bluuebunny/crossref_metadata_2025 huggingface dataset:
The association of serum uric acid with cognitive impairment and ATN biomarkers
Authors: Huang Shan , Wang Jun , Fan Dong-Yu , Luo Tong , Li Yanli , Tu Yun-Feng , Shen Ying-Ying , Zeng Gui-Hua , Chen Dong-Wan , Wang Ye-Ran , Chen Li-Yong , Wang Yan-Jiang , Guo Junhong
Published: July 2022

Background

Cognitive impairment (CI) has become a worldwide health problem. The relationship between CI and uric acid (UA) is contradictory.

Objective

We included participants with a full spectrum of CI, from cognitively unimpaired (CU) to dementia, from the Chongqing Ageing & Dementia Study (CADS).

Methods

First, we identified the relationships between serum UA (sUA) and cognitive function in different stages of CI. Second, we analyzed these relationships among different stages and types of CI. Finally, we explored the association between sUA and amyloid/tangle/neurodegeneration (ATN) biomarkers.

Results

We recruited 427 participants from the CADS, including 382 participants with mini-mental state examination (MMSE) evaluation. The levels of sUA were positively correlated with MMSE scores (p < 0.001), and the correlation was prominent in the course of dementia and in the type of Alzheimer’s disease (AD). The levels of UA had a positive correlation with plasma amyloid-β 42 (Aβ42) (p = 0.004). Higher levels of sUA weakened the correlation of MMSE scores with CSF ATN biomarkers and the correlation of CSF Aβ42 with tau.

Conclusion

UA is positively correlated with cognitive function, especially in the advanced stage of AD. The probable neuroprotective effects of sUA mainly act on Aβ42 and the downstream pathological cascade.
Neuronal and glial characterization in the rostrocaudal axis of the human anterior olfactory nucleus: Involvement in Parkinson’s disease
Authors: Villar-Conde Sandra , Astillero-Lopez Veronica , Gonzalez-Rodriguez Melania , Saiz-Sanchez Daniel , Ubeda-Banon Isabel , Flores-Cuadrado Alicia , Martinez-Marcos Alino
Published: July 2022

Hyposmia is one of the prodromal symptoms of Parkinson’s disease (PD) and a red flag in clinical diagnosis. Neuropathologically, this sign correlates with α-synuclein involvement in the anterior olfactory nucleus (AON). Neurodegeneration, microgliosis, and astrogliosis in AON are poorly studied, and bulbar AON is the focus of these studies with contradictory results. Additionally, male sex is a risk marker for developing PD, but sexual dimorphism of neural and glial populations in the AON has rarely been considered. The aim of this study was to analyze the density of NeuN, Iba-1, GFAP, and Lewy bodies (LBs), as well as the relationship of these cell type markers with pathology along the rostrocaudal axis of the AON (bulbar, retrobulbar, cortical anterior, and posterior divisions). Cavalieri, optical fractionator, and area fraction fractionator stereological approaches were used for the volume, cell populations and LBs densities, area fraction, and percentage of overlap. Iba-1 and α-syn intensities were measured using ImageJ. In non-PD (NPD) cases, the volume was lower in the AON at the extremes of the rostrocaudal axis than in the intermediate divisions. Cortical anterior AON volume decreased in PD compared with NPD cases. NeuN density decreased rostrocaudally in AON portions in NPD and PD cases. This occurred similarly in Iba-1 but only in PD samples. Iba-1 intensity significantly increased in bulbar AON between PD and NPD. No changes were found in astrocytes. Eight percent of NeuN, 0.1% of Iba-1, and 0.1% of GFAP areas overlapped with LBs area along the AON portions. The data indicate that bulbar AON, which is the most rostral portion in this axis, could play a major role in the pathology. This could be related to the larger area occupied by LBs in these divisions.
DeepMatch: Toward Lightweight in Point Cloud Registration
Authors: Qi Lizhe , Wu Fuwang , Ge Zuhao , Sun Yuquan
Published: July 2022

From source to target, point cloud registration solves for a rigid body transformation that aligns the two point clouds. IterativeClosest Point (ICP) and other traditional algorithms require a long registration time and are prone to fall into local optima. Learning-based algorithms such as Deep ClosestPoint (DCP) perform better than those traditional algorithms and escape from local optimality. However, they are still not perfectly robust and rely on the complex model design due to the extracted local features are susceptible to noise. In this study, we propose a lightweight point cloud registration algorithm, DeepMatch. DeepMatch extracts a point feature for each point, which is a spatial structure composed of each point itself, the center point of the point cloud, and the farthest point of each point. Because of the superiority of this per-point feature, the computing resources and time required by DeepMatch to complete the training are less than one-tenth of other learning-based algorithms with similar performance. In addition, experiments show that our algorithm achieves state-of-the-art (SOTA) performance on both clean, with Gaussian noise and unseen category datasets. Among them, on the unseen categories, compared to the previous best learning-based point cloud registration algorithms, the registration error of DeepMatch is reduced by two orders of magnitude, achieving the same performance as on the categories seen in training, which proves DeepMatch is generalizable in point cloud registration tasks. Finally, only our DeepMatch completes 100% recall on all three test sets.
A mechanistic model of ADHD as resulting from dopamine phasic/tonic imbalance during reinforcement learning
Authors: Véronneau-Veilleux Florence , Robaey Philippe , Ursino Mauro , Nekka Fahima
Published: July 2022

