Influenza Hospitalization Burden by Subtype, Age, Comorbidity, and Vaccination Status: 2012-2013 to 2018-2019 Seasons, Quebec, Canada.

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.

Timing and Predictors of Loss of Infectivity Among Healthcare Workers With Mild Primary and Recurrent COVID-19: A Prospective Observational Cohort Study.

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.

Single-dose Effectiveness of Mpox Vaccine in Quebec, Canada: Test-negative Design With and Without Adjustment for Self-reported Exposure Risk.

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.

Circulating Tfh cells are differentially modified by abatacept or TNF blockers, and predict treatment response in Rheumatoid Arthritis.

OBJECTIVE: CD4+CXCR5+PD-1hi follicular helper T (Tfh) cells dwell in the germinal centers (GCs) of lymphoid organs and participate in Rheumatoid Arthritis (RA) pathogenesis; the frequency of their circulating counterparts (cTfh-frequency) is expanded in RA and correlates with the pool of GC Tfh cells. Our objective was to study the effect of abatacept (ABT) or TNF blockers (TNFb) on the cTfh-frequency in RA. METHODS: Peripheral blood was drawn from seropositive-longstanding RA patients chronically receiving csDMARDS (n = 45), TNFb (n = 59), or ABT (n = 34), and healthy controls (HC) (n = 137). Also, patients with an incomplete response to csDMARDS (n = 41) who initiated TNFb (n = 19) or ABT (n = 22), were studied at 0 and 12 months. The cTfh-frequency was examined by cytometry. RESULTS: As compared with HC, an increased cTfh-frequency was seen in seropositive-longstanding RA chronically receiving csDMARDs or TNFb but not ABT. After escalating from csDMARDs, the cTfh-frequency did not vary in patients who were given TNFb but decreased to HC levels in those given ABT. In the ABT group, the baseline cTfh-frequency was higher for patients who attained 12M remission (12Mr), vs those who remained active (12Ma): 0m cutoff for remission >0.38% (Sens. 92%, Sp. 90%), OR 25.3. Conversely, in the TNFb group, the baseline cTfh-frequency was lower for 12Mr vs 12Ma: 0m cutoff for non-remission >0.44% (Sens. 67%, Sp. 90%), OR 8.5. CONCLUSION: ABT but not TNFb, is able to curtail the cTfh-frequency in RA. A higher baseline cTfh-frequency predicts a good response to ABT but a poor response to TNFb.

2023/24 mid-season influenza and Omicron XBB.1.5 vaccine effectiveness estimates from the Canadian Sentinel Practitioner Surveillance Network (SPSN).

The Canadian Sentinel Practitioner Surveillance Network reports mid-season 2023/24 influenza vaccine effectiveness (VE) of 63% (95% CI: 51-72) against influenza A(H1N1)pdm09, lower for clade 5a.2a.1 (56%; 95% CI: 33-71) than clade 5a.2a (67%; 95% CI: 48-80), and lowest against influenza A(H3N2) (40%; 95% CI: 5-61). The Omicron XBB.1.5 vaccine protected comparably well, with VE of 47% (95% CI: 21-65) against medically attended COVID-19, higher among people reporting a prior confirmed SARS-CoV-2 infection at 67% (95% CI: 28-85).

G-Protein-Gated Inwardly Rectifying Potassium (Kir3/GIRK) Channels Govern Synaptic Plasticity That Supports Hippocampal-Dependent Cognitive Functions in Male Mice.

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 CA3-CA1 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 CA3-CA1 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 long-term 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.SIGNIFICANCE STATEMENT Cognitive processes of learning and memory that rely on hippocampal synaptic plasticity processes are critically ruled by a finely tuned neural excitability. G-protein-gated inwardly rectifying K+ (GIRK) channels play a key role in maintaining resting membrane potential, cell excitability and inhibitory neurotransmission. Here, we demonstrate that modulation of GIRK channels activity, causing either function gain or function loss, transforms high-frequency stimulation (HFS)-induced long-term potentiation (LTP) into long-term depression (LTD), inducing deficits in hippocampal-dependent learning and memory. Together, our data show a crucial GIRK-activity-mediated mechanism that governs synaptic plasticity direction and modulates subsequent hippocampal-dependent cognitive functions.

