Pre-exposure Period Research Articles

Physiological and behavioral responses to novel saline conditions in an invasive treefrog.

Salinity can be an environmental stressor for anurans, as their highly permeable skin makes them prone to osmotic stress when exposed to saline conditions. However, certain anuran species have colonized areas near saltwater habitats, suggesting an ability to acclimate to saline conditions. Here, we evaluated physiological and behavioral responses to saline conditions in adult Cuban treefrogs (Osteopilus septentrionalis), an invasive anuran found throughout Florida. To examine their response to salinity, adult frogs were maintained in two treatments simulating a freshwater (0.5 ppt) or brackish (8.0 ppt) environment for 6 weeks. To assess their physiological response to this potential stressor, all frogs were submerged in a brackish solution to quantify individual weight change every 2 weeks. We found that frogs maintained in brackish solution lost more weight at Weeks 2 and 6 when compared to Week 0, suggesting that salinity may be an environmental stressor for Cuban treefrogs. Yet, the weight change at Week 4 was similar to the pre-exposure period, which may indicate that constant exposure to salinity may alter their physiological response to saline conditions. To supplement the physiological analyses, we investigated avoidance behavior towardsaline conditions by offering individuals a choice between freshwater or brackish environments. Our results showed that Cuban treefrogs chose freshwater environments more frequently and may thus avoid saline ones. This study reveals that salinity may induce plastic and avoidance responses in Cuban treefrogs, potentially allowing them to expand their range into areas typically stressful for most anurans.

EFFECT OF PRE-EXPOSURE ON THE INSECTICIDAL AND REPELLENCY PROPERTIES OF Citrus paradisi PEEL ESSENTIAL OIL AGAINST Tribolium castaneum

Although the use of essential oils (EOs) for pest control has gained popularity due to their biodegradability and ecological safety, a major concern regarding their use is stability. Therefore, this aspect deserves empirical studies to enable potential end users to adopt research findings on the pesticidal potential of EOs. This research investigated the insecticidal and repellence impacts of Soxhlet-extracted grapefruit peel (Citrus paradisi Macfad. (Rutaceae) Lane) EO pre-exposed to air for 0, 0.5, 1 and 2 h (before introducing insects) on Tribolium castaneum (Herbst) (Coleoptera: Tenebrionidae). The ethanol diluents were initially allowed to evaporate for 15 min in all treatments. Contact toxicity was tested on larval and adult stages at 5 and 15% concentrations of the EO, while repellency was tested at a 5% concentration. The impacts of EO on adult behavioural activity were also observed 24 h after exposure. Grapefruit EO was effective in controlling T. castaneum adults and larvae at higher doses. Exposure periods had an immediate significant effect on larvae and adult mortalities 1 and 6 h after the insects were introduced. At a 15% concentration, EO with a 0 h pre-exposure period had significantly higher adult and larva mortalities after 6 h than those of 0.5, 1 and 2 h pre-exposure. Regardless of oil pre-exposure, insects were repelled, especially in test periods between 12 and 30 min. Therefore, grapefruit EO could be formulated for increased stability when an immediate impact is needed.

Risk of acute liver injury following the nirmatrelvir/ritonavir use.

Elevations in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were reported as adverse events of nirmatrelvir/ritonavir users in the EPIC-HR trial. To quantify the risk and severity of acute liver injury (ALI) associated with nirmatrelvir/ritonavir use. This self-controlled case-series study was conducted using electronic medical records of patients with confirmed diagnosis of SARS-CoV-2 infection between 26th February 2022 and 12th February 2023 in Hong Kong. Among 2 409 848 patients with SARS-CoV-2 infection during the study period, 153 853 were prescribed with nirmatrelvir/ritonavir, of whom 834 (.5%) had incident ALI (moderate: 30.5%; moderate to severe: 18.9%; severe or fatal: 5.8%). Compared with the non-exposure period, risk of ALI increased significantly during the pre-exposure period (IRR = 38.13, 95% CI = 29.29-49.62) and remained elevated during the five-day nirmatrelvir/ritonavir treatment (IRR = 20.75, 95% CI = 17.06-25.25) and during wash-out period (IRR = 16.27, 95% CI = 13.23-20.01). Compared to the pre-exposure period, risk of ALI was not increased during the five-day nirmatrelvir/ritonavir treatment period (IRR = .54, 95% CI = .43-.70). Compared to 5469 non-nirmatrelvir/ritonavir users with incident ALI, nirmatrelvir/ritonavir users had less severe ALI by the severity index (p < .001) and peak INR (1.7 vs. 2.3; p < .001). ALI cases with nirmatrelvir/ritonavir use had lower risk of all-cause death (29.1% vs. 39.1%; OR = .64; p < .001) and no increase in risk of liver decompensation (1.0% vs. 1.3%; OR = .62; p = .230) compared to non-users. The risk of ALI associated with nirmatrelvir/ritonavir treatment for COVID-19 was elevated in the pre-exposure period, but not following nirmatrelvir/ritonavir initiation. ALI following nirmatrelvir/ritonavir treatment were mostly mild and less severe than ALI events in non-nirmatrelvir/ritonavir users.

