Manipulating the functionality and structures of π-conjugated polymers utilizing intramolecular noncovalent interactions towards efficient organic photovoltaics.

Careful control of electronic properties, structural order, and solubility of π-conjugated polymers is central to the improvement of organic photovoltaic (OPV) performance. In this work, we designed and synthesized a series of naphthobisthiadiazole-quaterthiophene copolymers by systematically replacing the alkyl groups with ester groups and changing the position of the fluorine groups in the quaterthiophene moiety. These alterations lowered the HOMO and LUMO energy levels and systematically varied the combination of intramolecular noncovalent interactions such as O⋯S and F⋯S interactions in the backbone. More importantly, although the introduction of such noncovalent interactions often lowers the solubility owing to the interlocking of backbone linkages, we found that careful design of the noncovalent interactions afforded polymers with relatively high solubility and high crystallinity at the same time. As a result, the power conversion efficiency of OPV cells that used fullerene (PC61BM) and nonfullerene (Y12) as the acceptor was improved. Our work offers important information for the development of high-performance π-conjugated polymers for OPVs.

Achieving water-floatable photocatalyst on recycled bamboo chopsticks.

Disposable bamboo chopsticks (DBCs) are difficult to recycle, which inevitably cause secondary pollution. Based on energy and environmental issues, we propose a facile strategy to fabricate floatable photocatalyst (fPC) coated onto DBCs, which can be flexibly used in water purification. The photocatalyst of titania and titanium carbide on bamboo (TiO2/TiC@b) was successfully constructed from TiC-Ti powders and DBCs using a coating technique followed heat treatment in carbon powder, and the fPC exhibited excellent photocatalytic activity under visible light irradation. The analysis results indicate that rutile TiO2 forms on TiC during heat treatment, achieving a low-density material with an average value of approximately 0.5233 g/cm3. The coatings of TiO2/TiC on the bamboo are firm and uniform, with a particle size of about 20-50 nm. XPS results show that a large amount of oxygen vacancies is generated, due to the reaction atmosphere of more carbon and less oxygen, further favoring to narrowing the band gap of TiO2. Furthermore, TiO2 formed on residual TiC would induce the formation of a heterojunction, which effectively inhibits the photogenerated electron-hole recombination via the charge transfer effect. Notably, the degradation of dye Rhodamine B (Rh.B) is 62.4% within 3 h, while a previous adsorption of 36.0% for 1 h. The excellent photocatalytic performance of TiO2/TiC@b can be attributed to the enhanced reaction at the water/air interface due to the reduced light loss in water, improved visible-light response, increased accessible area and charge transfer effect. Our findings show that the proposed strategy achieves a simple, low-cost, and mass-producible method to fabricate fPC onto the used DBCs, which is expected to applied in multiple fields, especially in waste recycling and water treatment.

Artificial intelligence in medicine: mitigating risks and maximizing benefits via quality assurance, quality control, and acceptance testing.

The adoption of artificial intelligence (AI) tools in medicine poses challenges to existing clinical workflows. This commentary discusses the necessity of context-specific quality assurance (QA), emphasizing the need for robust QA measures with quality control (QC) procedures that encompass (1) acceptance testing (AT) before clinical use, (2) continuous QC monitoring, and (3) adequate user training. The discussion also covers essential components of AT and QA, illustrated with real-world examples. We also highlight what we see as the shared responsibility of manufacturers or vendors, regulators, healthcare systems, medical physicists, and clinicians to enact appropriate testing and oversight to ensure a safe and equitable transformation of medicine through AI.

Anti-integrin αvß6 autoantibodies are a potential biomarker for ulcerative colitis-like immune checkpoint inhibitor-induced colitis.

