Real-world management of patients with neuromyelitis optica spectrum disorder using satralizumab: Results from a Japanese claims database.

BACKGROUND: Satralizumab, a humanized anti-interleukin-6 receptor monoclonal antibody, has been approved globally for the treatment of neuromyelitis optica spectrum disorder (NMOSD), based on positive results from two randomized, double-blind, phase 3 studies: SAkuraSky (NCT02028884) and SAkuraStar (NCT02073279). There remains an unmet need to understand the real-world management of NMOSD, especially in patients undergoing tapering of concomitant therapy. We examined real-world treatment patterns, including concomitant glucocorticoids and immunosuppressants, and relapse in satralizumab-treated patients with NMOSD, using a Japanese administrative hospital claims database. METHODS: We used retrospective data from the Medical Data Vision hospital-based administrative claims database. The index date was the date of first satralizumab prescription and the study period was set between August 2018 and March 2022. Patients were included in the overall population if they had a first prescription for satralizumab between August 2020 and March 2022, an International Classification of Disease, Version10 code of G36.0 prior to March 2022, and were observable for ≥90 days prior to the index date. The primary endpoint was the percentage of patients with relapse-free reduction of oral glucocorticoids to 0 mg/day at 360 days of continued satralizumab treatment. Secondary endpoints included time to relapse, number of relapses after the index date while being on continuous satralizumab treatment, annualized relapse rate before and after the index date, and concomitant medication use. Relapse and dose reduction were identified using definition specifically developed for this study. RESULTS: Of the 131 patients included in the overall population, most were female (90.8 %), aged 18-65 years (75.6 %), and were prescribed oral glucocorticoids (93.1 %). Azathioprine (19.1 %) and tacrolimus, a calcineurin inhibitor (18.3 %), were the most common immunosuppressants at index date. Six (4.6 %) patients had a history of biologic use (tocilizumab, 1 [0.8 %]; eculizumab, 5 [3.8 %]). Among 111 patients observable for 360 days pre-index, there were 0.6 ± 0.8 (mean ± SD) relapses during 360 days before the index date. The median (interquartile range) duration of satralizumab exposure was 197.0 (57.0-351.0) days. Most (125/131; 95.4 %) patients were relapse-free post-index; 6 (4.6 %) patients relapsed within 90 days after the index date, of which 2 had the first relapse within 7 days after the index date. Among 21 patients with 360-day follow-up, 6 (28.6 %) patients were on 0 mg/day dose of glucocorticoid prescription without relapse 360 days post-index. Of these 6 patients, 2 had no prescription of oral glucocorticoids at the index date and remained glucocorticoid- and relapse-free 360 days after the index date. CONCLUSION: These real-world data support the phase 3 clinical trials. Our results, over a median duration of satralizumab exposure of 197.0 days, showed that a majority (125/131, 95.4 %) of patients were relapse-free after initiating satralizumab treatment. The number of glucocorticoid-free patients without relapse increased over time under continuous satralizumab prescription. Further studies are needed to confirm if satralizumab can be used as a potential immunosuppressant- and glucocorticoid-sparing agent.

HLA typing of patients who developed subacute thyroiditis and Graves' disease after SARS-CoV-2 vaccination: a case report.