Attention deficit hyperactivity disorder (ADHD) is the most common neurodevelopmental disorder in children. Although the involvement of dopamine in this disorder seems to be established, the nature of dopaminergic dysfunction remains controversial. The purpose of this study was to test whether the key response characteristics of ADHD could be simulated by a mechanistic model that combines a decrease in tonic dopaminergic activity with an increase in phasic responses in cortical-striatal loops during learning reinforcement. To this end, we combined a dynamic model of dopamine with a neurocomputational model of the basal ganglia with multiple action channels. We also included a dynamic model of tonic and phasic dopamine release and control, and a learning procedure driven by tonic and phasic dopamine levels. In the model, the dopamine imbalance is the result of impaired presynaptic regulation of dopamine at the terminal level. Using this model, virtual individuals from a dopamine imbalance group and a control group were trained to associate four stimuli with four actions with fully informative reinforcement feedback. In a second phase, they were tested without feedback. Subjects in the dopamine imbalance group showed poorer performance with more variable reaction times due to the presence of fast and very slow responses, difficulty in choosing between stimuli even when they were of high intensity, and greater sensitivity to noise. Learning history was also significantly more variable in the dopamine imbalance group, explaining 75% of the variability in reaction time using quadratic regression. The response profile of the virtual subjects varied as a function of the learning history variability index to produce increasingly severe impairment, beginning with an increase in response variability alone, then accumulating a decrease in performance and finally a learning deficit. Although ADHD is certainly a heterogeneous disorder, these results suggest that typical features of ADHD can be explained by a phasic/tonic imbalance in dopaminergic activity alone.
What Models and Tools can Contribute to a Better Understanding of Brain Activity?
Authors: Goodfellow Marc , Andrzejak Ralph G. , Masoller Cristina , Lehnertz Klaus
Published: July 2022

Despite impressive scientific advances in understanding the structure and function of the human brain, big challenges remain. A deep understanding of healthy and aberrant brain activity at a wide range of temporal and spatial scales is needed. Here we discuss, from an interdisciplinary network perspective, the advancements in physical and mathematical modeling as well as in data analysis techniques that, in our opinion, have potential to further advance our understanding of brain structure and function.
A bibliometric and visualized analysis of early mobilization in intensive care unit from 2000 to 2021
Authors: Zhang Fan , Xia Qian , Zhang Lianlian , Wang Hui , Bai Yan , Wu Wenyan
Published: July 2022

Background

Early mobilization in the intensive care unit (ICU) is a hotspot. This study aims to provide a bibliometric perspective of the progress in this field.

Methods

We extracted publications on ICU early mobilization published in the Web of Science Core Collection database from 2000 to 2021. VOSviewer was used to construct co-occurrence and co-citation relationships for authors, references, and keywords; Citespace was used to visualize knowledge mapping of subject categories, countries, and keywords with the strongest citation bursts.

Results

A total of 4,570 publications were analyzed, with a steady increase in publications in the field of ICU early mobilization. From a macro perspective, research on ICU early mobilization involves multidisciplinary involvement, including critical care medicine, neurology, and nursing; as for the meso perspective, the United States is the major contributor. Needham DM and Schweickert WD are the key researchers in this field. Moreover, the core journal is Critical Care Medicine, with the most publications and citations. The microscopic level, dominated by references and keywords, illustrates that the hotspot and frontier of research on ICU early mobilization focus on ICU-acquired weakness, delirium, the prognosis of critical illness, and severe COVID-19.

Conclusion

This study presents a research landscape of ICU early mobilization from different perspectives. These findings will contribute to a better understanding of the current state of research in critical care medicine and provide the available information for future research ideas.
Structural Brain Network Reorganization Following Anterior Callosotomy for Colloid Cysts: Connectometry and Graph Analysis Results
Authors: Ciavarro Marco , Grande Eleonora , Bevacqua Giuseppina , Morace Roberta , Ambrosini Ettore , Pavone Luigi , Grillea Giovanni , Vangelista Tommaso , Esposito Vincenzo
Published: July 2022

Introduction:

The plasticity of the neural circuits after injuries has been extensively investigated over the last decades. Transcallosal microsurgery for lesions affecting the third ventricle offers an interesting opportunity to investigate the whole-brain white matter reorganization occurring after a selective resection of the genu of the corpus callosum (CC).

Method

Diffusion MRI (dMRI) data and neuropsychological testing were collected pre- and postoperatively in six patients with colloid cysts, surgically treated with a transcallosal-transgenual approach. Longitudinal connectometry analysis on dMRI data and graph analysis on structural connectivity matrix were implemented to analyze how white matter pathways and structural network topology reorganize after surgery.

Results

Although a significant worsening in cognitive functions (e.g., executive and memory functioning) at early postoperative, a recovery to the preoperative status was observed at 6 months. Connectometry analysis, beyond the decrease of quantitative anisotropy (QA) near the resection cavity, showed an increase of QA in the body and forceps major CC subregions, as well as in the left intra-hemispheric corticocortical associative fibers. Accordingly, a reorganization of structural network topology was observed between centrality increasing in the left hemisphere nodes together with a rise in connectivity strength among mid and posterior CC subregions and cortical nodes.

