Neurocognitive Disorders Associated with PCSK9 Inhibitors: a Pharmacovigilance Disproportionality Analysis.

PURPOSE: PCSK9 might affect central nervous system development, neuronal apoptosis, and differentiation. We investigate the neurocognitive adverse events associated with the use of PCSK9 inhibitors (alirocumab and evolocumab) using pharmacovigilance reports. METHODS: We used the World Health Organization pharmacovigilance database (VigiBase) to perform a disproportionality analysis comparing the proportion of neurocognitive adverse events reported with PCSK9 inhibitors versus the proportion of these effects reported since August 14, 2015 (date of first post-marketing report suspecting a PCSK9 inhibitor), for all drugs in the database. Associations between PCSK9 inhibitor use and neurocognitive adverse events were assessed using both proportional reporting ratio (PRR) and information component (IC). Complementary analyses were performed on other neurologic events, and different sensitivity analyses were conducted to evaluate the robustness of results. RESULTS: Among the 81,108 reports involving at least one PCSK9 inhibitor, 1,941 concerned the occurrence of neurocognitive disorders. Most of patients (52.3%) were aged 45-74 years, and 58.0% were women. Signals of disproportionate reporting were found for PCSK9 inhibitors (PRR 1.22, 95% CI 1.17; 1.28; IC 0.28, IC025 0.21) and for each drug individually. No signal of disproportionality was found for any of the other neurologic events investigated. Signals of disproportionate reporting were found for the positive control (benzodiazepines), but not for the negative control (aspirin). The results of the main analysis were confirmed by sensitivity analyses. CONCLUSIONS: This study identified a signal of neurocognitive disorders associated with PCSK9 inhibitors and encourages paying attention to at-risk populations.

Sweet-like syndrome and multiple COVID arm syndrome following COVID-19 vaccines: 'specific' patterns in a series of 192 patients.

The two clinico-pathological patterns are 'Sweet-like syndrome' and 'Multiple COVID-Arm'. 'Sweet-like syndrome' presents clinically as erythematous and oedematous papules or plaques, sometimes developing vesiculation or bullae. Histology shows classical Sweet syndrome with a diffuse dermal neutrophilic infiltrate, or an infiltrate of histiocyte-like immature myeloid cells consistent with a histiocytoid Sweet syndrome. 'Multiple COVID-arm' is characterized by multiple large inflammatory plaques with histological analyses showing a perivascular and interstitial inflammatory infiltrate with eosinophils.

Peripheral neuropathies after BRAF and/or MEK inhibitor treatment: A pharmacovigilance study.

Reports suggested the potential occurrence of peripheral neuropathies (PN) in patients treated with BRAF (BRAFi) and/or MEK inhibitors (MEKi) for BRAF-activated tumours. We aimed to better characterize these PN. We queried the French pharmacovigilance database for all cases of PN attributed to BRAFi and/or MEKi. Fifteen patients were identified. Two main clinical PN phenotypes were seen. Six patients presented a length-dependent, axonal polyneuropathy: symptoms were mostly sensory and affecting the lower limbs; management and outcome were variable. Nine patients developed a demyelinating polyradiculoneuropathy: symptoms affected the four limbs and included hypoesthesia, weakness and ataxia; cranial nerves were involved in four cases; most patients received intravenous immunoglobulins or glucocorticoids, with variable outcome; one patient was rechallenged with a different BRAFi/MEKi combination with a rapid relapse in symptoms. In conclusion, patients under BRAFi/MEKi therapy may develop treatment-induced PN. Two main phenotypes can occur: a symmetric, axonal, length-dependent polyneuropathy and a demyelinating polyradiculoneuropathy.

Ten-year trend of opioid and nonopioid analgesic use in the French adult population.