BACKGROUND: Cases of subacute thyroiditis (SAT) after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination have been reported. A human leukocyte antigen (HLA) allele, HLA-B*35, appears to be involved in the pathogenesis of SAT. CASE PRESENTATION: We conducted HLA typing of one patient with SAT and another with both SAT and Graves' disease (GD), which developed after SARS-CoV-2 vaccination. Patient 1, a 58-year-old Japanese man, was inoculated with a SARS-CoV-2 vaccine (BNT162b2; Pfizer, New York, NY, USA). He developed fever (38 °C), cervical pain, palpitations, and fatigue on day 10 after vaccination. Blood chemistry tests revealed thyrotoxicosis and elevated serum C-reactive protein (CRP) and slightly increased serum antithyroid-stimulating antibody (TSAb) levels. Thyroid ultrasonography revealed the characteristic findings of SAT. Patient 2, a 36-year-old Japanese woman, was inoculated twice with a SARS-CoV-2 vaccine (mRNA-1273; Moderna, Cambridge, MA, USA). She developed fever (37.8 °C) and thyroid gland pain on day 3 after the second vaccination. Blood chemistry tests revealed thyrotoxicosis and elevated serum CRP, TSAb, and antithyroid-stimulating hormone receptor antibody levels. Fever and thyroid gland pain persisted. Thyroid ultrasonography revealed the characteristic findings of SAT (i.e., slight swelling and a focal hypoechoic area with decreased blood flow). Prednisolone treatment was effective for SAT. However, thyrotoxicosis causing palpitations relapsed thereafter, for which thyroid scintigraphy with 99mtechnetium pertechnetate was conducted, and the patient was diagnosed with GD. Thiamazole treatment was then initiated, which led to improvement in symptoms. CONCLUSION: HLA typing revealed that both patients had the HLA-B*35:01, -C*04:01, and -DPB1*05:01 alleles. Only patient 2 had the HLA-DRB1*11:01 and HLA-DQB1*03:01 alleles. The HLA-B*35:01 and HLA-C*04:01 alleles appeared to be involved in the pathogenesis of SAT after SARS-CoV-2 vaccination, and the HLA-DRB1*11:01 and HLA-DQB1*03:01 alleles were speculated to be involved in the postvaccination pathogenesis of GD.

A patient with ketosis-prone type 2 diabetes showing nearly normalized glucose tolerance after recovery from severe diabetic ketoacidosis.

Unprovoked A-ß+ ketosis-prone type 2 diabetes (KPD) is characterized by the sudden onset of diabetic ketosis/ketoacidosis (DK/DKA) without precipitating factors, negative anti-islet autoantibodies ("A- "), and preservation of ß-cell function ("ß+ ") after recovery from DKA using insulin therapy. However, there have been few reports on glucose tolerance after recovery. We present a case of KPD with nearly normalized glucose tolerance after recovery from severe DKA. A 41-year-old obese woman first presented with unprovoked severe DKA, i.e., ketonuria, plasma glucose 570 mg/dL, pH 7.18, and HCO3 - 5.2 mmol/L, without anti-islet autoantibodies. She achieved insulin-free glycemic remission after recovery from DKA, leading to the diagnosis of KPD. Thereafter, 75 g oral glucose tolerance test showed impaired fasting glucose and time-in-range using intermittently scanned continuous glucose monitoring was 97% without medication. These findings suggest that, despite the initial severe DKA, some patients with KPD might achieve normalized glucose tolerance after recovery. The similar onset patterns of DKA necessitates appropriately distinguishing KPD from acute-onset type 1B (idiopathic) diabetes. Supplementary Information: The online version contains supplementary material available at 10.1007/s13340-022-00599-6.

HbA1c level may be a risk factor for oxygen therapy requirement in patients with coronavirus disease 2019.

INTRODUCTION: Many clinical studies have identified significant predictors or risk factors for the severity or mortality of coronavirus disease 2019 (COVID-19) cases. However, there are very limited reports on the risk factors for requiring oxygen therapy during hospitalization. In particular, we sought to investigate whether plasma glucose and HbA1c levels could be risk factors for oxygen therapy requirement. MATERIALS AND METHODS: A single-center, retrospective study was conducted of 131 COVID-19 patients hospitalized at Saitama Medical University Hospital between March 2020 and November 2020. To identify the risk factors for oxygen therapy requirement during hospitalization, a stepwise multivariate binary logistic regression analysis was performed using several clinical parameters commonly obtained on admission, including plasma glucose and HbA1c levels. RESULTS: Of the 131 patients with COVID-19, 33.6% (44/131) received oxygen therapy during hospitalization. According to the logistic regression analysis, male sex (odds ratio [OR]: 8.76, 95% confidence interval [CI]: 1.65-46.5, P < 0.05), age (OR: 1.07, 95% CI: 1.02-1.12, P < 0.01), HbA1c levels (OR: 1.94, 95% CI: 1.09-3.44, P < 0.05), and serum C-reactive protein (CRP) levels (OR: 2.22, 95% CI: 1.54-3.20, P < 0.01) emerged as independent variables associated with oxygen therapy requirement during hospitalization. CONCLUSIONS: In addition to male sex, age, and serum CRP levels, HbA1c levels on admission may serve as a risk factor for oxygen therapy requirement during the clinical course of COVID-19, irrespective of diabetes history and status. This may contribute to the efficient delegation of limited numbers of hospital beds to patients at risk for oxygen therapy requirement.