BACKGROUND: No specific biomarker for immune checkpoint inhibitor (ICI)-induced colitis has been established. Previously, we identified anti-integrin αvß6 autoantibodies in >90% of patients with ulcerative colitis (UC). Given that a subset of ICI-induced colitis is similar to UC, we aimed to clarify the relationship between such autoantibodies and ICI-induced colitis. METHODS: Serum anti-integrin αvß6 autoantibody levels were compared between 26 patients with ICI-induced colitis and 157 controls. Endoscopic images of ICI-induced colitis were centrally reviewed. Characteristics of anti-integrin αvß6 autoantibodies in the ICI-induced colitis patients were compared with those of UC patients. RESULTS: Anti-integrin αvß6 autoantibodies were found in 8/26 (30.8%) patients with ICI-induced colitis and 3/157 (1.9%) controls (P < 0.001). Patients with anti-integrin αvß6 autoantibodies had significantly more typical UC endoscopic features than those without the autoantibodies (P < 0.001). Anti-integrin αvß6 autoantibodies in ICI-induced colitis patients were associated with grade ≥3 colitis (P = 0.001) and steroid resistance (P = 0.005). Anti-integrin αvß6 autoantibody titers correlated with ICI-induced colitis disease activity. Anti-integrin αvß6 autoantibodies of ICI-induced colitis exhibited similar characteristics to those of UC. CONCLUSIONS: Anti-integrin αvß6 autoantibodies may serve as potential biomarkers for the diagnosis, classification, risk management, and monitoring the disease activity, of ICI-induced colitis.

Analysis of Factors Related to Variation in Dissolution Profiles Estimated from Continuously Conducted Dissolution Tests of Generic Products.

The development of generic pharmaceuticals involves a bioequivalence study to ensure the therapeutic equivalence of the test formulation to the original innovative product. The formulation characteristics of generic products are expected to be maintained in the long term after approval. This study analyzed the factors contributing to the changes in the dissolution profiles of approved products during their life cycles. Cumulative data on the dissolution similarity of 1675 products of 127 ingredients tested by official laboratories in Japan were assessed according to Japanese bioequivalence guidelines with slight modifications. The products showing dissimilarities in dissolution profiles were analyzed for reporting year, therapeutic category, co-development, physical properties of the active pharmaceutical ingredient (API), and suspected reasons for dissolution change. The increase in the number of dissimilar products is related to the co-development of generic products. Although the solubility of the API was not associated with the dissolution change in the analysis of the total dissolution data, control of the API particle size is suggested to be important for drugs with poorly soluble APIs. Additionally, a risk factor for dissolution changes in the test solutions at a certain pH was the presence of acidic or basic residues. These results indicate the importance of proper development through a thorough evaluation of the formulation and process factors affecting the dissolution properties throughout the product lifecycle.

Transversely graded polarization volume gratings fabricated by freeform holographic photoalignment.

Polarization volume gratings (PVGs) based on chiral nematic liquid crystals offer a great potential as polarization-dependent holographic optical elements, but it is not easy to fabricate PVGs with varying pattern periods in the transverse plane. Here, we fabricate a PVG with an in-plane gradient of the pattern period by performing two-beam interference photoalignment on a flexible polyimide substrate. The pattern period varies depending on the local interference angle, which is controlled by the bent shape of the flexible substrate. We demonstrate fabrication of a PVG with a linearly graded sub-micrometer period, showing the potential of the proposed method to fabricate designer PVGs.

A novel high-current, high-resolution, low-kinetic-energy electron source for inverse photoemission spectroscopy.

A high-current electron source for inverse photoemission spectroscopy is described. The source comprises a thermal cathode electron emission system, an electrostatic deflector-monochromator, and a lens system for variable kinetic energy (1.6-20 eV) at the target. When scaled to the energy resolution, the electron current is an order of magnitude higher than that of previously described electron sources developed in the context of electron energy loss spectroscopy. Surprisingly, the experimentally measured energy resolution turned out to be significantly better than calculated by standard programs, which include the electron-electron repulsion in the continuum approximation. The achieved currents are also significantly higher than predicted. We attribute this "inverse Boersch-effect" to a mechanism of velocity selection in the forward direction by binary electron-electron collisions.

Dependence of Exciton Binding Energy on Bandgap of Organic Semiconductors.

