Extracting immunological and clinical heterogeneity across autoimmune rheumatic diseases by cohort-wide immunophenotyping.

OBJECTIVE: Extracting immunological and clinical heterogeneity across autoimmune rheumatic diseases (AIRDs) is essential towards personalised medicine. METHODS: We conducted large-scale and cohort-wide immunophenotyping of 46 peripheral immune cells using Human Immunology Protocol of comprehensive 8-colour flow cytometric analysis. Dataset consisted of >1000 Japanese patients of 11 AIRDs with deep clinical information registered at the FLOW study, including rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). In-depth clinical and immunological characterisation was conducted for the identified RA patient clusters, including associations of inborn human genetics represented by Polygenic Risk Score (PRS). RESULTS: Multimodal clustering of immunophenotypes deciphered underlying disease-cell type network in immune cell, disease and patient cluster resolutions. This provided immune cell type specificity shared or distinct across AIRDs, such as close immunological network between mixed connective tissue disease and SLE. Individual patient-level clustering dissected patients with AIRD into several clusters with different immunological features. Of these, RA-like or SLE-like clusters were exclusively dominant, showing immunological differentiation between RA and SLE across AIRDs. In-depth clinical analysis of RA revealed that such patient clusters differentially defined clinical heterogeneity in disease activity and treatment responses, such as treatment resistance in patients with RA with SLE-like immunophenotypes. PRS based on RA case-control and within-case stratified genome-wide association studies were associated with clinical and immunological characteristics. This pointed immune cell type implicated in disease biology such as dendritic cells for RA-interstitial lung disease. CONCLUSION: Cohort-wide and cross-disease immunophenotyping elucidate clinically heterogeneous patient subtypes existing within single disease in immune cell type-specific manner.

Comparison of anti-IL-6 receptor and JAK inhibitors in patients with rheumatoid arthritis from the real-world practice FIRST study.

OBJECTIVES: A molecular-targeted drug that is suitable as the second choice for patients with rheumatoid arthritis (RA) who show an inadequate response to the first biological disease-modifying antirheumatic drug (bDMARD) is unknown. This study aimed to analyze the efficacy and safety of interleukin-6 receptor (IL-6Ri) and Janus kinase inhibitors (JAKis), often selected as molecular-targeted drugs for second or subsequent treatments. METHODS: The efficacy and safety of JAKis and IL-6Ri were compared using propensity score-based inverse probability of treatment weighting (PS-IPTW) using propensity scores after 26 weeks of therapy in patients with RA. RESULTS: The remission rate at week 26, determined by the clinical disease activity index (CDAI), and the incidence of infection were higher in the JAKis than in the IL-6Ri group. The CDAI trajectories were divided into four according to the growth mixture modeling. IL-6Ri demonstrated greater efficacy in RA patients with ineffective to single bDMARD therapy compared with those with multiple ineffective bDMARDs. In patients who failed to respond to one bDMARD, there was no significant difference in the CDAI remission rate at week 26 between the JAKis (29.1%) and IL-6Ri (21.8%) groups (p= 0.21). However, for patients who did not respond to at least two bDMARDs, the CDAI remission rate at week 26 was higher in the JAKis than in the IL-6Ri group. CONCLUSIONS: IL-6Ri offers a superior balance of efficacy and safety compared with JAKis for RA patients unresponsive to one bDMARD. However, JAKis may suit patients who do not respond to multiple bDMARDs.

Broken Screw Rotational Symmetry in the Near-Surface Electronic Structure of AB-Stacked Crystals.

We investigate the electronic structure of 2H-NbS_{2} and h-BN by angle-resolved photoemission spectroscopy (ARPES) and photoemission intensity calculations. Although in bulk form, these materials are expected to exhibit band degeneracy in the k_{z}=π/c plane due to screw rotation and time-reversal symmetries, we observe gapped band dispersion near the surface. We extract from first-principles calculations the near-surface electronic structure probed by ARPES and find that the calculated photoemission spectra from the near-surface region reproduce the gapped ARPES spectra. Our results show that the near-surface electronic structure can be qualitatively different from the bulk electronic structure due to partially broken nonsymmorphic symmetries.

Total synthesis of jamaicamide B.