Clinical Significance of Insulin Peptide-specific Interferon-γ-related Immune Responses in Ketosis-prone Type 2 Diabetes.

CONTEXT: Unprovoked A-ß+ ketosis-prone type 2 diabetes (KPD) is characterized by the sudden onset of diabetic ketosis/ketoacidosis (DK/DKA) without precipitating factors, negative anti-islet autoantibodies ("A-"), and preservation of ß-cell function ("ß+") after recovery from DKA. Although this phenotype often appears with acute hyperglycemia and DK/DKA just like acute-onset type 1 diabetes (AT1D), the involvement of anti-islet immune responses remains unknown. OBJECTIVE: We sought to clarify the immunological role of insulin-associated molecules in unprovoked A-ß+ KPD. METHODS: In this cross-sectional study, blood samples from 75 participants (42 with AT1D and 33 with KPD) were evaluated for interferon (IFN)-γ-secreting peripheral blood mononuclear cells (PBMCs) reactive to 4 insulin B-chain amino acid 9-23-related peptides (B:9-23rPep) using an enzyme-linked immunospot (ELISpot) assay. RESULTS: Overall, 36.4% (12/33) of KPD participants showed positive IFN-γ ELISpot assay results; the positivity rate in KPD was similar to that in AT1D (38.1%; 16/42) and statistically significantly higher than the previously reported rate in type 2 diabetes (8%; 2/25; P < .0167). Moreover, B:9-23rPep-specific IFN-γ-producing PBMC frequency was negatively correlated with age and ad lib serum C-peptide levels in all KPD participants and positively correlated with glycated hemoglobin A1c level in KPD participants with positive IFN-γ ELISpot results. CONCLUSION: These findings suggest the involvement of B:9-23rPep-specific IFN-γ-related immunoreactivity in the pathophysiology of some unprovoked A-ß+ KPD. Moreover, increased immunoreactivity may reflect transiently decreased ß-cell function and increased disease activity at the onset of DK/DKA, thereby playing a key role in DK/DKA development in this KPD phenotype.

Clinical features resembling subcutaneous insulin resistance observed in a patient with type 2 diabetes and severe COVID-19-associated pneumonia: a case report.

We report the case of a 52-year-old hyperglycemic woman with type 2 diabetes and severe coronavirus disease 2019 (COVID-19)-associated pneumonia, possibly involving the subcutaneous insulin resistance (SIR) syndrome. After admission for pneumonia, her average daily blood glucose (BG) levels remained at 300-400 mg/dL, although the required dosage of subcutaneous insulin markedly increased (~ 150 units/day; ~ 2.63 units/kg/day). Furthermore, the patient had generalized edema along with hypoalbuminemia, developed extensive abdominal purpuras, and had increased plasma D-dimer levels during treatment, suggestive of coagulation abnormalities. Therefore, intravenous infusion of regular insulin was initiated. The BG level subsequently decreased to < 200 mg/dL 2 days after administering 18 units/day of insulin infusion and 118 units/day of subcutaneous insulin, suggesting that subcutaneous insulin alone might have been ineffective in reducing hyperglycemia, which is clinically consistent with the characteristics of an SIR syndrome. Impaired skin microcirculation arising from coagulation abnormalities, subcutaneous edema associated with inflammation-related hypoalbuminemia or vascular hyperpermeability, and/or reduction in subcutaneous blood flow due to COVID-19-induced downregulation of angiotensin-converting enzyme 2 might be associated with the development of pathological conditions that resemble SIR syndrome, leading to impaired subcutaneous insulin absorption. Supplementary Information: The online version contains supplementary material available at 10.1007/s13340-021-00500-x.

Simultaneous development of Graves' disease and type 1 diabetes during anti-programmed cell death-1 therapy: A case report.

