Recovery of synaptic loss and depressive-like behavior induced by GATA1 through blocking of the neuroinflammatory response.

GATA1, a member of the GATA transcription factor family, is a critical factor in hematopoietic system development. In a previous study, we demonstrated the increased expression of GATA1 in the dorsolateral prefrontal cortex (dlPFC) of patients suffering from depression and described its role as a transcriptional repressor of synapse-related genes. In this study, we investigated how GATA1 globally altered gene expression using multi-omics approaches. Through the combined analyses of ChIPseq, mRNAseq, and small RNAseq, we profiled genes that are potentially affected by GATA1 in cultured cortical neurons, and Gene Ontology (GO) analysis revealed that GATA1 might be associated with immune-related functions. We hypothesized that GATA1 induces immune activation, which has detrimental effects including synapse loss and depressive-like behavior. To test this hypothesis, we first performed a microglial morphometric analysis of a brain having overexpression of GATA1 because microglia are the resident immune cells of the central nervous system. Fractal analysis showed that the ramification and process length of microglia decreased in brains having GATA1 overexpression compared to the control, suggesting that GATA1 overexpression increases the activation of microglia. Through flow cytometry and immunohistochemical analysis, we found that activated microglia showed pro-inflammatory phenotypes characterized by the expression of CD86 and CD68. Finally, we demonstrated that the effects of GATA1 overexpression including synapse loss and depressive-like behavior could be blocked by inhibiting microglial activation using minocycline. These results will elucidate the regulatory mechanisms of GATA1 that affect pathophysiological conditions such as depression and provide a potential target for the treatment of depression.

Synaptotagmin-4 induces anhedonic responses to chronic stress via BDNF signaling in the medial prefrontal cortex.

Stressful circumstances are significant contributors to mental illnesses such as major depressive disorder. Anhedonia, defined as loss of the ability to enjoy pleasure in pleasurable situations, including rewarding activities or social contexts, is considered a key symptom of depression. Although stress-induced depression is associated with anhedonia in humans and animals, the underlying molecular mechanisms of anhedonic responses remain poorly understood. In this study, we demonstrated that synaptotagmin-4 (SYT4), which is involved in the release of neurotransmitters and neurotrophic factors, is implicated in chronic stress-induced anhedonia. Employing chronic unpredictable stress (CUS), we evaluated two subpopulations of mice, susceptible (SUS, anhedonic) and resilient (RES, nonanhedonic), based on sucrose preference, which was strongly correlated with social reward. The FosTRAP (targeted recombination in active populations) system and optogenetic approach revealed that neural activity in the medial prefrontal cortex (mPFC) was significantly associated with CUS-induced anhedonic behavioral phenotypes. By conducting weighted gene coexpression network analysis of RNA sequencing data from the mPFC of SUS and RES mice, we identified Syt4 as a hub gene in a gene network that was unique to anhedonia. We also confirmed that Syt4 overexpression in the mPFC was pro-susceptible, while Syt4 knockdown was pro-resilient; the pro-susceptible effects of SYT4 were mediated through a reduction in brain-derived neurotrophic factor (BDNF)-tropomyosin receptor kinase B (TrkB) signaling in the mPFC. These findings suggest that SYT4-BDNF interactions in the mPFC represent a crucial regulatory mechanism of anhedonic susceptibility to chronic stress.

Cell type characterization of spatiotemporal gene co-expression modules in Down syndrome brain.

Down syndrome (DS) is the most common genetic cause of intellectual disability and increases the risk of other brain-related dysfunctions, like seizures, early-onset Alzheimer's disease, and autism. To reveal the molecular profiles of DS-associated brain phenotypes, we performed a meta-data analysis of the developmental DS brain transcriptome at cell type and co-expression module levels. In the DS brain, astrocyte-, microglia-, and endothelial cell-associated genes show upregulated patterns, whereas neuron- and oligodendrocyte-associated genes show downregulated patterns. Weighted gene co-expression network analysis identified cell type-enriched co-expressed gene modules. We present eight representative cell-type modules for neurons, astrocytes, oligodendrocytes, and microglia. We classified the neuron modules into glutamatergic and GABAergic neurons and associated them with detailed subtypes. Cell type modules were interpreted by analyzing spatiotemporal expression patterns, functional annotations, and co-expression networks of the modules. This study provides insight into the mechanisms underlying brain abnormalities in DS and related disorders.

