Medical researchers' perceptions regarding research evaluation: a web-based survey in Japan.

OBJECTIVES: Japanese medical academia continues to depend on quantitative indicators, contrary to the general trend in research evaluation. To understand this situation better and facilitate discussion, this study aimed to examine how Japanese medical researchers perceive quantitative indicators and qualitative factors of research evaluation and their differences by the researchers' characteristics. DESIGN: We employed a web-based cross-sectional survey and distributed the self-administered questionnaire to academic society members via the Japanese Association of Medical Sciences. PARTICIPANTS: We received 3139 valid responses representing Japanese medical researchers in any medical research field (basic, clinical and social medicine). OUTCOMES: The subjective importance of quantitative indicators and qualitative factors in evaluating researchers (eg, the journal impact factor (IF) or the originality of the research topic) was assessed on a four-point scale, with 1 indicating 'especially important' and 4 indicating 'not important'. The attitude towards various opinions in quantitative and qualitative research evaluation (eg, the possibility of research misconduct or susceptibility to unconscious bias) was also evaluated on a four-point scale, ranging from 1, 'strongly agree', to 4, 'completely disagree'. RESULTS: Notably, 67.4% of the medical researchers, particularly men, younger and basic medicine researchers, responded that the journal IF was important in researcher evaluation. Most researchers (88.8%) agreed that some important studies do not get properly evaluated in research evaluation using quantitative indicators. The respondents perceived quantitative indicators as possibly leading to misconduct, especially in basic medicine (strongly agree-basic, 22.7%; clinical, 11.7%; and social, 16.1%). According to the research fields, researchers consider different qualitative factors, such as the originality of the research topic (especially important-basic, 46.2%; social, 39.1%; and clinical, 32.0%) and the contribution to solving clinical and social problems (especially important-basic, 30.4%; clinical, 41.0%; and social, 52.0%), as important. Older researchers tended to believe that qualitative research evaluation was unaffected by unconscious bias. CONCLUSION: Despite recommendations from the Declaration on Research Assessment and the Leiden Manifesto to de-emphasise quantitative indicators, this study found that Japanese medical researchers have actually tended to prioritise the journal IF and other quantitative indicators based on English-language publications in their research evaluation. Therefore, constantly reviewing the research evaluation methods while respecting the viewpoints of researchers from different research fields, generations and genders is crucial.

In Vivo Brain Microdialysis.

Many biological molecules in the brain interstitial fluid are involved in neuronal functions. Therefore, measuring the levels of these molecules in the extracellular fluid would provide deep insights into the physiological/pathological mechanisms underlying brain functions/disorders. In vivo microdialysis is a powerful technique used to examine the extracellular levels of various molecules in the brains of living animals. In neuroscience research, this technique has been widely used to investigate relatively small molecules including neurotransmitters and amino acids. However, recent advances in technology have made it possible to assess large molecules in the brain interstitial fluid, such as signaling peptides and proteins, using microdialysis probes with high-molecular-weight cutoff membranes. This chapter describes an in vivo microdialysis method to collect and measure the levels of large biological molecules in the extracellular fluid of the brains of freely moving mice.

Intraday and interday variations of milk fatty acids in dairy cows in early and late lactation.

The composition of milk fatty acid (FA) was determined using Fourier-transform mid-infrared spectroscopy, which enables the rapid measurement of many samples. Milk FA is one indicator supporting the management of dairy cows and herds. This study aimed to determine an appropriate sampling method for milk FA in a practical farm condition based on intraday and interday variations in milk FA composition during early and late lactation stages. Milk samples were collected in the morning (07:00-08:00 h) and afternoon (16:30-17:30 h) for five consecutive days during early and late lactation. Within the day, de novo FA as the total FA basis was higher in the morning than in the afternoon, whereas preformed FA as the total FA basis was lower in the morning than in the afternoon. The weighted averages of milk FA composition according to milk yield collected in the morning and afternoon were significantly different between cows in early and late lactation; however, these were not significantly different among the consecutive five sampling days in each period. It was concluded that milk samples collected in the morning and afternoon for 1 day are suitable for milk FA determination. These results provide basic data for determining precise sampling methods for practical farms.

