Durable immune responses after BNT162b2 vaccination in home-dwelling old adults.

Objectives: Elderly are an understudied, high-risk group vulnerable to severe COVID-19. We comprehensively analyzed the durability of humoral and cellular immune responses after BNT162b2 vaccination and SARS-CoV-2 infection in elderly and younger adults. Methods: Home-dwelling old (n = 100, median 86 years) and younger adults (n = 449, median 38 years) were vaccinated with two doses of BNT162b2 vaccine at 3-week intervals and followed for 9-months. Vaccine-induced responses were compared to home-isolated COVID-19 patients (n = 183, median 47 years). Our analysis included neutralizing antibodies, spike-specific IgG, memory B-cells, IFN-γ and IL-2 secreting T-cells and sequencing of the T-cell receptor (TCR) repertoire. Results: Spike-specific breadth and depth of the CD4+ and CD8+ TCR repertoires were significantly lower in the elderly after one and two vaccinations. Both vaccinations boosted IFN-γ and IL-2 secreting spike-specific T-cells responses, with 96 % of the elderly and 100 % of the younger adults responding after the second dose, although responses were not maintained at 9-months. In contrast, T-cell responses persisted up to 12-months in infected patients. Spike-specific memory B-cells were induced after the first dose in 87 % of the younger adults compared to 38 % of the elderly, which increased to 83 % after the second dose. Memory B-cells were maintained at 9-months post-vaccination in both vaccination groups. Neutralizing antibody titers were estimated to last for 1-year in younger adults but only 6-months in the older vaccinees. Interestingly, infected older patients (n = 15, median 75 years) had more durable neutralizing titers estimated to last 14-months, 8-months longer than the older vaccinees. Conclusions: Vaccine-induced spike-specific IgG and neutralizing antibodies were consistently lower in the older than younger vaccinees. Overall, our data provide valuable insights into the kinetics of the humoral and cellular immune response in the elderly after SARS-CoV-2 vaccination or infection, highlighting the need for two doses, which can guide future vaccine design.Clinical trials.gov; NCT04706390.

Broader Epstein-Barr virus-specific T cell receptor repertoire in patients with multiple sclerosis.

Epstein-Barr virus (EBV) infection precedes multiple sclerosis (MS) pathology and cross-reactive antibodies might link EBV infection to CNS autoimmunity. As an altered anti-EBV T cell reaction was suggested in MS, we queried peripheral blood T cell receptor ß chain (TCRß) repertoires of 1,395 MS patients, 887 controls, and 35 monozygotic, MS-discordant twin pairs for multimer-confirmed, viral antigen-specific TCRß sequences. We detected more MHC-I-restricted EBV-specific TCRß sequences in MS patients. Differences in genetics or upbringing could be excluded by validation in monozygotic twin pairs discordant for MS. Anti-VLA-4 treatment amplified this observation, while interferon ß- or anti-CD20 treatment did not modulate EBV-specific T cell occurrence. In healthy individuals, EBV-specific CD8+ T cells were of an effector-memory phenotype in peripheral blood and cerebrospinal fluid. In MS patients, cerebrospinal fluid also contained EBV-specific central-memory CD8+ T cells, suggesting recent priming. Therefore, MS is not only preceded by EBV infection, but also associated with broader EBV-specific TCR repertoires, consistent with an ongoing anti-EBV immune reaction in MS.

Differences in SARS-CoV-2 Vaccine Response Dynamics Between Class-I- and Class-II-Specific T-Cell Receptors in Inflammatory Bowel Disease.