Jamaicamide B was isolated from the cyanobacterium Moorea producens in Jamaica and shows neurotoxicity. This unique mixed peptide-polyketide structure contains a pyrrolinone ring, a ß-methoxy enone, an (E)-olefin, an undetermined stereocenter at C9, an (E)-chloroolefin, and a terminal alkyne. We report herein the first total synthesis and structural confirmation of the marine natural product (9R)-jamaicamide B.

Effect of internal structure and resin deformability on drying rate and stress in convective drying of silica-latex coatings.

Latex paint is an aqueous dispersion of nano-sized polymer particles that can form a thin film by itself or mixed with rigid particles. We have developed an apparatus that can simultaneously measure drying rate and stress generation and have investigated the film formation process of a latex-only coating layer under convection drying. In the present study, we adopted the same method to investigate the film formation process of the silica-latex coating layer. As a result, we were able to systematically correlate the drying rate change by the equivalent thickness of latex particles accumulated with silica particles at the drying surface. Furthermore, it is unveiled that the drying rate in the former stage depends on drying temperature, while the drying rate changed to be dominated by silica content after the particle-packing layer was formed over the entire coating layer. On the other hand, the model we proposed for stress generation, considering the temperature effect on latex deformability, was found to be applicable to the present experimental system by replacing a portion of deformable particles with rigid particles.

Intravenous lipid emulsion for local anaesthetic systemic toxicity in pregnant women: a scoping review.

BACKGROUND: Local anaesthetic systemic toxicity (LAST) is a rare but life-threatening complication that can occur after local anaesthetic administration. Various clinical guidelines recommend an intravenous lipid emulsion as a treatment for local anaesthetic-induced cardiac arrest. However, its therapeutic application in pregnant patients has not yet been established. This scoping review aims to systematically identify and map the evidence on the efficacy and safety of intravenous lipid emulsion for treating LAST during pregnancy. METHOD: We searched electronic databases (Medline, Embase and Cochrane Central Register Controlled Trials) and a clinical registry (lipidrescue.org) from inception to Sep 30, 2022. No restriction was placed on the year of publication or the language. We included any study design containing primary data on obstetric patients with signs and symptoms of LAST. RESULTS: After eliminating duplicates, we screened 8,370 titles and abstracts, retrieving 41 full-text articles. We identified 22 women who developed LAST during pregnancy and childbirth, all presented as case reports or series. The most frequent causes of LAST were drug overdose and intravascular migration of the epidural catheter followed by wrong-route drug errors (i.e. intravenous anaesthetic administration). Of the 15 women who received lipid emulsions, all survived and none sustained lasting neurological or cardiovascular damage related to LAST. No adverse events or side effects following intravenous lipid emulsion administration were reported in mothers or neonates. Five of the seven women who did not receive lipid emulsions survived; however, the other two died. CONCLUSION: Studies on the efficacy and safety of lipids in pregnancy are scarce. Further studies with appropriate comparison groups are needed to provide more robust evidence. It will also be necessary to accumulate data-including adverse events-to enable clinicians to conduct risk-benefit analyses of lipids and to facilitate evidence-based decision-making for clinical practice.

Diverse Plantarflexor Module Characteristics Influence Immediate Effects of Plastic Ankle-Foot Orthosis on Gait Performance in Patients With Stroke: A Cross-sectional Study.

OBJECTIVE: To investigate the immediate effects of plastic ankle-foot orthosis (AFO) on locomotor performance in patients with stroke and determine how such effects might undergo alteration when distinct plantarflexor (PF) module subtypes are considered. DESIGN: Cross-sectional study. SETTING: Two university hospitals. PARTICIPANTS: Fifty-two patients with stroke and 21 of those without stroke (N=73). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Motor modules were identified through non-negative matrix factorization, and participants were classified into 3 groups: independent-normal-timing, independent-altered-timing, and merged PF modules. To assess the effects of the AFO, gait measurements reflecting locomotor performance were obtained with and without the presence of the plastic AFO for each group. RESULTS: The independent-altered-timing group had increased paretic propulsion, greater non-paretic step length, and faster walking speed after the administration of the plastic AFO; however, these significant changes were not observed in the independent-normal-timing and merged PF module groups. Notably, patients in the independent-normal-timing and merged PF module groups exhibited longer paretic stance times. CONCLUSION: This study suggests that the immediate effects of plastic AFO depend on the PF module subtype. These findings can potentially guide clinical decision-making regarding AFO selection for stroke rehabilitation in patients with diverse gait control characteristics.

Flowchart for predicting achieving the target area under the concentration-time curve of vancomycin in critically ill Japanese patients: A multicenter retrospective study.

