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Abstract Tissue factor (TF) is a cell surface protein that plays a role in blood clotting but is also commonly expressed in many cancers. Recent research implicated TF in cancer proliferation, metastasis, angiogenesis, and immune escape. Therefore, TF can be considered a viable therapeutic target against cancer. Herein, we developed and tested a TF-targeted near-infrared photoimmunotherapy (NIR-PIT) as a potential treatment for several types of cancer. Tisotumab, a TF antibody, was conjugated to IR700. The efficacy of TF-targeted NIR-PIT was investigated using multiple cancer cell lines (A431; epidermoid carcinoma, HPAF-II; pancreatic adenocarcinoma, HSC-2; oral carcinoma, HT1376-luc; bladder carcinoma, MDAMB231; breast adenocarcinoma, and SKOV3-luc; ovarian serous cystadenocarcinoma) in vitro. In vivo, the efficacy of TF-targeted NIR-PIT was evaluated in HPAF-II and A431 xenograft mouse models. Pathologic changes in these tumors after NIR-PIT were evaluated in these tumor models. All cancer lines demonstrated TF expression in vitro and in vivo. Additionally, TF expression was documented to localize to cancer cells in tumors. In vitro, TF-targeted NIR-PIT caused cell death in a light dose-dependent manner. In vivo, TF-targeted NIR-PIT suppressed tumor growth and improved survival rates compared to controls. Furthermore, in vivo NIR-PIT showed histological signs of cancer cell damage, such as cytoplasmic vacuolation, nuclear dysmorphism, and extracellular leakage of LDHA consistent with cell death. In conclusion, TF-targeted NIR-PIT holds promise as a treatment for multiple cancer models expressing TF, spanning multiple cancer types.

Familial Mediterranean Fever (FMF) is the most common hereditary autoinflammatory disease, characterized by recurrent fever, arthritis, rash, and serositis, and is caused by mutations in the MEFV gene coding for the pyrin protein. The primary treatment goal is to prevent acute attacks and minimize subclinical inflammation to avoid secondary amyloidosis with colchicine as the first-line treatment. However, 10-20% of patients are colchicine-resistant or intolerant. While the therapeutic potential of IL-6 inhibitors such as tocilizumab (TCZ) has been suggested, the detailed serum cytokine profiles after TCZ treatment in patients with FMF remain largely unexplored. This study focused on a sub-analysis of a clinical trial evaluating TCZ in patients with colchicine-resistant FMF (crFMF). We analyzed the serum cytokine profiles at 0, 2, 4, 8, 12, 16, 20, and 24 weeks in the TCZ and placebo groups. Our findings revealed a decrease in serum C-X-C motif chemokine ligand 1 and vascular endothelial growth factor levels in the TCZ group at week 4 compared to baseline, which persisted until week 24, indicating the potential of TCZ to manage crFMF by modulating specific inflammatory cytokines. Further research is required to confirm these findings and optimize the treatment strategies for FMF.

Regulatory T cells (Tregs) play a crucial role in mediating immunosuppression in the tumor microenvironment. Furthermore, Tregs contribute to the lack of efficacy and hyperprogressive disease upon Programmed cell death protein 1 (PD-1) blockade immunotherapy. Thus, Tregs are considered a promising therapeutic target, especially when combined with PD-1 blockade. However, systemic depletion of Tregs causes severe autoimmune adverse events, which poses a serious challenge to Treg-directed therapy. Here, we developed a novel treatment to locally and predominantly damage Tregs by near-infrared duocarmycin photorelease (NIR-DPR). In this technology, we prepared anti-CD25 F(ab’)2 conjugates, which site-specifically uncage duocarmycin in CD25-expressing cells upon exposure to NIR light. In vitro, CD25-targeted NIR-DPR significantly increased apoptosis of CD25-expressing HT2-A5E cells. When tumors were irradiated with NIR light in vivo, intratumoral CD25+ Treg populations decreased and Ki-67 and Interleukin-10 expression was suppressed, indicating impaired functioning of intratumoral CD25+ Tregs. CD25-targeted NIR-DPR suppressed tumor growth and improved survival in syngeneic murine tumor models. Of note, CD25-targeted NIR-DPR synergistically enhanced the efficacy of PD-1 blockade, especially in tumors with higher CD8+/Treg PD-1 ratios. Furthermore, the combination therapy induced significant anti-cancer immunity including maturation of dendritic cells, extensive intratumoral infiltration of cytotoxic CD8+ T cells, and increased differentiation into CD8+ memory T cells. Altogether, CD25-targeted NIR-DPR locally and predominantly targets Tregs in the tumor microenvironment and synergistically improves the efficacy of PD-1 blockade, suggesting that this combination therapy can be a rational anti-cancer combination immunotherapy.

In swash plate type axial piston pumps, slipper/swash plate sliding surfaces is subject to high fluctuating load. Therefore, the slippers are required to provide stable operation and reduce losses due to sliding. The behavior of the slipper fluctuates in a complex manner due to changes in the hydraulic pressure in the cylinder and inertial forces caused by the reciprocating motion of the piston. However, the time variation of the oil film thickness distribution of the slipper has not been measured. Furthermore, there are no measurements of the movement of the spherical joint connecting the slipper and piston, which affects the slipper behavior. In this study, the visualized sliding test rig with a sapphire glass swash plate was developed. The oil film thickness distribution of the slipper and the rotation of the slipper and the piston were measured continuously during one rotation of the pump.

To develop a method for predicting chronic toxicity of pharmaceuticals in Daphnia, we investigated the feasibility of combining the presence of drug-target orthologs in Daphnia magna, classification based on pharmacological effects, and ecotoxicity quantitative structure-activity relationship (QSAR) prediction. We established datasets on the chronic toxicity of pharmaceuticals in Daphnia, including information on therapeutic categories, target proteins, and the presence or absence of drug-target orthologs in D. magna, using literature and databases. Chronic toxicity was predicted using ecotoxicity prediction QSAR (Ecological Structure Activity Relationship and Kashinhou Tool for Ecotoxicity), and the differences between the predicted and measured values and the presence or absence of drug-target orthologs were examined. For pharmaceuticals without drug-target orthologs in D. magna or without expected specific actions, the ecotoxicity prediction QSAR analysis yielded acceptable predictions of the chronic toxicity of pharmaceuticals. In addition, a workflow model to assess the chronic toxicity of pharmaceuticals in Daphnia was proposed based on these evaluations and verified using an additional dataset. The addition of biological aspects such as drug-target orthologs and pharmacological effects would support the use of QSARs for predicting the chronic toxicity of pharmaceuticals in Daphnia.

Abstract Introduction Chemoimmunotherapy is widely used as the first‐line management of advanced non‐small cell lung cancer (NSCLC) in clinical settings. However, predictive factors associated with the development of immune‐related adverse events (irAEs) and prognostic factors for NSCLC patients undergoing chemoimmunotherapy remains largely unexplored. Therefore, in this study, we aimed to evaluate predictive factors for irAE development and prognostic factors associated with chemoimmunotherapy in NSCLC patients. Methods This study enrolled 199 patients with advanced and recurrent NSCLC who underwent chemoimmunotherapy across eight institutions in Nagano prefecture from December 2018 to January 2023. We examined predictive factors associated with irAE development and prognostic factors associated with overall survival (OS). Results Among the patients, 106 experienced irAEs, while 93 patients did not. A total of 44 (22.1%) patients developed multiple irAEs. High serum albumin levels (Alb >3.5 g/dL) emerged as an independent predictive factor associated with irAE development in logistic regression analysis (odds ratio; 2.35, 95% confidence interval 1.27–4.34, p = 0.007). Furthermore, the development of multiple irAEs (p = 0.016), lower lactate dehydrogenase level (

Introduction Reducing neonatal deaths in premature infants in low- and middle-income countries is key to reducing global neonatal mortality. International neonatal networks, along with patient registries of premature infants, have contributed to improving the quality of neonatal care; however, the involvement of low-to-middle-income countries was limited. This project aims to form an international collaboration among neonatal networks in Asia (AsianNeo), including low-, middle- and high-income countries (or regions). Specifically, it aims to determine outcomes in sick newborn infants, especially very low birth weight (VLBW) infants or very preterm infants, with a view to improving the quality of care for such infants.Methods and analysis Currently, AsianNeo comprises nine neonatal networks from Indonesia, Japan, Malaysia, Philippines, Singapore, South Korea, Sri Lanka, Taiwan and Thailand. AsianNeo will undertake the following four studies: (1) institutional questionnaire surveys investigating neonatal intensive care unit resources and the clinical management of sick newborn infants, with a focus on VLBW infants (nine countries/regions); (2) a retrospective cohort study to describe and compare the outcomes of VLBW infants among Asian countries and regions (four countries/regions); (3) a prospective cohort study to develop the AsianNeo registry of VLBW infants (six countries/regions); and (4) implementation and evaluation of educational and quality improvement projects in AsianNeo countries and regions (nine countries/regions).Ethics and dissemination The study protocol was approved by the Research Ethics Board of the National Center for Child Health and Development, Tokyo, Japan (reference number 2020–244, 2022–156). The study findings will be disseminated through educational programmes, quality improvement activities, conference presentations and medical journal publications.