T-cells specifically bind antigens to induce adaptive immune responses using highly specific molecular recognition, and a diverse T-cell repertoire with expansion of antigen-specific clones can indicate robust immune responses after infection or vaccination. For patients with inflammatory bowel disease (IBD), a spectrum of chronic intestinal inflammatory diseases usually requiring immunomodulatory treatment, the T-cell response has not been well characterized. Understanding the patient factors that result in strong vaccination responses is critical to guiding vaccination schedules and identifying mechanisms of T-cell responses in IBD and other immune-mediated conditions. Here we used T-cell receptor sequencing to show that T-cell responses in an IBD cohort were influenced by demographic and immune factors, relative to a control cohort of health care workers (HCWs). Subjects were sampled at the time of SARS-CoV-2 vaccination, and longitudinally afterwards; TCR Vß gene repertoires were sequenced and analyzed for COVID-19-specific clones. We observed significant differences in the overall strength of the T-cell response by age and vaccine type. We further stratified the T-cell response into Class-I- and Class-II-specific responses, showing that Ad26.COV2.S vector vaccine induced Class-I-biased T-cell responses, whereas mRNA vaccine types led to different responses, with mRNA-1273 vaccine inducing a more Class-I-deficient T-cell response compared to BNT162b2. Finally, we showed that these T-cell patterns were consistent with antibody levels from the same patients. Our results account for the surprising success of vaccination in nominally immuno-compromised IBD patients, while suggesting that a subset of IBD patients prone to deficiencies in T-cell response may warrant enhanced booster protocols.

The T-Cell Response to SARS-CoV-2 Vaccination in Inflammatory Bowel Disease is Augmented with Anti-TNF Therapy.

T-cell and antibody responses to severe acute respiratory syndrome coronavirus 2 vaccination in inflammatory bowel disease patients are poorly correlated. T-cell responses are preserved by most biologic therapies, but augmented by anti-tumor necrosis factor (anti-TNF) treatment. While anti-TNF therapy blunts the antibody response, cellular immunity after vaccination is robust.

The T-cell clonal response to SARS-CoV-2 vaccination in inflammatory bowel disease patients is augmented by anti-TNF therapy and often deficient in antibody-responders.

BACKGROUND: Vaccination against SARS-CoV-2 is a highly effective strategy to protect against infection, which is predominantly mediated by vaccine-induced antibodies. Postvaccination antibodies are robustly produced by those with inflammatory bowel disease (IBD) even on immune-modifying therapies but are blunted by anti-TNF therapy. In contrast, T-cell response which primarily determines long-term efficacy against disease progression,, is less well understood. We aimed to assess the post-vaccination T-cell response and its relationship to antibody responses in patients with inflammatory bowel disease (IBD) on immune-modifying therapies. METHODS: We evaluated IBD patients who completed SARS-CoV-2 vaccination using samples collected at four time points (dose 1, dose 2, 2 weeks after dose 2, 8 weeks after dose 2). T-cell clonal analysis was performed by T-cell Receptor (TCR) immunosequencing. The breadth (number of unique sequences to a given protein) and depth (relative abundance of all the unique sequences to a given protein) of the T-cell clonal response were quantified using reference datasets and were compared to antibody responses. RESULTS: Overall, 303 subjects were included (55% female; 5% with prior COVID) (Table). 53% received BNT262b (Pfizer), 42% mRNA-1273 (Moderna) and 5% Ad26CoV2 (J&J). The Spike-specific clonal response peaked 2 weeks after completion of the vaccine regimen (3- and 5-fold for breadth and depth, respectively); no changes were seen for non-Spike clones, suggesting vaccine specificity. Reduced T-cell clonal depth was associated with chronologic age, male sex, and immunomodulator treatment. It was preserved by non-anti-TNF biologic therapies, and augmented clonal depth was associated with anti-TNF treatment. TCR depth and breadth were associated with vaccine type; after adjusting for age and gender, Ad26CoV2 (J&J) exhibited weaker metrics than mRNA-1273 (Moderna) (p=0.01 for each) or BNT262b (Pfizer) (p=0.056 for depth). Antibody and T-cell responses were only modestly correlated. While those with robust humoral responses also had robust TCR clonal expansion, a substantial fraction of patients with high antibody levels had only a minimal T-cell clonal response. CONCLUSION: Age, sex and select immunotherapies are associated with the T-cell clonal response to SARS-CoV-2 vaccines, and T-cell responses are low in many patients despite high antibody levels. These factors, as well as differences seen by vaccine type may help guide reimmunization vaccine strategy in immune-impaired populations. Further study of the effects of anti-TNF therapy on vaccine responses are warranted.

Preoperative tranexamic acid does not reduce transfusion rates in major oncologic surgery: Results of a randomized, double-blind, and placebo-controlled trial.

