An Alzheimer Disease Challenge Model: 24-Hour Sleep Deprivation in Healthy Volunteers, Impact on Working Memory, and Reversal Effect of Pharmacological Intervention: A Randomized, Double-Blind, Placebo-Controlled, Crossover Study.

PURPOSE/BACKGROUND: Alzheimer disease (AD) is a public health issue because of the low number of symptomatic drugs and the difficulty to diagnose it at the prodromal stage. The need to develop new treatments and to validate sensitive tests for early diagnosis could be met by developing a challenge model reproducing cognitive impairments of AD. Therefore, we implemented a 24-hour sleep deprivation (SD) design on healthy volunteers in a randomized, double-blind, placebo-controlled, crossover study on 36 healthy volunteers. METHODS/PROCEDURE: To validate the SD model, cognitive tests were chosen to assess a transient worsening of cognitive functions after SD and a restoration under modafinil as positive control (one dose of 200 mg). Then, the same evaluations were replicated after 15 days of donepezil (5 mg/d) or memantine (10 mg/d). The working memory (WM) function was assessed by the N-back task and the rapid visual processing (RVP) task. FINDINGS/RESULTS: The accuracy of the N-back task and the reaction time of the RVP revealed the alteration of the WM with SD and its restoration with modafinil (changes in score after SD compared with baseline before SD), respectively, in the placebo group and in the modafinil group (-0.2% and +1.0% of satisfactory answers, P = 0.022; +21.3 and +1.9 milliseconds of reaction time, P = 0.025). Alzheimer disease drugs also tended to reverse this deterioration: the accuracy of the N-back task was more stable through SD (compared with -3.0% in the placebo group, respectively, in the memantine group and in the donepezil group: -1.4% and -1.6%, P = 0.027 and P = 0.092) and RVP reaction time was less impacted (compared with +41.3 milliseconds in the placebo group, respectively, in the memantine group and in the donepezil group: +16.1 and +29.3 milliseconds, P = 0.034 and P = 0.459). IMPLICATIONS/CONCLUSIONS: Our SD challenge model actually led to a worsening of WM that was moderated by both modafinil and AD drugs. To use this approach, the cognitive battery, the vulnerability of the subjects to SD, and the expected drug effect should be carefully considered.

Collection of human biological samples for research purpose: Key challenges and patients' perspectives.

The development and the access to collections of human biological samples is one of the major challenges for health research. In recent years, biological resource centres (BRCs) have developed in such a way that they provide all activities relating to the handling of samples. In this context, France is undoubtedly a pioneering country, because most of the biological collections available were created on the basis of themed research projects, which involved a particular donor phenotype. The round table was an opportunity to emphasise the persistence of some pitfalls particularly in relation to ensuring the consistency of different regulatory pathways. It also gave the opportunity to question and make recommendations on aspects of governance of biological collections and the BRCs, to state the challenges linked to scientific and economic valorisation and to consider the place of patients and the general public. The development of specific education in public health and research is essential to underline that these initiatives are necessary for developing new diagnostic and therapeutic procedures.

Methotrexate Is Not Superior to Placebo for Inducing Steroid-Free Remission, but Induces Steroid-Free Clinical Remission in a Larger Proportion of Patients With Ulcerative Colitis.

