Protection from SARS-CoV-2 Delta one year after mRNA-1273 vaccination in rhesus macaques coincides with anamnestic antibody response in the lung.

mRNA-1273 vaccine efficacy against SARS-CoV-2 Delta wanes over time; however, there are limited data on the impact of durability of immune responses on protection. Here, we immunized rhesus macaques and assessed immune responses over 1 year in blood and upper and lower airways. Serum neutralizing titers to Delta were 280 and 34 reciprocal ID50 at weeks 6 (peak) and 48 (challenge), respectively. Antibody-binding titers also decreased in bronchoalveolar lavage (BAL). Four days after Delta challenge, the virus was unculturable in BAL, and subgenomic RNA declined by ∼3-log10 compared with control animals. In nasal swabs, sgRNA was reduced by 1-log10, and the virus remained culturable. Anamnestic antibodies (590-fold increased titer) but not T cell responses were detected in BAL by day 4 post-challenge. mRNA-1273-mediated protection in the lungs is durable but delayed and potentially dependent on anamnestic antibody responses. Rapid and sustained protection in upper and lower airways may eventually require a boost.

mRNA-1273 or mRNA-Omicron boost in vaccinated macaques elicits similar B cell expansion, neutralizing responses, and protection from Omicron.

SARS-CoV-2 Omicron is highly transmissible and has substantial resistance to neutralization following immunization with ancestral spike-matched vaccines. It is unclear whether boosting with Omicron-matched vaccines would enhance protection. Here, nonhuman primates that received mRNA-1273 at weeks 0 and 4 were boosted at week 41 with mRNA-1273 or mRNA-Omicron. Neutralizing titers against D614G were 4,760 and 270 reciprocal ID50 at week 6 (peak) and week 41 (preboost), respectively, and 320 and 110 for Omicron. 2 weeks after the boost, titers against D614G and Omicron increased to 5,360 and 2,980 for mRNA-1273 boost and 2,670 and 1,930 for mRNA-Omicron, respectively. Similar increases against BA.2 were observed. Following either boost, 70%-80% of spike-specific B cells were cross-reactive against WA1 and Omicron. Equivalent control of virus replication in lower airways was observed following Omicron challenge 1 month after either boost. These data show that mRNA-1273 and mRNA-Omicron elicit comparable immunity and protection shortly after the boost.

mRNA-1273 protects against SARS-CoV-2 beta infection in nonhuman primates.

B.1.351 is the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant most resistant to antibody neutralization. We demonstrate how the dose and number of immunizations influence protection. Nonhuman primates received two doses of 30 or 100 µg of Moderna's mRNA-1273 vaccine, a single immunization of 30 µg, or no vaccine. Two doses of 100 µg of mRNA-1273 induced 50% inhibitory reciprocal serum dilution neutralizing antibody titers against live SARS-CoV-2 p.Asp614Gly and B.1.351 of 3,300 and 240, respectively. Higher neutralizing responses against B.1.617.2 were also observed after two doses compared to a single dose. After challenge with B.1.351, there was ~4- to 5-log10 reduction of viral subgenomic RNA and low to undetectable replication in bronchoalveolar lavages in the two-dose vaccine groups, with a 1-log10 reduction in nasal swabs in the 100-µg group. These data establish that a two-dose regimen of mRNA-1273 will be critical for providing upper and lower airway protection against major variants of concern.

A global survey on the attitudes of neurologists and psychiatrists about functional/psychogenic/dissociative/nonepileptic-seizures/attacks, in the search of its name.

PURPOSE: We conducted an observational study to investigate the opinions of neurologists and psychiatrists all around the world who are taking care of patients with seizures [epilepsy and functional seizures (FS)]. METHODS: Practicing neurologists and psychiatrists from around the world were invited to participate in an online survey. On 29th September 2022, an e-mail including a questionnaire was sent to the members of the International Research in Epilepsy (IR-Epil) Consortium. The study was closed on 1st March 2023. The survey, conducted in English, included questions about physicians' opinions about FS and anonymously collected data. RESULTS: In total, 1003 physicians from different regions of the world participated in the study. Both neurologists and psychiatrists identified "seizures" as their preferred term. Overall, the most preferred modifiers for "seizures" were "psychogenic" followed by "functional" by both groups. Most participants (57.9%) considered FS more difficult to treat compared to epilepsy. Both psychological and biological problems were considered as the underlying cause of FS by 61% of the respondents. Psychotherapy was considered the first treatment option for patients with FS (79.9%). CONCLUSION: Our study represents the first large-scale attempt of investigating physicians attitudes and opinions about a condition that is both frequent and clinically important. It shows that there is a broad spectrum of terms used by physicians to refer to FS. It also suggests that the biopsychosocial model has gained its status as a widely used framework to interpret and inform clinical practice on the management of patients.

