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The same pneumococcal conjugate vaccines (PCVs) have been used in adults and children in many settings. Differences in the epidemiology of pneumococcal disease between populations necessitates an adult-specific PCV. We aimed to assess the safety, tolerability, and immunogenicity of V116, an investigational 21-valent PCV designed for adults. This randomised, double-blind, active comparator controlled, international phase 3 trial enrolled adults with or without stable chronic medical conditions at 112 clinical sites in 11 countries or territories. Random assignment was performed using a central electronic interactive response technology system. Cohort 1 (≥50 years) was stratified by age (50–64, 65–74, 75–84, and ≥85 years) and randomised 1:1 to receive one intramuscular dose of V116, or the active comparator, PCV20. Cohort 2 (18–49 years) was randomised 2:1 to receive one intramuscular dose of V116 or PCV20. Pneumococcal serotype-specific opsonophagocytic activity (OPA) and IgG responses were measured before (day 1) and after vaccination (day 30). Four primary immunogenicity outcomes were assessed per-protocol. First, in cohort 1, non-inferiority of V116 to PCV20 was tested using serotype-specific OPA geometric mean titres (GMT) ratios for serotypes common to both vaccines; the lower bound of the 95% CI had to be greater than 0·5 for non-inferiority. Second, superiority of V116 to PCV20 was tested for OPA GMT ratios for the serotypes unique to V116; the lower bound of the 95% CI had to be greater than 2·0 for superiority. Third, superiority of V116 to PCV20 was evaluated by the proportions of participants with a four-fold or greater rise from day 1 to day 30 for serotypes unique to V116; the lower bound of the 95% CI of the differences in proportions (V116 – PCV20) had to be greater than 10% for superiority. Finally, in cohort 2, immunobridging was assessed for all 21 serotypes in V116 for adults aged 18–49 years to 50–64 years; the lower bound of the 95% CI for the OPA GMTs had to be greater than 0·5 for non-inferiority. The safety analysis included all randomly assigned participants who received study vaccine. The primary safety outcome was the proportion of participants with solicited injection site and solicited systemic adverse events until day 5 and vaccine-related serious adverse events up to 6 months after vaccination. This trial is registered at ClinicalTrials.gov (NCT05425732). Between July 13, and Nov 22, 2022, 2754 individuals were screened and 2663 participants were randomly assigned. 2656 individuals were vaccinated (1179 in V116 cohort 1; 1177 in PCV20 cohort 1; 200 in V116 cohort 2; and 100 in PCV20 cohort 2). V116 met non-inferiority criteria compared with PCV20 for the ten serotypes common to both vaccines at day 30 in cohort 1 (p<0·0001 for each common serotype). V116 met superiority criteria compared with PCV20 in cohort 1 for ten of the 11 serotypes unique to V116 at day 30 (OPA GMT ratio: p<0·0001 for all unique serotypes except 15C, which was p=0·41; four-fold or greater rise in OPA from day 1–30: p<0·0001 for all serotypes except 15C, which was p=0·67). Immune responses in V116 participants aged 18–49 years were non-inferior compared with V116 participants aged 50–64 years for all V116 serotypes (p<0·0001 for all V116 serotypes). In cohort 1, 685 (58·2%) of participants in V116, and 778 (66·2%) of participants in PCV20 reported one or more adverse event. In cohort 2, 164 (82·0%) participants in V116 and 79 participants (79·0%) in PCV20 reported one or more adverse event. Six deaths were reported, all in cohort 1, none of which were considered vaccine-related (in V116: one due to sepsis, one due to cerebrovascular accident, one due to myocardial infarction, and one due to hepatic cirrhosis and hepatic encephalopathy; in PCV20: one due to cardiac arrest and one due to abdominal abscess). There were no vaccine-related serious adverse events. V116 was non-inferior to PCV20 for the ten serotypes common to both vaccines and superior to PCV20 for all serotypes unique to V116, except for 15C. Immune responses successfully immunobridged between younger and older adults for all serotypes in V116. V116 was generally well tolerated with safety profile similar to PCV20. Merck Sharp & Dohme, subsidiary of Merck & Co, Rahway, NJ, USA (MSD).

