Citations

Objective Specific sedative hypnotic agents, administered to facilitate endotracheal intubation (ETI) in critically ill adults, may lead to adverse outcomes such as peri-intubation cardiovascular collapse. However, little is known from systematic investigations of the impact these individual agents have on cardiovascular function or other clinical outcomes. Data sources MEDLINE, Embase, CENTRAL, ClinicalTrials.gov, Scopus and Web of science databases. Study selection We conducted a systematic search for randomized and non-randomized studies that evaluated adult (≥18 years) critically ill patients who were sedated to facilitate ETI with ketamine, propofol, ketamine/propofol, etomidate, or a benzodiazepine and who had data on peri-intubation hemodynamics and at least one other outcome involving acute kidney injury, delirium, opioid use, intubation difficulty, sequential organ failure assessment, length of stay, or mortality. Eighty-five studies were identified for eligibility assessment with 23 included in the analysis. Data extraction Two reviewers independently screened articles, extracted data from selected articles, and assessed risk of bias using ROBINS-I for observational studies and revised Cochrane Risk of Bias tool for randomized controlled trials. Data synthesis Acute cardiovascular dysfunction (peri-intubation hemodynamic instability and/or cardiac arrest) was similar between etomidate and ketamine with more events seen when propofol versus non-propofol sedation was administered. However, exploratory meta-analysis demonstrated no difference between etomidate and ketamine (OR 1.05 [95%CI 0.60-1.84]) or between etomidate and propofol (OR 0.91 [95%CI 0.33-2.46]). Compared to ketamine, etomidate demonstrated lower survival to hospital discharge in the included studies in exploratory meta-analysis OR 0.76 (95%CI 0.62-0.92). Limited data existed for other outcomes with no discernible differences between sedative agents. Conclusions Acute cardiovascular dysfunction was more common when propofol, as compared to non-propofol sedation, was administered, although not statistically significant in exploratory meta-analysis. In addition, etomidate conferred lower survival to hospital discharge versus non-etomidate sedation, which was confirmed in exploratory meta-analysis of etomidate versus ketamine.

Inadequate light penetration in tissues restricts photodynamic therapy to treating only superficial tumors. To enable x-ray–excited photodynamic therapy (XPDT) that targets deep-seated tumors, we synthesized a nanoscintillator-photosensitizer complex containing 5% Eu-doped Y 2 O 3 fluorescing at 611 nanometers and decorated with SiO 2 containing the scintillation-coupled photosensitizer methylene blue and a polyethylene glycol coating [PEGylated Y 2 O 3 :Eu@SiO 2 -methylene blue (pYSM)]. When irradiated, pYSMs generate singlet oxygen species in vitro, causing cytotoxicity with hallmarks of immunogenic cell death (calreticulin translocation to the cell membrane). Intravenously administered pYSMs home passively to pancreatic tumor xenografts and, upon 10 gray irradiation, cause significant tumor regression ( P < 0.01). On combining XPDT with anti-PD1 immunotherapy, a distant nonirradiated tumor also regresses via an increase in intratumoral activated CD8 + cytotoxic T cells. Collectively, we advance a systemically delivered XPDT strategy that mediates an antitumor effect in both irradiated and nonirradiated (abscopal) tumors when coupled with immunotherapy, converting an immunologically “cold” tumor to an immunologically “hot” tumor.

AbstractEpilepsy syndromes are distinct electroclinical entities which have been recently defined by the International League Against Epilepsy Nosology and Definitions Task Force. Each syndrome is associated with “a characteristic cluster of clinical and EEG features, often supported by specific etiologic findings”. Syndromes often present in an age‐dependent manner, carry both prognostic and treatment implications, and are associated with a specific range of comorbidities. Syndromes are most commonly identified in young children and are less frequent in adults. Syndrome identification assists clinicians in selecting the highest yield investigations, the most effective therapies, and allows them to give more accurate prognoses both with regards to seizure control and potential remission as well as expected, associated comorbidities. This review outlines how syndromes are organized and defined, highlighting the characteristic features of the more common entities.Plain Language SummaryEpilepsy syndromes are identifiable entities that are characterized by specific seizure type(s) and EEG findings. Identification of an epilepsy syndrome often provides a clue to the underlying cause, helps clinicians select the most effective treatments, and provides information on the likely outcome.

