BERT based natural language processing for triage of adverse drug reaction reports shows close to human-level performance.

Post-marketing reports of suspected adverse drug reactions are important for establishing the safety profile of a medicinal product. However, a high influx of reports poses a challenge for regulatory authorities as a delay in identification of previously unknown adverse drug reactions can potentially be harmful to patients. In this study, we use natural language processing (NLP) to predict whether a report is of serious nature based solely on the free-text fields and adverse event terms in the report, potentially allowing reports mislabelled at time of reporting to be detected and prioritized for assessment. We consider four different NLP models at various levels of complexity, bootstrap their train-validation data split to eliminate random effects in the performance estimates and conduct prospective testing to avoid the risk of data leakage. Using a Swedish BERT based language model, continued language pre-training and final classification training, we achieve close to human-level performance in this task. Model architectures based on less complex technical foundation such as bag-of-words approaches and LSTM neural networks trained with random initiation of weights appear to perform less well, likely due to the lack of robustness that a base of general language training provides.

[The reporting of adverse drug reactions has been working well during the pandemic - but there is room for improvement]. / Spontanrapporteringen har fyllt sitt syfte under pandemin.

Reporting of suspected adverse drug reactions (ADRs), from healthcare professionals and from consumers, contributes to early detection of new safety risks with medicines. The reporting of adverse reactions has been working well during the pandemic but indicates at the same time a significant under-reporting (hidden statistics). The propensity to report clearly increases with enhanced communication. Consumer reports are an important complement to reports from health care professionals and contribute to valuable insights both within regulatory follow-up and research. Reporting of suspected ADRs is an important source that needs to be supplemented with other data sources for causality analysis. For reporting of suspected adverse reactions to continue to be a valuable tool in the search for new signals, we need to develop sustainable reporting systems and communication channels that meet our various needs in close cooperation between authorities and other actors.

Association between SARS-CoV-2 vaccination and healthcare contacts for menstrual disturbance and bleeding in women before and after menopause: nationwide, register based cohort study.

OBJECTIVES: To evaluate the risks of any menstrual disturbance and bleeding following SARS-CoV-2 vaccination in women who are premenopausal or postmenopausal. DESIGN: A nationwide, register based cohort study. SETTING: All inpatient and specialised outpatient care in Sweden from 27 December 2020 to 28 February 2022. A subset covering primary care for 40% of the Swedish female population was also included. PARTICIPANTS: 2 946 448 Swedish women aged 12-74 years were included. Pregnant women, women living in nursing homes, and women with history of any menstruation or bleeding disorders, breast cancer, cancer of female genital organs, or who underwent a hysterectomy between 1 January 2015 and 26 December 2020 were excluded. INTERVENTIONS: SARS-CoV-2 vaccination, by vaccine product (BNT162b2, mRNA-1273, or ChAdOx1 nCoV-19 (AZD1222)) and dose (unvaccinated and first, second, and third dose) over two time windows (one to seven days, considered the control period, and 8-90 days). MAIN OUTCOME MEASURES: Healthcare contact (admission to hospital or visit) for menstrual disturbance or bleeding before or after menopause (diagnosed with the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision codes N91, N92, N93, N95). RESULTS: 2 580 007 (87.6%) of 2 946 448 women received at least one SARS-CoV-2 vaccination and 1 652 472 (64.0%) 2 580 007 of vaccinated women received three doses before the end of follow-up. The highest risks for bleeding in women who were postmenopausal were observed after the third dose, in the one to seven days risk window (hazard ratio 1.28 (95% confidence interval 1.01 to 1.62)) and in the 8-90 days risk window (1.25 (1.04 to 1.50)). The impact of adjustment for covariates was modest. Risk of postmenopausal bleeding suggested a 23-33% increased risk after 8-90 days with BNT162b2 and mRNA-1273 after the third dose, but the association with ChAdOx1 nCoV-19 was less clear. For menstrual disturbance or bleeding in women who were premenopausal, adjustment for covariates almost completely removed the weak associations noted in the crude analyses. CONCLUSIONS: Weak and inconsistent associations were observed between SARS-CoV-2 vaccination and healthcare contacts for bleeding in women who are postmenopausal, and even less evidence was recorded of an association for menstrual disturbance or bleeding in women who were premenopausal. These findings do not provide substantial support for a causal association between SARS-CoV-2 vaccination and healthcare contacts related to menstrual or bleeding disorders.