We present the first case of simultaneous development of Graves' disease and type 1 diabetes during anti-programmed cell death 1 therapy. A 48-year-old man with parotid gland adenocarcinoma and lung metastasis had received five courses of nivolumab. Fourteen days after administration of the sixth course, his casual plasma glucose and hemoglobin A1c levels were 379 mg/dL and 7.2%, respectively. Furthermore, thyrotoxicosis was detected with a blood test. Serum total ketone body and thyroid-stimulating hormone receptor antibody levels increased, and serum C-peptide level decreased to 0.01 ng/mL thereafter. Thus, we concluded that he simultaneously developed anti-programmed cell death 1 therapy-associated type 1 diabetes and Graves' disease. Among Japanese patients with autoimmune polyglandular syndrome type III, the frequency of human leukocyte antigen-DRB1*04:05 is higher in those with both type 1 diabetes and Graves' disease. Our case had human leukocyte antigen-DRB1*04:05, which might be associated with the simultaneous development of the two diseases.

Bodyweight threshold for sudden onset of ketosis might exist in ketosis-prone type 2 diabetes patients.

Ketosis-prone type 2 diabetes is recognized as atypical diabetes. These patients are often male, characterized by obesity, sudden onset of ketosis and a transient decrease in insulin secretion capacity that can be recovered with temporal insulin therapy. Here, we report a male patient with ketosis-prone type 2 diabetes who was followed up for 8 years. During the follow-up period, his bodyweight fluctuated and he experienced four episodes of critical ketosis recurrence in association with bodyweight gain. He discontinued insulin therapy after each ketosis episode within the first 4 years, but thereafter, he had to continue insulin therapy because of decreased insulin secretion capacity. Interestingly, his peak bodyweight just before the repeated ketosis episode gradually decreased, and the insulin secretion capacity after the recovery from repeated ketosis decreased in parallel with his peak bodyweight. This long-term clinical course might be a clue to understand the pathophysiology of ketosis-prone type 2 diabetes.

Significance of peripheral mononuclear cells producing interferon-γ in response to insulin B:9-23-related peptides in subtypes of type 1 diabetes.

Type 1 diabetes is largely caused by ß-cell destruction through anti-islet autoimmunity. Reportedly, interferon (IFN)-γ-secreting peripheral blood mononuclear cells (PBMCs) specific to four insulin B-chain amino acid 9-23-related peptides (B:9-23rPep) were increased in type 1 diabetes participants. This study aimed to investigate the PBMC frequencies in subtypes of type 1 diabetes using enzyme-linked immunospot assay. In this cross-sectional study, peripheral blood samples were obtained from 148 participants including 72 with acute-onset type 1 diabetes (AT1D), 51 with slowly progressive insulin-dependent diabetes mellitus (SPIDDM), and 25 with type 2 diabetes. The frequency of B:9-23rPep-specific IFN-γ-producing PBMCs was significantly higher in AT1D participants than in SPIDDM and type 2 diabetes participants. Meanwhile, a significant inverse correlation was observed between the PMBC frequencies and insulin secretion capacity in SPIDDM participants. These findings suggest that the increased peripheral B:9-23rPep-specific IFN-γ immunoreactivity reflects decreased functional ß-cell mass and greater disease activity of type 1 diabetes.

The Role of Transcription Factors and Nuclear Pore Proteins in Controlling the Spatial Organization of the Yeast Genome.

Loss of nuclear pore complex (NPC) proteins, transcription factors (TFs), histone modification enzymes, Mediator, and factors involved in mRNA export disrupts the physical interaction of chromosomal sites with NPCs. Conditional inactivation and ectopic tethering experiments support a direct role for the TFs Gcn4 and Nup2 in mediating interaction with the NPC but suggest an indirect role for factors involved in mRNA export or transcription. A conserved "positioning domain" within Gcn4 controls interaction with the NPC and inter-chromosomal clustering and promotes transcription of target genes. Such a function may be quite common; a comprehensive screen reveals that tethering of most yeast TFs is sufficient to promote targeting to the NPC. While some TFs require Nup100, others do not, suggesting two distinct targeting mechanisms. These results highlight an important and underappreciated function of TFs in controlling the spatial organization of the yeast genome through interaction with the NPC.

Small RNAs detected in exosomes derived from the MH7A synovial fibroblast cell line with TNF-α stimulation.

