ImmunoPET imaging of Trop2 in patients with solid tumours.

Accurately predicting and selecting patients who can benefit from targeted or immunotherapy is crucial for precision therapy. Trophoblast cell surface antigen 2 (Trop2) has been extensively investigated as a pan-cancer biomarker expressed in various tumours and plays a crucial role in tumorigenesis through multiple signalling pathways. Our laboratory successfully developed two 68Ga-labelled nanobody tracers that can rapidly and specifically target Trop2. Of the two tracers, [68Ga]Ga-NOTA-T4, demonstrated excellent pharmacokinetics in preclinical mouse models and a beagle dog. Moreover, [68Ga]Ga-NOTA-T4 immuno-positron emission tomography (immunoPET) allowed noninvasive visualisation of Trop2 heterogeneous and differential expression in preclinical solid tumour models and ten patients with solid tumours. [68Ga]Ga-NOTA-T4 immunoPET could facilitate clinical decision-making through patient stratification and response monitoring during Trop2-targeted therapies.

Theory-based interventions aimed at promoting physical activity in pregnant women: A systematic review and meta-analysis of randomized controlled trials.

OBJECTIVES: The objectives were to assess (i) the quality of theory implementation, (ii) the application of behavior change techniques, and (iii) the effectiveness of theory-based interventions in promoting physical activity in pregnant women and improving maternal and neonatal outcomes. METHODS: A systematic search was conducted across 8 databases (Cumulative Index to Nursing and Allied Health Literature, the Cochrane Library, EMBASE, MEDLINE, APA PsycINFO, PubMed, SPORTDiscus, and Web of Science) to identify randomized controlled trials published from database inception to 8 July 2023. The Cochrane risk-of-bias 2.0 tool was used to evaluate the quality of the included studies. The theory coding scheme was used to measure the quality of theory implementation, and behavior change techniques were coded according to behavior change taxonomy (version 1). The meta-analysis was performed using RevMan 5.3. The Grading of Recommendations, Assessment, Development, and Evaluation Approach was used to assess the certainty of evidence. RESULTS: Eleven studies met the study criteria. Nine studies were based on one theory, while two studies were based on a combination of two theories. The quality of theory implementation was generally moderate. A total of 24 unique behavior change techniques were extracted. The most commonly used types of behavior change techniques were 'instruction on how to perform the behavior' (n = 9), 'goal setting' (behavior) (n = 8), 'action planning' (n = 7), and 'information about health consequences' (n = 7). Theory-based interventions significantly improved moderate-to-vigorous physical activity (standardized mean difference (SMD) = 0.17, 95 % confidence interval (CI) [0.04, 0.30], P = 0.01; moderate certainty of evidence), reduced the average gestational weight gain per week (mean difference (MD) = -0.06, 95 % CI [-0.11, -0.01], P = 0.02; moderate certainty of evidence), and decreased the incidence of gestational diabetes mellitus (risk ratio (RR) = 0.64, 95 % CI [0.46, 0.89], P = 0.008; high certainty of evidence). However, the effects of theory-based interventions on total physical activity, total gestational weight gain and the incidence of gestational hypertension and preterm delivery were unclear (P > 0.05). CONCLUSIONS: (i) Most of the studies exhibited a moderate level of theory implementation quality. (ii) The use of theories varies, but common behavior change techniques were found across studies. (iii) Theory-based interventions can improve physical activity and maternal and neonatal outcomes and appear to be safe. Appropriate health behavior theories and behavior change techniques should be fully utilized in future interventions. REGISTRATION: PROSPERO: CRD42023440886. TWEETABLE ABSTRACT: Theory-based interventions can improve physical activity and maternal and neonatal outcomes and appear to be safe. Appropriate health behavior theories and behavior change techniques should be fully utilized in the development of future interventions.

Tau pathology is associated with synaptic density and longitudinal synaptic loss in Alzheimer's disease.

