Risk of Urogenital Bacterial Infection with Sodium-Glucose Cotransporter-2 Inhibitors: A Retrospective Cohort Study Using a Claims Database.

INTRODUCTION: The association between sodium-glucose cotransporter-2 (SGLT2) inhibitors and the risk of urogenital infections remains controversial. This study aimed to investigate the association between SGLT2 inhibitors and the incidence of perineal soft tissue infections, including Fournier's gangrene (FG), genital bacterial infections, and urinary tract infections (UTIs), using administrative claims data in Japan. METHODS: In this retrospective cohort study, we utilized the JMDC Claims Database. The study included patients aged 18 years or older diagnosed with type 2 diabetes mellitus, identified by a diagnostic code, who received new prescriptions for SGLT2 inhibitors or dipeptidyl peptidase 4 (DPP-4) inhibitors between April 2014 and August 2020. Using one-to-one propensity score (PS) matching, we compared the incidence of perineal soft tissue infections, including FG, genital bacterial infection, and UTIs between groups treated with SGLT2 and DPP-4 inhibitors. Hazard ratios (HR) and their 95% confidence intervals (CI) were estimated using the Cox proportional hazards model. RESULTS: We identified 34,897 patients in the SGLT2 inhibitor group and 135,311 patients in the DPP-4 inhibitor group. After one-to-one PS matching, 31,665 pairs were generated. The mean age of the patients was 51 years, with approximately 70% being male. The use of SGLT2 inhibitors was associated with a decreased risk of UTI (HR 0.90, 95% CI 0.83-0.98) and an increased risk of genital bacterial infection (HR 1.23, 95% CI 1.03-1.46) compared to DPP-4 inhibitors. However, no significant association was observed with perineal soft tissue infection (HR 1.05, 95% CI 0.61-1.81). CONCLUSIONS: SGLT2 inhibitors were associated with a reduced risk of UTI and an increased risk of genital bacterial infection. They showed no significant association with perineal soft tissue infection when compared to DPP-4 inhibitors. Future research should explore broader demographics, focusing on the elderly and achieving gender balance, to gain a comprehensive understanding of infection risks.

Glucocorticoid treatment and clinical outcomes in patients with polymyalgia rheumatica: A cohort study using routinely collected health data.

OBJECTIVE: We aimed to describe the following in patients with polymyalgia rheumatica (PMR): (1) real-world glucocorticoid (GC) therapy, (2) improvement in inflammatory parameters associated with disease activity (C-reactive protein [CRP] level and erythrocyte sedimentation rate [ESR]), and (3) incidence of GC-related adverse events (AEs). METHODS: A cohort study was conducted using a Japanese electronic medical records database. We included newly diagnosed PMR patients aged≥50years with baseline CRP levels≥10mg/L and/or ESR>30mm/h and an initial GC dose of≥5mg/day. The outcomes were GC dose, inflammatory parameters, and GC-related AEs. RESULTS: A total of 373 PMR patients (mean age, 77.3 years) were analyzed. The median initial GC dose was 15.0mg/day, which gradually decreased to 3.5mg/day by week 52. The median cumulative GC dose at week 52 was 2455.0mg. The median CRP level on day 0 was 64.3mg/L, which decreased during weeks 4-52 (1.4-3.2mg/L). At week 52, 39.0% of patients had a CRP level>3.0mg/L. The cumulative incidence of GC-related AEs at week 52 was 49.0% for osteoporosis, 30.2% for diabetes, 14.9% for hypertension, 12.2% for peptic ulcer, 11.3% for dyslipidemia, 2.9% for glaucoma, and 4.3% for serious infection. The incidence of osteoporosis and diabetes increased with the GC dose. CONCLUSION: The incidence of GC-related AEs was associated with the GC dose in PMR patients. Further research is required to identify treatment strategies that can effectively control PMR disease activity while minimizing GC use.

Effect of sarilumab on unacceptable pain and inflammation control in Japanese patients with moderately-to-severely active rheumatoid arthritis: Post hoc analysis of a Phase III study (KAKEHASI).