Conclusion

A structural reorganization of intra- and inter-hemispheric connective fibers and structural network topology were observed following the resection of the genu of the CC. Beyond the postoperative transient cognitive impairment, it could be argued anterior CC resection does not preclude neural plasticity and may subserve the long-term postoperative cognitive recovery.
Bridging Therapies With Injectable Immunomodulatory Drugs in the Management of Multiple Sclerosis: A Delphi Survey of an Italian Expert Panel of Neurologists
Authors: Marfia Girolama Alessandra , Centonze Diego , Salvetti Marco , Ferraro Elisabetta , Panetta Valentina , Gasperini Claudio , Mirabella Massimiliano , Conte Antonella
Published: July 2022

Background

In multiple sclerosis (MS), bridging therapies are usually administered when switching from one therapy to another. Such treatments generally consist of injectable immunomodulatory drugs (interferon or glatiramer acetate), whose efficacy, safety, and tolerability data are consolidated for use even in fragile patients. We performed a nationwide survey to gather expert opinions regarding the most appropriate use of bridging therapies in MS.

Methods

An independent steering committee of Italian neurologists with expertise in MS treatment identified critical issues in the use of bridging therapies and formulated a questionnaire. This questionnaire was used to conduct a Delphi web survey, involving a panel of Italian neurologists with experience in MS treatment. Their anonymous opinions were collected in three sequential rounds. Consensus was defined as an interquartile range (IQR) ≤2.

Results

Responses were obtained from 38 experts (100%) in all three rounds. Injectable immunomodulatory drugs were considered first-line therapy in patients with mild-to-moderate disease activity and in women planning to become pregnant. In addition, the experts were confident about prescribing these drugs in patients at risk of cancer recurrence, while the panel agreed to discontinue any treatments in patients with uncontrolled cardiovascular or metabolic disorders. Moreover, bridging therapy with injectable immunomodulatory drugs was considered appropriate in order to protect the patient from disease reactivation when a prolonged washout was needed and also while waiting for the completion of the immunization schedule.

Conclusion

The results of this nationwide survey confirm that, among Italian neurologists, there was wide agreement on the use of bridging therapies with injectable immunomodulatory drugs in several conditions in order to minimize the risk of disease reactivation when a prolonged washout was required or when the immunization schedule still needed to be completed in patients planning to become pregnant and in patients at risk of cancer recurrence.
Association Between Post-procedure Cerebral Blood Flow Velocity and Severity of Brain Edema in Acute Ischemic Stroke With Early Endovascular Therapy
Authors: Pan Jie , Wu Huadong , Wu Tingting , Geng Yu , Yuan Ruozhen
Published: July 2022

Objectives

We aimed to investigate the association between post-procedure cerebral blood flow velocity (CBFV) and severity of brain edema in patients with acute ischemic stroke (AIS) who received early endovascular therapy (EVT).

Methods

We retrospectively included patients with AIS who received EVT within 24 h of onset between February 2016 and November 2021. Post-procedure CBFV of the middle cerebral artery was measured in the affected and the contralateral hemispheres using transcranial Doppler ultrasound. The severity of brain edema was measured using the three-level cerebral edema grading from the Safe Implementation of Thrombolysis in Stroke-Monitoring Study, with grades 2–3 indicating severe brain edema. The Association between CBFV parameters and severity of brain edema was analyzed.

Results

A total of 101 patients (mean age 64.2 years, 65.3% male) were included, of whom 56.3% (57/101) suffered brain edema [grade 1, 23 (22.8%); grade 2, 10 (9.9%); and grade 3, 24 (23.8%)]. Compared to patients with non-severe brain edema, patients with severe brain edema had lower affected/contralateral ratios of systolic CBFV (median 1 vs. 1.2, P = 0.020) and mean CBFV (median 0.9 vs. 1.3, P = 0.029). Multivariate logistic regression showed that severe brain edema was independently associated with affected/contralateral ratios of systolic CBFV [odds ratio (OR) = 0.289, 95% confidence interval (CI): 0.069–0.861, P = 0.028] and mean CBFV (OR = 0.278, 95% CI: 0.084–0.914, P = 0.035) after adjusting for potential confounders.

Conclusion

Post-procedure affected/contralateral ratio of CBFV may be a promising predictor of brain edema severity in patients with AIS who received early EVT.
Establishing a Baseline for Human Cortical Folding Morphological Variables: A Multisite Study
Authors: de Moraes Fernanda H. P. , Mello Victor B. B. , Tovar-Moll Fernanda , Mota Bruno
Published: July 2022

Differences in the way human cerebral cortices fold have been correlated to health, disease, development, and aging. However, to obtain a deeper understanding of the mechanisms that generate such differences, it is useful to derive one's morphometric variables from the first principles. This study explores one such set of variables that arise naturally from a model for universal self-similar cortical folding that was validated on comparative neuroanatomical data. We aim to establish a baseline for these variables across the human lifespan using a heterogeneous compilation of cross-sectional datasets as the first step to extending the model to incorporate the time evolution of brain morphology. We extracted the morphological features from structural MRI of 3,650 subjects: 3,095 healthy controls (CTL) and 555 patients with Alzheimer's Disease (AD) from 9 datasets, which were harmonized with a straightforward procedure to reduce the uncertainty due to heterogeneous acquisition and processing. The unprecedented possibility of analyzing such a large number of subjects in this framework allowed us to compare CTL and AD subjects' lifespan trajectories, testing if AD is a form of accelerated aging at the brain structural level. After validating this baseline from development to aging, we estimate the variables' uncertainties and show that Alzheimer's Disease is similar to premature aging when measuring global and local degeneration. This new methodology may allow future studies to explore the structural transition between healthy and pathological aging and may be essential to generate data for the cortical folding process simulations.
Contribution of Obstructive Sleep Apnoea to Cognitive Functioning of Males With Coronary Artery Disease: A Relationship With Endocrine and Inflammatory Biomarkers
Authors: Kazukauskiene Nijole , Fineberg Naomi A. , Podlipskyte Aurelija , Bunevicius Adomas , Linares Nicolás Francisco Narvaez , Poitras Marilou , Plamondon Hélène , Pranckeviciene Aiste , Gecaite-Stonciene Julija , Mickuviene Narseta , Varoneckas Giedrius , Burkauskas Julius
Published: July 2022