BACKGROUND AND OBJECTIVES: Allogeneic blood transfusions are associated with worse postoperative outcomes in oncologic surgery. The aim of this study was to introduce a preoperative intervention to reduce transfusion rates in this population. METHODS: Adult patients undergoing major oncologic surgery in five categories with similar transfusion rates were recruited. Enrollees received a single preoperative intravenous dose of placebo or tranexamic acid (1000 mg). The primary outcome measure was perioperative transfusion rate. Secondary outcome measures included: estimated blood loss, thromboembolic events, morbidity, hospital length of stay, and readmission rate. RESULTS: Seventy-six patients were enrolled, 39 in the tranexamic acid group and 37 in the placebo group, respectively. Demographics and surgery type were equivalent between groups. The transfusion rates were 8 out of 39 (20.5%) in the tranexamic acid group and 5 out of 37 (13.5%) in the placebo group, respectively (P = .418). Median estimated blood loss was 400 mL (interquartile range [IQR] = 150-600) in the tranexamic acid group compared with 300 mL (IQR = 150-800) in the placebo group (P = .983). There was one pulmonary embolism in each arm and no deep venous thrombosis (P > .999). CONCLUSION: Preoperative administration of tranexamic acid at a 1000 mg intravenous dose does not decrease transfusion rates or estimated blood loss in patients undergoing major oncologic surgery.

Interaction Between CRIPT and PSD-95 Is Required for Proper Dendritic Arborization in Hippocampal Neurons.

CRIPT, the cysteine-rich PDZ-binding protein, binds to the third PDZ domain of PSD-95 (postsynaptic density protein 95) family proteins and directly binds microtubules, linking PSD-95 family proteins to the neuronal cytoskeleton. Here, we show that overexpression of a full-length CRIPT leads to a modest decrease, and knockdown of CRIPT leads to an increase in dendritic branching in cultured rat hippocampal neurons. Overexpression of truncated CRIPT lacking the PDZ domain-binding motif, which does not bind to PSD-95, significantly decreases dendritic arborization. Conversely, overexpression of a full-length CRIPT significantly increases the number of immature and mature dendritic spines, and this effect is not observed when CRIPT∆PDZ is overexpressed. Competitive inhibition of CRIPT binding to the third PDZ domain of PSD-95 with PDZ3-binding peptides resulted in differential effects on dendritic arborization based on the origin of respective peptide sequence. These results highlight multifunctional roles of CRIPT during development and underscore the significance of the interaction between CRIPT and the third PDZ domain of PSD-95.

PTEN recruitment controls synaptic and cognitive function in Alzheimer's models.

Dyshomeostasis of amyloid-ß peptide (Aß) is responsible for synaptic malfunctions leading to cognitive deficits ranging from mild impairment to full-blown dementia in Alzheimer's disease. Aß appears to skew synaptic plasticity events toward depression. We found that inhibition of PTEN, a lipid phosphatase that is essential to long-term depression, rescued normal synaptic function and cognition in cellular and animal models of Alzheimer's disease. Conversely, transgenic mice that overexpressed PTEN displayed synaptic depression that mimicked and occluded Aß-induced depression. Mechanistically, Aß triggers a PDZ-dependent recruitment of PTEN into the postsynaptic compartment. Using a PTEN knock-in mouse lacking the PDZ motif, and a cell-permeable interfering peptide, we found that this mechanism is crucial for Aß-induced synaptic toxicity and cognitive dysfunction. Our results provide fundamental information on the molecular mechanisms of Aß-induced synaptic malfunction and may offer new mechanism-based therapeutic targets to counteract downstream Aß signaling.

Relative quantification of biomarkers using mixed-isotope labeling coupled with MS.

The identification and quantification of important biomarkers is a critical first step in the elucidation of biological systems. Biomarkers take many forms as cellular responses to stimuli and can be manifested during transcription, translation, and/or metabolic processing. Increasingly, researchers have relied upon mixed-isotope labeling (MIL) coupled with MS to perform relative quantification of biomarkers between two or more biological samples. MIL effectively tags biomarkers of interest for ease of identification and quantification within the mass spectrometer by using isotopic labels that introduce a heavy and light form of the tag. In addition to MIL coupled with MS, a number of other approaches have been used to quantify biomarkers including protein gel staining, enzymatic labeling, metabolic labeling, and several label-free approaches that generate quantitative data from the MS signal response. This review focuses on MIL techniques coupled with MS for the quantification of protein and small-molecule biomarkers.