Risk of Venous Thromboembolism With Gout Flares.

Previous studies demonstrated that the risk of venous thromboembolism (VTE) is increased in patients with gout, but not whether there was a temporal association between gout flare and VTE. This study was undertaken to evaluate potential temporal associations between gout flare and VTE. Data were obtained from electronic primary-care records from the UK's Clinical Practice Research Datalink, which links data from hospitalization and mortality registers. Using self-controlled case series analysis adjusted for season and age, we evaluated the temporal association between gout flare and VTE. The 90 days after primary-care consultation or hospitalization for gout flare was designated the exposed period. This was divided into three 30-day intervals. The baseline period was up to 2 years before the start of and up to 2 years after the end of the exposed period. The association between gout flare and VTE was measured using adjusted incidence rate ratios (IRRs) with 95% confidence intervals (95% CIs). In total, 314 patients met the inclusion criteria (age ≥18 years, incident gout, no presence of VTE or use of a primary-care anticoagulant prescription before the start of the pre-exposure period). Among the 314 patients, VTE incidence was significantly higher in the exposed period than in the baseline period (adjusted IRR 1.83, 95% CI 1.30-2.59). The adjusted IRR of VTE during the first 30 days after gout flare was 2.31 (95% CI 1.39-3.82) relative to the baseline period. No increase in the adjusted IRRs was observed in days 31-60 (adjusted IRR 1.49, 95% CI 0.79-2.81) and days 61-90 (adjusted IRR 1.67, 95% CI 0.91-3.06) relative to baseline. Results were consistent across sensitivity analyses. Among patients with gout, there was a transient increase in the rate of VTE within 30 days after primary-care consultation or hospitalization for gout flare.

Pre-exposure cognitive performance variability is associated with severity of respiratory infection

Using data from a longitudinal viral challenge study, we find that the post-exposure viral shedding and symptom severity are associated with a novel measure of pre-exposure cognitive performance variability (CPV), defined before viral exposure occurs. Each individual’s CPV score is computed from data collected from a repeated NeuroCognitive Performance Test (NCPT) over a 3 day pre-exposure period. Of the 18 NCPT measures reported by the tests, 6 contribute materially to the CPV score, prospectively differentiating the high from the low shedders. Among these 6 are the 4 clinical measures digSym-time, digSym-correct, trail-time, and reaction-time, commonly used for assessing cognitive executive functioning. CPV is found to be correlated with stress and also with several genes previously reported to be associated with cognitive development and dysfunction. A perturbation study over the number and timing of NCPT sessions indicates that as few as 5 sessions is sufficient to maintain high association between the CPV score and viral shedding, as long as the timing of these sessions is balanced over the three pre-exposure days. Our results suggest that variations in cognitive function are closely related to immunity and susceptibility to severe infection. Further studying these relationships may help us better understand the links between neurocognitive and neuroimmune systems which is timely in this COVID-19 pandemic era.

Serpinpc in Persons with Severe Hemophilia (PwH): Updated Results from a Multi-Center, Multi-Part, First-in-Human Study