BACKGROUND & AIMS: Parenteral methotrexate is an effective treatment for patients with Crohn's disease, but has never been adequately evaluated in patients with ulcerative colitis (UC). We conducted a randomized controlled trial to determine its safety and efficacy in patients with steroid-dependent UC. METHODS: We performed a double-blind, placebo-controlled trial to evaluate the efficacy of parenteral methotrexate (25 mg/wk) in 111 patients with corticosteroid-dependent UC at 26 medical centers in Europe from 2007 through 2013. Patients were given prednisone (10 to 40 mg/d) when the study began and were randomly assigned to groups (1:1) given placebo or methotrexate (intramuscularly or subcutaneously, 25 mg weekly) for 24 weeks. The primary end point was steroid-free remission (defined as a Mayo score ≤2 with no item >1 and complete withdrawal of steroids) at week 16. Secondary endpoints included clinical remission (defined as a Mayo clinical subscore ≤2 with no item >1) and endoscopic healing without steroids at weeks 16 and/or 24, remission without steroids at week 24, and remission at both weeks 16 and 24. RESULTS: Steroid-free remission at week 16 was achieved by 19 of 60 patients given methotrexate (31.7%) and 10 of 51 patients given placebo (19.6%)--a difference of 12.1% (95% confidence interval [CI]: -4.0% to 28.1%; P = .15). The proportion of patients in steroid-free clinical remission at week 16 was 41.7% in the methotrexate group and 23.5% in the placebo group, for a difference of 18.1% (95% CI: 1.1% to 35.2%; P = .04). The proportions of patients with steroid-free endoscopic healing at week 16 were 35% in the methotrexate group and 25.5% in the placebo group--a difference of 9.5% (95% CI: -7.5% to 26.5%; P = .28). No differences were observed in other secondary end points. More patients receiving placebo discontinued the study because of adverse events (47.1%), mostly caused by UC, than patients receiving methotrexate (26.7%; P = .03). A higher proportion of patients in the methotrexate group had nausea and vomiting (21.7%) than in the placebo group (3.9%; P = .006). CONCLUSIONS: In a randomized controlled trial, parenteral methotrexate was not superior to placebo for induction of steroid-free remission in patients with UC. However, methotrexate induced clinical remission without steroids in a significantly larger percentage of patients, resulting in fewer withdrawals from therapy due to active UC. ClinicalTrials.gov ID NCT00498589.

Von Willebrand factor as a biological sensor of blood flow to monitor percutaneous aortic valve interventions.

RATIONALE: Percutaneous aortic valve procedures are a major breakthrough in the management of patients with aortic stenosis. Residual gradient and residual aortic regurgitation are major predictors of midterm and long-term outcome after percutaneous aortic valve procedures. We hypothesized that (1) induction/recovery of high molecular weight (HMW) multimers of von Willebrand factor defect could be instantaneous after acute changes in blood flow, (2) a bedside point-of-care assay (platelet function analyzer-closure time adenine DI-phosphate [PFA-CADP]), reflecting HMW multimers changes, could be used to monitor in real-time percutaneous aortic valve procedures. OBJECTIVE: To investigate the time course of HMW multimers changes in models and patients with instantaneous induction/reversal of pathological high shear and its related bedside assessment. METHODS AND RESULTS: We investigated the time course of the induction/recovery of HMW multimers defects under instantaneous changes in shear stress in an aortic stenosis rabbit model and in patients undergoing implantation of a continuous flow left ventricular assist device. We further investigated the recovery of HMW multimers and monitored these changes with PFA-CADP in aortic stenosis patients undergoing transcatheter aortic valve implantation or balloon valvuloplasty. Experiments in the aortic stenosis rabbit model and in left ventricular assist device patients demonstrated that induction/recovery of HMW multimers occurs within 5 minutes. Transcatheter aortic valve implantation patients experienced an acute decrease in shear stress and a recovery of HMW multimers within minutes of implantation which was sustained overtime. In patients with residual high shear or with residual aortic regurgitation, no recovery of HMW multimers was observed. PFA-CADP profiles mimicked HMW multimers recovery both in transcatheter aortic valve implantation patients without aortic regurgitation (correction) and transcatheter aortic valve implantation patients with aortic regurgitation or balloon valvuloplasty patients (no correction). CONCLUSIONS: These results demonstrate that variations in von Willebrand factor multimeric pattern are highly dynamic, occurring within minutes after changes in blood flow. It also demonstrates that PFA-CADP can evaluate in real time the results of transcatheter aortic valve procedures.

French Jardé's law and European regulation on drug trials: Harmonization and implementation of new rules.

Jardé's law, concerning research studies in humans, was enacted in March 2012 but did not come into force until November 2016. This delay is largely explained by the adoption of a European regulation on clinical trials on medicinal products that will probably not be applicable until October 2018. In addition to covering the respective areas of the French and European legislation, the round table provided an opportunity to discuss the principal measures that will apply to future research, particularly those concerning the operational procedures of the ethics committees and the national committee for research in humans, as well as measures relating to the management of serious adverse effects, more specifically in phase I studies in subjects not presenting with any disorder. This round table also enabled the formulation of recommendations to better anticipate the practical difficulties that the regulatory changes might engender. Finally, we highlight the numerous challenges in terms of training that these important regulatory changes impose and the absolute necessity to best adapt the restrictions to those that are planned in numerous other European countries so that France remains competitive in terms of clinical research and so that French patients may continue to benefit rapidly from the most innovative treatments.

