Efficacy and Safety of Esaxerenone in Hypertensive Patients with Diabetes Mellitus Undergoing Treatment with Sodium-Glucose Cotransporter 2 Inhibitors (EAGLE-DH).

INTRODUCTION: The EAGLE-DH study assessed the efficacy and safety of esaxerenone in hypertensive patients with diabetes mellitus receiving sodium-glucose cotransporter 2 (SGLT2) inhibitors. METHODS: In this multicenter, open-label, prospective, interventional study, esaxerenone was started at 1.25 or 2.5 mg/day and could be gradually increased to 5 mg/day on the basis of blood pressure (BP) and serum potassium levels. Oral hypoglycemic or antihypertensive medications prior to obtaining consent was continued. Data were evaluated in the total population and creatinine-based estimated glomerular filtration rate (eGFR) subcohorts (eGFR ≥ 60 mL/min/1.73 m2 [G1-G2 subcohort] and 30 to < 60 mL/min/1.73 m2 [G3 subcohort]). RESULTS: In total, 93 patients were evaluated (G1-G2, n = 49; G3, n = 44). Morning home systolic/diastolic BP values (SBP/DBP) were significantly reduced from baseline to week 12 (- 11.8 ± 10.8/- 5.1 ± 6.3 mmHg, both P < 0.001) and week 24 (- 12.9 ± 10.5/- 5.7 ± 6.3 mmHg, both P < 0.001). Similar results were observed in both eGFR subcohorts. The urinary albumin-to-creatinine ratio significantly decreased from baseline to week 24 in the total population (geometric percentage change, - 49.1%, P < 0.001) and in both eGFR subcohorts. The incidences of treatment-emergent adverse events (TEAEs) and drug-related TEAEs were 45.2% and 12.9%, respectively; most were mild or moderate. Serum potassium levels increased over the first 2 weeks of esaxerenone treatment, gradually decreased by week 12, and remained constant to week 24. One patient in the G1-G2 subcohort had serum potassium levels ≥ 5.5 mEq/L. No patients had serum potassium ≥ 6.0 mEq/L. CONCLUSION: Esaxerenone effectively lowered BP, was safe, and showed renoprotective effects in hypertensive patients with diabetes mellitus receiving treatment with SGLT2 inhibitors. Esaxerenone and SGLT2 inhibitors did not interfere with either drug's efficacy and may reduce the frequency of serum potassium elevations, suggesting they are a compatible combination. CLINICAL TRIAL REGISTRATION: jRCTs031200273.

Pre-existing sarcopenia and swallowing outcomes in acute stroke patients.

BACKGROUND & AIMS: This study aimed to investigate the associations of pre-existing sarcopenia with swallowing function, oral intake level, and aspiration pneumonia in patients with acute stroke. METHODS: This observational study included patients (≥60 years of age) with acute ischemic stroke or intracerebral hemorrhage within 7 days of onset who were screened for sarcopenia, malnutrition, and swallowing difficulties in a stroke-care unit within 48 h of admission. Sarcopenia was defined by the Asian Working Group on Sarcopenia 2019 as having a low calf circumference, handgrip strength, and appendicular muscle mass index. The primary outcome was impaired oral intake (functional oral intake scale <5 points) at 3, 7, and 14 days after admission, and the secondary outcome was aspiration pneumonia during hospitalization. RESULTS: We enrolled 350 patients (median age of 77 years; 63% males) who underwent the aforementioned screening. Sarcopenia was diagnosed in 34% of patients, and malnutrition was found in 66% of patients with sarcopenia. When compared with the comparison group (defined as patients with either or both normal calf circumference and handgrip strength), the sarcopenia group had significantly lower tongue pressure and a higher prevalence of dysphagia. Sarcopenia was associated with functional oral intake scale <5 at 7 days (adjusted odds ratio [OR], 4.72; 95% confidence interval [CI], 1.91-11.71); p = 0.002) and 14 days (adjusted OR, 3.93; 95% CI, 1.47-10.53; p = 0.006) and with aspiration pneumonia during hospitalization (adjusted OR, 6.12; 95% CI, 1.63-22.94; p = 0.007). CONCLUSION: Acute stroke patients with sarcopenia may have weakness of the swallowing-related muscles which may lead to impaired oral intake and aspiration pneumonia.