Counseling about sudden unexpected death in epilepsy (SUDEP): A global survey of neurologists' opinions.

OBJECTIVE: To investigate the opinions and attitudes of neurologists on the counseling about sudden unexpected death in epilepsy (SUDEP) worldwide. METHODS: Practicing neurologists from around the world were invited to participate in an online survey. On February 18th, 2021, we emailed an invitation including a questionnaire (using Google-forms) to the lead neurologists from 50 countries. The survey anonymously collected the demographic data of the participants and answers to the questions about their opinions and attitudes toward counseling about SUDEP. RESULTS: In total, 1123 neurologists from 27 countries participated; 41.5% of the respondents reported they discuss the risk of SUDEP with patients and their care-givers only rarely. Specific subgroups of patients who should especially be told about this condition were considered to be those with poor antiseizure medication (ASM) adherence, frequent tonic-clonic seizures, or with drug-resistant epilepsy. The propensity to tell all patients with epilepsy (PWE) about SUDEP was higher among those with epilepsy fellowship. Having an epilepsy fellowship and working in an academic setting were factors associated with a comfortable discussion about SUDEP. There were significant differences between the world regions. CONCLUSION: Neurologists often do not discuss SUDEP with patients and their care-givers. While the results of this study may not be representative of practitioners in each country, it seems that there is a severe dissociation between the clinical significance of SUDEP and the amount of attention that is devoted to this matter in daily practice by many neurologists around the world.

Complementary and alternative medicine in epilepsy: A global survey of physicians' opinions.

PURPOSE: To investigate the opinions of physicians on the use of complementary and alternative medicine (CAM) in patients with epilepsy (PWE) worldwide. METHODS: Online survey addressed to neurologists and psychiatrists from different countries. RESULTS: Totally, 1112 physicians from 25 countries (different world region: Europe, North America, South America, Middle-East, Africa, Former Soviet Union Republics) participated; 804 (72.3%) believed that CAM might be helpful in PWE. The most commonly endorsed CAM included meditation (41%) and yoga (39%). Female sex, psychiatry specialization, and working in North and South America were associated with the belief that CAM is helpful in PWE. Two-hundred and forty five out of 1098 participants (22.3%) used/prescribed CAM to PWE; among them, 174 (71%) people perceived CAM to be less effective and 114 (46.5%) people found CAM to be safer than conventional antiseizure medications (ASMs). The most common reasons to prescribe CAM for PWE were: to satisfy the patient (49.9%), dissatisfaction with the efficacy (35.6%), and dissatisfaction with the adverse effects (31.2%) of conventional therapies. CONCLUSION: Although the evidence supporting the use of CAM for the treatment of epilepsy is extremely sparse, most physicians worldwide believe that it could be integrated with the use of conventional ASMs, at least in some patients. High-quality controlled trials are warranted to provide robust evidence on the usefulness of CAM options in PWE.

Prevalence of Mild Cognitive Impairment Among Older People in Kazakhstan and Potential Risk Factors: A Cross-sectional Study.

