Analysis of human neuronal cells carrying ASTN2 deletion associated with psychiatric disorders.

Recent genetic studies have found common genomic risk variants among psychiatric disorders, strongly suggesting the overlaps in their molecular and cellular mechanism. Our research group identified the variant in ASTN2 as one of the candidate risk factors across these psychiatric disorders by whole-genome copy number variation analysis. However, the alterations in the human neuronal cells resulting from ASTN2 variants identified in patients remain unknown. To address this, we used patient-derived and genome-edited iPS cells with ASTN2 deletion; cells were further differentiated into neuronal cells. A comprehensive gene expression analysis using genome-edited iPS cells with variants on both alleles revealed that the expression level of ZNF558, a gene specifically expressed in human forebrain neural progenitor cells, was greatly reduced in ASTN2-deleted neuronal cells. Furthermore, the expression of the mitophagy-related gene SPATA18, which is repressed by ZNF558, and mitophagy activity were increased in ASTN2-deleted neuronal cells. These phenotypes were also detected in neuronal cells differentiated from patient-derived iPS cells with heterozygous ASTN2 deletion. Our results suggest that ASTN2 deletion is related to the common pathogenic mechanism of psychiatric disorders by regulating mitophagy via ZNF558.

Mice with deficiency in Pcdh15, a gene associated with bipolar disorders, exhibit significantly elevated diurnal amplitudes of locomotion and body temperature.

Genetic factors significantly affect the pathogenesis of psychiatric disorders. However, the specific pathogenic mechanisms underlying these effects are not fully understood. Recent extensive genomic studies have implicated the protocadherin-related 15 (PCDH15) gene in the onset of psychiatric disorders, such as bipolar disorder (BD). To further investigate the pathogenesis of these psychiatric disorders, we developed a mouse model lacking Pcdh15. Notably, although PCDH15 is primarily identified as the causative gene of Usher syndrome, which presents with visual and auditory impairments, our mice with Pcdh15 homozygous deletion (Pcdh15-null) did not exhibit observable structural abnormalities in either the retina or the inner ear. The Pcdh15-null mice showed very high levels of spontaneous motor activity which was too disturbed to perform standard behavioral testing. However, the Pcdh15 heterozygous deletion mice (Pcdh15-het) exhibited enhanced spontaneous locomotor activity, reduced prepulse inhibition, and diminished cliff avoidance behavior. These observations agreed with the symptoms observed in patients with various psychiatric disorders and several mouse models of psychiatric diseases. Specifically, the hyperactivity may mirror the manic episodes in BD. To obtain a more physiological, long-term quantification of the hyperactive phenotype, we implanted nano tag® sensor chips in the animals, to enable the continuous monitoring of both activity and body temperature. During the light-off period, Pcdh15-null exhibited elevated activity and body temperature compared with wild-type (WT) mice. However, we observed a decreased body temperature during the light-on period. Comprehensive brain activity was visualized using c-Fos mapping, which was assessed during the activity and temperature peak and trough. There was a stark contrast between the distribution of c-Fos expression in Pcdh15-null and WT brains during both the light-on and light-off periods. These results provide valuable insights into the neural basis of the behavioral and thermal characteristics of Pcdh15-deletion mice. Therefore, Pcdh15-deletion mice can be a novel model for BD with mania and other psychiatric disorders, with a strong genetic component that satisfies both construct and surface validity.

Seabuckthorn (Hippophae rhamnoides, L.) pulp oil prevents ultraviolet-induced damage in human fibroblasts.

Seabuckthorn pulp oil (SBO) is used in beauty products because of its rich lipophilic substances with high nutraceutical and cosmeceutical potential. However, the mechanism through which SBO enhances skin elasticity remains unclear. Therefore, in this study, we examined the anti-photoaging activity of SBO in normal human dermal fibroblasts (NHDF) under ultraviolet (UV) irradiation. Pretreatment with SBO significantly suppressed UV-B-induced cell toxicity and collagen degradation, suggesting that SBO contains anti-photoaging substances. Further, palmitoleic acid, the main component of SBO, maintained cell viability and collagen levels in UV-B-irradiated NHDF by suppressing the expression of matrix metalloproteinase 1 and acted on the inhibition of p38 and JNK phosphorylation and nuclear translocation of nuclear factor-kappa B. These findings suggest the utility of SBO as an anti-photoaging agent.