Strongly bound excitons crucially affect the operation of organic optoelectronic devices. Nevertheless, precise experimental data on the exciton binding energy of organic semiconductors are lacking. In this study, we determine the exciton binding energy as the difference between the optical and transport bandgaps with a precision of 0.1 eV. In particular, electron affinities with a precision higher than 0.05 eV determined by low-energy inverse photoelectron spectroscopy allow us to determine the transport gap and the exciton binding energies with such high precision. Through a systematic comparison of a wide range of organic semiconductors, including 42 organic solar cell materials (15 nonfullerene acceptors, 4 fullerene acceptors, 13 low-bandgap polymers, 7 organic light-emitting diode materials, and 3 crystalline materials), we found that the exciton binding energy is one-quarter of the transport gap regardless of the materials. We interpret this unexpected relation from a hydrogen atom-like model, i.e., the quantized energy levels in a Coulomb potential between the positive and the negative charges.

Effects of Apex Size on Dissolution Profiles in the USP II Paddle Apparatus.

The use of apex vessels may solve coning problems associated with dissolution testing. However, excessive dissolution acceleration can reduce the discriminatory power. This study aimed to clarify how different apex vessel sizes affect the dissolution behavior of cone-forming formulations. Five apex vessels with different heights, centralities, and compendial vessels were used. The paddle rotation speed at which the coning phenomenon resolved was measured using standard particles of different densities. Three model formulations-USP prednisone tablets, atorvastatin calcium hydrate tablets, and levofloxacin fine granules-were selected, and dissolution tests were conducted at 30-100 revolutions per minute (rpm). Compared to the compendial vessels, the disappearance of standard particles at the apex base at lower paddle speeds in apex vessels was observed. Standard particles tended to remain in the center of the apex vessels and disappear at rotational speeds comparable to those of the compendial vessels. Dissolution increased in an apex height-dependent manner in the model formulations, except for the atorvastatin calcium hydrate tablets at 50 rpm. For levofloxacin fine granules, dissolution was also improved by reducing the paddle agitation speed to 30 rpm in the compendial vessels. Differences in apex centrality by 3 mm did not affect the dissolution rate. Our results indicate that apex vessels with low apex heights have a mount-resolving effect, but the degree of dissolution improvement by avoiding the coning phenomenon depends on the formulation characteristics used in the dissolution tests.

High-energy-resolution angle-resolved inverse-photoelectron spectroscopy apparatus for damage-free measurements of conduction band structures of functional materials.

The energy band structure of the conduction band (energy-momentum relation of electrons) is crucial to understanding the electron transport of crystalline materials. In this paper, we describe an angle-resolved low-energy inverse photoelectron spectroscopy (AR-LEIPS) apparatus that examines the conduction band structures of materials sensitive to the electron beam, such as organic semiconductors and organic-inorganic hybrid perovskites. The principle of this apparatus is based on AR inverse photoelectron spectroscopy. To minimize radiation damage and improve energy resolution, we employed our previous approach used in LEIPS [H. Yoshida, Chem. Phys. Lett. 539-540, 180 (2012)]. We obtained an overall energy resolution of 0.23 eV with a momentum resolution of 0.9 nm-1 at the electron kinetic energy of 2 eV or higher.

Bayesian uncertainty estimation for detection of long-tailed and unseen conditions in medical images.

Purpose: Deep supervised learning provides an effective approach for developing robust models for various computer-aided diagnosis tasks. However, there is often an underlying assumption that the frequencies of the samples between the different classes of the training dataset are either similar or balanced. In real-world medical data, the samples of positive classes often occur too infrequently to satisfy this assumption. Thus, there is an unmet need for deep-learning systems that can automatically identify and adapt to the real-world conditions of imbalanced data. Approach: We propose a deep Bayesian ensemble learning framework to address the representation learning problem of long-tailed and out-of-distribution (OOD) samples when training from medical images. By estimating the relative uncertainties of the input data, our framework can adapt to imbalanced data for learning generalizable classifiers. We trained and tested our framework on four public medical imaging datasets with various imbalance ratios and imaging modalities across three different learning tasks: semantic medical image segmentation, OOD detection, and in-domain generalization. We compared the performance of our framework with those of state-of-the-art comparator methods. Results: Our proposed framework outperformed the comparator models significantly across all performance metrics (pairwise t-test: p<0.01) in the semantic segmentation of high-resolution CT and MR images as well as in the detection of OOD samples (p<0.01), thereby showing significant improvement in handling the associated long-tailed data distribution. The results of the in-domain generalization also indicated that our framework can enhance the prediction of retinal glaucoma, contributing to clinical decision-making processes. Conclusions: Training of the proposed deep Bayesian ensemble learning framework with dynamic Monte-Carlo dropout and a combination of losses yielded the best generalization to unseen samples from imbalanced medical imaging datasets across different learning tasks.