BACKGROUND: There have been no epidemiological studies of mild cognitive impairment (MCI) in Central Asia. OBJECTIVE: The objective of this study was to describe the prevalence of, and risk factors for, MCI in an urban population in Kazakhstan. METHODS: Adults aged 60 years and over were randomly selected from registers of 15 polyclinics in Almaty. Of 790 eligible people, 668 agreed to participate (response rate 85%). Subjects were screened using the Montreal Cognitive Assessment (MoCA). Those who scored 26 or lower on the MoCA were assessed by a multidisciplinary team and a diagnosis of normal cognition, MCI or dementia was made. RESULTS: The median MoCA score was 22 and the prevalence of MCI was 30%. MoCA scores were lower, and MCI prevalence was higher, among those with less education and those with older age. There was no difference in MoCA scores or MCI prevalence by sex or ethnic group (Kazakh or Russian). High blood pressure, older age, and lower education were associated with increased odds of MCI in crude analyses but only age and education remained statistically significant in an adjusted logistic regression model. CONCLUSIONS: The prevalence of MCI in Kazakhstan is high. Higher levels of education may lead to lower prevalence of MCI in the future.

Phase-stable, multi-µJ femtosecond pulses from a repetition-rate tunable Ti:Sa-oscillator-seeded Yb-fiber amplifier.

We present a high-power, MHz-repetition-rate, phase-stable femtosecond laser system based on a phase-stabilized Ti:Sa oscillator and a multi-stage Yb-fiber chirped-pulse power amplifier. A 10-nm band around 1030 nm is split from the 7-fs oscillator output and serves as the seed for subsequent amplification by 54 dB to 80 W of average power. The µJ-level output is spectrally broadened in a solid-core fiber and compressed to ~30 fs with chirped mirrors. A pulse picker prior to power amplification allows for decreasing the repetition rate from 74 MHz by a factor of up to 4 without affecting the pulse parameters. To compensate for phase jitter added by the amplifier to the feed-forward phase-stabilized seeding pulses, a self-referencing feed-back loop is implemented at the system output. An integrated out-of-loop phase noise of less than 100 mrad was measured in the band from 0.4 Hz to 400 kHz, which to the best of our knowledge corresponds to the highest phase stability ever demonstrated for high-power, multi-MHz-repetition-rate ultrafast lasers. This system will enable experiments in attosecond physics at unprecedented repetition rates, it offers ideal prerequisites for the generation and field-resolved electro-optical sampling of high-power, broadband infrared pulses, and it is suitable for phase-stable white light generation.

Femtosecond Enhancement Cavities in the Nonlinear Regime.

We combine high-finesse optical resonators and spatial-spectral interferometry to a highly phase-sensitive investigation technique for nonlinear light-matter interactions. We experimentally validate an ab initio model for the nonlinear response of a resonator housing a gas target, permitting the global optimization of intracavity conversion processes like high-order harmonic generation. We predict the feasibility of driving intracavity high-order harmonic generation far beyond intensity limitations observed in state-of-the-art systems by exploiting the intracavity nonlinearity to compress the pulses in time.

Physicians' beliefs about brain surgery for drug-resistant epilepsy: A global survey.

PURPOSE: To investigate the opinions of physicians about brain surgery for drug-resistant epilepsy worldwide. METHODS: Practicing neurologists, psychiatrists, and neurosurgeons from around the world were invited to participate in an online survey. The survey anonymously collected data about demographics, years in clinical practice, discipline, nation, work setting, and answers to the questions about beliefs and attitudes about brain surgery for drug-resistant epilepsy. RESULTS: In total, 1410 physicians from 20 countries and different world regions participated. The propensity to discuss brain surgery with patients, who have drug-resistant seizures, was higher among men (versus women) [Odds Ratio (OR) 1.67, 95% CI 1.20-2.31; p = 0.002]. In comparison to neurologists, psychiatrists were less likely (OR 0.28, 95% CI 0.17-0.47; p < 0.001) and neurosurgeons were more likely (OR 2.00, 95% CI 1.08-3.72; p = 0.028) to discuss about it. Survey participants working in Africa, Asia, the Middle East, and the Former Union of Soviet Socialist Republics showed a lower propensity to discuss epilepsy surgery with patients. CONCLUSION: This study showed that on an international level, there is still a knowledge gap concerning epilepsy surgery and much needs to be done to identify and overcome barriers to epilepsy surgery for patients with drug-resistant seizures worldwide.

Attosecond intra-valence band dynamics and resonant-photoemission delays in W(110).

