Development of nanogap-rich hybrid gold nanostructures by use of two non-lithographic deposition techniques for a sensitive and reliable SERS biosensor.

Practical application of surface-enhanced Raman spectroscopy (SERS) has suffered from several limitations by heterogeneous distribution of hot-spots, such as high signal fluctuation and the resulting low reliability in detection. Herein, we develop a strategy of more sensitive and reliable SERS platform through designing spatially homogeneous gold nanoparticles (GNPs) on a uniform gold nanoisland (GNI) pattern. The proposed SERS substrate is successfully fabricated by combining two non-lithographic techniques of electron beam evaporation and convective self-assembly. These bottom-up methods allow a simple, cost-effective, and large-area fabrication. Compared to the SERS substrates obtained from two separate nanofabrication methods, Raman spectra measured by the samples with both GNPs and GNIs present a significant increase in the signal intensity as well as a notable improvement in signal fluctuation. The simulated near-field analyses demonstrate the formation of highly amplified plasmon modes within and at the gaps of the GNP-GNI interfaces. Moreover, the suggested SERS sensor is evaluated to detect the glucose concentration, exhibiting that the detection sensitivity is improved by more than 10 times compared to the sample with only GNI patterns and a fairly good spatial reproducibility of 7% is accomplished. It is believed that our suggestion could provide a potential for highly sensitive, low-cost, and reliable SERS biosensing platforms that include many advantages for healthcare devices. Supplementary Information: The online version contains supplementary material available at 10.1007/s13534-024-00381-4.

Magnetic Hollow Fibers of Covalent Organic Frameworks (COF) for Pollutant Degradation and Adsorptive Removal.

The shaping of covalent organic frameworks (COFs), requiring the conversion of non-processible COF powders into applicable architectures with additional functionality, remains a challenge. Using pre-electrospun polymer fibers as a sacrificial template, herein, we report a green synthesis of an architecture in the form of COF hollow fibers with an inner layer of peroxidase-like iron oxide nanoparticles as a catalytic material. When compared to peroxidase-like pristine iron oxide nanoparticles, these COF hollow fibers demonstrate higher catalytic breakdown of crystal violet due to their peroxidase-like activity via advanced oxidation process. Furthermore, as a potential adsorbent, hollow COF fibers exhibit significantly effective adsorption capacity and removal efficiency of organic solvent and oil from water. Because of their magnetic nature, COF hollow fibers can be easily recovered and have exhibited high recycling stability for both catalytic dye degradation and organic solvent removal from water.

Mott neurons with dual thermal dynamics for spatiotemporal computing.

Heat dissipation is a natural consequence of operating any electronic system. In nearly all computing systems, such heat is usually minimized by design and cooling. Here, we show that the temporal dynamics of internally produced heat in electronic devices can be engineered to both encode information within a single device and process information across multiple devices. In our demonstration, electronic NbOx Mott neurons, integrated on a flexible organic substrate, exhibit 18 biomimetic neuronal behaviours and frequency-based nociception within a single component by exploiting both the thermal dynamics of the Mott transition and the dynamical thermal interactions with the organic substrate. Further, multiple interconnected Mott neurons spatiotemporally communicate purely via heat, which we use for graph optimization by consuming over 106 times less energy when compared with the best digital processors. Thus, exploiting natural thermal processes in computing can lead to functionally dense, energy-efficient and radically novel mixed-physics computing primitives.

Language and sensory characteristics are reflected in voice-evoked responses in low birth weight children.

BACKGROUND: Children born with very low birth weight (VLBW) are at higher risk for cognitive impairment, including language deficits and sensorimotor difficulties. Voice-evoked response (P1m), which has been suggested as a language development biomarker in young children, remains unexplored for its efficacy in VLBW children. Furthermore, the relation between P1m and sensory difficulties in VLBW children remains unclear. METHODS: 40 children with VLBW were recruited at 5-to-6 years old (26 male, 14 female, mean age of months ± SD, 80.0 ± 4.9). We measured their voice-evoked brain response using child-customized magnetoencephalography (MEG) and examined the relation between P1m and language conceptual inference ability and sensory characteristics. RESULTS: The final sample comprised 36 children (23 boys, 13 girls; ages 61-86 months; gestational ages 24-36 weeks). As a result of multiple regression analysis, voice-evoked P1m in the left hemisphere was correlated significantly with language ability (ß = 0.414 P = 0.015) and sensory hypersensitivity (ß = 0.471 P = 0.005). CONCLUSION: Our findings indicate that the relation between P1m and language conceptual inference ability observed in term children in earlier studies is replicated in VLBW children, and suggests P1m intensity as a biomarker of sensory sensitivity characteristics. IMPACT: We investigated brain functions related to language development and sensory problems in very low birth-weight children. In very low birth weight children at early school age, brain responses to human voices are associated with language conceptual inference ability and sensory hypersensitivity. These findings promote a physiological understanding of both language development and sensory characteristics in very low birth weight children.