Clinical Outcomes of Total Wrist Arthroplasty in Patients With Rheumatoid Arthritis: Minimum 10-Year Follow-Up Study.

PURPOSE: We developed a semiconstrained total wrist prosthesis that was used in a series of patients with rheumatoid arthritis. We previously reported favorable clinical outcomes for up to 5 years after surgery; however, the longer-term outcomes remain unclear. The objective of this study was to evaluate the clinical outcomes of this wrist prosthesis for the treatment of severe wrist rheumatoid arthritis during a minimum 10 years of follow-up. METHODS: From 2010 through 2012, total wrist arthroplasty using the semiconstrained total wrist arthroplasty device was performed in 20 wrists in 20 patients with rheumatoid arthritis (five men and 15 women). The mean patient age was 64 years (range, 50-84 years). Preoperative radiographs showed Larsen grade IV changes in 16 wrists and grade V changes in four wrists. Patients were evaluated clinically and radiologically before surgery, 5 years after surgery, and 10 years or more after surgery. Evaluated parameters were the visual analog scale for pain, range of motion, Figgie score, and Disabilities of the Arm, Shoulder, and Hand score. RESULTS: The minimum 10-year follow-up clinical results (mean, 11.3 years) were available for all 14 surviving patients (three men and 11 women). Significant improvements in the mean visual analog scale for pain, Figgie score, and Disabilities of the Arm, Shoulder, and Hand score, compared with those before surgery, were maintained from 5 years after surgery to the final follow-up. The mean wrist flexion angle tended to slightly decrease at 5 years after surgery compared with that before surgery but remained similar from 5 years after surgery to the final follow-up. The increase in the mean wrist extension angle, compared with that before surgery, was maintained from 5 years after surgery to the final follow-up. Radiographic evaluation had already revealed implant loosening in five of the 19 wrists at 5 years after surgery, but there were no new cases of component loosening identified at the final follow-up. CONCLUSIONS: Total wrist arthroplasty using the semiconstrained arthroplasty system achieves favorable clinical outcomes with no serious complications requiring revision for 10 years after surgery. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV.

Dermoscopic image of the hairs in a very early lesion of tinea capitis caused by Trichophyton rubrum.

While the initial lesions of tinea capitis are often overlooked due to their small size and numerous hairs emerging from the follicle, it is crucial not to dismiss the partial presence of comma or harpin hairs and black spots.

Real-world epidemiology and treatment patterns of patients with locally advanced or metastatic urothelial carcinoma: Retrospective analysis of Diagnosis Procedure Combination claims data in Japan.

OBJECTIVES: Evaluate real-world epidemiologic trends and treatment patterns in newly diagnosed patients with locally advanced or metastatic urothelial carcinoma (la/mUC) in Japan. METHODS: This retrospective analysis included adults with newly diagnosed la/mUC in Japan (January 2015-December 2019) from a nationwide-linked electronic medical record Diagnostic Procedure Combination claims dataset. Outcomes included epidemiologic trends (incidence and prevalence), baseline demographics, clinical characteristics, and treatment patterns in newly diagnosed patients with la/mUC before (2015-2017) and after (2018-2019) approval of pembrolizumab in Japan. RESULTS: Of 975 patients included, 76.4% were men; 71.6% were aged 70 years or older. Most cases (70.5%) were of the bladder. Between 2015 and 2019, the annual age-adjusted incidence increased from 6.8 to 12.4 per 100 000; the annual age-adjusted period prevalence increased from 13.0 to 25.2 per 100 000; and 307 (31.5%) and 668 (68.5%) patients were diagnosed from 2015 to 2017 and 2018 to 2019, respectively. Overall, 731 (75%) patients received systemic anticancer therapy; all received 1 line and 50.2% received 2 lines of therapy; 78.3% of patients received gemcitabine plus platinum-based therapy and 2.2% received pembrolizumab as first-line treatment. First-line treatment rates increased from 69.4% to 77.5% after pembrolizumab approval. Of 367 patients who received second-line treatment, 22.3% received gemcitabine plus platinum-based therapy; 14.7% received pembrolizumab. CONCLUSIONS: In the Japanese regions considered, incidence and prevalence of newly diagnosed la/mUC increased over time and first-line treatment with pembrolizumab increased after approval.