INTRODUCTION: In therapeutic drug monitoring (TDM) of vancomycin (VCM), the area under the concentration-time curve (AUC) is related to the clinical efficacy and toxicity. Therefore, herein, we examined the factors associated with achieving the target AUC at follow-up and developed a decision flowchart for achieving the target AUC in critically ill patients. METHODS: This multicenter retrospective observational study was conducted at eight hospitals. We retrospectively analyzed data from patients who had received VCM in the intensive care unit from January 2020 to December 2022. Decision-tree (DT) analysis was performed using factors with p < 0.1 in univariate analysis as the independent variables. Case data were split up to two times, and four subgroups were included. The primary endpoint was achieving the target AUC at the follow-up TDM (AUCfollow-up) and target AUCfollow-up achievement was defined as an AUC of 400-600 µg‧h/mL. The initial AUC values were calculated with the 2-point concentrations (peak and trough) using the Bayesian estimation software Practical AUC-guided TDM (PAT). RESULTS: Among 70 patients (median age [interquartile range], 66 [56, 79] years; 50 % women), the AUCfollow-up was achieved in 70 % (49/70). Three factors were selected for the decision flow chart: predicted AUCfollow-up of 400-600 µg‧h/mL, dosing at 12-h intervals, and CCr of 130 mL/min/1.73 m2 or higher; the accuracy was adequate (92 %, R2 0.52). CONCLUSION: We successfully identified the factors associated with achieving the target AUC of VCM at follow-up TDM and developed a simple-to-use DT model. However, the validity of the findings needs to be evaluated.

Involvement of CX3CR1+ cells appearing in the abdominal cavity in the immunosuppressive environment immediately after gastric cancer surgery.

BACKGROUND: Gastric cancer is primarily treated by surgery; however, little is known about the changes in the intraperitoneal immune environment and the prognostic impact of surgery. Surgical stress and cancer-associated inflammation cause immune cells to mobilize into the abdominal cavity via numerous cytokines. One such cytokine, CX3CR1, has various immune-related functions that remain to be fully explained. We characterized the intraperitoneal immune environment by investigating CX3CR1+ cells in intraperitoneal lavage fluid during gastric cancer surgery. METHODS: Lavage fluid samples were obtained from a total of 41 patients who underwent gastrectomy. The relative expression of various genes was analyzed using quantitative real-time PCR. The association of each gene expression with clinicopathological features and surgical outcomes was examined. The fraction of CX3CR1+ cells was analyzed by flow cytometry. Cytokine profiles in lavage fluid samples were investigated using a cytometric beads array. RESULTS: CX3CR1high patients exhibited higher levels of perioperative inflammation in blood tests and more recurrences than CX3CR1low patients. CX3CR1high patients tended to exhibit higher pathological T and N stage than CX3CR1low patients. CX3CR1 was primarily expressed on myeloid-derived suppressor cells and tumor-associated macrophages. In particular, polymorphonuclear myeloid-derived suppressor cells were associated with perioperative inflammation, pathological N, and recurrences. These immunosuppressive cells were associated with a trend toward unfavorable prognosis. Moreover, CX3CR1 expression was correlated with programmed death-1 expression. CONCLUSIONS: Our results suggest that CX3CR1+ cells are associated with an acute inflammatory response, tumor-promotion, and recurrence. CX3CR1 expression could be taken advantage of as a beneficial therapeutic target for improving immunosuppressive state in the future. In addition, analysis of intra-abdominal CX3CR1+ cells could be useful for characterizing the immune environment after gastric cancer surgery.

Safety and dose-finding trial of tadalafil administered for fetus in labor: A phase I clinical study.

AIM: This study aimed to investigate the safety and efficacy of tadalafil in protecting the fetus from hypoxic stress caused by repeated labor pains during delivery and preventing fetal hypoxic-ischemic encephalopathy. METHODS: The study used a three-case cohort approach. Three patients were administered 10 mg tadalafil and monitored for serious adverse events. In the absence of serious tadalafil-associated adverse events as assessed by the Safety Evaluation Committee, three new patients were added to the study and treated with 20 mg/dose. The blood levels of tadalafil were recorded before and after 2, 4, 8, and 12 h of administration and 2 h after delivery. RESULTS: A total of seven patients were enrolled, and after excluding one patient who delivered before 37 weeks, tadalafil was administered to six patients. Maternal adverse events were considered acceptable from the maternal perspective, with grade 1 headache, anorexia, and myalgia and no obstetrical complications after delivery at both doses. No serious neonatal adverse events were associated with tadalafil. Tadalafil blood levels remained stable at both doses. In addition, the level of soluble fms-like tyrosine kinase-1 did not alter, while that of the placental growth factor differed significantly before and after tadalafil administration. CONCLUSIONS: The study confirmed the safety of tadalafil administration during delivery for both mothers and newborns. The stable tadalafil blood levels confirmed the efficacy of the tested administration regime at 12 h interval. These findings would assist in conducting phase II trials to further verify the optimal dose and safety of tadalafil.