A temporary regulation to manage an impending shortage due to extraordinary prescribing patterns of chloroquines observed during early phase of COVID-19 epidemic.

Background: Chloroquine and hydroxychloroquine (C/HC) received considerable international media attention due to anticipated treatment effect in COVID-19. This led to increased prescriptions threatening to generate product shortages for patients prescribed within approved indications.We evaluated effects of a temporary regulation mandating pharmacies to only dispense C/HC prescribed by physicians with defined specialties. Methods: Data from Region Stockholm, which include 2.4 out of 10 million Sweden's population, were used. Weekly time trends of prescriptions and requisitions of C/HC by prescriber's workplace during January to April 2020 were followed. Results: Numbers of unique individuals with filled prescriptions of chloroquine increased tenfold and of hydroxychloroquine more than threefold from January to March. In the first week of April, filled prescriptions of C/HC dropped. In the later weeks of April, the number of filled prescriptions was back at similar levels as before the SARS-CoV-2 outbreak.During January and February, specialists in rheumatology accounted for 686 out of all 979 prescriptions dispensed (70.1%) of C/HC. In March, a large proportion of prescriptions dispensed were from specialists not usually prescribing C/HC, and rheumatology accounted for 628 out of all 1,639 prescriptions (38.3%). In April, specialists in rheumatology accounted for 386 out of all 641 prescriptions dispensed (60.0%). Conclusion: After an observed increase in prescriptions of C/HC, a temporary regulation was introduced on 2nd April 2020 to reduce prescriptions from specialists not usually prescribing C/HC to avoid shortages for patients within approved indications. Subsequently, dispensed prescriptions decreased from April and remained at pre-COVID-19 levels thereafter.

A review of adverse events in animals and children after secondary exposure to transdermal hormone-containing medicinal products.

Background: Hormonal replacement therapy is widely used to treat conditions in humans, the most well-known indication being the relief of menopausal symptoms in women. Many of the hormone-containing products (HCP) are applied to the skin. This transdermal delivery poses a risk to animals and humans through secondary exposure, especially when product information is not strictly followed. The aim of this article is to raise awareness among veterinarians and human healthcare providers of this risk; based on evidence from spontaneous reporting of suspected adverse events (AEs) in animals and humans. Interventions are also explored to mitigate the risk of secondary exposure to transdermal HCP (THCP). Review of spontaneously reported suspected AEs: The Swedish Medical Products Agency has received several, mainly serious, AE reports in animals and children following secondary exposure to THCPs. The AE reports were reviewed together with worldwide data from the EudraVigilance Veterinary database and human EudraVigilance Data Analysis System. The clinical signs reported in animals included persistent signs of oestrus, poor growth rate and birth defects. In humans, reported clinical signs included precocious puberty, unresolved virilisation, accelerated growth rate and female infertility. Conclusions: It is important that THCP are used according to manufacturer's instructions and users are made aware of risks and mitigating measures. This review of AEs in animals and children provides evidence to show that the use of THCP poses a risk for secondary exposure. Efficient communication strategies that stretch across veterinary and human medicinal disciplines are required to raise mutual awareness and minimise the risk of AEs in animals and humans.

A survey of veterinary professionals in Sweden: Adverse event reporting and access to product safety information.