Effect of rice bran extract on in vitro rumen fermentation and methane production.

This study was done to investigate which components of rice bran (RB) are involved in the inhibition of methanogenesis by fractionating the rice bran and adding it to a rumen in vitro culture system. The RB extract obtained using ethanol and water was screened in an in vitro fermentation system. The experimental treatment conditions were as follows: a control group containing a substrate without supplements; substrates with 0.06 g of RB; 0.6 mL of ethanol; 0.6 mL of distilled water (DW); 0.6 mL of ethanol-soluble fraction (ESF); 0.06 g of ethanol-insoluble rice bran (EIRB); 0.6 mL of water-soluble fraction (WSF); and 0.06 g of water-insoluble rice bran (WIRB). Based on the result of the analysis, the addition of ESF significantly decreased CH4 and CH4 /g dry matter digested, methanogen population (p < 0.05), while gas and dry matter digestibility (DMD) were comparable with the control group. Total short-chain fatty acid (SCFA), and proportion of propionate were reduced, and the proportion of butyrate was increased by the addition of ethanol and ESF (p < 0.05). This result suggests that the supplementation of 10% ESF can substantially reduce methane production in vitro without a negative effect on substrate digestibility.

Valgus instability and related factors beyond 2 years following unlinked total elbow arthroplasty.

HYPOTHESIS AND BACKGROUND: Total elbow arthroplasty (TEA), categorized into linked and unlinked types, is a commonly reported treatment for rheumatoid arthritis of the elbow. Although unlinked TEA preserves bone, it may result in instability. This study aimed to assess the outcomes of unlinked TEA in rheumatoid arthritis of the elbow beyond 2 years and to identify factors correlating with postoperative valgus instability of unlinked TEA. METHODS: This study included patients who underwent TEA for rheumatoid arthritis of the elbow at our department between August 2009 and January 2017, with a follow-up period exceeding 2 years. Elbow joint range of motion (ROM) and clinical scores were evaluated preoperatively and at the final follow-up. Factors contributing to valgus instability, such as the Larsen grade, sex, age, side, preoperative ROM, postoperative ROM, implant placement, preoperative carrying angle, and the use of biological disease-modifying antirheumatic drugs (bDMARDs), were also assessed. RESULTS: This study encompassed 26 elbows from 23 patients, with a mean patient age at surgery of 64.8 years and a mean follow-up duration of 92.4 months. Significant improvements were observed in the ROM (extension: from -31° preoperatively to -21° postoperatively [P = .02], flexion: from 116° to137° [P < .001]), Japanese Orthopaedic Association-Japan Elbow Society Elbow Function Score (from 45.9 to 86.3 points [P < .001]), and Mayo Elbow Performance Score (from 43.6 to 91.7 points [P < .001]). At the last follow-up, 2 elbows exhibited radiolucent lines around the humeral stem, whereas 7 had valgus instability. Factors correlated with valgus instability included total arc at the final follow-up, preoperative carrying angle, and the use of bDMARDs. DISCUSSION AND CONCLUSION: Unlinked TEA demonstrated favorable midterm outcomes for rheumatoid arthritis of the elbow, albeit with occasional valgus instability. Surgeons should consider preoperative carrying angle and bDMARD use, and exercise caution regarding intraoperative extensions.

Skin mesenchymal niches maintain and protect AML-initiating stem cells.

