bluuebunny/crossref_metadata_2025 huggingface dataset:
Early Safety Discrimination Under Uncertainty in Trait Anxiety: An Event-Related Potential Study
Authors: Jin Yan , Zhang Lei , Chen Wei , Zheng Xifu
Published: June 2022

Detection of safety-threat signals during uncertainty is an important mechanism of developmental anxiety disorder (AD). Although extensive research has focused on the detection of uncertain threat signals in anxious individuals, relatively little attention has been given to the identification of safety signals during uncertainty, which is an important way to relieve anxiety in individuals with AD. To investigate this phenomenon, 16 subjects with high trait anxiety (HTA) and 16 with low trait anxiety (LTA) completed a modified cue-target task in certain and uncertain stimulus blocks. In the uncertain block, the cue was followed by a threat picture or safety picture in 20% of trials, respectively; in the certain block, the cue could be followed by a threat picture or a safety picture on 100% of trials. Behavioral responses and event-related potentials (ERPs) were recorded. The ERP results demonstrated that LTA participants exhibited larger P2 amplitudes in the detection of safety cues than of threat cues during the uncertain block, whereas HTA participants showed significant P2 amplitudes between the safety and threat cues during the certain block, impairing the detection of safety stimuli during uncertainty. However, all participants exhibited greater N2 amplitudes following threat cues in certainty or uncertainty conditions. These findings pertaining to the P2 amplitude suggested distinctive attentional biases between HTA and LTA individuals, whereas the N2 amplitude showed association learning in uncertain conditions, compensating for safety-threat detection in HTA individuals.
Investigation of Human Intrathecal Solute Transport Dynamics Using a Novel in vitro Cerebrospinal Fluid System Analog
Authors: Seiner Akari , Burla Goutham Kumar Reddy , Shrestha Dev , Bowen Mayumi , Horvath Joshua D. , Martin Bryn A.
Published: June 2022

Background

Understanding the relationship between cerebrospinal fluid (CSF) dynamics and intrathecal drug delivery (ITDD) injection parameters is essential to improve treatment of central nervous system (CNS) disorders.

Methods

An anatomically detailed in vitro model of the complete CSF system was constructed. Patient-specific cardiac- and respiratory-induced CSF oscillations were input to the model in the subarachnoid space and within the ventricles. CSF production was input at the lateral ventricles and CSF absorption at the superior sagittal sinus. A model small molecule simulated drug product containing fluorescein was imaged within the system over a period of 3-h post-lumbar ITDD injections and used to quantify the impact of (a) bolus injection volume and rate, (b) post-injection flush volume, rate, and timing, (c) injection location, and (d) type of injection device. For each experiment, neuraxial distribution of fluorescein in terms of spatial temporal concentration, area-under-the-curve (AUC), and percent of injected dose (%ID) to the brain was quantified at a time point 3-h post-injection.

Results

For all experiments conducted with ITDD administration in the lumbar spine, %ID to the brain did not exceed 11.6% at a time point 3-h post-injection. Addition of a 12 mL flush slightly increased solute transport to the brain up to +3.9%ID compared to without a flush (p < 0.01). Implantation of a lumbar catheter with the tip at an equivalent location to the lumbar placed needle, but with rostral tip orientation, resulted in a small improvement of 1.5%ID to the brain (p < 0.05). An increase of bolus volume from 5 to 20 mL improved solute transport to the brain from 5.0 to 6.3%ID, but this improvement was not statistically significant. Increasing bolus injection rate from 5 to 13.3 mL/min lacked improvement of solute transport to the brain, with a value of 6.3 compared to 5.7%ID.

Conclusion

The in vitro modeling approach allowed precisely controlled and repeatable parametric investigation of ITDD injection protocols and devices. In combination, the results predict that parametric changes in lumbar spine ITDD-injection related parameters and devices can alter %ID to the brain and be tuned to optimize therapeutic benefit to CNS targets.
The Relationship Between Self-Reported Misophonia Symptoms and Auditory Aversive Generalization Leaning: A Preliminary Report
Authors: Ward Richard T. , Gilbert Faith E. , Pouliot Jourdan , Chiasson Payton , McIlvanie Skylar , Traiser Caitlin , Riels Kierstin , Mears Ryan , Keil Andreas
Published: June 2022

Misophonia is characterized by excessive aversive reactions to specific “trigger” sounds. Although this disorder is increasingly recognized in the literature, its etiological mechanisms and maintaining factors are currently unclear. Several etiological models propose a role of Pavlovian conditioning, an associative learning process heavily researched in similar fear and anxiety-related disorders. In addition, generalization of learned associations has been noted as a potential causal or contributory factor. Building upon this framework, we hypothesized that Misophonia symptoms arise as a consequence of overgeneralized associative learning, in which aversive responses to a noxious event also occur in response to similar events. Alternatively, heightened discrimination between conditioned threat and safety cues may be present in participants high in Misophonia symptoms, as predicted by associative learning models of Misophonia. This preliminary report (n = 34) examines auditory generalization learning using self-reported behavioral (i.e., valence and arousal ratings) and EEG alpha power reduction. Participants listened to three sine tones differing in pitch, with one pitch (i.e., CS+) paired with an aversive loud white noise blast, prompting aversive Pavlovian generalization learning. We assessed the extent to which overgeneralization versus heightened discrimination learning is associated with self-reported Misophonia symptoms, by comparing aversive responses to the CS+ and other tones similar in pitch. Behaviorally, all participants learned the contingencies between CS+ and noxious noise, with individuals endorsing elevated Misophonia showing heightened aversive sensitivity to all stimuli, regardless of conditioning and independent of hyperacusis status. Across participants, parieto-occipital EEG alpha-band power reduction was most pronounced in response to the CS+ tone, and this difference was greater in those with self-reported Misophonia symptoms. The current preliminary findings do not support the notion that overgeneralization is a feature of self-reported emotional experience in Misophonia, but that heightened sensitivity and discrimination learning may be present at the neural level.
Acoustic Stimuli Can Improve and Impair Somatosensory Perception
Authors: Nuernberger Matthias , Schaller Denise , Klingner Carsten , Witte Otto , Brodoehl Stefan
Published: June 2022