Analysis of the Effects of Known Sleep-Support Supplements in Relation to Life Habits, Sleep Conditions, and Sleep Problems.

Sleep is a crucial component of health, and insomnia is among the most common and vexing of life-habit-related disorders. While dietary sleep-support supplements can improve sleep, choosing an effective dietary supplement can be challenging for users due to the wide variety of options available and the varying effects experienced by different individuals. In this study, to identify new criteria for estimating the effects of dietary supplements, we examined the relationships among the dietary supplements, the pre-conditions (PCs; defined as the life habits and sleep conditions before supplementation), and the sleep problems of subjects before supplementation. An open, randomized, cross-over intervention trial enrolling 160 subjects was conducted to test the efficacy of each dietary supplement (Analysis 1) and the relationships among dietary supplements, the PCs, and sleep problems (Analysis 2). To this end, l-theanine (200 mg/day), γ-aminobutyric acid (GABA) (111.1 mg/day), Apocynum venetum leaf extract (AVLE) (50 mg/day), and l-serine (300 mg/day) were administered to subjects. Before the first intervention period, life habits and sleep conditions were surveyed to identify each subject's PCs. For each combination of supplements and sleep problems, PCs were compared between subjects whose sleep problems were improved and subjects whose sleep problems were not improved via supplementation. All the tested supplements were found to ameliorate sleep problems significantly (Analysis 1). In Analysis 2, the PCs specific to improved subjects were found to differ depending on the dietary supplements and sleep problems. In addition, subjects who consumed dairy products often showed improvement in their sleep problems with all the tested supplements. This study suggests the possibility of personalizing sleep-support supplementation based on personal life habits, sleep conditions, and sleep problems, in addition to the known efficacy of dietary supplements.

Synthesis of thermoplastic chitin hexanoate-graft-poly(ε-caprolactone).

Herein, we report that chitin hexanoate-graft-poly(ε-caprolactone) (ChHex-g-PCL) is thermoplastic, as confirmed by the formation of a melt-pressed film. Chitin hexanoates with degrees of substitution (DSs) of 1.4-1.8 and bearing free hydroxy groups were first prepared by the hexanoylation of chitin using adjusted feed equivalents of hexanoyl chloride in the presence of pyridine and N,N-dimethyl-4-aminopyridine in 1-allyl-3-methylimidazolium bromide, an ionic liquid. Surface-initiated ring-opening graft polymerization of ε-caprolactone from the hydroxy groups of the chitin hexanoates was conducted in the presence of tin(II) 2-ethylhexanoate as the catalyst at 100 °C to produce (ChHex-g-PCL)s. The feed equivalent of the catalyst, reaction time, and DS value were found to affect the molar substitution and degree of polymerization of the PCL graft chains. Longer PCL graft chains formed their crystalline structures and the (ChHex-g-PCL)s largely contained uncrystallized chitin chains. Accordingly, these (ChHex-g-PCL)s exhibited melting points associated with the PCL graft chains, leading to thermoplasticity.

Synthesis of mixed chitin esters with long fatty and bulky acyl substituents in ionic liquid.