This article describes an innovative methodology to calibrate EM simulators, oriented to monolithic microwave integrated circuit design, in order to achieve the highest level of accuracy achievable in electromagnetic simulation. In particular, a two-stage measurement technique based on two types of network analyzer calibrations is adopted as a practical and accurate process for on-wafer S-parameter measurements of suitable test structures on semiconductor epitaxial wafers. Thus, a substrate parameter set for the electromagnetic simulator is appropriately identified by an optimization process that combines measurements of dedicated simple test structures and the corresponding models in the circuit simulator. The proposed approach allows one to accurately estimate the substrate characteristics without realizing expensive on-wafer structures that require a large substrate area. We will demonstrate, through several comparisons between measurements and electromagnetic simulations of different passive structures, how higher accuracy can be achieved, describing and quantifying the limitations that arise from commonly adopted calibration procedures for electromagnetic simulators.

Summary: Background: Noninvasive in vivo cell tracking is valuable in understanding the mechanisms that enhance anti-cancer immunity. We have recently developed a new method called phototruncation-assisted cell tracking (PACT), that uses photoconvertible cell tracking technology to detect in vivo cell migration. This method has the advantages of not requiring genetic engineering of cells and employing tissue-penetrant near-infrared light. Methods: We applied PACT to monitor the migration of immune cells between a tumour and its tumour-draining lymph node (TDLN) after near-infrared photoimmunotherapy (NIR-PIT). Findings: PACT showed a significant increase in the migration of dendritic cells (DCs) and macrophages from the tumour to the TDLN immediately after NIR-PIT. This migration by NIR-PIT was abrogated by inhibiting the sphingosine-1-phosphate pathway or Gαi signaling. These results were corroborated by intranodal immune cell profiles at two days post-treatment; NIR-PIT significantly induced DC maturation and increased and activated the CD8+ T cell population in the TDLN. Furthermore, PACT revealed that NIR-PIT significantly enhanced the migration of CD8+ T cells from the TDLN to the tumour four days post-treatment, which was consistent with the immunohistochemical assessment of tumour-infiltrating lymphocytes and tumour regression. Interpretation: Immune cells dramatically migrated between the tumour and TDLN following NIR-PIT, indicating its potential as an immune-stimulating therapy. Also, PACT is potentially applicable to a wide range of immunological research. Funding: This work was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Centre for Cancer Research (grant number: ZIA BC011513 and ZIA BC011506).

Abstract Environmental RNA (eRNA) has the potential as a non‐invasive tool for assessing the physiological status of macro‐organisms, yet the quantitative method for relative gene expression analysis is still underexplored. To bridge this gap, this study introduces a relative quantification method for eRNA, employing quantitative PCR (qPCR) to evaluate the expression of the antioxidant gene, catalase (cat), in the Japanese medaka Oryzias latipes exposed to two toxic chemicals for 96 h: chlorpyrifos (CPS) and carbamazepine. Our results showed that, in eRNA, genes frequently used as a reference for tissue or cells in conventional expression analysis correlated with each other. Also, one of them (elfa) exhibited less variability, showing its potential suitability as a reference gene in eRNA analyses. Additionally, cat expression levels in eRNA increased with increasing CPS concentrations, in a concentration‐response manner. These results suggest the promising potential of qPCR applications for eRNA in the monitoring of an organism's health and response to environmental changes. However, we observed disparities in gene expression levels of cat and beta‐actin (actb) between eRNA and whole fish body, indicating eRNA might have a biased origin. Further research is needed to uncover the origin of eRNA and determine the limitations and applicability domain of eRNA analysis.

Water flea Ceriodaphnia dubia has been widely used for risk assessments of chemicals and environmental contamination. In this study, the complete mitochondrial genome (mitogenome) of this species NIES strain was determined using short-read high throughput and long-read sequencing technologies. The mitogenome of C. dubia was 15,170 bp in length and consisted of 13 protein-coding genes (PCGs), 2 ribosomal RNAs (rRNAs), and 22 transfer RNAs (tRNAs). The gene order was identical to the pattern conserved across crustaceans. The complete mitogenome of the NIES strain will serve as genetical reference in ecological risk assessments in Japan, as well as resources for future phylogenetical studies using cladocerans.

Nephroblastomatosis (NBM) is a precursor of Wilms tumor. We herein report a case in which Wilms tumor was initially suspected and the affected kidney was removed. The tumor was subsequently diagnosed as intralobar NBM and a favorable outcome was achieved with postoperative chemotherapy. A 2-year-old boy who presented with gross hematuria was found to have an enlarged left kidney with hydronephrosis. Needle biopsy of the left kidney suggested Wilms tumor and left nephrectomy was performed. The tumor was histopathologically diagnosed as intralobar NBM. Although NBM is regarded as a precancerous lesion, a definite treatment plan has not yet been established. In the present case, we used a similar chemotherapy regimen to that for Wilms tumor. Eight years after the completion of chemotherapy, Wilms tumor has not developed or recurred. Appropriate management plans need to be developed by accumulating similar cases.

Abstract Background Administration of Janus kinase (JAK) inhibitors and biological disease-modifying antirheumatic drugs has dramatically improved even the clinical outcomes in patients with rheumatoid arthritis (RA) and an inadequate response to methotrexate (MTX). Dysregulation of JAK-STAT pathways via overproduction of cytokines, such as interleukin-6, is involved in the pathogenesis of RA. Filgotinib is a selective JAK1 inhibitor pending approval for use in RA. By inhibition of the JAK-STAT pathway, filgotinib is effective in suppressing disease activity and preventing the progression of joint destruction. Similarly, interleukin-6 inhibitors such as tocilizumab also inhibit the JAK-STAT pathways by inhibition of interleukin-6 signaling. We present the protocol for a study that will evaluate whether the effectiveness of filgotinib monotherapy is non-inferior to that of tocilizumab monotherapy in RA patients with an inadequate response to MTX. Methods This study is an interventional, multicenter, randomized, open-label, parallel-group, and non-inferiority clinical trial with a 52-week follow-up. Study participants will be 400 RA patients with at least moderate disease activity during treatment with MTX. Participants will be randomized in a 1:1 ratio to administer filgotinib monotherapy or subcutaneous tocilizumab monotherapy switched from MTX. We will evaluate disease activity by measuring clinical disease activity indices and by using musculoskeletal ultrasound (MSUS). The primary endpoint is the proportion of patients who achieve an American College of Rheumatology 50 response at week 12. Secondary endpoints are changes from baseline in the MSUS scores. We will also comprehensively analyze serum levels of multiple biomarkers, such as cytokines and chemokines. Discussion The study results are expected to show the non-inferiority of the effectiveness of filgotinib monotherapy to that of tocilizumab monotherapy in RA patients with inadequate response to MTX. The strength of this study is its prospective evaluation of therapeutic efficacy using not only clinical disease activity indices, but also MSUS, which accurately and objectively evaluates disease activity at the joint level among patients drawn from multiple centers with a standardized evaluation by MSUS. We will evaluate the effectiveness of both drugs by integrating multilateral assessments—clinical disease activity indices, MSUS findings, and serum biomarkers. Trial registration Japan Registry of Clinical Trials ( https://jrct.niph.go.jp ) jRCTs071200107. Registered on March 3, 2021. ClinicalTrials.gov NCT05090410. Registered on October 22, 2021.