Single-Dose Messenger RNA Vaccine Effectiveness Against Severe Acute Respiratory Syndrome Coronavirus 2 in Healthcare Workers Extending 16 Weeks Postvaccination: A Test-Negative Design From Québec, Canada.

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.

Persisting chemosensory impairments in 366 healthcare workers following COVID-19: an 11-month follow-up.

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.

Spatial Memory Training Counteracts Hippocampal GIRK Channel Decrease in the Transgenic APPSw,Ind J9 Alzheimer's Disease Mouse Model.

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-ß (Aß) accumulation in the hippocampus during aging alters GIRK channel expression in mutant ß-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.

Recognition Memory Induces Natural LTP-like Hippocampal Synaptic Excitation and Inhibition.

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.

Relative Severity of Common Human Coronaviruses and Influenza in Patients Hospitalized With Acute Respiratory Infection: Results From 8-Year Hospital-Based Surveillance in Quebec, Canada.

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.

Chemosensory Dysfunctions Induced by COVID-19 Can Persist up to 7 Months: A Study of Over 700 Healthcare Workers.

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.

Hippocampal long-term synaptic depression and memory deficits induced in early amyloidopathy are prevented by enhancing G-protein-gated inwardly rectifying potassium channel activity.

Hippocampal synaptic plasticity disruption by amyloid-ß (Aß) 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 Aß1-42 . In vitro electrophysiological recordings from slices showed that Aß1-42 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 Aß1-42 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 Aß1-42 . 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 Aß1-42 . However, immunohistochemical examination of our in vivo amyloidosis model showed Aß1-42 to down-regulate hippocampal GIRK1 subunit expression. Together, our results describe an Aß-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.

Effect of age at vaccination on the measles vaccine effectiveness and immunogenicity: systematic review and meta-analysis.

BACKGROUND: The objectives of this review were to evaluate the effect of age at administration of the first dose of a measles-containing vaccine (MCV1) on protection against measles and on antibody response after one- and two-dose measles vaccinations. METHODS: We conducted a systematic review of the PubMed/MEDLINE, Embase, Web of Science and Cochrane databases (1964-2017) to identify observational studies estimating vaccine effectiveness and/or measles attack rates by age at first vaccination as well as experimental studies comparing seroconversion by age at first vaccination. Random effect models were used to pool measles risk ratios (RR), measles odds ratios (OR) and seroconversion RR of MCV1 administered at < 9, 9-11 or ≥ 15 months compared with 12 or 12-14 months of age. RESULTS: We included 41 and 67 studies in the measles protection and immunogenicity analyses. Older age at MCV1, from 6 to ≥15 months, improved antibody response and measles protection among one-dose recipients. Pooled measles RR ranged from 3.56 (95%CI: 1.28, 9.88) for MCV1 at < 9 months to 0.48 (95%CI: 0.36, 0.63) for MCV1 at ≥15 months, both compared to 12-14 months. Pooled seroconversion RR ranged from 0.93 (95%CI: 0.90, 0.96) for MCV1 at 9-11 months to 1.03 (95%CI: 1.00, 1.06) for MCV1 at ≥15 months, both compared to 12 months. After a second dose, serological studies reported high seropositivity regardless of age at administration of MCV1 while epidemiological data based on few studies suggested lower protection with earlier age at MCV1. CONCLUSIONS: Earlier age at MCV1 decreases measles protection and immunogenicity after one dose and might still have an impact on vaccine failures after two doses of measles vaccine. While two-dose vaccination coverage is most critical to interrupt measles transmission, older age at first vaccination may be necessary to keep the high level of population immunity needed to maintain it.

Diagnostic validity of Doppler ultrasound in giant cell arteritis.