AIMS: Analgesics are the most widely used medicines worldwide. In parallel, opioid abuse has increased and is of major concern. The accessibility of pharmacologically powerful medicines and the addictovigilance signals in France about the risk of opiates addiction call for an overview of analgesic use. The objective of this study was to investigate the use of analgesics reimbursed in France over a 10-year period through its prevalence. METHODS: A cross-sectional study repeated yearly was conducted by using data from the French reimbursement database from 2006 to 2015. Analgesics were classified according to their pharmacological potency: prevalence of use for each category and sociodemographic characteristics of patients treated were analysed. RESULTS: The annual prevalence of analgesic use was high and increased during the study period (59.8%, 253 976 users in 2015). In 2015, prevalence was always higher in women and increased with age, except for those older than 84 years. Peripheral analgesics were the most used (55.3%, 234 739 users). The prevalence of weak analgesic use decreased (21.3%, 90 257 users), mainly due to the definitive withdrawal of dextropropoxyphene in France in 2011, which was not offset by an increase in the consumption of other weak analgesics. For strong analgesics (1.2%, 5129 users), morphine was the most widely used, with a dramatic increase in oxycodone use, especially in the elderly. CONCLUSION: The prevalence of analgesic use is high: approximately 31 million adults had at least 1 analgesic reimbursed in 2015. The most widely used analgesics were peripheral analgesics, far ahead of opioid analgesics.

Maternal Sensitivity and Child Secure Base Use in Early Childhood: Studies in Different Cultural Contexts.

This study tested whether maternal sensitivity and child security are related during early childhood and whether such an association is found in different cultural and social contexts. Mother-child dyads (N = 237) from four different countries (Colombia, Mexico, Peru, and the United States) were observed in naturalistic settings when children were between 36 and 72 months of age. Maternal and child behavior during interactions at home and in the playground were described using Q methodology. Findings reveal that across cultures, concurrent maternal sensitivity and more specific behavioral domains of maternal care (e.g., contributions to harmonious interactions and secure base support) are important for children's attachment security during early childhood. Implications for the study of attachment relationships beyond infancy and in diverse contexts are highlighted.

Cutaneous adverse drug reactions.

Cutaneous adverse drug reactions (ADRs) represent a heterogeneous field including various clinical patterns without specific features suggesting drug causality. Maculopapular exanthema and urticaria are the most common types of cutaneous ADR. Serious cutaneous ADRs, which may cause permanent sequelae or have fatal outcome, may represent 2% of all cutaneous ADR and must be quickly identified to guide their management. These serious reactions include bullous manifestations (epidermal necrolysis i.e. Stevens-Johnson syndrome and toxic epidermal necrolysis), drug reaction with eosinophilia and systemic symptoms (DRESS) and acute generalized exanthematous pustulosis (AGEP). Some risk factors for developing cutaneous ADRs have been identified, including immunosuppression, autoimmunity or genetic variants. All drugs can cause cutaneous ADRs, the most commonly implicated being antibiotics (especially aminopenicillins and sulfonamides), anticonvulsants, allopurinol, antineoplastic drugs, non-steroidal anti-inflammatory drugs and iodinated contrast media. Pathophysiology is related to immediate or delayed "idiosyncratic" immunologic mechanisms, i.e., usually not related to dose, and pharmacologic/toxic mechanisms, commonly dose-dependent and/or time-dependent. If an immuno-allergic mechanism is suspected, allergological explorations (including epicutaneous patch testing and/or intradermal test) are often possible to clarify drug causality, however these have a variable sensitivity according to the drug and to the ADR type. No in vivo or in vitro test can consistently confirm the drug causality. To determine the origin of a rash, a logical approach based on clinical characteristics, chronologic factors and elimination of differential diagnosis (especially infectious etiologies) is required, completed with a literature search. Reporting to pharmacovigilance system is therefore essential both to analyze drug causality at individual level, and to contribute to knowledge of the drug at population level, especially for serious cutaneous ADRs or in cases involving newly marketed drugs.

Is the secure base phenomenon evident here, there, and anywhere? A cross-cultural study of child behavior and experts' definitions.

The evolutionary rationale offered by Bowlby implies that secure base relationships are common in child-caregiver dyads and thus, child secure behavior observable across diverse social contexts and cultures. This study offers a test of the universality hypothesis. Trained observers in nine countries used the Attachment Q-set to describe the organization of children's behavior in naturalistic settings. Children (N = 547) were 10-72 months old. Child development experts (N = 81) from all countries provided definitions of optimal child secure base use. Findings indicate that children from all countries use their mother as a secure base. Children's organization of secure base behavior was modestly related to each other both within and across countries. Experts' descriptions of the optimally attached child were highly similar across cultures.