Intimal sarcoma is an extremely rare mesenchymal tumor arising in the great vessels. To date, intimal sarcoma has not been reported in patients with Lynch syndrome (LS), even though this syndrome lacks DNA mismatch repair ability genetically and is prone to various malignancies. This patient was diagnosed with LS by the Revised Amsterdam Criteria II, and she suffered from intimal sarcoma in the left pulmonary artery. She had a germline missense variant of PMS2 (c.1399G>A, pV467I) which is classified as a variant of unknown significance. In her intimal sarcoma, PMS2 expression was decreased. Additionally, it exhibited microsatellite instability and a high tumor mutational burden (69 mutations/Mb) which are features of mismatch repair deficiency, although PMS2 (c.1399G>A, pV467I) missense is a variant of unknown significance. The metastatic lesions of intimal sarcoma in this patient responded heterogeneously to pembrolizumab, an immune checkpoint inhibitor. Cytotoxic agents and radiation were also effective for some metastatic lesions, but some lesions, including her liver metastases, were resistant. The hypermutable nature of the LS genotype might acquire resistance to an immune checkpoint inhibitor and other cytotoxic agents such as occurred with her liver metastases.

Application of segment-structured tetrahedral amorphous carbon (ta-C) film on soft metal substrate is proposed to improve wear resistance of mechanical parts. It was generally considered that continuous structure ta-C film was effective when applied to hard materials because it could not follow deformation of substrate material and the film tended to delaminate. In contrast, by applying segment structure on ta-C film, tribological properties of ta-C film coated on soft substrate were further improved, and sliding surface exhibited excellent wear resistance even under high sliding loads. Effectiveness of the use of brass substrate in improving wear resistance was demonstrated through large-scale wear resistant test of valve-plate used in oil pump of construction machine. Segment-structured ta-C coated brass valve-plate reduced maximum wear by approximately 80 % as compared with uncoated brass plate.

TAFRO syndrome is a rare systemic inflammatory disorder with a fatal course. Nevertheless, a definitive treatment strategy has not yet been established. Anti-inflammatory therapies, including glucocorticoid treatment and immunosuppressants, have not been satisfactory. Therefore, new treatment options are needed for patients with TAFRO syndrome. The effectiveness of therapeutic plasma exchange (TPE) has mainly been reported in several case reports. In this case series study, we investigated the effect of TPE on TAFRO syndrome. We reviewed six consecutive cases with TAFRO syndrome treated at Shinshu University Hospital. All of them underwent TPE. A significant improvement in mean blood pressure, albumin, total bilirubin, and C-reactive protein was observed after TPE. Furthermore, early TPE treatment was suggested to have an impact on the prognosis. More intensive studies are needed to emphasize the overall conclusion obtained that TPE can be an effective/acceptable treatment option for TAFRO syndrome.

In this study, slipper/swash plate sliding test rigs were developed to measure oil film thickness distribution. For this purpose, fluorescence measurement was performed with a sapphire glass swash plate and a light emitting diode as the light source. The oil film thickness distribution was measured under various conditions by varying the rotation speed and the oil pressure supplied to the cylinder. The shape of the swash plate matched the oil film thickness distribution measured via the fluorescent method, thereby confirming the validity of the measurements. Furthermore, the maximum tilt azimuth angle of the slipper turned outward as the rotational speed increased.

In this study, we develop a vibration isolation system using an air suspension with a variable length slit restriction, clarify its dynamic characteristics and build a system that automatically adjusts an equivalent damping coefficient and an equilibrium position of a supported object. The proposed air suspension can provide an optimum damping coefficient by a damping adjustment mechanism. The optimum damping coefficient, which provides the minimum resonance amplitude, increases as mass of the supported object increases. The damping coefficient can be varied by varying slit length of the restriction. In order to vary slit length, the damping adjustment mechanism consists of a fixed plate, which has a partially circular groove and a rotating flat plate faced to the grooved plate. The variable length partially circular slit is formed by the two plates. The damping coefficient is almost proportional to an adjustment angle of the rotating flat plate in the adjustment mechanism. An optimum adjustment angle which provides the minimum resonance amplitude can be obtained by equation showing a relationship between the supported mass and the optimum adjustment angle. The proposed system consists of the air suspension, two pressure sensors measuring atmospheric pressure and static pressure in the cylinder and the reservoir tank, the damping adjustment mechanism, a servo motor rotating the flat plate to tune the adjustment angle and a micro-computer. The micro-computer calculates the optimum adjustment angle which is obtained from the measured pressure data and controls the servo motor to adjust the damping coefficient. The equivalent damping coefficient of the proposed air suspension does not depend on the amplitude even if the slit length is changed by the damping adjustment mechanism. Even if the mass increases up to three times of the nominal value, the minimum resonance amplitude is achieved by using the damping adjustment mechanism.

ABSTRACT Nelfinavir, an orally administered inhibitor of human immunodeficiency virus protease, inhibits the replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in vitro. We conducted a randomized controlled trial to evaluate the clinical efficacy and safety of nelfinavir in patients with SARS-CoV-2 infection. We included unvaccinated asymptomatic or mildly symptomatic adult patients who tested positive for SARS-CoV-2 infection within 3 days before enrollment. The patients were randomly assigned (1:1) to receive oral nelfinavir (750 mg; thrice daily for 14 days) combined with standard-of-care or standard-of-care alone. The primary endpoint was the time to viral clearance, confirmed using quantitative reverse-transcription PCR by assessors blinded to the assigned treatment. A total of 123 patients (63 in the nelfinavir group and 60 in the control group) were included. The median time to viral clearance was 8.0 (95% confidence interval [CI], 7.0 to 12.0) days in the nelfinavir group and 8.0 (95% CI, 7.0 to 10.0) days in the control group, with no significant difference between the treatment groups (hazard ratio, 0.815; 95% CI, 0.563 to 1.182; P = 0.1870). Adverse events were reported in 47 (74.6%) and 20 (33.3%) patients in the nelfinavir and control groups, respectively. The most common adverse event in the nelfinavir group was diarrhea (49.2%). Nelfinavir did not reduce the time to viral clearance in this setting. Our findings indicate that nelfinavir should not be recommended in asymptomatic or mildly symptomatic patients infected with SARS-CoV-2. The study is registered with the Japan Registry of Clinical Trials (jRCT2071200023). IMPORTANCE The anti-HIV drug nelfinavir suppresses the replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in vitro. However, its efficacy in patients with COVID-19 has not been studied. We conducted a multicenter, randomized controlled trial to evaluate the efficacy and safety of orally administered nelfinavir in patients with asymptomatic or mildly symptomatic COVID-19. Compared to standard-of-care alone, nelfinavir (750 mg, thrice daily) did not reduce the time to viral clearance, viral load, or the time to resolution of symptoms. More patients had adverse events in the nelfinavir group than in the control group (74.6% [47/63 patients] versus 33.3% [20/60 patients]). Our clinical study provides evidence that nelfinavir, despite its antiviral effects on SARS-CoV-2 in vitro, should not be recommended for the treatment of patients with COVID-19 having no or mild symptoms.

Abstract Immunoglobulin (Ig) G4-positive cells are rarely observed in the lungs of patients with idiopathic interstitial pneumonias (IIPs). IgG1 may be more pathogenic than IgG4, with IgG4 having both pathogenic and protective roles in IgG4-related disease (IgG4-RD). However, the role of both IgG1 and IgG4 in IIPs remains unclear. We hypothesized that patients with IgG4-positive interstitial pneumonia manifest different clinical characteristics than patients with IgG4-RD. Herein, we identified the correlation of the degree of infiltration of IgG1- and IgG4-positive cells with IIP prognosis, using a Japanese nationwide cloud-based database. We included eighty-eight patients diagnosed with IIPs after multidisciplinary discussion, from April 2009 to March 2014. IgG4-positive cell infiltration was identified in 12/88 patients with IIPs and 8/41 patients with idiopathic pulmonary fibrosis (IPF). Additionally, 31/88 patients with IIPs and 19/41 patients with IPF were diagnosed as having IgG1-positive cell infiltration. IgG4-positive IIPs tended to have a better prognosis. Conversely, overall survival in cases with IgG1-positive IPF was significantly worse. IIPs were prevalent with IgG1- or IgG4-positive cell infiltration. IgG1-positive cell infiltration in IPF significantly correlated with a worse prognosis. Overall, evaluating the degree of IgG1-positive cell infiltration may be prognostically useful in cases of IPF.