Rheumatoid arthritis (RA) is an autoimmune disease that causes the chronic inflammation of the joints. Intercellular communication containing synovial fibroblasts seems to play a major role in RA pathogenesis. In this study, to better understand intercellular communication related to RA pathogenesis, we identified exosomal microRNAs (miRNAs) derived from synovial fibroblasts. Exosomes were collected from an RA synovial fibroblast (RASF) cell line, namely, MH7A, with or without stimulation by tumor necrosis factor alpha (TNF-α). We used small RNA sequencing to analyze the profile of small RNAs, including miRNAs, in MH7A exosomes and cells. By using differential expression analysis, we identified four miRNAs (miR-155-5p, miR-146a-5p, miR-323a-5p, and miR-1307-3p) that are upregulated in exosomes with TNF-α stimulation. The identification of miR-155-5p and miR-146a-5p which have been reported in RA patients demonstrated the validity of our experimental model. Other two miRNAs were newly identified. miR-323a-5p was predicted to target the protein encoding gene CD6, which attenuates T-cell activation signals, and miR-1307-3p was predicted to target the protein encoding gene N-myc downstream-regulated gene 2 (NDRG2), which inhibits osteoclast-related gene expression. The results suggested that these miRNAs might be involved in RA pathogenesis. We hope our results will help us understand the role of RASF exosomes in RA pathogenesis.

Administration of thiamazole for Graves' disease might trigger the onset of type 1 diabetes.

Thiamazole might trigger the onset of type 1 diabetes.

High-throughput evaluation of T7 promoter variants using biased randomization and DNA barcoding.

Cis-regulatory elements (CREs) are one of the important factors in controlling gene expression and elucidation of their roles has been attracting great interest. We have developed an improved method for analyzing a large variety of mutant CRE sequences in a simple and high-throughput manner. In our approach, mutant CREs with unique barcode sequences were obtained by biased randomization in a single PCR amplification. The original T7 promoter sequence was randomized by biased randomization, and the target number of base substitutions was set to be within the range of 0 to 5. The DNA library and subsequent transcribed RNA library were sequenced by next generation sequencers (NGS) to quantify transcriptional activity of each mutant. We succeeded in producing a randomized T7 promoter library with high coverage rate at each target number of base substitutions. In a single NGS analysis, we quantified the transcriptional activity of 7847 T7 promoter variants. We confirmed that the bases from -9 to -7 play an important role in the transcriptional activity of the T7 promoter. This information coincides with the previous researches and demonstrated the validity of our methodology. Furthermore, using an in vitro transcription/translation system, we found that transcriptional activities of these T7 variants were well correlated with the resultant protein abundance. We demonstrate that our method enables simple and high-throughput analysis of the effects of various CRE mutations on transcriptional regulation.

Retrospective evaluation of the clinical characteristics associated with Corynebacterium species bacteremia.

OBJECTIVES: Corynebacterium spp. are becoming recognized as pathogens that potentially cause various infections. We aimed to evaluate the clinical characteristics associated with Corynebacterium spp. bacteremia. PATIENTS AND METHODS: We retrospectively reviewed the medical records of all adult patients who had positive blood cultures for Corynebacterium spp. in a single university hospital between January 2014 and December 2016. Patients were divided into a bacteremia group and a contamination group based on microbiological test results and clinical characteristics. Patients' characteristics, antimicrobial susceptibility of isolated species, antimicrobials administered, and patient outcomes were evaluated. RESULTS: Corynebacterium spp. were isolated from blood samples of 63 patients; Corynebacterium striatum was the predominant isolate. Twenty-eight patients were determined to have bacteremia. Younger age (p=0.023), shorter time to positivity (p=0.006), longer hospital stay (p=0.009), and presence of an indwelling vascular catheter (p=0.002) were observed more often in the bacteremia group compared to the contamination group. The source of infection in most patients with bacteremia was an intravenous catheter. All tested strains were susceptible to vancomycin. Four of the 27 patients with bacteremia died, despite administration of appropriate antimicrobial therapy. CONCLUSIONS: We found that younger age, shorter time to positivity, and presence of an indwelling catheter were related to bacteremia caused by Corynebacterium spp. Appropriate antimicrobials should be administered once Corynebacterium spp. are isolated from the blood and bacteremia is suspected.