OBJECTIVE: The aim of this study is to investigate the effects of sarilumab on unacceptable pain [UP; visual analogue scale (VAS) >40 mm] and inflammation in patients with moderately-to-severely active rheumatoid arthritis. METHODS: In this post hoc analysis of the KAKEHASI study, 243 patients received methotrexate with sarilumab 150 or 200 mg or placebo every other week, over 52 weeks. The proportion of patients with UP and correlations of changes in pain VAS from baseline with uncontrolled inflammation (C-reactive protein ≥1 mg/dl) and disease activity indices were assessed. RESULTS: Almost 80% of patients (192/243) had UP at baseline, including ∼60% of patients with uncontrolled inflammation. Among patients receiving sarilumab, inflammation decreased rapidly, with 90% of patients achieving controlled inflammation by Week 2, while 63.1% continued to have UP. The proportion of patients with UP further decreased by Week 16 (28.5%, sarilumab vs. 64.0%, placebo). By Week 52, only ∼10% of patients had UP. Changes in pain VAS correlated with most disease activity indices and patient-reported outcomes. However, marked correlations between changes in pain VAS and C-reactive protein were observed only at Week 16. CONCLUSION: Sarilumab treatment reduced UP and inflammation in Japanese patients with rheumatoid arthritis.

Clinical features of polymyalgia rheumatica patients in Japan: Analysis of real-world data from 2015 to 2020.

OBJECTIVES: To assess clinical features in patients with polymyalgia rheumatica (PMR) in Japan by the International Classification of Disease (ICD)-10 code assignment. METHODS: Demographics, treatment patterns, and concomitant diseases (identified using ICD-10 code only) in patients who were assigned the PMR ICD-10 code M35.3 at least once between 1 January 2015 and 31 December 2020 were aggregated from a nationwide medical information database owned by the Health, Clinic, and Education Information Evaluation Institute. RESULTS: The cumulative number of patients with PMR was 6325 (mean [standard deviation] age, 74.3 [11.4] years; male:female, 1:1.3). Most patients were >50 years (96.5%) with >33% between 70 and 79 years. Glucocorticoids were prescribed in ∼54% of patients within 30 days of PMR code assignment. All other drug types were prescribed in <5% of patients. Hypertension, diabetes mellitus, rheumatoid arthritis, and osteoporosis were noted in >25% and giant cell arteritis in 1% of patients. During the study period, 4075 patients were newly assigned the PMR code and 62% were prescribed glucocorticoids within 30 days. CONCLUSIONS: This is the first retrospective real-world data analysis describing the clinical features of PMR in a large patient population from Japan. Further studies of prevalence, incidence, and clinical features are warranted in patients with PMR.

Pharmacokinetics, pharmacodynamics, and safety of single-dose subcutaneous sarilumab with or without methotrexate in Japanese patients with rheumatoid arthritis: Two single-dose studies.

OBJECTIVES: To assess the safety and pharmacokinetics (PK) of single-dose subcutaneous (SC) sarilumab or tocilizumab SC ± methotrexate (MTX) and to assess the pharmacodynamics (PD) of sarilumab SC or tocilizumab SC monotherapy in Japanese rheumatoid arthritis (RA) patients. METHODS: TDU13402 was a randomized, double-blind, placebo-controlled, single-ascending dose Phase 1 study (NCT01850680). Twenty-four patients (6 per treatment group) received sarilumab 50, 100, or 200 mg plus MTX or placebo (2 per cohort) on Day (D) 1; PK and safety were assessed through D57. PDY14191 was a randomized, open-label, single-dose study (NCT02404558). Thirty patients (15 per arm) received sarilumab 150 mg or tocilizumab 162 mg on D1; PK, PD, and safety were assessed through D43. RESULTS: TDU13402: mean serum sarilumab exposure increased in a greater than dose proportional manner from 50 to 200 mg dose with no clinically meaningful increase in treatment-emergent adverse events (TEAEs). PDY14191: PK profiles of single-dose sarilumab 150 mg or tocilizumab 162 mg were similar; some numerical differences in PD profiles and TEAEs were observed. Neutrophil count decrease/neutropenia was the most frequently reported TEAE with sarilumab treatment in both studies. CONCLUSIONS: PK, PD, and safety profiles of single-dose sarilumab SC with/without MTX were consistent with results anticipated in Japanese patients with RA.

Haemoglobin changes and disease activity in Japanese patients with rheumatoid arthritis treated with sarilumab.