The black soldier larvae meal (BSFLM) has been the most extensively studied insect protein source in shrimp nutrition. However, both the availability and prices of BSFLM are still a constraint for its widespread use as an ingredient in animal feeds. The present study investigated the growth and economic performance of post-larval (PL) P. vannamei fed nursery diets with a progressive replacement of fish meal (FML) for BSFLM at 0, 25, 50, 75, and 100%. These replacements corresponded to a dietary inclusion (% of the diet, as-is) of FML and BSFLM of 16.50 and 6.33%, 11.00 and 13.04%, 5.50 and 19.74%, and 0 and 26.46%, respectively. A total of 102,647 shrimp at the age of PL15 with 2.7 ± 0.2 mg body weight (BW) were stocked in fifty 1.5 m3 tanks under 1369 PLs/m3 (2053 ± 33 PLs/tank) and reared for 42 days. Final shrimp survival (90.5 ± 7.6%), daily weight gain (14.7 ± 1.1 mg/day), and apparent feed intake (0.67 ± 0.03 g of feed per stocked shrimp) were unaffected by dietary treatment. The highest gained yield (791 ± 52 and 776 ± 38 g/m3) and final BW (621 ± 7.2 and 632 ± 7.2 mg) were attained when FML was replaced for BSFLM at 50 and 75% with the lowest at 0% (726 ± 34 g/m3 and 598 ± 8.1 mg, respectively). Shrimp fed diets with 0 and 100% replacement of FML exhibited the highest feed conversion ratio (1.25 ± 0.04 and 1.24 ± 0.08) compared to those fed a diet with 50% (1.16 ± 0.06). At a price of USD 2.00/kg, BSFLM demonstrated a favorable ROI (return of investment) when compared to FML, irrespective of the replacement level. With 25 and 50% replacement, BSFLM remained cost-competitive up to 3.50 USD/kg. At 75% FML replacement, there were no significant differences in ROI with a price range of 2.00 up to 3.04 USD/kg. At full replacement, ROI dropped significantly at a BSFLM price of 2.50 USD/kg and beyond. It can be concluded that FML can be fully replaced for BSFLM in well-balanced nursery diets for P. vannamei. Although the full replacement of FML for BSFLM was successfully accomplished, the competitive ROI was sustained only when the price of BSFLM did not exceed 3.04 USD/kg at its dietary highest inclusion of 19.74%. Further research may be necessary to fine-tune cost-effective inclusion levels of BSFLM to optimize the economic outcomes while considering the fluctuating prices of FML.

Introduction: Laparoscopic sleeve gastrectomy (LSG) for morbidly obese patients often result in remission of type 2 diabetes (T2DM), but diabetes relapses in some of those patients. The frequency of T2DM relapse in Asians and the factors involved have not been adequately investigated. Methods: The J-SMART study was conducted on 322 Japanese subjects with body mass index (BMI) ≥ 32 kg/m2 who underwent LSG at 10 accredited centers in Japan between 2011 and 2014. Of these, 82 T2DM subjects with diabetes in complete or partial remission at 1 year after LSG and followed postoperatively for 5 years were included in the subgroup analysis, and classified into two groups: diabetes remission maintained and diabetes relapse. Results: The mean age of all included subjects was 49.2 years, median BMI was 41.5 kg/m2, and median was HbA1c 6.7%. Compared with the diabetes remission maintained group, the diabetes relapse group at 5 years after LSG had significantly higher preoperative HbA1c, number of antidiabetic medications, and high-density lipoprotein cholesterol level; and lower BMI and homeostasis model assessment-beta cell function (HOMA-β). As many as 83.0% of the subjects were able to achieve HbA1c < 7% at 5 years after LSG, but 26.8% of the subjects had diabetes relapse. Preoperative HbA1c significantly contributed to diabetes relapse (odds ratio 1.54, p = 0.049). In addition, the diabetes relapse group tended to have lower percent total weight loss (%TWL) at 1 year after LSG and higher percent weight regain (%WR) from postoperative nadir weight, compared with the diabetes remission maintained group. The hazard ratio for diabetes relapse was 3.14-fold higher in subjects with %TWL ≥ 20% and %WR ≥ 25%, and 5.46-fold higher in those with %TWL < 20% and %WR ≥ 25%, compared with %TWL ≥ 20% and %WR < 25%. Conclusion: While LSG provides a high remission rate for T2DM, relapse is not uncommon. Preoperative HbA1c, poor weight loss and excess weight regain after LSG contribute to diabetes relapse, suggesting the importance of treatment strategies focusing on these factors.

It is suggested that activation of receptor for advanced glycation end products (RAGE) induces proinflammatory response in diabetic nerve tissues. Macrophage infiltration is invoked in the pathogenesis of diabetic polyneuropathy (DPN), while the association between macrophage and RAGE activation and the downstream effects of macrophages remain to be fully clarified in DPN. This study explored the role of RAGE in the pathogenesis of DPN through the modified macrophages. Infiltrating proinflammatory macrophages impaired insulin sensitivity, atrophied the neurons in dorsal root ganglion, and slowed retrograde axonal transport (RAT) in the sciatic nerve of type 1 diabetic mice. RAGE-null mice showed an increase in the population of antiinflammatory macrophages, accompanied by intact insulin sensitivity, normalized ganglion cells, and RAT. BM transplantation from RAGE-null mice to diabetic mice protected the peripheral nerve deficits, suggesting that RAGE is a major determinant for the polarity of macrophages in DPN. In vitro coculture analyses revealed proinflammatory macrophage–elicited insulin resistance in the primary neuronal cells isolated from dorsal root ganglia. Applying time-lapse recording disclosed a direct impact of proinflammatory macrophage and insulin resistance on the RAT deficits in primary neuronal cultures. These results provide a potentially novel insight into the development of RAGE-related DPN.

Pembrolizumab-induced adrenal insufficiency (AI) is recognized as a rare immune-related adverse event (irAE) that can be fatal if diagnosis is delayed. Clinical features of AI in patients with advanced non-small cell lung cancer (NSCLC) who received pembrolizumab as the first-line treatment were observed. Five out of 49 patients with untreated advanced NSCLC developed AI between April 2017 and February 2021. Of the 5 patients, 4 developed AI with a grade >3 and were hospitalized. The median time of the onset of AI from the start of first-line treatment was 4.63 months. All the patients improved after corticosteroid replacement therapy. The efficacy of treatment was complete response in 1 patient and partial response in 4 patients. Median progression-free survival was 37.7 months, and overall survival had not been reached. This case series revealed the efficacy of immunotherapy in AI as an irAE.

Abstract Background Degenerative aortic arch aneurysms are known to develop through a pathological process of arterial atherosclerosis, which could be accompanied by peripheral artery diseases and resultant development of intrapelvic collateral arteries to the ischemic lower limbs. The aim of this study was to investigate the relationship between peripheral collateral circulation and postoperative paraplegia after total arch repair with a frozen elephant trunk in patients with degenerative aortic arch aneurysms and peripheral artery diseases. Methods Between October 2014 and March 2020, 27 patients (20 men; 69.8 ± 7.7 years old) underwent total arch repair with a frozen elephant trunk. Two of the 27 patients developed paraplegia postoperatively. The patients were divided into two groups, spinal cord ischemia (SCI) group (2 patients) and no-SCI group (25 patients). The aortic shagginess score, arterial calcification (subclavian artery; hypogastric artery) score, and the number of hypogastric artery branches, assessed using preoperative contrast-enhanced computed tomography images, were compared between the two groups. Results The ankle brachial artery pressure index (i.e., lower side value each patient) was lower in the SCI group than that in the no-SCI group (0.64, 0.71, and 1.09±0.07, respectively). There was no difference between the two groups in the arterial calcification scores or the aortic shagginess score. The number of hypogastric artery branches was greater in the SCI group than in the no-SCI group (66, 66, and 30.7±7.5, respectively). Conclusions Enhanced collateral circulation to the ischemic lower limbs in patients with combination of degenerative aortic arch aneurysms and peripheral artery diseases may be involved in paraplegia the upper thoracic spinal cord injury after total arch repair with a frozen elephant trunk.