Clinicogenomic characteristics and synthetic lethal implications of germline homologous recombination-deficient hepatocellular carcinoma.

BACKGROUNDS AND AIMS: We performed an in-depth examination of pathogenic germline variants (PGVs) and somatic variants in DNA damage response (DDR) genes in hepatocellular carcinoma (HCC) to explore their clinical and genomic impacts. APPROACH AND RESULTS: We used a merged whole-exome or RNA sequencing data set derived from in-house ( n = 230) and The Cancer Genome Atlas ( n = 362) databases of multiethnic HCC samples. We also evaluated synthetic lethal approaches targeting mutations in homologous recombination (HR) genes using HCC cells selected from five genomic databases of cancer cell lines. A total of 110 PGVs in DDR pathways in 96 patients were selected. Of the PGV carriers, 44 were HR-altered and found to be independently associated with poorer disease-free survival after hepatectomy. The most frequently altered HR gene in both germline and somatic tissues was POLQ , and this variant was detected in 22.7% (10/44) and 23.8% (5/21) of all the corresponding carriers, respectively. PGVs in HR were significantly associated with upregulation of proliferation and replication-related genes and familial risk of HCC. Samples harboring PGVs in HR with loss of heterozygosity were most strongly correlated with the genomic footprints of deficient HR, such as mutation burden and denovoSig2 (analogous to Catalogue of Somatic Mutations in Cancer [COSMIC] 3), and poor outcome. Pharmacologic experiments with HCC cells defective in BRCA2 or POLQ suggested that tumors with this phenotype are synthetic lethal with poly(ADP-ribose) polymerase inhibitors. CONCLUSIONS: Our findings suggest that germline HR defects in HCC tend to confer a poor prognosis and result in distinctive genomic scarring. Tests of the clinical benefits of HR-directed treatments in the affected patients are needed.

SELENBP1 overexpression in the prefrontal cortex underlies negative symptoms of schizophrenia.

The selenium-binding protein 1 (SELENBP1) has been reported to be up-regulated in the prefrontal cortex (PFC) of schizophrenia patients in postmortem reports. However, no causative link between SELENBP1 and schizophrenia has yet been established. Here, we provide evidence linking the upregulation of SELENBP1 in the PFC of mice with the negative symptoms of schizophrenia. We verified the levels of SELENBP1 transcripts in postmortem PFC brain tissues from patients with schizophrenia and matched healthy controls. We also generated transgenic mice expressing human SELENBP1 (hSELENBP1 Tg) and examined their neuropathological features, intrinsic firing properties of PFC 2/3-layer pyramidal neurons, and frontal cortex (FC) electroencephalographic (EEG) responses to auditory stimuli. Schizophrenia-like behaviors in hSELENBP1 Tg mice and mice expressing Selenbp1 in the FC were assessed. SELENBP1 transcript levels were higher in the brains of patients with schizophrenia than in those of matched healthy controls. The hSELENBP1 Tg mice displayed negative endophenotype behaviors, including heterotopias- and ectopias-like anatomical deformities in upper-layer cortical neurons and social withdrawal, deficits in nesting, and anhedonia-like behavior. Additionally, hSELENBP1 Tg mice exhibited reduced excitabilities of PFC 2/3-layer pyramidal neurons and abnormalities in EEG biomarkers observed in schizophrenia. Furthermore, mice overexpressing Selenbp1 in FC showed deficits in sociability. These results suggest that upregulation of SELENBP1 in the PFC causes asociality, a negative symptom of schizophrenia.