Relationship between maternal mortality and ritodrine hydrochloride as a tocolytic agent in Japan.

AIM: In Japan, unlike Western countries, tocolytic agents are administered in long-term protocols to treat threatened preterm labor. Evaluating the side effects of this practice is crucial. We examined whether ritodrine hydrochloride had been administered in cases of maternal death, aiming to investigate any relationship between ritodrine administration and maternal death. METHODS: This retrospective cohort study used reports of maternal deaths from multiple institutions in Japan between 2010 and 2020. Data on the reported cases were retrospectively analyzed, and data on the route of administration, administered dose, and clinical findings, including causes of maternal death, were extracted. The amount of tocolytic agents was compared between maternal deaths with ritodrine administration and those without. RESULTS: A total of 390 maternal deaths were reported to the Maternal Death Exploratory Committee in Japan during the study period. Ritodrine hydrochloride was administered in 32 of these cases. The frequencies (n) and median doses (range) of oral or intravenous ritodrine hydrochloride were 34.4% (11) and 945 (5-2100) mg and 84.4% (27) and 4032 (50-18 680) mg, respectively. Frequencies of perinatal cardiomyopathy, cerebral hemorrhage, diabetic ketoacidosis, and pulmonary edema as causes of maternal death were significantly higher with ritodrine administration than without it. CONCLUSIONS: Our results suggest a relationship between long-term administration of ritodrine hydrochloride and an increased risk of maternal death due to perinatal cardiomyopathy, cerebral hemorrhage, diabetic ketoacidosis, and pulmonary edema. In cases where ritodrine should be administered to prevent preterm labor, careful management and monitoring of maternal symptoms are required.

The efficacy of vaginal treatment for non-Lactobacillus dominant endometrial microbiota-A case-control study.

AIM: Reduced Lactobacillus occupancy in the uterine microflora has been associated with implantation failure. This study aimed to evaluate a treatment for improving the uterine microflora. METHODS: This study included patients diagnosed with repeated implantation failure-defined as failure to achieve pregnancy after two or more transfers of viable embryos-who were classified as non-Lactobacillus dominant. Treatment A comprised oral administration of antibiotics for 1 week, followed by oral probiotic butyrate tablets (3 g/day) for approximately 30 days. Treatment B comprised a 1-week course of oral (750 mg/day) and vaginal (250 mg/day) metronidazole, followed by a 1-week intravaginal administration of probiotic capsules (1 capsule/day) and continued oral administration of probiotics (1 capsule/day). Both treatments were compared in terms of efficacy in improving vaginal flora. Improvement was defined as Lactobacillus occupancy >90% or an increase in Lactobacillus occupancy >20%. RESULTS: Seven (41.2%) of 17 patients in the Treatment A group improved in response to the treatment. Contrastingly, 9 (90.0%) of 10 patients improved in the Treatment B group (p = 0.0127). Following treatment, Lactobacillus occupancy in the Treatment B group (62.9% ± 12.7%) was significantly higher than that in the Treatment A group (5.7% ± 9.8%) (p = 0.0242). CONCLUSIONS: This study demonstrates the effectiveness of combining antibiotics and probiotics in vaginal formulations for treating abnormal uterine microflora. However, its potential impact on in vitro fertilization outcomes remains unclear and warrants further investigation through larger, more comprehensive studies.

Piperacillin/tazobactam-induced sudden severe thrombocytopenia in a patient with a pressure ulcer: a case report.