This study revealed that mixed chitin esters with long fatty and bulky acyl substituents were efficiently synthesized by acylation using acyl chlorides in the presence of pyridine and N,N-dimethyl-4-aminopyridine in an ionic liquid, 1-allyl-3-methylimidazolium bromide (AMIMBr), at 100 °C for 24 h. A stearoyl group was selected as the first substituent, which was combined with different long fatty and bulky acyl groups as the second substituents. In addition to IR analysis of the products, which suggested progress of the acylation, 1H NMR measurement was allowed for structural confirmation for high degrees of substitution (DSs) of the desired derivatives in CDCl3/CF3CO2H solvents. Crystalline structures and thermal property of the products were evaluated by powder X-ray diffraction and differential scanning calorimetry measurements, respectively. All the products showed film formability by casting from solutions in chloroform or chloroform/trifluoroacetic acid solvents. The occurrence of halogen exchange between acyl chlorides and AMIMBr in the present system was speculated to produce highly reactive acyl bromides in situ, which efficiently reacted with hydroxy groups in chitin to obtain high DS products.

Fabrication of highly flexible nanochitin film and its composite film with anionic polysaccharide.

This study investigated the fabrication of a nanochitin film via the aggregation of scaled-down chitin nanofibers (SD-ChNFs). A self-assembled ChNF film, which was prepared by regeneration from a chitin/ionic liquid ion gel using methanol, followed by filtration, was treated with aqueous NaOH for deacetylation and subsequently disintegrated by cationization and electrostatic repulsion in 1.0 mol/L aqueous acetic acid with ultrasonication to give a SD-ChNF dispersion. Isolation of the SD-ChNFs via filtration of the dispersion resulted in a highly flexible self-assembled ChNF film that bent and twisted easily. The film exhibited superior mechanical properties compared to the parent self-assembled ChNF film, where the flexibility was further enhanced by the compositing the SD-ChNFs with an anionic polysaccharide, namely ι-carrageenan, via multi-point ionic cross-linking. These enhanced mechanical properties and efficient compositing properties were attributed to the scaling down of the ChNFs.

Hyperthermia with Chemotherapy for Unresectable Gastric Cancer in a Patient with a Vagus Nerve Stimulator Implant: A Case Report.

BACKGROUND Radiofrequency (RF) hyperthermia is commonly used as an adjunct to established treatment modalities such as chemotherapy and radiotherapy for the management of cancer patients. This case report aims to introduce the use of hyperthermia, in combination with chemotherapy, for the treatment of unresectable gastric cancer in a patient implanted with a vagus nerve stimulator (VNS). CASE REPORT A 55-year-old man with dermatomyositis, laryngeal squamous cell carcinoma in situ and double synchronous gastric cancer was found to have unresectable gastric disease during surgery despite neoadjuvant chemotherapy. Postoperatively, he received chemotherapy with RF hyperthermia. The patient had a VNS implant to treat epileptic seizures. VNS failure due to RF hyperthermia was an area of significant concern, and the procedures were completed with a full preparation to manage epileptic seizures in the event of its anticipated occurrence. Twenty-one thermotherapies were performed over 21 weeks. After 3 courses of S-1 chemotherapy (12 weeks) with RF hyperthermia without any adverse events, the regimen was changed to S-1+ CDDP combination chemotherapy (SP) and RF hyperthermia. The patient continued to receive treatment with a decrease in the size of the primary gastric tumors as well as lymph node metastases, without major adverse events, until he died due to disseminated disease. CONCLUSIONS We report the first case of unresectable gastric cancer with VNS implants in which chemo-hyperthermal therapy was safe and successful. This case report highlights the importance of providing a multidisciplinary treatment with appropriate measures for patients with intractable cancer who have received special treatments for underlying comorbidities.

Preparation of Amylose-Oligo[(R)-3-hydroxybutyrate] Inclusion Complex by Vine-Twining Polymerization.