OBJECTIVES: To assess the validity of Doppler ultrasound in the diagnosis of giant cell arteritis (GCA), using the American College of Rheumatology (ACR) criteria and biopsy and using as gold standard the patient's definitive clinical diagnosis. METHODS: An observational, descriptive and analytical study of 451 consecutive patients with suspected GCA was conducted, and the clinical history and ultrasound findings of the patients were reviewed. The validity of ACR criteria, temporal arteritis biopsy (TAB) and Doppler ultrasound in the diagnosis of GCA was calculated using the final diagnosis of the doctor in charge as the gold standard. RESULTS: The validity and security of the diagnostic tests used were as follows: ACR criteria had 65.37% sensitivity and 62.89% specificity; positive predictive value [PPV] 70%; negative predictive value [NPV] 57.82%, likelihood ratio [LR] + 1.7619 and LR - 0.5506. Doppler ultrasonography had 91.60% sensitivity and 95.83% specificity; PPV 96.62%; NPV 89.76%, LR + 21.81 and LR - 0.0876; TA biopsy 42.86% sensitivity and 100% specificity; PPV 100%; NPV 35.71% and LR - 0.5714. CONCLUSIONS: The halo sign, especially if bilateral, is a strong predictor of GCA with a level of accuracy sufficient to recommend its introduction into clinical practice and, in our opinion, should be considered in future classification criteria sets.

Correction: Experimental Treatment with Favipiravir for Ebola Virus Disease (the JIKI Trial): A Historically Controlled, Single-Arm Proof-of-Concept Trial in Guinea.

[This corrects the article DOI: 10.1371/journal.pmed.1001967.].

Experimental Treatment with Favipiravir for Ebola Virus Disease (the JIKI Trial): A Historically Controlled, Single-Arm Proof-of-Concept Trial in Guinea.

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 ≥ 1 y, weight ≥ 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, ≥13 y, n = 99; young children, ≤6 y, n = 12). Here we present the results obtained in the 99 adults and adolescents. Of these, 55 had a baseline Ct value ≥ 20 (Group A Ct ≥ 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 log10 genome copies/ml. Mortality was 20% (95% CI 11.6%-32.4%) in Group A Ct ≥ 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 ≥110 µmol/l in 48% of patients in Group A Ct ≥ 20 (≥300 µmol/l in 14%) and in 90% of patients in Group A Ct < 20 (≥300 µmol/l in 44%). In Group A Ct ≥ 20, 17% of patients with baseline creatinine ≥110 µmol/l died, versus 97% in Group A Ct < 20. In patients who survived, the mean decrease in viral load was 0.33 log10 copies/ml per day of follow-up. RNA viral load values and mortality were not significantly different between adults starting favipiravir within <72 h of symptoms compared to others. Favipiravir was well tolerated. 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.

Effectiveness of BNT162b2 Vaccine Against Omicron-SARS-CoV-2 Subvariants in Children 5-11 Years of Age in Quebec, Canada, January 2022 to January 2023.

BACKGROUND: In premarketing clinical trials conducted before Omicron emergence, BNT162b2 vaccine efficacy against COVID-19 was 90% in children. We conducted postmarketing evaluation of 1- and 2-dose vaccine effectiveness (VE) against Omicron BA.1, BA.2 and BA.4/5 subvariants in 5- to 11-year olds. METHODS: We estimated VE against SARS-CoV-2 infection using a test-negative design. Specimens collected between January 9, 2022, and January 7, 2023, from children 5-11 years old in Quebec, Canada, and tested by nucleic acid amplification test were eligible. We estimated VE by time since last vaccine dose, interval between doses and by period of Omicron subvariant predominance. RESULTS: A total of 48,826 NAATs were included in overall analysis. From 14-55 to 56-385 days postvaccination, 2-dose VE against symptomatic infection decreased from 68% (95% CI, 62-74) to 25% (95% CI, 11-36). Two-dose VE with restriction to specimens collected from acute care hospitals (emergency rooms or wards) did not decline but was stable at ~40%. VE against symptomatic infection remained comparable at any interval between doses but increased with longer interval among children tested in acute care settings, from 18% (95% CI, -17 to 44) with 21- to 55-day interval to 69% (95% CI, 43-86) with ≥84-day interval. Two-dose VE against symptomatic infection dropped from 70% (95% CI, 63-76) during BA.1, to 32% (95% CI, 13-47) with BA.2 and to nonprotective during BA.4/5 dominance. CONCLUSIONS: In children 5-11 years of age, VE against symptomatic infection was stable at any interval between doses but decreased with time since the last dose and against more divergent omicron subvariants.