The associations of synaptic loss with amyloid-ß (Aß) and tau pathology measured by positron emission tomography (PET) and plasma analysis in Alzheimer's disease (AD) patients are unknown. Seventy-five participants, including 26 AD patients, 19 mild cognitive impairment (MCI) patients, and 30 normal controls (NCs), underwent [18F]SynVesT-1 PET/MR scans to assess synaptic density and [18F]florbetapir and [18F]MK6240 PET/CT scans to evaluate Aß plaques and tau tangles. Among them, 19 AD patients, 12 MCI patients, and 29 NCs had plasma Aß42/40 and p-tau181 levels measured by the Simoa platform. Twenty-three individuals, 6 AD patients, 4 MCI patients, and 13 NCs, underwent [18F]SynVesT-1 PET/MRI and [18F]MK6240 PET/CT scans during a one-year follow-up assessment. The associations of Aß and tau pathology with cross-sectional and longitudinal synaptic loss were investigated using Pearson correlation analyses, generalized linear models and mediation analyses. AD patients exhibited lower synaptic density than NCs and MCI patients. In the whole cohort, global Aß deposition was associated with synaptic loss in the medial (r = -0.431, p < 0.001) and lateral (r = -0.406, p < 0.001) temporal lobes. Synaptic density in almost all regions was related to the corresponding regional tau tangles independent of global Aß deposition in the whole cohort and stratified groups. Synaptic density in the medial and lateral temporal lobes was correlated with plasma Aß42/40 (r = 0.300, p = 0.020/r = 0.289, p = 0.025) and plasma p-tau 181 (r = -0.412, p = 0.001/r = -0.529, p < 0.001) levels in the whole cohort. Mediation analyses revealed that tau tangles mediated the relationship between Aß plaques and synaptic density in the whole cohort. Baseline tau pathology was positively associated with longitudinal synaptic loss. This study suggested that tau burden is strongly linked to synaptic density independent of Aß plaques, and also can predict longitudinal synaptic loss.

PET/CT study of dopamine transporter (DAT) binding with the triple reuptake inhibitor toludesvenlafaxine in rats and humans.

PURPOSE: Toludesvenlafaxine is a recently developed antidepressant that belongs to the triple reuptake inhibitor class. Despite the in vitro evidence that toludesvenlafaxine inhibits the reuptake of serotonin (5-HT), norepinephrine (NE) and dopamine (DA), there is no in vivo evidence that toludesvenlafaxine binds to DAT and increases DA level, a mechanism thought to contribute to its favorable clinical performance. METHODS: Positron emission tomography/computed tomography (PET/CT) was used to examine the DAT binding capacity in healthy rats and human subjects and microdialysis was used to examine the striatal DA level in rats. [18F]FECNT and [11C]CFT were used as PET/CT radioactive tracer for rat and human studies, respectively. RESULTS: In rats, 9 mg/kg of toludesvenlafaxine hydrochloride (i.v.) followed by an infusion of 3 mg/kg via minipump led to the binding rate to striatum DAT at 3.7 - 32.41% and to hypothalamus DAT at 5.91 - 17.52% during the 45 min scanning period. 32 mg/kg oral administration with toludesvenlafaxine hydrochloride significantly increased the striatal DA level with the AUC0 - 180 min increased by 63.9%. In healthy volunteers, 160 mg daily toludesvenlafaxine hydrochloride sustained-release tablets for 4 days led to an average occupancy rates of DAT at 8.04% ± 7.75% and 8.09% ± 7.00%, respectively, in basal ganglion 6 h and 10 h postdose. CONCLUSION: These results represent the first to confirm the binding of toludesvenlafaxine to DAT in both rats and humans using PET/CT, and its elevation of brain DA level, which may help understand the unique pharmacological and functional effects of triple reuptake inhibitors such as toludesvenlafaxine. GOV IDENTIFIERS: NCT05905120. Registered 14 June 2023. (retrospectively registered).

Prevalence, distribution characteristic and risk factors of lumbar vertebral axial rotation in patients with lumbar disc herniation: a retrospective study.

This retrospective study aimed to investigate the impact of lumbar disc herniation (LDH) on vertebral axial rotation (VAR) in the lumbar spine, focusing on both close and distant neighboring vertebrae. A total of 516 patients with LDH and an equal number of healthy individuals were included in the study, matched for age and gender. The degree of axial rotation for each lumbar spine vertebra was assessed using the Nash-Moe index. The results revealed that the prevalence of VAR in the lumbar spine was significantly higher in the LDH group compared to the Control group (65.7% vs 46.7%, P < 0.001). Among the LDH group, the L2 vertebra had the highest frequency of VAR (49.5%), followed by L1 (45.1%), and then L3 to L5 (33.6%, 8.9%, 3.1%, respectively). A similar pattern was observed in the Control group (L2, 39.8%; L1, 34.6%; L3, 23.2%; L4, 3.1%; L5, 0.8%). Furthermore, the study found that disc herniation was associated with a higher incidence of VAR not only in close neighboring vertebrae but also in distant neighboring vertebrae. This indicates that the biomechanical influence of LDH extends beyond just the immediate adjacent vertebrae. To identify potential risk factors for VAR in LDH patients, multivariate analysis was performed. The results revealed that age was an independent risk factor for VAR (OR 1.022, 95% CI [1.011, 1.034], P < 0.001). However, the duration of symptoms and presence of back pain were not found to be significant risk factors for VAR.