Data on terrestrial ferns species richness, abundance, and functional traits in Mashpi Rainforest Biodiversity Reserve in the Ecuadorian Chocó.

This data paper summarizes the data of a first survey of terrestrial ferns at Mashpi Biodiversity Reserve, an Ecuadorian Chocó forest relict, one of the most biodiverse areas in the world. We established 10 permanent plots of 400 m2 distributed in two elevational levels (800 and 1000 m a.s.l.) to register all species per plot and the abundance per species. In addition, we measured two morphological leaf functional traits of the species. We include a file with three tables, the first one includes a species list with scientific names and vouchers. The second one includes the abundance of each species per plot. The third one contains measurements of the leaf length and leaf thickness of several leaf samples of 28 species, representing the leaf functional traits of the species. This article also includes a table with coordinates and elevations of the plots and five figures with information about the number of genus and species per family, geographic location of plots and, the methodology for data collection. These data can be useful for plant ecologists to assess future changes of fern species composition and leaf functional traits of ferns caused by climate change and other threats at the study area.

French pharmacovigilance survey of casirivimab - imdevimab monoclonal antibodies in coronavirus disease (COVID-19).

INTRODUCTION: Casirivimab and imdevimab (Ronapreve®) are two recombinant human monoclonal antibodies (mAbs) that bind to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein, preventing the virus from entering cells. In March 2021, this drug was granted emergency use authorisation (EUA) in France for early treatment of COVID-19 in patients at increased risk of progression to severe COVID-19. In August/September 2021, the indication was expanded to COVID-19 prevention (pre- or post-exposure prophylaxis) and treatment of hospitalised patients requiring non-invasive oxygen therapy. The aim of the study was to better describe the adverse drug reaction (ADR) profile and detect safety signals of this new drug used in COVID-19 treatment. METHODS: We described ADR profile with casirivimab/imdevimab reported as suspect/interacting drug to the French pharmacovigilance network and the pharmaceutical company between 17/03/2021 and 30/06/2022. Data presented correspond to the 2 periods of the pharmacovigilance survey: the first carried out by the pharmaceutical company for curative and prophylactic uses and the second by Toulouse university regional pharmacovigilance center (RPVC). RESULTS: A total of 384 reports were analysed and 256 were "serious". ADR profile was comparable between the 2 periods and between curative and prophylactic use, corresponding to expected ADRs such as infusion-related reactions and hypersensitivity, inefficiencies or worsened infections and deaths. Two potential pharmacovigilance signals were also studied: acute pulmonary oedemas and sudden deaths. DISCUSSION: No pharmacovigilance signal emerged from this 15 months French pharmacovigilance survey. Moreover data from published studies are also reassuring. This pharmacovigilance survey was the first one for the new version of EUA and with a new ADR reporting process i.e. declaration to the RPVC instead of the pharmaceutical company. Casirivimab/imdevimab is no longer used in France today but we continue to monitor this drug for any future evidence of resurgent activity on a new variant of Sars-CoV-2.

Drug reactions with eosinophilia and systemic symptoms induced by immune checkpoint inhibitors: an international cohort of 13 cases.

Among dermatologic adverse events induced by immune checkpoint inhibitors (ICI), drug reactions with eosinophilia and systemic symptoms (DRESS) have been very rarely reported. The objective of this study is to better define the clinical and histologic features, treatment and prognosis of ICI-related DRESS. This retrospective case series was conducted between 01 January 2015 and 31 December 2021 by the dermatology departments of five international networks involved in drug reactions. Inclusion criteria were age ≥18 years old, DRESS with Regiscar score ≥4 (probable or certain) and ICI as a suspect drug. Clinical, biologic and follow-up data were extracted from the medical charts. Thirteen patients were included. The median time to onset was 22 days (3-11). No patients had a high-risk drug introduced in the past 3 months. A majority of patients presented fever (92%), diffuse exanthema (77%) and facial edema (69%). Biologic features included hypereosinophilia in eight patients (61.5%), hyperlymphocytosis in 3 (23%), elevated liver function tests in 11 (85%, grade 1 or 2 in most cases) and renal involvement in 5 (38%). Two patients (15%) had lung involvement. PCR evidence of viral replication was detected in five patients (38.5%). Treatment involved discontinuation of the suspect ICI and systemic steroids with variable dose and duration regimens. Among the four patients in which ipilimumab + nivolumab combination therapy was initially suspected, one was rechallenged with nivolumab monotherapy with good tolerance. Five patients were switched to another anti-PD-1 plus low-dose systemic steroids, with good tolerance in four cases. No patient died because of DRESS. DRESS induced by ICI are rare and of moderate severity. A consensus for management is still pending.