The integration of stimuli from different sensory modalities forms the basis for human perception. While the relevant impact of visual stimuli on the perception of other sensory modalities is recognized, much less is known about the impact of auditory stimuli on general sensory processing. This study aims to investigate the effect of acoustic stimuli on the processing of somatosensory stimuli using real noise (i.e., unpleasant everyday noise, RN) and neutral white noise (WN). To this purpose, we studied 20 healthy human subjects between 20 and 29 years of age (mean: 24, SD: ±1.9 years sex ratio 1:1). Somatosensory perception was evaluated using mechanical detection threshold (MDT) of the skin on the back of the dominant hand. To investigate the underlying mechanisms in the brain, fMRI was performed while applying acoustic stimulation (RN and WN) and tactile stimulation of the dominant hand. Here we show that acoustic stimulation with noise alters the perception of touch on the skin. We found that the effect of RN andWNdiffered.RNleads to an improved tactile perception, whereasWNimpaired tactile perception. These changes go along with significant differences in brain activity and connectivity.WNis associated with a significant increase in brain activity in multiple brain areas such as the auditory and somatosensory cortex, parietal association cortex, and the thalamus compared toRN. With tactile stimulation of the skin, the flow of information in these brain areas is altered. While withRNthe information flow from the thalamus to the somatosensory cortex is prominent, the network activity pattern changes underWNrevealing an increase in interaction between multiple networks. Unpleasant noise inhibits the multisensory integration and enables a more efficient unimodal perception in the somatosensory system, improving perception. Whether this is to be interpreted as a temporary increase in phasic alertness or by a stronger filter function of the thalamus with a preference for unimodal stimuli is still open for debate.
Epigenetic Effects of Addictive Drugs in the Nucleus Accumbens
Authors: Anderson Ethan M. , Taniguchi Makoto
Published: June 2022

Substance use induces long-lasting behavioral changes and drug craving. Increasing evidence suggests that epigenetic gene regulation contributes to the development and expression of these long-lasting behavioral alterations. Here we systematically review extensive evidence from rodent models of drug-induced changes in epigenetic regulation and epigenetic regulator proteins. We focus on histone acetylation and histone methylation in a brain region important for drug-related behaviors: the nucleus accumbens. We also discuss how experimentally altering these epigenetic regulators via systemically administered compounds or nucleus accumbens-specific manipulations demonstrate the importance of these proteins in the behavioral effects of drugs and suggest potential therapeutic value to treat people with substance use disorder. Finally, we discuss limitations and future directions for the field of epigenetic studies in the behavioral effects of addictive drugs and suggest how to use these insights to develop efficacious treatments.
Impaired Neurodevelopmental Genes in Slovenian Autistic Children Elucidate the Comorbidity of Autism With Other Developmental Disorders
Authors: Krgovic Danijela , Gorenjak Mario , Rihar Nika , Opalic Iva , Stangler Herodez Spela , Gregoric Kumperscak Hojka , Dovc Peter , Kokalj Vokac Nadja
Published: June 2022

Autism spectrum disorders (ASD) represent a phenotypically heterogeneous group of patients that strongly intertwine with other neurodevelopmental disorders (NDDs), with genetics playing a significant role in their etiology. Whole exome sequencing (WES) has become predominant in molecular diagnostics for ASD by considerably increasing the diagnostic yield. However, the proportion of undiagnosed patients still remains high due to complex clinical presentation, reduced penetrance, and lack of segregation analysis or clinical information. Thus, reverse phenotyping, where we first identified a possible genetic cause and then determine its clinical relevance, has been shown to be a more efficient approach. WES was performed on 147 Slovenian pediatric patients with suspected ASD. Data analysis was focused on identifying ultrarare or “single event” variants in ASD-associated genes and further expanded to NDD-associated genes. Protein function and gene prioritization were performed on detected clinically relevant variants to determine their role in ASD etiology and phenotype. Reverse phenotyping revealed a pathogenic or likely pathogenic variant in ASD-associated genes in 20.4% of patients, with subsequent segregation analysis indicating that 14 were de novo variants and 1 was presumed compound heterozygous. The diagnostic yield was further increased by 2.7% by the analysis of ultrarare or “single event” variants in all NDD-associated genes. Protein function analysis established that genes in which variants of unknown significance (VUS) were detected were predominantly the cause of intellectual disability (ID), and in most cases, features of ASD as well. Using such an approach, variants in rarely described ASD-associated genes, such as SIN3B, NR4A2, and GRIA1, were detected. By expanding the analysis to include functionally similar NDD genes, variants in KCNK9, GNE, and other genes were identified. These would probably have been missed by classic genotype–phenotype analysis. Our study thus demonstrates that in patients with ASD, analysis of ultrarare or “single event” variants obtained using WES with the inclusion of functionally similar genes and reverse phenotyping obtained a higher diagnostic yield despite limited clinical data. The present study also demonstrates that most of the causative genes in our cohort were involved in the syndromic form of ASD and confirms their comorbidity with other developmental disorders.
Early Life Adversity and Neuropsychiatric Disease: Differential Outcomes and Translational Relevance of Rodent Models
Authors: Waters Renée C. , Gould Elizabeth
Published: June 2022