Time-resolved photoelectron spectroscopy with attosecond precision provides new insights into the photoelectric effect and gives information about the timing of photoemission from different electronic states within the electronic band structure of solids. Electron transport, scattering phenomena and electron-electron correlation effects can be observed on attosecond time scales by timing photoemission from valence band states against that from core states. However, accessing intraband effects was so far particularly challenging due to the simultaneous requirements on energy, momentum and time resolution. Here we report on an experiment utilizing intracavity generated attosecond pulse trains to meet these demands at high flux and high photon energies to measure intraband delays between sp- and d-band states in the valence band photoemission from tungsten and investigate final-state effects in resonant photoemission.

Evaluation of mRNA-1273 against SARS-CoV-2 B.1.351 Infection in Nonhuman Primates.

BACKGROUND: Vaccine efficacy against the B.1.351 variant following mRNA-1273 vaccination in humans has not been determined. Nonhuman primates (NHP) are a useful model for demonstrating whether mRNA-1273 mediates protection against B.1.351. METHODS: Nonhuman primates received 30 or 100 µg of mRNA-1273 as a prime-boost vaccine at 0 and 4 weeks, a single immunization of 30 µg at week 0, or no vaccine. Antibody and T cell responses were assessed in blood, bronchioalveolar lavages (BAL), and nasal washes. Viral replication in BAL and nasal swabs were determined by qRT-PCR for sgRNA, and histopathology and viral antigen quantification were performed on lung tissue post-challenge. RESULTS: Eight weeks post-boost, 100 µg x2 of mRNA-1273 induced reciprocal ID 50 neutralizing geometric mean titers against live SARS-CoV-2 D614G and B.1.351 of 3300 and 240, respectively, and 430 and 84 for the 30 µg x2 group. There were no detectable neutralizing antibodies against B.1351 after the single immunization of 30 µg. On day 2 following B.1.351 challenge, sgRNA in BAL was undetectable in 6 of 8 NHP that received 100 µg x2 of mRNA-1273, and there was a ∼2-log reduction in sgRNA in NHP that received two doses of 30 µg compared to controls. In nasal swabs, there was a 1-log 10 reduction observed in the 100 µg x2 group. There was limited inflammation or viral antigen in lungs of vaccinated NHP post-challenge. CONCLUSIONS: Immunization with two doses of mRNA-1273 achieves effective immunity that rapidly controls lower and upper airway viral replication against the B.1.351 variant in NHP.

Immune Correlates of Protection by mRNA-1273 Immunization against SARS-CoV-2 Infection in Nonhuman Primates.

Immune correlates of protection can be used as surrogate endpoints for vaccine efficacy. The nonhuman primate (NHP) model of SARS-CoV-2 infection replicates key features of human infection and may be used to define immune correlates of protection following vaccination. Here, NHP received either no vaccine or doses ranging from 0.3 - 100 µg of mRNA-1273, a mRNA vaccine encoding the prefusion-stabilized SARS-CoV-2 spike (S-2P) protein encapsulated in a lipid nanoparticle. mRNA-1273 vaccination elicited robust circulating and mucosal antibody responses in a dose-dependent manner. Viral replication was significantly reduced in bronchoalveolar lavages and nasal swabs following SARS-CoV-2 challenge in vaccinated animals and was most strongly correlated with levels of anti-S antibody binding and neutralizing activity. Consistent with antibodies being a correlate of protection, passive transfer of vaccine-induced IgG to naïve hamsters was sufficient to mediate protection. Taken together, these data show that mRNA-1273 vaccine-induced humoral immune responses are a mechanistic correlate of protection against SARS-CoV-2 infection in NHP. ONE-SENTENCE SUMMARY: mRNA-1273 vaccine-induced antibody responses are a mechanistic correlate of protection against SARS-CoV-2 infection in NHP.

Protective antibodies elicited by SARS-CoV-2 spike protein vaccination are boosted in the lung after challenge in nonhuman primates.