Flexible High Lithium-Ion Conducting PEO-Based Solid Polymer Electrolyte with Liquid Plasticizers for High Performance Solid-State Lithium Batteries.

Lithium-ion secondary batteries (LIB) with high energy density have attracted much attention for electric vehicle (EV) applications. However, LIBs have a safety problem because these batteries contain a flammable organic electrolyte. As such, all-solid secondary batteries that are not flammable have been extensively reported recently. In this study, we have focused on polymer electrolytes, which is flexible and is expected to address the safety problem. However, the conventional polymer electrolytes have low electrial conductivity at room temperature. Various attempts have been made to solve this problem, such as the addition of inorganic fillers and ionic liquids; however, these composite polymer electrolytes have not yet reached a practical level of lithium-ion conductivity. In this study, high electrical conductivity and lithium dendrite formation-free PEO based composite electrolytes are developed with both a filler of Li6,4La3Zr1.4Ta0.6O12 and liquid plasticizers of tetraethylene glycol dimethyl ether and 1,2 dimethoxyethane. The proposed flexible polymer electrolyte shows a high electrical conduciviy of 6.01×10-4 S cm-1 at 25 °C.

Tunnel-Structured Phosphate Exhibiting High Proton Conductivity and Thermal Stability over a Wide Intermediate Temperature Range.

For the practical application of fuel cells in vehicles, it is a challenge to develop a proton solid electrolyte that coexhibits thermal stability and high proton conductivity at wide intermediate temperatures. Here, we report on the tunnel structured phosphate KNi1-xH2x(PO3)3·yH2O, which exhibits high proton conductivity at room temperature up to 500 °C, with the conductivity value reaching 1.7 × 10-2 S cm-1 at 275 °C for x = 0.18. This material, composed of the smallest cations that form the tunnel framework with face-shared (KO6) and (NiO6) chains and PO4 tetrahedral chains, retained the rigid framework up to 600 °C. Two oxygen sites of water molecules located adjacent to each other along the PO4 tetrahedral chains in the tunnel provided the proton conduction pathway. The sample maintained a conductivity of 5.0 × 10-3 S cm-1 for 10 h at 150 °C while changing the measurement atmosphere to a N2 gas flow, a 4% H2-96% Ar gas flow, and an O2 gas flow. The conductivity value at x = 0.18 obtained from the DC measurement was in the order of 10-6 S cm-1, close to the instrument's measurement limit. These results demonstrate that tunnel phosphate has potential as a proton solid electrolyte for next-generation fuel cells.

Extremely Low Frequency, Extremely Low Magnetic Environment for depression: An open-label trial.

Mitochondrial dysfunction has been suggested to play a role in depression pathogenesis. This clinical trial (jRCTs042220011) was conducted to evaluate whether depression symptoms could be alleviated by an Extremely Low Frequency, Extremely Low Magnetic Environment (ELF-ELME), which has been found in basic research studies to enhance mitochondrial membrane potential. Participants were exposed to the ELF-ELME via a head-mounted magnetic field device (10 µTesla, 4 ms, 1-8 Hz/8 s) worn for 2 h per day for 8 consecutive weeks. Four male patients with treatment-resistant depression were enrolled. Significant reductions from baseline in the average total Montgomery-Åsberg Depression Rating Scale (MADRS) score were observed at 4, 6, and 8 weeks. ELF-ELME appears to ameliorate depressive symptoms in patients with major depressive disorder safely and effectively, suggesting that it could be used as an alternative treatment for depressive patients who do not prefer to take antidepressants and in combination with antidepressant therapy for patients who only partially respond to pharmacotherapy.

Synthesis of bioengineered heparin chemically and biologically similar to porcine-derived products and convertible to low MW heparin.