Introduction

Our exploratory study aimed to determine whether obstructive sleep apnoea (OSA) could affect cognitive functioning in males with coronary artery disease (CAD), and whether such impact could be associated with changes in thyroid hormones and inflammatory marker regulation on cognitive functioning.

Method

We evaluated different endocrine and inflammatory biomarkers, including free triiodothyronine [fT3], free tetraiodothyronine [fT4], N-terminal pro-B-type natriuretic peptide [NT-pro-BNP], and high-sensitivity C-reactive protein [hs-CRP] serum levels in 328 males (x¯ = 57 ± 10 years), undergoing cardiac rehabilitation after an acute coronary event. Participants underwent full-night polysomnography and were classified in mild/non-OSA (n = 253) and OSA (n = 75) according to an apnoea-hypopnoea index ≥ 15 event/h. Cognitive functioning testing included the Digit Span Test, Digit Symbol Test (DSST), and Trail Making Test. Analyses of variance assessed the impact of OSA on cognitive functioning and possible relationships of fT3/fT4, NT-pro-BNP and with hs-CRP on cognitive measures.

Results

Significant group (OSA, mild/non-OSA) × NT-pro-BNP (<157.0 vs. ≥157.0, ng/L) interactions were found for the DSST raw score (F(2,324) = 3.58, p = 0.014). Decomposition of interactions showed that the DSST scores of the OSA group with NT-pro-BNP ≥ 157.0 ng/L (M = 33.2; SD = 8.1) were significantly lower, p = 0.031, than those of the mild/non-OSA with NT-pro-BNP < 157.0 ng/L (M = 37.7; SD = 8.9).

Conclusion

These findings indicate that males with OSA and clinically elevated NT-pro-BNP levels experienced inferior psychomotor performance compared to those without OSA and reduced NT-pro-BNP levels.
A Temporospatial Study of Sympathetic Skin Response and Electroencephalogram in Oral Mucosa Thermal Perception
Authors: Zhang Hao , Hu Shengjing , Wang Zhangang , Li Xiang , Wang Suogang , Chen Gang
Published: July 2022

Objective

To investigate the temporospatial changes in sympathetic skin response (SSR) and electroencephalogram (EEG) under thermal stimuli and to draw a topographic map of SSR threshold temperature of the oral mucosa.

Materials and Methods

A total of 40 healthy volunteers (24 men, 16 women, mean age of 23 ± 3) were enrolled. Thermal stimuli were applied to the 35 partitions of oral mucosa starting from 36°C at the gradience of 1°C and the lowest temperature evoked SSR was defined as SSR threshold temperature. SSR and EEG signals at 45, 48, 51, and 54°C were then recorded synchronously.

Results

The SSR threshold temperature increased from the anterior areas to the posterior areas. No significant difference between bilateral corresponding areas or between genders was observed. The SSR amplitude value increased from 45 to 54°C in the same area, while the highest value was recorded on the tip of the tongue and decreased backwardly from the anterior area. There were significant differences in latency of SSR between the tip of the tongue and the molar areas of the oral cavity (p < 0.05). Reduction in the alpha frequency band was observed after thermal stimuli, and there were statistical differences between baseline and thermal stimuli in all four degrees of temperatures (p < 0.05).

Conclusion

The result of the experiment revealed that the autonomic and central nervous system (CNS) played important roles in thermal perception of oral mucosa and could be helpful for better understanding of pathological mechanism of burning mouth syndrome (BMS).
Disruption of Functional Brain Networks Underlies the Handwriting Deficit in Children With Developmental Dyslexia
Authors: Liu Zhengyan , Li Junjun , Bi Hong-Yan , Xu Min , Yang Yang
Published: July 2022

Developmental dyslexia (DD) is a neurological-based learning disorder that affects 5-17.5% of children. Handwriting difficulty is a prevailing symptom of dyslexia, but its neural mechanisms remain elusive. Using functional magnetic resonance imaging (fMRI), this study examined functional brain networks associated with handwriting in a copying task in Chinese children with DD (n = 17) and age-matched children (n = 36). We found that dyslexics showed reduced network connectivity between the sensory-motor network (SMN) and the visual network (VN), and between the default mode network (DMN) and the ventral attention network (VAN) during handwriting, but not during drawing geometric figures. Moreover, the connectivity strength of the networks showing group differences was correlated with handwriting speed, reading and working memory, suggesting that the handwriting deficit in DD is linked with disruption of a large-scale brain network supporting motoric, linguistic and executive control processes. Taken together, this study demonstrates the alternations of functional brain networks that underly the handwriting deficit in Chinese dyslexia, providing a new clue for the neural basis of DD.
The Metabolic Syndrome Is Associated With Lower Cognitive Performance and Reduced White Matter Integrity in Midlife: The CARDIA Study
Authors: Dintica Christina S. , Hoang Tina , Allen Norrina , Sidney Stephen , Yaffe Kristine
Published: July 2022

Background

Cardiovascular disease risk factors play a critical role in brain aging. The metabolic syndrome (MetS), a constellation of cardiovascular risk factors, has been associated with poorer cognition in old age; however, it is unclear if it is connected to brain health earlier in life.

