Respiratory-like movements during an apnea test.

Background: Despite the possible occurrence of spontaneous movements during an apnea test, respiratory-like movements are rare. Case Presentation: A 51-year-old man was transferred to our hospital when a sudden disturbance of consciousness developed into cardiac arrest. After spontaneous circulation returned, we diagnosed bilateral cerebellar hemorrhage. He remained comatose with dilated pupils, absent brainstem reflexes, spontaneous breathing, and electrocerebral activity. After being considered brain dead, his family opted for organ donation. The first legal brain death examination on day 5 was aborted because of respiratory-like movements mimicking repetitive abdominal respiration during the apnea test. However, an enhanced magnetic resonance image of the head indicated no blood flow and somatosensory evoked potential testing revealed no brain-derived potentials. Conclusion: Respiratory-like movements can occur during the apnea test in patients considered brain dead. Further research is required to understand this phenomenon.

Gastric inflammatory myofibroblastic tumor presented with severe anemia and inflammation: a case report.

BACKGROUND: Inflammatory myofibroblastic tumor (IMT) is a rare stromal tumor, often found in children and young adults, and most commonly occurs in the lungs. Surgical resection is considered the standard treatment for localized IMT, although only limited data exist. Gastric IMT in adults is extremely rare, and there are no established guidelines for its treatment. CASE PRESENTATION: A 69-year-old male presented with persistent fatigue and weakness. Laboratory examination revealed severe anemia and inflammation. Upper gastrointestinal endoscopy at admission revealed a 40-mm type I softish tumor in the lesser curvature of the gastric body, without apparent hemorrhage. Repeated biopsies, including partial resection with snare, failed to give a definitive diagnosis. Computed tomography (CT) revealed a massive lesion at the gastric body, protruding into the gastric lumen, which was consistent with the gastric tumor. After admission, the patient developed anemia refractory to frequent blood transfusions despite the absence of apparent gastrointestinal bleeding. In addition, the patient had recurrent fevers of 38 °C or higher, and persistent high inflammatory levels. Fluorodeoxyglucose-positron emission tomography (FDG-PET) CT 1 month after the first visit exhibited an increased FDG uptake in the gastric tumor. In addition, this CT scan revealed a rapid increase in tumor size to 75 mm. It was suspected that the undiagnosed gastric tumor caused these serious clinical symptoms, and he underwent distal gastrectomy and cholecystectomy. The gross image of the tumor showed an 80-mm cauliflower-like shape with a gelatinous texture. The histopathological diagnosis was IMT. The postoperative course was uneventful, and the patient's symptoms subsided drastically, improving both anemia and systemic inflammation. The patient has shown no recurrence or relapse of the symptoms over one and a half years. CONCLUSIONS: In this case, the tumor resection finally enabled the diagnosis of IMT and resolved the clinical symptoms. Despite its predominantly benign morphological nature, some cases of IMT present clinically adverse courses. Surgical treatment may lead to its final diagnosis and improvement of clinical symptoms.

Deep learning-based classification of adequate sonographic images for self-diagnosing deep vein thrombosis.

BACKGROUND: Pulmonary thromboembolism is a serious disease that often occurs in disaster victims evacuated to shelters. Deep vein thrombosis is the most common reason for pulmonary thromboembolism, and early prevention is important. Medical technicians often perform ultrasonography as part of mobile medical screenings of disaster victims but reaching all isolated and scattered shelters is difficult. Therefore, deep vein thrombosis medical screening methods that can be easily performed by anyone are needed. The purpose of this study was to develop a method to automatically identify cross-sectional images suitable for deep vein thrombosis diagnosis so disaster victims can self-assess their risk of deep vein thrombosis. METHODS: Ultrasonographic images of the popliteal vein were acquired in 20 subjects using stationary and portable ultrasound diagnostic equipment. Images were obtained by frame split from video. Images were classified as "Satisfactory," "Moderately satisfactory," and "Unsatisfactory" according to the level of popliteal vein visualization. Fine-tuning and classification were performed using ResNet101, a deep learning model. RESULTS: Acquiring images with portable ultrasound diagnostic equipment resulted in a classification accuracy of 0.76 and an area under the receiver operating characteristic curve of 0.89. Acquiring images with stationary ultrasound diagnostic equipment resulted in a classification accuracy of 0.73 and an area under the receiver operating characteristic curve of 0.88. CONCLUSION: A method for automatically identifying appropriate diagnostic cross-sectional ultrasonographic images of the popliteal vein was developed. This elemental technology is sufficiently accurate to automatically self-assess the risk of deep vein thrombosis by disaster victims.