In this study, we attempted to prepare an amylose-oligo[(R)-3-hydroxybutyrate] (ORHB) inclusion complex using a vine-twining polymerization approach. Our previous studies indicated that glucan phosphorylase (GP)-catalyzed enzymatic polymerization in the presence of appropriate hydrophobic guest polymers produces the corresponding amylose-polymer inclusion complexes, a process named vine-twining polymerization. When vine-twining polymerization was conducted in the presence of ORHB under general enzymatic polymerization conditions (45 °C), the enzymatically produced amylose did not undergo complexation with ORHB. However, using a maltotriose primer in the same polymerization system at 70 °C for 48 h to obtain water-soluble amylose, called single amylose, followed by cooling the system over 7 h to 45 °C, successfully induced the formation of the inclusion complex. Furthermore, enzymatic polymerization initiated from a longer primer under the same conditions induced the partial formation of the inclusion complex. The structures of the different products were analyzed by X-ray diffraction, 1H-NMR, and IR measurements. The mechanism of formation of the inclusion complexes discussed in the study is proposed based on the additional experimental results.

Preparation and gelation behaviors of poly(2-oxazoline)-grafted chitin nanofibers.

Based on our previous work on successful gelation of poly(2-methyl-2-oxazoline)-grafted chitin nanofibers (ChNFs) with high polar media, in this study, we investigated the preparation and gelation behaviors of the ChNFs having different poly(2-alkyl-2-oxazoline) graft chains, that is, poly(2-methyl-2-oxazoline), poly(2-isopropyl-2-oxazoline), and poly(2-butyl-2-oxazoline), with various disperse media. The grafting was carried out by reactions of living propagating ends of poly(2-alkyl-2-oxazoline)s with amino groups present on the self-assembled ChNFs, which were obtained from a chitin ion gel. The products formed gels in the reaction mixtures, which could be converted into hydrogels. All the products with the three poly(2-alkyl-2-oxazoline) graft chains formed gels with high polar media. Besides, gelation of the product with poly(2-butyl-2-oxazoline) was observed by immersing it in relatively non-polar media such as benzyl alcohol, ethyl acetate, and toluene. The formation process of network structures by the grafting of poly(2-alkyl-2-oxazoline)s on ChNFs is proposed to induce gelation of the products.

Efficacy of Hyperthermia in Treatment of Recurrent Metastatic Breast Cancer After Long-Term Chemotherapy: A Report of 2 Cases.

BACKGROUND Breast cancer has a long-term prognosis with various multimodality treatments. This report introduces the effectiveness of radiofrequency (RF) hyperthermia in the long-term treatment for recurrent/metastatic breast cancer. CASE REPORT In the first case, the patient had bone and liver metastases during the course of chemotherapy, hormone therapy, and radiotherapy for 27 years after curative resection of breast cancer. Finally, she received RF hyperthermia alone for liver metastasis and showed a decrease in tumor markers and reduction in liver metastasis on computed tomography (CT). In the second case, the patient underwent curative resection for multiple occurrences on the left side of the breast. She received postoperative chemotherapy combined with hormone therapy but had metachronous local recurrences. She continued hormone therapy after 2 local recurrence resections; unfortunately, she had bone, liver, and lung metastases and pleural dissemination. Eventually, the patient received RF hyperthermia combined with oral chemotherapy. Her tumor markers decreased, and CT showed disappearance of lung metastasis and improved pleural dissemination. Furthermore, the reduction of chemotherapy adverse events due to hyperthermia allowed the patient to continue chemotherapy and improved her quality of life. CONCLUSIONS We present 2 cases in which RF hyperthermia had a positive effect despite the presence of a recurrent tumor after various types of surgery, chemotherapy, and radiotherapy. This report suggests that the addition of RF hyperthermia to conventional multidisciplinary therapies may enhance the therapeutic effect of these treatments and improve the quality of life in patients with recurrent breast cancer.

Evaluation of artificial crystalline structure from amylose analog polysaccharide without hydroxy groups at C-2 position.

In this study, we found that a new artificial crystalline structure was fabricated from an amylose analog polysaccharide without hydroxy groups at the C-2 position, i.e., 2-deoxyamylose. The polysaccharide with a well-defined structure was synthesized by facile thermostable α-glucan phosphorylase-catalyzed enzymatic polymerization. Powder X-ray diffraction (XRD) analysis of the product indicated the formation of a specific crystalline structure that was completely different from the well-known double helix of the natural polysaccharide, amylose. Molecular dynamics simulations showed that the isolated chains of 2-deoxyamylose spontaneously assembled to a novel double helix based on building blocks with controlled hydrophobicity arising from pyranose ring stacking. The simulation results corresponded with the XRD patterns.