Abstract Background It is difficult to distinguish between multicentric Castleman’s disease (MCD) and IgG4-related lung disease (IgG4-LD), an IgG4-related disease (IgG4-RD) in the lung. Methods We focused on IL-6, which is elevated in MCD, to distinguish between MCD and IgG4-LD by RNAscope, a highly sensitive RNA in situ method. Six cases of MCD and four cases of IgG4-LD were selected. Results In all cases of MCD and IgG4-LD, 10 or more IgG4-positive cells were found in one high-power field. All MCD cases were inconsistent with the pathological IgG4-related comprehensive diagnostic criteria, but 2 of 6 cases had an IgG4/IgG ratio greater than 40%. In all IgG4-LD cases, histological features were consistent with the pathological IgG4-RD comprehensive diagnostic criteria. IL-6 expression was observed in all MCD and IgG4-LD cases except for one IgG4-LD biopsy. IL-6-expressing cells were mainly identified in the stroma. Sites of IL-6 expression were not characteristic and were sparse. IL-6 expression tended to be higher in MCD compared with IgG4-LD. A positive correlation was found between the IL-6 H-score and serum IL-6 level. Conclusion Differences in IL-6 expression may help distinguish between MCD and IgG4-LD. In addition, the presence of high IL-6 levels may help elucidate the pathological mechanisms of IgG4-LD.

Abstract Background Pseudoaneurysm of the mitral-aortic intervalvular fibrosa (P-MAIVF) is a rare complication of infective endocarditis and aortic valve replacement. Ruptured P-MAIVF and angina due to compression of the coronary arteries are severe complications of this condition. Case presentation We report a case of P-MAIVF that was diagnosed accidentally during a routine checkup. The patient was asymptomatic; however, she had a systolic murmur. She had a history of infective endocarditis, which was treated conservatively without open-heart surgery. In addition, she was diagnosed with aortic valve stenosis, aortic valve regurgitation, bicuspid aortic valve, right coronary artery stenosis, and an ascending aortic aneurysm. She was treated with surgery, which involved patch closure of P-MAIVF with aortic valve replacement, coronary artery bypass grafting, and ascending aorta replacement. After the operation, echocardiography showed no leakage from the P-MAIVF. Conclusions It is necessary to have knowledge of P-MAIVF. Following up cases of infective endocarditis and post-aortic valve replacement using echocardiography is important for both, diagnosing P-MAIVF and preventing serious complications such rupture and angina.

Abstract Background Data on long-term cosmetic outcome, overall survival, and disease-free survival of endoscope-assisted partial mastectomy (EAPM) for breast cancer are scarce. Thus, we examined these outcomes after a 10-year follow-up period, and compared with conventional conservative method (CCM). Patients and methods Data on 257 patients with stage ≤ IIA breast cancer who underwent CCM (n = 125) or EAPM (n = 132) were analyzed. Cosmetic outcome at 2, 5, and 10 years was evaluated by 5 criteria (breast retraction assessment, nipple deviation, atrophy, skin change, scar). For overall mortality, breast cancer-specific mortality, and recurrence, the risk by operation method was tested by Cox proportional hazard models. Results EAPM performed significantly better than CCM in terms of cosmetic outcomes for location B at 2, 5, and 10 year-follow ups. As for cosmetic outcomes by individual criteria, EAPM had significantly higher proportions of satisfactory results for scar across all follow-up periods, and atrophy at 2-year and 10-year follow-up. There were no significant differences in terms of overall mortality, breast cancer-specific mortality, and recurrence between EAPM and CCM. The rates of patients who experienced local recurrence were similar between CCM and EAPM. Conclusion EAPM is better than CCM in terms of long-term cosmetic outcome, especially for location B. As a surgical treatment for breast cancer, EAPM is comparable to CCM in terms of mortality and recurrence.

The quality-assured preparation of crushed and diluted preparations for children is a challenge. In this study, a multicenter study was conducted to validate the preparation method for the quality assurance of baclofen powder, clonidine powder, and hydrocortisone powder prepared from tablets according to a previously established method. In-hospital preparations were prepared at five medical facilities under different crushing and mixing conditions. After storage in closed bottles, in-use bottles, and laminated paper for 120 days, ingredients stability, drug elution, and content uniformity after packaging were evaluated. All three ingredients were maintained at between 90% and 110% of their initial content for 120 days under packaging conditions of 25 ± 2 °C and 60 ± 5% relative humidity, with no change in dissolution in all formulations made at all five facilities. The content uniformity was also acceptable. The established method may contribute to quality-assured pediatric dosage form modification.

Abstract Background Left atrial dissection is a rare complication of cardiac surgery, most commonly associated with mitral valve surgery. Herein, we report on the successful conservative treatment of left atrial dissection while avoiding anticoagulation therapy. Case presentation A 64-year-old man developed left atrial dissection during operation for acute type A aortic dissection, most likely due to retrograde cardioplegia cannulation. As there was no connection between the left atrial dissection cavity and the left atrium on enhanced computed tomography, we did not administer anticoagulants to prevent expansion of the left atrial dissection cavity. However, the patient developed atrial fibrillation, which was successfully managed by beta-blocker and amiodarone administration. Follow-up imaging showed gradual left atrial dissection reduction, and the patient was started on anticoagulation therapy. Conclusion We were able to resolve left atrial dissection by preventing the use of anticoagulation therapy in the acute stage by managing the atrial fibrillation with antiarrhythmic drugs.

Abstract Background The geriatric nutritional risk index (GNRI) is a simple and useful marker for predicting prognosis and treatment efficacy among patients with various cancers. However, to the best of our knowledge, there are no previous reports regarding the prognostic value of GNRI among patients with non‐small cell lung cancer (NSCLC) who were treated with immune checkpoint inhibitors (ICIs). Methods We retrospectively evaluated 85 patients with previously treated advanced NSCLC who were administered ICIs at Shinshu University Hospital between February 2016 and October 2020. Progression‐free survival (PFS) and overall survival (OS) were compared between groups with high (≥89.5) and low (