Human papillomavirus vaccine impact on invasive cervical cancer in Japan: Preliminary results from cancer statistics and the MINT study.

The first prophylactic vaccine against human papillomavirus (HPV) 16 and HPV18 was licensed in Japan in 2009. HPV vaccine effectiveness against high-grade cervical lesions has been demonstrated among young Japanese women, but evidence of its effects on invasive cervical cancer (ICC) is lacking. Using data from two different cancer registries, we compared recent trends of new ICC cases by age group using Poisson regression analysis. We also analyzed time trends in HPV16/18 prevalence among 1414 Japanese women aged <40 years newly diagnosed with ICC in the past decade. Based on the population-based cancer registry, the incidence of ICC among young women aged 20-29 years showed a significant decline from 3.6 to 2.8 per 100 000 women-years during 2016-2019, but no similar decline was observed for older age groups (p < 0.01). Similarly, using data from the gynecological cancer registry of the Japan Society of Obstetrics and Gynecology, the annual number of ICCs among women aged 20-29 years also decreased from 256 cases to 135 cases during 2011-2020 (p < 0.0001). Furthermore, a declining trend in HPV16/18 prevalence in ICC was observed only among women aged 20-29 years during 2017-2022 (90.5%-64.7%, p = 0.05; Cochran-Armitage trend test). This is the first report to suggest population-level effects of HPV vaccination on ICC in Japan. Although the declining trend in HPV16/18 prevalence among young women with ICC supports a causal linkage between vaccination and results from cancer registries, further studies are warranted to confirm that our findings are attributable to vaccination.

Oxygen vacancies induced band gap narrowing for efficient visible-light response in carbon-doped TiO2.

The band gap of rutile TiO2 has been narrowed, via the formation of oxygen vacancies (OVs) during heat treatment in carbon powder (cHT) with embedding TiO2 coatings. The narrowed band gap efficiently improves the visible light response of TiO2 coatings, to further enhance the visible-light-driven photocatalytic activity. The change in OVs during cHT has been studied by manipulation of cHT temperature and time. The effect of OVs on the band structure of nonstoichiometric TiO2-x has been further calculated by first-principles calculations. With raising the temperature, SEM images show that the nano-size fiber-like structure forms on the surface of TiO2 coatings, and the amount of the fiber-like structure significantly increases and their size changes from nano to micro under 800 °C, contributing to cause an increase in accessible surface area. The UV-Vis results reveal that the band gap of TiO2 has been narrowed during cHT, due to the formed oxygen vacancies. The XPS results further confirm that the formation of surface defects including OVs, and the XPS depth profile further shows the decreased relative amount of O whereas increased relative amount of carbon. Notably, after cHT for TiO2 coatings, the photocatalytic activity first increases then decreases with raising the temperature, achieving approximately 3 times at 850 °C. The first-principles calculation suggest that the OVs in TiO2 coatings with localized electrons could facilitate the band gap narrowing, further favoring to enhance the photocatalytic activity under visible light.

Anti-integrin αvß6 autoantibodies in patients with primary sclerosing cholangitis.