OBJECTIVES: Anaemia is a frequent extra-articular manifestation in rheumatoid arthritis (RA); haemoglobin level changes are associated with changes in disease activity. This post-hoc analysis assessed potential relationships between haemoglobin and disease activity in Japanese patients with RA, enrolled in the KAKEHASI study (NCT02293902). METHODS: In this study, adult patients with moderate-to-severe active RA, who had an inadequate response to methotrexate, were randomised to subcutaneous sarilumab 150 mg every 2 weeks (q2w) or 200 mg q2w or placebo for 24 weeks. Post-hoc analyses were conducted on changes in haemoglobin and proportion of anaemic patients, using a mixed-effects model for repeated measures assuming an unstructured covariance. Relationships between haemoglobin and efficacy measures were explored. RESULTS: At baseline, nearly half of patients had anaemia, defined by World Health Organization criteria (haemoglobin <12 g/dL, female; or <13 g/dL, male). At Week 24, the least squares mean change in haemoglobin levels was greater in sarilumab groups than for placebo (150 mg: 1.23 g/dL, 200 mg: 1.19 g/dL, placebo: 0.17 g/dL; p=0.0002 for both doses vs. placebo). By Week 24, the proportion of patients with anaemia was 17.8%, 22.9%, and 30.1% for sarilumab 150 mg, 200 mg, and placebo, respectively. CONCLUSIONS: In Japanese patients with RA, both doses of sarilumab were associated with greater improvement in haemoglobin levels and reduction in proportion of patients with anaemia, compared with placebo. Sarilumab may be a suitable treatment for patients with RA and anaemia.

Immunogenicity of sarilumab and impact on safety and efficacy in Japanese patients with rheumatoid arthritis: analysis of two Phase 3 randomised clinical trials.

OBJECTIVES: To describe the immunogenicity profile of sarilumab in Japanese patients with rheumatoid arthritis (RA). METHODS: Patients enrolled in the KAKEHASI and HARUKA studies were included in our analysis. In these studies, patients received sarilumab 150 mg or 200 mg every 2 weeks for 52 or 28 weeks in combination with methotrexate (MTX) (KAKEHASI), or for 52 weeks as monotherapy or in combination with non-MTX conventional synthetic disease-modifying anti-rheumatic drugs (HARUKA). Anti-drug antibodies (ADAs) and neutralising antibodies (NAbs) were assessed in the pooled population. RESULTS: Positive ADA assay responses occurred in 10/149 (7.1%) patients treated with sarilumab 150 mg and 13/185 (7.0%) patients treated with sarilumab 200 mg, with persistent responses in 2 (1.4%) and 4 (2.2%) patients, respectively. Peak ADA titre was 30. No patients treated with the 150 mg dose and one patient (0.5%) treated with the 200 mg dose exhibited NAbs. There was no evidence of an association between ADA formation and hypersensitivity reactions or reduced efficacy. CONCLUSIONS: ADAs, which occurred at a low frequency and titre, did not affect the safety or efficacy of sarilumab 150 or 200 mg administered as monotherapy or combination therapy in Japanese patients with RA in the KAKEHASI or HARUKA studies.

Metabolic engineering of Corynebacterium glutamicum for hyperproduction of polymer-grade L- and D-lactic acid.

Strain development is critical for microbial production of bio-based chemicals. The stereo-complex form of polylactic acid, a complex of poly-L- and poly-D-lactic acid, is a promising polymer candidate due to its high thermotolerance. Here, we developed Corynebacterium glutamicum strains producing high amounts of L- and D-lactic acid through intensive metabolic engineering. Chromosomal overexpression of genes encoding the glycolytic enzymes, glucokinase, glyceraldehyde-3-phosphate dehydrogenase, phosphofructokinase, triosephosphate isomerase, and enolase, increased L- and D-lactic acid concentration by 146% and 56%, respectively. Chromosomal integration of two genes involved in the Entner-Doudoroff pathway (6-phosphogluconate dehydratase and 2-dehydro-3-deoxyphosphogluconate aldolase), together with a gene encoding glucose-6-phosphate dehydrogenase from Zymomonas mobilis, to bypass the carbon flow from glucose, further increased L- and D-lactic acid concentration by 11% and 44%, respectively. Finally, additional chromosomal overexpression of a gene encoding NADH dehydrogenase to modulate the redox balance resulted in the production of 212 g/L L-lactic acid with a 97.9% yield and 264 g/L D-lactic acid with a 95.0% yield. The optical purity of both L- and D-lactic acid was 99.9%. Because the constructed metabolically engineered strains were devoid of plasmids and antibiotic resistance genes and were cultivated in mineral salts medium, these strains could contribute to the cost-effective production of the stereo-complex form of polylactic acid in practical scale.