GLUT1-mediated microglial proinflammatory activation contributes to the development of stress-induced spatial learning and memory dysfunction in mice.

BACKGROUND: Stress is a recognized risk factor for cognitive decline, which triggers neuroinflammation involving microglial activation. However, the specific mechanism for microglial activation under stress and affects learning and memory remains unclear. METHODS: The chronic stress mouse model was utilized to explore the relationship between microglial activation and spatial memory impairment. The effect of hippocampal hyperglycemia on microglial activation was evaluated through hippocampal glucose-infusion and the incubation of BV2 cells with high glucose. The gain-and loss-of-function experiments were conducted to investigate the role of GLUT1 in microglial proinflammatory activation. An adeno-associated virus (AAV) was employed to specifically knockdown of GLUT1 in hippocampal microglia to assess its impact on stressed-mice. RESULTS: Herein, we found that chronic stress induced remarkable hippocampal microglial proinflammatory activation and neuroinflammation, which were involved in the development of stress-related spatial learning and memory impairment. Mechanistically, elevated hippocampal glucose level post-stress was revealed to be a key regulator of proinflammatory microglial activation via specifically increasing the expression of microglial GLUT1. GLUT1 overexpression promoted microglial proinflammatory phenotype while inhibiting GLUT1 function mitigated this effect under high glucose. Furthermore, specific downregulation of hippocampal microglial GLUT1 in stressed-mice relieved microglial proinflammatory activation, neuroinflammation, and spatial learning and memory injury. Finally, the NF-κB signaling pathway was demonstrated to be involved in the regulatory effect of GLUT1 on microglia. CONCLUSIONS: We demonstrate that elevated glucose and GLUT1 expression induce microglia proinflammatory activation, contributing to stress-associated spatial memory dysfunction. These findings highlight significant interplay between metabolism and inflammation, presenting a possible therapeutic target for stress-related cognitive disorders.

pH-sensitive release of nitric oxide gas using peptide-graphene co-assembled hybrid nanosheets.

Nitric oxide (NO) donating drugs such as organic nitrates have been used to treat cardiovascular diseases for more than a century. These donors primarily produce NO systemically. It is however sometimes desirable to control the amount, location, and time of NO delivery. We present the design of a novel pH-sensitive NO release system that is achieved by the synthesis of dipeptide diphenylalanine (FF) and graphene oxide (GO) co-assembled hybrid nanosheets (termed as FF@GO) through weak molecular interactions. These hybrid nanosheets were characterised by using X-ray diffraction, Raman spectroscopy, Fourier transform infrared spectroscopy, zeta potential measurements, X-ray photoelectron spectroscopy, scanning and transmission electron microscopies. The weak molecular interactions, which include electrostatic, hydrogen bonding and π-π stacking, are pH sensitive due to the presence of carboxylic acid and amine functionalities on GO and the dipeptide building blocks. Herein, we demonstrate that this formulation can be loaded with NO gas with the dipeptide acting as an arresting agent to inhibit NO burst release at neutral pH; however, at acidic pH it is capable of releasing NO at the rate of up to 0.6 µM per minute, comparable to the amount of NO produced by healthy endothelium. In conclusion, the innovative conjugation of dipeptide with graphene can store and release NO gas under physiologically relevant concentrations in a pH-responsive manner. pH responsive NO-releasing organic-inorganic nanohybrids may prove useful for the treatment of cardiovascular diseases and other pathologies.

Development and validation of machine learning models to predict frailty risk for elderly.