Objective Early‐onset Alzheimer's disease (EOAD) and late‐onset Alzheimer's disease (LOAD) differ in many respects. Here, we address the issue of possible differences in fibrillar amyloid pathology as measured by positron emission tomography (PET), which remains unresolved due to the lack of large‐scale comparative studies. Methods Three hundred ninety‐nine cognitively impaired participants younger than 65 years of age from the multicenter Longitudinal Early‐onset Alzheimer's Disease Study (LEADS) and 450 cognitively impaired participants older than 65 years from the Alzheimer's Disease Neuroimaging Initiative (ADNI) underwent clinical assessment, brain magnetic resonance imaging (MRI), and amyloid PET and were included in this study. We compared amyloid PET outcomes (positivity rate based on visual read and quantified tracer uptake expressed as Centiloids [CLs]) between the 2 cohorts and studied their association with age, sex, APOE genotype, and cognition. Results The amyloid positivity rate was higher in LEADS (78%, 95% confidence interval [CI] = 74–82) than in ADNI (71%, 95% CI = 67–75, p = 0.02). Lower Mini‐Mental State Examination (MMSE) and APOE4 genotype increased the odds of amyloid positivity in both cohorts. Visually positive scans had higher CLs in LEADS (EOAD, mean = 95.3 ± 26.1) than in ADNI (LOAD, mean = 80.9 ± 36.8, p < 0.0001), predominantly in parietal cortex/precuneus, superior temporal, and frontal cortices. In amyloid‐positive patients, (1) CLs were higher in female patients in both cohorts; (2) APOE4 carriership was associated with lower CLs in EOAD, which was not observed in LOAD; and (3) correlations between CLs and MMSE scores were significantly stronger in EOAD than in LOAD. Interpretation Differences in the burden of amyloid pathology may contribute to differences in clinical and anatomic patterns in sporadic EOAD and LOAD, and have implications for optimizing therapeutic strategies in each group. ANN NEUROL 2025;98:236–248

Aim Cognitive and behavioral phenomena define behavioral variant frontotemporal dementia (bvFTD), but neuropsychiatric symptoms (NPS) outside the core criteria are common throughout the illness. Identifying how NPS cluster in bvFTD may guide development of future therapies. Methods Participants ( n = 354) with sporadic and genetic bvFTD were enrolled in the ARTFL LEFFTDS Longitudinal Frontotemporal Lobar Degeneration Consortium. Dementia stage was defined as early (CDR® plus NACC FTLD ≤1) or advanced (CDR® plus NACC FTLD ≥1). Baseline and annual follow‐up visit data were analyzed to compare NPS across stages of bvFTD. Psychiatric states were captured using the Neuropsychiatric Inventory‐Questionnaire and Clinician Judgment of Symptoms. Polychoric cluster analysis was used to describe NPS clusters. Results NPS were highly prevalent (≥90%) in early and late bvFTD. Four NPS clusters were identified based on magnitude of factor loadings: affective, disinhibited, compulsive, and psychosis. Neuropsychiatric symptoms fluctuated across visits. In the affective cluster, depression showed the least visit‐to‐visit stability. In the disinhibited cluster, elation showed the least stability. Symptoms in the psychosis and compulsive clusters (hallucinations, delusions, obsessions/compulsions, and hyperorality) were largely stable, persisting from visit‐to‐visit in more than 50% of cases. Symptoms in the affective and disinhibited cluster were associated with the highest caregiver burden, while symptoms in the obsessive cluster were associated with the most functional impairment. Conclusion NPS in bvFTD are frequent and cluster into four discrete groups. The fluctuating nature of some NPS in bvFTD suggests that they may not be reliable markers of disease progression or stage.