Introduction SerpinPC is a recombinant serine protease inhibitor (SERPIN), whose specificity and kinetics aim to rebalance hemostasis for PwH. SerpinPC is designed to increase the amount of thrombin at sites of tissue damage by reducing the activity level of circulating activated protein C (APC) and thereby prolong the activity of prothrombinase. The normal levels and activity of the zymogen precursor protein C are likely maintained due to SerpinPC's specificity for the active form. Methods AP-0101 is an ongoing first in human open label multicenter study utilizing an adaptive design to investigate the safety, tolerability and pharmacokinetics of subcutaneous doses of SerpinPC in male participants with severe hemophilia A or B (HemA, HemB). Reduction in the annualized bleeding rates (ABRs) was also assessed. AP-0101 consists of 5 parts: Part 1 was a Single Ascending Dose Study completed in 15 healthy male subjects and in 12 male PwH (Part 1b: 0.1 to 1.2 mg/kg, 4 cohorts). All 12 PwH in Part 1b chose to participate in Part 2. Part 2 enrolled 23 male PwH (19 HemA and 4 HemB) who were not on replacement factor prophylaxis to receive SerpinPC at 0.3, 0.6 or 1.2 mg/kg, administered as a subcutaneous injection every 4 weeks over a 24-week period (6 total doses). In Part 3, subjects who completed Part 2 receive a flat dose of 60mg of SerpinPC every 4 weeks for 48 weeks. Part 4 is a further extension in which subjects who completed Part 3 receive 1.2mg/kg of SerpinPC every 2 weeks for 24 weeks. Part 5 is an additional extension in which subjects who complete Part 4 receive 1.2mg/kg of SerpinPC every 2 weeks for a further 52 weeks. ResultsUpdated results from Part 3 and 4 - with an estimated follow-up of 48 and 24 weeks respectively - are expected for presentation at the meeting. In Part 2, one subject with a history of a skin disorder discontinued treatment due to an injection site reaction. No other treatment-related adverse events were observed. There was no reported sustained elevation in D-dimer throughout the 24-week study. Two subjects had anti-drug antibodies and remained on treatment without apparent impact on ABRs. In the highest dose cohort, SerpinPC reduced the self-reported 'all bleeds ABR' by 88% during the pre-specified assessment period as compared with the 'all bleeds ABR' prospectively measured during the pre-exposure observation period. The self-reported spontaneous joint bleeds ABR was reduced by 94%. ABR reductions appeared to be similar between the HemA and HemB subgroups. Conclusions The results from Parts 1 and 2 suggest that SerpinPC was well-tolerated in subjects. Reduction in ABR in Part 2 provides preliminary evidence of activity for SerpinPC as a prophylactic agent in preventing bleeding in PwH. The effects of length of treatment and exposure will be further examined in Parts 3-5. More clinical trials are planned to evaluate the benefit and risk profile of SerpinPC in PwH.

Changes in Cancer Screening Rates Following a New Cancer Diagnosis in a Primary Care Patient Panel

Although screenings for breast and colorectal cancer are widely recommended, patient screening rates vary greatly and remain below public health targets, and primary care physicians' (PCPs') counseling and referrals play critical roles in patients' use of cancer screenings. Recent adverse events may influence PCPs' decision-making, but it remains unknown whether cancer screening rates of PCPs' patients change after PCPs are exposed to new cancer diagnoses. To investigate whether PCPs' exposures to patients with new diagnoses of breast or colorectal cancer were associated with changes in screening rates for other patients subsequently visiting the affected PCPs. This cohort study used stacked difference-in-differences analyses of all-payer claims data for New Hampshire and Maine in 2009 to 2015. Participants were PCPs caring for patients. Data analysis was performed from June 2020 to May 2022. New diagnosis of a PCP's patient with breast cancer or colorectal cancer. Patients' breast and colorectal cancer screening rates within 1 year of a PCP visit. The sample included 3158 PCPs (1819 male PCPs [57.6%]) caring for 1 920 189 patients (1 073 408 female patients [55.9%]; mean [SD] age, 41.0 [21.9] years) aged 18 to 64 years. During the study period, 898 PCPs had a patient with a new diagnosis of breast cancer and 370 PCPs had a patient with a new diagnosis of colorectal cancer. In the preexposure period, 68 837 female patients (37.3% of those visiting a PCP) underwent breast cancer screening within 1 year of the visit, and 13 137 patients (10.1% of those visiting a PCP) underwent colorectal cancer screening within 1 year of the visit. For both cancer types, after exposure to a new cancer diagnosis, PCPs' cancer screening rates displayed a rapid, sustained increase. Breast cancer screening rates increased by 4.5 percentage points (95% CI, 3.0-6.1 percentage points; P < .001). Colorectal cancer screening rates increased by 1.3 percentage points (95% CI, 0.3-2.2 percentage points; P = .01). Observed breast cancer screening increases were higher for male PCPs than for female PCPs (3.1 percentage points; 95% CI, 0.4-5.8 percentage points; P = .03). This study found significant, sustained increases in cancer screening rates for patients visiting PCPs recently exposed to new breast and colorectal cancer diagnoses. These findings suggest that PCPs may update practice patterns on the basis of recent patient diagnoses. Future work should assess whether salient cues to PCPs about patient diagnoses when clinically appropriate can improve screening practices.

Incidence and patterns of persistent opioid use in children following appendectomy