BACKGROUND: Patients with primary sclerosing cholangitis (PSC) possess autoantibodies against biliary epithelial cells. However, the target molecules remain unknown. METHODS: The sera of patients with PSC and controls were subjected to enzyme-linked immunosorbent assays to detect autoantibodies using recombinant integrin proteins. Integrin αvß6 expression in the bile duct tissues was examined using immunofluorescence. The blocking activity of the autoantibodies was examined using solid-phase binding assays. RESULTS: Anti-integrin αvß6 antibodies were detected in 49/55 (89.1%) patients with PSC and 5/150 (3.3%) controls (P < 0.001), with a sensitivity and specificity of 89.1% and 96.7%, respectively, for PSC diagnosis. When focusing on the presence or absence of IBD, the proportion of the positive antibodies in PSC with IBD was 97.2% (35/36) and that in PSC alone was 73.7% (14/19) (P = 0.008). Integrin αvß6 was expressed in bile duct epithelial cells. Immunoglobulin (Ig)G from 15/33 patients with PSC blocked integrin αvß6-fibronectin binding through an RGD (Arg-Gly-Asp) tripeptide motif. CONCLUSIONS: Autoantibodies against integrin αvß6 were detected in most patients with PSC; anti-integrin αvß6 antibody may serve as a potential diagnostic biomarker for PSC.

ELF3 suppresses gallbladder cancer development through downregulation of the EREG/EGFR/mTOR complex 1 signalling pathway.

The prognosis of gallbladder cancer (GBC) remains poor, and a better understanding of GBC molecular mechanisms is important. Genome sequencing of human GBC has demonstrated that loss-of-function mutations of E74-like ETS transcription factor 3 (ELF3) are frequently observed, with ELF3 considered to be a tumour suppressor in GBC. To clarify the underlying molecular mechanisms by which ELF3 suppresses GBC development, we performed in vivo analysis using a combination of autochthonous and allograft mouse models. We first evaluated the clinical significance of ELF3 expression in human GBC tissues and found that low ELF3 expression was associated with advanced clinical stage and deep tumour invasion. For in vivo analysis, we generated Pdx1-Cre; KrasG12D ; Trp53R172H ; Elf3f/f (KPCE) mice and Pdx1-Cre; KrasG12D ; Trp53R172H ; Elf3wt/wt (KPC) mice as a control and analysed their gallbladders histologically. KPCE mice developed larger papillary lesions in the gallbladder than those developed by KPC mice. Organoids established from the gallbladders of KPCE and KPC mice were analysed in vitro. RNA sequencing showed upregulated expression of epiregulin (Ereg) in KPCE organoids, and western blotting revealed that EGFR/mechanical targets of rapamycin complex 1 (mTORC1) were upregulated in KPCE organoids. In addition, ChIP assays on Elf3-overexpressing KPCE organoids showed that ELF3 directly regulated Ereg. Ereg deletion in KPCE organoids (using CRISPR/Cas9) induced EGFR/mTORC1 downregulation, indicating that ELF3 controlled EGFR/mTORC1 activity through regulation of Ereg expression. We also generated allograft mouse models using KPCE and KPC organoids and found that KPCE organoid allograft tumours exhibited poorly differentiated structures with mTORC1 upregulation and mesenchymal phenotype, which were suppressed by Ereg deletion. Furthermore, EGFR/mTORC1 inhibition suppressed cell proliferation and epithelial-mesenchymal transition in KPCE organoids. Our results suggest that ELF3 suppresses GBC development via downregulation of EREG/EGFR/mTORC1 signalling. EGFR/mTORC1 inhibition is a potential therapeutic option for GBC with ELF3 mutation. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Adipose tissue area is a predictive biomarker for the efficacy of pegylated liposomal doxorubicin in platinum-refractory/resistant ovarian cancer.

