenge often co-occurred with temporality (77/228). OCEBM 4 (i.e., case series and case-control studies) was the most frequent level of evidence (2078 studies). Between 2013 and 2019, there was a three-fold increase in clinical assessments of reports of ADRs compared with a less than two-fold increase in studies supported by higher levels of evidence (i.e., OCEBM 1-3). We identified an increased rate between 2013 and 2019 in disproportionality analyses (about 15 studies per year), mostly from academia. CONCLUSIONS: Most signals were supported by temporality and dechallenge/rechallenge, but clear reporting of judgments on causality remains infrequent. The number of studies supported only by anecdotal reports of ADRs increased from year to year. The impact of a growing number of signals of disproportionate reporting communicated without an accompanying clinical assessment should be evaluated.

Aspergillus welwitschiae: A Potential amylases Producer.

Amylases, glycoside hydrolases widely used in several industrial processes, can be produced by many animals, plants, bacteria, and fungi. Fungal amylases from Aspergillus sp. hold remarkable importance in biotechnological applications for presenting a great catalysis efficiency in a wide range of pH and temperature. The production of amylases is mainly dependent on the genetic background of the species, i.e., Aspergillus strains, and abiotic factors. Among the major producers of amylases are the species of Aspergillus section Nigri, including Aspergillus welwitschiae. In this study, Aspergillus welwitschiae strains were evaluated for their ability to produce extracellular amylases. Among the 24 strains, wild Aspergillus welwitschiae UELAs 15.262 and mutant A. welwitschiae UELAs 15.262/35 strains showed greater potential for amylases production. The A. welwitschiae UELAs 15.262 produced more amylases (8645 U/mg) when compared to A. welwitschiae UELAs 15.262/35 (6666 U/mg). The amylases activity from partially purified crude enzymatic extract of A. welwitschiae UELAs 15.262 strain obtained at pH 5.5, 60 °C, resulted in 1.98-fold (3837 U/mg) increase in enzymatic activity. Likewise, the amylases activity from partially purified crude extract of A. welwitschiae UELAs 15.262/35 obtained at pH 5.0, 60 °C resulted in 2.2-fold (9077 U/mg) increase in amylases activity. The presence of metallic ions (Cu2+ and Fe3+) also provided an increase of amylases activity for both strains. To our knowledge, this is the first study reporting the ability of Aspergillus welwitschiae strains in order to produce amylases.

Correlations between Peak Nasal Inspiratory Flow, Acoustic Rhinometry, 4-Phase Rhinomanometry and Reported Nasal Symptoms.

Background: Rhinomanometry, acoustic rhinometry (AR) and peak nasal inspiratory flow (PNIF) are popular methods for nasal patency evaluation. The aim of the present study was to compare these three methods with the reported nasal symptoms to determine the best diagnostic tool to assess nasal obstruction. Methods: 101 subjects were evaluated using PNIF, 4-phase rhinomanometry (4PR), AR, Visual Analogue Scale for nasal obstruction (VAS-NO) and Sino-Nasal Outcome Test (SNOT-22). Correlations among PNIF, 4PR, AR, VAS-NO and SNOT-22 were obtained. Results: VAS-NO and SNOT-22 were moderately correlated with each other (r = 0.54, p < 0.001). 4PR was moderately correlated with PNIF (r = −0.31, p = 0.0016) and AR (r = −0.5, p < 0.001). VAS-NO was mildly correlated with PNIF (r = −0.29, p = 0.0034). SNOT-22 was moderately correlated with PNIF (r = −0.31, p = 0.0017). After dividing the population into symptomatic and asymptomatic subjects, based on their VAS-NO score, the former showed significantly lower PNIF values (p = 0.009) and higher 4PR values (p = 0.013) compared to the latter ones. Conclusion: PNIF and 4PR showed a significant moderate correlation with each other, but PNIF showed a significant correlation (weak-moderate) with the reported nasal symptom scores.

