A Predictive Model for Cancer-Associated Thrombosis in Japanese Cancer Patients: Findings from the J-Khorana Registry.

Background Although the close relationship between cancer and venous thromboembolism (VTE) has been identified, risk stratification for VTE in Japanese patients with cancer remains unclear. Objectives This study aimed to validate the Khorana VTE risk assessment score (KRS) for VTE diagnosis and establish an optimal predictive model for VTE in Japanese patients with cancer. Methods A total of 7,955 Japanese patients with cancer were subdivided into low- (0), intermediate- (1-2), and high-score (3) groups according to the KRS. Using 37 explanatory variables, a total of 2,833 patients with cancer were divided into derivation and validation cohorts (5:5). A risk model for Japanese participants was developed using the derivation cohort data. Results The prevalence of VTE in low-, intermediate-, and high-score patients was 1.2, 2.5, and 4.3%, respectively. Logistic regression analysis demonstrated that cancer stage (III-IV) and KRS ≥ 2 were independent and significant predictors of VTE onset. The risk model for VTE assigned 1 point to body mass index ≥25 kg/m 2 and 2 points each to the prevalence of osteochondral cancer and D-dimer level ≥1.47 µg/mL. The areas under the curve of the risk model were 0.763 and 0.656 in the derivation and validation cohorts, respectively. Conclusion The KRS was useful in Japanese patients, and our new predictive model may be helpful for the diagnosis of VTE in Japanese patients with cancer.

Comparison of the Incidence of Adverse Events Between Japanese and Non-Japanese Healthy Subjects in Phase I Studies: A Systematic Review and Meta-Analysis.

BACKGROUND AND OBJECTIVE: Ethnic and racial differences are key factors affecting the results of clinical studies. However, the influence of these factors on the efficacy and safety of medicinal products remains unclear. Race-dependent nature is considered to be one of the factors causing differences in clinical findings, and we investigated its influence on the safety evaluation of drugs. METHODS: We searched PubMed and a Japan drug approval list to find relevant studies, and extracted phase I studies conducted with Japanese and non-Japanese participants using the same protocol and at the same study site. Pooled estimates of odds ratios (ORs) for the incidence of major adverse events in Japanese and non-Japanese participants were calculated, using a DerSimonian-Laird method with a random-effects model. RESULTS: Odds ratios for some adverse events in the active drug arm were significantly lower in Japanese participants: headaches [OR 0.65 (95% confidence interval [CI] 0.52-0.82), p = 0.0003], neurological disorders NEC [OR 0.70 (95% CI 0.53-0.93), p = 0.0135] in a High-Level Group Term, nervous system disorders [OR 0.64 (95% CI 0.49-0.82), p = 0.0004], infections and infestations [OR 0.71 (95% CI 0.53-0.95), p = 0.0202], and musculoskeletal and connective tissue disorders [OR 0.66 (95% CI 0.48-0.91, p = 0.0107] in the System Organ Class. CONCLUSIONS: Our research suggested that racial factors such as race-dependent nature influence a drug safety assessment. With knowledge of these differences, it is expected that Japan will actively conduct multi-regional clinical trials, in which more diverse populations are included.

Factors Related to Placebo Response in Randomized, Double-Blind Clinical Trials of Antidepressants in Children and Adolescents: A Meta-regression Analysis.

BACKGROUND AND OBJECTIVE: Many randomized clinical trials (RCTs) for antidepressants in children and adolescents have failed to demonstrate efficacy due to a high placebo response. The aim of this study was to identify the potential factors affecting placebo response using meta-regression analysis of RCTs for antidepressants in children and adolescents using the Children's Depressive Rating Scale-Revised (CDRS-R) as the outcome. METHODS: PubMed and ClinicalTrials.gov were searched for randomized, double-blind, placebo-controlled trials of antidepressants for the acute treatment of major depressive disorder in children and adolescents. The outcome used in the present study was the mean change of the CDRS-R total score from baseline to the last assessment for the primary efficacy in the placebo arm. Potential factors related to the placebo response, such as study design, operational, and patient factors, were explored using meta-regression. RESULTS: The analyses included 23 trials. On multivariable meta-regression, setting up a placebo lead-in period was significantly associated with a smaller placebo response in the CDRS-R. CONCLUSION: Setting up a placebo lead-in period should be considered in future clinical trials of antidepressants in adolescents and children.