Atorvastatin decreases computed tomography and S100-assessed brain ischemia after subarachnoid aneurysmal hemorrhage: a comparative study.

OBJECTIVE: Statins, which improve the bioavailability of endogenous nitric oxide and upregulate endothelial nitric oxide synthase, have been used to prevent cerebral vasospasm after aneurysmal subarachnoid hemorrhage. The objective of this study was to determine whether statin therapy diminished vasospasm-induced ischemia as assessed using daily measurements of serum S100B, a biomarker for cerebral ischemia, and computed tomography measurement of ischemic lesion volume. DESIGN: Single-center study of cases and historical controls. SETTING: Neurointensive care unit in a university hospital. PATIENTS: Consecutive patients with aneurysmal subarachnoid hemorrhage treated with clipping or coiling within 96 hrs of symptom onset (n = 278) were included from April 2004 to October 2007. INTERVENTION: Oral atorvastatin, 40 mg/day for 21 days, was used routinely starting on December 1, 2005, in 142 patients, who were compared with the 136 patients managed earlier. MEASUREMENTS AND MAIN RESULTS: Ischemic lesion size was measured using computed tomography on the last available scan and serum S100B was assayed daily for 15 days after admission. Angiographic narrowing was semiquantitatively assessed in patients with vasospasm. In the overall population, cerebral vasospasm was significantly less common in the statin-treated group. Severity of vasospasm, as assessed on the most severe angiogram, was lowered with statin. Statins significantly reduced volume of ischemia in patients with vasospasm and an uncomplicated coiling procedure. S100B levels were significantly lower in statin-treated patients, and the decrease was greatest among high-grade patients (World Federation of Neurological Surgeons 3-5). No differences were found between statin-treated and untreated groups regarding rescue therapy intensity or 1-yr clinical outcomes. CONCLUSIONS: Atorvastatin reduces the incidence, the severity and the ischemic consequences of vasospasm as assessed on computed tomography. In high-grade World Federation of Neurological Surgeons patients, atorvastatin decreases serum levels of S100B, a biomarker of brain ischemia. Despite these positive effects on biomarkers, no improvement of outcome was seen in the overall population, although there was a tendency for a better clinical outcome in high-grade patients.

Comparative study of the adverse event profile of hydroxychloroquine before and during the Sars-CoV2 pandemic.

AIMS: At the beginning of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, there were no clinically-tested medications for the effective treatment of coronavirus disease. In this context, on 5 March 2020, the French Public Health Council issued several recommendations for the therapeutic management of this new disease, including the use of hydroxychloroquine (HCQ). An unexpected cardiovascular safety signal was quickly identified as being more frequent than expected thanks to the reports of adverse drug reactions (ADRs) submitted to French regional pharmacovigilance centres (RPVC). The objective of this study was to compare all ADRs reported with HCQ used in its usual indication, collected before the pandemic period (1985 to 31 December, 2019) with those reported with the coronavirus disease 2019 (COVID-19) indication (1 January to 21 July, 2020). METHODS: For this purpose, reports were extracted from the French pharmacovigilance database and analysed for these two periods. RESULTS: Our study showed a different safety profile in COVID-19 patients with more cardiac disorders (57% of ADRs versus 5% before the pandemic period), especially QT interval prolongation, resulting from an interaction with azithromycin in more than 20% of cases. Hepatobiliary disorders were also significantly more frequent. CONCLUSIONS: These observations could be associated with the effect of the virus itself on the various organs, the profile of the patients treated, and concomitant drug treatments.

