Association of a Third Dose of BNT162b2 Vaccine With Incidence of SARS-CoV-2 Infection Among Health Care Workers in Israel.

Importance: Administration of a BNT162b2 booster dose (Pfizer-BioNTech) to fully vaccinated individuals aged 60 years and older was significantly associated with lower risk of SARS-CoV-2 infection and severe illness. Data are lacking on the effectiveness of booster doses for younger individuals and health care workers. Objective: To estimate the association of a BNT162b2 booster dose with SARS-CoV-2 infections among health care workers who were previously vaccinated with a 2-dose series of BNT162b2. Design, Setting, and Participants: This was a prospective cohort study conducted at a tertiary medical center in Tel Aviv, Israel. The study cohort included 1928 immunocompetent health care workers who were previously vaccinated with a 2-dose series of BNT162b2, and had enrolled between August 8 and 19, 2021, with final follow-up reported through September 20, 2021. Screening for SARS-CoV-2 infection was performed every 14 days. Anti-spike protein receptor binding domain IgG titers were determined at baseline and 1 month after enrollment. Cox regression with time-dependent analysis was used to estimate hazard ratios of SARS-CoV-2 infection between booster-immunized status and 2-dose vaccinated (booster-nonimmunized) status. Exposures: Vaccination with a booster dose of BNT162b2 vaccine. Main Outcomes and Measures: The primary outcome was SARS-CoV-2 infection, as confirmed by reverse transcriptase-polymerase chain reaction. Results: Among 1928 participants, the median age was 44 years (IQR, 36-52 years) and 1381 were women (71.6%). Participants completed the 2-dose vaccination series a median of 210 days (IQR, 205-213 days) before study enrollment. A total of 1650 participants (85.6%) received the booster dose. During a median follow-up of 39 days (IQR, 35-41 days), SARS-CoV-2 infection occurred in 44 participants (incidence rate, 60.2 per 100 000 person-days); 31 (70.5%) were symptomatic. Five SARS-CoV-2 infections occurred in booster-immunized participants and 39 in booster-nonimmunized participants (incidence rate, 12.8 vs 116 per 100 000 person-days, respectively). In a time-dependent Cox regression analysis, the adjusted hazard ratio of SARS-CoV-2 infection for booster-immunized vs booster-nonimmunized participants was 0.07 (95% CI, 0.02-0.20). Conclusions and Relevance: Among health care workers at a single center in Israel who were previously vaccinated with a 2-dose series of BNT162b2, administration of a booster dose compared with not receiving one was associated with a significantly lower rate of SARS-CoV-2 infection over a median of 39 days of follow-up. Ongoing surveillance is required to assess durability of the findings.

Prevalence of Iron Deficiency and Iron Deficiency Anemia in Strenuously Training Male Army Recruits.

OBJECTIVES: The objectives of our study were to determine the effect of strenuous physical training on the prevalence of iron deficiency anemia (IDA), iron deficiency (ID) with normal hemoglobin (Hb), and anemia without ID. METHODS: Our study was a prospective observational study. We followed 115 healthy male recruits in the Israel Defense Forces elite units during 15 months of training. Blood samples were collected at recruitment and at 6-, 9- and 15-month follow-ups. RESULTS: Upon recruitment, anemia (Hb < 14 g/dL), ID, and ID anemia (IDA) were diagnosed in 28, 31, and 9% of individuals, respectively. Sixty-three subjects (54%) were followed for 6 months; 9 of them (14%) developed new-onset IDA. Among them, the prevalence of anemia rose from 19 to 52%, and ID from 33 to 35%. At the 15-month follow-up, 29% had developed new-onset IDA and 65% showed evidence of ID. CONCLUSION: We report a high prevalence of anemia, ID, and IDA among young healthy males participating in prolonged strenuous training programs. These findings can be partly explained by the physiological changes associated with strenuous physical activity. Further investigations aiming to develop specific diagnostic guidelines for this unique population are warranted.

Impaired Serotonergic Brainstem Function during and after Seizures.