Visible-Light-Driven Hydroacylation of Unactivated Alkenes Using Readily Available Acyl Donors.

Herein, we report visible-light-driven hydroacylation of unactivated alkenes. We employed benzimidazolines as new acyl donors and achieved perfect regioselectivity, high functional-group tolerance, and excellent substrate generality. We also performed mechanistic experiments to elucidate the detailed reaction mechanism. This is the first example of (1) hydroacylation of unactivated alkenes using (2) easily prepared acyl donors under (3) visible-light irradiation. Our findings offer a new strategy to synthesize a wide variety of ketones under mild conditions.

Current Status, Issues and Future Prospects of Personalized Medicine for Each Disease.

In recent years, with the advancement of next-generation sequencing (NGS) technology, gene panel tests have been approved in the field of cancer diseases, and approaches to prescribe optimal molecular target drugs to patients are being developed. In the field of rare diseases, whole-genome and whole-exome analysis has been used to identify the causative genes of undiagnosed diseases and to diagnose patients' diseases, and further progress in personalized medicine is expected. In order to promote personalized medicine in the future, we investigated the current status and progress of personalized medicine in disease areas other than cancer and rare diseases, where personalized medicine is most advanced. We selected rheumatoid arthritis and psoriasis as the inflammatory disease, in addition to Alzheimer's disease. These diseases have high unmet needs for personalized medicine from the viewpoints of disease mechanisms, diagnostic biomarkers, therapeutic drugs with diagnostic markers and treatment satisfaction. In rheumatoid arthritis and psoriasis, there are many therapeutic options; however, diagnostic methods have not been developed to select the best treatment for each patient. In addition, there are few effective therapeutic agents in Alzheimer's disease, although clinical trials of many candidate drugs have been conducted. In rheumatoid arthritis and psoriasis, further elucidation of the disease mechanism is desired to enable the selection of appropriate therapeutic agents according to the patient profile. In the case of Alzheimer's disease, progress in preventive medicine is desired through the establishment of an early diagnosis method as well as the research and development of innovative therapeutic agents. To this end, we hope for further research and development of diagnostic markers and new drugs through progress in comprehensive data analysis such as comprehensive genomic and transcriptomic information. Furthermore, new types of markers such as miRNAs and the gut microbiome are desired to be utilized in clinical diagnostics.

Pathway trajectory analysis with tensor imputation reveals drug-induced single-cell transcriptomic landscape.

Genome-wide identification of single-cell transcriptomic responses of drugs in various human cells is a challenging issue in medical and pharmaceutical research. Here we present a computational method, tensor-based imputation of gene-expression data at the single-cell level (TIGERS), which reveals the drug-induced single-cell transcriptomic landscape. With this algorithm, we predict missing drug-induced single-cell gene-expression data with tensor imputation, and identify trajectories of regulated pathways considering intercellular heterogeneity. Tensor imputation outperformed existing imputation methods for data completion, and provided cell-type-specific transcriptomic responses for unobserved drugs. For example, TIGERS correctly predicted the cell-type-specific expression of maker genes for pancreatic islets. Pathway trajectory analysis of the imputed gene-expression profiles of all combinations of drugs and human cells identified single-cell-specific drug activities and pathway trajectories that reflect drug-induced changes in pathway regulation. The proposed method is expected to expand our understanding of the single-cell mechanisms of drugs at the pathway level.

Gene regulatory network analysis defines transcriptome landscape with alternative splicing of human umbilical vein endothelial cells during replicative senescence.