It is now well-established that early life adversity (ELA) predisposes individuals to develop several neuropsychiatric conditions, including anxiety disorders, and major depressive disorder. However, ELA is a very broad term, encompassing multiple types of negative childhood experiences, including physical, sexual and emotional abuse, physical and emotional neglect, as well as trauma associated with chronic illness, family separation, natural disasters, accidents, and witnessing a violent crime. Emerging literature suggests that in humans, different types of adverse experiences are more or less likely to produce susceptibilities to certain conditions that involve affective dysfunction. To investigate the driving mechanisms underlying the connection between experience and subsequent disease, neuroscientists have developed several rodent models of ELA, including pain exposure, maternal deprivation, and limited resources. These studies have also shown that different types of ELA paradigms produce different but somewhat overlapping behavioral phenotypes. In this review, we first investigate the types of ELA that may be driving different neuropsychiatric outcomes and brain changes in humans. We next evaluate whether rodent models of ELA can provide translationally relevant information regarding links between specific types of experience and changes in neural circuits underlying dysfunction.
Case Report: Morphologic and Functional Characteristics of Intestinal Mucosa in a Child With Short Bowel Syndrome After Treatment With Teduglutide: Evidence in Favor of GLP-2 Analog Safety
Authors: Falco Enrico Costantino , Lezo Antonella , Calvo Pierluigi , Rigazio Caterina , Opramolla Anna , Verdun Ludovica , Cenacchi Giovanna , Pellegrini Marianna , Spada Marco , Canavese Gabriella
Published: June 2022

Teduglutide is a glucagon-like peptide-2 (GLP-2) analog employed in patients with short bowel syndrome (SBS) to reduce the need of parenteral nutrition in these patients, by virtue of its effects on enteric function. The experimental studies reported that the stimulating action of GLP-2 on epithelial turnover implies the potential development of dysplastic and neoplastic lesion. However, the clinical trials could not detect preneoplastic lesions on histologic material, and in a recent pilot study the occurrence of polyps was similar before and after treatment and included only low-grade dysplastic lesions. Another clue in GLP-2 function in stimulating mucosal restore is its enhancement through cooperation with epidermal growth factor (EGF). In this study, we analyzed gastroscopy and colonoscopy samplings from a child successfully weaned off parenteral nutrition with teduglutide. Villous and crypt structure was regular both in duodenal and in colonic samplings; in properly oriented villi, villus/crypt ratio was regular. The absorptive epithelium demonstrated a regular morphology. No atypia was detected in enterocytes, along epithelial structures. At the ultrastructural analysis, only a few enterocytes with vacuolized cytoplasm were observed. An S-phase marker Ki67 stained nuclei in the transitional amplifying zone, while nuclei stained by the cell cycle regulatory proteins p21 and p27 were placed in the differentiated epithelium of the duodenal villi and colonic crypts, as in the control cases. The counts of enterocytes immunostained with the same antisera, evaluated with image analysis software, were in the range of control cases. The ratio of the number of epidermal growth factor receptor (EGFR) signals/the number of centromere probe of chromosome 7 (CEP7) signals was less than 2. The findings available from this single patient are consistent with good preservation of functional capability of intestinal epithelium after treatment with GLP-2, given the histologic and ultrastructural features of enterocytes. In addition, the findings from cell cycle regulatory proteins immunolocalization and quantitative analysis show that cell renewal machinery in our case is comparable to control cases. The gene of the receptor EGFR is regularly expressed in enteric epithelium of our case. Morphologic and functional data from our patient improve evidence in favor of the safety of GLP-2 employ in SBS.
High CBX8 Expression Leads to Poor Prognosis in Laryngeal Squamous Cell Carcinoma by Inducing EMT by Activating the Wnt/β-Catenin Signaling Pathway
Authors: Meng Qingchao , Li Lei , Wang Liping
Published: June 2022

Background

In this study, we detected the expression of chromobox protein homolog 8 (CBX8) in laryngeal squamous cell carcinoma (LSCC) and its influence on the occurrence and progression of LSCC.