Chemoenzymatic synthesis of carboxylate-terminated maltooligosaccharides and their use for cross-linking of chitin.

In this paper, we report chemoenzymatic synthesis of maltooligosaccharides having carboxylate groups at both ends (carboxylate-terminated maltooligosaccharides, GlcA-Glcn-GlcCOONa). The products were further used as cross-linker for water-soluble chitin (WSCh) to obtain network chitins. The synthesis of GlcA-Glcn-GlcCOONa was achieved by thermostable phosphorylase-catalyzed enzymatic α-glucuronylation using α-d-glucuronic acid 1-phosphate with a carboxylated maltooligosaccharide, which was prepared by chemical oxidation at the reducing end of maltoheptaose with sodium hypoiodite. The structures of GlcA-Glcn-GlcCOONa were evaluated by 1H NMR and MALDI-TOF mass spectra. The obtained GlcA-Glcn-GlcCOONa were used as cross-linker for WSCh by condensation in the presence of condensing agent. The reaction mixtures totally turned into hydrogel form in most cases. Morphologies of lyophilized samples (cryogels) from the hydrogels were evaluated by SEM measurement. The hydrogels could be converted into films by pressing. Furthermore, mechanical properties of the hydrogels and films were investigated by compression and tensile tests, respectively.

Preparation of chitin-based fluorescent hollow particles by Pickering emulsion polymerization using functional chitin nanofibers.

This study investigated the preparation of chitin-based fluorescent hollow particles by Pickering emulsion polymerization of styrene using bifunctional chitin nanofibers (ChNFs) as stabilizer, giving CNF-based composite particles, followed by solubilizing out inner polystyrene. In addition to the introduction of anionic maleyl groups on ChNFs to improve dispersibility in aqueous ammonia, polymerizable methacryl groups were substituted on ChNFs as second functionalization to provide ability in copolymerization with styrene for stabilization of hollow structures. Consequently, after the formation of styrene-in-water Pickering emulsion using the bifunctional ChNFs as stabilizer, radical polymerization was conducted in the presence of potassium persulfate as an initiator to produce the composite particles. The hollow particles were then fabricated by solubilizing out inner polystyrene with toluene, which stably dispersed in water. Encapsulation of a fluorescent dye, pyrene, into the cavity of the hollow particles was achieved by hydrophobic interaction with polystyrene present on the inner walls, which could be released by treatment of the resulting fluorescent hollow particles with surfactant, oleyl alcohol, in water. The same Pickering emulsion polymerization system was also performed in the presence of a pyrene derivative having a polymerizable group to obtain fluorescent composite/hollow particles with pyrene moieties covalently bound to polystyrene.

Preparation of Reswellable Amorphous Porous Celluloses through Hydrogelation from Ionic Liquid Solutions.

In this study, we have performed the preparation of reswellable amorphous porous celluloses through regeneration from hydrogels. The cellulose hydrogels were first prepared from solutions with an ionic liquid, 1-butyl-3-methylimidazolium chloride (BMIMCl), in different concentrations. Lyophilization of the hydrogels efficiently produced the regenerated celluloses. The powder X-ray diffraction and scanning electron microscopic measurements of the products suggest an amorphous structure and porous morphology, respectively. Furthermore, the pore sizes of the regenerated celluloses, or in turn, the network sizes of cellulose chains in the hydrogels, were dependent on the concentrations of the initially prepared solutions with BMIMCl, which also affected the tensile mechanical properties. It was suggested that the dissolution states of the cellulose chains in the solutions were different, in accordance with the concentrations, which representatively dominated the pore and network sizes of the above materials. When the porous celluloses were immersed in water, reswelling was observed to regenerate the hydrogels.