Genetic characterization and phylogenetic analysis of the Nigella sativa (black seed) plastome.

In this study, the complete plastome sequence of Nigella sativa (black seed), was analyzed for the first time. The plastome spans approximately 154,120 bp, comprising four sections: the Large Single-Copy (LSC) (85,538 bp), the Small Single-Copy (SSC) (17,984 bp), and two Inverted Repeat (IR) regions (25,299 bp). A comparative study of N. sativa's plastome with ten other species from various genera in the Ranunculaceae family reveals substantial structural variations. The contraction of the inverted repeat region in N. sativa influences the boundaries of single-copy regions, resulting in a shorter plastome size than other species. When comparing the plastome of N. sativa with those of its related species, significant divergence is observed, particularly except for N. damascena. Among these, the plastome of A. glaucifolium displays the highest average pairwise sequence divergence (0.2851) with N. sativa, followed by A. raddeana (0.2290) and A. coerulea (0.1222). Furthermore, the study identified 12 distinct hotspot regions characterized by elevated Pi values (> 0.1). These regions include trnH-GUG-psbA, matK-trnQ-UUG, psbK-trnR-UCU, atpF-atpI, rpoB-psbD, ycf3-ndhJ, ndhC-cemA, petA-psaJ, trnN-GUU-ndhF, trnV-GAC-rps12, ycf2-trnI-CAU, and ndhA-ycf1. Approximately, 24 tandem and 48 palindromic and forward repeats were detected in N. sativa plastome. The analysis revealed 32 microsatellites with the majority being mononucleotide repeats. In the N. sativa plastome, phenylalanine had the highest number of codons (1982 codons), while alanine was the least common amino acid with 260 codons. A phylogenetic tree, constructed using protein-coding genes, revealed a distinct monophyletic clade comprising N. sativa and N. damascene, closely aligned with the Cimicifugeae tribe and exhibiting robust support. This plastome provides valuable genetic information for precise species identification, phylogenetic resolution, and evolutionary studies of N. sativa.

Risk assessment of cyclohexasiloxane D6 in cosmetic products.

Dodecamethylcyclohexasiloxane (D6) is a siloxane substance mainly used in cosmetics and personal care products. While octamethylcyclotetrasiloxane (D4) and decamethylcyclopentasiloxane (D5) were once commonly used in personal care products, their usage has been restricted due to the classification as persistent, bioaccumulative, and toxic (PBT)/very persistent and very bio-accumulative (vPvB) substances. While D6 has emerged as a substitute for D4 and D5, the risk assessment for D6 remains limited compared to the evaluations for D4 and D5. To address this gap, we conducted a comprehensive risk assessment of D6. In this study, we reviewed the toxicity information on D6 and calculated the exposure level to D6, considering the content of D6 in cosmetic products. No observed adverse effect level (NOAEL) of 1500 mg/kg bw/day was established in a repeated dose toxicity study after oral administration to rats. Negative results were found in tests on the ocular and skin irritation, skin sensitization, and genotoxicity of D6. According to the product content of up to 48% of D6 reported in 2012, the Systemic Exposure Dose (SED) was 5.4E-06 to 7.04 mg/kg bw/day for a 60 kg adult using the exposure factors from Korean cosmetic usage. The Margin of Safety was estimated to be between 35.5 and 4.63E+07, posing a potential health risk of D6 according to the maximum concentration and the product type. Further consideration of the potential of D6 as PBT or vPvB is also required.

DEHP (di(2-ethylhexyl)phthalate) stimulates skin pigmentation by perturbing cytoskeletal homeostasis.