The standard treatment for an infected pressure ulcer (PU) with osteomyelitis is debridement, wound coverage and antibiotic administration. However, systemic administration of antibiotics in patients with osteomyelitis is controversial, and the optimal treatment duration for chronic osteomyelitis has not been standardised. We report a case of sudden severe thrombocytopenia induced by piperacillin/tazobactam (PIPC/TAZ) in a patient with PU-related osteomyelitis. A 57-year-old male patient with paraplegia, using a wheelchair full-time, presented to our plastic surgery department with infection of a stage IV hard-to-heal ischial PU. We surgically debrided the necrotising tissue and raised an ipsilateral biceps femoris musculocutaneous propeller flap for wound coverage. Polymicrobial infections, including Pseudomonas aeruginosa, were detected in the bone biopsy sample; therefore, systemic PIPC/TAZ was administered for the osteomyelitis. Unexpectedly, during the next 12 days of antibiotic administration, the patient's platelet count acutely dropped to 1×103/µl over three days. Based on a series of examinations, PIPC/TAZ was suspected to be the most likely cause of the severe thrombocytopenia. After drug discontinuation, the thrombocytopenia gradually improved. PIPC/TAZ is one of the most widely used antibiotic combinations in the plastic surgery field; it is conventionally administered for hard-to-heal wounds such as PUs and diabetic foot. The present case suggests that surgeons must take special precautions for patients undergoing PIPC/TAZ treatment. In this report, PIPC/TAZ-induced thrombocytopenia and the efficacy of antibiotic treatment for PU-related osteomyelitis are discussed in light of the available literature.

Modes of delivery and indications in women with COVID-19: a regional observational study in Japan.

BACKGROUND: During the coronavirus disease (COVID-19) pandemic, caesarean section (CS) has been the preferred deliver method for pregnant women with COVID-19 in order to limit the use of hospital beds and prevent morbidity among healthcare workers. METHODS: To evaluate delivery methods used during the COVID-19 pandemic as well as the rates of adverse events and healthcare worker morbidity associated with caesarean deliveries. METHODS: We investigated maternal and neonatal backgrounds, delivery methods, indications and complication rates among pregnant women with COVID-19 from December 2020 to August 2022 in Mie Prefecture, Japan. The predominant mutation period was classified as the pre-Delta, Delta and Omicron epoch. RESULTS: Of the 1291 pregnant women with COVID-19, 59 delivered; 23 had a vaginal delivery and 36 underwent CS. Thirteen underwent CS with no medical indications other than mild COVID-19, all during the Omicron epoch. Neonatal complications occurred significantly more often in CS than in vaginal delivery. COVID-19 in healthcare workers was not attributable to the delivery process. CONCLUSION: The number of CS with no medical indications and neonatal complications related to CS increased during the COVID-19 pandemic. Although this study included centres that performed vaginal deliveries during COVID-19, there were no cases of COVID-19 in healthcare workers. It is possible that the number of CS and neonatal complications could have been reduced by establishing a system for vaginal delivery in pregnant women with recent-onset COVID-19, given that there were no cases of COVID-19 among the healthcare workers included in the study.

We evaluated the incidence of adverse events associated with caesarean section (CS) deliveries and the morbidity of health care workers, which increased during the coronavirus infection pandemic. Maternal and neonatal background, delivery methods, indications and complication rates of pregnant women with COVID-19 from December 2020 to August 2022 in Mie Prefecture were investigated by time of onset. Of the 1291 pregnant women with COVID-19, 59 delivered while affected; 23 underwent vaginal delivery and 36 CS. Of these, 13 who underwent CS in the omicron epoch had no medical indication other than mild COVID-19. Neonatal complications were significantly more common with CS than with vaginal delivery, and there was no occurrence of COVID-19 in healthcare workers. In this study, there were no cases of COVID-19 among health care workers; establishing a system to perform vaginal delivery for pregnant women with COVID-19 could have reduced the number of CS and neonatal complications.

Prognostic relevance of tumor-resident memory T cells in metastatic lymph nodes of esophageal squamous cell carcinoma.

Tumor-resident memory T (TRM ) cells in primary tumors are reportedly associated with a favorable prognosis in several malignancies. However, the behaviors and functions of TRM cells in regional lymph nodes (LNs) of esophageal cancer remain poorly understood. The aim of this study was to elucidate the effects of TRM cells in regional LNs of esophageal cancer on clinicopathological findings and prognosis. Specimens of esophageal cancer and primary metastatic LNs (recurrent nerve LNs) were obtained from 84 patients who underwent radical esophagectomy between 2011 and 2017. We performed immunohistochemistry to enumerate and analyze TRM cells, and used flow cytometry to investigate the function of TRM cells. TRM cells were observed in both metastatic LNs and primary tumors. TRM cell-rich specimens exhibited reduced lymphatic invasion and LN metastasis and prolonged survival compared with TRM cell-poor specimens. TRM cells in metastatic LNs were more significantly associated with enhanced survival than TRM cells in primary tumors. TRM cells expressed high levels of granzyme B as a cytotoxicity marker. Our results suggested that high TRM cell infiltration in metastatic LNs improves survival even though LN metastasis is commonly associated with poor prognosis. TRM cells possibly contribute to antitumor immunity in regional LNs.