Methods

Pancancer analysis of CBX8 was analyzed by TCGA database and its expression in LSCC.The expression of CBX8 in 30 pairs of LSCC and adjacent tissues was analyzed by quantitative real-time PCR(qRT-PCR)and immunohistochemical assays, and its association with the prognosis and clinicopathological features of LSCC was further evaluated. A CBX8 knockdown model was constructed in AMC-HN-8 and Hep2 cell lines. The effects of CBX8 on LSCC cell proliferation, migration, invasion and apoptosis were detected by CCK8,EdU,wound healing, Transwell and flow cytometry assays. Levels of apoptosis-related protein, WNT/β-catenin signaling pathway and epithelial to mesenchymal transition (EMT) proteins, including Bax, Bcl2, β-catenin, DKK1, GSK3β, N-cadherin, E-cadherin and Snail1, in LSCC cells were detected by Western blotting.

Results

CBX8 was overexpressed in LSCC. High expression of CBX8 in LSCC patients led to shorter overall survival and correlated with tumor stage and lymphatic metastasis. After CBX8 knockdown, the proliferation of AMC-HN-8 and Hep2 cells slowed, and the number of EdU-positive cells decreased. Wound healing slowed down, and the number of Transwell invading cells decreased. The percentage of apoptotic cells increased. The expression levels of Bcl2, β-catenin, N-cadherin and Snail11 proteins were significantly reduced in the CBX8 knockdown cells, while Bax, DKK1, GSK3β and E-cadherin significantly increased with their corresponding controls.

Conclusion

CBX8 is highly expressed in LSCC and induces the EMT process by activating the Wnt/β-catenin signaling pathway to promote LSCC cell proliferation and migration and inhibit apoptosis, resulting in poor prognosis.
Characterizing Features of Human Circulating B Cells Carrying CLL-Like Stereotyped Immunoglobulin Rearrangements
Authors: Bagnara Davide , Colombo Monica , Reverberi Daniele , Matis Serena , Massara Rosanna , Cardente Niccolò , Ubezio Gianluca , Agostini Vanessa , Agnelli Luca , Neri Antonino , Cardillo Martina , Vergani Stefano , Ghiotto Fabio , Mazzarello Andrea Nicola , Morabito Fortunato , Cutrona Giovanna , Ferrarini Manlio , Fais Franco
Published: June 2022

Chronic Lymphocytic Leukemia (CLL) is characterized by the accumulation of monoclonal CD5+ B cells with low surface immunoglobulins (IG). About 40% of CLL clones utilize quasi-identical B cell receptors, defined as stereotyped BCR. CLL-like stereotyped-IG rearrangements are present in normal B cells as a part of the public IG repertoire. In this study, we collected details on the representation and features of CLL-like stereotyped-IG in the IGH repertoire of B-cell subpopulations purified from the peripheral blood of nine healthy donors. The B-cell subpopulations were also fractioned according to the expression of surface CD5 molecules and IG light chain, IGκ and IGλ. IG rearrangements, obtained by high throughput sequencing, were scanned for the presence of CLL-like stereotyped-IG. CLL-like stereotyped-IG did not accumulate preferentially in the CD5+ B cells, nor in specific B-cell subpopulations or the CD5+ cell fraction thereof, and their distribution was not restricted to a single IG light chain type. CLL-like stereotyped-IG shared with the corresponding CLL stereotype rearrangements the IGHV mutational status. Instead, for other features such as IGHV genes and frequency, CLL stereotyped-IGs presented a CLL-like subset specific behavior which could, or could not, be consistent with CLL stereotyped-IGs. Therefore, as opposed to the immuno-phenotype, the features of the CLL stereotyped-IG repertoire suggest a CLL stereotyped subset-specific ontogeny. Overall, these findings suggest that the immune-genotype can provide essential details in tracking and defining the CLL cell of origin.
Arginase: Mechanisms and Clinical Application in Hematologic Malignancy
Authors: Du Zefan , Li Tianwen , Huang Junbin , Chen Yun , Chen Chun
Published: June 2022

Compared to normal tissues and cells, the metabolic patterns of tumor illnesses are more complex, and there are hallmarks of metabolic reprogramming in energy metabolism, lipid metabolism, and amino acid metabolism. When tumor cells are in a state of fast growth, they are susceptible to food shortage, resulting in growth suppression. Using this metabolic sensitivity of tumor cells to construct amino acid consumption therapy does not harm the function of normal cells, which is the focus of metabolic therapy research at the moment. As a non-essential amino acid, arginine is involved in numerous crucial biological processes, including the signaling system, cell proliferation, and material metabolism. Rapidly dividing tumor cells are more likely to be deficient in arginine; hence, utilizing arginase to consume arginine can suppress tumor growth. Due to the absence of arginine succinate synthase, arginine succinate lyase, and ornithine carbamoyl transferase in some blood tumors, arginases may be employed to treat blood tumors. By investigating the mechanism of arginase treatment and the mechanism of drug resistance in greater depth, arginase treatment becomes more successful in hematological cancers and a new anti-cancer agent in clinical practice.
Primary Neuroendocrine Tumors of the Endometrium: Management and Outcomes
Authors: Zhang Jingjing , Pang Li
Published: June 2022

Objective

To analyze clinical behavior of, optimal treatment regimens for, outcomes, and prognosis of 170 patients with neuroendocrine tumors (NETs) of the endometrium.

Methods

The Surveillance, Epidemiology, and End Results database was used to identify patients with endometrial NETs diagnosed between 2004 and 2015. Clinical features and treatment regimens were analyzed, and 5-year overall survival (OS) and cancer-specific survival (CSS) were compared among different stages and treatment regimens. Univariate and multivariate analyses were performed to identify independent prognostic factors associated with endometrial NETs. Finally, prognosis was compared between small- and large-cell neuroendocrine carcinoma (SCNEC and LCNEC, respectively) of the endometrium.