AIMS: Early identification and intervention of the frailty of the elderly will help lighten the burden of social medical care and improve the quality of life of the elderly. Therefore, we used machine learning (ML) algorithm to develop models to predict frailty risk in the elderly. DESIGN: A prospective cohort study. METHODS: We collected data on 6997 elderly people from Chinese Longitudinal Healthy Longevity Study wave 6-7 surveys (2011-2012, 2014). After the baseline survey in 1998 (wave 1), the project conducted follow-up surveys (wave 2-8) in 2000-2018. The osteoporotic fractures index was used to assess frailty. Four ML algorithms (random forest [RF], support vector machine, XGBoost and logistic regression [LR]) were used to develop models to identify the risk factors of frailty and predict the risk of frailty. Different ML models were used for the prediction of frailty risk in the elderly and frailty risk was trained on a cohort of 4385 elderly people with frailty (split into a training cohort [75%] and internal validation cohort [25%]). The best-performing model for each study outcome was tested in an external validation cohort of 6997 elderly people with frailty pooled from the surveys (wave 6-7). Model performance was assessed by receiver operating curve and F2-score. RESULTS: Among the four ML models, the F2-score values were similar (0.91 vs. 0.91 vs. 0.88 vs. 0.90), and the area under the curve (AUC) values of RF model was the highest (0.75), followed by LR model (0.74). In the final two models, the AUC values of RF and LR model were similar (0.77 vs. 0.76) and their accuracy was identical (87.4% vs. 87.4%). CONCLUSION: Our study developed a preliminary prediction model based on two different ML approaches to help predict frailty risk in the elderly. IMPACT: The presented models from this study can be used to inform healthcare providers to predict the frailty probability among older adults and maybe help guide the development of effective frailty risk management interventions. IMPLICATIONS FOR THE PROFESSION AND/OR PATIENT CARE: Detecting frailty at an early stage and implementing timely targeted interventions may help to improve the allocation of health care resources and to reduce frailty-related burden. Identifying risk factors for frailty could be beneficial to provide tailored and personalized care intervention for older adults to more accurately prevent or improve their frail conditions so as to improve their quality of life. REPORTING METHOD: The study has adhered to STROBE guidelines. PATIENT OR PUBLIC CONTRIBUTION: No patient or public contribution.

Pharmacokinetic Interactions Between Tegoprazan and the Combination of Clarithromycin, Amoxicillin and Bismuth in Healthy Chinese Subjects: An Open-Label, Single-Center, Multiple-Dosage, Self-Controlled, Phase I Trial.

BACKGROUND: Tegoprazan is a potassium-competitive acid blocker that inhibits gastric acid and which may be used for eradicating Helicobacter pylori. This study focuses on the pharmacokinetic interaction and safety between tegoprazan and the combination of clarithromycin, amoxicillin and bismuth in healthy Chinese subjects. METHODS: An open-label, three-period, single-center, multiple-dosage, single-sequence, phase I trial was conducted in 22 healthy subjects. In period 1, the subjects took tegoprazan 50 mg twice daily for 7 days, and in period 2 they were administered clarithromycin 500 mg, amoxicillin 1000 mg and bismuth potassium citrate 600 mg twice daily for 7 days (days 14-20). Tegoprazan, clarithromycin, amoxicillin and bismuth potassium citrate were then administered in combination for 7 days (days 21-27) in period 3. Blood samples were collected up to 12 h after the last dose of each period. Safety assessments were performed in each period. RESULTS: The geometric mean ratios (GMRs) [90% confidence interval (CI)] of maximum plasma concentration at steady state (Cmax,ss) and area under the plasma concentration-time curve over the dosing interval (AUCτ) at steady state were 195.93% (175.52-218.71%) and 287.54% (263.28-314.04%) for tegoprazan and 423.23% (382.57-468.22%) and 385.61% (354.62-419.30%) for tegoprazan metabolite M1, respectively. The GMRs (90% CI) of Cmax,ss and AUCτ were 83.69% (77.44-90.45%) and 110.30% (102.74-118.41%) for clarithromycin, 126.25% (114.73-138.93%) and 146.94% (135.33-159.55%) for 14-hydroxyclarithromycin, 75.89% (69.73-82.60%) and 94.34% (87.94-101.20%) for amoxicillin, and 158.43% (125.43-200.11%) and 183.63% (156.42-215.58%) for bismuth, respectively. All reported adverse events were mild. The frequency of adverse events during the coadministration stage was not higher than that during the single- or triple-drug administration stages. CONCLUSION: The plasma exposure of tegoprazan, M1, 14-hydroxyclarithromycin and bismuth was increased after the coadministration of tegoprazan, clarithromycin, amoxicillin and bismuth. The coadministration exhibited favorable safety and tolerability. CLINICAL TRIALS REGISTRATION: CTR20230643.

Preclinical development of novel PD-L1 tracers and first-in-human study of [68Ga]Ga-NOTA-RW102 in patients with lung cancers.