Heparins have been invaluable therapeutic anticoagulant polysaccharides for over a century, whether used as unfractionated heparin or as low molecular weight heparin (LMWH) derivatives. However, heparin production by extraction from animal tissues presents multiple challenges, including the risk of adulteration, contamination, prion and viral impurities, limited supply, insecure supply chain, and significant batch-to-batch variability. The use of animal-derived heparin also raises ethical and religious concerns, as well as carries the risk of transmitting zoonotic diseases. Chemoenzymatic synthesis of animal-free heparin products would offer several advantages, including reliable and scalable production processes, improved purity and consistency, and the ability to produce heparin polysaccharides with molecular weight, structural, and functional properties equivalent to those of the United States Pharmacopeia (USP) heparin, currently only sourced from porcine intestinal mucosa. We report a scalable process for the production of bioengineered heparin that is biologically and compositionally similar to USP heparin. This process relies on enzymes from the heparin biosynthetic pathway, immobilized on an inert support and requires a tailored N-sulfoheparosan with N-sulfo levels similar to those of porcine heparins. We also report the conversion of our bioengineered heparin into a LMWH that is biologically and compositionally similar to USP enoxaparin. Ultimately, we demonstrate major advances to a process to provide a potential clinical and sustainable alternative to porcine-derived heparin products.

Phenotypes for general behavior, activity, and body temperature in 3q29 deletion model mice.

Whole genome analysis has identified rare copy number variations (CNV) that are strongly involved in the pathogenesis of psychiatric disorders, and 3q29 deletion has been found to have the largest effect size. The 3q29 deletion mice model (3q29-del mice) has been established as a good pathological model for schizophrenia based on phenotypic analysis; however, circadian rhythm and sleep, which are also closely related to neuropsychiatric disorders, have not been investigated. In this study, our aims were to reevaluate the pathogenesis of 3q29-del by recreating model mice and analyzing their behavior and to identify novel new insights into the temporal activity and temperature fluctuations of the mouse model using a recently developed small implantable accelerometer chip, Nano-tag. We generated 3q29-del mice using genome editing technology and reevaluated common behavioral phenotypes. We next implanted Nano-tag in the abdominal cavity of mice for continuous measurements of long-time activity and body temperature. Our model mice exhibited weight loss similar to that of other mice reported previously. A general behavioral battery test in the model mice revealed phenotypes similar to those observed in mouse models of schizophrenia, including increased rearing frequency. Intraperitoneal implantation of Nano-tag, a miniature acceleration sensor, resulted in hypersensitive and rapid increases in the activity and body temperature of 3q29-del mice upon switching to lights-off condition. Similar to the 3q29-del mice reported previously, these mice are a promising model animals for schizophrenia. Successive quantitative analysis may provide results that could help in treating sleep disorders closely associated with neuropsychiatric disorders.

Assessing the Real-World, Long-Term Impact of Lemborexant on Sleep Quality in a Home-Based Clinical Study.

Purpose: Both subjective and objective evaluations are essential for the treatment of insomnia. Lemborexant has been shown to be effective in the long-term based solely on a subjective basis, and no long-term objective measures have been evaluated under natural sleep conditions. Small, lightweight sleep electroencephalogram (EEG) monitor was used, instead of polysomnography, to objectively evaluate sleep at home 4 and 12 weeks after lemborexant treatment. Patients and Methods: Adults and elderly subjects with insomnia disorder, per the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, were enrolled in this open-label, single-arm, single-center trial. Objective and subjective measures of sleep were prospectively assessed. Sleep disturbance, excessive sleepiness, and depressive symptoms were assessed using questionnaires. Results: A total of 45 subjects were screened, of which 33 were enrolled. Paired t-tests were conducted to evaluate changes in sleep variables and compared with the baseline; subjects showed significant improvements in objective sleep efficiency (SE) and subjective sleep parameters at weeks 4 and 12 following treatment with lemborexant. When baseline values were taken into account, a repeated-multivariate analysis of variance (MANOVA) revealed statistically significant changes in the objective measures. Sleep disturbance, excessive sleepiness, and depressive symptoms improved after three months of lemborexant treatment. Conclusion: Furthermore, lemborexant therapy improved nocturnal sleep, when measured objectively using sleep EEG monitoring at home, and improved daytime sleepiness and depressive symptoms in older adults with insomnia disorder.

Coracoclavicular and acromioclavicular ligament reconstruction with a double-bundle semitendinosus autograft and cortical buttons for chronic acromioclavicular joint dislocations: clinical and imaging outcomes.