Results

There were 20, 8, 47, and 95 patients with stage I, II, III, and IV NET, respectively. The 5-year OS rates of patients in each stage were 59.86%, 42.86%, 32.75%, and 6.04%, respectively. The 5-year CSS survival rates were 59.86%, 50.0%, 38.33%, and 6.39%, respectively. In the multivariate analysis, American Joint Committee on Cancer (AJCC) stage and treatment were associated with poor OS, while AJCC stage, nodal metastasis, and treatment were associated with poor CSS. Neither pathological type nor distant metastasis was associated with prognosis. The rate of distant metastasis was significantly higher for LCNEC than for SCNEC, while 5-year OS and CSS rates were significantly lower.

Conclusion

Complete surgical treatment should be selected regardless of staging for patients with endometrial NETs. For early-stage disease, individualized postoperative treatment with single chemotherapy or radiotherapy may improve OS and CSS. For advanced-stage disease, comprehensive postoperative adjuvant therapy may improve OS and CSS.
Prognostic Factor Analysis and Model Construction of Triple-Negative Metaplastic Breast Carcinoma After Surgery
Authors: Zhu Keying , Chen Yuyuan , Guo Rong , Dai Lanyi , Wang Jiankui , Tang Yiyin , Zhou Shaoqiang , Chen Dedian , Huang Sheng
Published: June 2022

Objective

The study aimed to analyze the prognostic factors of patients with triple-negative (TN) metaplastic breast carcinoma (MpBC) after surgery and to construct a nomogram for forecasting the 3-, 5-, and 8-year overall survival (OS).

Methods

A total of 998 patients extracted from the Surveillance, Epidemiology, and End Results (SEER) database were assigned to either the training or validation group at random in a ratio of 7:3. The clinical characteristics of patients in the training and validation sets were compared, and multivariate Cox regression analysis was used to identify the independent risk variables for the OS of patients with TN MpBC after surgery. These selected parameters were estimated through the Kaplan–Meier (KM) curves using the log-rank test. The nomogram for predicting the OS was constructed and validated by performing the concordance index (C-index), receiver operating characteristics (ROC) curves with area under the receiver operating characteristic curves (AUC), calibration curves, and decision curve analyses (DCAs). Patients were then stratified as high-risk and low-risk, and KM curves were performed.

Results

Multivariate Cox regression analysis indicated that factors including age, marital status, clinical stage at diagnosis, chemotherapy, and regional node status were independent predictors of prognosis in patients with MpBC after surgery. Separate KM curves for the screened variables revealed the same statistical results as with Cox regression analysis. A prediction model was created and virtualized via nomogram based on these findings. For the training and validation cohorts, the C-index of the nomogram was 0.730 and 0.719, respectively. The AUC values of the 3-, 5-, and 8-year OS were 0.758, 0.757, and 0.785 in the training group, and 0.736, 0.735, and 0.736 for 3, 5, and 8 years in the validation group, respectively. The difference in the OS between the real observation and the forecast was quite constant according to the calibration curves. The generated clinical applicability of the nomogram was further demonstrated by the DCA analysis. In all the training and validation sets, the KM curves for the different risk subgroups revealed substantial differences in survival probabilities (P <0.001).

Conclusion

The study showed a nomogram that was built from a parametric survival model based on the SEER database, which can be used to make an accurate prediction of the prognosis of patients with TN MpBC after surgery.
Incidental Findings Among Youth Participating in Multimodal Imaging Research: Characteristics of Findings and Description of a Management Approach
Authors: Roane Jessica L. , Mio Megan , Viner Jacqueline , Bettridge Ariel , Heyn Chinthaka , Roifman Idan , Selkirk Beth , Kertes Peter , MacIntosh Bradley J. , Thayalasuthan Vivekanandan , Detzler Garry , Endre Ruby , Jimenez-Juan Laura , Henry Blair , Murray Brian J. , Goldstein Benjamin I.
Published: June 2022

Research imaging in healthy and clinical youth populations yields incidental findings that require a management strategy. Our primary objective was to document the frequency and nature of incidental findings within a research group integrating multiple imaging modalities. A second objective was to describe the evolution of an approach to handling incidental findings. A case example was included to display the intricacies of some of these scenarios. Youth, ages 13–20 years, with bipolar disorder, familial risk for bipolar disorder, or healthy controls, obtained one or a combination of neuroimaging, cardio-thoracic imaging, retinal imaging, and carotid imaging. All images were systematically reviewed for incidental findings. Overall, of 223 participants (n = 102 healthy controls), 59% (n = 131) had a brain magnetic resonance imaging (MRI) incidental finding and 27% (n = 60) had at least one incidental brain finding requiring non-urgent follow-up. In addition, of 109 participants with chest/cardiac MRI and carotid ultrasound, 3% (n = 3) had chest findings, 2% (n = 2) had cardiac findings, and 1% (n = 1) had a carotid finding. Of 165 youth with retinal imaging, 1% (n = 2) had incidental findings. While the vast majority of these incidental findings were of a non-serious, non-urgent nature, there were noteworthy exceptions. Imaging research groups need a system that emphasizes the value of clinical review of research images and one that is collaborative and responsive in order to inform follow-up plans. Rating systems that have been developed and used in neuroimaging for the classification of incidental findings can be adapted for use in areas other than the brain. Regardless of severity, incidental findings may raise anxiety in youth participants and their parents. The optimal threshold is one that balances transparency with utility.
ARID2, a Rare Cause of Coffin–Siris Syndrome: A Clinical Description of Two Cases
Authors: Wang Xiaoyan , Wu Haiying , Sun Hui , Wang Lili , Chen Linqi
Published: June 2022

