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Background Influenza immunization programs aim to reduce the risk and burden of severe outcomes. To inform optimal program strategies, we monitored influenza hospitalizations over 7 seasons, stratified by age, comorbidity, and vaccination status. Methods We assembled data from 4 hospitals involved in an active surveillance network with systematic collection of nasal samples and polymerase chain reaction testing for influenza virus in all patients admitted through the emergency department with acute respiratory infection during the 2012–2013 to 2018–2019 influenza seasons in Quebec, Canada. We estimated seasonal, population-based incidence of influenza-associated hospitalizations by subtype predominance, age, comorbidity, and vaccine status, and derived the number needed to vaccinate to prevent 1 hospitalization per stratum. Results The average seasonal incidence of influenza-associated hospitalization was 89/100 000 (95% confidence interval, 86–93), lower during A(H1N1) (49–82/100 000) than A(H3N2) seasons (73–143/100 000). Overall risk followed a J-shaped age pattern, highest among infants 0–5 months and adults ≥75 years old. Hospitalization risks were highest for children <5 years old during A(H1N1) but for highest adults aged ≥75 years during A(H3N2) seasons. Age-adjusted hospitalization risks were 7-fold higher among individuals with versus without comorbid conditions (214 vs 30/100 000, respectively). The number needed to vaccinate to prevent hospitalization was 82-fold lower for ≥75-years-olds with comorbid conditions (n = 1995), who comprised 39% of all hospitalizations, than for healthy 18–64-year-olds (n = 163 488), who comprised just 6% of all hospitalizations. Conclusions In the context of broad-based influenza immunization programs (targeted or universal), severe outcome risks should be simultaneously examined by subtype, age, comorbidity, and vaccine status. Policymakers require such detail to prioritize promotional efforts and expenditures toward the greatest and most efficient program impact. [ABSTRACT FROM AUTHOR]

Background There is a need to understand the duration of infectivity of primary and recurrent coronavirus disease 2019 (COVID-19) and identify predictors of loss of infectivity. Methods Prospective observational cohort study with serial viral culture, rapid antigen detection test (RADT) and reverse transcription polymerase chain reaction (RT-PCR) on nasopharyngeal specimens of healthcare workers with COVID-19. The primary outcome was viral culture positivity as indicative of infectivity. Predictors of loss of infectivity were determined using multivariate regression model. The performance of the US Centers for Disease Control and Prevention (CDC) criteria (fever resolution, symptom improvement, and negative RADT) to predict loss of infectivity was also investigated. Results In total, 121 participants (91 female [79.3%]; average age, 40 years) were enrolled. Most (n = 107, 88.4%) had received ≥3 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine doses, and 20 (16.5%) had COVID-19 previously. Viral culture positivity decreased from 71.9% (87/121) on day 5 of infection to 18.2% (22/121) on day 10. Participants with recurrent COVID-19 had a lower likelihood of infectivity than those with primary COVID-19 at each follow-up (day 5 odds ratio [OR], 0.14; P <.001]; day 7 OR, 0.04; P =.003]) and were all non-infective by day 10 (P =.02). Independent predictors of infectivity included prior COVID-19 (adjusted OR [aOR] on day 5, 0.005; P =.003), an RT-PCR cycle threshold [Ct] value <23 (aOR on day 5, 22.75; P <.001) but not symptom improvement or RADT result. The CDC criteria would identify 36% (24/67) of all non-infectious individuals on day 7. However, 17% (5/29) of those meeting all the criteria had a positive viral culture. Conclusions Infectivity of recurrent COVID-19 is shorter than primary infections. Loss of infectivity algorithms could be optimized. [ABSTRACT FROM AUTHOR]