BACKGROUND: There are few clinical and radiographic studies of coracoclavicular (CC) ligament reconstruction in chronic acromioclavicular (AC) joint dislocation. Additionally, reported AC joint reduction rates vary. HYPOTHESIS: Arthroscopically assisted double-bundle semitendinosus tendon autografts with CC and AC ligament reconstruction for AC joint reconstruction provide AC joint stability and improved function at the final visit. METHODS: In this retrospective study of prospectively collected data, 21 patients surgically treated for chronic AC joint dislocation (Rockwood III-V) were assessed clinically and radiographically preoperatively, and at day 1, 3 months, 12 months, and at a final visit (>24 months) postoperatively. Clinical assessments included Constant and American Shoulder and Elbow Surgeons scores. The CC vertical distance (CCD) on the affected and unaffected sides [CCD ratio (%)] on the anterosuperior view were measured. AC joint vertical reduction loss was defined as an increase in the CCD ratio of >25%. Horizontal AC joint instability was evaluated on axillary views. Pearsons' correlation coefficients were generated to examine the relationships among postoperative clinical scores, CCD ratio, interval from injury to surgery, and age at the time of surgery. RESULTS: Twenty-one shoulders in 21 patients (mean age, 40.0 years at the time of surgery; 16 men, 5 women) were evaluated with a mean 31.7-month follow-up period. The mean Constant scores, American Shoulder and Elbow Surgeons scores, and CCD ratios significantly improved from preoperatively to the final visit (57.4 ± 10.1, 49.1 ± 12.1, 101.6 ± 64.1 preoperatively; 89.6 ± 5.3, 96.5 ± 4.2, 9.9 ± 34.5 at the final visit, respectively [P < .001 for all]). Vertical AC and horizontal AC joint instability were observed in 4 shoulders (19.0%) and in 1 shoulder (4.8%), respectively. However, there was no significant correlation between the increase in CCD and clinical scores at the final visit (Constant score; r = 0.179, P = .438: American Shoulder and Elbow Surgeons score; r = -0.260, P = .256) or the interval from injury to surgery (r = 0.099, P = .669) or age at the time of surgery (r = 0.019, P = .935). No clinical complications were associated with clinical symptoms. CONCLUSIONS: Patients who underwent the index procedure achieved significant improvement in shoulder function without complications related clinical symptom after a mean follow-up interval of 31.7 months. In contrast, the rates of total ACJ instability in the vertical and horizontal planes were unsatisfactory but compatible with those in previous studies.

Effect of single-administration of D-sorbitol pretreatment on the bitterness and continued willingness to take asenapine: a randomized, single-blind, placebo-controlled, crossover trial.

BACKGROUND: Asenapine has unique orally-related side effects, such as a bitter taste induced by sublingual administration, which often results in discontinuation of the medication. While the FDA has approved black-cherry-flavored asenapine, several countries have prescribed only unflavored versions. Specifically, Asians commonly report experiencing the bitterness of asenapine because they are more sensitive to bitter tastes than other ethnic groups. In this study, with the aim of improving adherence by reducing the bitterness of asenapine, we investigated the effects of D-sorbitol, which reduced the bitterness parameters of taste sensors in our previous basic study on the bitterness and continuity of asenapine among patients with schizophrenia. METHODS: Twenty adult patients with schizophrenia were included in this single-blind, placebo-controlled, crossover trial. Participants rinsed their mouths with single-administration of D-sorbitol or a placebo prior to each administration of asenapine. We then conducted the questionnaires and assessed changes in the bitterness of asenapine (primary end point) and willingness to continue its use (secondary end point). RESULTS: D-sorbitol significantly improved the bitterness of asenapine (p = 0.038). Although it did not significantly increase the willingness to continue asenapine (p = 0.180), it did show improvement over the placebo in enhancing willingness to continue, especially in patients who were not accustomed to its taste. CONCLUSION: Our findings indicate that single-administration of D-sorbitol significantly reduces the bitterness of asenapine. In countries where flavored asenapine is not available, this finding could benefit patients who were not accustomed to its bitter taste. TRIAL REGISTRATION: This study was registered in the Japan Registry of Clinical Trials (jRCTs041210019) on May 14, 2021.

Effect of Dapagliflozin on Serum Uric Acid Levels in Patients with Advanced Chronic Kidney Disease.