Abstract Objectives The aim of this trial is to evaluate the antiviral efficacy, clinical efficacy, and safety of nelfinavir in patients with asymptomatic and mild COVID-19. Trial design The study is designed as a multicenter, open-label, blinded outcome assessment, parallel group, investigator-initiated, exploratory, randomized (1:1 ratio) controlled clinical trial. Participants Asymptomatic and mild COVID-19 patients will be enrolled in 10 university and teaching hospitals in Japan. The inclusion and exclusion criteria are as follows: Inclusion criteria: (1) Japanese male or female patients aged ≥ 20 years (2) SARS-CoV-2 detected from a respiratory tract specimen (e.g., nasopharyngeal swab or saliva) using PCR, LAMP, or an antigen test within 3 days before obtaining the informed consent (3) Provide informed consent Exclusion criteria: (1) Symptoms developed ≥ 8 days prior to enrolment (2) SpO2 < 96 % (room air) (3) Any of the following screening criteria: a) ALT or AST ≥ 5 × upper limit of the reference range b) Child-Pugh class B or C c) Serum creatinine ≥ 2 × upper limit of the reference range and creatinine clearance < 30 mL/min (4) Poorly controlled diabetes (random blood glucose ≥ 200 mg/dL or HbA1c ≥ 7.0%, despite treatment) (5) Unsuitable serious complications based on the assessment of either the principal investigator or the sub-investigator (6) Hemophiliac or patients with a marked hemorrhagic tendency (7) Severe diarrhea (8) Hypersensitivity to the investigational drug (9) Breastfeeding or pregnancy (10) With childbearing potential and rejecting contraceptive methods during the study period from the initial administration of the investigational drug (11) Receiving rifampicin within the previous 2 weeks (12) Participated in other clinical trials and received drugs within the previous 12 weeks (13) Undergoing treatment for HIV infection (14) History of SARS-CoV-2 vaccination or wishes to be vaccinated against SARS-CoV-2 (15) Deemed inappropriate (for miscellaneous reasons) based on the assessment of either the principal investigator or the sub-investigator Intervention and comparator Patients who meet the inclusion criteria and do not meet any of the exclusion criteria will be randomized to either the nelfinavir group or the symptomatic treatment group. The nelfinavir group will be administered 750 mg of nelfinavir orally, three times daily for 14 days (treatment period). However, if a participant tests negative on two consecutive PCR tests of saliva samples, administration of the investigational drug for that participant can be discontinued at the discretion of the investigators. The symptomatic treatment group will not be administered the investigational drug, but all other study procedures and conditions will be the same for both groups for the duration of the treatment period. After the treatment period of 14 days, each group will be followed up for 14 days (observational period). Main outcomes The primary endpoint is the time to negative conversion of SARS-CoV-2. During the study period from Day 1 to Day 28, two consecutive negative PCR results of saliva samples will be considered as the negative conversion of the virus. The secondary efficacy endpoints are as follows: For patients with both asymptomatic and mild disease: area under the curve of viral load, half decay period of viral load, body temperature at each time point, all-cause mortality, incidence rate of pneumonia, percentage of patients with newly developed pneumonia, rate of oxygen administration, and the percentage of patients who require oxygen administration. For asymptomatic patients: incidence of symptomatic COVID-19, incidence of fever (≥ 37.0 °C for two consecutive days), incidence of cough For patients with mild disease: incidence of defervescence (< 37.0 °C), incidence of recovery from clinical symptoms, incidence of improvement of each symptom The secondary safety endpoints are adverse events and clinical examinations. Randomization Patients will be randomized to either the nelfinavir group or the symptomatic treatment group using the electric data capture system (1:1 ratio, dynamic allocation based on severity [asymptomatic], and age [< 60 years]). Blinding (masking) Only the assessors of the primary outcome will be blinded (blinded outcome assessment). Numbers to be randomized (sample size) The sample size was determined based on our power analysis to reject the null hypothesis, S (t | z =1) = S (t | z = 0) where S is a survival function, t is time to negative conversion, and z denotes randomization group, by the log-rank test with a two-sided p value of 0.05. We estimated viral dynamic parameters by fitting a nonlinear mixed-effects model to reported viral load data, and simulated our primary endpoint from viral-load time-courses that were realized from sets of viral dynamics parameters sampled from the estimated probability distribution of the parameters (sample size: 2000; 1000 each for randomization group). From this estimation of the hazard ratio between the randomization groups for the event of negative conversion using this simulation dataset, the required number of events for rejecting our null hypothesis with a power of 0.80 felled 97.345 by plugging the estimated hazard ratio, 1.79, in Freedman’s equation. Therefore, we decided the required number of randomizations to be 120 after consideration of the frequency of censoring and the anticipated rate of withdrawal caused by factors such as withdrawal of consent. Trial Status Protocol version 6.0 of February 12, 2021. Recruitment started on July 22, 2020 and is anticipated to be completed by March 31, 2022. Trial registration This trial was registered in Japan Registry of Clinical Trials (jRCT) ( jRCT2071200023 ) on 21 July 21, 2020. Full protocol The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol. The study protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (Additional file 2).

Abstract Background This study was performed to clarify the treatment outcome of patients with primary mediastinal germ cell tumors (PMGCTs), focusing on the clinical manifestations and management during definitive therapy and long‐term follow‐up. Methods In this study, we retrospectively reviewed the medical records of patients with PMGCTs treated at Shinshu University School of Medicine, and examined the clinical profiles and treatment outcomes of 22 patients (mean age of 29 years) with primary mediastinal GCTs treated at our hospital between 1983 and 2019. Results Five patients were diagnosed with pure seminoma and 17 had nonseminomatous GCT. A total of 21 patients were treated with cisplatin‐based chemotherapy and 15 patients (68.2%) underwent thoracic surgery after chemotherapy. Although all cases of nonseminomatous GCT were negative for tumor markers after cisplatin‐based chemotherapy, two cases showed variable GCT cells and two had somatic components (angiosarcoma and rhabdomyosarcoma) in resected specimens. Three relapsed soon after surgery. Growing teratoma syndrome developed during chemotherapy in four cases. Urgent thoracic surgery was performed in three patients, but one case was inoperable. The calculated 10‐year overall survival rates were 100% in mediastinal seminoma and 64.7% in NSGCT. During follow‐up, second non‐GCT malignancies developed in three patients (colon cancer, 190 months; thyroid cancer, 260 months; non‐small cell lung cancer, 250 months after the initial chemotherapy) and one patient with primary mediastinal seminoma was associated with multiple type I endocrine tumors. Conclusions Our experiences demonstrated that long‐term survival and/or cure can be achieved with adequate chemotherapy followed by local surgical treatment even in patients with mediastinal GCTs. However, the clinical manifestations and biological behaviors during and/or after chemotherapy were complex and varied. In addition, the development of secondary malignancies should be taken into consideration for long‐term follow‐up. Clinicians should be aware of the various clinical features and secondary malignancies in primary mediastinal GCTs.

Abstract When patients with PNH present with abdominal symptoms, thrombosis‐induced gastrointestinal injury should be considered; computed tomography and esophagogastroduodenoscopy may help make the diagnosis of this potentially serious complication.

Alport syndrome (AS) is a hereditary glomerular nephritis caused by mutation in one of the type IV collagen genes α3/α4/α5 that encode the heterotrimer COL4A3/4/5. Failure to form a heterotrimer due to mutation leads to the dysfunction of the glomerular basement membrane, and end-stage renal disease. Previous reports have suggested the involvement of the receptor tyrosine kinase discoidin domain receptor (DDR) 1 in the progression of AS pathology. However, due to the similarity between DDR1 and DDR2, the role of DDR2 in AS pathology is unclear. Here, we investigated the involvement of DDR2 in AS using the X-linked AS mouse model. Mice were treated subcutaneously with saline or antisense oligonucleotide (ASO; 5 mg/kg or 15 mg/kg per week) for 8 weeks. Renal function parameters and renal histology were analyzed, and the gene expressions of inflammatory cytokines were determined in renal tissues. The expression level of DDR2 was highly elevated in kidney tissues of AS mice. Knockdown of Ddr2 using Ddr2-specific ASO decreased the Ddr2 expression. However, the DDR2 ASO treatment did not improve the proteinuria or decrease the BUN level. DDR2 ASO also did not significantly ameliorate the renal injury, inflammation and fibrosis in AS mice. These results showed that Ddr2 knockdown by ASO had no notable effect on the progression of AS indicating that DDR2 may not be critically involved in AS pathology. This finding may provide useful information and further understanding of the role of DDRs in AS.

Abstract Aquatic heavy metal pollution is a growing concern. To facilitate heavy metal monitoring in water, we developed transgenic Daphnia that are highly sensitive to heavy metals and respond to them rapidly. Metallothionein A, which was a metal response gene, and its promoter region was obtained from Daphnia magna. A chimeric gene fusing the promoter region with a green fluorescent protein (GFP) gene was integrated into D. magna using the TALEN technique and transgenic Daphnia named D. magna MetalloG were produced. When D. magna MetalloG was exposed to heavy metal solutions for 1 h, GFP expression was induced only in their midgut and hepatopancreas. The lowest concentrations of heavy metals that activated GFP expression were 1.2 µM Zn2+, 130 nM Cu2+, and 70 nM Cd2+. Heavy metal exposure for 24 h could lower the thresholds even further. D. magna MetalloG facilitates aqueous heavy metal detection and might enhance water quality monitoring.

Abstract Background AminoIndex™ Cancer Screening (AICS (lung)) was developed as a screening test for lung cancer using a multivariate analysis of plasma-free amino acid (PFAA) profiles. According to the developed index composed of PFAA, the probability of lung cancer was categorized into AICS (lung) ranks A, B, and C in order of increasing risk. The aim of the present study was to investigate the relationship between the preoperative AICS (lung) rank and surgical outcomes in patients who underwent curative resection for non-small cell lung cancer (NSCLC). Methods Preoperative blood samples were collected from 297 patients who underwent curative resection for NSCLC between 2006 and 2015. PFAA concentrations were measured. The relationship between the preoperative AICS (lung) rank and clinicopathological factors was examined. The effects of the preoperative AICS (lung) rank on postoperative outcomes were also analyzed. Results The AICS (lung) rank was A in 93 patients (31.3%), B in 82 (27.6%), and C in 122 (41.1%). The AICS (lung) rank did not correlate with any clinicopathological factors, except for age. Based on follow-up data (median follow-up period of 6 years), postoperative recurrence was observed in 22 rank A patients (23.7%), 15 rank B (18.3%) and 49 rank C (40.2%). In the univariate analysis, preoperative AICS (lung) rank C was a worse factor of recurrence-free survival (p = 0.0002). The multivariate analysis identified preoperative AICS (lung) rank C (HR: 2.17, p = 0.0005) as a significant predictor of postoperative recurrence, particularly in patients with early-stage disease or adenocarcinoma. Conclusion Preoperative AICS (lung) rank C is a high-risk predictor of postoperative recurrence in patients undergoing curative resection for NSCLC.