BACKGROUND: The programmed cell death protein-1 (PD-1)/programmed death receptor ligand 1 (PD-L1) axis critically facilitates cancer cells' immune evasion. Antibody therapeutics targeting the PD-1/PD-L1 axis have shown remarkable efficacy in various tumors. Immuno-positron emission tomography (ImmunoPET) imaging of PD-L1 expression may help reshape solid tumors' immunotherapy landscape. METHODS: By immunizing an alpaca with recombinant human PD-L1, three clones of the variable domain of the heavy chain of heavy-chain only antibody (VHH) were screened, and RW102 with high binding affinity was selected for further studies. ABDRW102, a VHH derivative, was further engineered by fusing RW102 with the albumin binder ABD035. Based on the two targeting vectors, four PD-L1-specific tracers ([68Ga]Ga-NOTA-RW102, [68Ga]Ga-NOTA-ABDRW102, [64Cu]Cu-NOTA-ABDRW102, and [89Zr]Zr-DFO-ABDRW102) with different circulation times were developed. The diagnostic efficacies were thoroughly evaluated in preclinical solid tumor models, followed by a first-in-human translational investigation of [68Ga]Ga-NOTA-RW102 in patients with non-small cell lung cancer (NSCLC). RESULTS: While RW102 has a high binding affinity to PD-L1 with an excellent KD value of 15.29 pM, ABDRW102 simultaneously binds to human PD-L1 and human serum albumin with an excellent KD value of 3.71 pM and 3.38 pM, respectively. Radiotracers derived from RW102 and ABDRW102 have different in vivo circulation times. In preclinical studies, [68Ga]Ga-NOTA-RW102 immunoPET imaging allowed same-day annotation of differential PD-L1 expression with specificity, while [64Cu]Cu-NOTA-ABDRW102 and [89Zr]Zr-DFO-ABDRW102 enabled longitudinal visualization of PD-L1. More importantly, a pilot clinical trial shows the safety and diagnostic value of [68Ga]Ga-NOTA-RW102 immunoPET imaging in patients with NSCLCs and its potential to predict immune-related adverse effects following PD-L1-targeted immunotherapies. CONCLUSIONS: We developed and validated a series of PD-L1-targeted tracers. Initial preclinical and clinical evidence indicates that immunoPET imaging with [68Ga]Ga-NOTA-RW102 holds promise in visualizing differential PD-L1 expression, selecting patients for PD-L1-targeted immunotherapies, and monitoring immune-related adverse effects in patients receiving PD-L1-targeted treatments. TRIAL REGISTRATION NUMBER: NCT06165874.

Effectiveness of fecal DNA syndecan-2 methylation testing for detection of colorectal cancer in a high-risk Chinese population.

BACKGROUND: Colorectal cancer (CRC) is among the most prevalent and life-threatening malignancies worldwide. Syndecan-2 methylation (mSDC2) testing has emerged as a widely used biomarker for early detection of CRC in stool and serum samples. Cancer (CRC) is among the most prevalent and life-threatening malignancies worldwide. mSDC2 testing has emerged as a widely used biomarker for early detection of CRC in stool and serum samples. AIM: To validate the effectiveness of fecal DNA mSDC2 testing in the detection of CRC among a high-risk Chinese population to provide evidence-based data for the development of diagnostic and/or screening guidelines for CRC in China. METHODS: A high-risk Chinese cohort consisting of 1130 individuals aged 40-79 years was selected for evaluation via fecal mSDC2 testing. Sensitivity and specificity for CRC, advanced adenoma (AA) and advanced colorectal neoplasia (ACN) were determined. High-risk factors for the incidence of colorectal lesions were determined and a logistic regression model was constructed to reflect the efficacy of the test. RESULTS: A total of 1035 high-risk individuals were included in this study according to established criteria. Among them, 16 suffered from CRC (1.55%), 65 from AA (6.28%) and 189 from non-AAs (18.26%); 150 patients were diagnosed with polyps (14.49%). Diagnoses were established based upon colonoscopic and pathological examinations. Sensitivities of the mSDC2 test for CRC and AA were 87.50% and 40.00%, respectively; specificities were 95.61% for other groups. Positive predictive values of the mSDC2 test for CRC, AA and ACN were 16.09%, 29.89% and 45.98%, respectively; the negative predictive value for CRC was 99.79%. After adjusting for other high-risk covariates, mSDC2 test positivity was found to be a significant risk factor for the occurrence of ACN (P < 0.001). CONCLUSION: Our findings confirmed that offering fecal mSDC2 testing and colonoscopy in combination for CRC screening is effective for earlier detection of malignant colorectal lesions in a high-risk Chinese population.

Linking white matter hyperintensities to regional cortical thinning, amyloid deposition, and synaptic density loss in Alzheimer's disease.