BACKGROUND: Pharmacovigilance based on spontaneously reported suspected adverse events (AEs) from veterinary professionals is a powerful tool for detecting potential risks of using medicinal products. However, it is heavily dependent on the voluntary participation of veterinary professionals. Estimates suggest that over 90% of suspected AEs remain unreported. This survey was conducted to accumulate information on current practices and attitudes of Swedish veterinary professionals in relation to AE reporting and their perceptions of the accessibility of updated product safety information. METHODS: Swedish veterinary professionals were surveyed using a web-based questionnaire prepared by the Swedish Medical Products Agency (SMPA). The survey included three sections with 13 questions and was distributed via several communication channels, including the Swedish Veterinary Association. RESULTS: The survey was answered by 412 veterinary professionals, including veterinarians and licensed veterinary nurses. The survey identified that most veterinarians comply with national legislation by reporting directly to the SMPA, but not all observed AEs are reported. Veterinary professionals indicated that it is important to have an easy and efficient reporting system, preferably directly from an electronic medical records system. Feedback is considered important. Veterinary nursing staff could potentially improve the reporting rate of suspected AEs in Sweden. The degree of knowledge relating to the reporting of AEs varies among professionals, thus impacting on reporting frequency. A single source of product safety information is mainly used, and improvements are required to enhance accessibility and distribution of updated product safety information. CONCLUSIONS: The insight gained from this survey will be used to influence attitudes and facilitate adaptations needed to fulfil the requirements of the European Union regulations. To reduce underreporting of AEs and facilitate access to updated product safety information, various approaches are required including educational interventions, new digital reporting tools and adaption of communication strategies.

[Medicinal products in unauthorised indications]. / Rutinmässig off label-utvärdering bör inte göras av Läkemedelsverket.

The Medical Products Agency (MPA) has conducted the assessment presented in this manuscript within the remits of a Government assignment to the MPA. No new safety concern, and consequently no need for regulatory action, has been identified in relation to off-label use of rituximab in patients with active MS. While there is plausible pharmacodynamic, early phase clinical trial, and non-interventional data on effectiveness to support the biological effects of rituximab in MS, the magnitude of efficacy in relation to a well-defined population and posology has not been reliably confirmed from a regulatory perspective. From the MPA regulatory perspective, the benefit-risk balance for rituximab in patients with MS is at this stage considered undetermined. The overall recommendation of the MPA is to not create a specific procedure intended for systematically implemented benefit-risk evaluations of medicinal products in unauthorised indications.

Comparative characterization of digestate versus pig slurry and cow manure - Chemical composition and effects on soil microbial activity.

The growing number of biogas plants in Europe has resulted in increased production of nutrient-rich digestate with great potential as fertilizer for arable land. The nutrient composition of digestate varies with the substrate treated in the biogas plant and may contain compounds that stimulate or inhibit soil microbial activity. This study compared 20 digestates (D) with 10 pig slurries (PS) and 10 cow manures (CM) regarding their chemical content and their effect on soil microbial activities, i.e. potential ammonia oxidation rate (PAO) and soil respiration. The results showed no significant differences within the D group when divided based on substrate type. i.e. manure dominated vs. other organic waste materials in any of the tests. In general D contained significantly higher concentrations of ammonium while the concentrations of total carbon and volatile fatty acids were higher in PS and CM than in D. The D showed both stimulating and inhibiting effects on PAO, while all CM and all PS except one showed inhibiting effects on PAO. However, PAO activity was negatively correlated with the content of volatile fatty acids in the residues indicating that these compounds may be the cause of the inhibition. The maximum respiration activity (hpeakmax) was lower and the time point for the maximum respiration activity (tpeakmax) occurred earlier for D compared with CM and PS. This earlier peak time could be indicative of a high proportion of easily degradable carbon in D compared with PS and CM. However, the utilization rate of carbon, i.e. the proportion of added organic C converted to CO2-C during 12days, did not differ significantly between D, PS and CM, indicating that overall carbon quality in the different fertilizers was still roughly comparable. In short, our results suggest that digestates were different compared with PS and CM but without posing a higher risk with respect to their impact on soil microbial activity.