Methods

We investigated the association of MetS (n = 534, 18.5%) vs. no MetS (n = 2,346, 81.5%) with cognition in midlife within the prospective study, Coronary Artery Risk Development in Young Adults (CARDIA). At midlife (mean age 50), MetS was defined using National Cholesterol Education Program guidelines. At the 5-year follow-up, a cognitive battery was administered including tests of processing speed (Digit Symbol Substitution Test, DSST), executive function (the Stroop Test), verbal memory (Rey Auditory Verbal Learning Test, RAVLT), verbal fluency (category and letter fluency), and global cognitive function (Montreal Cognitive Assessment, MoCA). A sub-sample (n = 453) underwent brain MRI.

Results

Participants with MetS had worse performance on tests of verbal fluency, processing speed, executive function, and verbal memory (p < 0.05), but not on global cognition. MetS was also associated with lower frontal, parietal, temporal, and total white matter integrity (p < 0.05), as assessed with fractional anisotropy.

Conclusions

MetS is associated with lower cognition and microstructural brain alterations already at midlife, suggesting that MetS should be targeted earlier in life in order to prevent adverse brain and cognitive outcomes.
Pickering Emulsions Stabilized by Tea Water-Insoluble Protein Nanoparticles From Tea Residues: Responsiveness to Ionic Strength
Authors: Ren Zhongyang , Chen Zhongzheng , Zhang Yuanyuan , Lin Xiaorong , Weng Wuyin , Li Bin
Published: July 2022

Tea water-insoluble protein nanoparticles (TWIPNs) can be applied to stabilize Pickering emulsions. However, the effect of ionic strength (0–400 mmol/L) on the characteristics of Pickering emulsions stabilized by TWIPNs (TWIPNPEs) including volume-averaged particle size (d4,3), zeta potential, microstructure and rheological properties is still unclear. Therefore, this work researched the effect of ionic strength on the characteristics of TWIPNPEs. The d4,3 of TWIPNPEs in the aquatic phase increased with the increase in ionic strength (0–400 mmol/L), which was higher than that in the SDS phase. Furthermore, the flocculation index of TWIPNPEs significantly (P < 0.05) increased from 24.48 to 152.92% with the increase in ionic strength. This could be verified from the microstructure observation. These results indicated that ionic strength could promote the flocculation of TWIPNPEs. Besides, the absolute values of zeta potential under different ionic strengths were above 40 mV in favor of the stabilization of TWIPNPEs. The viscosity of TWIPNPEs as a pseudoplastic fluid became thin when shear rate increased from 0.1 to 100 s−1. The viscoelasticity of TWIPNPEs increased with increasing ionic strength to make TWIPNPEs form a gel-like Pickering emulsion. the possible mechanism of flocculation stability of TWIPNPEs under different ionic strengths was propose. TWIPNs adsorbed to the oil-water interface would prompt flocculation between different emulsion droplets under the high ionic strength to form gel-like behavior verified by CLSM. These results on the characteristics of TWIPNPEs in a wide ionic strength range would provide the theoretical basis for applying Pickering emulsions stabilized by plant proteins in the food industry.
Sarcopenia Was a Poor Prognostic Predictor for Patients With Advanced Lung Cancer Treated With Immune Checkpoint Inhibitors
Authors: Li Shuluan , Liu Zhou , Ren Ya , Liu Jinying , Lv Shiqi , He Pin , Yang Yajing , Sun Yanfen , Chang Jianhua , Luo Dehong , Cong Minghua
Published: July 2022

Background

It remains not well known whether skeletal muscle mass (SMM) loss has any impact on the effectiveness of immune checkpoint inhibitors (ICIs) in patients with advanced lung cancer. We aimed to evaluate the association between SMM and clinical outcome of patients with advanced lung cancer receiving ICIs as first line or second line.

Materials and Methods

From March 1st, 2019 to March 31st, 2021 at our hospital, 34 patients with advanced lung cancer treated with first-line or second-line ICIs were enrolled retrospectively. The estimation of skeletal muscle index (SMI) for sarcopenia was assessed at the level of the third lumbar vertebra (L3) on computed tomography (CT) images obtained within 4 weeks before initiation of ICIs treatment. The impact of sarcopenia (low SMI) on progression free survival (PFS) was analyzed using Kaplan-Meier method and log-rank tests. The effect of various variables on PFS was evaluated using Cox proportional hazards regression model with univariate and multivariate analysis. The impact on treatment response including objective response rate (ORR) and disease control rate (DCR) and immunotherapy related adverse events (irAEs) between patients with and without sarcopenia was compared by the chi-squared test. The comparison of SMI value between patients with objective response (OR), disease control (DC) and those without OR and DC was used student t-test or Mann-Whitney U test.