BACKGROUND: Endothelial cell senescence is the state of permanent cell cycle arrest and plays a critical role in the pathogenesis of age-related diseases. However, a comprehensive understanding of the gene regulatory network, including genome-wide alternative splicing machinery, involved in endothelial cell senescence is lacking. RESULTS: We thoroughly described the transcriptome landscape of replicative senescent human umbilical vein endothelial cells. Genes with high connectivity showing a monotonic expression increase or decrease with the culture period were defined as hub genes in the co-expression network. Computational network analysis of these genes led to the identification of canonical and non-canonical senescence pathways, such as E2F and SIRT2 signaling, which were down-regulated in lipid metabolism, and chromosome organization processes pathways. Additionally, we showed that endothelial cell senescence involves alternative splicing. Importantly, the first and last exon types of splicing, as observed in FLT1 and ACACA, were preferentially altered among the alternatively spliced genes during endothelial senescence. We further identified novel microexons in PRUNE2 and PSAP, each containing 9 nt, which were altered within the specific domain during endothelial senescence. CONCLUSIONS: These findings unveil the comprehensive transcriptome pathway and novel signaling regulated by RNA processing, including gene expression and splicing, in replicative endothelial senescence.

Observation and theoretical calculations of voltage-induced large magnetocapacitance beyond 330% in MgO-based magnetic tunnel junctions.

Magnetic tunnel junctions (MTJs) in the field of spintronics have received enormous attention owing to their fascinating spin phenomena for fundamental physics and potential applications. MTJs exhibit a large tunnel magnetoresistance (TMR) at room temperature. However, TMR depends strongly on the bias voltage, which reduces the magnitude of TMR. On the other hand, tunnel magnetocapacitance (TMC), which has also been observed in MTJs, can be increased when subjecting to a biasing voltage, thus exhibiting one of the most interesting spin phenomena. Here we report a large voltage-induced TMC beyond 330% in MgO-based MTJs, which is the largest value ever reported for MTJs. The voltage dependence and frequency characteristics of TMC can be explained by the newly proposed Debye-Fröhlich model using Zhang-sigmoid theory, parabolic barrier approximation, and spin-dependent drift diffusion model. Moreover, we predict that the voltage-induced TMC ratio could reach over 3000% in MTJs. It is a reality now that MTJs can be used as capacitors that are small in size, broadly ranged in frequencies and controllable by a voltage. Our theoretical and experimental findings provide a deeper understanding on the exact mechanism of voltage-induced AC spin transports in spintronic devices. Our research may open new avenues to the development of spintronics applications, such as highly sensitive magnetic sensors, high performance non-volatile memories, multi-functional spin logic devices, voltage controlled electronic components, and energy storage devices.

Clinical course of 2019 novel coronavirus disease (COVID-19) in individuals present during the outbreak on the Diamond Princess cruise ship.

We investigated the clinical course of individuals with 2019 novel coronavirus disease (COVID-19) who were transferred from the Diamond Princess cruise ship to 12 local hospitals. The conditions and clinical courses of patients with pneumonia were compared with those of patients without pneumonia. Among 70 patients (median age: 67 years) analyzed, the major symptoms were fever (64.3%), cough (54.3%), and general fatigue (24.3%). Forty-three patients (61.4%) had pneumonia. Higher body temperature, heart rate, and respiratory rate as well as higher of lactate dehydrogenase (LDH), aspartate aminotransferase (AST), and C-reactive protein (CRP) levels and lower serum albumin level and lymphocyte count were associated with the presence of pneumonia. Ground-glass opacity was found in 97.7% of the patients with pneumonia. Patients were administered neuraminidase inhibitors (20%), lopinavir/ritonavir (32.9%), and ciclesonide inhalation (11.4%). Mechanical ventilation and veno-venous extracorporeal membrane oxygenation was performed on 14 (20%) and 2 (2.9%) patients, respectively; two patients died. The median duration of intubation was 12 days. The patients with COVID-19 transferred to local hospitals during the outbreak had severe conditions and needed close monitoring. The severity of COVID-19 depends on the presence of pneumonia. High serum LDH, AST and CRP levels and low serum albumin level and lymphocyte count were found to be predictors of pneumonia. It was challenging for local hospitals to admit and treat these patients during the outbreak of COVID-19. Assessment of severity was crucial to manage a large number of patients.

