Ultraflexible organic light-emitting diodes for optogenetic nerve stimulation.

Organic electronic devices implemented on flexible thin films are attracting increased attention for biomedical applications because they possess extraordinary conformity to curved surfaces. A neuronal device equipped with an organic light-emitting diode (OLED), used in combination with animals that are genetically engineered to include a light-gated ion channel, would enable cell type-specific stimulation to neurons as well as conformal contact to brain tissue and peripheral soft tissue. This potential application of the OLEDs requires strong luminescence, well over the neuronal excitation threshold in addition to flexibility. Compatibility with neuroimaging techniques such as MRI provides a method to investigate the evoked activities in the whole brain. Here, we developed an ultrathin, flexible, MRI-compatible OLED device and demonstrated the activation of channelrhodopsin-2-expressing neurons in animals. Optical stimulation from the OLED attached to nerve fibers induced contractions in the innervated muscles. Mechanical damage to the tissues was significantly reduced because of the flexibility. Owing to the MRI compatibility, neuronal activities induced by direct optical stimulation of the brain were visualized using MRI. The OLED provides an optical interface for modulating the activity of soft neuronal tissues.

Number of consulting medical institutions and risk of polypharmacy in community-dwelling older people under a healthcare system with free access: a cross-sectional study in Japan.

BACKGROUND: Under the Japanese free access healthcare system, patients are allowed to consult multiple medical institutions (including clinics and hospitals for general or specialist consultation) without primary care referral. This potentially increases the risk of polypharmacy. We examined the association between the number of consulting medical institutions and polypharmacy under a healthcare system with free access. METHODS: Via a self-administered questionnaire, we identified people aged ≥65 years with ≥1 disease and ≥1 consulting medical institution in a Japanese city in 2016. The exposure of interest was the number of consulting medical institutions (1, 2, or ≥3) and the outcome was polypharmacy (use of ≥6 types of drugs). We performed a multivariate logistic regression analysis, adjusting for age, sex, household economy, and the number and type of comorbidities. To minimize confounding effects, we also performed propensity-score-matched analysis, categorizing patients into two groups: 1 and ≥2 consulting medical institutions. RESULTS: Of 993 eligible individuals (mean (standard deviation) age: 75.1 (6.5) years, men: 52.6%), 15.7% (156/993) showed polypharmacy. Proportions of polypharmacy were 9.7% (50/516), 16.6% (55/332), and 35.2% (51/145) for people who consulted 1, 2, and ≥3 medical institutions, respectively. Relative to people who consulted 1 medical institution, adjusted odds ratios (95% confidence intervals) for polypharmacy were 1.50 (0.94-2.37) and 3.34 (1.98-5.65) for those who consulted 2 and ≥3 medical institutions, respectively. In propensity score matching, of 516 and 477 patients who consulted 1 and ≥2 medical institutions, 307 pairs were generated. The proportion of polypharmacy was 10.8% (33/307) and 17.3% (53/307), respectively (P = 0.020). The odds ratio for polypharmacy (≥2 vs. 1 consulting medical institution) was 1.73 (95% confidence interval 1.09-2.76). CONCLUSIONS: Patients who consulted more medical institutions were more likely to show polypharmacy. The results could encourage physicians and pharmacists to collect medication information more actively and conduct appropriate medication reviews. Strengthening primary care is needed to address the polypharmacy issue, especially in countries with healthcare systems with free access.

Development of SAAP3D force field and the application to replica-exchange Monte Carlo simulation for chignolin and C-peptide.

Single amino acid potential (SAAP) would be a prominent factor to determine peptide conformations. To prove this hypothesis, we previously developed SAAP force field for molecular simulation of polypeptides. In this study, the force field was renovated to SAAP3D force field by applying more accurate three-dimensional main-chain parameters, instead of the original two-dimensional ones, for the amino acids having a long side-chain. To demonstrate effectiveness of the SAAP3D force field, replica-exchange Monte Carlo (REMC) simulation was performed for two benchmark short peptides, chignolin (H-GYDPETGTWG-OH) and C-peptide (CHO-AETAAAKFLRAHA-NH2). For chignolin, REMC/SAAP3D simulation correctly produced native ß-turn structures, whose minimal all-atom root-mean-square deviation value measured from the native NMR structure (except for H) was 1.2 Å, at 300 K in implicit water, along with misfolded ß-hairpin structures with unpacked aromatic side chains of Tyr2 and Trp9. Similar results were obtained for chignolin analog [G1Y,G10Y], which folded more tightly to the native ß-turn structure than chignolin did. For C-peptide, on the other hand, the α-helix content was larger than the ß content on average, suggesting a significant helix-forming propensity. When the imidazole side chain of His12 was protonated (i.e., [His12Hip]), the α content became larger. These observations as well as the representative structures obtained by clustering analysis were in reasonable agreement not only with the structures of C-peptide that were determined in this study by NMR in 30% CD3CD in H2O at 298 K but also with the experimental and theoretical behaviors having been reported for protonated C-peptide. Thus, accuracy of the SAAP force field was improved by applying three-dimensional main-chain parameters, supporting prominent importance of SAAP for peptide conformations.