Clinical Characteristics and Risk Factors of Extensive Macular Atrophy with Pseudodrusen: The EMAP Case-Control National Clinical Trial.

PURPOSE: To assess the association of clinical and biological factors with extensive macular atrophy with pseudodrusen (EMAP) characterized by bilateral macular atrophy occurring in patients aged 50 to 60 years and a rapid progression to legal blindness within 5 to 10 years. DESIGN: A national matched case-control study. PARTICIPANTS: Participants were recruited in 10 French Departments of Ophthalmology and their associated clinical investigation centers. All 115 patients with EMAP had symptoms before the age of 55 years due to bilateral extensive macular atrophy with a larger vertical axis and diffuse pseudodrusen. Three controls without age-related macular degeneration (AMD) or retinal disease at fundus examination were matched for each patient with EMAP by gender, age, and geographic area (in total 415). METHODS: Subjects and controls underwent an eye examination including color, red-free autofluorescent fundus photographs and spectral-domain optical coherence tomography with macular analysis. The interviews collected demographic, lifestyle, family and personal medical history, medications, and biological data. Associations of risk factors were estimated using conditional logistic regression. MAIN OUTCOME MEASURES: Extensive macular atrophy with pseudodrusen status (cases vs. controls). RESULTS: Extensive macular atrophy with pseudodrusen most frequently affected women (70 women, 45 men). After multivariate adjustment, family history of glaucoma or AMD was strongly associated with EMAP (odds ratio [OR], 2.3, P = 0.008 and OR, 1.5, P = 0.01, respectively). No association was found with cardiac diseases or their risk factors. Mild and moderate kidney disease and higher neutrophil rate were associated with a reduced risk of EMAP (OR, 0.58, P = 0.04; OR, 0.34, P = 0.01; and OR, 0.59, P = 0.003, respectively). On the contrary, eosinophilia (OR, 1.6; P = 0.0002), lymphocytosis (OR, 1.84; P = 0.0002), increased erythrocyte sedimentation rate (OR, 6.5; P = 0.0005), decreased CH50 (P = 0.001), and high plasma C3 level (P = 0.023) were significantly associated with a higher risk of EMAP. CONCLUSIONS: This study documents an association between EMAP and family history of AMD and glaucoma, a clear female predominance, and a systemic inflammatory profile. The reduced CH50 and increased C3 plasma values could reflect a more severe complement pathway dysfunction than in AMD, leading to early pseudodrusen and rapid development of geographic atrophy. There is no association of EMAP with AMD cardiac diseases or cardiac risks, including cigarette smoking.

Endothelial Dysfunction and Pre-Existing Cognitive Disorders in Stroke Patients.

BACKGROUND: The origin of pre-existing cognitive impairment in stroke patients remains controversial, with a vascular or a degenerative hypothesis. OBJECTIVE: To determine whether endothelial dysfunction is associated with pre-existing cognitive problems, lesion load and biological anomalies in stroke patients. METHODS: Patients originated from the prospective STROKDEM study. The baseline cognitive state, assessed using the IQ-CODE, and risk factors for stroke were recorded at inclusion. Patients with an IQ-CODE score >64 were excluded. Endothelial function was determined 72 h after stroke symptom onset by non-invasive digital measurement of endothelium-dependent flow-mediated dilation and calculation of the reactive hyperemia index (RHI). RHI ≤ 1.67 indicated endothelial dysfunction. Different biomarkers of endothelial dysfunction were analysed in blood or plasma. All patients underwent MRI 72 h after stroke symptom onset. RESULTS: A total of 86 patients were included (52 males; mean age 63.5 ± 11.5 years). Patients with abnormal RHI have hypertension or antihypertensive treatment more often. The baseline IQ-CODE was abnormal in 33 (38.4%) patients, indicating a pre-existing cognitive problem. Baseline IQ-CODE > 48 was observed in 15 patients (28.3%) with normal RHI and in 18 patients (54.6%) with abnormal RHI (p = 0.016). The RHI median was significantly lower in patients with abnormal IQ-CODE. Abnormal RHI was associated with a significantly higher median FAZEKAS score (2.5 vs. 2; p = 0.008), a significantly higher frequency of periventricular lesions (p = 0.015), more white matter lesions (p = 0.007) and a significantly higher cerebral atrophy score (p < 0.001) on MRI. Vascular biomarkers significantly associated with abnormal RHI were MCP-1 (p = 0.009), MIP_1a (p = 0.042), and homocysteinemia (p < 0.05). CONCLUSIONS: A vascular mechanism may be responsible for cognitive problems pre-existing stroke. The measurement of endothelial dysfunction after stroke could become an important element of follow-up, providing an indication of the functional and cognitive prognosis of stroke patients.