The goal of the present dissertation was to explore the relationship between the neuromodulator adenosine and seizures kindled in various brain structures. The intent was to (1) determine whether adenosine analogs exert their anticonvulsive effects via action at the seizure focus, (2) compare the actions of adenosine agonists on amygdala, hippocampus, and caudate nucleus kindled seizures, and (3) assess and compare the anticonvulsive effects of the two adenosine analogs, L-PIA and NECA, which may display different adenosine receptor subtype specificity. Chemitrodes were implanted in the amygdala, hippocampus, or caudate nucleus of Long-Evans rats. Rats were electrically stimulated once daily until full generalized seizures appeared (i.e., kindled). Once kindled, various doses (0.001-5.0 ug/0.5 ul) of the adenosine analogs, L-phenylisopropyladenosine (L-PIA), N-ethylcarboximidoadenosine (NECA) or vehicle (0.5 ul) were injected into the focus of the seizure 5 minutes prior to electrical stimulation. The afterdischarge and behavioral seizure stages were measured. The results demonstrated that both L-PIA and NECA have powerful anticonvulsive effects when injected directly into the seizure focus of kindled rats. However, L-PIA and NECA displayed different effectiveness in the brain regions tested. L-PIA was more effective than NECA against amygdala and hippocampus kindled seizures. In caudate nucleus kindled seizures, both L-PIA and NECA were effective anticonvulsants. NECA was slightly more potent than L-PIA. The regional differences in efficacy of the two adenosine analogs suggest that the anticonvulsive effects of the analogs on kindled seizures may be mediated through different adenosine receptor subtypes. Thus, L-PIA, an Al adenosine subtype agonist, may exert its effects in the amygdala, hippocampus, and caudate nucleus, where Al binding has been demonstrated, while NECA, an A2 adenosine receptor agonist, may only be effective in the caudate nucleus which has A2 adenosine binding sites.

Plasma tau phosphorylated at threonine 217 (p-tau217) and plasma tau phosphorylated at threonine 181 (p-tau181) are associated with Alzheimer's disease tau pathology. We compared the diagnostic value of both biomarkers in cognitively unimpaired participants and patients with a clinical diagnosis of mild cognitive impairment, Alzheimer's disease syndromes, or frontotemporal lobar degeneration (FTLD) syndromes. In this retrospective multicohort diagnostic performance study, we analysed plasma samples, obtained from patients aged 18–99 years old who had been diagnosed with Alzheimer's disease syndromes (Alzheimer's disease dementia, logopenic variant primary progressive aphasia, or posterior cortical atrophy), FTLD syndromes (corticobasal syndrome, progressive supranuclear palsy, behavioural variant frontotemporal dementia, non-fluent variant primary progressive aphasia, or semantic variant primary progressive aphasia), or mild cognitive impairment; the participants were from the University of California San Francisco (UCSF) Memory and Aging Center, San Francisco, CA, USA, and the Advancing Research and Treatment for Frontotemporal Lobar Degeneration Consortium (ARTFL; 17 sites in the USA and two in Canada). Participants from both cohorts were carefully characterised, including assessments of CSF p-tau181, amyloid-PET or tau-PET (or both), and clinical and cognitive evaluations. Plasma p-tau181 and p-tau217 were measured using electrochemiluminescence-based assays, which differed only in the biotinylated antibody epitope specificity. Receiver operating characteristic analyses were used to determine diagnostic accuracy of both plasma markers using clinical diagnosis, neuropathological findings, and amyloid-PET and tau-PET measures as gold standards. Difference between two area under the curve (AUC) analyses were tested with the Delong test. Data were collected from 593 participants (443 from UCSF and 150 from ARTFL, mean age 64 years [SD 13], 294 [50%] women) between July 1 and Nov 30, 2020. Plasma p-tau217 and p-tau181 were correlated (r=0·90, p<0·0001). Both p-tau217 and p-tau181 concentrations were increased in people with Alzheimer's disease syndromes (n=75, mean age 65 years [SD 10]) relative to cognitively unimpaired controls (n=118, mean age 61 years [SD 18]; AUC=0·98 [95% CI 0·95–1·00] for p-tau217, AUC=0·97 [0·94–0·99] for p-tau181; pdiff=0·31) and in pathology-confirmed Alzheimer's disease (n=15, mean age 73 years [SD 12]) versus pathologically confirmed FTLD (n=68, mean age 67 years [SD 8]; AUC=0·96 [0·92–1·00] for p-tau217, AUC=0·91 [0·82–1·00] for p-tau181; pdiff=0·22). P-tau217 outperformed p-tau181 in differentiating patients with Alzheimer's disease syndromes (n=75) from those with FTLD syndromes (n=274, mean age 67 years [SD 9]; AUC=0·93 [0·91–0·96] for p-tau217, AUC=0·91 [0·88–0·94] for p-tau181; pdiff=0·01). P-tau217 was a stronger indicator of amyloid-PET positivity (n=146, AUC=0·91 [0·88–0·94]) than was p-tau181 (n=214, AUC=0·89 [0·86–0·93]; pdiff=0·049). Tau-PET binding in the temporal cortex was more strongly associated with p-tau217 than p-tau181 (r=0·80 vs r=0·72; pdiff<0·0001, n=230). Both p-tau217 and p-tau181 had excellent diagnostic performance for differentiating patients with Alzheimer's disease syndromes from other neurodegenerative disorders. There was some evidence in favour of p-tau217 compared with p-tau181 for differential diagnosis of Alzheimer's disease syndromes versus FTLD syndromes, as an indication of amyloid-PET-positivity, and for stronger correlations with tau-PET signal. Pending replication in independent, diverse, and older cohorts, plasma p-tau217 and p-tau181 could be useful screening tools to identify individuals with underlying amyloid and Alzheimer's disease tau pathology. US National Institutes of Health, State of California Department of Health Services, Rainwater Charitable Foundation, Michael J Fox foundation, Association for Frontotemporal Degeneration, Alzheimer's Association.