Magnetic sentinel lymph node biopsy in a murine tumour model.

The magnetic technique for sentinel node biopsy provides a radioisotope-free alternative for staging breast cancer. It requires refinement to reduce "residual iron content" at injection sites by maximising lymphatic uptake to prevent "void artefacts" on magnetic resonance imaging (MRI), which could adversely affect clinical use. The site and timing of injection of magnetic tracer was evaluated in a murine tumour model (right hind limb) in 24 wild type mice. Right-sided intratumoural and left sided subcutaneous injection of magnetic tracer and assessment of nodal iron uptake on MRI, surgical excision and histopathological grading at time frames up to 24 hours were performed. Rapid iron uptake on MRI, smaller "void artefacts"(P<0.001) and a significant increase in iron content with time were identified in the subcutaneous injection group (r=0.937; P<0.001).Subcutaneous injection and increasing delay between tracer injection and surgery is beneficial for lymphatic iron uptake. FROM THE CLINICAL EDITOR: Sentinel lymph node biopsy (SLNB) has been the standard of care in breast cancer management for some time. Recent development has seen the introduction of magnetic tracer for SLNB. In this article, the authors investigated the refined use of magnetic tracer in determining the optimal timing of administration and the location of injection. The findings should provide more data on the future use of this new technique.

Effects of ring size and polar functional groups on the glutathione peroxidase-like antioxidant activity of water-soluble cyclic selenides.

To elucidate the effects of ring structure and a substituent on the glutathione peroxidase- (GPx-) like antioxidant activities of aliphatic selenides, series of water-soluble cyclic selenides with variable ring size and polar functional groups were synthesized, and their antioxidant activities were evaluated by NADPH-coupled assay using H2O2 and glutathione (GSH) in water and also by NMR spectroscopy using H2O2 and dithiothreitol (DTT(red)) in methanol. Strong correlations were found among the GPx-like activity in water, the second-order rate constants for the oxidation of the selenides, and the HOMO energy levels calculated in water. The results support the conclusion that the oxidation process is the rate-determining step of the catalytic cycle. On the other hand, such correlations were not obtained for the activity observed in methanol. The optimal ring size was determined to be five. The type of substituent (NH2 < OH < CO2H) and the number can also control the activity, whereas the stereoconfiguration has only marginal effects on the activity in water. In methanol, however, the activity rank could not be explained by the simple scenarios applicable in water.

Characteristics and in-hospital mortality of patients with COVID-19 from the first to fifth waves of the pandemic in 2020 and 2021 in the Japanese Medical Data Vision database.

Objectives: We aimed to describe patient characteristics, healthcare utilization, and in-hospital mortality among patients with COVID-19 in Japan across waves. Methods: Using a large-scale hospital-based database, we identified patients hospitalized for COVID-19 in the first (January-June 2020), second (June-October 2020), third (October 2020-February 2021), fourth (March-June 2021), and fifth (June-December 2021) waves. We summarized patient characteristics, healthcare utilization, and in-hospital mortality during each wave and performed multivariable logistic regression analyses for in-hospital mortality. Results: From the first to fifth waves, the number of patients (mean age ± standard deviation, years) was 2958 (61.2 ± 22.8), 7981 (55.6 ± 25.3), 18,788 (63.6 ± 22.9), 17,729 (60.6 ± 22.6), and 23,656 (51.2 ± 22.3), respectively. There were 190 (6.4%), 363 (4.5%), 1261 (6.7%), 1081 (6.1%), and 762 (3.2%) in-hospital deaths, respectively. The adjusted odds ratios for in-hospital deaths (95% confidence interval) were 0.78 (0.65-0.95), 0.94 (0.79-1.12), 0.99 (0.84-1.18), 0.77 (0.65-0.92), in the second to fifth waves, respectively, compared with the first wave. Conclusions: In-hospital COVID-19 mortality improved from the first to the second wave; however, during the third and fourth waves, mortality was as serious as in the first wave. Although in-hospital mortality during the fifth wave improved, careful monitoring is needed for upcoming waves, considering changing patient and viral characteristics.