Impaired breathing, cardiac function, and arousal during and after seizures are important causes of morbidity and mortality. Previous work suggests that these changes are associated with depressed brainstem function in the ictal and post-ictal periods. Lower brainstem serotonergic systems are postulated to play an important role in cardiorespiratory changes during and after seizures, whereas upper brainstem serotonergic and other systems regulate arousal. However, direct demonstration of seizure-associated neuronal activity changes in brainstem serotonergic regions has been lacking. Here, we performed multiunit and single-unit recordings from medullary raphe and midbrain dorsal raphe nuclei in an established rat seizure model while measuring changes in breathing rate and depth as well as heart rate. Serotonergic neurons were identified by immunohistochemistry. Respiratory rate, tidal volume, and minute ventilation were all significantly decreased during and after seizures in this model. We found that population firing of neurons in the medullary and midbrain raphe on multiunit recordings was significantly decreased during the ictal and post-ictal periods. Single-unit recordings from identified serotonergic neurons in the medullary raphe revealed highly consistently decreased firing during and after seizures. In contrast, firing of midbrain raphe serotonergic neurons was more variable, with a mixture of increases and decreases. The markedly suppressed firing of medullary serotonergic neurons supports their possible role in simultaneously impaired cardiorespiratory function in seizures. Decreased arousal likely arises from depressed population activity of several neuronal pools in the upper brainstem and forebrain. These findings have important implications for preventing morbidity and mortality in people living with epilepsy. SIGNIFICANCE STATEMENT: Seizures often cause impaired breathing, cardiac dysfunction, and loss of consciousness. The brainstem and, specifically, brainstem serotonin neurons are thought to play an important role in controlling breathing, cardiac function, and arousal. We used an established rat seizure model to study the overall neuronal activity in the brainstem as well as firing of specific serotonin neurons while measuring cardiorespiratory function. Our results demonstrated overall decreases in brainstem neuronal activity and marked downregulation of lower brainstem serotonin neuronal firing in association with decreased breathing and heart rate during and after seizures. These findings point the way toward new treatments to augment brainstem function and serotonin, aiming to prevent seizure complications and reduce morbidity and mortality in people living with epilepsy.

Optogenetic stimulation of cholinergic brainstem neurons during focal limbic seizures: Effects on cortical physiology.

Focal temporal lobe seizures often cause impaired cortical function and loss of consciousness. Recent work suggests that the mechanism for depressed cortical function during focal seizures may depend on decreased subcortical cholinergic arousal, which leads to a sleep-like state of cortical slow-wave activity. To test this hypothesis, we sought to directly activate subcortical cholinergic neurons during focal limbic seizures to determine the effects on cortical function. Here we used an optogenetic approach to selectively stimulate cholinergic brainstem neurons in the pedunculopontine tegmental nucleus during focal limbic seizures induced in a lightly anesthetized rat model. We found an increase in cortical gamma activity and a decrease in delta activity in response to cholinergic stimulation. These findings support the mechanistic role of reduced subcortical cholinergic arousal in causing cortical dysfunction during seizures. Through further work, electrical or optogenetic stimulation of subcortical arousal networks may ultimately lead to new treatments aimed at preventing cortical dysfunction during seizures.

Competition driven by retinal waves promotes morphological and functional synaptic development of neurons in the superior colliculus.

Prior to eye opening, waves of spontaneous activity sweep across the developing retina. These "retinal waves," together with genetically encoded molecular mechanisms, mediate the formation of visual maps in the brain. However, the specific role of wave activity in synapse development in retino-recipient brain regions is unclear. Here we compare the functional development of synapses and the morphological development of neurons in the superior colliculus (SC) of wild-type (WT) and transgenic (ß2-TG) mice in which retinal wave propagation is spatially truncated (Xu HP, Furman M, Mineur YS, Chen H, King SL, Zenisek D, Zhou ZJ, Butts DA, Tian N, Picciotto MR, Crair MC. Neuron 70: 1115-1127, 2011). We use two recently developed brain slice preparations to examine neurons and synapses in the binocular vs. mainly monocular SC. We find that retinocollicular synaptic strength is reduced whereas the number of retinal inputs is increased in the binocular SC of ß2-TG mice compared with WT mice. In contrast, in the mainly monocular SC the number of retinal inputs is normal in ß2-TG mice, but, transiently, synapses are abnormally strong, possibly because of enhanced activity-dependent competition between local, "small" retinal wave domains. These findings demonstrate that retinal wave size plays an instructive role in the synaptic and morphological development of SC neurons, possibly through a competitive process among retinofugal axons.