Genetic characterization of third- or fourth-generation cephalosporin-resistant avian pathogenic Escherichia coli isolated from broilers.

The third- or fourth-generation cephalosporins (3GC or 4 GC) are classified as "critically important antimicrobials for human medicine" by WHO, but resistance to these drugs is increasing rapidly in avian pathogenic E. coli (APEC). This study investigated the distribution and genetic characteristics of 3GC- or 4 GC-resistant APEC isolates from five major integrated broiler operations in Korea. The prevalence of 3GC- or 4GC-resistant APEC isolates in 1-week-old broilers was the highest in farms of operation C (53.3%); however, the highest prevalence of these isolates in 4-week-old broilers was the highest on the farms of operation A (60.0%), followed by operations E (50.0%) and C (35.7%). All 49 3GC- or 4GC-resistant APEC isolates had at least one ß-lactamase-encoding gene. The most common ß-lactamase-encoding genes was extended-spectrum ß-lactamase gene, bla CTX-M-15, detected in 24 isolates (49.0%), followed by bla TEM-1 (32.7%). Sixteen isolates (32.7%) harbored class 1 integrons, and four isolates (8.2%) showed different gene cassette-arrangements. However, only 1 of 26 isolates harboring class 2 integrons carried a gene cassette. Furthermore, both CRISPR 1 and 2 arrays were detected in most isolates (36 isolates; 73.5%), followed by CRISPR 2 (18.4%) and CRISPR 1 (4.1%). Interestingly, CRISPR 2 was significantly more prevalent in multidrug resistant (MDR)-APEC isolates than in non-MDR APEC isolates, whereas CRISPR 3 and 4 were significantly more prevalent in non-MDR APEC isolates (each 11.1%; p < 0.05). None of the protospacers of CRISPR arrays were directly associated with antimicrobial resistance. Our findings indicate that the distribution and characteristics of 3GC or 4GC-resistant APEC isolates differed among the integrated broiler operations; moreover, improved management protocols are needed to control the horizontal transmission of 3GC or 4GC-resistant APEC isolates.

Continuous centrifugal microfluidics (CCM) isolates heterogeneous circulating tumor cells via full automation.

Understanding cancer heterogeneity is essential to finding diverse genetic mutations in metastatic cancers. Thus, it is critical to isolate all types of CTCs to identify accurate cancer information from patients. Moreover, full automation robustly capturing the full spectrum of CTCs is an urgent need for CTC diagnosis to be routine clinical practice. Methods: Here we report the full capture of heterogeneous CTC populations using fully automated, negative depletion-based continuous centrifugal microfluidics (CCM). Results: The CCM system demonstrated high performance (recovery rates exceeding 90% and WBC depletion rate of 99.9%) across a wide range of phenotypes (EpCAM(+), EpCAM(-), small-, large-sized, and cluster) and cancers (lung, breast, and bladder). Applied in 30 lung adenocarcinoma patients harboring epidermal growth factor receptor (EGFR) mutations, the system isolated diverse phenotypes of CTCs in marker expression and size, implying the importance of unbiased isolation. Genetic analyses of intra-patient samples comparing cell-free DNA with CCM-isolated CTCs yielded perfect concordance, and CTC enumeration using our technique was correlated with clinical progression as well as response to EGFR inhibitors. Conclusion: Our system also introduces technical advances which assure rapid, reliable, and reproducible results, thus enabling a more comprehensive application of robust CTC analysis in clinical practice.

Distribution of CRISPR in Escherichia coli Isolated from Bulk Tank Milk and Its Potential Relationship with Virulence.