Calcium channel blocker exposure and psoriasis risk: Pharmacovigilance investigation and literature data.

INTRODUCTION: Evidence regarding a possible association between psoriatic manifestations and use of calcium channel blockers (CCBs) is sparse. Currently, psoriatic manifestations are not listed in the summary of product characteristics (SmPC) of CCBs. In this context, we aimed to investigate the association between psoriasis and CCB exposure. METHODS: We reviewed spontaneous reports recorded in the French national pharmacovigilance database (FPVD) between 1985 and 2019. The association between CCB exposure and risk of psoriasis was assessed using the case/non-case method. We also analyzed literature data. RESULTS: Ninety-four reports of psoriatic manifestations after CCB exposure were recorded in the FPVD. Both induction and exacerbation cases were observed. Time to onset was less than 2 years in 64% of reports and outcome was favorable in 71% of reports after CCB discontinuation. These features were concordant with those of literature reports. The reporting odds ratio (ROR) was 2.45 (95% CI 1.99-3.02). Concomitant use of betablockers or angiotensin II receptor blockers did not interact with the association between CCB exposure and psoriasis risk. The ROR for the stratum "use of angiotensin converting enzyme inhibitors" (ACEI) was 2.14 (95% CI 1.29-3.55), while the ROR for the stratum ACEI non-use was 0.12 (95% CI 0.10-0.15). Large-scale epidemiologic studies were focused only on first diagnoses and did not include exacerbations; psoriasis risk was therefore probably underestimated. CONCLUSION: We found a statistically significant association between CCB exposure and psoriasis risk, which constitutes a safety signal. This risk is a class effect, time to onset is mostly less than 2 years and outcome is favorable after CCB discontinuation. Psoriasis should be mentioned in the SmPCs of all CCBs, and healthcare workers should be aware of this risk. Attention should be paid to patients taking CCB and ACEI concomitantly.

Liquid formulation of ifosfamide increased risk of encephalopathy: A case-control study in a pediatric population.

BACKGROUND: Several clusters of encephalopathy occurred after the market change from Holoxan® (ifosfamide lyophilized powder) to Ifosfamide EG® (liquid formulation) and justified a formal survey in 2015. In June 2016, the regulatory authority decided to apply a precautionary measure in reducing the shelf life of Ifosfamide EG® at 7 months. One-year study from spontaneous reports lead to suspect a potential residual risk. Due to the many limitations associated with spontaneous notifications, we performed a multicentric observational study, aiming to better explore this pharmacovigilance signal. METHODS: We performed a case-control study in pediatric oncology Departments of 25 university hospitals between July 1st, 2016 and July 1st, 2018. All children (<18 y.o.) receiving liquid formulation or lyophilized powder formulation during the study period were included. Patients with at least one occurrence of encephalopathy were considered as cases. Logistic regression model was used to estimate the odds ratio of encephalopathy between exposure groups. RESULTS: During the study period, 52 cases and 495 controls were included. A residual over-risk of encephalopathy was associated with ifosfamide 7-month shelf-life liquid formulation compared to lyophilized powder (adjusted OR 1.91, 95% CI: 1.03-3.53). CONCLUSIONS: Observed difference does not seem to be related to the pathology treated, the doses used, the co-medications, a meningeal localization and/or an irradiation of the central nervous system. This study confirms data from spontaneous reports that led to the precautionary measure for the liquid formulation. Even if the risk of encephalopathy seems reduced, our study suggests the persistence of a residual risk of encephalopathy associated with liquid formulation compared to the lyophilized powder.

Experience of diffusion tensor imaging and 1H spectroscopy for outcome prediction in severe traumatic brain injury: Preliminary results.