Leukemia cutis or leukemic cell infiltration in skin is one of the common extramedullary manifestations of acute myeloid leukemia (AML) and signifies a poorer prognosis. However, its pathogenesis and maintenance remain understudied. Here, we report massive AML cell infiltration in the skin in a transplantation-induced MLL-AF9 AML mouse model. These AML cells could regenerate AML after transplantation. Prospective niche characterization revealed that skin harbored mesenchymal progenitor cells (MPCs) with a similar phenotype as BM mesenchymal stem cells. These skin MPCs protected AML-initiating stem cells (LSCs) from chemotherapy in vitro partially via mitochondrial transfer. Furthermore, Lama4 deletion in skin MPCs promoted AML LSC proliferation and chemoresistance. Importantly, more chemoresistant AML LSCs appeared to be retained in Lama4-/- mouse skin after cytarabine treatment. Our study reveals the characteristics and previously unrecognized roles of skin mesenchymal niches in maintaining and protecting AML LSCs during chemotherapy, meriting future exploration of their impact on AML relapse.

Consideration of serum IL-36α and ß levels trends in two patients with chikungunya fever.

Key Clinical Message: IL-36 might play a role as an initial immune mechanism against chikungunya fever, and regulating IL-36 production could be a potential treatment approach for this condition. Abstract: Two Japanese siblings visited Cook Islands in 2015 and developed Chikungunya fever upon their return. The sister experienced high fever, joint pain, and leg swelling, while the brother had joint pain and a rash. Both siblings had a confirmed CHIKV infection and continued to experience prolonged joint pain, with the sister enduring chronic pain for about a year. In this study, the levels of IL-36 in the serum of two siblings who were infected with chikungunya fever during the acute and recovery phases were compared using ELISA. IL-36 is a cytokine that induces inflammation and is produced by cells in tissues such as the skin and mucosa. It was hypothesized that IL-36 may be involved in persistent joint pain after chikungunya fever infection. Both siblings experienced long-lasting joint pain after chikungunya fever infection. The levels of IL-36α and IL-36ß decreased by 56 days after infection. In the results, IL-36 plays an important role in host immunity and may act as part of the immune response during chikungunya virus infection. Inhibiting the release of IL-36 could be a promising approach for developing new treatment methods for chikungunya fever.

Psoriasis-like skin rash triggered by a local infection in a patient with eosinophilic granulomatosis with polyangiitis that was well controlled by mepolizumab treatment.

Key Clinical message: A patient with eosinophilic granulomatosis with polyangiitis, who was well-controlled by pharmacotherapy, developed a psoriasis-like rash due to a local infection. It represents the consequence of an immunologic imbalance. Abstract: A 48-year-old woman was diagnosed with eosinophilic granulomatosis with polyangiitis and treated with mepolizumab. While on treatment, she developed a psoriasis-like rash on her lower legs following a local ear infection. The rash promptly disappeared after the ear infection cleared and did not recur. The psoriasis-like rash that appeared was pathologically similar to psoriasis. Excessive production of inflammatory cytokines by the immune system is believed to be involved in the pathogenesis of psoriasis vulgaris. These cytokines are known to induce inflammatory responses and promote epidermal cell proliferation. It is possible that mepolizumab treatment suppressed Th2-type cytokines, while the local ear infection temporarily induced a strong Th1-type immunity. This immunologic imbalance may have led to the development of a psoriasis-like rash.

A case of pyoderma gangrenosum around the urethral meatus aggravated by COVID-19 infection and further worsened due to the development of pyogenic osteomyelitis 8 years after urostomy.

After the infection with COVID-19, pyoderma gangrenosum worsened and further led to necrosis following pyogenic osteomyelitis. Infection is a major exacerbating factor in pyoderma gangrenosum.

Molecular Mechanisms of Exercise-induced Hippocampal Neurogenesis and Antidepressant Effects.