Escherichia coli is one of the most common causes of mastitis on dairy farms around the world, but its clinical severity is determined by a combination of virulence factors. Recently, clustered regularly interspaced short palindromic repeat (CRISPR) arrays have been reported as a novel typing method because of their usefulness in discriminating pathogenic bacterial isolates. Therefore, this study aimed to investigate the virulence potential of E. coli isolated from bulk tank milk, not from mastitis, and to analyze its pathogenic characterization using the CRISPR typing method. In total, 164 (89.6%) out of 183 E. coli isolated from the bulk tank milk of 290 farms carried one or more of eighteen virulence genes. The most prevalent virulence gene was fimH (80.9%), followed by iss (38.3%), traT (26.8%), ompT (25.7%), afa/draBC (24.0%), and univcnf (21.9%). Moreover, the phylogenetic group with the highest prevalence was B1 (64.0%), followed by A (20.1%), D (8.5%), and C (7.3%) (p < 0.05). Among the four CRISPR loci, only two, CRISPR 1 and CRISPR 2, were found. Interestingly, the distribution of CRISPR 1 was significantly higher in groups A and B1 compared to that of CRISPR 2 (p < 0.05), but there were no significant differences in groups C and D. The prevalence of CRISPR 1 by virulence gene ranged from 91.8% to 100%, whereas that of CRISPR 2 ranged from 57.5% to 93.9%. The distribution of CRISPR 1 was significantly higher in fimH, ompT, afa/draBC, and univcnf genes than that of CRISPR 2 (p < 0.05). The most prevalent E. coli sequence types (EST) among 26 ESTs was EST 22 (45.1%), followed by EST 4 (23.2%), EST 16 (20.1%), EST 25 (19.5%), and EST 24 (18.3%). Interestingly, four genes, fimH, ompT, afa/draBC, and univcnf, had a significantly higher prevalence in both EST 4 and EST 22 (p < 0.05). Among the seven protospacers derived from CRISPR 1, protospacer 163 had the highest prevalence (20.4%), and it only existed in EST 4 and EST 22. This study suggests that the CRISPR sequence-typing approach can help to clarify and trace virulence potential, although the E. coli isolates were from normal bulk tank milk and not from mastitis.

Comparison of antimicrobial resistance and molecular characterization of Escherichia coli isolates from layer breeder farms in Korea.

In Korea, 4 big layer companies that possess one grandparent and 3 parent stocks are in charge of 100% of the layer chicken industry. In this study, we investigated the antimicrobial resistance of commensal 578 E. coli isolated from 20 flocks of 4-layer breeder farms (A, B, C, and D), moreover, compared the characteristics of their resistance and virulence genes. Isolates from farms B and D showed significantly higher resistance to the ß-lactam antimicrobials (amoxicillin, ampicillin, and 1st-, 2nd-, and 3rd-generation cephalosporins). However, resistance to ciprofloxacin, nalidixic acid, and tetracycline was significantly higher in the isolates from farm A (P < 0.05). Interestingly, the isolates from farm C showed significantly lower resistance to most antimicrobials tested in this study. The isolates from farms B, C, and D showed the high multiple resistance to the 3 antimicrobial classes. Furthermore, the isolates from farm A showed the highest multiple resistance against the 5 classes. Among the 412 ß-lactam-resistant isolates, 123 (29.9%) carried blaTEM-1, but the distribution was significantly different among the farms from 17.5% to 51.4% (P < 0.05). Similarly, the most prevalent tetracycline resistance gene in the isolates from farms B, C, and D was tetA (50.0-77.0%); however, the isolates from farm A showed the highest prevalence in tetB (70.6%). The distribution of quinolone (qnrB, qnrD, and qnrS) and sulfonamide (su12)-resistant genes were also significantly different among the farms but that of chloramphenicol (catA1)- and aminoglycoside (aac [3]-II, and aac [6']-Ib)-resistant genes possessed no significant difference among the farms. Moreover, the isolates from farm C showed significantly higher prevalence in virulence genes (iroN, ompT, hlyF, and iss) than the other 3 farms (P < 0.05). Furthermore, the phenotypic and genotypic characteristics of E. coli isolates were significantly different among the farms, and improved management protocols are required to control of horizontal and vertical transmission of avian disease, including the dissemination of resistant bacteria in breeder flocks.