Going beyond students: an association between mixed-hand preference and schizotypy subscales in a general population.

Research on the sub-clinical condition of schizotypy suggests that it is associated with mixed handedness. To date, however, this research has focussed on undergraduate populations. If the association between schizotypy and mixed-handedness is the result of an underlying neurological trait, it is important to demonstrate that the effect extends to the general population. With this in mind, 699 participants were drawn from a wide community sample. Schizotypy was measured using the Psychosis Proneness Questionnaire and handedness was assessed using the Annett inventory. To avoid the sometimes arbitrary definitions of left-, right- and mixed-handed, regression analyses were used to explore the data. There was no evidence of a difference in schizotypy between individuals with a left- or right-hand preference. People with a mixed-hand preference, however, had higher scores on PER-MAG (Perceptual Aberration and Magical Ideation) and HYP-IMP (Hypomania and Impulsive Non-Conformity) scales (positive traits). No effect was observed for the SAN (Social Anhedonia) and PAN (Physical Anhedonia) scales (negative traits). The nature of the association between schizotypy and handedness observed in the current study is similar to that reported for student populations. The possibility that the association is related to response biases or a biological mechanism is discussed.

A hit-and-miss investigation of asymmetries in wheelchair navigation.

In contrast to the leftward inattention caused by right parietal damage, normal brain function shows a subtle neglect of the right and left sides in peripersonal and extrapersonal space, respectively. This study explored how these attentional biases cause healthy individuals to collide with objects on the right. In Experiment 1, participants navigated manual and electric wheelchairs through a narrow doorway. More rightward collisions were observed for the electric, but not the manual, wheelchair. Experiment 2 demonstrated that the rightward deviation for electric wheelchairs increased for wider doorways. Experiment 3 established that the rightward deviation is not the result of task-related vestibular input, using a remote control device to operate the wheelchair. The rightward deviation persisted in Experiment 4 when the doorway was removed, suggesting that the bias is the result of a mis-bisection of space. In Experiment 5, the rightward bias was replicated using an electric scooter, which is steered using handlebars. Finally, Experiment 6 required participants to point to the middle of the doorway, using a laser, before moving the scooter. Rightward mis-bisection was observed in both conditions. Rightward mis-bisection of lines in extrapersonal space provides the most parsimonious explanation of the rightward collisions and deviations.

Neural mechanisms underlying spatial realignment during adaptation to optical wedge prisms.

Visuomotor adaptation to a shift in visual input produced by prismatic lenses is an example of dynamic sensory-motor plasticity within the brain. Prism adaptation is readily induced in healthy individuals, and is thought to reflect the brain's ability to compensate for drifts in spatial calibration between different sensory systems. The neural correlate of this form of functional plasticity is largely unknown, although current models predict the involvement of parieto-cerebellar circuits. Recent studies that have employed event-related functional magnetic resonance imaging (fMRI) to identify brain regions associated with prism adaptation have discovered patterns of parietal and cerebellar modulation as participants corrected their visuomotor errors during the early part of adaptation. However, the role of these regions in the later stage of adaptation, when 'spatial realignment' or true adaptation is predicted to occur, remains unclear. Here, we used fMRI to quantify the distinctive patterns of parieto-cerebellar activity as visuomotor adaptation develops. We directly contrasted activation patterns during the initial error correction phase of visuomotor adaptation with that during the later spatial realignment phase, and found significant recruitment of the parieto-cerebellar network--with activations in the right inferior parietal lobe and the right posterior cerebellum. These findings provide the first evidence of both cerebellar and parietal involvement during the spatial realignment phase of prism adaptation.

The relationship between hand preference, hand performance, and general cognitive ability.