Data Monitoring Committees and clinical trials: From scientific justification to organisation.

Clinical trials often last several months or even several years. As the trial progresses, it can be tempting to find out whether the data obtained already answers the question posed at the start of the trial in order to stop inclusions or monitoring earlier. However, knowing and taking into account interim results can sometimes compromise the integrity of the results, which is counterproductive. To minimise this risk and ensure that the treatments are assessed reliably, safety and/or efficacy criteria are monitored during the study by a Data Monitoring Committee. After receiving the results confidentially, the Data Monitoring Committee assesses the benefit/risk ratio of the study treatment and recommends that the trial be continued, modified or terminated. Data Monitoring Committee members issuing these recommendations have an important responsibility: a hasty decision to end the trial may lead to inconclusive results unable to answer the initial question and, inversely, delaying the decision to end the trial may expose the subjects to potentially ineffective or even harmful interventions. The Data Monitoring Committee's task is therefore particularly complex. With this in mind, the round table discussion at the Giens workshops was a chance to review the scientific justification for creating Data Monitoring Committees and to recall the need for their members to receive comprehensive training on the complexities of multiple analyses, confidentiality requirements applying to the results and the need for them to be aware that recommendations to end a trial must be based on data that is robust enough to assess the benefit/risk ratio of the treatment studied.

Influence of chronic ethanol consumption on the neurological severity in patients with acute cerebral ischemia.

BACKGROUND AND PURPOSE: We tested the hypothesis that excessive chronic ethanol consumption is associated with more severe ischemic strokes. METHODS: We recruited patients with supratentorial cerebral ischemia within 48 hours of symptom onset. We defined heavy drinkers by a weekly consumption of ethanol of ≥300 g and severe strokes by a National Institutes of Health Stroke Scale score≥6. RESULTS: Of 436 patients, 60 were heavy drinkers. Being a heavy drinker was independently associated with baseline National Institutes of Health Stroke Scale scores≥6 (odds ratio, 2.35; 95% confidence interval, 1.12-5.26; P=0.023) at the logistic regression analysis. This result was not modified with the propensity analysis. CONCLUSION: An excessive chronic ethanol consumption is associated with higher baseline stroke severity.

Circulating markers of endothelial dysfunction and platelet activation in patients with severe symptomatic cerebral small vessel disease.

BACKGROUND: Small deep infarcts (SDI), also called lacunar infarcts, resulting from the occlusion of deep branch arteries, account for 25% of ischemic strokes. The physiopathology of the disease remains largely unknown. However, evidence about the role of endothelial dysfunction has emerged. Whereas chronic platelet activation is of major importance in acute thrombosis of large atherosclerotic arteries, its role in SDI remains unclear. Frequently associated risk factors are hypertension and diabetes mellitus. The aim of this study was to determine platelet and endothelial activation in patients with recent SDI in comparison to population-based control subjects matched for age, sex and vascular risk factors. METHODS: Platelet activation markers (activated glycoprotein IIb/IIIa, P-selectin and platelet microparticles), shear-induced platelet aggregation (SIPA) studied in the SIPAgreg device at 4,000 s(-1), endothelial activation markers [including von Willebrand factor (vWF) antigen and homocysteine] and high-sensitivity C-reactive protein (hsCRP) were measured in 74 consecutive patients with recent SDI, in whom detectable large artery atherosclerosis or cardiac embolism had been ruled out. Blood samples were collected 1 and 3 months after symptom onset. These factors were also measured in 74 population-based controls with no stroke history and matched for age, sex, hypertension and diabetes. RESULTS: One month after symptom onset, the patients had similar levels of platelet activation to matched controls (p > 0.40 for all comparisons). In contrast, endothelial activation parameters were increased in patients in comparison to controls (vWF: p = 0.002 and homocysteinemia/creatinemia: p = 0.025). The level of hsCRP was slightly increased in patients compared to controls (p = 0.059). At 3 months, we observed a significant decrease in vWF and hsCRP levels in patients (median change in vWF = 10%, p = 0.004; median change in hsCRP = 0.4 mg/l, p = 0.02). Homocysteine levels and all platelet parameters remained unchanged at this time compared to at 1 month. CONCLUSIONS: Our results confirm that chronic platelet activation, when compared to controls matched for age, sex and vascular risk factors, did not seem to play a central role in the pathophysiology of lacunar stroke. In contrast, we found markers of endothelial dysfunction, the role of which in the occurrence of lacunar infarction has still to be clarified in further studies.