Takotsubo syndrome as an overlooked and elusive cause of a single episode of dyspnea in young women: a case report.

BACKGROUND: Dyspnea is a common symptom in patients presenting to the emergency department. It has a variety of causes that range from non-urgent to life-threatening. One episode of dyspnea in a healthy young person is easy to overlook. However, if the symptoms occur after physically or emotionally stressful events, careful evaluation needs to be undertaken because it may be associated with Takotsubo syndrome, which is rarely expected but can be fatal. Herein, we report the case of Takotsubo syndrome in a healthy young woman who arrived at the emergency department after experiencing a short single episode of dyspnea following a minor surgery. CASE PRESENTATION: A 23-year old woman with no underlying chronic disease underwent closed reduction surgery for a nasal bone fracture under general anesthesia (with sevoflurane as the anesthetic). Approximately 5 h later, she presented to the emergency department with dyspnea, which improved soon upon arrival at the emergency department. There were no other symptoms. The dyspnea occurred about 5 h after being discharged on observation, with an uneventful postoperative course. Her electrocardiogram and chest X-ray findings were unremarkable. On testing, troponin I and creatine kinase myocardial band levels were elevated at 6.122 ng/mL and 11.2 µg/L (reference ranges: 0.000-0.046 ng/mL and 0.0-5.0 µg/L), respectively. Bedside echocardiography revealed an ejection fraction of 25%, with mid-ventricular and apical akinesia and basal hyperkinesia. The pulmonary and coronary angiographic computed tomographic scans were unremarkable. Hence, apical Takotsubo syndrome was suspected. A follow-up echocardiogram taken 5 days after admission showed full recovery with a normalized ejection fraction (60%) and no regional wall motion abnormality. The patient was discharged on the sixth day with no other complications. CONCLUSION: When atypical symptoms, such as transient dyspnea, manifest, it becomes necessary to suspect and diagnose Takotsubo syndrome to ensure timely and appropriate medical management, especially when a preceding stressful event, such as minor surgery has occurred. It might be helpful to perform bedside point-of-care echocardiography to check for regional wall motion abnormalities that are typically associated with Takotsubo syndrome.

Diagnostic Performance of Three-Phase Bone Scintigraphy and Digital Infrared Thermography Imaging for Chronic Post-Traumatic Complex Regional Pain Syndrome.

This study aimed to evaluate the diagnostic performance of three-phase bone scintigraphy (TPBS) and digital infrared thermography imaging (DITI) in the chronic post-traumatic CRPS and propose new imaging diagnostic criteria that combine the two tests. We retrospectively enrolled 44 patients with suspected symptoms of CRPS from various injuries during obligatory military service. We analyzed the following findings: (1) uptake pattern on TPBS, (2) uptake ratios of affected and unaffected sides in each phase of TPBS, (3) difference in body skin temperature on DITI. New criteria combining the above findings were also evaluated. Eighteen patients were finally defined as CRPS according to the Budapest criteria. Uptake pattern and uptake ratio in blood pool phase on the TPBS were significantly different between CRPS and non-CRPS groups (both p < 0.05). The DITI could not discriminate significantly between the groups (p = 0.334). The diagnostic criteria considering both the pattern analysis and quantitative analysis in TPBS exhibited the highest positive likelihood ratio. On the other hand, the diagnostic criteria combining DITI and TPBS showed the lowest negative likelihood ratio value. TPBS can be useful in diagnosing chronic post-traumatic CRPS. Moreover, we can suggest that different diagnostic criteria be applied depending on the purpose.

Characteristics of High-Level Aminoglycoside-Resistant Enterococcus faecalis Isolated from Bulk Tank Milk in Korea.