Adjuvanted soluble protein vaccines have been used extensively in humans for protection against various viral infections based on their robust induction of antibody responses. Here, soluble prefusion-stabilized spike protein trimers (preS dTM) from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) were formulated with the adjuvant AS03 and administered twice to nonhuman primates (NHPs). Binding and functional neutralization assays and systems serology revealed that the vaccinated NHP developed AS03-dependent multifunctional humoral responses that targeted distinct domains of the spike protein and bound to a variety of Fc receptors mediating immune cell effector functions in vitro. The neutralizing 50% inhibitory concentration titers for pseudovirus and live SARS-CoV-2 were higher than titers for a panel of human convalescent serum samples. NHPs were challenged intranasally and intratracheally with a high dose (3 × 106 plaque forming units) of SARS-CoV-2 (USA-WA1/2020 isolate). Two days after challenge, vaccinated NHPs showed rapid control of viral replication in both the upper and lower airways. Vaccinated NHPs also had increased spike protein-specific immunoglobulin G (IgG) antibody responses in the lung as early as 2 days after challenge. Moreover, passive transfer of vaccine-induced IgG to hamsters mediated protection from subsequent SARS-CoV-2 challenge. These data show that antibodies induced by the AS03-adjuvanted preS dTM vaccine were sufficient to mediate protection against SARS-CoV-2 in NHPs and that rapid anamnestic antibody responses in the lung may be a key mechanism for protection.

Immune correlates of protection by mRNA-1273 vaccine against SARS-CoV-2 in nonhuman primates.

Immune correlates of protection can be used as surrogate endpoints for vaccine efficacy. Here, nonhuman primates (NHPs) received either no vaccine or doses ranging from 0.3 to 100 µg of the mRNA-1273 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine. mRNA-1273 vaccination elicited circulating and mucosal antibody responses in a dose-dependent manner. Viral replication was significantly reduced in bronchoalveolar lavages and nasal swabs after SARS-CoV-2 challenge in vaccinated animals and most strongly correlated with levels of anti­S antibody and neutralizing activity. Lower antibody levels were needed for reduction of viral replication in the lower airway than in the upper airway. Passive transfer of mRNA-1273­induced immunoglobulin G to naïve hamsters was sufficient to mediate protection. Thus, mRNA-1273 vaccine­induced humoral immune responses are a mechanistic correlate of protection against SARS-CoV-2 in NHPs.

Protection from SARS-CoV-2 Delta one year after mRNA-1273 vaccination in nonhuman primates is coincident with an anamnestic antibody response in the lower airway.

mRNA-1273 vaccine efficacy against SARS-CoV-2 Delta wanes over time; however, there are limited data on the impact of durability of immune responses on protection. We immunized rhesus macaques at weeks 0 and 4 and assessed immune responses over one year in blood, upper and lower airways. Serum neutralizing titers to Delta were 280 and 34 reciprocal ID 50 at weeks 6 (peak) and 48 (challenge), respectively. Antibody binding titers also decreased in bronchoalveolar lavage (BAL). Four days after challenge, virus was unculturable in BAL and subgenomic RNA declined ∼3-log 10 compared to control animals. In nasal swabs, sgRNA declined 1-log 10 and virus remained culturable. Anamnestic antibody responses (590-fold increase) but not T cell responses were detected in BAL by day 4 post-challenge. mRNA-1273-mediated protection in the lungs is durable but delayed and potentially dependent on anamnestic antibody responses. Rapid and sustained protection in upper and lower airways may eventually require a boost.

Protection against SARS-CoV-2 Beta Variant in mRNA-1273 Boosted Nonhuman Primates.

Neutralizing antibody responses gradually wane after vaccination with mRNA-1273 against several variants of concern (VOC), and additional boost vaccinations may be required to sustain immunity and protection. Here, we evaluated the immune responses in nonhuman primates that received 100 µg of mRNA-1273 vaccine at 0 and 4 weeks and were boosted at week 29 with mRNA-1273 (homologous) or mRNA-1273.ß (heterologous), which encompasses the spike sequence of the B.1.351 (beta or ß) variant. Reciprocal ID 50 pseudovirus neutralizing antibody geometric mean titers (GMT) against live SARS-CoV-2 D614G and the ß variant, were 4700 and 765, respectively, at week 6, the peak of primary response, and 644 and 553, respectively, at a 5-month post-vaccination memory time point. Two weeks following homologous or heterologous boost ß-specific reciprocal ID 50 GMT were 5000 and 3000, respectively. At week 38, animals were challenged in the upper and lower airway with the ß variant. Two days post-challenge, viral replication was low to undetectable in both BAL and nasal swabs in most of the boosted animals. These data show that boosting with the homologous mRNA-1273 vaccine six months after primary immunization provides up to a 20-fold increase in neutralizing antibody responses across all VOC, which may be required to sustain high-level protection against severe disease, especially for at-risk populations. ONE-SENTENCE SUMMARY: mRNA-1273 boosted nonhuman primates have increased immune responses and are protected against SARS-CoV-2 beta infection.