Introduction During the 2022 mpox outbreak, the province of Quebec, Canada, prioritized first doses for pre-exposure vaccination of people at high mpox risk, delaying second doses due to limited supply. We estimated single-dose mpox vaccine effectiveness (VE) adjusting for virus exposure risk based only on surrogate indicators available within administrative databases (eg, clinical record of sexually transmitted infections) or supplemented by self-reported risk factor information (eg, sexual contacts). Methods We conducted a test-negative case-control study between 19 June and 24 September 2022. Information from administrative databases was supplemented by questionnaire collection of self-reported risk factors specific to the 3-week period before testing. Two study populations were assessed: all within the administrative databases (All-Admin) and the subset completing the questionnaire (Sub-Quest). Logistic regression models adjusted for age, calendar-time and exposure-risk, the latter based on administrative indicators only (All-Admin and Sub-Quest) or with questionnaire supplementation (Sub-Quest). Results There were 532 All-Admin participants, of which 199 (37%) belonged to Sub-Quest. With exposure-risk adjustment based only on administrative indicators, single-dose VE estimates were similar among All-Admin and Sub-Quest populations at 35% (95% confidence interval [CI]:−2 to 59) and 30% (95% CI:−38 to 64), respectively. With adjustment supplemented by questionnaire information, the Sub-Quest VE estimate increased to 65% (95% CI:1–87), with overlapping confidence intervals. Conclusions Using only administrative data, we estimate one vaccine dose reduced the mpox risk by about one-third; whereas, additionally adjusting for self-reported risk factor information revealed greater vaccine benefit, with one dose instead estimated to reduce the mpox risk by about two-thirds. Inadequate exposure-risk adjustment may substantially under-estimate mpox VE. [ABSTRACT FROM AUTHOR]

G-protein-gated inwardly rectifying potassium (GIRK) channels are critical determinants of neuronal excitability. They have been proposed as potential targets to restore excitatory/inhibitory balance in acute amyloidosis models, where hyperexcitability is a hallmark. However, the role of GIRK signaling in transgenic mice models of Alzheimer's disease (AD) is largely unknown. Here, we study whether progressive amyloid-β (Aβ) accumulation in the hippocampus during aging alters GIRK channel expression in mutant β-amyloid precursor protein (APPSw,Ind J9) transgenic AD mice. Additionally, we examine the impact of spatial memory training in a hippocampal-dependent task, on protein expression of GIRK subunits and Regulator of G-protein signaling 7 (RGS7) in the hippocampus of APPSw,Ind J9 mice. Firstly, we found a reduction in GIRK2 expression (the main neuronal GIRK channels subunit) in the hippocampus of 6-month-old APPSw,Ind J9 mice. Moreover, we found an aging effect on GIRK2 and GIRK3 subunits in both wild type (WT) and APPSw,Ind J9 mice. Finally, when 6-month-old animals were challenged to a spatial memory training, GIRK2 expression in the APPSw,Ind J9 mice were normalized to WT levels. Together, our results support the evidence that GIRK2 could account for the excitatory/inhibitory neurotransmission imbalance found in AD models, and training in a cognitive hippocampal dependent task may have therapeutic benefits of reversing this effect and lessen early AD deficits. [ABSTRACT FROM AUTHOR]

Synaptic plasticity is a cellular process involved in learning and memory by which specific patterns of neural activity adapt the synaptic strength and efficacy of the synaptic transmission. Its induction is governed by fine tuning between excitatory/inhibitory synaptic transmission. In experimental conditions, synaptic plasticity can be artificially evoked at hippocampal CA1 pyramidal neurons by repeated stimulation of Schaffer collaterals. However, long-lasting synaptic modifications studies during memory formation in physiological conditions in freely moving animals are very scarce. Here, to study synaptic plasticity phenomena during recognition memory in the dorsal hippocampus, field postsynaptic potentials (fPSPs) evoked at the CA3–CA1 synapse were recorded in freely moving mice during object-recognition task performance. Paired pulse stimuli were applied to Schaffer collaterals at the moment that the animal explored a new or a familiar object along different phases of the test. Stimulation evoked a complex synaptic response composed of an ionotropic excitatory glutamatergic fEPSP, followed by two inhibitory responses, an ionotropic, GABAA-mediated fIPSP and a metabotropic, G-protein-gated inwardly rectifying potassium (GirK) channel-mediated fIPSP. Our data showed the induction of LTP-like enhancements for both the glutamatergic and GirK-dependent components of the dorsal hippocampal CA3–CA1 synapse during the exploration of novel but not familiar objects. These results support the contention that synaptic plasticity processes that underlie hippocampal-dependent memory are sustained by fine tuning mechanisms that control excitatory and inhibitory neurotransmission balance. [ABSTRACT FROM AUTHOR]