Enterococci, which are considered environmental mastitis-causing pathogens, have easily acquired aminoglycoside-resistant genes that encode various aminoglycoside-modifying enzymes (AME). Therefore, this study was conducted to compare the distribution of high-level aminoglycoside-resistant (HLAR) and multidrug-resistant (MDR) Enterococcus faecalis (E. faecalis) bacteria isolated from bulk tank milk in four dairy companies in Korea. Moreover, it analyzed the characteristics of their antimicrobial resistance genes and virulence factors. Among the 301 E. faecalis bacteria studied, 185 (61.5%) showed HLAR with no significant differences among the dairy companies. Furthermore, 129 (69.7%) of the 185 HLAR E. faecalis showed MDR without significant differences among companies. In contrast, HLAR E. faecalis from companies A, B, and C were significantly higher in resistance to the four classes than those in company D, which had the highest MDR ability against the three antimicrobial classes (p < 0.05). In addition, in the distribution of AME genes, 72 (38.9%) and 36 (19.5%) of the isolates carried both aac(6')Ie-aph(2″)-la and ant(6)-Ia genes, and the ant (6)-Ia gene alone, respectively, with significant differences among the companies (p < 0.05). In the distribution of virulence genes, the ace (99.5%), efa A (98.9%), and cad 1 (98.4%) genes were significantly prevalent (p < 0.05). Thus, our results support that an advanced management program by companies is required to minimize the dissemination of antimicrobial resistance and virulence factors.

Brain-immune interactions in neuropsychiatric disorders: Lessons from transcriptome studies for molecular targeting.

Understanding the pathophysiological mechanisms of neuropsychiatric disorders has been a challenging quest for neurobiologists. Recent years have witnessed enormous technological advances in the field of neuroimmunology, blurring boundaries between the central nervous system and the periphery. Consequently, the discipline has expanded to cover interactions between the nervous and immune systems in health and diseases. The complex interplay between the peripheral and central immune pathways in neuropsychiatric disorders has recently been documented in various studies, but the genetic determinants remain elusive. Recent transcriptome studies have identified dysregulated genes involved in peripheral immune cell activation, blood-brain barrier integrity, glial cell activation, and synaptic plasticity in major depressive disorder, bipolar disorder, autism spectrum disorder, and schizophrenia. Herein, the key transcriptomic techniques applied in investigating differentially expressed genes and pathways responsible for altered brain-immune interactions in neuropsychiatric disorders are discussed. The application of transcriptomics that can aid in identifying molecular targets in various neuropsychiatric disorders is highlighted.

Myelination defects in the medial prefrontal cortex of Fkbp5 knockout mice.

The hypothalamic-pituitary-adrenal (HPA) axis plays a principal role in stress response regulation and has been implicated in the etiology of stress-related disorders. The HPA axis regulates the normal synthesis and release of glucocorticoids; dysregulation of the HPA axis causes abnormal responses to stress. FK506-binding protein 5 (FKBP5), a co-chaperone of heat shock protein 90 in the glucocorticoid receptor (GR) molecular complex, is a key GR sensitivity regulator. FKBP5 single nucleotide polymorphisms are associated with dysregulated HPA axis and increased risk of stress-related disorders, including posttraumatic stress disorder (PTSD) and depression. In this study, we profiled the microRNAs (miRNAs) in the medial prefrontal cortex of Fkbp5 knockout (Fkbp5-/- ) mice and identified the target genes of differentially expressed miRNAs using sequence-based miRNA target prediction. Gene ontology analysis revealed that the differentially expressed miRNAs were involved in nervous system development, regulation of cell migration, and intracellular signal transduction. The validation of the expression of predicted target genes using quantitative polymerase chain reaction revealed that the expression of axon development-related genes, specifically actin-binding LIM protein 1 (Ablim1), lemur tyrosine kinase 2 (Lmtk2), kinesin family member 5c (Kif5c), neurofascin (Nfasc), and ephrin type-A receptor 4 (Epha4), was significantly decreased, while that of brain-derived neurotrophic factor (Bdnf) was significantly increased in the brain of Fkbp5-/- mice. These results suggest that axonal development-related genes can serve as potential targets in future studies focused on understanding the pathophysiology of PTSD.