Background

Coffin-Siris syndrome (CSS) is a multiple congenital anomaly syndrome characterized by coarse facial features, sparse scalp hair, hypertrichosis, and hypo/aplastic digital nails and phalanges. Mutations in the BAF (SWI/SNF)-complex subunits (SMARCE1, SMARCB1, SMARCA4, SMARCA2, ARID1B, and ARID1A) have been shown to cause CSS. People diagnosed with BAF pathway related diseases are increasing, and ARID2 (NM_152641.4) is the least common of these genes. Mutations in the ARID2 gene is the cause for Coffin-Siris syndrome 6 (CSS6). By now only 16 individuals with CSS have been reported to have pathogenic variants in ARID2.

Case Presentation

In this article, we introduced two individuals with clinical features consistent with CSS6 (Coffin-Siris syndrome 6). This article increases the number of reported cases, provides better phenotypic information for this rare syndrome, and allows everyone to better understand the disease.

Conclusion

Our observations indicate that ARID2 mutations could have variable phenotypes, even in patients from the same family.
Novel Treatments for Pediatric Relapsed or Refractory Acute B-Cell Lineage Lymphoblastic Leukemia: Precision Medicine Era
Authors: Mengxuan Shang , Fen Zhou , Runming Jin
Published: June 2022

With the markedly increased cure rate for children with newly diagnosed pediatric B-cell acute lymphoblastic leukemia (B-ALL), relapse and refractory B-ALL (R/R B-ALL) remain the primary cause of death worldwide due to the limitations of multidrug chemotherapy. As we now have a more profound understanding of R/R ALL, including the mechanism of recurrence and drug resistance, prognostic indicators, genotypic changes and so on, we can use newly emerging technologies to identify operational molecular targets and find sensitive drugs for individualized treatment. In addition, more promising and innovative immunotherapies and molecular targeted drugs that are expected to kill leukemic cells more effectively while maintaining low toxicity to achieve minimal residual disease (MRD) negativity and better bridge hematopoietic stem cell transplantation (HSCT) have also been widely developed. To date, the prognosis of pediatric patients with R/R B-ALL has been enhanced markedly thanks to the development of novel drugs. This article reviews the new advancements of several promising strategies for pediatric R/R B-ALL.
Thiamine May Be Beneficial for Patients With Ventilator-Associated Pneumonia in the Intensive Care Unit: A Retrospective Study Based on the MIMIC-IV Database
Authors: Zhang Luming , Li Shaojin , Lu Xuehao , Liu Yu , Ren Yinlong , Huang Tao , Lyu Jun , Yin Haiyan
Published: June 2022

Background: Ventilator-associated pneumonia (VAP) is a common infection complication in intensive care units (ICU). It not only prolongs mechanical ventilation and ICU and hospital stays, but also increases medical costs and increases the mortality risk of patients. Although many studies have found that thiamine supplementation in critically ill patients may improve prognoses, there is still no research or evidence that thiamine supplementation is beneficial for patients with VAP. The purpose of this study was to determine the association between thiamine and the prognoses of patients with VAP.

Methods: This study retrospectively collected all patients with VAP in the ICU from the Medical Information Mart for Intensive Care-IV database. The outcomes were ICU and in-hospital mortality. Patients were divided into the no-thiamine and thiamine groups depending upon whether or not they had received supplementation. Associations between thiamine and the outcomes were tested using Kaplan-Meier (KM) survival curves and Cox proportional-hazards regression models. The statistical methods of propensity-score matching (PSM) and inverse probability weighting (IPW) based on the XGBoost model were also applied to ensure the robustness of our findings.

Results: The study finally included 1,654 patients with VAP, comprising 1,151 and 503 in the no-thiamine and thiamine groups, respectively. The KM survival curves indicated that the survival probability differed significantly between the two groups. After multivariate COX regression adjusted for confounding factors, the hazard ratio (95% confidence interval) values for ICU and in-hospital mortality in the thiamine group were 0.57 (0.37, 0.88) and 0.64 (0.45, 0.92), respectively. Moreover, the results of the PSM and IPW analyses were consistent with the original population.