Background The prevalence of post-COVID conditions (PCC) and associated physical, psychological, and cognitive symptoms was assessed among Quebec healthcare workers (HCWs) with coronavirus disease 2019 (COVID-19). Methods This case-control study compared 6061 symptomatic HCWs with polymerase chain reaction–confirmed COVID-19 between July 2020 and May 2021 with a random sample of 4390 symptomatic HCWs who were test-negative controls. The prevalence of physical symptoms lasting ≥4 weeks (PCC4w) or ≥12 weeks (PCC12w) was estimated among hospitalized and nonhospitalized cases. In multivariate models, sociodemographic and clinical characteristics, as well as vaccine history, were evaluated as potential risk factors. Prevalence ratios compared 4 aspects of self-reported cognitive dysfunction among PCC cases to controls, adjusting for psychological distress and fatigue. Results PCC4w and PCC12w prevalences of 46% (2746/5943) and 40% (653/1746), respectively, were observed among nonhospitalized cases and 76% (90/118) and 68% (27/37), respectively, among hospitalized cases. Hospitalization, female sex, and age were associated with higher PCC risk. A substantial proportion of nonhospitalized PCC4w cases often or very often reported cognitive dysfunction, including concentration (33%) or organizing (23%) difficulties, forgetfulness (20%), and loss of necessary items (10%). All 4 aspects of cognitive dysfunction were associated with PCC4w symptoms, psychological distress, and fatigue. Conclusions PCC may be a frequent sequela of ambulatory COVID-19 in working-age adults, with important effects on cognition. With so many HCWs infected, the implications for quality healthcare delivery could be profound if cognitive dysfunction and other severe PCC symptoms persist in a professionally disabling way. Further evaluation of PCC prevalence and prognosis is warranted. [ABSTRACT FROM AUTHOR]

Background In Canada, first and second doses of messenger RNA (mRNA) vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) were uniquely spaced 16 weeks apart. We estimated 1- and 2-dose mRNA vaccine effectiveness (VE) among healthcare workers (HCWs) in Québec, Canada, including protection against varying outcome severity, variants of concern (VOCs), and the stability of single-dose protection up to 16 weeks postvaccination. Methods A test-negative design compared vaccination among SARS-CoV-2 test–positive and weekly matched (10:1), randomly sampled, test-negative HCWs using linked surveillance and immunization databases. Vaccine status was defined by 1 dose ≥14 days or 2 doses ≥7 days before illness onset or specimen collection. Adjusted VE was estimated by conditional logistic regression. Results Primary analysis included 5316 cases and 53 160 controls. Single-dose VE was 70% (95% confidence interval [CI], 68%–73%) against SARS-CoV-2 infection; 73% (95% CI, 71%–75%) against illness; and 97% (95% CI, 92%–99%) against hospitalization. Two-dose VE was 86% (95% CI, 81%–90%) and 93% (95% CI, 89%–95%), respectively, with no hospitalizations. VE was higher for non-VOCs than VOCs (73% Alpha) among single-dose recipients but not 2-dose recipients. Across 16 weeks, no decline in single-dose VE was observed, with appropriate stratification based upon prioritized vaccination determined by higher vs lower likelihood of direct patient contact. Conclusions One mRNA vaccine dose provided substantial and sustained protection to HCWs extending at least 4 months postvaccination. In circumstances of vaccine shortage, delaying the second dose may be a pertinent public health strategy. [ABSTRACT FROM AUTHOR]

Olfactory and gustatory dysfunctions (OD, GD) are prevalent symptoms following COVID-19 and persist in 6%–44% of individuals post-infection. As only few reports have described their prognosis after 6 months, our main objective was to assess the prevalence of OD and GD 11-month post-COVID-19. We also aimed to determine intraclass correlation coefficients (ICC) of chemosensory self-ratings for the follow-up of chemosensory sensitivity. We designed an observational study and distributed an online questionnaire assessing chemosensory function to healthcare workers with a RT-PCR-confirmed SARS-CoV-2 infection 5- and 11-month post-COVID-19. Specifically, we assessed olfaction, gustation, and trigeminal sensitivity (10-point visual analog scale) and function (4-point Likert scale). We further measured clinically relevant OD using the Chemosensory Perception Test, a psychophysical test designed to provide a reliable remote olfactory evaluation. We included a total of 366 participants (mean [SD] age of 44.8 (11.7) years old). They completed the last online questionnaire 10.6 months (0.7) after the onset of COVID-19 symptoms. Of all participants, 307 (83.9%) and 301 (82.2%) individuals retrospectively reported lower olfactory or gustatory sensitivity during the acute phase of COVID-19. At the time of evaluation, 184 (50.3%) and 163 (44.5%) indicated reduced chemosensory sensitivity, 32.2% reported impairment of olfactory function while 24.9% exhibited clinically relevant OD. Olfactory sensitivity had a high test–retest reliability (ICC: 0.818; 95% CI: 0.760–0.860). This study suggests that chemosensory dysfunctions persist in a third of COVID-19 patients 11 months after COVID-19. OD appears to be a common symptom of post-COVID-19 important to consider when treating patients. [ABSTRACT FROM AUTHOR]