INTRODUCTION: We investigated the association between white matter hyperintensities (WMH) and regional cortical thickness, amyloid and tau deposition, and synaptic density in the WMH-connected cortex using multimodal images. METHODS: We included 107 participants (59 with Alzheimer's disease [AD]; 27 with mild cognitive impairment; 21 cognitively normal controls) with amyloid beta (Aß) positivity on amyloid positron emission tomography (PET). The cortex connected to WMH was identified using probabilistic tractography. RESULTS: We found that WMH connected to the cortex with more severe regional degeneration as measured by cortical thickness, Aß and tau deposition, and synaptic vesicle glycoprotein 2 A (SV2A) density using 18F-SynVesT-1 PET. In addition, higher ratios of Aß in the deep WMH-connected versus WMH-unconnected cortex were significantly related to lower cognitive scores. Last, the cortical thickness of WMH-connected cortex reduced more than WMH-unconnected cortex over 12 months. DISCUSSION: Our results suggest that WMH may be associated with AD-intrinsic processes of degeneration, in addition to vascular mechanisms. HIGHLIGHTS: We studied white matter hyperintensities (WMHs) and WMH-connected cortical changes. WMHs are associated with more severe regional cortical degeneration. Findings suggest WMHs may be associated with Alzheimer's disease-intrinsic processes of degeneration.

Presynaptic density determined by SV2A PET is closely associated with postsynaptic metabotropic glutamate receptor 5 availability and independent of amyloid pathology in early cognitive impairment.

INTRODUCTION: Metabotropic glutamate receptor 5 (mGluR5) is involved in regulating integrative brain function and synaptic transmission. Aberrant mGluR5 signaling and relevant synaptic failure play a key role in the pathophysiological mechanism of Alzheimer's disease (AD). METHODS: Ten cognitively impaired (CI) individuals and 10 healthy controls (HCs) underwent [18F]SynVesT-1 and [18F]PSS232 positron emission tomography (PET)/magnetic resonance to assess synaptic density and mGluR5 availability. The associations between mGluR5 availability and synaptic density were examined. A mediation analysis was performed to investigate the possible mediating effects of mGluR5 availability and synaptic loss on the relationship between amyloid deposition and cognition. RESULTS: CI patients exhibited lower mGluR5 availability and synaptic density in the medial temporal lobe than HCs. Regional synaptic density was closely associated with regional mGluR5 availability. mGluR5 availability and synaptic loss partially mediated the relationship between amyloid deposition and cognition. CONCLUSIONS: Reductions in mGluR5 availability and synaptic density exhibit similar spatial patterns in AD and are closely linked. HIGHLIGHTS: Cognitively impaired patients exhibited lower mGluR5 availability and synaptic density in the medial temporal lobe than HCs. Reductions in mGluR5 availability and synaptic density exhibit similar spatial patterns in AD. Regional synaptic density was closely associated with regional mGluR5 availability. mGluR5 availability and synaptic loss partially mediated the relationship between amyloid deposition and global cognition. With further research, modulating mGluR5 availability might be a potential therapeutic strategy for improving synaptic function in AD.

In vitro evaluation of PET radiotracers reflecting multidimensionality of Alzheimer's disease: building more roadmaps for clinical translation.

In the current issue of American Journal of Nuclear Medicine and Molecular Imaging, Vasdev et al. presented a work entitled "In Vitro Evaluation of PET Radiotracers for Imaging Synaptic Density, the Acetylcholine Transporter, AMPA-tarp-γ8 and Muscarinic M4 receptors in Alzheimer's disease". In which, in vitro autoradiography studies using radioligands were employed as a valuable tool to gain more insights for potential clinical translation. In this invited perspective, we would like to briefly introduce the current state of AD diagnosis, especially PET imaging on synapse, and highlight the advances of PET imaging in pre-clinic and clinic that might assist on precise therapy in the future.

Relationship Between Reactive Astrocytes, by [18F]SMBT-1 Imaging, with Amyloid-Beta, Tau, Glucose Metabolism, and TSPO in Mouse Models of Alzheimer's Disease.