BackgroundThe past 5 years have witnessed a concerted national effort to assuage the rising tide of the opioid misuse in our country. Surgical procedures often serve as the initial exposure of children to opioids, however the trajectory of use following these exposures remains unclear. We hypothesized that opioid exposure following appendectomy would increase the risk of persistent opioid use among publicly insured children. Study designA retrospective longitudinal cohort study was conducted on South Carolina Medicaid enrollees who underwent appendectomy between January 2014 and December 2017 using administrative claims data. The primary outcome was chronic opioid use. Generalized linear models and finite mixture models were employed in analysis. Results1789 Medicaid pediatric patients underwent appendectomy and met inclusion criteria. The mean age was 11.1 years and 40.6% were female. Most patients (94.6%) did not receive opioids prior to surgery. Opioid prescribing ≥90 days after surgery (chronic opioid use) occurred in 127 (7.1%) patients, of which 102 (80.3%) had no opioid use in the preexposure period. Risk factors for chronic opioid use included non-naïve opioid status, re-hospitalization more than 30 days following surgery, multiple opioid prescribers, age, and multiple antidepressants/antipsychotic prescriptions.Group-based trajectory analysis demonstrated four distinct post-surgical opioid use patterns: no opioid use (91.3%), later use (6.7%), slow wean (1.9%), and higher use throughout (0.4%). ConclusionOpioid exposure after appendectomy may serve as a priming event for persistent opioid use in some children. Eighty percent of children who developed post-surgical persistent opioid use had not received opioids in the 90 days leading up to surgery. Several mutable and immutable factors were identified to target future efforts toward opioid minimization in this at-risk patient population. Level of evidenceIII.

Association between proton pump inhibitor use and risk of pneumonia in children: nationwide self-controlled case series study in Sweden

ObjectiveTo evaluate the association between use of proton pump inhibitors (PPIs) and risk of pneumonia in children.DesignNationwide register-based self-controlled case series study.SettingSweden, July 2006 to December 2016.ParticipantsChildren aged <18 years...

Chronic effects of cerium dioxide nanoparticles on biological nitrogen removal and nitrous oxide emission: Insight into impact mechanism and performance recovery potential

The influence of cerium dioxide nanoparticles (CeO2 NPs) on biological nitrogen removal and associated nitrous oxide (N2O) emission has seldom been addressed yet. Herein, the chronic effect of CeO2 NPs on the nitrogen transformation processes during wastewater treatment and the impacted system's self-recovery potential after CeO2 NP stress removal were investigated. CeO2 NP of 10–50 mg/L induced significant declines of the ammonia nitrogen (NH4+-N) and the total nitrogen removal efficiencies, but triggered the nitrite accumulation and the N2O emission. The N2O reductase (NOS) activity was negatively correlated with the N2O emission level, and the inhibition of NOS activity under CeO2 NP stress was probably due to the depressions of the sludge denitrifiers' metabolic activities. The NH4+-N removal efficiency was successfully regained after the recovery period although the N2O emission level was still higher than the pre-exposure period, which was probably due to the residual CeO2 NPs inside the activated sludge.

Adaptation of O157:H7 and non-O157 Escherichia coli strains in orange juice and subsequent resistance to UV-C radiation

This study assessed the acid-adaptation of pathogenic and non-pathogenic strains of Escherichia coli in orange juice and the microbial resistance to the subsequent UV-C radiation treatment. Nine Shiga toxin-producing E. coli (STEC) and one strain of a non-pathogenic surrogate E. coli were used in this study. Each E. coli strain was inoculated in orange juice, following pre-exposure during 0, 1, 2, and 3 h at 10 °C. Then, the inoculated juices with the ten different strains separately were exposed to 0 and 2 J/cm2 of UV-C radiation. The D value (i.e., the UV-C dose in J/cm2 required to cause a one-log reduction in the target microorganism) was calculated. Further, the resistance coefficient [RC; i.e., the ratio between the D-values for the control condition (D0h) and each pre-exposure tested time (D1h,D2h, D3h)] were determined. The results indicated that the resistance of E. coli was influenced by the pre-exposure period in the orange juice, with increased resistance to UV-C observed for periods >2 h. Furthermore, the sensitivity of cells to subsequent UV-C treatment was found to be strain-dependent. The results may allow the development of more reliable UV-C radiation processes for orange juice processing aiming the inactivation of pathogenic E. coli.

Protective Effects of Non-Encapsulated and Microencapsulated Lactobacillus Delbrueckii Subsp. Bulgaricus in Rainbow Trout (Oncorhynchus Mykiss) Exposed to Lead (Pb) Via Diet