Earable Ω (OMEGA): A Novel Clenching Interface Using Ear Canal Sensing for Human Metacarpophalangeal Joint Control by Functional Electrical Stimulation.

(1) Background: A mouth-free interface is required for functional electrical stimulation (FES) in people with spinal cord injuries. We developed a novel system for clenching the human metacarpophalangeal (MP) joint using an earphone-type ear canal movement sensor. Experiments to control joint angle and joint stiffness were performed using the developed system. (2) Methods: The proposed FES used an equilibrium point control signal and stiffness control signal: electrical agonist-antagonist ratio and electrical agonist-antagonist sum. An angle sensor was used to acquire the joint angle, and system identification was utilized to measure joint stiffness using the external force of a robot arm. Each experiment included six and five subjects, respectively. (3) Results: While the joint angle could be controlled well by clenching with some hysteresis and delay in three subjects, it could not be controlled relatively well after hyperextension in the other subjects, which revealed a calibration problem and a change in the characteristics of the human MP joint caused by hyperextension. The joint stiffness increased with the clenching amplitude in five subjects. In addition, the results indicated that viscosity can be controlled. (4) Conclusions: The developed system can control joint angle and stiffness. In future research, we will develop a method to show that this system can control the equilibrium point and stiffness simultaneously.

Inter-limb Asymmetry of Equilibrium Regulation in the Legs of 10-11-Year-Old Boys during Overground Sprinting.

Short-distance running at top speed is important in field sports. Previous studies have analyzed kinematic and kinetic properties of sprinting in adults, but equivalent knowledge in children is underexplored. Quantifying relevant aspects of children's sprinting is useful for classifying their running skills and providing effective coaching based on motor control theory. This study aimed to clarify differences in equilibrium regulation in more- and less-skilled boy sprinters. Five 10-11-year-old boys regularly participating in lessons at the Mizuno running school performed 30-meter and 50-meter field track sprints, and the kinematic and electromyography findings were recorded. Equilibrium-point-based synergy analysis was then applied to estimate their respective virtual trajectories. The virtual trajectory is an equilibrium time sequence that indicates how the central nervous system controls a skeletal system with multiple muscles. The results suggested that: (1) the equilibrium of the right and left legs was regulated differently, although together the legs showed similar kinematics; (2) in the first type of virtual trajectory (type-I) in one leg, the equilibria after foot-strike were regulated intermittently during the early swing phase; (3) in the second type of virtual trajectory (type-II) in the other leg, the equilibria after foot-strike were continuously regulated during the early swing phase; and (4) the less-skilled child runners showed a slow equilibrium action response in both types of virtual trajectory during the early swing phase. These findings provide insights for "tailor-made" coaching based on the type of leg control during sprinting.Clinical relevance-Information on gait asymmetry would be beneficial not only for coaching to improve sprint training but also from clinical and injury perspectives.

[Three cases of COVID-19 in elderly patients with delayed release from isolation due to persistent positive polymerase chain reaction findings].

The coronavirus disease 2019 (COVID-19) infection has spread worldwide, with no sign of its control in Japan yet. Eight elderly COVID-19 patients over 90 years of age were treated at our hospital. We herein report three cases with characteristic progression. Case 1 was a 91-year-old female patient diagnosed with bacterial pneumonia previously who did not show improvement with medication; thus, she was transferred to our hospital 16 days after the onset. She was diagnosed with COVID-19 using the SARS-CoV-2 polymerase chain reaction (PCR) test. Favipiravir, methylprednisolone, and unfractionated heparin were administered, but she only tested negative 68 days after the onset, at which point she was discharged. However, she was transferred back to our hospital 80 days after the onset since she tested positive again. She was transferred to another hospital 110 days after the onset without testing negative. Case 2 was a 102-year-old female. Despite being a mild case, it took 32 days to obtain negative PCR findings, leading to a decline in the activities of daily living. Case 3 was a 90-year-old male patient treated with favipiravir, dexamethasone, and unfractionated heparin, but his condition deteriorated. He never tested negative for PCR and ultimately died 20 days after the onset. Reports suggest that PCR positivity does not necessarily indicate infectivity, but there are no clear criteria for lifting a quarantine. Therefore, PCR negativity is often sought for "peace of mind." In the current situation where hospitals are fully occupied, clear criteria for lifting the quarantine should be promptly determined. After the completion of treatment, it is more important to monitor symptoms and take standard precautions, such as daily health monitoring, wearing a mask, and keeping an appropriate distance from others, than to obtain a negative PCR result.