Effect of child health status on parents' allowing children to participate in pediatric research.

BACKGROUND: To identify motivational factors linked to child health status that affected the likelihood of parents' allowing their child to participate in pediatric research. METHODS: Parents were invited to return their completed questionnaires anonymously to assess motivational factors and factors that might improve participation in pediatric research. RESULTS: Of 573 eligible parents, 261 returned the completed questionnaires. Of these, 126 were parents of healthy children (group 1), whereas 135 were parents of sick children who were divided into two groups according to the severity of their pathology, i.e., 99 ambulatory children (group 2) and 36 nonambulatory children (group 3). The main factor motivating participation in a pediatric clinical research study was "direct benefits for their child" (87.7%, 100%, and 100% for groups 1, 2, and 3, respectively). The other factors differed significantly between the three groups, depending on the child's health status (all p < 0.05). Factors that might have a positive impact on parental consent to the participation of their child in a pediatric clinical research study differed significantly (χ2 test, all p ≤ 0.04), depending on the child's health status. The main factor was "a better understanding of the study and its regulation" for the healthy children and ambulatory sick children groups (31.2% and 82.1%, respectively), whereas this was the third factor for the nonambulatory sick children group (50%). CONCLUSIONS: Innovative strategies should be developed based on a child's health status to improve information provision when seeking a child's participation in pediatric research. Parents would like to spend more time in discussions with investigators.

Cytomegalovirus in donors for fecal microbiota transplantation, the phantom menace?

BACKGROUND: Fecal Microbiota Transplantation (FMT) has become the preferred treatment for recurrent Clostridioides difficile Infections (CDI). However, donor screening is a complex process that varies between countries. The primary objective of screening is to prevent the transfer of potential pathogens from the donor to the recipient via feces. Many guidelines recommend Cytomegalovirus (CMV) testing as part of donor screening, but is the risk of CMV transmission well supported by evidence? MATERIALS/METHODS: A French prospective cross-sectional multicenter single-arm study estimated the frequency of detection of CMV in the stool of voluntary healthy donors selected for FMT. All preselected donors were tested for CMV antibodies in blood, and if positive, CMV DNA PCR was performed on whole blood and stool. For samples CMV positive in stool PCR, or case of serological markers positive for IgM, we planned isolation of CMV in cell culture. RESULTS: From June 1, 2016, to July 31, 2017, 500 healthy donors (250 per center) were recruited and 483 included. Of these, 301 were CMV seronegative, and 182 tested positive for CMV IgM and/or IgG. Stool CMV PCR was performed in 162 donors. In two cases, the initial analysis was positive, but below the limit of quantification. Repeated PCR tests using Siemens and Altostar assays were negative. No infectious CMV could be detected in cell culture of these two samples and in the stool of 6 CMV IgM-positive donors. CONCLUSIONS: Our study shows that healthy volunteers with positive CMV serology do not shed CMV DNA in their stool, as detected by PCR or cell culture. This study provides another argument to remove CMV screening for FMT donors.

Are anxiety and depression associated with cognition and cardiovascular function in young male and female adults?