It is estimated that approximately 280 million people worldwide suffer from depression. Depression is a common disease to us all, and the socioeconomic loss caused by depression is very large. However, there is currently a problem that many depressed patients do not respond to existing antidepressants, including selective serotonin reuptake inhibitors (SSRIs). Therefore, novel and effective therapeutic agents are highly desirable. It has been reported that exercise has preventive effects on depression (antidepressant effects) and that serotonin, whose release increases in the brain with exercise, is involved in exercise-induced antidepressant effects. We focused on the action of serotonin and investigated its role in the antidepressant effect of exercise using gene knockout mice, and then, we found that serotonin type 3 (5-HT3) receptors play an essential role in the antidepressant effect of exercise. We then further investigated the antidepressant effects mediated by 5-HT3 receptors. Our detailed analyses revealed that neurons expressing 5-HT3 receptors are abundant in the subgranular zone of the hippocampal dentate gyrus and produce insulin-like growth factor-1 (IGF-1). In addition, we newly found that the stimulation of 5-HT3 receptors by agonists promotes IGF-1 release in the hippocampus and increases hippocampal neurogenesis via the IGF-1 signaling pathway, resulting in antidepressant effects. Furthermore, we further showed that a 5-HT3 receptor agonist increases hippocampal neurogenesis and exhibits antidepressant effects in mice with depressive-like behavior. A comparison with the effects of existing antidepressant SSRIs revealed that the 5-HT3 receptor-mediated antidepressant action is a new therapeutic mechanism that differs from existing drugs. Our findings suggest a novel 5-HT3 receptor-IGF-1 mechanism, which could lead to the development of new antidepressant drugs for depression based on the molecular mechanism of exercise-induced antidepressant effects and could bring significant benefits to many depressed patients who do not respond to existing drugs such as SSRIs.

Modification of dietary rumen degradable starch content by chemical processing of feed ingredients: A meta-analysis.

The efficiency of starch utilization in ruminant feed can be enhanced by reducing the degradation of starch in the rumen. Chemical processing of feed ingredients may modify such ruminal starch degradation. This study aimed to evaluate the chemical processing of ruminant feed ingredients on rumen degradable starch (RDS) and starch degradation kinetics in the rumen. A database was constructed from a total of 34 articles, consisted of 100 observations. The articles were searched and identified from the Scopus platform. Data were analyzed by using the fixed effect model. The types of chemical processing in this study included sodium hydroxide, ammonia, potassium aluminum, urea, formaldehyde, and organic acid. Results indicated that chemical processing significantly reduced the RDS content (p < 0.001) and the immediately soluble fraction (p < 0.001) and increased the value of slowly degradable fraction (p < 0.001) and starch absorption in the small intestine (p < 0.01). Formaldehyde was particularly effective to decrease the RDS (p < 0.05). The RDS contents in corn and wheat were reduced by the chemical processing (p < 0.05), but not with that of barley. It can be concluded that chemical processing is effective in reducing starch degradation of ruminant feeds and may enhance its utilization by ruminants.

Characterization of the bone marrow niche in patients with chronic myeloid leukemia identifies CXCL14 as a new therapeutic option.

Although tyrosine kinase inhibitors (TKIs) are effective in treating chronic myeloid leukemia (CML), they often fail to eradicate the leukemia-initiating stem cells (LSCs), causing disease persistence and relapse. Evidence indicates that LSC persistence may be because of bone marrow (BM) niche protection; however, little is known about the underlying mechanisms. Herein, we molecularly and functionally characterize BM niches in patients with CML at diagnosis and reveal the altered niche composition and function in these patients. Long-term culture initiating cell assay showed that the mesenchymal stem cells from patients with CML displayed an enhanced supporting capacity for normal and CML BM CD34+CD38- cells. Molecularly, RNA sequencing detected dysregulated cytokine and growth factor expression in the BM cellular niches of patients with CML. Among them, CXCL14 was lost in the BM cellular niches in contrast to its expression in healthy BM. Restoring CXCL14 significantly inhibited CML LSC maintenance and enhanced their response to imatinib in vitro, and CML engraftment in vivo in NSG-SGM3 mice. Importantly, CXCL14 treatment dramatically inhibited CML engraftment in patient-derived xenografted NSG-SGM3 mice, even to a greater degree than imatinib, and this inhibition persisted in patients with suboptimal TKI response. Mechanistically, CXCL14 upregulated inflammatory cytokine signaling but downregulated mTOR signaling and oxidative phosphorylation in CML LSCs. Together, we have discovered a suppressive role of CXCL14 in CML LSC growth. CXCL14 might offer a treatment option targeting CML LSCs.