Abstract The present study was designed to investigate the effects of dietary non-encapsulated and microencapsulated Lactobacillus delbrueckii subsp. bulgaricus on growth performance, intestinal enzymatic activities, antioxidant capacity and hepato-biochemical parameters of rainbow trout before or after exposure to lead via diet. Fingerling fish (16 ± 4 g) were divided into four groups: negative control (NC), positive control (PC), probiotic (PR) and encapsulated probiotic (EN-PR). During the pre-exposure period (days 0–45), fish in the NC and PC groups received the basal diet, whereas fish in the PR and EN-PR groups were fed with basal diet containing 108 CFU g−1 feed of non-encapsulated and microencapsulated probiotic, respectively. During the exposure period (days 46–66), the fish in the probiotic and PC groups were co-treated with 500 μg g−1 feed of lead nitrate. Blood, liver and gut samples were taken at days 0, 45, 52, 59 and 66. The results revealed that growth performance and intestinal enzymatic activities were significantly (P&lt;0.05) improved in the probiotic groups compared to the NC group (day 45). Dietary exposure to lead resulted in the highest levels of liver aspartate aminotransferase (AST), liver alkaline phosphatase (ALP) and serum malondialdehyde (MDA), and the lowest activities of serum superoxide dismutase (SOD) and catalase (CAT) in the PC group (day 66). The levels of liver ALP were significantly (P&lt;0.05) lower in the probiotic groups compared to the NC and PC groups prior to and after exposure to dietary lead. Serum levels of total protein, albumin, SOD, CAT and glutathione (GSH) were significantly increased in fish fed with both non-encapsulated and microencapsulated probiotics (P&lt;0.05). However, microencapsulated probiotic showed the greatest potential for alleviation of the disturbed activities of intestinal and hepatic enzymes, and improvement of serum biochemical and antioxidant parameters. Our findings suggest that L. delbrueckii subsp. bulgaricus, particularly in the microencapsulated form, can be used as a potential probiotic to protect rainbow trout from dietborne lead toxicity.

COVID-19: Using the Right Tools at the Right Time

COVID-19, caused by SARS-CoV2, first described in several cases of pneumonia in Wuhan, China in December 2020 has now become a disease that is now present throughout the world. Multiple evidence-based measures and therapeutics are now available for the prevention and treatment of COVID-19. Many therapeutics have been studied and some even continue to be used without compelling evidence to suggest efficacy. Critical to the prevention and successful identification of treatments for COVID-19 has been an appreciation of the multiple stages of this disease. A previous paper published in February 2021 presented a consensus framework of relevant stages of COVID-19 authored by 35 physicians and scientist from multiple disciplines and countries. This framework included: three periods: the period of pre-exposure, the incubation period, the period of detectable viral replication, and five phases: the viral symptom phase, the early inflammatory phase, the secondary infection phase, the multisystem inflammatory phase, and the tail phase. This common terminology has served as a framework to guide COVID-19 therapeutics studied or currently in use. We now have a greater understanding of this disease and an update framework with two preclinical periods, the Pre-exposure Period and the Incubation Period, followed by four clinical phases, the Early Viral Upper Respiratory Non-hypoxic Phase, the Early Inflammatory Lower Respiratory Hypoxic Phase, the Secondary Symptomatic Phase and the Late Phase. We also have more evidence regarding the role of improved ventilation, the effectiveness of different masks, several highly effective vaccines, and a few effective antiviral, immunomodulatory, and supportive therapies. As there has been substantial progress made in understanding this disease and the role of various interventions, both nonpharmacological and pharmacological and changes over time in characteristics of SARS-CoV-2 such as a shorter incubation period and different susceptibility to various therapeutics, it is appropriate to put forth this update.

Influence of Prolonged Serotonin and Ergovaline Pre-Exposure on Vasoconstriction Ex Vivo.

Ergot alkaloid mycotoxins interfere in many functions associated with serotonergic neurotransmitters. Therefore, the objective was to evaluate whether the association of serotonin (5-hydroxytryptamine, 5-HT) and ergot alkaloids during a 24 h pre-incubation could affect the vascular contractile response to ergot alkaloids. To evaluate the effects of 24 h exposure to 5-HT and ergot alkaloids (ergovaline, ERV), two assays were conducted. The first assay determined the half-maximal inhibitory concentration (IC50) following the 24 h pre-exposure period, while the second assay evaluated the effect of IC50 concentrations of 5-HT and ERV either individually or in combination. There was an interaction between previous exposure to 5-HT and ERV. Previous exposure to 5-HT at the IC50 concentration of 7.57 × 10−7 M reduced the contractile response by more than 50% of control, while the exposure to ERV at IC50 dose of 1.57 × 10−10 M tended to decrease (p = 0.081) vessel contractility with a response higher than 50% of control. The 24 h previous exposure to both 5-HT and ERV did not potentiate the inhibitory response of blood vessels in comparison with incubation with each compound alone. These results suggest receptor competition between 5-HT and ERV. More studies are necessary to determine the potential of 5-HT to treat toxicosis caused by ergot alkaloids.

Risk of fracture in antidepressant users with concurrent use of benzodiazepines: A self-controlled case-series analysis.