Conclusion: Thiamine supplementation may reduce ICU and in-hospital mortality in patients with VAP in the ICU. Thiamine is an inexpensive and safe drug, and so further clinical trials should be conducted to provide more-solid evidence on whether it improves the prognosis of patients with VAP.
Chasing the Ghost: Hyperinflammation Does Not Cause Sepsis
Authors: Shapiro Leland , Scherger Sias , Franco-Paredes Carlos , Gharamti Amal A. , Fraulino David , Henao-Martinez Andrés F.
Published: June 2022

Sepsis is infection sufficient to cause illness in the infected host, and more severe forms of sepsis can result in organ malfunction or death. Severe forms of Coronavirus disease-2019 (COVID-19), or disease following infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are examples of sepsis. Following infection, sepsis is thought to result from excessive inflammation generated in the infected host, also referred to as a cytokine storm. Sepsis can result in organ malfunction or death. Since COVID-19 is an example of sepsis, the hyperinflammation concept has influenced scientific investigation and treatment approaches to COVID-19. However, decades of laboratory study and more than 100 clinical trials designed to quell inflammation have failed to reduce sepsis mortality. We examine theoretical support underlying widespread belief that hyperinflammation or cytokine storm causes sepsis. Our analysis shows substantial weakness of the hyperinflammation approach to sepsis that includes conceptual confusion and failure to establish a cause-and-effect relationship between hyperinflammation and sepsis. We conclude that anti-inflammation approaches to sepsis therapy have little chance of future success. Therefore, anti-inflammation approaches to treat COVID-19 are likewise at high risk for failure. We find persistence of the cytokine storm concept in sepsis perplexing. Although treatment approaches based on the hyperinflammation concept of pathogenesis have failed, the concept has shown remarkable resilience and appears to be unfalsifiable. An approach to understanding this resilience is to consider the hyperinflammation or cytokine storm concept an example of a scientific paradigm. Thomas Kuhn developed the idea that paradigms generate rules of investigation that both shape and restrict scientific progress. Intrinsic features of scientific paradigms include resistance to falsification in the face of contradictory data and inability of experimentation to generate alternatives to a failing paradigm. We call for rejection of the concept that hyperinflammation or cytokine storm causes sepsis. Using the hyperinflammation or cytokine storm paradigm to guide COVID-19 treatments is likewise unlikely to provide progress. Resources should be redirected to more promising avenues of investigation and treatment.
Toward a Physics of Interdependence for Autonomous Human-Machine Systems: The Case of the Uber Fatal Accident, 2018
Authors: Lawless William
Published: June 2022

Computational autonomy has begun to receive significant attention, but neither the theory nor the physics is sufficiently able to design and operate an autonomous human-machine team or system (HMS). In this physics-in-progress, we review the shift from laboratory studies, which have been unable to advance the science of autonomy, to a theory of autonomy in open and uncertain environments based on autonomous human systems along with supporting evidence in the field. We attribute the need for this shift to the social sciences being primarily focused on a science of individual agents, whether for humans or machines, a focus that has been unable to generalize to new situations, new applications, and new theory. Specifically, the failure of traditional systems predicated on the individual to observe, replicate, or model what it means to even be the social is at the very heart of the impediment to be conquered and overcome as a prelude to the mathematical physics we explore. As part of this review, we present case studies but with a focus on how an autonomous human system investigated the first self-driving car fatality; how a human-machine team failed to prevent that fatality; and how an autonomous human-machine system might approach the same problem in the future. To advance the science, we reject the aggregation of independence among teammates as a viable scientific approach for teams, and instead explore what we know about a physics of interdependence for an HMS. We discuss our review, the theory of interdependence, and we close with generalizations and future plans.
Membrane Transport Proteins Expressed in the Renal Tubular Epithelial Cells of Seawater and Freshwater Teleost Fishes
Authors: Kato Akira , Nagashima Ayumi , Hosono Kohei , Romero Michael F.
Published: June 2022

The kidney is an important organ that maintains body fluid homeostasis in seawater and freshwater teleost fishes. Seawater teleosts excrete sulfate and magnesium in small amounts of isotonic urine, and freshwater teleosts excrete water in large amounts of hypo-osmotic urine. The volume, osmolality, and ionic compositions of the urine are regulated mainly by membrane transport proteins expressed in the renal tubular epithelial cells. Gene expression, immunohistochemical, and functional analyses of the fish kidney identified membrane transport proteins involved in the secretion of sulfate and magnesium ions by the proximal tubules and reduction of urine volume by the collecting ducts in seawater teleosts, and excretion of water as hypotonic urine by the distal tubules and collecting ducts in freshwater teleosts. These studies promote an understanding of how the kidney contributes to the seawater and freshwater acclimation of teleosts at the molecular level.
Grain Legume Yield Responses to Rhizobia Inoculants and Phosphorus Supplementation Under Ghana Soils: A Meta-Synthesis
Authors: Buernor Alfred Balenor , Kabiru Muhammad Rabiu , Bechtaoui Noura , Jibrin Jibrin Mohammed , Asante Michael , Bouraqqadi Anis , Dahhani Sara , Ouhdouch Yedir , Hafidi Mohamed , Jemo Martin
Published: June 2022