Psychological Effects on Healthcare Workers during the COVID-19 Outbreak: A Single-center Study at a Tertiary Hospital in Tokyo, Japan.

Objective The present study analyzed the psychological status of healthcare workers in Japan and the influencing factors during the 2019 coronavirus disease pandemic. Methods An online survey was conducted from July 22 to August 21, 2020. A total of 328 of the 1,029 medical staff members in our university hospital participated in the study. Their mental health was assessed using the 12-item General Health Questionnaire. A multivariate regression analysis was performed to identify the factors associated with the mental health outcomes. Results Of the respondents, 78.0% reported psychological distress. Overall, we found that women, non-physicians, those who lived alone, and younger respondents had significantly greater psychological distress than their counterparts. The multivariate regression analysis showed that four factors were extracted as independent 12-item General Health Questionnaire-related factors: the lack of a sense of mission as a medical professional, the burden of the change in the quality of work, the lack of understanding about virus infectivity, and a strong sense of duty. Conclusion In summary, we found a high prevalence of psychological distress among healthcare workers during the 2019 coronavirus disease outbreak in Japan. Independent risk factors for psychological distress were the burden of the change in the quality of work, the lack of understanding about virus infectivity, a sense of responsibility, and the lack of a strong motivation and drive to help.

Low-grade ductal carcinoma in situ (DCIS) arising in a fibroadenoma of the breast during 5 years follow-up: A case report.

RATIONALE: Fibroadenoma (FA) is a common type of benign breast tumors but ductal carcinoma in situ (DCIS) rarely arises within this tumor type. PATIENT CONCERNS: This case report presents a non-symptomatic 61-year-old woman with FA that was coincidentally found during a breast cancer screening program performed 5 years ago by her city of residence. She had subsequently been followed-up with mammography and breast ultrasound (US). US showed a slightly enlarged tumor and dynamic magnetic resonance imaging (MRI) indicated malignancy within the FA. DIAGNOSIS: The pathological examination revealed low-grade DCIS within the FA. INTERVENTIONS: The patient underwent a core needle biopsy followed by breast-conserving therapy with sentinel lymph node biopsy and then postoperative radiation therapy. OUTCOMES: Currently, she has been followed-up for 2 years without no signs of recurrence. LESSONS: Careful observation with US followed by dynamic MRI is essential in the early diagnosis of DCIS originating in a FA.

Mechanical factors affecting the foot eversion moment during the stance phase of running in non-rearfoot strikers.

This study aimed to identify the primary factors that induce rearfoot external eversion moments due to ground reaction force (GRF) in non-rearfoot strikers. The data were compared with those of rearfoot strikers. Totally, 11 healthy males who were habitually non-rearfoot strikers ran barefoot. Rearfoot external eversion/inversion moments due to GRF (Mtot) were decomposed into two components based on mediolateral (Mxy) and vertical (Mz) GRFs. The height of the ankle joint centre and the mediolateral distance from the centre of pressure (COP) to the ankle joint centre (a_cop) were calculated as the lever arms to the Mxy and Mz components. Just after foot contact, non-rearfoot strikers demonstrated a significantly larger Mz, which was strongly dependent on a_cop and produced most of the Mtot, whereas Mxy dominated Mtot in rearfoot strikers. During the consecutive loading phase, non-rearfoot strikers demonstrated a significantly larger Mxy, which was strongly dependent on the mediolateral GRF and substantially contributed to Mtot, unlike the rearfoot strikers, whose Mtot was almost dominated by Mz during the loading phase. It was found that since the factor of generating the moment differs depending on the foot contact pattern, the strategies for suppressing the moment may be different for each foot contact pattern.