Despite the fracture risk associated with both antidepressant (AD) medication and benzodiazepines (BDZs), they are commonly prescribed simultaneously. However, studies elucidating the effects of concurrent use of BDZs and ADs on the risk fracture are scant. The objective of this study was to evaluate the risk of fracture associated with concurrent use of BDZs in AD users, using a self-controlled case-series analysis. A self-controlled case-series analysis, in which the participants act as their own control, was conducted using the Korean National Health Insurance Service-National Sample Cohort database (2002-2015). We studied AD users who were prescribed BDZs and diagnosed with a fracture. The risk periods were subdivided into consecutive periods (1-30, 31-60, and>60days) after receiving a BDZ. A 2-week pre-exposure period and a 2-week post-exposure period were also included. The incidence rate ratio (IRR) was estimated after adjusting for age and use of co-medications. A total of 3020 patients were identified during the study period. There was an increased fracture risk in the first 30days following BDZ use (IRR: 1.88, 95% confidence interval [CI] 1.66-2.12), in the 31-60-day period (1.73, 95% CI 1.48-2.02), and beyond the 60-day period (IRR: 1.68, 95% CI 1.47-1.91). The risks of fracture were greater in men and older patients. The concomitant use of BDZs and ADs was related to a significant increase in fracture risk. AD users should be aware of the fracture risk with concomitant BDZ use, especially for first-time BDZ users and for elderly patients.

Association between 9-month isoniazid prophylaxis of latent tuberculosis and severe hepatitis in patients treated with TNF inhibitors

To investigate associations between isoniazid for latent tuberculosis and risk of severe hepatitis, affecting patients with rheumatoid arthritis or ankylosing spondylitis whose treatment includes tumor necrosis factor inhibitors. Our self-controlled case series study analyzed Taiwan’s National Health Insurance Database from 2003 to 2015 to identify RA or AS patients, aged ≥ 20 years, receiving TNF inhibitors and a 9-month single isoniazid treatment. The outcome of interest was hospitalization due to severe hepatitis. We defined risk periods by isoniazid exposure (days): 1–28, 29–56, 57–84, 85–168, 169–252, and 253–280. To compare risk of severe hepatitis in exposed and non-exposed periods, we performed conditional Poisson regressions to generate incidence rate ratios (IRR) and 95% confidence intervals, with adjustment of patients’ baseline covariates including age, sex, HBV, HCV and related medication. Of 54,267 RA patients and 137,889 AS patients identified between 2000 and 2015, 11,221 (20.7%) RA and 4,208 (3.1%) AS patients underwent TNFi therapy, with 722 (5%) receiving isoniazid for latent tuberculosis. We identified 31 incident cases (4.3%) of hospitalization due to severe hepatitis. Of these hospitalization events, 5 occurred in the exposed periods, 25 occurred in the INH unexposed periods, and 1 occurred in the pre-exposure period. Compared with non-exposure, the risk of severe hepatitis was higher in exposed periods (incidence rate ratio [IRR]: 5.1, 95% CI: 1.57–16.55), especially 57–84 days (IRR: 17.29, 95% CI: 3.11–96.25) and 85–168 days (IRR:10.55, 95% CI: 1.90–58.51). The INH related fatal hepatotoxicity was not identified in our study. Our findings suggest an association between risk of severe hepatitis and exposure to isoniazid in patients with RA or AS under TNFi therapy, particularly within the exposed period 57–168 days. A close monitoring of liver function is mandatory to minimize the risk, especially within the first 6 months after initiation of 9 months isoniazid.

Association between methylphenidate and risk of myocardial infarction: A multinational self-controlled case series study.

To investigate the association between use of methylphenidate and risk of myocardial infarction among Asians. We conducted a multinational self-controlled case series study using nationwide healthcare databases of South Korea (2002-2018), Taiwan (2004-2015), and Hong Kong (2001-2016). Of patients with myocardial infarction who were also prescribed methylphenidate within the observation period, methylphenidate use was classified into four mutually exclusive periods by each person-day: exposed (exposed to methylphenidate), pre-exposure (prior to the first methylphenidate prescription), washout (after the end of methylphenidate treatment), and baseline (unexposed to methylphenidate). Risk of myocardial infarction among the three periods of methylphenidate use was compared to the baseline period using conditional Poisson regression analysis to estimate incidence rate ratios (IRRs) with 95% confidence intervals (CIs). We identified 2104, 484, and 30 patients from South Korea, Taiwan, and Hong Kong, respectively. Risk of myocardial infarction was the highest during the pre-exposure period in all three populations: South Korea, pre-exposure (IRR 3.17, 95% CI 3.04-3.32), exposed (1.05, 1.00-1.11), washout (1.92, 1.80-2.04); Taiwan, pre-exposure (1.97, 1.78-2.17), exposed (0.72, 0.65-0.80), washout (0.56, 0.46-0.68); Hong Kong, pre-exposure (18.09, 8.19-39.96), exposed (9.32, 3.44-25.28), washout (7.69, 1.72-34.41). Following stratification for age and sex, the trends remained analogous to the main findings across all three populations. Although a positive association between initiating methylphenidate and the onset of myocardial infarction was observed, the risk was the highest in the period before its initiation. Thus, this multinational study suggests there was no causal relationship between methylphenidate and myocardial infarction among Asians.