Identification and functional characterization of Candida albicans mannose-ethanolamine phosphotransferase (Mcd4p).

Glycosylphosphatidylinositol (GPI) is an important compound for the growth of fungi, because GPI-anchored proteins including glycosyltransferases and adhesins are involved in cell-wall integrity, adhesion, and nutrient uptake in this organism. In this study, we examined orf19.5244 in the genome database of the pathogenic fungus Candida albicans, a homologue of the Saccharomyces cerevisiae mannose-ethanolamine phosphotransferase gene, MCD4, which plays a role in GPI synthesis. Expression of this homologue, designated CaMCD4, restored cell growth in a defective conditional mcd4 mutant of S. cerevisiae, Scmcd4t, in which expression of native MCD4 was repressed in the presence of doxycycline (Dox). Analysis of radiolabeled lipids showed that the accumulation of abnormal GPI anchor precursors in Scmcd4t decreased markedly upon expression of CaMCD4. Moreover, we constructed a single mutant (Camcd4/CaMCD4) and a conditional double mutant (Camcd4/Camcd4t) at the MCD4 locus of C. albicans. Repression of CaMCD4 expression by Dox led to a decrease in growth and appearance of abnormal morphology in C. albicans, both in vitro and in a silkworm infection model. These results suggest that CaMcd4p is indispensable for growth of C. albicans both in vitro and in infected hosts and a candidate target for the development of new antifungals.

Large deformity correction in medial open-wedge high tibial osteotomy may cause degeneration of patellofemoral cartilage: A retrospective study.

To evaluate retrospectively any association between the degree of deformity correction by medial open-wedge high tibial osteotomy (HTO) and patellofemoral joint degeneration. We hypothesized that development of patellofemoral joint degeneration depended on the degree of intraoperative deformity correction.Fifty-seven patients who underwent medial open-wedge HTO for treatment of osteoarthritis in one knee were included in this study. Knees were classified into degeneration (D) and non-degeneration (ND) groups according to worsening of the patellar and/or femoral trochlear cartilage at the time of hardware removal (D group, 27 knees) and no degeneration or improvement (ND group, 30 knees). We compared pre- to post-surgery change in hip-knee-ankle angle (HKA) and medial-proximal-tibial angle (MPTA), open-wedge HTO correction angle, and arthroscopic findings between groups.Mean age, height, weight, and body mass index were 54.1 ±â€Š9.9 years, 160.4 ±â€Š8.7 cm, 66.4 ±â€Š12.1 kg, and 25.7 ±â€Š3.3 kg/m, respectively. Change in both HKA and MPTA differed significantly between groups. The MPTA cut-off values to predict patellofemoral degeneration were determined to be 10°, associated with an AUC of 0.75 (95% confidence interval [CI] 0.62-0.87).This study evaluated retrospectively the effect of the correction angle during medial open-wedge HTO on patellofemoral joint degeneration. If deformity correction exceeds an MPTA of 10° during open-wedge HTO, degeneration of patellofemoral joint needs to be considered.Level of evidence: Level IV.

Decoding Transcriptome Dynamics of Genome-Encoded Polyadenylation and Autoregulation with Small-Molecule Modulators of Alternative Polyadenylation.

Alternative polyadenylation (APA) plays a critical role in regulating gene expression. However, the balance between genome-encoded APA processing and autoregulation by APA modulating RNA binding protein (RBP) factors is not well understood. We discovered two potent small-molecule modulators of APA (T4 and T5) that promote distal-to-proximal (DtoP) APA usage in multiple transcripts. Monotonically responsive APA events, induced by short exposure to T4 or T5, were defined in the transcriptome, allowing clear isolation of the genomic sequence features and RBP motifs associated with DtoP regulation. We found that longer vulnerable introns, enriched with distinctive A-rich motifs, were preferentially affected by DtoP APA, thus defining a core set of genes with genomically encoded DtoP regulation. Through APA response pattern and compound-small interfering RNA epistasis analysis of APA-associated RBP factors, we further demonstrated that DtoP APA usage is partly modulated by altered autoregulation of polyadenylate binding nuclear protein-1 signaling.