Background Ebola virus disease (EVD) is a highly lethal condition for which no specific treatment has proven efficacy. In September 2014, while the Ebola outbreak was at its peak, the World Health Organization released a short list of drugs suitable for EVD research. Favipiravir, an antiviral developed for the treatment of severe influenza, was one of these. In late 2014, the conditions for starting a randomized Ebola trial were not fulfilled for two reasons. One was the perception that, given the high number of patients presenting simultaneously and the very high mortality rate of the disease, it was ethically unacceptable to allocate patients from within the same family or village to receive or not receive an experimental drug, using a randomization process impossible to understand by very sick patients. The other was that, in the context of rumors and distrust of Ebola treatment centers, using a randomized design at the outset might lead even more patients to refuse to seek care. Therefore, we chose to conduct a multicenter non-randomized trial, in which all patients would receive favipiravir along with standardized care. The objectives of the trial were to test the feasibility and acceptability of an emergency trial in the context of a large Ebola outbreak, and to collect data on the safety and effectiveness of favipiravir in reducing mortality and viral load in patients with EVD. The trial was not aimed at directly informing future guidelines on Ebola treatment but at quickly gathering standardized preliminary data to optimize the design of future studies. Methods and Findings Inclusion criteria were positive Ebola virus reverse transcription PCR (RT-PCR) test, age [greater than or equal to] 1 y, weight [greater than or equal to] 10 kg, ability to take oral drugs, and informed consent. All participants received oral favipiravir (day 0: 6,000 mg; day 1 to day 9: 2,400 mg/d). Semi-quantitative Ebola virus RT-PCR (results expressed in 'cycle threshold' [Ct]) and biochemistry tests were performed at day 0, day 2, day 4, end of symptoms, day 14, and day 30. Frozen samples were shipped to a reference biosafety level 4 laboratory for RNA viral load measurement using a quantitative reference technique (genome copies/milliliter). Outcomes were mortality, viral load evolution, and adverse events. The analysis was stratified by age and Ct value. A 'target value' of mortality was defined a priori for each stratum, to guide the interpretation of interim and final analysis. Between 17 December 2014 and 8 April 2015, 126 patients were included, of whom 111 were analyzed (adults and adolescents, [greater than or equal to]13 y, n = 99; young children, [less than or equal to]6 y, n = 12). Here we present the results obtained in the 99 adults and adolescents. Of these, 55 had a baseline Ct value [greater than or equal to] 20 (Group A Ct [greater than or equal to] 20), and 44 had a baseline Ct value < 20 (Group A Ct < 20). Ct values and RNA viral loads were well correlated, with Ct = 20 corresponding to RNA viral load = 7.7 log.sub.10 genome copies/ml. Mortality was 20% (95% CI 11.6%-32.4%) in Group A Ct [greater than or equal to] 20 and 91% (95% CI 78.8%-91.1%) in Group A Ct < 20. Both mortality 95% CIs included the predefined target value (30% and 85%, respectively). Baseline serum creatinine was [greater than or equal to]110 [mu]mol/l in 48% of patients in Group A Ct [greater than or equal to] 20 ([greater than or equal to]300 [mu]mol/l in 14%) and in 90% of patients in Group A Ct < 20 ([greater than or equal to]300 [mu]mol/l in 44%). In Group A Ct [greater than or equal to] 20, 17% of patients with baseline creatinine [greater than or equal to]110 [mu]mol/l died, versus 97% in Group A Ct < 20. In patients who survived, the mean decrease in viral load was 0.33 log.sub.10 copies/ml per day of follow-up. RNA viral load values and mortality were not significantly different between adults starting favipiravir within Conclusions In the context of an outbreak at its peak, with crowded care centers, randomizing patients to receive either standard care or standard care plus an experimental drug was not felt to be appropriate. We did a non-randomized trial. This trial reaches nuanced conclusions. On the one hand, we do not conclude on the efficacy of the drug, and our conclusions on tolerance, although encouraging, are not as firm as they could have been if we had used randomization. On the other hand, we learned about how to quickly set up and run an Ebola trial, in close relationship with the community and non-governmental organizations; we integrated research into care so that it improved care; and we generated knowledge on EVD that is useful to further research. Our data illustrate the frequency of renal dysfunction and the powerful prognostic value of low Ct values. They suggest that drug trials in EVD should systematically stratify analyses by baseline Ct value, as a surrogate of viral load. They also suggest that favipiravir monotherapy merits further study in patients with medium to high viremia, but not in those with very high viremia. Trial registration ClinicalTrials.gov NCT02329054, Author(s): Daouda Sissoko 1,2, Cedric Laouenan 3,4, Elin Folkesson 5, Abdoul-Bing M'Lebing 6, Abdoul-Habib Beavogui 7, Sylvain Baize 8,9, Alseny-Modet Camara 5, Piet Maes 10,11, Susan Shepherd 6, Christine Danel [...]