Objective Sodium-glucose cotransporter 2 (SGLT2) inhibitors, which are hypoglycemic agents, have been shown to be cardioprotective through a variety of mechanisms, and the effect of lowering uric acid (UA) levels may be one of the mechanisms. In the present retrospective study, we investigated the changes in serum UA levels in patients with chronic kidney disease (CKD) treated with SGLT2 inhibitors. Methods We included 31 patients with CKD who were newly started on dapagliflozin for renal protection and evaluated trends in various parameters, including serum UA levels and UA excretion from urine. Results The patients' median age was 71 years old, 20 patients were men, 7 patients had diabetes, and the median estimated glomerular filtration rate was 33.9 mL/min/1.73 m2 (CKD stage 3: 21 cases, stage 4: 10 cases). The differences in UA and fractional excretion of UA after three weeks and three months of prescription showed significantly decreased UA values and an increased fractional excretion of UA. Conclusion Our findings suggest that dapagliflozin can lower serum UA levels via increased UA excretion, even in patients with advanced CKD.

Design of Cell-Adhesive Shellac Derivatives and Endowment of Photoswitchable Cell-Adhesion Properties.

The emergence of new biodegradable cell-adhesion materials is an attractive topic in biomaterial chemistry, particularly for the development of cell incubation scaffolds and drug encapsulation materials used in in situ regenerative therapy. Shellac is a natural resin with unique film-forming properties and high miscibility with various chemicals, in addition to being biodegradable and nontoxic to biological systems. However, since native shellac does not adhere to mammalian cells, there have been no reports of using shellac to develop cell-adhesive biomaterials. In this study, we report on the development of cell-adhesive shellac derivatives through slight chemical modification. Shellac is a mixture of oligoesters that consists of hydroxyl fatty acids and resin acids, and therefore, all oligomers have one carboxylic acid group at the terminal. We discovered that a simple modification of hydrophobic chemical groups, particularly those containing aromatic groups in the ester form, could dramatically improve cell-adhesion properties for mammalian cells. Furthermore, by using photocleavable esters containing aromatic groups, we successfully endowed photoswitchable properties in cell adhesion. Given that shellac is a low-cost, biodegradable, and nontoxic natural resin, the modified shellacs have the potential to become new and attractive biomaterials applicable to in situ regenerative therapy.

Subcutaneously Transplanted Fresh Cartilage in Allogeneic and Xenogeneic Immunocompetent Mouse.

Cartilage is considered to be immune privileged in general. Clinically, live cells are removed from subcutaneously transplanted allogeneic cartilage mainly for preservation and for infection control. However, because maintaining cartilage feature requires live chondrocyte, it would be beneficial to subcutaneously transplant cartilage with live chondrocyte even if it was allogeneic. We harvested femoral head from 3-week-old male C57BL/6 mice, subcutaneously transplanted to 6-week-old male mice, BALB/c, BALB/c nu/nu, or C57BL/6-Tg (enhanced green fluorescent protein [EGFP] under the control of the CMV-IE enhancer, chicken beta-actin promoter, rabbit beta-globin genomic DNA [CAG promoter]), as allogeneic, allogeneic immunodeficient control, or syngeneic transplantation. We also transplanted cartilaginous particles from human induced pluripotent stem cells derived from human leukocyte antigen homozygous donor to 6-week-old male mice either BALB/c and BALB/c nu/nu as xenogeneic or xenogeneic immunodeficient control. The transplantation periods were 1, 2, 3, 4, 8, 12, and 24 weeks. As the result, we did not observe exposure of the transplant or apparent macroscopic inflammatory in all samples. Histological analysis suggested that the femoral head showed focal ossification and thinning in syngeneic transplantation. In allogeneic transplantation, slight invasion of CD3 (+) T cell and the denaturation of the cartilage were observed, suggesting immune reaction against allogeneic cartilage. In xenogeneic transplantation, slight invasion of CD3 (+) cell and CD4 (+) cell and the structure of the perichondrium-like tissue got unclear, suggesting slight immune reaction against xenogeneic cartilage. Our findings suggest that we should carefully investigate for appropriate procedure to control immune reaction against allogeneic cartilage with live chondrocyte and to maintain its cartilage feature for long time.