Synapse maturation is enhanced in the binocular region of the retinocollicular map prior to eye opening.

In the developing visual system of mammals, retinal axons from the two eyes compete for postsynaptic partners. After eye opening, this process is regulated in part by homeostatically constrained competition for synaptic connectivity with target neurons. However, prior to eye opening, the functional and synaptic basis of binocular map development is unclear. To examine the role of binocular interactions during early stages of visual map development, we performed in vitro patch-clamp recordings from the superior colliculus (SC) of neonatal mice. Using newly designed slice preparations, we compared retinocollicular synapse development in the medial SC, which receives binocular input, and the lateral SC, which is predominantly monocular. Surprisingly, we found that at P6-7, when eye-specific segregation has just emerged, retinocollicular synapses were stronger and more mature and dendritic arbors were more elaborate in the medial than the lateral SC. Furthermore, monocular enucleation of the ipsilateral eye at P0 selectively reduced synaptic strength and dendritic branching in the medial SC and abolished the differences normally observed between the two slices at P6-7. This specifically implicates binocular interactions in the development of retinocollicular connectivity prior to eye opening. Our findings contrast with the predictions of a constrained-connectivity model of binocular map development and suggest instead that binocular competition prior to eye opening enhances retinocollicular synaptic strength and the morphological development of retino-recipient neurons.

Alteration of the perceived path of a non-pursued target during smooth pursuit: analysis by a neural network model.

During pursuit of a circularly moving target, the perceived movement of a second circularly moving target is altered. The perceived movement of the non-pursued target is different from both its real movement path and its retinal path. In the present paper this phenomenon is studied using a physiologically based neural network model. Simulation results were compared to psychophysical findings in human subjects. Model simulations enabled us to suggest an explanation for this phenomenon in terms of underlying physiological mechanisms and to estimate the contribution of the efferent eye-movement signal to the perceptual process.

Self-organizing neural network model of motion processing in the visual cortex during smooth pursuit.

A physiologically based neural network model was constructed to study cortical motion processing during pursuit eye movements. The model consists of three layers of computational units, simulating information processing by direction selective neurons in the primary visual cortex (V1), motion selective neurons in the middle-temporal area, and pursuit selective neurons in the middle-superior-temporal (MST) area. MST units integrate visual and eye-movement related information, and their connections develop during an unsupervised training process. The resulting MST units represent a transition from retinal to real-world reference frame. By analyzing the model connectivity, mechanisms underlying the functions performed by the network are studied.

Impaired consciousness in partial seizures is bimodally distributed.

OBJECTIVE: To investigate whether impaired consciousness in partial seizures can usually be attributed to specific deficits in the content of consciousness or to a more general decrease in the overall level of consciousness. METHODS: Prospective testing during partial seizures was performed in patients with epilepsy using the Responsiveness in Epilepsy Scale (n = 83 partial seizures, 30 patients). Results were compared with responsiveness scores in a cohort of patients with severe traumatic brain injury evaluated with the JFK Coma Recovery Scale-Revised (n = 552 test administrations, 184 patients). RESULTS: Standardized testing during partial seizures reveals a bimodal scoring distribution, such that most patients were either fully impaired or relatively spared in their ability to respond on multiple cognitive tests. Seizures with impaired performance on initial test items remained consistently impaired on subsequent items, while other seizures showed spared performance throughout. In the comparison group, we found that scores of patients with brain injury were more evenly distributed across the full range in severity of impairment. CONCLUSIONS: Partial seizures can often be cleanly separated into those with vs without overall impaired responsiveness. Results from similar testing in a comparison group of patients with brain injury suggest that the bimodal nature of Responsiveness in Epilepsy Scale scores is not a result of scale bias but may be a finding unique to partial seizures. These findings support a model in which seizures either propagate or do not propagate to key structures that regulate overall arousal and thalamocortical function. Future investigations are needed to relate these behavioral findings to the physiology underlying impaired consciousness in partial seizures.

And yet it moves: perceptual illusions and neural mechanisms of pursuit compensation during smooth pursuit eye movements.