The G-protein-gated inwardly rectifying potassium (Kir3/GIRK) channel is the effector of many G-protein-coupled receptors (GPCRs). Its dysfunction has been linked to the pathophysiology of Down syndrome, Alzheimer's and Parkinson's diseases, psychiatric disorders, epilepsy, drug addiction, or alcoholism. In the hippocampus, GIRK channels decrease excitability of the cells and contribute to resting membrane potential and inhibitory neurotransmission. Here, to elucidate the role of GIRK channels activity in the maintenance of hippocampal-dependent cognitive functions, their involvement in controlling neuronal excitability at different levels of complexity was examined in C57BL/6 male mice. For that purpose, GIRK activity in the dorsal hippocampus CA32CA1 synapse was pharmacologically modulated by two drugs: ML297, a GIRK channel opener, and Tertiapin-Q (TQ), a GIRK channel blocker. Ex vivo, using dorsal hippocampal slices, we studied the effect of pharmacological GIRK modulation on synaptic plasticity processes induced in CA1 by Schaffer collateral stimulation. In vivo, we performed acute intracerebroventricular (i.c.v.) injections of the two GIRK modulators to study their contribution to electrophysiological properties and synaptic plasticity of dorsal hippocampal CA32CA1 synapse, and to learning and memory capabilities during hippocampal-dependent tasks. We found that pharmacological disruption of GIRK channel activity by i.c.v. injections, causing either function gain or function loss, induced learning and memory deficits by a mechanism involving neural excitability impairments and alterations in the induction and maintenance of longterm synaptic plasticity processes. These results support the contention that an accurate control of GIRK activity must take place in the hippocampus to sustain cognitive functions. [ABSTRACT FROM AUTHOR]

Background: Few data exist concerning the role of common human coronaviruses (HCoVs) in patients hospitalized for acute respiratory infection (ARI) and the severity of these infections compared with influenza.Methods: Prospective data on the viral etiology of ARI hospitalizations during the peaks of 8 influenza seasons (from 2011-2012 to 2018-2019) in Quebec, Canada, were used to compare patients with HCoV and those with influenza infections; generalized estimation equations models were used for multivariate analyses.Results: We identified 340 HCoV infections, which affected 11.6% of children (n = 136) and 5.2% of adults (n = 204) hospitalized with ARI. The majority of children (75%) with HCoV infections were also coinfected with other respiratory viruses, compared with 24% of the adults (P < .001). No deaths were recorded in children; 5.8% of adults with HCoV monoinfection died, compared with 4.2% of those with influenza monoinfection (P = .23). The risk of pneumonia was nonsignificantly lower in children with HCoV than in those with influenza, but these risks were similarly high in adults. Markers of severity (length of stay, intensive care unit admissions, and case-fatality ratio) were comparable between these infections in multivariate analyses, in both children and adults.Conclusions: In children and adults hospitalized with ARI, HCoV infections were less frequent than influenza infections, but were as severe as influenza monoinfections. [ABSTRACT FROM AUTHOR]

Several studies have revealed either self-reported chemosensory alterations in large groups or objective quantified chemosensory impairments in smaller populations of patients diagnosed with COVID-19. However, due to the great variability in published results regarding COVID-19-induced chemosensory impairments and their follow-up, prognosis for chemosensory functions in patients with such complaints remains unclear. Our objective is to describe the various chemosensory alterations associated with COVID-19 and their prevalence and evolution after infection. A cross-sectional study of 704 healthcare workers with a RT–PCR-confirmed SARS-CoV-2 infection between 2020 February 28 and 2020 June 14 was conducted 3–7 months after onset of symptoms. Data were collected with an online questionnaire. Outcomes included differences in reported chemosensory self-assessment of olfactory, gustatory, and trigeminal functions across time points and Chemosensory Perception Test scores from an easy-to-use at-home self-administered chemosensory test. Among the 704 participants, 593 (84.2%) were women, the mean (SD) age was 42 (12) years, and the questionnaire was answered on average 4.8 (0.8) months after COVID-19. During COVID-19, a decrease in olfactory, gustatory, and trigeminal sensitivities was reported by 81.3%, 81.5%, and 48.0%, respectively. Three to 7 months later, reduced sensitivity was still reported by 52.0%, 41.9%, and 23.3%, respectively. Chemosensory Perception Test scores indicate that 19.5% of participants had objective olfactory impairment. These data suggest a significant proportion of COVID-19 cases have persistent chemosensory impairments at 3–7 months after their infection, but the majority of those who had completely lost their olfactory, gustatory, and trigeminal sensitivities have improved. [ABSTRACT FROM AUTHOR]