A discrete number of studies have been conducted on the effects of rhizobia (Rhz) inoculants, phosphorus (P) management, and combined application of Rhz and P fertilizer on the enhancement of grain legume yield across soils of Ghana and elsewhere. However, the extent to which the various inoculated Rhz strains, P application, and combined application of Rhz + P studies contribute to improving yield, performed on a comprehensive analysis approach, and profit farmers are yet to be understood. This study reviewed different experimental studies conducted on soybean (Glycine max (L.) Merr.), cowpea (Vigna unguiculata [L.] Walp), and groundnut (Arachis hypogaea [L.]) to which Rhz inoculants, P supplements, or Rhz + P combination were applied to improve the yield in Ghana. Multiple-step search combinations of published articles and multivariate analysis computing approaches were used to assess the effects of Rhz inoculation, P application, or both application of Rhz and P on yield variation. The random forest (RF) regression model was further employed to quantify the relative importance of various predictor variables on yield. The meta-analysis results showed that cowpea exhibited the highest (61.7%) and groundnut (19.8%) the lowest average yield change. The RF regression model revealed that the combined application of Rhz and P fertilizer (10.5%) and Rhz inoculation alone (7.8%) were the highest explanatory variables to predict yield variation in soybean. The Rhz + P combination, Rhz inoculation, and genotype wang-Kae explained 11.6, 10.02, and 8.04% of yield variability for cowpea, respectively. The yield in the inoculated plants increased by 1.48-, 1.26-, and 1.16-fold when compared to that in the non-inoculated cowpea plants following inoculation with BR 3299, KNUST 1002, and KNUST 1006 strains, respectively. KNUST 1006 strain exhibited the highest yield increase ratio (1.3-fold) in groundnut plants. Inoculants formulation with a viable concentration of 109 cells g−1 and a minimum inoculum rate of 1.0 × 106 cells seed−1 achieved the highest average yield change for soybean but not for cowpea and groundnut. The meta-analysis calls for prospective studies to investigate the minimum rate of bacterial cells required for optimum inoculation responses in cowpea and groundnut.
Identification, Molecular Cloning, and Functional Characterization of a Coniferyl Alcohol Acyltransferase Involved in the Biosynthesis of Dibenzocyclooctadiene Lignans in Schisandra chinensis
Authors: Qiang Ting-Yan , Liu Jiu-Shi , Dong Yu-Qing , Mu Xin-Lu , Chen Yu , Luo Hong-Mei , Zhang Ben-Gang , Liu Hai-Tao
Published: June 2022

Schisandra chinensis owes its therapeutic efficacy to the dibenzocyclooctadiene lignans, which are limited to the Schisandraceae family and whose biosynthetic pathway has not been elucidated. Coniferyl alcohol is the synthetic precursor of various types of lignans and can be acetylated to form coniferyl acetate by coniferyl alcohol acyltransferase (CFAT), which belongs to the BAHD acyltransferase family. This catalytic reaction is important because it is the first committed step of the hypothetical biosynthetic pathway in which coniferyl alcohol gives rise to dibenzocyclooctadiene lignans. However, the gene encoding CFAT in S. chinensis has not been identified. In this study, firstly we identified 37 ScBAHD genes from the transcriptome datasets of S. chinensis. According to bioinformatics, phylogenetic, and expression profile analyses, 1 BAHD gene, named ScBAHD1, was cloned from S. chinensis. The heterologous expression in Escherichia coli and in vitro activity assays revealed that the recombinant enzyme of ScBAHD1 exhibits acetyltransferase activity with coniferyl alcohol and some other alcohol substrates by using acetyl-CoA as the acetyl donor, which indicates ScBAHD1 functions as ScCFAT. Subcellular localization analysis showed that ScCFAT is mainly located in the cytoplasm. In addition, we generated a three-dimensional (3D) structure of ScCFAT by homology modeling and explored the conformational interaction between protein and ligands by molecular docking simulations. Overall, this study identified the first enzyme with catalytic activity from the Schisandraceae family and laid foundations for future investigations to complete the biosynthetic pathway of dibenzocyclooctadiene lignans.
Genetic Groups of Fine-Aroma Native Cacao Based on Morphological and Sensory Descriptors in Northeast Peru
Authors: Oliva-Cruz Manuel , Goñas Malluri , Bobadilla Leidy G. , Rubio Karol B. , Escobedo-Ocampo Patricia , García Rosero Ligia M. , Rojas Briceño Nilton B. , Maicelo-Quintana Jorge L.
Published: June 2022

The northeastern region of Peru is one of the centers of origin of cocoa due to the great diversity of this cultivar. The objective of this study is, therefore, to search for different genetic groups of 146 ecotypes of fine-aroma native cacao from the northeastern region of Peru, based on the morphological descriptors of pods, seeds, sensory, yield, and sampling altitude. The data were analyzed using multivariate statistics; a cluster analysis was performed with the numerical and categorical variables, followed by a principal component analysis (PCA) and the DGC (Di Rienzo, Guzmán y Casanoves) mean comparison test for the numerical data. Contingency tables and the multiple correspondence analysis (MCA) were performed for the categorical data. We differentiated 5 genetic groups; helpfully, sensory characteristics of the flowers and pod, size and weight of the seeds, and pod index were in fact crucial in separating the groups. The ecotypes of the groups labeled as “Indes” and “Bagüinos” reported the best sensory characteristics with high floral and fruity notes and with a good yield expressed in pod index (13.88 and 11.88, respectively). Furthermore, these ecotypes are found at medium and high altitudes, above 500 m a.s.l., a factor that enables them to express their sensory and yield attributes. On the contrary, the ecotypes known as “Toribianos” and “Cajas” report the highest pod indices (20.77 and 16.78, respectively), resulting in low productivity. In the future, the variability of the ecotypes found will help establish genetic improvement programs that contribute to the development of cocoa farming in general.