Reactive astrocytes play an important role in the development of Alzheimer's disease (AD). Here, we aimed to investigate the temporospatial relationships among monoamine oxidase-B, tau and amyloid-ß (Aß), translocator protein, and glucose metabolism by using multitracer imaging in AD transgenic mouse models. Positron emission tomography (PET) imaging with [18F]SMBT-1 (monoamine oxidase-B), [18F]florbetapir (Aß), [18F]PM-PBB3 (tau), [18F]fluorodeoxyglucose (FDG), and [18F]DPA-714 (translocator protein) was carried out in 5- and 10-month-old APP/PS1, 11-month-old 3×Tg mice, and aged-matched wild-type mice. The brain regional referenced standard uptake value (SUVR) was computed with the cerebellum as the reference region. Immunofluorescence staining was performed on mouse brain tissue slices. [18F]SMBT-1 and [18F]florbetapir SUVRs were greater in the cortex and hippocampus of 10-month-old APP/PS1 mice than in those of 5-month-old APP/PS1 mice and wild-type mice. No significant difference in the regional [18F]FDG or [18F]DPA-714 SUVRs was observed in the brains of 5- or 10-month-old APP/PS1 mice or wild-type mice. No significant difference in the SUVRs of any tracer was observed between 11-month-old 3×Tg mice and age-matched wild-type mice. A positive correlation between the SUVRs of [18F]florbetapir and [18F]DPA-714 in the cortex and hippocampus was observed among the transgenic mice. Immunostaining validated the distribution of MAO-B and limited Aß and tau pathology in 11-month-old 3×Tg mice; and Aß deposits in brain tissue from 10-month-old APP/PS1 mice. In summary, these findings provide in vivo evidence that an increase in astrocyte [18F]SMBT-1 accompanies Aß accumulation in APP/PS1 models of AD amyloidosis.

How to assess the long-term recovery outcomes of patients with cauda equina syndrome before surgery: a retrospective cohort study.

BACKGROUND: Factors influencing recovery after decompression surgery for cauda equina syndrome (CES) are not completely identified. We aimed to investigate the most valuable predictors (MVPs) of poor postoperative recovery (PPR) in patients with CES and construct a nomogram for discerning those who will experience PPR. METHODS: 356 patients with CES secondary to lumbar degenerative diseases treated at *** Hospital were randomly divided into training (N=238) and validation (N=118) cohorts at a 2:1 ratio. Moreover, 92 patients from the **** Hospital composed the testing cohort. Least Absolute Shrinkage and Selection Operator regression (LASSO) was used for selecting MVPs. The nomogram was developed by integrating coefficients of MVPs in the logistic regression, and its discrimination, calibration, and clinical utility were validated in all three cohorts. RESULTS: After 3 to 5 years of follow-up, the residual rates of bladder dysfunction, bowel dysfunction, sexual dysfunction, and saddle anesthesia were 41.9%, 44.1%, 63.7%, and 29.0%, respectively. MVPs included stress urinary incontinence, overactive bladder, low stream, difficult defecation, fecal incontinence, and saddle anesthesia in order. The discriminatory ability of the nomogram was up to 0.896, 0.919, and 0.848 in the training, validation, and testing cohorts, respectively. Besides, the nomogram showed good calibration and clinical utility in all cohorts. Furthermore, the optimal cut-off value of the nomogram score for distinguishing those who will experience PPR was 148.02, above which postoperative outcomes tend to be poor. CONCLUSION: The first pre-treatment nomogram for discerning CES patients who will experience PPR was developed and validated, which will aid clinicians in clinical decision-making.

Reduced-Volume Irradiation of Uninvolved Neck in Patients With Nasopharyngeal Cancer: Updated Results From an Open-Label, Noninferiority, Multicenter, Randomized Phase III Trial.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.We previously reported comparable 3-year regional relapse-free survival (RRFS) using elective upper-neck irradiation (UNI) in N0-1 nasopharyngeal carcinoma (NPC) compared with standard whole-neck irradiation (WNI). Here, we present the prespecified 5-year overall survival (OS), RRFS, late toxicity, and additional analyses. In this randomized trial, patients received UNI (n = 224) or WNI (n = 222) for an uninvolved neck. After a median follow-up of 74 months, the UNI and WNI groups had similar 5-year OS (95.9% v 93.1%, hazard ratio [HR], 0.63 [95% CI, 0.30 to 1.35]; P = .24) and RRFS (95.0% v 94.9%, HR, 0.96 [95% CI, 0.43 to 2.13]; P = .91) rates. The 5-year disease-free survivors in the UNI group had a lower frequency of hypothyroidism (34% v 48%; P = .004), neck tissue damage (29% v 46%; P < .001), dysphagia (14% v 27%; P = .002), and lower-neck common carotid artery stenosis (15% v 26%; P = .043). The UNI group had higher postradiotherapy circulating lymphocyte counts than the WNI group (median: 400 cells/µL v 335 cells/µL, P = .007). In conclusion, these updated data confirmed that UNI of the uninvolved neck is a standard of care in N0-1 NPC, providing outstanding efficacy and reduced long-term toxicity, and might retain more immune function.

Effectiveness of web-based interventions for women with urinary incontinence: protocol for a systematic review and meta-analysis of randomised controlled trials.