Divalent cations increase the conjugation efficiency of the incompatibility P-7 group plasmid pCAR1 among different Pseudomonas hosts.

The incompatibility (Inc) P-7 group plasmid pCAR1 can be efficiently transferred among bacteria in artificial microcosms in the presence of divalent cations Ca2+ and Mg2+. One-on-one mating assays between Pseudomonas strains with different plasmids showed that the promotion of conjugation efficiency by divalent cations was exhibited in other plasmids, including pB10 and NAH7; however, this effect was larger in IncP-7 plasmids. The impact on pCAR1 conjugation differed according to donor-recipient pairs, and conjugation efficiency promotion was clearly detected between the donors P. resinovorans CA10dm4 and P. fluorescens Pf0-1 and the recipients P. putida KT2440 and CA10dm4. Transcriptome analyses showed that pCAR1 gene expression did not respond to cation changes, including the tra/trh genes involved in its transfer. However, the transcription of oprH genes, encoding putative outer-membrane proteins in both the donor and the recipient, were commonly upregulated under cation-limited conditions. The conjugation frequency of pCAR1 in the KT2440 oprH mutant was found not to respond to cations. This effect was partially recovered by complementation with the oprH gene, suggesting that OprH is involved in the increase of pCAR1 conjugation efficiency by divalent cations.

Clinical application of effective atomic number for classifying non-calcified coronary plaques by dual-energy computed tomography.

BACKGROUND AND AIMS: Coronary computed tomography (CT) angiography allows non-invasive classification of non-calcified coronary plaques (NCCPs) based on Hounsfield unit (HU) values. This methodology, however, is somewhat limited for reliable classification of NCCPs. Therefore, we evaluated the effective atomic number (EAN) for classifying NCCPs by single-source dual-energy CT with fast tube voltage switching (SSDECT). METHODS: We prospectively enrolled 18 patients undergoing both SSDECT and intravascular ultrasonography (IVUS). Monochromatic images at 70 keV and EAN images were reconstructed from SSDECT data sets. Regions of interest (ROIs) within NCCPs were placed on IVUS-matched SSDECT images, and mean HU values and EANs for soft and fibrous plaques, classified using IVUS, were compared with an unpaired t-test. RESULTS: We placed 96 ROIs in 29 soft plaques and 37 ROIs in 15 fibrous plaques in 12 coronary arteries of 11 patients. The mean HU value in soft plaques (58.2 ± 32.8 HU) was significantly lower than that in fibrous plaques (103.9 ± 48.3 HU) (p < 0.001). The mean EAN in soft plaques (8.7 ± 0.5) was also significantly lower than that in fibrous plaques (9.6 ± 0.5) (p < 0.0001). Area under the curve for EAN (0.91) was significantly higher than that for HU value (0.79) in receiver operating characteristic curve analysis (p = 0.046). With a cutoff EAN of 9.3, sensitivity was 90% and specificity, 87%; whereas with a cutoff HU value of 55.0 HU, sensitivity was 62% and specificity, 93%. CONCLUSIONS: EAN measurement by SSDECT can be clinically useful for accurately classifying soft and fibrous coronary plaques.

CT Findings of Axillary Tuberculosis Lymphadenitis: A Case Detected by Breast Cancer Screening Examination.

We report the first description of CT findings of axillary tuberculous lymphadenitis confirmed by the pathological specimen. The breast cancer screening examination is one of the prime methods of detection of axillary tuberculous lymphadenitis. The most common site of axillary tuberculous lymphadenitis is the deep axilla. Screening mammography often fails to cover the whole axilla. The presence on the contrast-enhanced CT of unilateral multiple circumscribed dense nodes, some of which have large and dotted calcifications, might suggest tuberculous lymphadenitis in axillary region.

Comparisons of the transferability of plasmids pCAR1, pB10, R388, and NAH7 among Pseudomonas putida at different cell densities.

The transferability of plasmids pCAR1, pB10, R388, and NAH7 was compared using the same donor-recipient system at different cell density combinations in liquid or on a solid surface. pCAR1 was efficiently transferred in liquid, whereas the other plasmids were preferentially transferred on a solid surface. Difference of liquid or solid affected the transfer frequency especially at lower cell densities.