Analizar las características clínicas y de metabolismo óseo de una serie de pacientes con fracturas vertebrales tras la suspensión de denosumab (DMab). Estudio observacional retrospectivo de 10 pacientes con fracturas vertebrales tras suspender DMab atendidas en el Servicio de Reumatología de un hospital español de tercer nivel entre 2015 y 2018. Se registraron un total de 49 fracturas espontáneas tras una media de 6 dosis de DMab y transcurridos 10,9 meses desde la suspensión del fármaco. El 90% había recibido tratamiento previo, 7 de 10 bisfosfonatos orales. Tras la suspensión, CTX y P1NP estaban elevados y la media de T-score en cuello femoral y columna lumbar fue menor que previo a DMab. Las vértebras más afectadas fueron L3, L5, D6, D7, D9 y D11. La descripción de nuevos casos de fracturas vertebrales múltiples en los meses posteriores a la suspensión de DMab subraya la preocupación emergente en la comunidad científica siendo preciso apoyar en evidencias sólidas las nuevas recomendaciones sobre su manejo. Analyse clinical and bone metabolism features in a case series of patients with multiple vertebral fractures after discontinuation of denosumab (DMab). An observational descriptive study analysing data from ten patients with multiple vertebral fractures after DMab discontinuation that were admitted to our rheumatology department between 2015 and 2018. There were a total of 49 spontaneous fractures after an average of 6 DMab doses and 10.9 months from discontinuation. Ninety percent had already received treatment other than DMab 7 of 10 oral bisphosphonates. After discontinuation, CTX and P1NP remained elevated and mean T-score for femoral neck and lumbar spine was lower than before treatment. The most affected vertebrae were L3, L5, D6, D7, D9 and D11. This report of ten new cases suffering multiple vertebral fractures early after discontinuation of DMab highlights the emerging concern on the subject in the scientific community and the need to clarify its pathogenic mechanism, and to support by solid evidence the new recommendations on its management. [ABSTRACT FROM AUTHOR]

Hippocampal synaptic plasticity disruption by amyloid‐β (Aβ) peptides + thought to be responsible for learning and memory impairments in Alzheimer's disease (AD) early stage. Failures in neuronal excitability maintenance seems to be an underlying mechanism. G‐protein‐gated inwardly rectifying potassium (GirK) channels control neural excitability by hyperpolarization in response to many G‐protein‐coupled receptors activation. Here, in early in vitro and in vivo amyloidosis mouse models, we study whether GirK channels take part of the hippocampal synaptic plasticity impairments generated by Aβ1–42. In vitro electrophysiological recordings from slices showed that Aβ1–42 alters synaptic plasticity by switching high‐frequency stimulation (HFS) induced long‐term potentiation (LTP) to long‐term depression (LTD), which led to in vivo hippocampal‐dependent memory deficits. Remarkably, selective pharmacological activation of GirK channels with ML297 rescued both HFS‐induced LTP and habituation memory from Aβ1–42 action. Moreover, when GirK channels were specifically blocked by Tertiapin‐Q, their activation with ML297 failed to rescue LTP from the HFS‐dependent LTD induced by Aβ1–42. On the other hand, the molecular analysis of the recorded slices by western blot showed that the expression of GIRK1/2 subunits, which form the prototypical GirK channel in the hippocampus, was not significantly regulated by Aβ1–42. However, immunohistochemical examination of our in vivo amyloidosis model showed Aβ1–42 to down‐regulate hippocampal GIRK1 subunit expression. Together, our results describe an Aβ‐mediated deleterious synaptic mechanism that modifies the induction threshold for hippocampal LTP/LTD and underlies memory alterations observed in amyloidosis models. In this scenario, GirK activation assures memory formation by preventing the transformation of HFS‐induced LTP into LTD. [ABSTRACT FROM AUTHOR]