Molecular mechanisms driving disease course and response to therapy in ulcerative colitis (UC) are not well understood. Here, we use RNAseq to define pre-treatment rectal gene expression, and fecal microbiota profiles, in 206 pediatric UC patients receiving standardised therapy. We validate our key findings in adult and paediatric UC cohorts of 408 participants. We observe a marked suppression of mitochondrial genes and function across cohorts in active UC, and that increasing disease severity is notable for enrichment of adenoma/adenocarcinoma and innate immune genes. A subset of severity genes improves prediction of corticosteroid-induced remission in the discovery cohort; this gene signature is also associated with response to anti-TNFα and anti-α 4 β 7 integrin in adults. The severity and therapeutic response gene signatures were in turn associated with shifts in microbes previously implicated in mucosal homeostasis. Our data provide insights into UC pathogenesis, and may prioritise future therapies for nonresponders to current approaches. The severity of ulcerative colitis, and response to treatment, is highly variable. Here, the authors examine rectal gene expression signatures and faecal microbiomes of children and adults with the disease and provide new insights in to pathogenesis.

Background Plasma phosphorylated tau (p-tau) has emerged as a promising biomarker for Alzheimer’s disease (AD). Studies have reported strong associations between p-tau and tau-PET that are mainly driven by differences between amyloid-positive and amyloid-negative patients. However, the relationship between p-tau and tau-PET is less characterized within cognitively impaired patients with a biomarker-supported diagnosis of AD. We conducted a head-to-head comparison between plasma p-tau217 and tau-PET in patients at the clinical stage of AD and further assessed their relationships with demographic, clinical, and biomarker variables. Methods We retrospectively included 87 amyloid-positive patients diagnosed with MCI or dementia due to AD who underwent structural MRI, amyloid-PET ( 11 C-PIB), tau-PET ( 18 F-flortaucipir, FTP), and blood draw assessments within 1 year (age = 66 ± 10, 48% female). Amyloid-PET was quantified in Centiloids (CL) while cortical tau-PET binding was measured using standardized uptake value ratios (SUVRs) referenced against inferior cerebellar cortex. Plasma p-tau217 concentrations were measured using an electrochemiluminescence-based assay on the Meso Scale Discovery platform. MRI-derived cortical volume was quantified with FreeSurfer. Mini-Mental State Examination (MMSE) scores were available at baseline ( n  = 85) and follow-up visits ( n  = 28; 1.5 ± 0.7 years). Results Plasma p-tau217 and cortical FTP-SUVR were correlated ( r  = 0.61, p  < .001), especially in temporo-parietal and dorsolateral frontal cortices. Both higher p-tau217 and FTP-SUVR values were associated with younger age, female sex, and lower cortical volume, but not with APOE-ε4 carriership. PIB-PET Centiloids were weakly correlated with FTP-SUVR ( r  = 0.26, p  = 0.02), but not with p-tau217 ( r  = 0.10, p  = 0.36). Regional PET-plasma associations varied with amyloid burden, with p-tau217 being more strongly associated with tau-PET in temporal cortex among patients with moderate amyloid-PET burden, and with tau-PET in primary cortices among patients with high amyloid-PET burden. Higher p-tau217 and FTP-SUVR values were independently associated with lower MMSE scores cross-sectionally, while only baseline FTP-SUVR predicted longitudinal MMSE decline when both biomarkers were included in the same model. Conclusion Plasma p-tau217 and tau-PET are strongly correlated in amyloid-PET-positive patients with MCI or dementia due to AD, and they exhibited comparable patterns of associations with demographic variables and with markers of downstream neurodegeneration.