INTRODUCTION: Urinary incontinence (UI) is one of the most common chronic diseases among women, which can endanger their physical and mental health and incur a heavy financial burden on both individuals and society. Web-based interventions (WBIs) have been applied to manage women's UI, but their effectiveness has remained inconclusive. This systematic review and meta-analysis aims to explore the effectiveness of WBIs on self-reported symptom severity, condition-specific quality of life, adherence to pelvic floor muscle training (primary outcomes) and other extensive secondary outcomes among women with UI. We also aimed to investigate whether intervention characteristics (format, interactivity and main technology) have impacts on the effectiveness of primary outcomes. METHODS AND ANALYSIS: This systematic review protocol was developed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols guidelines. 10 electronic databases will be comprehensively searched from their inception to 1 May 2024, along with grey literature searches and manual reviews of relevant reference lists to identify eligible randomised controlled trials. The methodological quality of the included studies will be assessed by two reviewers based on the Cochrane Risk of Bias Tool. Meta-analyses will be conducted via Stata V.12.0. Leave-one-out sensitivity analyses will be performed, and publication bias will be evaluated using funnel plots and Egger's test. Subgroup analyses regarding intervention format, interactivity and main technology will be carried out. ETHICS AND DISSEMINATION: No ethics approval is needed for this review since no primary data are to be collected. The results of this review will help develop an optimal WBI for women with UI, thereby providing them with maximum benefits. The findings will be disseminated via a peer-reviewed journal or conference presentation. PROSPERO REGISTRATION NUMBER: CRD42023435047.

APOE ε4 is associated with decreased synaptic density in cognitively impaired participants.

INTRODUCTION: We aimed to investigate the effect of apolipoprotein E4 (APOE) ε4 on synaptic density in cognitively impaired (CI) participants. METHODS: One hundred ten CI participants underwent amyloid positron emission tomography (PET) with 18 F-florbetapir and synaptic density PET with 18 F-SynVesT-1. We evaluated the influence of APOE ε4 allele on synaptic density and investigated the effects of ε4 genotype on the associations of synaptic density with Alzheimer's disease (AD) biomarkers. The mediation effects of AD biomarkers on ε4-associated synaptic density loss were analyzed. RESULTS: Compared with non-carriers, APOE ε4 allele carriers exhibited significant synaptic loss in the medial temporal lobe. Amyloid beta (Aß) and tau pathology mediated the effects of APOE ε4 on synaptic density to different extents. The associations between synaptic density and tau pathology were regulated by the APOE ε4 genotype. DISCUSSION: The APOE ε4 allele was associated with decreased synaptic density in CI individuals and may be driven by AD biomarkers.

ImmunoPET/CT imaging of clear cell renal cell carcinoma with [18F]RCCB6: a first-in-human study.

PURPOSE: The cluster of differentiation (CD70) is a potential biomarker of clear cell renal cell carcinoma (ccRCC). This study aims to develop CD70-targeted immuno-positron emission tomography/computed tomography (immunoPET/CT) imaging tracers and explore the diagnostic value in preclinical studies and the potential value in detecting metastases in ccRCC patients. METHODS: Four novel CD70-specific single-domain antibodies (sdAbs) were produced and labelled with 18F by the aluminium fluoride restrained complexing agent (AlF-RESCA) method to develop radiotracers. The visualisation properties of the tracers were evaluated in a subcutaneous ccRCC patient-derived xenograft (PDX) model. In a registered prospective clinical trial (NCT06148220), six patients with pathologically confirmed RCC were included and underwent immunoPET/CT examination exploiting one of the developed tracers (i.e., [18F]RCCB6). RESULTS: We engineered four sdAbs (His-tagged RCCB3 and RCCB6, His-tag-free RB3 and RB6) specifically targeting recombinant human CD70 without cross-reactivity to murine CD70. ImmunoPET/CT imaging with [18F]RCCB3 and [18F]RCCB6 demonstrated a high tumour-to-background ratio in a subcutaneous ccRCC PDX model, with the latter showing better diagnostic potential supported by higher tumour uptake and lower bone accumulation. In comparison, [18F]RB6, developed by sequence optimisation, has significantly lower kidney accumulation than that of [18F]RCCB6. In a pilot translational study, [18F]RCCB6 immunoPET/CT displayed ccRCC metastases in multiple patients and demonstrated improved imaging contrast and diagnostic value than 18F-FDG PET/CT in a patient with ccRCC. CONCLUSION: The work successfully developed a series of CD70-targeted immunoPET/CT imaging tracers. Of them, [18F]RCCB6 clearly and specifically identified inoculated ccRCCs in preclinical studies. Clinical translation of [18F]RCCB6 suggests potential for identifying recurrence and/or metastasis in ccRCC patients.