An autopsy case of vertebrobasilar dolichoectasia under hemodialysis due to autosomal dominant polycystic kidney disease.

A 60-year-old male with end-stage kidney disease due to autosomal polycystic kidney disease began maintenance hemodialysis in 2005. A brain CT scan showed dilatation of left vertebral artery, basilar artery, bilateral post cerebral artery, and middle cerebral artery. At the time, he was diagnosed as vertebrobasilar dolichoectasia. He was once admitted to our hospital for ischemic stroke. After discharge, he was treated with anticoagulant agent from 2010 to 2012 without any new stroke events. In March, 2012, he was admitted to our hospital for an evaluation of diplopia and left hemiplegia. Brain MRI showed acute ischemia of bilateral pons and right temporal lobe. He was once recovered with urokinase and argatroban, but 3 months after admission, he died with sudden hypotension and impaired consciousness. Autopsy revealed that subarachnoid hemorrhage due to the rupture of basilar artery aneurysm was responsible for this event.

Effects of three different nucleoid-associated proteins encoded on IncP-7 plasmid pCAR1 on host Pseudomonas putida KT2440.

Nucleoid-associated proteins (NAPs), which fold bacterial DNA and influence gene transcription, are considered to be global transcriptional regulators of genes on both plasmids and the host chromosome. Incompatibility P-7 group plasmid pCAR1 carries genes encoding three NAPs: H-NS family protein Pmr, NdpA-like protein Pnd, and HU-like protein Phu. In this study, the effects of single or double disruption of pmr, pnd, and phu were assessed in host Pseudomonas putida KT2440. When pmr and pnd or pmr and phu were simultaneously disrupted, both the segregational stability and the structural stability of pCAR1 were markedly decreased, suggesting that Pmr, Pnd, and Phu act as plasmid-stabilizing factors in addition to their established roles in replication and partition systems. The transfer frequency of pCAR1 was significantly decreased in these double mutants. The segregational and structural instability of pCAR1 in the double mutants was recovered by complementation of pmr, whereas no recovery of transfer deficiency was observed. Comprehensive phenotype comparisons showed that the host metabolism of carbon compounds, which was reduced by pCAR1 carriage, was restored by disruption of the NAP gene(s). Transcriptome analyses of mutants indicated that transcription of genes for energy production, conversion, inorganic ion transport, and metabolism were commonly affected; however, how their products altered the phenotypes of mutants was not clear. The findings of this study indicated that Pmr, Pnd, and Phu act synergistically to affect pCAR1 replication, maintenance, and transfer, as well as to alter the host metabolic phenotype.

Analysis of coronary arterial calcification components with coronary CT angiography using single-source dual-energy CT with fast tube voltage switching.

Clinical cardiac applications of single-source dual-energy computed tomography (DECT) have recently been introduced. This study aimed to analyze the components of coronary arterial calcification (CAC) in vivo by material decomposition achieved with DECT. We reconstructed computed tomography (CT) angiography images for 51 consecutive patients with CACs who had undergone electrocardiography-gated coronary CT angiography by single-source DECT with fast tube voltage switching. We placed regions of interest (ROIs) within the CAC with margins of at least 0.5 mm to minimize partial volume averaging. We compared histograms for the effective atomic number (EAN) and the median, mean, and maximum EANs for each CAC with the theoretical EANs for possible CAC components, including hydroxyapatite (HA), calcium oxalate monohydrate (COM), and dicalcium phosphate dehydrate. We also investigated the in vivo EAN for COM and in vitro EAN for HA by our phantom experiment. Analysis of the CAC components was feasible in 177 ROIs from 28 patients. The median EAN was 13.8 ± 0.8 (95% confidence interval 13.7-13.9), which is similar to the theoretical EAN for COM (13.8). The EAN for HA in vitro was 16.5 ± 0.1, which was slightly higher than the theoretical EAN value for HA (16.1). Notably, the median EAN in 144 ROIs (81.4%) was between 11.2 and 14.4, which is the reported range of the in vivo EAN for COM. Our results suggest that COM might be a more frequent CAC component than previously reported.