Background: In 2014–2015, we assessed favipiravir tolerance and efficacy in patients with Ebola virus (EBOV) disease (EVD) in Guinea (JIKI trial). Because the drug had never been used before for this indication and that high concentrations of the drugs were needed to achieve antiviral efficacy against EBOV, a pharmacokinetic model had been used to propose relevant dosing regimen. Here we report the favipiravir plasma concentrations that were achieved in participants in the JIKI trial and put them in perspective with the model-based targeted concentrations. Methods and findings: Pre-dose drug concentrations were collected at Day-2 and Day-4 of treatment in 66 patients of the JIKI trial and compared to those predicted by the model taking into account patient’s individual characteristics. At Day-2, the observed concentrations were slightly lower than the model predictions adjusted for patient’s characteristics (median value of 46.1 versus 54.3 μg/mL for observed and predicted concentrations, respectively, p = 0.012). However, the concentrations dropped at Day-4, which was not anticipated by the model (median values of 25.9 and 64.4 μg/mL for observed and predicted concentrations, respectively, p<10−6). There was no significant relationship between favipiravir concentrations and EBOV viral kinetics or mortality. Conclusions: Favipiravir plasma concentrations in the JIKI trial failed to achieve the target exposure defined before the trial. Furthermore, the drug concentration experienced an unanticipated drop between Day-2 and Day-4. The origin of this drop could be due to severe sepsis conditions and/or to intrinsic properties of favipiravir metabolism. Dose-ranging studies should be performed in healthy volunteers to assess the concentrations and the tolerance that could be achieved with high doses. Trial registration: ClinicalTrials.gov [ABSTRACT FROM AUTHOR]

Background: In early stages of Alzheimer's disease, disruption of learning and memory processes that rely on hippocampal performance correlates with aberrant patterns of synchronous neuronal activity that arise prior to evident neurodegeneration. These disturbances emerge as a result of neuronal hyperexcitability and synaptic dysfunction induced by soluble forms of amyloid‐β (Aβ) peptide, which trigger an imbalance between excitatory and inhibitory neurotransmission systems. The molecular mechanisms underlying these alterations remain unclear but functional evidence points to alteration of neuronal excitability playing a pivotal role in early Aβ‐induced AD pathogenesis. Although Aβ1‐42 and Aβ1‐40 are widely known for their clinical relevance, Aβ25‐35 has been proposed as the biologically active fragment. In contrast to other Aβ isoforms, Aβ25‐35 does not generate ion‐permeable pores in neuronal membrane, but it has been shown to induce major neuropathological signs related to early AD stages. Hence, it has been extensively used to study the pathophysiological events related to Aβ‐induced neuronal dysfunction. It remains to be explored, however, whether Aβ25‐35 mimics the neurotoxic effects on the hippocampus exhibited by other clinically relevant species such as Aβ1‐42 (Sánchez‐Rodriguez et al., 2017, 2019, 2020). Methods: Here, we systematically characterized the effects of Aβ25‐35 on hippocampal function at different —behavior, networks and synapses— levels of complexity in behaving mice prepared for chronic intracerebroventricular injections. Likewise, animals were implanted with electrodes for in vivo recordings at the hippocampal CA1 area and electrical stimulation of the Schaffer collateral pathway. Results: Our data showed evident learning and memory impairments in hippocampal‐dependent tasks such as novel object recognition and open field habituation tests. Underlying these deficits, local field potential (LFP) recordings revealed an altered oscillatory activity. Additionally, theta and gamma rhythms, crucially involved in successful memory encoding, were abnormally increased. Lastly, we also found impairments in long‐term synaptic plasticity at the CA3‐CA1 synapse, where Aβ25‐35 transformed long‐term potentiation (LTP) into long‐term depression (LTD). Conclusions: Taken together, these results support the notion that Aβ25‐35‐mediated effects on synaptic properties and neural network activity mimicked those exerted by Aβ1‐42. Thus, we verified the potentiality of the Aβ25‐35 peptide to study the hippocampal pathophysiology of early amyloidosis. [ABSTRACT FROM AUTHOR]