Changes in the acetogenic population in a mesophilic anaerobic digester in response to increasing ammonia concentration.

Changes in the acetogenic population were investigated in an experimental laboratory-scale biogas reactor (37°C) subjected to gradually elevated ammonia levels (0.8 to 6.9 g NH(4)(+)-N L(-1)). A shift from aceticlastic acetate degradation to syntrophic acetate oxidation had previously been confirmed in this reactor. In a parallel control reactor, operating at constant ammonia levels (0.65-0.90 g NH(4)(+)-N L(-1)), acetate degradation proceeded via the aceticlastic pathway throughout the operating period (660 d). The acetogenic populations in the reactors were analysed using degenerated primers designed to target the functional gene encoding a key enzyme of the acetyl-CoA pathway, 10-formyltetrahydrofolate synthetase (FTHFS). The analysis consisted of terminal restriction fragment length polymorphism (T-RFLP) analysis coupled with the construction of clone libraries, and quantitative PCR (qPCR) analysis. The T-RFLP data obtained were statistically analysed by non-metric multidimensional scaling. The most abundant FTHFS genes recovered in the clone libraries were assigned to terminal restriction fragments of the T-RFLP profile. The results of the investigation clearly indicated that increased ammonia concentration substantially influenced the putative acetogenic population structure and caused two distinct shifts of the most abundant members; however, the identity of the dominating species remains unknown, as none of the genes had been identified previously. Despite the shifts in the population, the qPCR analysis revealed a relatively stable abundance of the acetogenic population throughout the operation.

Persistence and spread of Salmonella enterica serovar Weltevreden in soil and on spinach plants.

Several outbreaks caused by pathogenic bacteria are related to the consumption of raw produce contaminated by animal manure. The majority of these outbreaks have been linked to Salmonella spp. We examined the ability of Salmonella enterica serovar Weltevreden to persist and survive in manure and soil as well as disseminate to, and persist on, spinach roots and leaves. Significantly higher numbers of S. Weltevreden inoculated into manure and applied to soil before planting spinach were found in soil than in pot cultures, where the pathogen had been inoculated directly into soil 14 days postplanting. Moreover, the pathogen seemed to disperse from manure to spinach roots, as we observed a continuous increase in the number of contaminated replicate pot cultures throughout the evaluation period. We also found that, in some cases, S. Weltevreden present in the phyllosphere had the ability to persist for the entire evaluation period (21 days), with only slight reductions in cell numbers. The results from the present study show that S. Weltevreden is capable of persisting in soil, roots and shoots for prolonged periods, indicating the importance of strict monitoring of untreated animal manure before considering its application to agricultural land.

Specific interactions between arbuscular mycorrhizal fungi and plant growth-promoting bacteria: as revealed by different combinations.

The interactions between two plant growth-promoting rhizobacteria (PGPR, Pseudomonas fluorescens SBW25 and Paenibacillus brasilensis PB177), two arbuscular mycorrhizal (AM) fungi (Glomus mosseae and Glomus intraradices) and one pathogenic fungus (Microdochium nivale) were investigated on winter wheat (Triticum aestivum cultivar Tarso) in a greenhouse trial. PB177, but not SBW25, had strong inhibitory effects on M. nivale in dual culture plate assays. The results from the greenhouse experiment show very specific interactions; for example, the two AM fungi react differently when interacting with the same bacteria on plants. Glomus intraradices (single inoculation or together with SBW25) increased plant dry weight on M. nivale-infested plants, suggesting that the pathogenic fungus is counteracted by G. intraradices, but PB177 inhibited this positive effect. This is an example of two completely different reactions between the same AM fungus and two species of bacteria, previously known to enhance plant growth and inhibit pathogens. When searching for plant growth-promoting microorganisms, it is therefore important to test for the most suitable combination of plant, bacteria and fungi in order to achieve satisfactory plant growth benefits.