POS0225 RISK OF MAJOR CARDIOVASCULAR EVENT ACROSS JAK INHIBITOR TREATED PATIENTS: ANALYSIS OF A NATIONAL CLAIM DATABASE

Background:Inhibiting a specific JAK may impede more than one pathway, explaining both the efficacy and adverse effects observed with JAK inhibitors (JAKi). Among those, there have been recent concerns about potential thromboembolic risks with these drugs. As patients enrolled are not representative of all patients who may receive JAKi, data from trials are unlikely to provide definitive answers. Real impact of JAKi in real life on major cardiovascular events is not known.Objectives:To evaluate the risk of venous and arterial thromboembolic events with the use of JAKi in a real-world setting.Methods:A self-controlled case series analysis (method in which individuals act as their own control) was performed using data from the French national healthcare insurance system SNDS (“Système National des Données de Santé”), which included all anonymized individual level data about sociodemographic data, outpatient healthcare dispensed, hospital discharge summaries, and registration status for a list of 30 long term diseases. All patients treated by JAKi (baricitinib or tofacitinib) for rheumatoid arthritis, psoriasis arthritis and/or inflammatory bowel disease, and with at least one thromboembolic event (venous (VTE): deep vein thrombosis (DVT), pulmonary embolism (PE), arterial (ATE): acute coronary syndrome (ACS), myocardial infarction (MI), transient ischemic attack (TIA) and stroke) between 2017/11/01 and 2019/06/30 were included in the study. Associations were evaluated by incidence rate ratios (IRR), which compare the rate of events during exposed periods with rate of event during all other observed time periods. Exposed periods were defined as i) exposure to JAKi, ii) the month following exposure (post-exposure 1-30 days), and iii) long-term post-exposure (31 to 60 days). A pre-exposure period of 7 days was individualized to identify event-dependent probabilities of exposure and potential reverse causality bias, and all other periods were considered as non-exposed periods.Results:Among the 5,870 patients treated with JAKi between 2017/11/01 and 2019/06/30, 94 presented an incident thromboembolic event and were included. Almost two thirds were female (n=61, 64.9%), and median age was 65.4 [IQR: 55.5; 75.8] years. Most of patients have a rheumatoid arthritis (n=91, 96.8%), 62 (66.0%) were treated by baricitinib, and 32 (34.0%) by tofacitinib. Almost half (n=42, 44.7%) presented a venous thromboembolism, mainly DVT (n=31, 33.0%), and 52 (55.3%) presented an arterial thromboembolism, mainly MI (n=16, 17.0%) and stroke (n=14, 14.9%). Eleven patients (11.7%) died during the study period. The median time of occurrence of VTE was 4.3 [IQR: 2.5; 8.9] months, and 6.1 [IQR: 3.3; 9.2] months for ATE.The median duration of exposure was 6.0 [IQR: 3.3; 10.1] months for VTE, and 12.0 [IQR: 4.8; 15.3] months for ATE. The IRR for VTE and ATE were increased during exposure, and during the 30 days following exposure (Table 1). The IRR for VTE was only increased during exposure and in the early post-exposure phase contrary to the IRR for ATE that was also increased in the pre-exposure 7-Day period. Analysis conducted on survival patients confirmed results.Table 1.NPatient-yearsIRR95%CIVenous thromboembolic eventsNon-exposure (reference)83975.01-Pre-exposure to JAK-i1135.24.70.6-38.0Exposure to JAK-i272090.59.84.1-23.3Post-exposure 1-30 d5369.06.21.9-19.9Post-exposure 31-60 d1139.01.50.2-12.6Arterial thromboembolic eventsNon-exposure (reference)74076.81-Pre-exposure to JAK-i3344.111.52.8-46.8Exposure to JAK-i326363.87.42.9-18.7Post-exposure 1-30 d8659.211.53.8-34.6Post-exposure 31-60 d2132.24.30.8-22.0Conclusion:The present study found an increased risk of VTE and ATE for baricitinib and tofacitinib. The risk persists in the month following the discontinuation of treatment but disappears after day 30 post-exposure.Disclosure of Interests:Amandine Gouverneur: None declared, Jérôme Avouac Consultant of: JA has/had consultancy relationship and/or has received research funding in the area of potential treatments for rheumatoid arthritis from (last three years): Abbvie, Galapagos, Pfizer, Bristol Myers Squibb, Sanofi, Nordic Pharma, Chugai and MSD., Grant/research support from: JA has/had consultancy relationship and/or has received research funding in the area of potential treatments for rheumatoid arthritis from (last three years): Abbvie, Galapagos, Pfizer, Bristol Myers Squibb, Sanofi, Nordic Pharma, Chugai and MSD., Clément Prati: None declared, Jean-Luc Cracowski: None declared, Thierry Schaeverbeke Consultant of: TS consultancy and/or research fundings: Abbvie, Lilly, Pfizer, Galapagos, Novartis, BMS, Medac, NordicPharma, Biogen, Mylan, Janssen., Grant/research support from: TS consultancy and/or research fundings: Abbvie, Lilly, Pfizer, Galapagos, Novartis, BMS, Medac, NordicPharma, Biogen, Mylan, Janssen., Antoine Pariente Grant/research support from: AP reports acting as an independant expert towards the French Medicines Agency (Agence Nationale de Securité du Médicament et des Produits de Santé, ANSM) and the European Medicines Agency (EMA). AP coordinates the DRUGS Systematised Assessment in real-liFe EnviRonment (DRUGS-SAFER) programme funded by the Agence Nationale de Sécurité du Médicament et des Produits de Santé (ANSM)., Marie-Elise Truchetet Consultant of: has/had consultancy relationship and/or has received research funding in the area of potential treatments for rheumatoid arthritis and spondyloarthritis and their complications from (last three years): Abbvie, Galapagos, Lilly, Medac, Novartis, Pfizer, and Roche., Grant/research support from: has/had consultancy relationship and/or has received research funding in the area of potential treatments for rheumatoid arthritis and spondyloarthritis and their complications from (last three years): Abbvie, Galapagos, Lilly, Medac, Novartis, Pfizer, and Roche.