Can a genetic profile be related to performance in young talent track and field athletes? A pilot study

Abstract Aim: This study analyzed the influences of ACE and ACTN3 gene variants in sprinters, jumpers, and endurance young athletes of track and field. Methods: 36 school-level competitors of both sex (15 girls and 21 boys; aged 16.4 ± 1.2 years; training experience 4 ± 1.2 years) practitioners of different sport disciplines (i.e., sprint, jump, and endurance athletes) participated in the study. The deoxyribonucleic acid (DNA) was extracted from peripheral blood using a standard protocol. Anthropometric measurements, 30 m sprint, squat jump (SJ), and maximal oxygen uptake (VO2max) tests were measured. Results: Genotype distribution of the ACE and ACTN3 genes did not differ between groups. In ACE DD and ACTN3 RX genotypes, the SJ test was bigger in sprinters and jumpers than in the endurance runners. In contrast, when analyzing the ACE ID genotype, sprinters had higher SJ than endurance athletes. Moreover, in the ACE DD genotype, the sprinters and jumpers' athletes had lower time in 30 m tests compared to endurance runners. However, the ACE ID and ACTN3 RX genotypes was greater aerobic fitness in endurance runners than in jumpers' athletes. Conclusion: Although the genetic profile is not a unique factor for determining athletic performance, the ACE DD and ACTN3 RX genotypes seem to favor athletic performance in power and sprint versus endurance sports. Thus, this study evidenced that assessing genetic variants could be used as an auxiliary way to predict a favorable profile for the identification of young talents of track and field.

Molecular analysis of Aspergillus section Nigri isolated from onion samples reveals the prevalence of A. welwitschiae.

The aim of this study was to isolate Aspergillus section Nigri from onion samples bought in supermarkets and to analyze the fungal isolates by means of molecular data in order to differentiate A. niger and A. welwitschiae species from the other non-toxigenic species of black aspergilli, and detect genes involved in the biosynthesis of ochratoxin A and fumonisin B2. Aspergillus section Nigri were found in 98% (94/96) of the onion samples. Based on the results of multiplex PCR (performed on 500 randomly selected strains), 97.4% of the Aspergillus section Nigri strains were recognized as A. niger/A. welwitschiae. Around half of them were subjected to partial sequencing of the CaM gene to distinguish one from the other. A total of 97.9% of the isolates were identified as A. welwitschiae and only 2.1% as A. niger. The fum8 gene, involved in fumonisin B2 biosynthesis, was found in 36% of A. welwitschiae isolates, but radH and pks genes, involved in ochratoxin A biosynthesis, were found in only 2.8%. The presence/absence of fum8 gene in the A. welwitschiae genome is closely associated with ability/inability of the isolates to produce fumonisin in vitro. Based on these results, we suggest that in-depth studies are conducted to investigate the presence of fumonisins in onion bulbs.

Signals of adverse drug reactions communicated by pharmacovigilance stakeholders: protocol for a scoping review of the global literature.

BACKGROUND: Signals of adverse drug reactions (ADRs) form the basis of some regulatory risk-minimization actions in pharmacovigilance. Reviews of limited scope have highlighted that such signals are mostly supported by reports of ADRs or multiple types of evidence. The time that elapses between a report of a suspected ADR and the communication of a signal has not been systematically characterized. Neither has the features of reports of suspected ADRs that authors used to support putative causal relationships, although difficulties with establishing causal relationships between medicinal products and adverse events have been highlighted. The objectives of this study will be to describe the evidence underpinning signals in pharmacovigilance, the features of reports of ADRs supporting signals, and the time that it takes to communicate a signal. METHODS: We shall retrieve records from PubMed, EMBASE, Web of Science, and PsycINFO (from inception onwards), without language/design restrictions, and apply backward citation screening. We shall hand-search the websites of 35 regulatory agencies/authorities, restricted publications from the Uppsala Monitoring Centre, and drug bulletins. Signals will be requested from the competent stakeholder, if absent from websites. We shall use VigiBase, the World Health Organization's Global Individual Case Safety Report database, to determine the dates on which ADRs were reported. We shall manage records using EndNote (v. 8.2); one reviewer will screen titles/abstracts and full texts, a second will cross-validate the findings, and a third will arbitrate disagreements. Data will be charted via the Systematic Reviews Data Repository, following the same procedures as for data retrieval. Evidence will be categorized according to the Oxford Centre for Evidence-Based Medicine Levels of Evidence. Features of reports of ADRs will be coded. Tables will display frequencies of types of evidence and features of reports of ADRs. We shall use plots or pictograms (if appropriate) to represent the time from the first report of a suspected ADR to a signal. DISCUSSION: We expect the findings from this review will allow a better understanding of global patterns of similarities or differences in terms of supporting evidence and timing of communications and identify relevant research questions for future systematic reviews. SYSTEMATIC REVIEW REGISTRATION: osf.io/a4xns.