Equilibrium-point control of human elbow-joint movement under isometric environment by using multichannel functional electrical stimulation.

Functional electrical stimulation (FES) is considered an effective technique for aiding quadriplegic persons. However, the human musculoskeletal system has highly non-linearity and redundancy. It is thus difficult to stably and accurately control limbs using FES. In this paper, we propose a simple FES method that is consistent with the motion-control mechanism observed in humans. We focus on joint motion by a pair of agonist-antagonist muscles of the musculoskeletal system, and define the "electrical agonist-antagonist muscle ratio (EAA ratio)" and "electrical agonist-antagonist muscle activity (EAA activity)" in light of the agonist-antagonist muscle ratio and agonist-antagonist muscle activity, respectively, to extract the equilibrium point and joint stiffness from electromyography (EMG) signals. These notions, the agonist-antagonist muscle ratio and agonist-antagonist muscle activity, are based on the hypothesis that the equilibrium point and stiffness of the agonist-antagonist motion system are controlled by the central nervous system. We derived the transfer function between the input EAA ratio and force output of the end-point. We performed some experiments in an isometric environment using six subjects. This transfer-function model is expressed as a cascade-coupled dead time element and a second-order system. High-speed, high-precision, smooth control of the hand force were achieved through the agonist-antagonist muscle stimulation pattern determined by this transfer function model.

Single-cell analyses revealed transfer ranges of IncP-1, IncP-7, and IncP-9 plasmids in a soil bacterial community.

The conjugative transfer ranges of three different plasmids of the incompatibility groups IncP-1 (pBP136), IncP-7 (pCAR1), and IncP-9 (NAH7) were investigated in soil bacterial communities by culture-dependent and culture-independent methods. Pseudomonas putida, a donor of each plasmid, was mated with soil bacteria, and green fluorescent protein (GFP), encoded on the plasmid, was used as a reporter protein for successful transfer. GFP-expressing transconjugants were detected and separated at the single-cell level by flow cytometry. Each cell was then analyzed by PCR and sequencing of its 16S rRNA gene following either whole-genome amplification or cultivation. A large number of bacteria within the phylum Proteobacteria was identified as transconjugants for pBP136 by both culture-dependent and culture-independent methods. Transconjugants belonging to the phyla Actinobacteria, Bacteroidetes, and Firmicutes were detected only by the culture-independent method. Members of the genus Pseudomonas (class Gammaproteobacteria) were identified as major transconjugants of pCAR1 and NAH7 by both methods, whereas Delftia species (class Betaproteobacteria) were detected only by the culture-independent method. The transconjugants represented a minority of the soil bacteria. Although pCAR1-containing Delftia strains could not be cultivated after a one-to-one filter mating assay between the donor and cultivable Delftia strains as recipients, fluorescence in situ hybridization detected pCAR1-containing Delftia cells, suggesting that Delftia was a "transient" host of pCAR1.

Resected pleomorphic carcinoma of the gallbladder.

Pleomorphic carcinoma is a rare lesion and the literature contains few reports of pleomorphic carcinoma of the gallbladder. The present study reports a rare case of primary pleomorphic carcinoma of the gallbladder for which we were able to perform curative surgery. A 77-year-old woman with dementia developed nausea and anorexia, and computed tomography demonstrated irregular thickening of the gallbladder wall. Drip infusion cholangiography and endoscopic retrograde cholangiopancreatography revealed no stenosis of the common and intrahepatic bile ducts. We suspected carcinoma of the gallbladder without lymph node metastasis and invasion to the common bile duct. We guessed it to be resectable and performed open laparotomy. At operation, the fundus of the gallbladder was adherent to the transverse colon, but no lymph node and distant metastases were detected. Therefore, we performed curative cholecystectomy with partial colectomy. Histopathology and immunostaining showed coexistence of an adenocarcinoma, squamous cell carcinoma and sarcomatous tumor of spindle-shaped cell, as well as transition zones between these tumors. We diagnosed stage I pleomorphic carcinoma of the gallbladder. No recurrence has been observed for one and a half years. The biological behavior of pleomorphic carcinoma of the gallbladder remains unknown. It will be necessary to accumulate more case reports of this tumor in order to define diagnostic criteria.