Rabies vaccination and multiple sclerosis relapse: A retrospective cohort study

BackgroundNo studies assessing rabies vaccine (RV) tolerability in persons with multiple sclerosis (MS) have been conducted. Given the lack of safety data, RV is recommended essentially only for post-exposure prophylaxis, which is difficult to administer effectively in many rabies-endemic countries. We sought to determine whether RV administration as pre-exposure prophylaxis was associated with MS relapse. MethodsThis retrospective cohort study compared the clinical courses of MS patients in the year before and after rabies vaccination. The year before vaccination was defined as the pre-exposure risk period, the three months thereafter as the exposure-risk period, and the following nine months as the post-risk period. All adult MS patients immunized with RV between 2014 and 2018 and with available medical records in the two-year window were included. The primary outcome was the incidence of symptomatic MS relapse in the exposure-risk period versus the pre-exposure period. ResultsFifty-five patients received at least one dose of RV. Most (38/55, 69%) were female; mean age was 38.5 years (SD ±9.2). While 21 (38%) patients experienced 24 relapses in the year before vaccination, only three (5%) experienced one relapse each in the post-vaccination exposure-risk period; three others (5%) experienced a total of four relapses in the subsequent post-risk period. The annualized relapse rates in the pre-exposure, exposure-risk, and post-risk periods were 0.44, 0.22, and 0.10, respectively (rate ratio for exposure-risk to pre-exposure periods, 0.509 [95% CI 0.098–1.677]). ConclusionsIn this cohort, rabies vaccination was not associated with clinical MS relapse. Larger, prospective studies are needed to confirm these results.

Tolerance of three fungal species to lithium and cobalt: Implications for bioleaching of spent rechargeable Li-ion batteries.

This paper aims to quantify the growth and organic acid production of Aspergillus niger, Penicillium chrysogenum and Penicillium simplicissimum when these fungi are exposed to varying levels of lithium (Li) and cobalt (Co). The study also tests whether pre-exposing the fungi to these metals enables the fungi to develop tolerance to Li or Co. When cultures of A. niger, P. chrysogenum or P. simplicissimum were exposed to 250mgl-1 of Li or Co, biomass production and excretion of organic acids were significantly inhibited after 5days of growth compared to cultures grown in the absence of these metals. Pre-exposing cultures of A. niger to 250mgl-1 of Li or Co for 20days significantly increased biomass production when the fungus was subsequently sub-cultured into 250 or 500mgl-1 of Li or Co. However, pre-exposure of P. chrysogenum or P. simplicissimum to 250mgl-1 of Li or Co for 20days did not increase biomass production. Aspergillus niger, but not the Penicillium species, developed tolerance to Li and to Co during the 20-day pre-exposure period. Therefore, processes that utilize fungal bioleaching with A. niger to mobilize and recover valuable metals such as Li or Co should consider a pre-exposure step for fungi to improve their tolerance to metal toxicity. Fungi may have the ability to extract valuable metals such as Li and Co from spent rechargeable batteries. However, the toxicity of the extracted metals can inhibit fungal growth and organic acid production. Pre-exposure to metals may alleviate toxicity for some fungal species. This knowledge can be used to improve the design of bioleaching protocols, increasing the potential for fungal bioleaching to become an economical and environmentally friendly method of recovering Li and Co from spent batteries.