Regulation of behavioral response to stress by microRNA-690.

Psychiatric disorders are affected by genetic susceptibility and environmental adversities. Therefore, the regulation of gene expression under certain environments, such as stress, is a key issue in psychiatric disorders. MicroRNAs (miRNAs) have been implicated as post-transcriptional regulators of several biological processes, which can be differentially controlled through the targeting of multiple mRNAs. However, studies reporting the functions of miRNAs in relation to stress are lacking. In this study, we identified a significant increase in the expression of miRNA-690 (miR-690) in the medial prefrontal cortex (mPFC) of FK506-binding protein 51 knock-out (Fkbp5 KO) mice. In addition, the expression pattern of miR-690 was similar to the sucrose preference of the same group in WT and Fkbp5 KO mice. miR-690 was injected into the mPFC using a recombinant adeno-associated virus mediated gene delivery method. After recovery, miR-690 overexpressing mice were exposed to restraint stress for 2 weeks. In the sucrose preference test and forced swim test, the stressed miR-690 overexpressing mice showed higher sucrose preference and lower immobility time, respectively, than stressed mice injected with the control virus. In the novel object recognition test, the stressed miR-690 overexpressing mice interacted longer with the novel object than those injected with the control virus. These results showed that miR-690 might play a role in stress resilience and could provide new insights into the epigenetic regulation of stress-associated biological functions and diseases, such as depression and post-traumatic stress disorder.

Diagnosis of complex regional pain syndrome type 1 in patients with corticobasal degeneration: a case report.

We report a rare case of a patient with corticobasal degeneration (CBD) who was also diagnosed with complex regional pain syndrome type I (CRPS I), which has similar clinical characteristics. A 76-year-old man who had been diagnosed with CBD several years prior presented with asymmetric severe pain, postural instability, limb rigidity, limb dystonia, tremor, ideomotor apraxia, and bradykinesia especially on his left upper extremity on admission at our rehabilitation center. Additional physical examination showed darkened skin color change, edema, reduced skin elasticity, cold skin temperature, wet skin, and limited range of motion (ROM) of the left side compared to the right side. A three-phase bone scan was done resulting CRPS I. Therefore, we initiated treatment for CRPS I, including steroid pulse therapies and non-steroidal anti-inflammatory drugs (NSAID); subsequently, his left extremity pain reduced from a visual analogue scale (VAS) score of 8-9 to 3 and his functional level also improved. To the best of our knowledge, this is the first case report of a CBD patient being also diagnosed with CRPS I. Due to the similar clinical characteristics that two diseases share, we would like to inform the physicians the importance of differentiating the CRPS I from CBD for the quick proper management.

Correction: Stepwise stroke recognition through clinical information, vital signs, and initial labs (CIVIL): Electronic health record-based observational cohort study.

[This corrects the article DOI: 10.1371/journal.pone.0231113.].

A Bibliometric Analysis Using Alternative Metrics for Articles in the Annals of Rehabilitation Medicine.

OBJECTIVE: To investigate the articles in the Annals of Rehabilitation Medicine (ARM) using a bibliometric analysis to verify whether there is a correlation between the topics of interest for expert groups and the public media. METHODS: A total of 1,088 ARM articles from the third issue of 2011 to the third issue of 2019 were analyzed. We conducted a bibliometric analysis of the articles using conventional metrics (CM) and alternative metrics (AM). The CM was investigated by collating the type of publication, number of citations, and the specific field of rehabilitation medicine for each article. The AM was analyzed using the Altmetric Attention Score (AAS) provided by Altmetric, the leading AM company. The correlation between the number of citations and the AAS was tested using the Spearman rank correlation coefficient. RESULTS: The combined ratio of original articles and case reports was over 90% in this study; however, the total distribution was significantly different compared to previous bibliometric studies (p<0.05). There were 233 articles that satisfied both conditions of at least one citation and at least one AAS point. The number of citations and the AAS were found to have a statistically significant positive linear correlation on a scatter plot (r=0.216, p=0.001). CONCLUSION: There is a significant correlation between AM and CM, which means itis important to increase the dissemination of academic knowledge through the public media and increase the status of the journal by increasing the citation-related index.