Abstract Background The lung immune prognostic index (LIPI) is a marker that combines the derived neutrophil‐to‐lymphocyte ratio (dNLR) and serum lactate dehydrogenase (LDH) level and is a recently reported prognostic factor of immune checkpoint inhibitor therapy for non‐small cell lung cancer (NSCLC). However, there are no reports regarding the prognostic value of LIPI in small cell lung cancer (SCLC). Methods We retrospectively enrolled 171 patients diagnosed with SCLC and treated at Shinshu University School of Medicine between January 2003 and November 2019. Progression‐free survival (PFS) and overall survival (OS) were compared according to LIPI, and we investigated whether LIPI could be a prognostic factor in SCLC using the Kaplan‐Meier method and univariate and multivariate Cox models. Results The median OS of the LIPI 0 group was significantly longer than that of the LIPI 1 plus 2 group (21.0 vs. 11.6 months, P

Abstract Background Older patients with type 2 diabetes mellitus (T2DM) have an increased risk of bone fracture independent of their bone mineral density (BMD), which is explained mainly by the deteriorated bone quality in T2DM compared to that in non-diabetic adults. Sodium-glucose co-transporter (SGLT) 2 inhibitors have been studied in several trials in T2DM, and the Canagliflozin Cardiovascular Assessment Study showed an increased fracture risk related to treatment with the SGLT2 inhibitor canagliflozin, although no evidence of increased fracture risk with treatment with other SGLT2 inhibitors has been reported. The mechanism of the difference in the fracture risk between the SGLT2 inhibitors is unknown, but the differences among the SGLT2 inhibitors in the selectivity of SGLT2 against SGLT1 may affect bone metabolism, since among the SGLT2 inhibitors the selectivity of canagliflozin is lowest. We will investigate whether the SGLT2 inhibitor luseogliflozin, which has the higher SGLT2 selectivity, affects bone metabolism by using high-resolution, peripheral quantitative computed tomography (HR-pQCT) which provides direct in vivo morphometric information about the bone microarchitecture. Methods/design This is a single-center, randomized, open-label, active-controlled, parallel pilot trial. Eligible participants are older (age ≥ 60 years) individuals with T2DM with HbA1c levels at 7.0–8.9%. A total of 24 participants will be allocated to either the luseogliflozin group (taking luseogliflozin) or the control group (taking metformin) in a 1:1 ratio to compare the groups’ changes in bone microarchitecture of the radius and tibia which are analyzed by HR-pQCT before and at 48 weeks after the administration of each medication. The laboratory data associated with glycemic control and bone metabolism will be collected every 12 weeks during the study. Recruitment began in June 2019. Discussion The reason that we use metformin as an active control is to avoid yielding differences in glycemic control between the luseogliflozin and control groups. Besides, metformin is considered to have a neutral effect on bone. This trial should reveal the effect of luseogliflozin on bone metabolism in older patients with T2DM. Trial registration The study was registered with the University Hospital Medical Information Network ( UMIN000036202 ) on 1 April 2019 and with the Japan Registry of Clinicla Trials ( jRCTs071180061 ) on 14 March 2019.

Abstract Background Previous analyses of combined pulmonary fibrosis and emphysema (CPFE) cohorts have provided conflicting data on the survival of patients with CPFE. Therefore, the aim of this study was to investigate the clinical prognosis of acute exacerbations (AE) of CPFE. Methods We retrospectively reviewed the medical records of patients who had been treated at the Shinshu University Hospital (Matsumoto, Japan) between 2003 and 2017. We identified 21 patients with AE of CPFE and 41 patients with AE of idiopathic pulmonary fibrosis (IPF) and estimated their prognoses using the Kaplan–Meier method. Results Treatment content and respiratory management were not significantly different between the two groups before and after exacerbation. At the time of AE, the median serum Krebs von den Lungen-6 level was significantly lower in the CPFE group (Krebs von den Lungen-6: 966 U/μL; white blood cell count: 8810 /μL) than that in the IPF group (Krebs von den Lungen-6: 2130 U/μL, p

Abstract Background With advances in diagnostic imaging such as ultrasonography (US), computed tomography (CT), and 99mTc-MIBI-sestamibi (MIBI) scintigraphy, localized diagnosis of hyperparathyroidism (pHPT) has become possible with considerable accuracy. However, even with the use of these imaging techniques, since intrathyroid parathyroid tumors exist as a mass within the thyroid, it is often difficult to distinguish from thyroid masses. Although there have been various reports on US images of intraparathyroid tumors, we experienced a case with US images that were distinct from previous reports. Herein we present a case of an intrathyroid parathyroid adenoma (IPA) that was difficult to diagnose, with a main focus on US images. Case presentation A 53-year-old man with a diagnosis of hyperparathyroidism was referred to our department in December 2018. Ultrasonography revealed a tumor that was located in the inferior pole of the right lobe of the thyroid gland and no parathyroid mass was observed. The tumor had an irregular round shape and showed heterogeneous hyperechogenicity with a defined margin, but within it, there were a few irregular and hypoechogenic area with unclear margins, while the tumor had a mosaic appearance at first glance. Although 99mTc-MIBI scintigraphy showed accumulation at the same location in delayed phase, it was difficult to determine the presence of a parathyroid tumor on the image. The patient underwent an operation on April 2019 and the tumor could not be identified on both naked eye and palpation. We used US intraoperatively to define the location and resected the tumor. A parathyroid adenoma was diagnosed by frozen section and the final diagnosis was an intrathyroid parathyroid adenoma. Conclusion We experienced an IPA presenting an US image that was atypical and has previously not been reported. IPA has no established US image to confirm the diagnosis and even with the use of other imaging techniques, a definitive diagnosis often cannot be established. Thus, our recommendation based on the current situation is that operation with intraoperative diagnosis using frozen section should be conducted if hypercalcemia and high I-PTH are observed and when localization sites in MIBI and US coincide.

Purpose: Carbon ion beams have several physical and biological advantages compared with conventional radiation for cancer therapy. The objective of this study is to evaluate the safety and effectiveness of 2-fraction carbon ion radiation therapy (CIRT) in patients with hepatocellular carcinoma (HCC). Methods and Materials: Between December 2008 and March 2013, 57 patients with localized HCC were treated with CIRT at a total dose of 45 Gy (relative biological effectiveness) in 2 fractions and retrospectively analyzed after long-term observation. The main endpoints of this study were treatment-related toxicity and local tumor control. Toxicity was assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0. Changes in the Child-Pugh score from before to after CIRT were also examined to evaluate hepatic toxicity. Local control was defined as no progression of the irradiated lesion according to the modified Response Evaluation Criteria in Solid Tumors. Results: The median age of the patients was 75 years (range, 49-89 years). Of these patients, 41 had a newly diagnosed lesion, and 16 had residual or recurrent lesions after previous treatments. The median follow-up duration was 54 months (range, 7-103 months). All surviving patients were followed for more than 51 months. Two patients experienced grade 3 acute skin reactions, but no other grade 3 or higher toxicities were observed in any organ. No patient exhibited an increase in the Child-Pugh score of 2 or more points after CIRT. The local tumor control rates at 1, 3, and 5 years were 98%, 91%, and 91% after CIRT, respectively. All lesions that failed to respond to previous treatments were successfully controlled by CIRT. The 1-, 3-, and 5-year overall survival rates were 97%, 67%, and 45%, respectively. Conclusions: Two-fraction CIRT was a well-tolerated and effective treatment for patients with HCC.