There is an unmet medical need for noninvasive imaging of regional brain oxygenation to manage stroke, tumor, and neurodegenerative diseases. Oxygenation imaging from magnetic susceptibility in MRI is a promising new technique to measure local venous oxygen extraction fraction (OEF) along the cerebral venous vasculature. However, this approach has not been tested in vivo at different levels of oxygenation. The primary goal of this study was to test whether susceptibility imaging of oxygenation can detect OEF changes induced by hypercapnia, via CO2 inhalation, within selected a priori brain regions. Ten healthy subjects were scanned at 3T with a 32-channel head coil. The end-tidal CO2 (ETCO2) was monitored continuously and inspired gases were adjusted to achieve steady-state conditions of eucapnia (41±3mmHg) and hypercapnia (50±4mmHg). Gradient echo phase images and pseudo-continuous arterial spin labeling (pcASL) images were acquired to measure regional OEF and CBF respectively during eucapnia and hypercapnia. By assuming constant cerebral oxygen consumption throughout both gas states, regional CBF values were computed to predict the local change in OEF in each brain region. Hypercapnia induced a relative decrease in OEF of −42.3% in the straight sinus, −39.9% in the internal cerebral veins, and approximately −50% in pial vessels draining each of the occipital, parietal, and frontal cortical areas. Across volunteers, regional changes in OEF correlated with changes in ETCO2. The reductions in regional OEF (via phase images) were significantly correlated (P<0.05) with predicted reductions in OEF derived from CBF data (via pcASL images). These findings suggest that susceptibility imaging is a promising technique for OEF measurements, and may serve as a clinical biomarker for brain conditions with aberrant regional oxygenation. •There is an unmet clinical need for noninvasive oxygenation imaging in the brain.•We tested a new quantitative susceptibility MRI method to measure regional cerebral oxygenation.•We measured reduced oxygen extraction fraction during hypercapnic challenge in cerebral veins.•Oxygenation changes correlated with changes in end-tidal CO2 in subjects.•Oxygenation changes related with predicted changes made from separate perfusion MRI measures.

With the potential development of new disease-modifying Alzheimer’s disease (AD) therapies, simple, widely available screening tests are needed to identify which individuals, who are experiencing symptoms of cognitive or behavioral decline, should be further evaluated for initiation of treatment. A blood-based test for AD would be a less invasive and less expensive screening tool than the currently approved cerebrospinal fluid or amyloid β positron emission tomography (PET) diagnostic tests. We examined whether plasma tau phosphorylated at residue 181 (pTau181) could differentiate between clinically diagnosed or autopsy-confirmed AD and frontotemporal lobar degeneration. Plasma pTau181 concentrations were increased by 3.5-fold in AD compared to controls and differentiated AD from both clinically diagnosed (receiver operating characteristic area under the curve of 0.894) and autopsy-confirmed frontotemporal lobar degeneration (area under the curve of 0.878). Plasma pTau181 identified individuals who were amyloid β-PET-positive regardless of clinical diagnosis and correlated with cortical tau protein deposition measured by 18 F-flortaucipir PET. Plasma pTau181 may be useful to screen for tau pathology associated with AD. Plasma pTau181 concentrations are elevated specifically in patients diagnosed with Alzheimer’s disease compared to those diagnosed with frontotemporal lobar degeneration or elderly controls, supporting its further development as a blood-based biomarker for AD.