The idea that handedness indicates something about a person's cognitive ability and personality is a perennial issue. A variety of models have been put forward to explain this relationship and predict a range of outcomes from higher levels of cognitive ability in left-handers or moderate right-handers to lower levels of achievement in left- or mixed-handers. We tested these models using a sample (n = 895) drawn from the BRAINnet database (www.brainnet.net). Participants completed a general cognitive ability (GCA) scale and a test of hand preference/performance. Moderate right-handers, as indexed by their performance measures, had higher GCA scores compared with strong left- or right-handers. The performance measure also showed lower levels of GCA for left-handers compared with right-handers. The hand preference data showed little or no association with cognitive ability-perhaps because this measure clusters individuals toward the extremes of the handedness distribution. While adding support to Annett's heterozygous advantage model, which predicts a cognitive disadvantage for strong left- or right-handers, the data also confirm recent research showing a GCA disadvantage for left-handers. Although this study demonstrates that handedness is related to cognitive ability, the effects are subtle and might only be identified in large-scale studies with sensitive measures of hand performance.

Pseudoneglect for the bisection of mental number lines.

Patients with unilateral neglect of the left side bisect physical lines to the right whereas individuals with an intact brain bisect lines slightly to the left (pseudoneglect). Similarly, for mental number lines, which are arranged in a left-to-right ascending sequence, neglect patients bisect to the right. This study determined whether individuals with an intact brain show pseudoneglect for mental number lines. In Experiment 1, participants were presented with visual number triplets (e.g., 16, 36, 55) and determined whether the numerical distance was greater on the left or right side of the inner number. Despite changing the spatial configuration of the stimuli, or their temporal order, the numerical length on the left was consistently overestimated. The fact that the bias was unaffected by physical stimulus changes demonstrates that the bias is based on a mental representation. The leftward bias was also observed for sets of negative numbers (Experiment 2)--demonstrating not only that the number line extends into negative space but also that the bias is not the result of an arithmetic distortion caused by logarithmic scaling. The leftward bias could be caused by a rounding-down effect. Using numbers that were prone to large or small rounding-down errors, Experiment 3 showed no effect of rounding down. The task demands were changed in Experiment 4 so that participants determined whether the inner number was the true arithmetic centre or not. Participants mistook inner numbers shifted to the left to be the true numerical centre--reflecting leftward overestimation. The task was applied to 3 patients with right parietal damage with severe, moderate, or no spatial neglect (Experiment 5). A rightward bias was observed, which depended on the severity of neglect symptoms. Together, the data demonstrate a reliable and robust leftward bias for mental number line bisection, which reverses in clinical neglect. The bias mirrors pseudoneglect for physical lines and most likely reflects an expansion of the space occupied by lower numbers on the left side of the line and a contraction of space for higher numbers located on the right.

The neural basis of selection-for-action.

The selection of objects in the visual environment is important in everyday life when acting in a goal-directed manner. Here we used functional magnetic resonance imaging (fMRI) to investigate brain activity while healthy subjects (N=15) selectively reached to grasp a three-dimensional (3D) target stimulus presented either in isolation or in the presence of 3D non-target stimuli. A pneumatic MRI compatible apparatus was designed to precisely control the presentation of 3D graspable stimuli within the scanner. During scanning subjects were instructed to reach and grasp towards a target presented at an unknown location either in isolation or flanked by two distractor objects. Results indicated that reaching towards and grasping the target object in the presence of other non-target stimuli was associated with greater activation within the contralateral primary motor cortex and the precuneus as compared to the execution of reach-to-grasp movements towards the target presented in isolation. We conclude that the presence of non-targets evokes a differential level of neural activity within areas responsible for the planning and execution of selective reach-to-grasp movement.

Posterior parietal cortex control of reach-to-grasp movements in humans.

The aim of the present study was to ascertain the neural correlates for the integration of visual information with the control of the reach-to-grasp action in the healthy human brain. Nine adult subjects (18-38 years; four females and five males) were scanned using functional magnetic resonance imaging while reaching-to-grasp a three-dimensional target. Results demonstrated differential activation of the parietal cortices according to the number of potential targets to be taken into account before movement initiation and the variability of target location. Comparing conditions where a target object that can appear at an unpredictable location with conditions where the target object appears at a predictable location revealed activations in the left superior parietal lobule, the left parieto-occipital sulcus and the right intraparietal sulcus. Results are discussed in terms of visual selective attention and action planning.