Multi-omics monitoring of drug response in rheumatoid arthritis in pursuit of molecular remission.

Sustained clinical remission (CR) without drug treatment has not been achieved in patients with rheumatoid arthritis (RA). This implies a substantial difference between CR and the healthy state, but it has yet to be quantified. We report a longitudinal monitoring of the drug response at multi-omics levels in the peripheral blood of patients with RA. Our data reveal that drug treatments alter the molecular profile closer to that of HCs at the transcriptome, serum proteome, and immunophenotype level. Patient follow-up suggests that the molecular profile after drug treatments is associated with long-term stable CR. In addition, we identify molecular signatures that are resistant to drug treatments. These signatures are associated with RA independently of known disease severity indexes and are largely explained by the imbalance of neutrophils, monocytes, and lymphocytes. This high-dimensional phenotyping provides a quantitative measure of molecular remission and illustrates a multi-omics approach to understanding drug response.

Anti-tumor efficacy of a novel CLK inhibitor via targeting RNA splicing and MYC-dependent vulnerability.

The modulation of pre-mRNA splicing is proposed as an attractive anti-neoplastic strategy, especially for the cancers that exhibit aberrant pre-mRNA splicing. Here, we discovered that T-025 functions as an orally available and potent inhibitor of Cdc2-like kinases (CLKs), evolutionally conserved kinases that facilitate exon recognition in the splicing machinery. Treatment with T-025 reduced CLK-dependent phosphorylation, resulting in the induction of skipped exons, cell death, and growth suppression in vitro and in vivo Further, through growth inhibitory characterization, we identified high CLK2 expression or MYC amplification as a sensitive-associated biomarker of T-025. Mechanistically, the level of CLK2 expression correlated with the magnitude of global skipped exons in response to T-025 treatment. MYC activation, which altered pre-mRNA splicing without the transcriptional regulation of CLKs, rendered cancer cells vulnerable to CLK inhibitors with synergistic cell death. Finally, we demonstrated in vivo anti-tumor efficacy of T-025 in an allograft model of spontaneous, MYC-driven breast cancer, at well-tolerated dosage. Collectively, our results suggest that the novel CLK inhibitor could have therapeutic benefits, especially for MYC-driven cancer patients.

Impact of pancreaticoduodenal arcade dilation on postoperative outcomes after pancreaticoduodenectomy.

BACKGROUND: The aim of this study was to investigate the impact of pancreaticoduodenal arcade (PDA) dilation on postoperative outcomes after pancreaticoduodenectomy. METHODS: Consecutive patients submitted to pancreaticoduodenectomy between 2008 and 2016 underwent preoperative multi-detector computed tomography, the images of which were re-reviewed. The patients were categorized according to the grade of PDA dilation into 3 groups (remarkably-dilated, slightly-dilated, and non-dilated). RESULTS: Among the 443 patients, 25 patients (5.6%) were categorized as remarkably-dilated PDA and 24 patients (5.4%) as having slightly-dilated PDA. The patients with remarkably-dilated PDA had undergone pancreaticoduodenectomy with additional surgical maneuvers to restore celiac arterial flow as needed, and had an uneventful postoperative recovery relative to those with non-dilated PDA. In contrast, patients with slightly-dilated PDA underwent only pancreaticoduodenectomy without additional surgical maneuvers, and developed clinically relevant postoperative pancreatic fistula (POPF) more frequently than those with non-dilated PDA (42% vs. 21%, P = 0.021). Moreover, slightly-dilated PDA was shown to be an independent risk factor for clinically relevant POPF (odds ratio = 2.719, P = 0.042). DISCUSSION: For patients with PDA dilation requiring pancreaticoduodenectomy, a preoperative evaluation of the vascular anatomy, intraoperative assessment of the celiac arterial flow, and additional surgical maneuvers might be necessary to reduce the risk of postoperative complications.