A Feasibility Study of Drug-Drug Interaction Signal Detection in Regular Pharmacovigilance.

INTRODUCTION: Adverse drug reactions related to drug-drug interactions cause harm to patients. There is a body of research on signal detection for drug interactions in collections of individual case reports, but limited use in regular pharmacovigilance. OBJECTIVE: The aim of this study was to evaluate the feasibility of signal detection of drug-drug interactions in collections of individual case reports of suspected adverse drug reactions. METHODS: This study was conducted in VigiBase, the WHO global database of individual case safety reports. The data lock point was 31 August 2016, which provided 13.6 million reports for analysis after deduplication. Statistical signal detection was performed using a previously developed predictive model for possible drug interactions. The model accounts for an interaction disproportionality measure, expressed suspicion of an interaction by the reporter, potential for interaction through cytochrome P450 activity of drugs, and reported information indicative of unexpected therapeutic response or altered therapeutic effect. Triage filters focused the preliminary signal assessment on combinations relating to serious adverse events with case series of no more than 30 reports from at least two countries, with at least one report during the previous 2 years. Additional filters sought to eliminate already known drug interactions through text mining of standard literature sources. Preliminary signal assessment was performed by a multidisciplinary group of pharmacovigilance professionals from Uppsala Monitoring Centre and collaborating organizations, whereas in-depth signal assessment was performed by experienced pharmacovigilance assessors. RESULTS: We performed preliminary signal assessment for 407 unique drug pairs. Of these, 157 drug pairs were considered already known to interact, whereas 232 were closed after preliminary assessment for other reasons. Ten drug pairs were subjected to in-depth signal assessment and an additional eight were decided to be kept under review awaiting additional reports. The triage filters had a major impact in focusing our preliminary signal assessment on just 14% of the statistical signals generated by the predictive model for drug interactions. In-depth assessment led to three signals communicated with the broader pharmacovigilance community, six closed signals and one to be kept under review. CONCLUSION: This study shows that signals of adverse drug interactions can be detected through broad statistical screening of individual case reports. It further shows that signal assessment related to possible drug interactions requires more detailed information on the temporal relationship between different drugs and the adverse event. Future research may consider whether interaction signal detection should be performed not for individual adverse event terms but for pairs of drugs across a spectrum of adverse events.

Isolation and Identification of Aspergillus Section Nigri, and Genotype Associated with Ochratoxin A and Fumonisin B2 Production in Garlic Marketed in Brazil.

The garlic contains sulfur bioactive compounds responsible for medicinal properties. The decrease of these compounds due to inadequate storage conditions reduces the beneficial properties and favors infection by microorganisms. Several studies have shown high frequency of garlic infected with Aspergillus section Nigri that potentially produce mycotoxin. Garlic samples were collected in markets of Brazil and a total of 32 samples (of 36) had the fungal infection with predominant genus Aspergillus (50.3%), Penicillium (34.7%), and Fusarium (11%). A total of 63% (649/1031) of infection with Aspergillus section Nigri, of which 60 isolates were selected for analysis of genetic variability that resulted in 4 clusters. Representatives of clusters were identified by the calmodulin gene. Isolates from cluster I were subdivided into A-I and identified as A. niger (16 isolates) and the isolates of clusters B-I, II, and III were identified as A. welwitschiae (43 isolates). Besides, an isolate of the IV-cluster was identified by A. luchuensis. Further, we used the multiplex PCR to verify genotypes of 59 isolates, and none of these had OTA production-associated genotype. Moreover, 19 A. welwitschiae and 15 A. niger were FB2 production-associated genotype. Our study is the first report to the incidence of garlic infection in Brazil and to show that A. welwitschiae causes most of these infections.