Safety and efficacy of anifrolumab therapy in systemic lupus erythematosus in real-world clinical practice: LOOPS registry.

OBJECTIVES: To determine the safety and efficacy of anifrolumab in patients with systemic lupus erythematosus (SLE) classified based on the Lupus Low Disease Activity State (LLDAS) in real-world clinical practice. METHODS: This retrospective observational study involved SLE patients who started anifrolumab therapy. The primary end point was the retention rate over 26 weeks after initiating anifrolumab therapy; 45 patients followed up for 12 weeks or longer were analyzed in the following groups to determine the safety and efficacy up to week 12 after treatment initiation: 1) non-LLDAS achievement group and 2) minor flare group. Safety and efficacy were compared between the minor flare group and the standard of care (SoC) group (treated by adding glucocorticoids (GCs) or immunosuppressants) after adjustment with inverse probability of treatment weighting using propensity score (PS-IPTW). RESULTS: The retention rate of anifrolumab was 89.7% at week 26.The LLDAS achievement rates at week 12 were 42.9% and 66.7% in the non-LLDAS achievement and minor flare groups, respectively. In both groups, GC doses and SELENA-SLEDAI score significantly decreased. When the anifrolumab group with minor flare was compared with the SoC group or the GC dose increase group, the GC dose and SLEDAI score were significantly lower in the anifrolumab group than in both groups; there was no significant difference in LLDAS achievement. CONCLUSIONS: At week 26 after initiating anifrolumab therapy, ∼90% patients remained on therapy. Anifrolumab might lower disease activity without initiating GCs and reduce GC doses, especially in patients who experience minor flares after LLDAS achievement.

Reduced homovanillic acid, SDF-1α and SCGF-ß levels in cerebrospinal fluid are related to depressive states in systemic lupus erythematosus.

OBJECTIVE: This study aimed to seek a new method of evaluation and surrogate markers for diffuse neuropsychiatric SLE (NPSLE). METHODS: We enrolled 44 patients with SLE between 2017 and 2020 who fulfilled at least one of three specific inclusion criteria: high disease activity, abnormal findings (cerebrospinal fluid [CSF] examination, brain MRI, or electroencephalography), or history of neuropsychiatric illness. Psychiatric symptom rating scales (PSYRATS) were evaluated retrospectively. The primary end point was the PSYRATS positivity rate in SLE patients who had not been diagnosed with diffuse NPSLE. RESULTS: Based on the 1999 ACR classifications, 7 out of the 44 patients evaluated using PSYRATS had been diagnosed with diffuse NPSLE. PSYRATS positivity was seen in 13 out of 37 SLE patients (35.1%) who had not been diagnosed with diffuse NPSLE, and all these patients were positive for Montgomery-Åsberg Depression Rating Scale (MADRS), an indicator of depression state in PSYRATS. Additionally, in the 20 SLE patients exhibiting depression symptoms who were MADRS-positive, CSF concentrations of the neuroinflammatory markers homovanillic acid (HVA; P = 0.0400), stromal cell-derived factor-1α (SDF-1α; P = 0.0431) and stem cell growth factor-ß (SCGF-1ß; P = 0.0061) were significantly reduced compared with the 24 MADRS-negative SLE patients, and the levels of HVA, SDF-1α and SCGF-1ß correlated with one another (P < 0.05). CONCLUSION: Many patients with active SLE have subclinical depression, and MADRS evaluation of neuropsychiatric symptoms is useful for detecting them. Additionally, the decrease in CSF levels of HVA, SDF-1 α and SCGF-1ß reflects the same pathology, and these may serve as surrogate markers.

TGF-ß3 in differentiation and function of Tph-like cells and its relevance to disease activity in patients with systemic lupus erythematosus.