OBJECTIVE: The objective of the study is to test whether multimodal magnetic resonance imaging can provide a reliable outcome prediction of the clinical status, focusing on consciousness at 1 year after severe traumatic brain injury (TBI). DESIGN: Single center prospective cohort with consecutive inclusions. SETTING: Critical Care Neurosurgical Unit of a university hospital. PATIENTS: Forty-three TBI patients not responding to simple orders after sedation cessation and 15 healthy controls. INTERVENTIONS: A multimodal magnetic resonance imaging combining morphologic sequences, diffusion tensor imaging (DTI), and H proton magnetic resonance spectroscopy (MRS) was performed 24 +/- 11 days after severe TBI. The ability of DTI and MRS to predict 1-year outcome was assessed by linear discriminant analysis (LDA). Robustness of the classification was tested using a bootstrap procedure. MEASUREMENTS AND MAIN RESULTS: Fractional anisotropy (FA) was computed as the mean of values at discrete brain sites in the infratentorial and supratentorial regions. The N-acetyl aspartate/creatine (NAA/Cr) ratio was measured in the thalamus, lenticular nucleus, insular cortex, occipital periventricular white matter, and pons. After 1 year, 19 (44%) patients had unfavorable outcomes (death, persistent vegetative state, or minimally conscious state) and 24 (56%) favorable outcomes (normal consciousness with or without functional impairments). Analysis of variance was performed to compare FA and NAA/Cr in the two outcome groups and controls. FA and MRS findings showed highly significant differences between the outcome groups, with significant variables by LDA being supratentorial FA, NAA/Cr (pons), NAA/Cr (thalamus), NAA/Cr (insula), and infratentorial FA. LDA of combined FA and MRS data clearly separated the unfavorable outcome, favorable outcome, and control groups, with no overlap. Unfavorable outcome was predicted with up to 86% sensitivity and 97% specificity; these values were better than those obtained with DTI or MRS alone. CONCLUSION: FA and NAA/Cr hold potential as quantitative outcome-prediction tools at the subacute phase of TBI.

S100B as an additional prognostic marker in subarachnoid aneurysmal hemorrhage.

OBJECTIVES: Studies of new neuroprotective approaches in patients with subarachnoid aneurysmal hemorrhage and better family information would benefit from the development of laboratory markers of brain ischemia. The goal of this study was to evaluate mean 15-day S100B for predicting outcomes after subarachnoid aneurysmal hemorrhage. DESIGN: Single center prospective cohort with consecutive inclusions. SETTING: Anesthesiology and Critical Care Neurosurgical Unit of a university hospital. PATIENTS: One hundred nine patients admitted within 48 hrs after subarachnoid aneurysmal hemorrhage onset and treated by surgical clipping or coiling within 48 hrs following admission. INTERVENTIONS: We recorded initial World Federation of Neurologic Surgeons and Fisher grades; comorbidities; initial severity; aneurysm location; presence of acute hydrocephalus; presence of intraventricular hemorrhage; initial seizures and neurogenic lung edema; initial troponin values; treatment of aneurysm; and occurrence of vasospasm. MEASUREMENTS AND MAIN RESULTS: S100B was assayed daily over the first 15 days. Glasgow Outcome Scores were recorded at intensive care unit discharge and after 6 and 12 months. The main outcome criterion was the 12-month Glasgow Outcome Scale score dichotomized as poor (Glasgow Outcome Scale 1-3) or good (Glasgow Outcome Scale 4-5). Seventy percent of patients had good 12-month outcome. Poor outcome was associated with higher initial World Federation of Neurologic Surgeons and Fisher scores, neurogenic lung edema, high mean 15-day S100B but not initial, troponin initial value, intraventricular hemorrhage, angiographically documented vasospasm, all in an univariate manner. After multivariate analysis, only mean 15-day S100B value significantly predicted outcome (p < 0.0005). The best cutoff for the mean 15-day S100B value was 0.23 microg/L (specificity 0.90, 95% confidence interval [CI] 0.81-0.95; sensitivity 0.91, 95% CI 0.75-0.98; area under the curve 0.98, 95% CI 0.87-0.99). CONCLUSION: S100B elevation over the first 15 days after subarachnoid aneurysmal hemorrhage is associated with poor outcome after subarachnoid aneurysmal hemorrhage. This result supports the use of S100B as a surrogate marker for brain ischemia in patients with subarachnoid aneurysmal hemorrhage.