Results

Both in univariate and multivariate analysis, sarcopenia and treatment lines were the predictive factors for PFS (p < 0.05). Patients with sarcopenia had significantly shorter PFS than that of non-sarcopenic ones [6.57 vs. 16.2 months, hazard ratios (HR) = 2.947 and 3.542, and 95% confidence interval (CI): 1.123–13.183 and 1.11–11.308, p = 0.022 and 0.033]. No significant difference in ORR and irAEs was found. Patients with sarcopenia had lower DCR than those without sarcopenia. The mean SMI value of DCR group and non-DCR group was 32.94 ± 5.49 and 44.77 ± 9.06 cm2/m2, respectively (p = 0.008).

Conclusion

Sarcopenia before immunotherapy might be a significant predictor for poor prognosis including shorter PFS and lower DCR in patients with advanced lung cancer treated with ICIs as first line or second line.
The Role of Branched-Chain Amino Acids and Branched-Chain α-Keto Acid Dehydrogenase Kinase in Metabolic Disorders
Authors: Du Chuang , Liu Wen-Jie , Yang Jing , Zhao Shan-Shan , Liu Hui-Xin
Published: July 2022

Branched-chain amino acids (BCAAs), composed of leucine, isoleucine, and valine, are important essential amino acids in human physiology. Decades of studies have revealed their roles in protein synthesis, regulating neurotransmitter synthesis, and the mechanistic target of rapamycin (mTOR). BCAAs are found to be related to many metabolic disorders, such as insulin resistance, obesity, and heart failure. Also, many diseases are related to the alteration of the BCAA catabolism enzyme branched-chain α-keto acid dehydrogenase kinase (BCKDK), including maple syrup urine disease, human autism with epilepsy, and so on. In this review, diseases and the corresponding therapies are discussed after the introduction of the catabolism and detection methods of BCAAs and BCKDK. Also, the interaction between microbiota and BCAAs is highlighted.
MRD in Venetoclax-Based Treatment for AML: Does it Really Matter?
Authors: Bernardi Massimo , Ferrara Felicetto , Carrabba Matteo Giovanni , Mastaglio Sara , Lorentino Francesca , Vago Luca , Ciceri Fabio
Published: July 2022

The prognosis of newly diagnosed patients with acute myeloid leukemia is still unfavorable in the majority of cases within the intermediate and mainly adverse genetic risk group but also in a considerable fraction of favorable-risk patients, mainly due to recurrence of disease after complete remission achievement or, less frequently, primary refractoriness. Besides genetic classification at diagnosis, post-treatment prognostic factors include measurable residual disease evaluation in patients in complete remission and in most cases measurable residual disease (MRD) positivity predicts hematologic relapse potentially allowing early therapeutic intervention. Currently, the most commonly used methods for detection of minimal residual disease are multiparameter flow cytometry and quantitative PCR, applicable to around 90% and 50% of patients, respectively. In addition, in > 90% of acute myeloid leukemia (AML) patients, molecular aberrations can be identified by next-generation sequencing, a technology that is widely used in clinical practice for the initial mutational screening at the time of diagnosis but more often, for MRD detection because its flexibility allows almost every mutated gene to be used as an MRD marker. Threshold levels of residual disease and correlation with outcome have been thoroughly studied and established in younger patients treated with intensive induction and consolidation chemotherapy as well as after allogeneic transplantation. Yet, experience on MRD monitoring and interpretation in patients treated with low-intensity regimens, including new agents, is still limited. The updated armamentarium of anti-leukemic agents includes the BCL-2 inhibitor venetoclax, which demonstrated good tolerability, high response rates, and prolonged overall survival when combined with hypomethylating agents or low dose cytarabine in patients considered elderly/”unfit” to tolerate intensive regimens. Although remissions with negative minimal residual disease clearly translated into improved outcomes after intensive treatments, data supporting the same evidence in patients receiving low-intensity venetoclax-based treatments are not still consolidated. We here review and discuss more recent data on the minimal residual disease interpretation and role in AML patients treated with venetoclax-based combinations.
Deep Learning for Automated Contouring of Gross Tumor Volumes in Esophageal Cancer
Authors: Jin Linzhi , Chen Qi , Shi Aiwei , Wang Xiaomin , Ren Runchuan , Zheng Anping , Song Ping , Zhang Yaowen , Wang Nan , Wang Chenyu , Wang Nengchao , Cheng Xinyu , Wang Shaobin , Ge Hong
Published: July 2022

Purpose

The aim of this study was to propose and evaluate a novel three-dimensional (3D) V-Net and two-dimensional (2D) U-Net mixed (VUMix-Net) architecture for a fully automatic and accurate gross tumor volume (GTV) in esophageal cancer (EC)–delineated contours.

Methods

We collected the computed tomography (CT) scans of 215 EC patients. 3D V-Net, 2D U-Net, and VUMix-Net were developed and further applied simultaneously to delineate GTVs. The Dice similarity coefficient (DSC) and 95th-percentile Hausdorff distance (95HD) were used as quantitative metrics to evaluate the performance of the three models in ECs from different segments. The CT data of 20 patients were randomly selected as the ground truth (GT) masks, and the corresponding delineation results were generated by artificial intelligence (AI). Score differences between the two groups (GT versus AI) and the evaluation consistency were compared.

Results

In all patients, there was a significant difference in the 2D DSCs from U-Net, V-Net, and VUMix-Net (p=0.01). In addition, VUMix-Net showed achieved better 3D-DSC and 95HD values. There was a significant difference among the 3D-DSC (mean ± STD) and 95HD values for upper-, middle-, and lower-segment EC (p<0.001), and the middle EC values were the best. In middle-segment EC, VUMix-Net achieved the highest 2D-DSC values (p<0.001) and lowest 95HD values (p=0.044).