OBJECTIVES: T peripheral helper (Tph) cells have major roles in pathological processes in SLE. We sought to clarify the mechanisms of Tph cell differentiation and their relevance to clinical features in patients with SLE. METHOD: Phenotypes and functions of Tph cell-related markers in human CD4+ T cells purified from volunteers or patients were analysed using flow cytometry and quantitative PCR. Renal biopsy specimens from patients with LN were probed by multicolour immunofluorescence staining. RESULTS: Among multiple cytokines, transforming growth factor (TGF)-ß3 characteristically induced programmed cell death protein 1 (PD-1)hi musculoaponeurotic fibrosarcoma (MAF)+, IL-21+IL-10+ Tph-like cells with a marked upregulation of related genes including PDCD-1, MAF, SOX4 and CXCL13. The induction of Tph-like cells by TGF-ß3 was suppressed by the neutralization of TGF-ß type II receptor (TGF-ßR2). TGF-ß3-induced Tph-like cells efficiently promoted the differentiation of class-switch memory B cells into plasmocytes, resulting in enhanced antibody production. The proportion of Tph cells in the peripheral blood was significantly increased in patients with SLE than in healthy volunteers in concordance with disease activity and severity of organ manifestations such as LN. TGF-ß3 was strongly expressed on macrophages, which was associated with the accumulation of CD4+ C-X-C chemokine receptor (CXCR5)-PD-1+ Tph cells, in the renal tissue of patients with active LN. CONCLUSION: The induction of Tph-like cells by TGF-ß3 mainly produced from tissue macrophages plays a pivotal role in the pathological processes of active LN by enhancing B-cell differentiation in patients with SLE.

Semiconducting Electronic Structure of the Ferromagnetic Spinel HgCr_{2}Se_{4} Revealed by Soft-X-Ray Angle-Resolved Photoemission Spectroscopy.

We study the electronic structure of the ferromagnetic spinel HgCr_{2}Se_{4} by soft-x-ray angle-resolved photoemission spectroscopy (SX-ARPES) and first-principles calculations. While a theoretical study has predicted that this material is a magnetic Weyl semimetal, SX-ARPES measurements give direct evidence for a semiconducting state in the ferromagnetic phase. Band calculations based on the density functional theory with hybrid functionals reproduce the experimentally determined band gap value, and the calculated band dispersion matches well with ARPES experiments. We conclude that the theoretical prediction of a Weyl semimetal state in HgCr_{2}Se_{4} underestimates the band gap, and this material is a ferromagnetic semiconductor.

Delayed Eating Schedule Raises Mean Glucose Levels in Young Adult Males: a Randomized Controlled Cross-Over Trial.

BACKGROUND: Misalignment of meals to the biological clock may cause adverse effects on glucose metabolism. However, the effects of repeated different eating schedules (early compared with late) on glucose concentration throughout the day are poorly understood. OBJECTIVES: We examined the effects of different eating schedules on the 24-h glucose response using a continuous glucose monitor (CGM). METHODS: Eight young adult males (age, 20.9 ± 3.4 y; body mass index: 21.3 ± 1.8 kg/m2) each followed 2 different eating schedules (early [08:30, 13:30, and 19:30] and late [12:00, 17:00, and 23:00]) in random order. These diet interventions were conducted for 8 d, with an experimental period of 3 d and 2 nights (from dinner on day 7) after 7 d of free living. The 3 meals in each intervention were nutritionally equivalent (55% carbohydrate, 15% protein, and 30% fat). The 24-h mean interstitial glucose concentration on day 8 was obtained under controlled conditions using the CGM (primary outcome). These concentrations were compared among the following 3 schedules using Dunnett's test, with the early eating schedule as reference (1 compared with 2 and 1 compared with 3): 1) early eating schedule (control), 2) late eating schedule according to the clock time (08:00 on day 8 to 08:00 on day 9), and 3) late eating schedule according to the time elapsed since the first meal for 24 h. RESULTS: The 24-h mean ± SD interstitial glucose concentrations when participants followed the late eating schedule were higher than those when they followed the early eating schedule in terms of clock time (91.2 ± 2.9 compared with 99.2 ± 4.6 mg/dL, P = 0.003) and time elapsed (91.2 ± 2.9 compared with 98.3 ± 3.8 mg/dL, P < 0.001). CONCLUSIONS: A late eating schedule increases the mean 24-h interstitial glucose concentration in young adult males. This insight will have useful implications in determining meal timings, especially for those with conditions such as diabetes.