Background: Hippocampal synaptic plasticity disruption by amyloid‐β (Aβ) peptides is thought to be responsible for learning and memory impairments in Alzheimer's disease (AD) early stage. Failures in neuronal excitability maintenance seems to be an underlying mechanism. G‐protein‐gated inwardly‐rectifying potassium (GirK) channels control neural excitability by hyperpolarization in response to many G‐protein‐coupled receptors activation. Method: Here, in early in vitro and in vivo amyloidosis mouse models, we study whether GirK channels take part of the hippocampal synaptic plasticity impairments generated by Aβ1‐42. In vitro electrophysiological recordings from slices showed that Aβ1‐42 alters synaptic plasticity by switching high frequency stimulation (HFS) induced long‐term potentiation (LTP) to long‐term depression (LTD), which led to in vivo hippocampal‐dependent memory deficits. Result: Remarkably, selective pharmacological activation of GirK channels with ML297 rescued both HFS‐induced LTP and habituation memory from Aβ1‐42 action. Moreover, when GirK channels were specifically blocked by Tertiapin‐Q, their activation with ML297 failed to rescue LTP from the HFS‐dependent LTD induced by Aβ1‐42. On the other hand, the molecular analysis of the recorded slices by western blot showed that expression of GIRK1/2 subunits, which form the prototypical GirK channel in the hippocampus, was not significantly regulated by Aβ1‐42. However, immunohistochemical examination of our in vivo amyloidosis model showed Aβ1‐42 to downregulate hippocampal GIRK1 subunit expression. Conclusion: Together, our results describe an Aβ‐mediated deleterious synaptic mechanism that modifies the induction threshold for hippocampal LTP/LTD and underlies memory alterations observed in amyloidosis models. In this scenario, GirK activation assures memory formation by preventing the transformation of HFS‐induced LTP into LTD. [ABSTRACT FROM AUTHOR]

In early Alzheimer disease (AD) models synaptic failures and upstreaming aberrant patterns of network synchronous activity result in hippocampal-dependent memory deficits. In such initial stage, soluble forms of Amyloid-β (Aβ) peptides have been shown to play a causal role. Among different Aβ species, Aβ25–35 has been identified as the biologically active fragment, as induces major neuropathological signs related to early AD stages. Consequently, it has been extensively used to acutely explore the pathophysiological events related with neuronal dysfunction induced by soluble Aβ forms. However, the synaptic mechanisms underlying its toxic effects on hippocampal-dependent memory remain unresolved. Here, in an in vivo model of amyloidosis generated by intracerebroventricular injections of Aβ25–35 we studied the synaptic dysfunction mechanisms underlying hippocampal cognitive deficits. At the synaptic level, long-term potentiation (LTP) of synaptic excitation and inhibition was induced in CA1 region by high frequency simulation (HFS) applied to Schaffer collaterals. Aβ25–35 was found to alter metaplastic mechanisms of plasticity, facilitating long-term depression (LTD) of both types of LTP. In addition, aberrant synchronization of hippocampal network activity was found while at the behavioral level, deficits in hippocampal-dependent habituation and recognition memories emerged. Together, our results provide a substrate for synaptic disruption mechanism underlying hippocampal cognitive deficits present in Aβ25–35 amyloidosis model. [ABSTRACT FROM AUTHOR]

During the height of the global COVID-19 pandemic, the test-negative design (TND) was extensively used in many countries to evaluate COVID-19 vaccine effectiveness (VE). Typically, the TND involves the recruitment of care-seeking individuals who meet a common clinical case definition. All participants are then tested for an infection of interest. To review and describe the variation in TND methodology, and disclosure of potential biases, as applied to the evaluation of COVID-19 VE during the early vaccination phase of the pandemic. We conducted a systematic review by searching four biomedical databases using defined keywords to identify peer-reviewed articles published between January 1, 2020, and January 25, 2022. We included only original articles that employed a TND to estimate VE of COVID-19 vaccines in which cases and controls were evaluated based on SARS-CoV-2 laboratory test results. We identified 96 studies, 35 of which met the defined criteria. Most studies were from North America (16 studies) and targeted the general population (28 studies). Outcome case definitions were based primarily on COVID-19-like symptoms; however, several papers did not consider or specify symptoms. Cases and controls had the same inclusion criteria in only half of the studies. Most studies relied upon administrative or hospital databases assembled for a different (non-evaluation) clinical purpose. Potential unmeasured confounding (20 studies), misclassification of current SARS-CoV-2 infection (16 studies) and selection bias (10 studies) were disclosed as limitations by some studies. We observed potentially meaningful deviations from the validated design in the application of the TND during the COVID-19 pandemic. [ABSTRACT FROM AUTHOR]