Retrospective evaluation of the clinical characteristics associated with Corynebacterium species bacteremia

ABSTRACT Objectives: Corynebacterium spp. are becoming recognized as pathogens that potentially cause various infections. We aimed to evaluate the clinical characteristics associated with Corynebacterium spp. bacteremia. Patients and methods: We retrospectively reviewed the medical records of all adult patients who had positive blood cultures for Corynebacterium spp. in a single university hospital between January 2014 and December 2016. Patients were divided into a bacteremia group and a contamination group based on microbiological test results and clinical characteristics. Patients' characteristics, antimicrobial susceptibility of isolated species, antimicrobials administered, and patient outcomes were evaluated. Results: Corynebacterium spp. were isolated from blood samples of 63 patients; Corynebacterium striatum was the predominant isolate. Twenty-eight patients were determined to have bacteremia. Younger age (p = 0.023), shorter time to positivity (p = 0.006), longer hospital stay (p = 0.009), and presence of an indwelling vascular catheter (p = 0.002) were observed more often in the bacteremia group compared to the contamination group. The source of infection in most patients with bacteremia was an intravenous catheter. All tested strains were susceptible to vancomycin. Four of the 27 patients with bacteremia died, despite administration of appropriate antimicrobial therapy. Conclusions: We found that younger age, shorter time to positivity, and presence of an indwelling catheter were related to bacteremia caused by Corynebacterium spp. Appropriate antimicrobials should be administered once Corynebacterium spp. are isolated from the blood and bacteremia is suspected.

Comparison of the Frequency of Angioedema Attack, before and during Pregnancy, in a Patient with Type I Hereditary Angioedema.

The patient was a 38-year-old Japanese woman who had been diagnosed with hereditary angioedema type I at 7 years of age based on her family history. She had undergone four pregnancies. She gave birth to a healthy baby girl after her first pregnancy and had reported few episodes of angioedema. However, she subsequently required abortions due to frequent angioedema episodes that occurred during her three subsequent pregnancies. Thus, our patient showed two clinical pregnancy courses. After treating her with C1-inhibitor concentrate, her symptoms of angioedema disappeared. The preventive use of C1 inhibitor concentrates should be considered in hereditary angioedema (HAE) patients with frequent angioedema attacks during pregnancy.

Impact of interventions by an antimicrobial stewardship program team on appropriate antimicrobial therapy in patients with bacteremic urinary tract infection.

BACKGROUND: Inappropriate antimicrobial therapy often leads to poor outcomes. This study aimed to evaluate the impact of an antimicrobial stewardship program (ASP) team on appropriate therapy, in patients with bacteremic urinary tract infection (UTI). PATIENTS AND METHODS: We retrospectively reviewed the interventions by the ASP team in 807 patients with bacteremic UTI. Interventions were divided into 3 groups: group A (conventional report), group B (conventional report and written alert on the chart), and group C (conventional report and oral recommendation with/without written alert). The appropriateness of antimicrobial therapy was assessed at 2 time points, based on blood culture results. RESULTS: The ASP team estimated that 166 and 576 patients received inappropriate antimicrobial therapy based on the results of Gram staining, and final report, respectively. Appropriate therapy after intervention was administered to 53.2% of group A, 63.5% of group B, and 89.3% of group C patients, respectively. Mortality was significantly lower in patients of de-escalation than in those with no antimicrobial changes, without prolonged hospital stay. CONCLUSION: This study provides one plausible benchmark for appropriate antimicrobial therapy by ASP, while observer bias and survivor treatment selection bias exist, and further studies including evaluation for severity are needed.

Erratum: Precise genome-wide base editing by the CRISPR Nickase system in yeast.

A correction to this Article has been published and is linked from the HTML version of this paper. The error has been fixed in the paper.

Nuclear Pore Complexes: A Scaffold Regulating Developmental Transcription?

Nuclear pore complexes (NPCs) have a conserved, but poorly understood, role in transcriptional regulation. Recently, in Developmental Cell, Raices et al. argued that tissue-specific nuclear pore proteins (Nups) act as scaffolds that recruit the transcription factor Mef2C to the NPC, promoting transcription of NPC-associated genes during muscle development.