Enhanced production of d-lactate from mixed sugars in Corynebacterium glutamicum by overexpression of glycolytic genes encoding phosphofructokinase and triosephosphate isomerase.

The use of mixed sugars containing glucose and xylose in lignocellulosic biomass is desirable for the microbial production of chemicals and fuels. We investigated the effect of individual or simultaneous overexpression of glycolytic genes on d-lactate production from a mixture of glucose and xylose by a recombinant xylose-assimilating Corynebacterium glutamicum strain. The individual overexpression of genes encoding phosphofructokinase (PFK) and triosephosphate isomerase (TPI) increased d-lactate production rate by 71% and 34%, respectively, with corresponding increases (2.4- and 1.8-fold) in the glucose consumption; however, the amount of xylose consumed not altered. d-Lactate yield was also increased by 5.5%, but only in the strain overexpressing the gene encoding PFK. In the parent strain and the strains overexpressing the genes encoding PFK or TPI, a reduction in d-lactate production occurred at approximately 900 mM after 32 h. However, the strain that simultaneously overexpressed the genes encoding PFK and TPI continued to produce d-lactate after 32 h, with the eventual production of 1326 mM after production for 80 h in mineral salts medium. Our findings contribute to the cost-effective, large-scale production of d-lactate from mixed sugars.

Stable (sila)difluoromethylboranes via C-F activation of fluoroform derivatives.

Lithium 1,3-bis(2,6-diisopropylphenyl)-2,3-dihydro-1H-1,3,2-diazaborol-2-uide activates the C-F linkage of fluoroform (CF3H) and the Ruppert-Prakash reagent (CF3SiMe3) to provide difluoromethyl-substituted boranes as air-stable compounds.

Induction and antagonism of pica induced by teriparatide in rats.

Intermittent subcutaneous injection of teriparatide, an active fragment of human parathyroid hormone, is clinically used for the treatment of osteoporosis. Patients suffer from nausea, which is one of the side effects teriparatide induces; however, the etiology of teriparatide-induced nausea remains unknown. We have reported pica, kaolin ingestion behavior, can be used as an assessment of nausea-related response in rats. In this study, we investigated the characteristics of teriparatide-induced pica and the abilities of anti-emetic drugs to inhibit teriparatide-induced pica. Male and female adolescent (4-week-old), young (8-week-old), and adult (30-week-old) naive rats, and ovariectomized (OVX: 17-week-old) and sham-operated (17-week-old) rats subcutaneously received teriparatide (0.4 mg/kg, n=4), and their kaolin and food intakes were monitored for 24 h after the injection. Among the tested rats, we found that OVX rats, rather than male, female, and sham-operated rats, showed marked teriparatide-induced pica (0 mg/kg: 0.17±0.07 g, 0.4 mg/kg: 6.18±0.91 g). Teriparatide-induced pica in OVX rats was inhibited by intraperitoneal pretreatment with serotonin 5-HT3 (granisetron 0.5 mg/kg), dopamine D2 (prochlorperazine 0.5 mg/kg), neurokinin NK1 (fosaprepitant 1 mg/kg), and histamine H1 (diphenhydramine 10 mg/kg) receptor antagonists to 70%, 11%, 19%, and 59% of that in vehicle-treated control, respectively. These results suggest that teriparatide-induced pica in OVX rats has the potential to reflect teriparatide-induced nausea; 5-HT3, D2, NK1, and H1 receptor activation is involved in the development of this behavior; antagonists of these receptors have the potential to be medical candidates used as treatments for teriparatide-induced nausea in human patients.

Overexpression of the phosphofructokinase encoding gene is crucial for achieving high production of D-lactate in Corynebacterium glutamicum under oxygen deprivation.