The Changing Landscape of Respiratory Viruses Contributing to Hospitalizations in Quebec, Canada: Results From an Active Hospital-Based Surveillance Study.

BACKGROUND: A comprehensive description of the combined effect of SARS-CoV-2 and respiratory viruses other than SARS-CoV-2 (ORVs) on acute respiratory infection (ARI) hospitalizations is lacking. OBJECTIVE: This study aimed to compare the viral etiology of ARI hospitalizations before the pandemic (8 prepandemic influenza seasons, 2012-13 to 2019-20) and during 3 pandemic years (periods of increased SARS-CoV-2 and ORV circulation in 2020-21, 2021-22, and 2022-23) from an active hospital-based surveillance network in Quebec, Canada. METHODS: We compared the detection of ORVs and SARS-CoV-2 during 3 pandemic years to that in 8 prepandemic influenza seasons among patients hospitalized with ARI who were tested systematically by the same multiplex polymerase chain reaction (PCR) assay during periods of intense respiratory virus (RV) circulation. The proportions of infections between prepandemic and pandemic years were compared by using appropriate statistical tests. RESULTS: During prepandemic influenza seasons, overall RV detection was 92.7% (1384/1493) (respiratory syncytial virus [RSV]: 721/1493, 48.3%; coinfections: 456/1493, 30.5%) in children (<18 years) and 62.8% (2723/4339) (influenza: 1742/4339, 40.1%; coinfections: 264/4339, 6.1%) in adults. Overall RV detection in children was lower during pandemic years but increased from 58.6% (17/29) in 2020-21 (all ORVs; coinfections: 7/29, 24.1%) to 90.3% (308/341) in 2021-22 (ORVs: 278/341, 82%; SARS-CoV-2: 30/341, 8.8%; coinfections: 110/341, 32.3%) and 88.9% (361/406) in 2022-23 (ORVs: 339/406, 84%; SARS-CoV-2: 22/406, 5.4%; coinfections: 128/406, 31.5%). In adults, overall RV detection was also lower during pandemic years but increased from 43.7% (333/762) in 2020-21 (ORVs: 26/762, 3.4%; SARS-CoV-2: 307/762, 40.3%; coinfections: 7/762, 0.9%) to 57.8% (731/1265) in 2021-22 (ORVs: 179/1265, 14.2%; SARS-CoV-2: 552/1265, 43.6%; coinfections: 42/1265, 3.3%) and 50.1% (746/1488) in 2022-23 (ORVs: 409/1488, 27.5%; SARS-CoV-2: 337/1488, 22.6%; coinfections: 36/1488, 2.4%). No influenza or RSV was detected in 2020-21; however, their detection increased in the 2 subsequent years but did not reach prepandemic levels. Compared to the prepandemic period, the peaks of RSV hospitalization shifted in 2021-22 (16 weeks earlier) and 2022-23 (15 weeks earlier). Moreover, the peaks of influenza hospitalization shifted in 2021-22 (17 weeks later) and 2022-23 (4 weeks earlier). Age distribution was different compared to the prepandemic period, especially during the first pandemic year. CONCLUSIONS: Significant shifts in viral etiology, seasonality, and age distribution of ARI hospitalizations occurred during the 3 pandemic years. Changes in age distribution observed in our study may reflect modifications in the landscape of circulating RVs and their contribution to ARI hospitalizations. During the pandemic period, SARS-CoV-2 had a low contribution to pediatric ARI hospitalizations, while it was the main contributor to adult ARI hospitalizations during the first 2 seasons and dropped below ORVs during the third pandemic season. Evolving RVs epidemiology underscores the need for increased scrutiny of ARI hospitalization etiology to inform tailored public health recommendations.

Test negative design for vaccine effectiveness estimation in the context of the COVID-19 pandemic: A systematic methodology review.

BACKGROUND: 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. OBJECTIVES: 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. METHODS: 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. 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. CONCLUSION: We observed potentially meaningful deviations from the validated design in the application of the TND during the COVID-19 pandemic.