BACKGROUND: Pegylated liposomal doxorubicin (PLD), an anthracycline agent, is widely used as a treatment option for platinum-refractory/resistant epithelial ovarian cancer (EOC). Although only a subset of patients with platinum-refractory/resistant EOC derive benefit from PLD, predictive biomarkers for patients who will respond to the drug have not yet been established. Here, we evaluated the relationship between adipose tissue status and PLD efficacy in patients with platinum-refractory/resistant EOC. METHODS: Patients with platinum-refractory/resistant EOC who were treated with single-agent PLD were included in this retrospective cohort study. Adipose tissue areas including visceral adipose tissue area (VATA), subcutaneous adipose tissue area (SATA), and visceral to subcutaneous adipose tissue area ratio (VSR) were calculated prior to the initiation of PLD using computed tomography images. The associations of adipose tissue areas with objective response rate (ORR) and patient survival were evaluated. RESULTS: Forty-four patients with platinum-refractory/resistant EOC who received single-agent PLD were included. Subjects were categorized into high and low groups according to the median VATA, SATA, and VSR values, and body mass index (BMI). The ORR of PLD was significantly lower in the VSR-high group than in the VSR-low group (p = 0.0089). Patients in the high VSR group showed significantly shorter progression-free survival (PFS) compared with patients in the low VSR group (median, 4.0 vs. 8.5 months; p = 0.020). In the multivariable analysis, high VSR was a significant prognostic factor for shorter PFS (hazard ratio, 2.07; 95% confidence interval, 1.05-4.19; p = 0.035). VATA, SATA, and BMI showed no significant association with ORR and survival of patients who received PLD. CONCLUSIONS: High VSR is associated with lower ORR and shorter PFS in patients with platinum-refractory/resistant EOC who received single-agent PLD. VSR is a robust predictive biomarker for the efficacy of PLD.

Oleic acid-induced interleukin-36γ: A possible link between facial skin redness and sebum.

BACKGROUND: Redness of the facial skin is an important cosmetic concern. Although qualitative and quantitative modifications of sebum on the skin surface are major pathogenic factors of chronic inflammatory skin conditions, the relationship between skin redness, sebum, and mild inflammation on the cheeks of healthy subjects remains elusive. AIMS: We aimed to explore the correlation between cheek redness and sebum and inflammatory cytokines in the stratum corneum (SC) of healthy subjects. We also examined the effects of representative sebum lipids on the gene expression of inflammatory cytokines in cultured keratinocytes. PATIENTS/METHODS: This study included 198 healthy participants. Skin sebum was analyzed using flow injection analysis, and skin redness was assessed using a spectrophotometer. Inflammatory cytokines in tape-stripped SC were measured using enzyme-linked immunosorbent assay. RESULTS: Cheek redness parameters positively correlated with the amount of skin sebum and the proportion of monounsaturated free fatty acids (C16:1 and C18:1) in the sebum. They also positively correlated with the interleukin (IL)-36γ/IL-37 ratio in the SC. Among the representative sebum lipids examined, oleic acid (C18:1, cis-9) dose- and time-dependently regulated the mRNA expression of IL-36γ and IL-37 in cultured keratinocytes, and this effect was attenuated by the N-methyl-D-aspartate (NMDA)-type glutamate receptor antagonist, MK801. CONCLUSIONS: Skin surface sebum may be related to cheek redness in healthy subjects, and oleic acid-induced IL-36γ through NMDA-type glutamate receptors may be a link between them. Our study provides a possible skincare strategy for mitigating unfavorable increase in skin redness by targeting the facial skin sebum, particularly oleic acid.

Generic Drug Shortage in Japan: GMP Noncompliance and Associated Quality Issues.

Government campaigns to replace off-patent brand pharmaceuticals with low cost generic products in national health insurance systems have apparently increased their production in the last two decades in Japan. The contamination of a batch of generic itraconazole tablets with the sleep inducer rilmazafone caused significant adverse events and related accidents in 2020, amidst increasing use of the generic products in healthcare. Investigations revealed many Good Manufacturing Practice (GMP) violations and other evidence of poor quality management in the manufacturing/marketing authorization holder (MAH). Urgent inspection of other MAHs found multiple cases of GMP noncompliance that resulted in temporary administrative suspension. Various quality issues, including nonconformity in stability monitoring, in these generic MAHs resulted in prolonged suspension of product shipments and shortages in medical institutions. These problems highlighted long-standing issues in quality management by MAHs and inspections by authorities, which had been neglected during rapid production expansion. This review introduces these manufacturing control and management problems and their countermeasures, and discusses the impact of habitual inadequate development processes that disregard the quality-by-design (QbD) perspective as the root cause of the issues.