We previously reported on the impacts of the overexpression of individual genes of the glycolytic pathway encoding glucokinase (GLK), glyceraldehyde phosphate dehydrogenase (GAPDH), phosphofructokinase (PFK), triosephosphate isomerase (TPI), and bisphosphate aldolase (FBA) on D-lactate productivity in Corynebacterium glutamicum under oxygen-deprived conditions. Searching for synergies, in the current study, we simultaneously overexpressed the five glycolytic genes in a stepwise fashion to evaluate the effect of the cumulative overexpression of glycolytic genes on D-lactate production. Interestingly, the final D-lactate concentration markedly differed depending on whether or not the PFK encoding gene was overexpressed when combined with overexpressing other glycolytic genes. The simultaneous overexpression of the GLK, GAPDH, TPI, and FBA encoding genes led to the highest initial D-lactate concentration at 10 h. However, this particular recombinant strain dramatically slowed producing D-lactate when a concentration of 1300 mM was reached, typically after 32 h. In contrast, the strain overexpressing the PFK encoding gene together with the GLK, GAPDH, TPI, and FBA encoding genes showed 12.7 % lower initial D-lactate concentration at 10 h than that observed with the strain overexpressing the genes coding for GLK, GAPDH, TPI, and FBA. However, this recombinant strain continued to produce D-lactate after 32 h, reaching 2169 mM after a mineral salts medium bioprocess incubation period of 80 h. These results suggest that overexpression of the PFK encoding gene is essential for achieving high production of D-lactate. Our findings provide interesting options to explore for using C. glutamicum for cost-efficient production of D-lactate at the industrial scale.

Once-weekly teriparatide increases bone mineral density in the distal 1/10 radius, but not in the distal 1/3 radius.

Teriparatide significantly increases bone mineral density (BMD) of the lumbar vertebrae and femur and has a strong effect in reducing the risk of bone fractures. However, few detailed investigations with dual-energy X-ray absorptiometry (DXA) of the effects of teriparatide on the radius have been reported; specifically, there are no reports of the use of once-weekly teriparatide. In this study, the effect of once-weekly teriparatide in increasing BMD was examined in the distal 1/10 of the radius and the distal 1/3 of the radius using a DXA system for the radius. In addition, the effect of radius positioning, especially accurate correction of rotation and inclination before and after administration of teriparatide, was evaluated in an assessment of its efficacy. It was found that when positioning was corrected, a significant increase in BMD in the distal 1/10 of the radius was observed after 6 months of once-weekly teriparatide. In the distal 1/3 of the radius, no significant increase of BMD was observed. This suggests that when DXA scans of the radius are analyzed with appropriate positioning, weekly teriparatide significantly increases BMD in the distal 1/10 of the radius, which is rich in cancellous bone.

[A case of adenocarcinoma of small intestine surviving for many years].

In adenocarcinoma of the small intestine, delays in diagnosis are frequent. The majority of patients present with advancedstage disease, and have either lymph node involvement or distant metastatic disease. Surgical resection is a mainstay in treatment of this disease, and the effectiveness of chemotherapy for advanced-stage or metastatic disease has been reported. We report a case of adenocarcinoma of the small intestine surviving for many years after surgical resection and chemotherapy. A 47-year-old woman underwent a small intestine resection, because she had a small intestinal tumor with obstruction. Histopathological examination revealed moderately-differentiated adenocarcinoma with lymph node metastasis. Adjuvant chemotherapy with S-1 was administered for a year, but in March 2006, a recurrent lesion at the right ovary was detected, and she underwent right adnexectomy. Because the ascites cytology revealed class V, chemotherapy was administered. In December 2008, CA19-9 elevated and magnetic resonance imaging showed a tumor behind the uterus, which was diagnosed as a recurrent disease. Because the tumor invaded the rectum, she received a low anterior resection, hysterectomy, and left adnexectomy. After surgical resection, UFT/UZEL was administered for half a year. In July 2010, computed tomography showed multiple lung metastases, and chemotherapy was performed again. However, the regimen was changed because her tumor marker elevated. She is being treated using a combination of cisplatin and irinotecan.

Ultrafine cellulose fibers produced by Asaia bogorensis, an acetic acid bacterium.