Protection against SARS-CoV-2 Beta variant in mRNA-1273 vaccine-boosted nonhuman primates.

Neutralizing antibody responses gradually wane against several variants of concern (VOCs) after vaccination with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine messenger RNA-1273 (mRNA-1273). We evaluated the immune responses in nonhuman primates that received a primary vaccination series of mRNA-1273 and were boosted about 6 months later with either homologous mRNA-1273 or heterologous mRNA-1273.ß, which encompasses the spike sequence of the B.1.351 Beta variant. After boost, animals had increased neutralizing antibody responses across all VOCs, which was sustained for at least 8 weeks after boost. Nine weeks after boost, animals were challenged with the SARS-CoV-2 Beta variant. Viral replication was low to undetectable in bronchoalveolar lavage and significantly reduced in nasal swabs in all boosted animals, suggesting that booster vaccinations may be required to sustain immunity and protection.

Vaccination with SARS-CoV-2 Spike Protein and AS03 Adjuvant Induces Rapid Anamnestic Antibodies in the Lung and Protects Against Virus Challenge in Nonhuman Primates.

Adjuvanted soluble protein vaccines have been used extensively in humans for protection against various viral infections based on their robust induction of antibody responses. Here, soluble prefusion-stabilized spike trimers (preS dTM) from the severe acute respiratory syndrome coronavirus (SARS-CoV-2) were formulated with the adjuvant AS03 and administered twice to nonhuman primates (NHP). Binding and functional neutralization assays and systems serology revealed that NHP developed AS03-dependent multi-functional humoral responses that targeted multiple spike domains and bound to a variety of antibody FC receptors mediating effector functions in vitro. Pseudovirus and live virus neutralizing IC50 titers were on average greater than 1000 and significantly higher than a panel of human convalescent sera. NHP were challenged intranasally and intratracheally with a high dose (3×106 PFU) of SARS-CoV-2 (USA-WA1/2020 isolate). Two days post-challenge, vaccinated NHP showed rapid control of viral replication in both the upper and lower airways. Notably, vaccinated NHP also had increased spike-specific IgG antibody responses in the lung as early as 2 days post challenge. Moreover, vaccine-induced IgG mediated protection from SARS-CoV-2 challenge following passive transfer to hamsters. These data show that antibodies induced by the AS03-adjuvanted preS dTM vaccine are sufficient to mediate protection against SARS-CoV-2 and support the evaluation of this vaccine in human clinical trials.

High-flux ultrafast extreme-ultraviolet photoemission spectroscopy at 18.4 MHz pulse repetition rate.

Laser-dressed photoelectron spectroscopy, employing extreme-ultraviolet attosecond pulses obtained by femtosecond-laser-driven high-order harmonic generation, grants access to atomic-scale electron dynamics. Limited by space charge effects determining the admissible number of photoelectrons ejected during each laser pulse, multidimensional (i.e. spatially or angle-resolved) attosecond photoelectron spectroscopy of solids and nanostructures requires high-photon-energy, broadband high harmonic sources operating at high repetition rates. Here, we present a high-conversion-efficiency, 18.4-MHz-repetition-rate cavity-enhanced high harmonic source emitting 5 × 105 photons per pulse in the 25-to-60-eV range, releasing 1 × 1010 photoelectrons per second from a 10-µm-diameter spot on tungsten, at space charge distortions of only a few tens of meV. Broadband, time-of-flight photoelectron detection with nearly 100% temporal duty cycle evidences a count rate improvement between two and three orders of magnitude over state-of-the-art attosecond photoelectron spectroscopy experiments under identical space charge conditions. The measurement time reduction and the photon energy scalability render this technology viable for next-generation, high-repetition-rate, multidimensional attosecond metrology.