Introduction: The psychosocial background of subjects with severe obesity developed from childhood onset obesity (CO) and their outcomes after bariatric surgery have not been fully investigated. Methods: 305 subjects were enrolled in the J-SMART study, which examined the effects of laparoscopic sleeve gastrectomy (LSG) in Japan, and categorized into two groups: CO defined as onset up to 13 years of age (CO group) and post-puberty onset obesity defined as onset after 13 years of age (PPO group). The subjects were followed up for at least 2 years and up to 5 years after LSG. Changes in physical parameters and remission of obesity-related comorbidities were assessed at 2 years after LSG. Weight regain (WR) was also assessed by evaluating the nadir weight after LSG and maximum weight thereafter during follow-up period. Results: The mean postoperative follow-up period was 3.0 ± 1.1 years. 40.0% of the subjects had CO and these subjects had higher BMI and HOMA-β, and lower age, HbA1c, HDL cholesterol, and visceral/subcutaneous fat area ratio compared to those with PPO. The CO group was also characterized by having higher rates of mental retardation, developmental disorders and obesity in either parent, and lower rate of marriage compared to the PPO group. Two years after LSG, there were no differences in total weight loss and remission rates of diabetes, dyslipidemia and sleep apnea syndrome between the two groups, although remission rate of hypertension was higher in the CO group. The CO group also had a higher rate of WR after LSG than the PPO group, with CO, BMI, mental disorder and binge eating contributing to WR. Conclusion: This study suggests that CO might be associated with genetic and psychosocial factors. CO and PPO probably differ in pathogenesis and may require different treatment strategies.

Idiopathic pulmonary fibrosis (IPF), a fibrosing interstitial lung disease, predominantly affects the elderly and is associated with a high mortality risk. Nintedanib, a tyrosine kinase inhibitor, significantly reduces IPF progression. However, data on the tolerability and efficacy of nintedanib in the elderly with IPF are limited. Therefore, this study aimed to examine the tolerability and efficacy of nintedanib in the elderly with IPF in a real-world setting. Medical records of 19 elderly IPF patients (≥ 75 years) and 46 non-elderly IPF patients (< 75 years) newly administered nintedanib were retrospectively analyzed. We compared the forced vital capacity (FVC) level, incidence and severity of adverse events, and continuation rates of nintedanib between the two groups. FVC and percent predicted diffusing capacity of the lung for carbon monoxide (DLco) were lower in the elderly IPF group at baseline. Although the elderly IPF patients had a significantly higher incidence of adverse events, such as diarrhea, nausea, and elevation of hepatic enzymes, the rate of discontinuation of nintedanib owing to adverse events was not different between the groups. The continuation rates of nintedanib treatment at 6 months and 1 year in the elderly IPF group were equivalent. Furthermore, there was a similar trend in the reduction of the annual FVC decline after nintedanib initiation between the groups. Our study demonstrated that nintedanib was tolerable in both the IPF patient groups in a real-world setting. Proper management of adverse events in the elderly with IPF would lead to a better clinical outcome.

Mycobacterium farcinogenes is the causative agent of bovine farcy. M. farcinogenes shares common properties with rapidly growing mycobacteria, and distinguishing between M. farcinogenes and M. fortuitum is reportedly complex and challenging. Moreover, few studies have isolated M. farcinogenes from human clinical samples.A previously healthy 37-year-old male construction worker presented to the emergency department after a severe injury and was diagnosed with a Gustilo-Anderson type ⅢA fracture. After an uneventful postoperative period of two months, he experienced pain and serous discharge from the upper shin and lower calf region. Frequent debridement provided no relief, and the pathology cultures of the tissue were negative. However, M. farcinogenes was isolated from the fluid of the wound. The patient’s symptoms gradually improved with anti-mycobacterial drug treatment.Nontuberculous mycobacterial infections, including those caused by M. farcinogenes, should be considered in patients developing soft tissue infections despite negative pyogenic bacterial cultures several months after sustaining an open fracture.

The fish acute toxicity test (TG203; OECD, 2019) is frequently used and highly embedded in hazard and risk assessment globally. The test estimates the concentration of a chemical that kills 50% of the fish (LC50) over a 96 h exposure and is considered one of the most severe scientific procedures undertaken. Over the years, discussions at the Organisation for Economic Co-operation and Development (OECD) have resulted in changes to the test which reduce the number of fish used, as well as the development of a (potential) replacement test (TG236, OECD, 2013). However, refinement of the mortality endpoint with an earlier (moribundity) endpoint was not considered feasible during the Test Guideline’s (TG) last update in 2019. Several stakeholders met at a UK-based workshop to discuss how TG203 can be refined, and identified two key opportunities to reduce fish suffering: (1) application of clinical signs that predict mortality and (2) shortening the test duration. However, several aspects need to be addressed before these refinements can be adopted. TG203 has required recording of major categories of sublethal clinical signs since its conception, with the option to record more detailed signs introduced in the 2019 update. However, in the absence of guidance, differences in identification, recording and reporting of clinical signs between technicians and laboratories is likely to have generated piecemeal data of varying quality. Harmonisation of reporting templates, and training in clinical sign recognition and recording are needed to standardise clinical sign data. This is critical to enable robust data-driven detection of clinical signs that predict mortality. Discussions suggested that the 96 h duration of TG203 cannot stand up to scientific scrutiny. Feedback and data from UK contract research organisations (CROs) conducting the test were that a substantial proportion of mortalities occur in the first 24 h. Refinement of TG203 by shortening the test duration would reduce suffering (and test failure rate) but requires a mechanism to correct new results to previous 96 h LC50 data. The actions needed to implement both refinement opportunities are summarised here within a roadmap. A shift in regulatory assessment, where the 96 h LC50 is a familiar base for decisions, will also be critical.

Abstract Background and aims We have started a new population‐based endoscopic gastric cancer screening program in Kurashiki city with consideration of Helicobacter pylori infection status based on endoscopic features. We aimed to verify the feasibility of this attempt in a prospective case‐registration study (UMIN000028629). Methods Data were collected from 1784 subjects without past eradication of H. pylori and who underwent endoscopic gastric cancer screening in Kurashiki Central Hospital Preventive Healthcare Plaza from September 2017 to June 2018. Endoscopic judgment of H. pylori infection status was made according to the Kyoto classification of gastritis. For comparison, a combination serum test of anti‐H. pylori antibody and pepsinogen I and II, the ABC method, was used. Results The endoscopic diagnoses were nongastritis, 1215 (68.1%); active or inactive gastritis, 469 (26.3%); and undefined, 23 (1.3%). With the ABC method as a reference standard, the false‐negative rate of the endoscopic judgment for H. pylori infection was 16.3% (95% confidence interval: 13.1%‐20.0%). Most false‐negative cases were of Group B in the ABC method, which is considered gastritis with mild mucosal atrophy. Antibody titers in this population were mostly in the weak‐positive range but clinically significant elevation of the antibody suggesting current infection was observed in some cases. Conclusions Endoscopic diagnosis of H. pylori infection status in a population‐based gastric cancer screening program is mostly reliable, but false‐negative results may occur, especially in patients with mild gastric atrophy. To avoid this limitation, we recommend adding H. pylori antibody test to the program.

Abstract Aim Laparoscopic sleeve gastrectomy (LSG) is becoming popular in Japan, but insufficient weight loss is often observed in patients after LSG. We investigated the effect of LSG on obesity‐related comorbidities and identified the background characteristics of Japanese patients with insufficient weight loss after LSG. Methods In this multi‐institutional retrospective study at 10 certified bariatric institutions, 322 Japanese patients who underwent LSG with a follow‐up period of more than 2 years were analyzed. Anthropometry, obesity‐related comorbidities and psychosocial background data were collected. Weight loss was expressed as 2‐year percent total weight loss (%TWL). Results Mean age, body weight, body mass index (BMI) and glycated hemoglobin were 46.9 years, 119.2 kg, 43.7 kg/m2 and 7.1%, respectively. Prevalence of mental disorders was 26.3%. Mean BMI declined to 30.3 kg/m2 at 2 years and %TWL was 29.9%. Improvements in the markers and prevalence of obesity‐related comorbidities were observed. Remission rates of diabetes, dyslipidemia and hypertension were 75.6%, 59.7% and 41.8%, respectively. %TWL at the respective cut‐off level of diabetes remission was 20.8%. Lower remission rates of diabetes in patients with %TWL