Increase in rotavirus prevalence with the emergence of genotype G9P[8] in replacement of genotype G12P[6] in Sabah, Malaysia.

Rotaviruses are major causative agents of acute diarrhea in children under 5 years of age in Malaysia. However, a rotavirus vaccine has not been included in the national vaccination program. To date, only two studies have been carried out in the state of Sabah, Malaysia, although children in this state are at risk of diarrheal diseases. Previous studies showed that 16%-17% of cases of diarrhea were caused by rotaviruses and that equine-like G3 rotavirus strains are predominant. Because the prevalence of rotaviruses and their genotype distribution vary over time, this study was conducted at four government healthcare facilities from September 2019 through February 2020. Our study revealed that the proportion of rotavirus diarrhea increased significantly to 37.2% (51/137) after the emergence of the G9P[8] genotype in replacement of the G12P[8] genotype. Although equine-like G3P[8] strains remain the predominant rotaviruses circulating among children, the Sabahan G9P[8] strain belonged to lineage VI and was phylogenetically related to strains from other countries. A comparison of the Sabahan G9 strains with the G9 vaccine strains used in the RotaSiil and Rotavac vaccines revealed several mismatches in neutralizing epitopes, indicating that these vaccines might not be effective in Sabahan children. However, a vaccine trial may be necessary to understand the precise effects of vaccination.

Histological Analysis of a Mouse Model of the 22q11.2 Microdeletion Syndrome.

22q11.2 deletion syndrome (22q11.2DS) is associated with a high risk of developing various psychiatric and developmental disorders, including schizophrenia and early-onset Parkinson's disease. Recently, a mouse model of this disease, Del(3.0Mb)/+, mimicking the 3.0 Mb deletion which is most frequently found in patients with 22q11.2DS, was generated. The behavior of this mouse model was extensively studied and several abnormalities related to the symptoms of 22q11.2DS were found. However, the histological features of their brains have been little addressed. Here we describe the cytoarchitectures of the brains of Del(3.0Mb)/+ mice. First, we investigated the overall histology of the embryonic and adult cerebral cortices, but they were indistinguishable from the wild type. However, the morphologies of individual neurons were slightly but significantly changed from the wild type counterparts in a region-specific manner. The dendritic branches and/or dendritic spine densities of neurons in the medial prefrontal cortex, nucleus accumbens, and primary somatosensory cortex were reduced. We also observed reduced axon innervation of dopaminergic neurons into the prefrontal cortex. Given these affected neurons function together as the dopamine system to control animal behaviors, the impairment we observed may explain a part of the abnormal behaviors of Del(3.0Mb)/+ mice and the psychiatric symptoms of 22q11.2DS.

Mechanistic study of Al2O3 coating effects on lithium deposition and dissolution reaction.

Lithium metal anodes show great promise for use in next-generation secondary batteries, but they suffer from lithium dendrite growth, as well as other issues, which cause safety problems and result in a loss of capacity with time. The use of artificial inorganic solid electrolyte interphase (SEI) layers, such as those comprising Al2O3, is a promising way to mitigate these disadvantages, but the mechanism behind these observed improvements remains poorly understood. Therefore, in this study, using pulsed laser deposition (PLD), the surface of a Cu electrode was coated with a physicochemically stable and mechanically strong Al2O3 thin film, and the effects of the film coating on the lithium deposition and dissolution behaviour were investigated. When the morphology of the deposits was evaluated by scanning electron microscopy, small lithium nuclei (approximately 0.2 µm in diameter) were observed to be deposited uniformly over the entire surface of the uncoated Cu electrode in the initial electrodeposition, and these grew into needle-like crystals from the nuclei. After 60 min of electrodeposition, the needle-like precipitates had aggregated and grown into three-dimensional structures with dendritic form. In contrast, on the surface of the Cu electrode modified with Al2O3 by PLD for 1 h, lithium clusters of about 50 µm in diameter were found to be aggregated and precipitated in the initial stages of electrodeposition. Notably, this is the first report of lithium deposition on Al2O3 thin films. With further cycling, the precipitates grew into two-dimensional flat plates. Analysis of the SEI film formed during the first deposition reaction revealed that the Al2O3 coating reduced the thickness of the SEI compared to that of the uncoated electrode. Therefore, the Al2O3 coating suppressed the decomposition of the electrolyte with the Cu electrode. The use of Al2O3 coatings results in (i) the growth of two-dimensional lithium clusters with an island shape on the Al2O3 thin film, and these could ensure a uniform electron conduction path to the electrode; in addition, (ii) the inhibited electrolyte decomposition caused by the low-surface-area lithium clusters and the low electronic conductivity of the Al2O3 thin film. These improve the coulombic efficiency and cycling behaviour.