A new ice core from West Antarctica shows that, during the last ice age, abrupt Northern Hemisphere climate variations were followed two centuries later by a response in Antarctica, suggesting an oceanic propagation of the climate signal to the Southern Hemisphere high latitudes. Climate seesaw swings north to south The bipolar seesaw theory explains certain abrupt episodes of climate change as a consequence of an interhemispheric redistribution of heat; when one polar region is warming, the other cools. So far, it has been unclear if the Northern Hemisphere is forcing the Southern Hemisphere or vice versa, and whether the seesaw operates via oceanic or atmospheric mechanisms. This study, synthesizing data from several climate laboratories, uses high-resolution data from the recently drilled WAIS Divide Antarctic ice core, combined with data from Greenland, to show that during much of the past 65,000 years, the north has led the south for both cooling and warming events. Abrupt Northern Hemisphere climate variations were followed two centuries later by a response in Antarctica, suggesting an oceanic propagation of the climate signal to the Southern Hemisphere high latitudes. The last glacial period exhibited abrupt Dansgaard–Oeschger climatic oscillations, evidence of which is preserved in a variety of Northern Hemisphere palaeoclimate archives 1 . Ice cores show that Antarctica cooled during the warm phases of the Greenland Dansgaard–Oeschger cycle and vice versa 2 , 3 , suggesting an interhemispheric redistribution of heat through a mechanism called the bipolar seesaw 4 , 5 , 6 . Variations in the Atlantic meridional overturning circulation (AMOC) strength are thought to have been important, but much uncertainty remains regarding the dynamics and trigger of these abrupt events 7 , 8 , 9 . Key information is contained in the relative phasing of hemispheric climate variations, yet the large, poorly constrained difference between gas age and ice age and the relatively low resolution of methane records from Antarctic ice cores have so far precluded methane-based synchronization at the required sub-centennial precision 2 , 3 , 10 . Here we use a recently drilled high-accumulation Antarctic ice core to show that, on average, abrupt Greenland warming leads the corresponding Antarctic cooling onset by 218 ± 92 years (2 σ ) for Dansgaard–Oeschger events, including the Bølling event; Greenland cooling leads the corresponding onset of Antarctic warming by 208 ± 96 years. Our results demonstrate a north-to-south directionality of the abrupt climatic signal, which is propagated to the Southern Hemisphere high latitudes by oceanic rather than atmospheric processes. The similar interpolar phasing of warming and cooling transitions suggests that the transfer time of the climatic signal is independent of the AMOC background state. Our findings confirm a central role for ocean circulation in the bipolar seesaw and provide clear criteria for assessing hypotheses and model simulations of Dansgaard–Oeschger dynamics.

PurposeThe primary aim of the present study was to evaluate if PET/MR induced management changes versus standard of care imaging (SCI) in treated colorectal cancer patients. The secondary aim was to assess the staging performance of PET/MR and of SCI versus the final oncologic stage.MethodsTreated CRC patients who underwent PET/MR with 18F-FDG and SCI between January 2016 and October 2018 were enrolled in this retrospective study. Their medical records were evaluated to ascertain if PET/MR had impacted on their clinical management versus SCI. The final oncologic stage, as reported in the electronic medical record, was considered the true stage of disease.ResultsA total of 39 patients who underwent 42 PET/MR studies were included, mean age 56.7 years (range 39–75 years), 26 males, and 13 females. PET/MR changed clinical management 15/42 times (35.7%, standard error ± 7.4%); these 15 changes in management were due to upstaging in 9/42 (21.5%) and downstaging in 6/42 (14.2%). The differences in management prompted by SCI versus PET/MR were statistically significant, and PET/MR outperformed SCI (P value < 0.001; odds ratio = 2.8). In relation to the secondary outcome, PET/MR outperformed the SCI in accuracy of oncologic staging (P value = 0.016; odds ratio = 4.6).ConclusionsPET/MR is a promising imaging tool in the evaluation of treated CRC and might change the management in these patients. However, multicenter prospective studies with larger patient samples are required in order to confirm these preliminary results.

PurposeThe role of positron emission tomography/magnetic resonance (PET/MR) in evaluating the local extent of rectal cancer remains uncertain. This study aimed to investigate the possible role of PET/MR versus magnetic resonance (MR) in clinically staging rectal cancer.MethodsThis retrospective two-center cohort study of 62 patients with untreated rectal cancer investigated the possible role of baseline staging PET/MR versus stand-alone MR in determination of clinical stage. Two readers reviewed T and N stage, mesorectal fascia involvement, tumor length, distance from the anal verge, sphincter involvement, and extramural vascular invasion (EMVI). Sigmoidoscopy, digital rectal examination, and follow-up imaging, along with surgery when available, served as the reference standard.ResultsPET/MR outperformed MR in evaluating tumor size (42.5 ± 21.03 mm per the reference standard, 54 ± 20.45 mm by stand-alone MR, and 44 ± 20 mm by PET/MR, P = 0.004), and in identifying N status (correct by MR in 36/62 patients [58%] and by PET/MR in 49/62 cases [79%]; P = 0.02) and external sphincter infiltration (correct by MR in 6/10 and by PET/MR in 9/10; P = 0.003). No statistically significant differences were observed in relation to any other features.ConclusionPET/MR provides a more precise assessment of the local extent of rectal cancers in evaluating cancer length, N status, and external sphincter involvement. PET/MR offers the opportunity to improve clinical decision-making, especially when evaluating low rectal tumors with possible external sphincter involvement.