Changes in etiology and severity of dysphagia with aging.

PURPOSE: To investigate characteristics of dysphagia in the oldest-old population and the effect of aging on swallowing physiology. METHODS: 418 (364 men, 54 women) patients who underwent videofluoroscopic swallow study (VFSS) for dysphagia were included. The patients were divided into an older group, group I (60-79 years old, n = 275) and the oldest-old group, group II (80-96 years old, n = 143). Sex, cognition, duration of symptoms, BMI (body mass index), frailty index derived from comprehensive geriatric assessment (FI-CGA), penetration aspiration scale (PAS), and videofluoroscopic dysphagia scale (VDS) scores and the etiologies of dysphagia were compared between the groups. The correlation analysis of BMI and FI-CGA with dysphagia severity and age was performed. RESULTS: The proportion of males, K-MMSE scores, the duration of symptoms, BMI scores and FI-CGA were significantly greater in group I than II. The PAS and VDS scores were significantly higher in group II than I. The proportion of CNS disorders was significantly higher in group I than in group II. The proportion of poor general medical condition was significantly higher in group II than in group I. A negative correlation between BMI and dysphagia severity and a positive correlation between FI-CGA and dysphagia severity were observed. CONCLUSION: Dysphagia tends to be more severe in the oldest-old, and can be caused by health conditions unrelated to swallowing. Malnutrition and frailty correlated positively with dysphagia severity, irrespective of age.

Stepwise stroke recognition through clinical information, vital signs, and initial labs (CIVIL): Electronic health record-based observational cohort study.

BACKGROUND: Stroke recognition systems have been developed to reduce time delays, however, a comprehensive triaging score identifying stroke subtypes is needed to guide appropriate management. We aimed to develop a prehospital scoring system for rapid stroke recognition and identify stroke subtype simultaneously. METHODS AND FINDINGS: In prospective database of regional emergency and stroke center, Clinical Information, Vital signs, and Initial Labs (CIVIL) of 1,599 patients suspected of acute stroke was analyzed from an automatically-stored electronic health record. Final confirmation was performed with neuroimaging. Using multiple regression analyses, we determined independent predictors of tier 1 (true-stroke or not), tier 2 (hemorrhagic stroke or not), and tier 3 (emergent large vessel occlusion [ELVO] or not). The diagnostic performance of the stepwise CIVIL scoring system was investigated using internal validation. A new scoring system characterized by a stepwise clinical assessment has been developed in three tiers. Tier 1: Seven CIVIL-AS3A2P items (total score from -7 to +6) were deduced for true stroke as Age (≥ 60 years); Stroke risks without Seizure or psychiatric disease, extreme Sugar; "any Asymmetry", "not Ambulating"; abnormal blood Pressure at a cut-off point ≥ 1 with diagnostic sensitivity of 82.1%, specificity of 56.4%. Tier 2: Four items for hemorrhagic stroke were identified as the CIVIL-MAPS indicating Mental change, Age below 60 years, high blood Pressure, no Stroke risks with cut-point ≥ 2 (sensitivity 47.5%, specificity 85.4%). Tier 3: For ELVO diagnosis: we applied with CIVIL-GFAST items (Gaze, Face, Arm, Speech) with cut-point ≥ 3 (sensitivity 66.5%, specificity 79.8%). The main limitation of this study is its retrospective nature and require a prospective validation of the CIVIL scoring system. CONCLUSIONS: The CIVIL score is a comprehensive and versatile system that recognizes strokes and identifies the stroke subtype simultaneously.