Abstract Hippocampal atrophy on magnetic resonance imaging is an important biomarker in Alzheimer's disease (AD). While hippocampal atrophy was thought to result from tau tangles in AD, different neuropathologies can lead to hippocampal atrophy, especially TAR DNA‐binding protein 43 (TDP‐43) pathology. In this narrative review, we evaluate existing studies on the relative contribution of tau and TDP‐43 pathology to medial temporal lobe (MTL) atrophy. We report a clear association of both tau and TDP‐43 neuropathology with MTL atrophy, even after correcting for other neuropathologies. Next, we discuss a potential synergism between tau and TDP‐43 and the relative timing of the effects of both neuropathologies. Finally, avenues for future research will be discussed. A better understanding of the interplay between tau and TDP‐43 neuropathologies and their effect on atrophy will help with the development of more specific biomarkers for limbic‐predominant age‐related TDP‐43 encephalopathy and pinpointing of the optimal timing for testing anti‐tau and anti‐TDP‐43 treatments in trials. Highlights Both tau and TAR DNA‐binding protein 43 (TDP‐43) pathology contribute to medial temporal lobe atrophy. There is a positive association between tau and TDP‐43 and potentially a synergism. It is unclear if tau and TDP‐43 have an additive or synergistic effect on atrophy. The relative timing of the tau and TDP‐43 effects on atrophy remains unclear. Clarifying the interplay between tau and TDP‐43 will help improve magnetic resonance imaging biomarkers.

Abstract INTRODUCTION Early‐onset and late‐onset Alzheimer's disease (EOAD and LOAD, respectively) have distinct clinical manifestations, with prior work based on small samples suggesting unique patterns of neurodegeneration. The current study performed a head‐to‐head comparison of cortical atrophy in EOAD and LOAD, using two large and well‐characterized cohorts (LEADS and ADNI). METHODS We analyzed brain structural magnetic resonance imaging (MRI) data acquired from 377 sporadic EOAD patients and 317 sporadicLOAD patients who were amyloid positive and had mild cognitive impairment (MCI) or mild dementia (i.e., early‐stage AD), along with cognitively unimpaired participants. RESULTS After controlling for the level of cognitive impairment, we found a double dissociation between AD clinical phenotype and localization/magnitude of atrophy, characterized by predominant neocortical involvement in EOAD and more focal anterior medial temporal involvement in LOAD. DISCUSSION Our findings point to the clinical utility of MRI‐based biomarkers of atrophy in differentiating between EOAD and LOAD, which may be useful for diagnosis, prognostication, and treatment. Highlights Early‐onset Alzheimer's disease (EOAD) and late‐onset AD (LOAD) patients showed distinct and overlapping cortical atrophy patterns. EOAD patients showed prominent atrophy in widespread neocortical regions. LOAD patients showed prominent atrophy in the anterior medial temporal lobe. Regional atrophy was correlated with the severity of global cognitive impairment. Results were comparable when the sample was stratified for mild cognitive impairment (MCI) and dementia.

Objective: To develop and validate 2 predictive models, the Diabetes Remission Index (DRI) and the Weight loss–adjusted DRI (W-DRI), for assessing type 2 diabetes (T2D) remission following metabolic and bariatric surgery (MBS). Background: MBS, including Roux-en-Y gastric bypass and sleeve gastrectomy, is highly effective in achieving T2D remission, but outcomes vary across populations. Predicting remission remains critical for individualized patient care and optimizing surgical outcomes. Existing tools focus on general outcomes, and a specific model incorporating weight loss data has been lacking. Methods: This multicenter, retrospective cohort study included patients with T2D and overweight/obesity (body mass index: ≥27 kg/m 2 ) who underwent Roux-en-Y gastric bypass or sleeve gastrectomy between 2008 and 2018. Institution 1 (I-1) data (n = 503) were used to develop and internally validate the models, whereas Institution 2 (I-2) data (n = 409) were used for external validation. The DRI model incorporated preoperative variables, and the W-DRI model, in addition, included postsurgical weight loss. Predictive accuracy was assessed using area under the Receiver Operating Characteristic curve [area under the curve (AUC)], calibration plots, and stratified analyses. Results: In I-1, 44.7% of patients achieved T2D remission, with a DRI model AUC of 0.80. In I-2, 52.6% achieved remission, with a model AUC of 0.78. Incorporating weight loss improved W-DRI predictive accuracy (AUC: 0.82 in I-1, 0.79 in I-2). Calibration plots demonstrated strong agreement between predicted and observed remission rates. An online DRI and W-DRI calculator is available through the Mayo Clinic webpage (https://newsnetwork.mayoclinic.org/dri-calculator/). Conclusions: The DRI and W-DRI models accurately predict T2D remission post-MBS, enabling personalized patient care and informed decision-making. Further validation across diverse populations is warranted.