The results of recent studies suggested that emotional disorders (such as anxiety and depression), cognitive impairments and cardiovascular disorders are related on the subclinical level. These major health issues are often concomitant and have complex, sex-dependent relationships; it is therefore important to study these issues concomitantly in the general population, in order to gain a better understanding of early-stage subclinical relationships between these conditions. The objective of this exploratory study was to assess correlations between anxiety, depression, cognition, and endothelial function in young adults from the general population. Endothelial function (via the reactive hyperaemia index (RHI) was assessed with a plethysmographic device. Depression and anxiety were self-reported via the Beck Disorder Inventory II and the State-Trait Anxiety Inventory, respectively. The Cambridge Neuropsychological Test Automated Battery was used to measure performances in visuospatial memory, visuospatial working memory, and sustained attention. Performances in inhibition and flexibility were evaluated with the Color Word Interference Test. Forty-four young adults (21 males; mean ± standard deviation age: 25.8 ± 1.1; 23 females; mean age: 25.6 ± 1.4) were included in the study. Anxiety was correlated with a low RHI (r = -0.40, p = 0.015, 95% CI [-0.64, -0.08]). In females, the depression score was positively correlated with the number of errors in the visuospatial memory task (r = 0.42, p = 0.049; 95% CI [-0.002, 0.70]) and visuospatial working memory (r = 0.57, p = 0.005; 95% CI [0.10, 0.79]). In males, high anxiety and depression scores were negatively correlated with the number of errors in visuospatial working memory task (anxiety: r = -0.77, p = 0.001; 95% CI [-0.91, -0.43]; depression r = -0.61, p = 0.004, 95% CI [-0.82, -0.22], respectively). However, the relationship between cognitive performance and RHI was not significant. Our data suggest that anxiety and depression could be differentially related to cognitive and endothelial functions in a non-clinical population of young adults. More research is needed to confirm these results, understand the pathophysiological mechanisms in more details, and assess the importance of a sex-specific approach.

Drug repurposing: From the discovery of a useful pharmacological effect to making the treatment available to the patient.

The repurposing of a medicine already on the market to a new indication could be an opportunity to respond rapidly to a therapeutic need not yet covered, particularly in the context of rare and neglected diseases, or health emergencies. However, at each stage, difficulties may arise that will prevent the repurposed drug from being provided to patients. Beyond fortuity or a systematic strategy to detect a useful pharmacological effect, the implementation of the preclinical and clinical stages is sometimes complicated by the difficulty of accessing the molecule and its pharmaceutical data. Furthermore, relevant clinical results will not always be sufficient to ensure that a marketing authorisation is obtained or that patients receive satisfactory care. In addition to describing these various obstacles, the round table provided an opportunity to put forward recommendations for overcoming them, in particular the creation of a public-private partnership structure with sufficient funding to be able to offer individualised support for projects up to and including the marketing application.

A revisited version of the disputatio for pharmacological training: An educational study.

OBJECTIVE: The disputatio is a pedagogical method existing since the Middle-Ages where students had to debate about a question asked by a "master", exercising their thinking and oratory skills. To move away from traditional vertical teaching methods, the disputatio has been revived by pharmacologists. Thus, for almost three successive years, several groups of young French pharmacologists and therapists confronted their ideas concerning a medical question at a therapeutic impasse. The aim here is to describe the initial feedback received from participants. METHODS: An anonymous questionnaire was sent by email in May 2023 to the participants of the different disputationes of 2019, 2022 and 2023. Participants were asked about different aspects of their feelings before, during and after the disputatio, using the 5-point Likert scale. They were also asked to describe the event in 2 to 5 words. Finally, participants could leave their comments in a free-field and were asked to give an overall satisfaction score out of 10. RESULTS: Out of the 39 participants, 27 (69.2%) answered the questionnaire. Although 50% of respondents reported a feeling of anxiety before participating, most enjoyed the expert talks as well as working with people they did not know. Besides, over 66% reported having underestimated the skills they could share with colleagues from different backgrounds. Over 55% of respondents reported progress in methodology, and over 83% in pharmacology and/or therapeutics. Participants reported an overall satisfaction score of 8.6/10, and the main terms used to describe the event were "sharing", "enriching" and "meeting". CONCLUSION: The disputatio is an innovative training program whose pedagogical and human values were underlined by most of the participants. Beyond pharmacology and therapeutics, the principle of disputatio could be extended to other disciplines, spanning the centuries.

Serum neutralization of SARS coronavirus 2 Omicron sublineages BA.1 and BA.2 and cellular immune responses 3 months after booster vaccination.