Conclusion

The new model (VUMix-Net) showed certain advantages in delineating the GTVs of EC. Additionally, it can generate the GTVs of EC that meet clinical requirements and have the same quality as human-generated contours. The system demonstrated the best performance for the ECs of the middle segment.
Immune Lymphocyte Infiltrate and its Prognostic Value in Triple-Negative Breast Cancer
Authors: Huertas-Caro Carlos Alexander , Ramirez Mayra Alejandra , Gonzalez-Torres Henry J. , Sanabria-Salas María Carolina , Serrano-Gómez Silvia J.
Published: July 2022

Triple-negative breast cancer (TNBC) occurs more frequently in young (<50 years) non-Hispanic black and Hispanic/Latina women. It is considered the most aggressive subtype of breast cancer, although, recently, immune infiltrate has been associated with long-term survival, lower risk of death and recurrence, and response to neoadjuvant chemotherapy. The aim of this review was to evaluate the clinical impact of the immune infiltrate in TNBC by discussing whether its prognostic value varies across different populations. A comprehensive systematic search in databases such as PubMed and Web of Science was conducted to include papers focused on tumor-infiltrating lymphocytes (TILs) in TNBC in different population groups and that were published before January 2021. TNBC patients with higher levels of TILs had longer overall survival and disease-free survival times compared with TNBC patients with low TIL levels. Similar results were observed for CD4+, CD8+ TIL populations. On the other hand, patients with high TIL levels showed a higher rate of pathological complete response regardless of the population group (Asian, European, and American). These results altogether suggest that TIL subpopulations might have a prognostic role in TNBC, but the underlying mechanism needs to be elucidated. Although the prognosis value of TILs was not found different between the population groups analyzed in the revised literature, further studies including underrepresented populations with different genetic ancestries are still necessary to conclude in this regard.
Feasibility of a Novel Sparse Orthogonal Collimator–Based Preclinical Total Marrow Irradiation for Enhanced Dosimetric Conformality
Authors: Abdelhamid Amr M. H. , Jiang Lu , Zuro Darren , Liu An , Madabushi Srideshikan Sargur , Ghimire Hemendra , Wong Jeffrey Y. C. , Saldi Simonetta , Fulcheri Christian , Zucchetti Claudio , Pierini Antonio , Sheng Ke , Aristei Cynthia , Hui Susanta K.
Published: July 2022

Total marrow irradiation (TMI) has significantly improved radiation conditioning for hematopoietic cell transplantation in hematologic diseases by reducing conditioning-induced toxicities and improving survival outcomes in relapsed/refractory patients. Recently, preclinical three-dimensional image–guided TMI has been developed to enhance mechanistic understanding of the role of TMI and to support the development of experimental therapeutics. However, a dosimetric comparison between preclinical and clinical TMI reveals that the preclinical TMI treatment lacks the ability to reduce the dose to some of the vital organs that are very close to the skeletal system and thus limits the ability to evaluate radiobiological relevance. To overcome this limit, we introduce a novel Sparse Orthogonal Collimator (SOC)–based TMI and evaluate its ability to enhance dosimetric conformality. The SOC-TMI–based dose modulation technique significantly improves TMI treatment planning by reducing radiation exposures to critical organs that are close to the skeletal system that leads to reducing the gap between clinical and preclinical TMI.
Role of ubiquitin specific proteases in the immune microenvironment of prostate cancer: A new direction
Authors: Guo Jinhui , Zhao Jie , Sun Litao , Yang Chen
Published: July 2022

Regulation of ubiquitination is associated with multiple processes of tumorigenesis and development, including regulation of the tumor immune microenvironment. Deubiquitinating enzymes (DUBs) can remove ubiquitin chains from substrates, thereby stabilizing target proteins and altering and remodeling biological processes. During tumorigenesis, deubiquitination-altered biological processes are closely related to tumor metabolism, stemness, and the immune microenvironment. Recently, tumor microenvironment (TME) modulation strategies have attracted considerable attention in cancer immunotherapy. Targeting immunosuppressive mechanisms in the TME has revolutionized cancer therapy. Prostate cancer (PC) is one of the most common cancers and the second most common cause of cancer-related death in men worldwide. While immune checkpoint inhibition has produced meaningful therapeutic effects in many cancer types, clinical trials of anti-CTLA4 or anti-PD1 have not shown a clear advantage in PC patients. TME affects PC progression and also enables tumor cell immune evasion by activating the PD-1/PD-L1 axis. Over the past few decades, an increasing number of studies have demonstrated that deubiquitination in PC immune microenvironment may modulate the host immune system’s response to the tumor. As the largest and most diverse group of DUBs, ubiquitin-specific proteases (USPs) play an important role in regulating T cell development and function. According to current studies, USPs exhibit a high expression signature in PC and may promote tumorigenesis. Elevated expression of USPs often indicates poor tumor prognosis, suggesting that USPs are expected to develop as the markers of tumor prognosis and even potential drug targets for anti-tumor therapy. Herein, we first summarized recent advances of USPs in PC and focused on the relationship between USPs and immunity. Additionally, we clarified the resistance mechanisms of USPs to targeted drugs in PC. Finally, we reviewed the major achievement of targeting USPs in cancers.
Spontaneous breathing approach in mild congenital diaphragmatic hernia: A resuscitation algorithm
Authors: Horn-Oudshoorn Emily J. J. , Knol Ronny , Cochius-den Otter Suzan C. M. , te Pas Arjan B. , Hooper Stuart B. , Roberts Calum T. , Rafat Neysan , Schaible Thomas , de Boode Willem P. , van der Lee Robin , Debeer Anne , Kipfmueller Florian , Roehr Charles C. , Reiss Irwin K. M. , DeKoninck Philip L. J.
Published: July 2022