Perivascular localized cells commit erythropoiesis in PDGF-B-expressing solid tumors.

BACKGROUND: Tumors possess incessant growth features, and expansion of their masses demands sufficient oxygen supply by red blood cells (RBCs). In adult mammals, the bone marrow (BM) is the main organ regulating hematopoiesis with dedicated manners. Other than BM, extramedullary hematopoiesis is discovered in various pathophysiological settings. However, whether tumors can contribute to hematopoiesis is completely unknown. Accumulating evidence shows that, in the tumor microenvironment (TME), perivascular localized cells retain progenitor cell properties and can differentiate into other cells. Here, we sought to better understand whether and how perivascular localized pericytes in tumors manipulate hematopoiesis. METHODS: To test if vascular cells can differentiate into RBCs, genome-wide expression profiling was performed using mouse-derived pericytes. Genetic tracing of perivascular localized cells employing NG2-CreERT2:R26R-tdTomato mouse strain was used to validate the findings in vivo. Fluorescence-activated cell sorting (FACS), single-cell sequencing, and colony formation assays were applied for biological studies. The production of erythroid differentiation-specific cytokine, erythropoietin (EPO), in TME was checked using quantitative polymerase chain reaction (qPCR), enzyme-linked immunosorbent assay (ELISA, magnetic-activated cell sorting and immunohistochemistry. To investigate BM function in tumor erythropoiesis, BM transplantation mouse models were employed. RESULTS: Genome-wide expression profiling showed that in response to platelet-derived growth factor subunit B (PDGF-B), neural/glial antigen 2 (NG2)+ perivascular localized cells exhibited hematopoietic stem and progenitor-like features and underwent differentiation towards the erythroid lineage. PDGF-B simultaneously targeted cancer-associated fibroblasts to produce high levels of EPO, a crucial hormone that necessitates erythropoiesis. FACS analysis using genetic tracing of NG2+ cells in tumors defined the perivascular localized cell-derived subpopulation of hematopoietic cells. Single-cell sequencing and colony formation assays validated the fact that, upon PDGF-B stimulation, NG2+ cells isolated from tumors acted as erythroblast progenitor cells, which were distinctive from the canonical BM hematopoietic stem cells. CONCLUSIONS: Our data provide a new concept of hematopoiesis within tumor tissues and novel mechanistic insights into perivascular localized cell-derived erythroid cells within TME. Targeting tumor hematopoiesis is a novel therapeutic concept for treating various cancers that may have profound impacts on cancer therapy.

Diagnostic Utility of TUNEL Staining for Degenerative Keratoacanthoma Requiring Pathologic Differentiation from Seborrheic Keratosis.

Tumors developed in 2 old women presented with pathological findings similar to seborrheic keratosis, although the clinical feature of tumor showed typical keratoacanthoma. In addition to these two cases, we compared the pathological findings of a total of four cases, one case each of keratoacanthoma and seborrheic keratosis, which were clinically and histopathological typical. These two cases and the typical keratoacanthoma showed cell apoptosis by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining and infiltration of cytotoxic T cells. The keratoacanthoma in the decompensated stage may be histologically similar to seborrheic keratosis. TUNEL staining can help in the diagnosis of fading keratoacanthoma.