Efficacy of completion pancreatectomy for recurrence of adenocarcinoma in the remnant pancreas.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer, with a high rate of recurrence even after complete surgical resection. The aim of this study was to investigate the impact of completion pancreatectomy (CP) on the clinical course of patients with recurrent PDAC in the remnant pancreas. MATERIALS AND METHODS: Between January 2008 and December 2014, 194 patients underwent curative-intent surgical resection (initial pancreatectomy [IP]) for PDAC at our institution. The treatment and survival outcomes were evaluated according to the patterns of recurrence. RESULTS: Among 194 patients with IP, 127 patients (65.5%) developed recurrence. Of them, 11 patients (8.7%) developed recurrence in the remnant pancreas and were treated by CP. They showed a significantly longer median survival after the recurrence than the 28 patients who developed unresectable local recurrence and were treated by systemic chemotherapy (44 mo versus 11 mo, P = 0.014) or the 66 patients who developed distant metastasis and were treated by systemic chemotherapy (44 mo versus 13 mo, P = 0.024). Moreover, the median survival after CP was longer in the patients who received adjuvant chemotherapy after CP than in those who did not receive adjuvant chemotherapy (44 mo versus 14 mo, P = 0.002). CONCLUSIONS: This study demonstrated that PDAC patients with resectable local recurrence in the remnant pancreas, who were treated by CP, had better survival outcomes than those with other patterns of recurrence. CP combined with adjuvant chemotherapy appeared to yield greater survival benefit.

Positional relationships of abdominal aortic branches for contrast radiography of the inferior mesenteric artery using the coeliac trunk and superior mesenteric artery as landmarks.

PURPOSE: To establish a method by which angiography of the inferior mesenteric artery (IMA) can be performed smoothly, we investigated the relative locations of the coeliac trunk (CT), superior mesenteric artery (SMA), IMA, and left renal artery (LtRA). METHODS: From a total of 60 cadavers, 32 cadavers with few arteriosclerotic lesions and little vascular tortuosity were selected for the study. The abdominal aorta (Ao) were removed and incised on both lateral side, along the vertical axis and transected into the ventral and dorsal sides. The intravascular lumen on the ventral side of the Ao was photographed using a digital camera, and the horizontal and vertical diameters of the sites of confluence of the CT, SMA, and IMA, were measured on the computer screen. We also calculated the distances between the branches, including the CT, SMA, IMA, LtRA, and the common iliac artery (CoI). RESULTS: Although the SMA-IMA distance did not correlate with the CT-SMA distance, the ratio of the SMA-IMA to CT-CoI distance was four times greater than the ratio of the CT-SMA to CT-CoI distance. CONCLUSIONS: The site of branching of the IMA can be inferred to some extent from the CT and SMA distance.

Fatal delayed rupture of the subclavian artery in a patient with first-rib fracture caused by blunt trauma.

This case highlights the probable association of significantly displaced posterior first-rib fracture and jagged edges of the fracture line following blunt chest trauma with delayed ipsilateral subclavian artery rupture. Early angiography and first-rib repair should promptly be considered under such circumstances.

CLK-dependent exon recognition and conjoined gene formation revealed with a novel small molecule inhibitor.

CDC-like kinase phosphorylation of serine/arginine-rich proteins is central to RNA splicing reactions. Yet, the genomic network of CDC-like kinase-dependent RNA processing events remains poorly defined. Here, we explore the connectivity of genomic CDC-like kinase splicing functions by applying graduated, short-exposure, pharmacological CDC-like kinase inhibition using a novel small molecule (T3) with very high potency, selectivity, and cell-based stability. Using RNA-Seq, we define CDC-like kinase-responsive alternative splicing events, the large majority of which monotonically increase or decrease with increasing CDC-like kinase inhibition. We show that distinct RNA-binding motifs are associated with T3 response in skipped exons. Unexpectedly, we observe dose-dependent conjoined gene transcription, which is associated with motif enrichment in the last and second exons of upstream and downstream partners, respectively. siRNA knockdown of CLK2-associated genes significantly increases conjoined gene formation. Collectively, our results reveal an unexpected role for CDC-like kinase in conjoined gene formation, via regulation of 3'-end processing and associated splicing factors.The phosphorylation of serine/arginine-rich proteins by CDC-like kinase is a central regulatory mechanism for RNA splicing reactions. Here, the authors synthesize a novel small molecule CLK inhibitor and map CLK-responsive alternative splicing events and discover an effect on conjoined gene transcription.