Background

Infants with a congenital diaphragmatic hernia (CDH) and expected mild pulmonary hypoplasia have an estimated survival rate of 90%. Current guidelines for delivery room management do not consider the individual patient's disease severity, but an individualized approach with spontaneous breathing instead of routine mechanical ventilation could be beneficial for the mildest cases. We developed a resuscitation algorithm for this individualized approach serving two purposes: improving the success rate by structuring the approach and providing a guideline for other centers.

Methods

An initial algorithm was discussed with all local stakeholders. Afterwards, the resulting algorithm was refined using input from international experts.

Results

Eligible CDH infants: left-sided defect, observed to expected lung-to-head ratio ≥50%, gestational age at birth ≥37.0 weeks, and no major associated structural or genetic abnormalities. To facilitate fetal-to-neonatal transition, we propose to start stabilization with non-invasive respiratory support and to adjust this individually.

Conclusions

Infants with mild CDH might benefit from an individualized approach for neonatal resuscitation. Herein, we present an algorithm that could serve as guidance for centers implementing this.
Case Report: Cardiac Multiple Thrombus and Pulmonary Embolism Associated With Mycoplasma Pneumonia Infection in a Child
Authors: Zhang Tongqiang , Zheng Jiafeng , Wang Hongbo , Xu Yongsheng , Ning Jing , Cai Chunquan
Published: July 2022

Mycoplasma pneumoniae (MP) is a common pathogen of lower respiratory tract infection in children and adolescents. Some patients with MP infection are self-limiting, while with the increase of severe or refractory Mycoplasma pneumoniae pneumonia (MPP) in recent years, there is a great increase in reports of thromboembolism in multiple organs, including lung, brain, spleen, and peripheral arteries. Cardiac multiple thrombi and pulmonary embolism associated with MP infection have not been reported. The most effective treatment option for cardiac thrombus was surgical resection for fear of thrombus detachment and causing new thromboembolism. Herein, we present a patient with cardiac multiple thrombi and pulmonary embolism in MPP for the first time. In our case, the child recovered after conservative medical treatment, which provides a therapeutic option for children with cardiac multiple thrombi.
Model-Informed Drug Development of New Cefoperazone Sodium and Sulbactam Sodium Combination (3:1): Pharmacokinetic/Pharmacodynamic Analysis and Antibacterial Efficacy Against Enterobacteriaceae
Authors: Ji Xi-Wei , Zhu Xiao , Li Yun , Xue Feng , Kuan Isabelle Hui San , He Qing-Feng , Meng Xiang-Rui , Xiang Xiao-Qiang , Cui Yi-Min , Zheng Bo
Published: July 2022

Objective: Cefoperazone/sulbactam is a commonly used antibiotic combination against the extended-spectrum beta-lactamases (ESBLs)-producing bacteria. The objective of this study was to evaluate the efficacy of a new cefoperazone/sulbactam combination (3:1) for Enterobacteriaceae infection via model-informed drug development (MIDD) approaches.

Methods: Sulperazon [cefoperazone/sulbactam (2:1)] was used as a control. Pharmacokinetic (PK) data was collected from a clinical phase I trial. Minimum inhibitory concentrations (MICs) were determined using two-fold broth microdilution method. The percent time that the free drug concentration exceeded the minimum inhibitory concentration (%fT>MIC) was used as the pharmacokinetic/pharmacodynamic indicator correlated with efficacy. Models were developed to characterize the PK profile of cefoperazone and sulbactam. Monte Carlo simulations were employed to determine the investigational regimens of cefoperazone/sulbactam (3:1) for the treatment of infections caused by Enterobacteriaceae based on the probability of target attainment (PTA) against the tested bacteria.

Results: Two 2-compartment models were developed to describe the PK profiles of cefoperazone and sulbactam. Simulation results following the single-dose showed that the regimens of cefoperazone/sulbactam combinations in the ratios of 3:1 and 2:1 achieved similar PTA against the tested bacteria. Simulation results from the multiple-dose showed that the dosing regimen of cefoperazone/sulbactam (4 g, TID, 3 g:1 g) showed slightly better antibacterial effect than cefoperazone/sulbactam (6 g, BID, 4 g:2 g) against the Escherichia coli (ESBL−) and Klebsiella pneumoniae (ESBL−). For the other tested bacteria, the above regimens achieved a similar PTA.

Conclusions: Cefoperazone/sulbactam (3:1) showed similar bactericidal activity to sulperazon [cefoperazone/sulbactam (2:1)] against the tested bacteria. For the ESBL-producing and cefoperazone-resistant E. coli and K. pneumoniae, Cefoperazone/sulbactam (3:1) did not exhibit advantage as anticipated. Our study indicated that further clinical trials should be carried out cautiously to avoid the potential risks of not achieving the expected target.