Comparison of patient characteristics and in-hospital mortality between patients with COVID-19 in 2020 and those with influenza in 2017-2020: a multicenter, retrospective cohort study in Japan.

BACKGROUND: COVID-19 has worse mortality than influenza in American and European studies, but evidence from the Western Pacific region is scarce. METHODS: Using a large-scale multicenter inpatient claims data in Japan, we identified individuals hospitalised with COVID-19 in 2020 or influenza in 2017-2020. We compared patient characteristics, supportive care, and in-hospital mortality, with multivariable logistic regression analyses for in-hospital mortality overall, by age group, and among patients with mechanical ventilation. FINDINGS: We identified 16,790 COVID-19 patients and 27,870 influenza patients, with the different age distribution (peak at 70-89 years in COVID-19 vs. bimodal peaks at 0-9 and 80-89 years in influenza). On admission, the use of mechanical ventilation was similar in both groups (1·4% vs. 1·4%) but higher in the COVID-19 group (3·3% vs. 2·5%; p<0·0001) during the entire hospitalisation. The crude in-hospital mortality was 5·1% (856/16,790) for COVID-19 and 2·8% (791/27,870) for influenza. Adjusted for potential confounders, the in-hospital mortality was higher for COVID-19 than for influenza (adjusted odds ratio [aOR] 1·83, 95% confidence interval [CI] 1·64-2·04). In age-stratified analyses, the aOR (95%CI) were 0·78 (0·56-1·08) and 2·05 (1·83-2·30) in patients aged 20-69 years and ≥70 years, respectively (p-for-interaction<0·0001). Among patients with mechanical ventilation, the aOR was 0·79 (0·59-1·05). INTERPRETATION: Patients hospitalised with COVID-19 in Japan were more likely to die than those with influenza. However, this was mainly driven by findings in older people, and there was no difference once mechanical ventilation was started. FUNDING: Ministry of Health, Labour and Welfare of Japan (21AA2007).

An MRI-compatible and quantifiable mechanical stimulator for allodynia in a rat model of neuropathic pain.

We developed an MRI-compatible and quantifiable mechanical stimulator for rats. Functional MRI (fMRI) was used to investigate brain activations resulting from mechanical stimulation in normal rats and in a rat model of neuropathic pain. In the previous MRI-compatible mechanical stimulator, stimulation intensity was not adjustable. In this study, the strength of mechanical stimulation was controlled by von Frey filaments, which were used for mechanical nociception assessment. It provides us to investigate correlations between behavioral sensitivities in von Frey tests and BOLD signal changes during mechanical stimulation. In order to transmit mechanical force to a stimulation site under the strong magnetic field of a 7-T MRI system, a tube-rod structure consisting of nonmagnetic materials was used. The mechanical stimulation evoked a change in blood oxygenation level dependent (BOLD) signals in normal rats. Changes in brain activation were investigated at around- and supra-threshold conditions of mechanical nociception using the filaments for 15 g and 60 g forces. The mechanical stimulation from the 60-g-force filament, which was over the mechanical nociceptive threshold, induced strong brain activation in the areas related to nociceptive pain perception. This result was consistent with that associated with strong electrical stimulation. Mechanical stimulation in the neuropathic pain model evoked brain activity even at around-threshold conditions of mechanical nociception. Higher brain activity in the neuropathic pain model compared with normal rats was considered to be associated with allodynia.

A survey on low-dose oral contraceptive transactions at pharmacies.

Low-dose oral contraceptives (OCs) were approved by the Japanese Ministry of Health, Labor and Welfare in 1999. However, few women use low-dose OCs (married 1.9%, unmarried 0.7%). A survey of pharmacies was conducted to determine the current status of OC transactions. Of the 449 pharmacies randomly selected from each prefecture in Japan, 408 agreed to be interviewed. The survey results indicated that few pharmacies (15.1% of the total) stocked low-dose OCs. Even among pharmacies where they were available, only a few (13.5%) offered a wide variety of low-dose OCs for immediate dispensing. The price of low-dose OCs varied widely (yen 1,167-yen 7,000). In many pharmacies, the amount of space and interior structure were not adequate for users to seek advice on and receive low-dose OCs. The survey revealed that the current environment of many pharmacies is not adequate for users to visit, consult on OC use, and receive their prescriptions. To promote wider use of low-dose OCs, the facilities of pharmacies as well as the behavior of pharmacists need to be improved to safeguard the privacy of users.