Adverse Events in Twitter-Development of a Benchmark Reference Dataset: Results from IMI WEB-RADR.

INTRODUCTION AND OBJECTIVE: Social media has been suggested as a source for safety information, supplementing existing safety surveillance data sources. This article summarises the activities undertaken, and the associated challenges, to create a benchmark reference dataset that can be used to evaluate the performance of automated methods and systems for adverse event recognition. METHODS: A retrospective analysis of public English-language Twitter posts (Tweets) was performed. We sampled 57,473 Tweets out of 5,645,336 Tweets created between 1 March, 2012 and 1 March, 2015 that mentioned at least one of six medicinal products of interest (insulin glargine, levetiracetam, methylphenidate, sorafenib, terbinafine, zolpidem). Products, adverse events, indications, product-event combinations, and product-indication combinations were extracted and coded by two independent teams of safety reviewers. RESULTS: The benchmark reference dataset consisted of 1056 positive controls ("adverse event Tweets") and 56,417 negative controls ("non-adverse event Tweets"). The 1056 adverse event Tweets contained 1396 product-event combinations referring to personal adverse event experiences, comprising 292 different MedDRA® Preferred Terms. The 1171 product-event combinations (83.9%) were confined to four MedDRA® System Organ Classes. The 195 Tweets (18.5%) contained indication information, comprising 25 different Preferred Terms. CONCLUSIONS: A manually curated benchmark reference dataset based on Twitter data has been created and is made available to the research community to evaluate the performance of automated methods and systems for adverse event recognition in unstructured free-text information.

The α -Tomatine Exhibits Antiproliferative Activity, Rupture of Cell Membranes and Induces the Expression of APC Gene in the Human Colorectal Adenocarcinoma Cell Line (Ht-29)

Abstract The α-tomatine is a steroidal glycoalkaloid found in immature tomatoes (Lycopersicon esculentum) that has important biological functions including the inhibition of cancer cell growth and preventing metastasis. This study aimed to evaluate the effects of α-tomatine on cytotoxicity, cellular proliferation, apoptosis, and mRNA expression of APC, CCNA2, β-catenin, CASP9, BAK, BAX and BCL-XL in colorectal adenocarcinoma cell line HT-29. HT29 cells were treated with three concentrations of α-tomatine (0.1, 1 and 10 µg/mL), although only the 1 µg/mL concentration of α-tomatine was used to evaluate genetic expression patterns by real time-PCR. Results showed that α-tomatine was cytotoxic only at the 10 µg/mL concentration. Cell proliferation was significantly inhibited after the first 24 hours of treatment only with concentrations of 10 µg/mL. In contrast, there were no significant differences in apoptosis for any treatment. In the gene expression studies, only APC expression was significantly altered by α-tomatine treatment. In conclusion, α-tomatine has antiproliferative activity in the first 24h of treatment, does not induce apoptosis in this cell line and causes disruption of cell membranes, thereby increasing the expression of APC gene related to cell cycle.

Aspergillus section Flavi diversity and the role of A. novoparasiticus in aflatoxin contamination in the sugarcane production chain.

The presence of Aspergillus section Flavi and aflatoxins in sugarcane as well as in by-products, such as molasses, sugar, yeast cream and dried yeast, collected from different fields and processing plants in São Paulo state, were investigated throughout the sugarcane production chain. A total of 246 samples was collected and analyzed and 226 isolates of Aspergillus section Flavi were isolated. Aspergillus section Flavi strains were found in sugarcane juice, milled sugarcane, stalk, soil and dried yeast samples. Among the isolates of Aspergillus section Flavi submitted to polyphasic identification (n = 57), Aspergillus novoparasiticus and Aspergillus arachidicola were predominantly found. A significant proportion of the isolates (84.5%) were found to have morphological and physiological characteristics of A. novoparasiticus. Most samples, with the exception of sugar, showed some aflatoxin contamination. The highest level was in dried yeast with an average of 2.55 µg/kg and maximum value of 10.19 µg/kg. This is the first report of contamination of sugarcane by A. novoparasiticus.