The ability to synthesize cellulose by Asaia bogorensis, a member of the acetic acid bacteria, was studied in two substrains, AJ and JCM. Although both strains have identical 16S rDNA sequence, only the AJ strain formed a solid pellicle at the air-liquid interface in static culture medium, and we analyzed this pellicle using a variety of techniques. In the presence of cellulase, glucose and cellobiose were released from the pellicle suggesting that it is made of cellulose. Field emission electron microscopy allowed the visualization of a 3D knitted structure with ultrafine microfibrils (approximately 5-20 nm in width) in cellulose from A. bogorensis compared with the 40-100 nm wide microfibrils observed in cellulose isolated from Gluconacetobacter xylinus, suggesting differences in the mechanism of cellulose biosynthesis or organization of cellulose synthesizing sites in these two related bacterial species. Identifying these differences will lead to a better understanding of cellulose biosynthesis in bacteria.

Optimal risk management of human alveolar echinococcosis with vermifuge.

In this study, we develop a bioeconomic model of human alveolar echinococcosis (HAE) and formulate the optimal strategies for managing the infection risks in humans by applying optimal control theory. The model has the following novel features: (i) the complex transmission cycle of HAE has been tractably incorporated into the framework of optimal control problems and (ii) the volume of vermifuge spreading to manage the risk is considered a control variable. With this model, we first obtain the stability conditions for the transmission dynamics under the condition of constant control. Second, we explicitly introduce a control variable of vermifuge spreading into the analysis by considering the associated control costs. In this optimal control problem, we have successfully derived a set of conditions for a bang-bang control and singular control, which are mainly characterized by the prevalence of infection in voles and foxes and the remaining time of control. The analytical results are demonstrated by numerical analysis and we discuss the effects of the parameter values on the optimal strategy and the transmission cycle. We find that when the prevalence of infection in foxes is low and the prevalence of infection in voles is sufficiently high, the optimal strategy is to expend no effort in vermifuge spreading.

Selective CB1 cannabinoid receptor antagonist, SR141716A, attenuates liver injury induced by Concanavalin A.

AIM: The aim of this study was to investigate the hepatoprotective activity of a selective cannabinoid receptor 1 (CB1) antagonist, SR141716A, in a Concanavalin A (Con A)-induced mouse liver injury model and to determine whether SR141716A has an effect on the production of inflammatory cytokines and chemokines induced by Con A. RESULTS: Injection of Con A (20 mg/kg) to mice developed hepatitis determined by plasma alanine aminotransferase (ALT) and aspartate aminotransferase (AST) elevation and necrosis in the liver. Pretreatment with SR141716A (30 mg/kg) significantly reduced plasma AST and ALT level, protected against necrosis in the liver, and significantly reduced plasma cytokine and chemokine levels, including TNFalpha, IFN-gamma, CXCL9, MIP1-alpha, and IL-10 and no change decreased in IL-4. CONCLUSIONS: The selective CB1 antagonist, SR141716A, exerts a hepatoprotective effect on Con A-induced liver injury in mice by attenuating the increase in cytokine and chemokine levels and inhibiting hepatocyte injury. These findings raise the possibility of using CB1 antagonists as anti-inflammatory drugs for treating hepatitis as well as other inflammatory diseases.

[Rectal perforation in a patient treated with combination chemotherapy for lung cancer].

A 74-year old man was treated with first-cycle chemotherapy of paclitaxel (70 mg/m2=110 mg day 1, 8, 15) and carboplatin (AUC5=500 mg day 1) for lung cancer (c-T3N2M0, stage III A). On day 6 abdominal pain appeared, while on day 7 abdominal CT showed a perforation of the digestive tract. Thirty-three hours after the onset he underwent Hartmann operation during which we recognized a perforation 1.7 cm in size in the rectum. Although the cause of the perforation was unknown from the pathological findings, anticancer agents were suspected to be involved. Perforation should be taken into consideration in connection with acute abdominal disease after chemotherapy.

Synthesis and structure-activity relationships of oxamyl dipeptide caspase inhibitors developed for the treatment of liver disease.

The P4 region of a series of oxamyl dipeptide caspase inhibitors was optimized by the combination of anti-apoptotic activity in the Jurkat/Fas (JFas) cellular assay and membrane permeability in the PAMPA assay. Two highly potent anti-apoptotic agents with moderate membrane permeability, 29 and 36, showed strong in vivo efficacy in a murine model of alpha-Fas-induced liver injury.