OBJECTIVES: We investigated serum neutralizing activity against BA.1 and BA.2 Omicron sublineages and T cell response before and 3 months after administration of the booster vaccine in healthcare workers (HCWs). METHODS: HCWs aged 18-65 years who were vaccinated and received booster doses of the BNT162b2 vaccine were included. Anti-SARS coronavirus 2 IgG levels and cellular response (through interferon γ ELISpot assay) were evaluated in all participants, and neutralizing antibodies against Delta, BA.1, and BA.2 were evaluated in participants with at least one follow-up visit 1 or 3 months after the administration of the booster dose. RESULTS: Among 118 HCWs who received the booster dose, 102 and 84 participants attended the 1-month and 3-month visits, respectively. Before the booster vaccine dose, a low serum neutralizing activity against Delta, BA.1, and BA.2 was detectable in only 39/102 (38.2%), 8/102 (7.8%), and 12/102 (11.8%) participants, respectively. At 3 months, neutralizing antibodies against Delta, BA.1, and BA.2 were detected in 84/84 (100%), 79/84 (94%), and 77/84 (92%) participants, respectively. Geometric mean titres of neutralizing antibodies against BA.1 and BA.2 were 2.2-fold and 2.8-fold reduced compared with those for Delta. From 1 to 3 months after the administration of the booster dose, participants with a recent history of SARS coronavirus 2 infection (n = 21/84) had persistent levels of S1 reactive specific T cells and neutralizing antibodies against Delta and BA.2 and 2.2-fold increase in neutralizing antibodies against BA.1 (p 0.014). Conversely, neutralizing antibody titres against Delta (2.5-fold decrease, p < 0.0001), BA.1 (1.5-fold, p 0.02), and BA.2 (2-fold, p < 0.0001) declined from 1 to 3 months after the administration of the booster dose in individuals without any recent infection. DISCUSSION: The booster vaccine dose provided significant and similar response against BA.1 and BA.2 Omicron sublineages; however, the immune response declined in the absence of recent infection.

Long-COVID cognitive impairments and reproductive hormone deficits in men may stem from GnRH neuronal death.

BACKGROUND: We have recently demonstrated a causal link between loss of gonadotropin-releasing hormone (GnRH), the master molecule regulating reproduction, and cognitive deficits during pathological aging, including Down syndrome and Alzheimer's disease. Olfactory and cognitive alterations, which persist in some COVID-19 patients, and long-term hypotestosteronaemia in SARS-CoV-2-infected men are also reminiscent of the consequences of deficient GnRH, suggesting that GnRH system neuroinvasion could underlie certain post-COVID symptoms and thus lead to accelerated or exacerbated cognitive decline. METHODS: We explored the hormonal profile of COVID-19 patients and targets of SARS-CoV-2 infection in post-mortem patient brains and human fetal tissue. FINDINGS: We found that persistent hypotestosteronaemia in some men could indeed be of hypothalamic origin, favouring post-COVID cognitive or neurological symptoms, and that changes in testosterone levels and body weight over time were inversely correlated. Infection of olfactory sensory neurons and multifunctional hypothalamic glia called tanycytes highlighted at least two viable neuroinvasion routes. Furthermore, GnRH neurons themselves were dying in all patient brains studied, dramatically reducing GnRH expression. Human fetal olfactory and vomeronasal epithelia, from which GnRH neurons arise, and fetal GnRH neurons also appeared susceptible to infection. INTERPRETATION: Putative GnRH neuron and tanycyte dysfunction following SARS-CoV-2 neuroinvasion could be responsible for serious reproductive, metabolic, and mental health consequences in long-COVID and lead to an increased risk of neurodevelopmental and neurodegenerative pathologies over time in all age groups. FUNDING: European Research Council (ERC) grant agreements No 810331, No 725149, No 804236, the European Union Horizon 2020 research and innovation program No 847941, the Fondation pour la Recherche Médicale (FRM) and the Agence Nationale de la Recherche en Santé (ANRS) No ECTZ200878 Long Covid 2021 ANRS0167 SIGNAL, Agence Nationale de la recherche (ANR) grant agreements No ANR-19-CE16-0021-02, No ANR-11-LABEX-0009, No. ANR-10-LABEX-0046, No. ANR-16-IDEX-0004, Inserm Cross-Cutting Scientific Program HuDeCA, the CHU Lille Bonus H, the UK Medical Research Council (MRC) and National Institute of Health and care Research (NIHR).