Pursuit eye movements are smooth rotations of the eye aimed at tracking moving objects. During pursuit, the visual system "compensates" for the eye movements, and transforms image movements captured by the eye from retinal to extra-retinal coordinates, for world-centered perception and action. When this function is impaired such as in schizophrenia, subjects misattribute retinal movements generated by their own eye movements to external sources. Surprisingly, even in healthy subjects pursuit compensation is incomplete, and results in illusory perception of motion. Neurophysiological, psychophysical and imaging studies elucidated many aspects of the neural substrates of visual processing during pursuit, including where and how in the cortex visual and non-visual signals interact to produce extra-retinal perception of motion. Here we review current understanding of motion processing in the visual cortex during pursuit and its relation to perception, from a broad perspective drawing from electrophysiology, fMRI, psychophysics and computational modeling. We discuss the experimental findings in the context of theories of pursuit compensation, and review some of the open questions in the field.

An instructive role for patterned spontaneous retinal activity in mouse visual map development.

Complex neural circuits in the mammalian brain develop through a combination of genetic instruction and activity-dependent refinement. The relative role of these factors and the form of neuronal activity responsible for circuit development is a matter of significant debate. In the mammalian visual system, retinal ganglion cell projections to the brain are mapped with respect to retinotopic location and eye of origin. We manipulated the pattern of spontaneous retinal waves present during development without changing overall activity levels through the transgenic expression of ß2-nicotinic acetylcholine receptors in retinal ganglion cells of mice. We used this manipulation to demonstrate that spontaneous retinal activity is not just permissive, but instructive in the emergence of eye-specific segregation and retinotopic refinement in the mouse visual system. This suggests that specific patterns of spontaneous activity throughout the developing brain are essential in the emergence of specific and distinct patterns of neuronal connectivity.

Relationship of functional mitral regurgitation to new-onset atrial fibrillation in acute myocardial infarction.

BACKGROUND/OBJECTIVE: The role of factors that increase left atrial pressure or cause acute left atrial dilatation is frequently emphasised in the pathogenesis of atrial fibrillation (AF) in patients with acute myocardial infarction (AMI). This study was designed to test the hypothesis that functional mitral regurgitation (FMR) occurring after AMI may promote AF by producing left atrial volume overload. SETTING: Intensive care unit of a tertiary care hospital. PATIENTS AND METHODS: 1920 patients admitted with AMI were studied. Patients with known AF were excluded. FMR was classified using echocardiography into three groups: none; mild FMR and moderate or severe FMR. The relationship between FMR and AF occurring at any time during the hospital course was examined using multivariable logistic regression. RESULTS: Mild FMR was present in 744 patients (38.8%) and moderate or severe FMR was present in 150 patients (7.8%). AF developed in 51 (5.0%), 83 (11.2%) and 28 (18.7%) patients with no FMR, mild FMR and moderate or severe FMR, respectively (p trend <0.001). In multivariable logistic regression, both mild (odds ratio (OR) 1.6; 95% CI 1.1 to 2.3, p=0.02) and moderate or severe FMR (OR 2.1; 95% CI 1.2 to 3.6, p=0.007) were independent predictors of AF. There was a significant interaction between the left ventricular ejection fraction and FMR (p=0.003) such that mild FMR was predictive of AF only in patients with a reduced (<45%) ejection fraction. CONCLUSIONS: There is a graded independent association between the severity of FMR and the new onset of AF in patients with AMI.

Similarity effect and optimal control of multiple-choice decision making.

Decision making with several choice options is central to cognition. To elucidate the neural mechanisms of such decisions, we investigated a recurrent cortical circuit model in which fluctuating spiking neural dynamics underlie trial-by-trial stochastic decisions. The model encodes a continuous analog stimulus feature and is thus applicable to multiple-choice decisions. Importantly, the continuous network captures similarity between alternatives and possible overlaps in their neural representation. Model simulations accounted for behavioral as well as single-unit neurophysiological data from a recent monkey experiment and revealed testable predictions about the patterns of error rate as a function of the similarity between the correct and actual choices. We also found that the similarity and number of options affect speed and accuracy of responses. A mechanism is proposed for flexible control of speed-accuracy tradeoff, based on a simple top-down signal to the decision circuit that may vary nonmonotonically with the number of choice alternatives.