Sensory evaluation of the bitterness of asenapine using D-sorbitol pretreatment: single-blind, placebo-controlled, crossover trial.

BACKGROUND: Antipsychotics are essential in the acute treatment of and maintenance therapy for schizophrenia, but medication adherence and long-term treatment continuity are needed to maximize their effectiveness. Each antipsychotic has various side effects, which may affect adherence. Some patients with schizophrenia are reluctant to take asenapine because of its unique oral-related side effects, such as the bitter taste caused by sublingual administration. Our previous basic research found that D-sorbitol lowered the bitterness parameters of the taste sensors. However, whether D-sorbitol has the same effect in patients remains unclear. Therefore, using a D-sorbitol solution, we aim to evaluate changes in the bitterness of asenapine among patients with schizophrenia. METHODS: In this single-blind, placebo-controlled, crossover trial, we plan to recruit 20 adult patients with schizophrenia spectrum disorder who take sublingual asenapine tablets. The participants will be divided into two groups (n = 10 each). Each group will be given a D-sorbitol or placebo solution on the first day for rinsing before taking the sublingual asenapine tablets. After a 1-day interval, the participants will rinse their mouths again with a different liquid. Questionnaires regarding changes in taste and the willingness to continue asenapine will be conducted before the start of the study and after each rinse. The primary and secondary end points will be a taste evaluation of bitterness, and the willingness to continue asenapine, respectively. Differences in questionnaire scores between the D-sorbitol and placebo solutions will be calculated and analyzed using a McNemar test. DISCUSSION: This study aims to determine the efficacy of D-sorbitol in masking the bitter taste of asenapine. To our knowledge, it is the first intervention study using D-sorbitol for bitter taste of asenapine in patients with schizophrenia. Evidence of the efficacy of D-sorbitol could result in D-sorbitol pretreatment being an easy and inexpensive means of improving adherence to asenapine. TRIAL REGISTRATION: This study was registered in the Japan Registry of Clinical Trials jRCTs041210019, on May 14, 2021. Ethics approval was obtained from the Nagoya University Clinical Research Review Board.

Prognostic Implications of Urinary Potassium to Creatinine Ratio in Patients With Predialysis Chronic Kidney Disease: A Cohort Study.

OBJECTIVES: Although a low or high serum potassium level in chronic kidney disease (CKD) is associated with worsening renal function and increased cardiovascular disease (CVD) events, urinary potassium excretion has been found to predict adverse health outcomes with conflicting results. We conducted a cohort study to determine whether urinary potassium to creatinine (K/Cr) ratio is an independent risk for further deterioration in renal function or increased CVD events. METHODS: We identified 650 predialysis patients with CKD hospitalized for an educational program regarding CKD between January 2010 and December 2018. The study outcomes were CKD progression and incident CVD events, with baseline urinary K/Cr ratio categorized into quartiles-Q1, < 19.8; Q2, 19.9-27.7; Q3, 27.8-37.9; and Q4, > 38.0. RESULTS: During follow-up (median, 35 months), 509 CKD progressions and 129 incident CVD events were identified. Sixty two patients died during follow-up. Multivariate Cox proportional hazard model showed that after adjustment for demographic factors and laboratory data, patients in Q1 had a 2.02-fold higher risk of worsening renal function than those in Q4 (95% confidence interval, 1.50-2.71; P < .001), whereas urinary K/Cr ratio had no association with the incidence of CVD events. Similarly, inverse probability weighting analysis showed an increased risk of CKD progression in the lowest quartile. Furthermore, the association between low fractional excretion of potassium and worsening renal function was confirmed. CONCLUSION: A low urinary K/Cr ratio is independently associated with worsening renal function but not with a risk of incident CVD event in predialysis patients with CKD.