AbstractBackgroundThe clinical significance of natural and treatment‐emergent antibodies specific for amustaline/glutathione pathogen‐reduced red blood cells (PRRBCs) is not known.Study Design and MethodsA Phase 3, randomized clinical trial of PRRBCs (ReCePI) compared PRRBCs with conventional RBCs in cardiac or thoracic‐aorta surgery. Subjects transfused during and for 7 days after surgery were screened for PRRBC‐specific antibodies at baseline, 28 and 75 days post‐surgery. Subjects with treatment‐emergent antibodies were assessed for evidence of hemolysis. Cryopreserved subject RBC samples were assayed by flow cytometry for circulating PRRBCs using an acridine‐specific (2S197‐2M1) monoclonal antibody, and for human IgG‐coated RBCs. RBC‐surface acridine density was quantitated using a commercial calibrated phycoerythrin (PE)‐bead panel.ResultsFive of 159 (3.1%) PRRBC and zero of 162 conventional RBC recipients developed treatment‐emergent PRRBC‐specific IgG, low titer antibodies detected 26–80 days post‐surgery after exposure to 1–3 PRRBC units, without clinical evidence of hemolysis. DAT and eluate were weak (w+) positive and PRRBC‐specific in one subject. A monocyte monolayer assay (MMA) was non‐reactive in the three subjects with an interpretable result. Flow cytometry demonstrated circulating PRRBCs in all five subjects expressing surface acridine concentrations at the limit of detection (approximately 150–301 PE molecules/RBC) compared with freshly transfused PRRBCs (approximately 7500 PE molecules/RBC). In some samples, loss of surface acridine expression could not be distinguished from clearance of the PRRBCs.DiscussionTreatment‐emergent PRRBC‐specific antibodies with the characteristics of nonclinically significant antibodies were detected in five subjects transfused with PRRBCs. Flow cytometry demonstrated persistent circulating PRRBCs with minimal surface acridine expression. (www.ClinicalTrials.gov Identifier NCT03459287).

Abstract INTRODUCTION Early‐onset Alzheimer's disease (EOAD) manifests prior to the age of 65, and affects 4%–8% of patients with Alzheimer's disease (AD). The current analyses sought to examine longitudinal cognitive trajectories of participants with early‐onset dementia. METHODS Data from 307 cognitively normal (CN) volunteer participants and those with amyloid‐positive EOAD or amyloid‐negative cognitive impairment (EOnonAD) were compared. Cognitive trajectories across a comprehensive cognitive battery spanning 42 months were examined using mixed‐effects modeling. RESULTS The EOAD group displayed worse cognition at baseline relative to EOnonAD and CN groups, and more aggressive declines in cognition over time. The largest effects were observed on measures of executive functioning domains, while memory declines were blunted in EOAD. DISCUSSION EOAD declined 2–4× faster than EOnonAD, and EOAD pathology is not restricted to memory networks. Early identification of deficits is critical to ensure that individuals with sporadic EOAD can be considered for treatment using disease‐modifying medications. Highlights Represents the most comprehensive longitudinal characterization of sporadic EOAD to date. The trajectory of cognitive declines was steep for EOAD participants and worse than for other groups. Executive functioning measures exhibited the greatest declines over time in EOAD.