Ionic liquid induces flexibility and thermoplasticity in cellulose film.

It is still challenging to melt-process cellulose. In this paper, we proposed a method for the formation of thermally processable flexible cellulose films via gelation from its solution in ionic liquid (1-butyl-3-methylimidazolium chloride; BMIMCl). Cotton, as a source of cellulose, was dissolved (5 wt%) in BMIMCl and subsequently placed in different amounts of water. The obtained ion gels were dried at 60 °C for 24 h; during drying process, water was removed while BMIMCl was retained. It was found that the amount of retained BMIMCl had a critical role in determining the mechanical properties of the films. It was suspected that the processing conditions altered the degree of crystallinity of cellulose in the films as evidenced by X-ray diffraction measurement. The ionic liquid, i.e., BMIMCl induced the plasticity into the films, so that thermal processability to different shapes became possible.

Correction to "Formation of Supramolecular Soft Materials from Amylosic Inclusion Complexes with Designed Guest Polymers Obtained by Vine-Twining Polymerization".

[This corrects the article DOI: 10.1021/acsomega.9b00238.].

Formation of Supramolecular Soft Materials from Amylosic Inclusion Complexes with Designed Guest Polymers Obtained by Vine-Twining Polymerization.

Amylose forms supramolecular inclusion complexes with polymeric guests in the phosphorylase-catalyzed enzymatic polymerization field, so-called "vine-twining polymerization". However, such inclusion complexes have not exhibited specific properties and processability as functional supramolecular materials. In this study, we found that amylosic inclusion complexes, which were obtained by vine-twining polymerization using a designed guest polymer, that is, an amphiphilic triblock copolymer poly(2-methyl-2-oxazoline-block-tetrahydrofuran-block-2-methyl-2-oxazoline), exhibited gel and film formation properties. The characterization results of the products suggested that enzymatically elongated amylose chains complexed with the polytetrahydrofuran block in the triblock copolymer. Accordingly, the outer poly(2-methyl-2-oxazoline) blocks constructed hydrophilic spaces among the inclusion complex segments. Furthermore, the presence of such outer blocks affected the lower regularity of crystalline alignment among the inclusion complex segments in the products. Such higher-order structures probably induced the formation of supramolecular soft materials, such as gels and films.

Microwave treatment of breast milk for prevention of cytomegalovirus infection.

BACKGROUND: Breast milk (BM) is the best nutrition for very preterm infants (VPI), except when provided by human cytomegalovirus (HCMV)-seropositive mothers. Given that VPI are at high risk of developing a sepsis-like syndrome or cholestasis, methods for prevention of HCMV infection via BM have been investigated. Although Holder pasteurization (HP) is the gold standard, HP needs special instruments. Microwave (MW) is available anywhere, therefore, we performed this study to determine whether MW can be used for HCMV prevention. METHODS: Human cytomegalovirus Towne strain was added to formula, followed by heating procedure using HP or MW (at 500 W for 20, 30, 40, or 60 s). HFL-III cells were seeded in culture dishes. Aliquots of HCMV-milk samples after heating were inoculated onto susceptible cell monolayers. The number of plaques was counted to determine the viral titer. The determination of HCMV-DNA copies was also performed. RESULTS: Addition of HCMV for a viral load of 5.0 × 103 plaque-forming units (p.f.u.)/mL achieved 772 p.f.u./mL at baseline, with a decrease to 257 p.f.u./mL after MW radiation for 20 s. No plaque was detected after HP or MW for 30, 40, and 60 s. The temperature of the breast milk reached 60°C after MW radiation for 40 s. The number of HCMV-DNA copies did not change with MW. CONCLUSIONS: Microwave at 500 W for 40 s can be used as a prevention strategy for HCMV transmission. Further research including the loss of bioactive properties in BM is required prior to clinical application.