Comparison of in vitro screening methods for evaluating the effects of pharmaceutical excipients on membrane permeability.

The effects of pharmaceutical excipients on intestinal drug absorption have been highlighted and careful excipient selection is required to develop biologically equivalent formulations. This study aimed to evaluate the effects of excipients on drug permeability and compare the characteristics of in vitro screening methods. Three in vitro models, the commercial precoated parallel artificial membrane permeability assay (PAMPA), PermeaPadTM, and Caco-2 monolayer, were used to evaluate the effects of 14 excipients on the permeability of several drugs with different biopharmaceutical classification system classes. Concentration-dependent effects were analyzed to distinguish non-specific effects. The permeability of low-permeability drugs was increased by excipients such as hydroxypropyl cellulose and povidone K30 in the precoated PAMPA model, whereas PermeaPadTM maintained membrane integrity at higher concentrations. Conversely, croscarmellose sodium and sodium lauryl sulfate (SLS) decreased the permeability of highly permeable drugs in both precoated PAMPA and PermeaPadTM assays in a concentration-dependent manner. In Caco-2 monolayer assays, most excipients showed minimal effects on drug permeability. However, SLS significantly reduces the permeability of highly permeable drugs at concentrations above the critical micelle concentration, thereby compromising the integrity of the cell monolayer. Our results suggested that most of excipients, except SLS, did not affect the membrane permeation of drugs at clinically used concentrations. The pre-coated PAMPA model demonstrated high sensitivity to excipient effects, making it suitable for conservative evaluation. The PermeaPadTM and Caco-2 models allowed assessment at higher excipient concentrations, with PermeaPadTM being particularly useful for excipients that cause toxicity in Caco-2 cells.

Morphology and Alignment Transition of Hexabenzocoronene (HBC) Mesogen Films by Bar Coating: Effect of Coating Speed.

Films of the discotic liquid crystalline hexabenzocoronene (HBC) derivative, HBC-1,3,5-Ph-C12, were prepared on the quartz substrate by the bar-coating method. Depending on the coating speed, regularly spaced stripes or continuous films were observed. In the former case, columns of the HBC derivatives align more along the stripes, which are perpendicular to the coating direction, whereas in the latter case, columns of the HBC derivatives in the film align more along the coating direction. These distinctive structures are confirmed via polarized optical microscopy (POM), polarized UV-vis spectroscopy, and grazing incidence small-angle X-ray scattering measurements.

Age Is a Risk Factor for Olaparib Dose Modification and Discontinuation in Patients With Ovarian Cancer.

Background/Aim: Olaparib, a poly (ADP-ribose) polymerase inhibitor, is widely used as maintenance therapy for ovarian cancer. Dose modification, such as dose reduction and treatment interruption, are frequently performed to manage adverse events (AEs) of olaparib. By identifying patients at high risk for dose modification before administration, interventions related to appropriate control of AEs can be implemented. This study aimed to evaluate risk factors of olaparib dose modification and its clinical usefulness. Patients and Methods: Sixty patients with ovarian cancer who received olaparib were included in this retrospective cohort study. Associations between patients' characteristics and dose modification were evaluated by multivariate logistic regression analysis. We also examined whether risk factors of dose modification were associated with treatment discontinuation due to AEs. Results: Twenty-five (41.7%) patients required dose modification. Patients who required dose modification were significantly older (p=0.018) and tended to be more underweight (p=0.078) than those who did not require dose modification. In multivariate analysis, increasing age was significantly associated with dose modification (odds ratio=1.056; 95% confidence interval=1.002-1.112; p=0.034). The optimal cutoff of age as a risk factor for dose modification, calculated from receiver operating characteristic curves, was 65.0 years. Patients aged 65.0 years and older were significantly more likely to discontinue olaparib owing to AEs (p=0.0437). Conclusion: Age is a risk factor of olaparib dose modification due to AEs. Older patients, who frequently require dose modification, are more likely to discontinue olaparib, suggesting that strict management of AEs is particularly necessary in this patient group.

AI and machine learning in medical imaging: key points from development to translation.

Innovation in medical imaging artificial intelligence (AI)/machine learning (ML) demands extensive data collection, algorithmic advancements, and rigorous performance assessments encompassing aspects such as generalizability, uncertainty, bias, fairness, trustworthiness, and interpretability. Achieving widespread integration of AI/ML algorithms into diverse clinical tasks will demand a steadfast commitment to overcoming issues in model design, development, and performance assessment. The complexities of AI/ML clinical translation present substantial challenges, requiring engagement with relevant stakeholders, assessment of cost-effectiveness for user and patient benefit, timely dissemination of information relevant to robust functioning throughout the AI/ML lifecycle, consideration of regulatory compliance, and feedback loops for real-world performance evidence. This commentary addresses several hurdles for the development and adoption of AI/ML technologies in medical imaging. Comprehensive attention to these underlying and often subtle factors is critical not only for tackling the challenges but also for exploring novel opportunities for the advancement of AI in radiology.

Anti-integrin αvß6 antibody in Takayasu arteritis patients with or without ulcerative colitis.

Background: It has been well documented that Takayasu arteritis (TAK) and ulcerative colitis (UC) coexist in the same patients. HLA-B*52 characterizes the co-occurrence, which is one of the common genetic features between these two diseases, indicating shared underlying pathologic mechanisms. Anti-integrin αvß6 antibody (Ab) is present in sera of UC patients in a highly specific manner. We investigated if there were any associations between anti-integrin αvß6 Ab and TAK, considering the risk HLA alleles. Methods: A total of 227 Japanese TAK patients were recruited in the current study and their serum samples were subjected to measurement of anti-integrin αvß6 Ab by ELISA. The clinical information, including the co-occurrence of UC, was collected. The HLA allele carrier status was determined by Luminex or genotype imputation. Results: The information about the presence of UC was available for 165 patients, among which eight (4.84%) patients had UC. Anti-integrin αvß6 antibody was identified in 7 out of 8 TAK subjects with UC (87.5%) while only 5 out of 157 (3.18%) TAK subjects without UC had the antibody (OR 121, p=7.46×10-8). A total of 99 out of 218 (45.4%) patients were HLA-B*52 carriers. There was no significant association between the presence of anti-integrin αvß6 Ab and HLA-B*52 carrier status in those without UC (OR 2.01, 95% CI 0.33-12.4, p = 0.189). Conclusions: The prevalence of anti-integrin αvß6 Ab was high in TAK patients with UC, but not in the absence of concomitant UC. The effect of HLA-B*52 on anti-integrin αvß6 Ab production would be minimal.

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.

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.

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.

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.