Phthalates are extensively employed plasticizers crucial for conferring flexibility and plasticity to polyvinyl chloride. Phthalates, including DEHP (di(2-ethylhexyl)phthalate), present in diverse products, have been identified in fine dust and are capable of infiltrating the body, potentially posing health hazards. Importantly, melanocytes, existing at the basal layer of the epidermis, are susceptible to toxic substances. In our study, we employed the 3D human pigmented epidermis model, MelanoDerm™, along with the B16F10 murine melanoma cell line, to examine the influence of DEHP exposure on melanocytes. The exposure to low concentrations of DEHP (~ 5 µM), resulted in the extension of melanocyte dendrites, indicating the stimulation of melanocytes. Analysis of gene expression and protein profiles unveiled the up-regulation of MITF, Arpc2, and TRP1 genes subsequent to DEHP exposure, indicating alterations in cytoskeletal and melanosome-related genetic and protein components in melanocytes. Notably, increased pigmentation was observed in MelanoDerm™ following DEHP exposure. DEHP-stimulated reactive oxygen species generation appeared to be involved in these events since the antioxidant, ascorbic acid attenuated ROS generation and MITF upregulation. Collectively, our study demonstrated that DEHP exposure can induce cytoskeletal disturbance and skin pigmentation through oxidative stress.

Change of Segmental Motion Following Total Ankle Arthroplasty Using a 3-Dimensional Multi-segment Foot Model.

Background: Total ankle arthroplasty (TAA) enhances patients' subjective outcomes with respect to pain and function. The aim of this study was to analyze the biomechanical changes of the affected limb following TAA using gait analysis with a 3-dimensional multi-segment foot model (3D MFM). Methods: We reviewed medical records, simple radiographs, and gait analyses using a 3D MFM of patients who underwent TAA for severe varus ankle arthritis. Preoperative and postoperative gait data of 24 patients were compared. Postoperative gait analyses were done at least 1 year after surgery. Results: TAA significantly increased stride length (p = 0.024). The total range of motion of all planes in the hindfoot and forefoot showed no significant changes between preoperative and postoperative states. Hindfoot was significantly plantarflexed and pronated after TAA, while forefoot was significantly supinated in all phases. After appropriate calculations, the genuine coronal motion of the hindfoot showed no changes after TAA in all phases. Conclusions: TAA did not result in biomechanical improvements of segmental motions in the forefoot and hindfoot, except for changes to the bony structures. Therefore, it is important to point out to patients that TAA will not result in significant improvement of ankle function and range of motion. Clinicians can consider this information during preoperative counseling.

Unveiling the protective role of anthocyanin in rice: insights into drought-induced oxidative stress and metabolic regulation.

This study investigates the impact of anthocyanin treatment on rice plants under drought stress, focusing on phenotypic, molecular, and biochemical responses. Anthocyanin were treated to one month old plants one week before the droughtexposure. Drought stress was imposed by using 10% polyethylene glycol (PEG 6000). Anthocyanin-treated plants exhibited significant enhancements in various traits, including growth parameters and reproductive characteristics, under normal conditions. When subjected to drought stress, these plants displayed resilience, maintaining or improving essential morphological and physiological features compared to non-treated counterparts. Notably, anthocyanin application mitigated drought-induced oxidative stress, as evidenced by reduced levels of reactive oxygen species (ROS) and lipid membrane peroxidation. The study also elucidates the regulatory role of anthocyanins in the expression of flavonoid biosynthetic genes, leading to increased levels of key secondary metabolites. Furthermore, anthocyanin treatment influenced the levels of stress-related signaling molecules, including melatonin, proline, abscisic acid (ABA), and salicylic acid (SA), contributing to enhanced stress tolerance. The enzymatic activity of antioxidants and the expression of drought-responsive genes were modulated by anthocyanins, emphasizing their role in antioxidant defense and stress response. Additionally, anthocyanin treatment positively influenced macronutrient concentrations, particularly calcium ion (Ca+), potassium ion (K+), and sodium ion (Na+), essential for cell wall and membrane stability. The findings collectively highlight the multifaceted protective effects of anthocyanins, positioning them as potential key players in conferring resilience to drought stress in rice plants. The study provides valuable insights into the molecular and physiological mechanisms underlying anthocyanin-mediated enhancement of drought stress tolerance, suggesting promising applications in agricultural practices for sustainable crop production.

Healthy lifestyle and prostate cancer risk in the Million Veteran Program.

BACKGROUND: This study aims to assess the impact of healthy lifestyle on prostate cancer (PCa) risk in a diverse population. METHODS: Data for 281,923 men from the Million Veteran Program (MVP), a nationwide, health system-based cohort study, were analyzed. Self-reported information at enrollment included smoking status, exercise, diet, family history of PCa, and race/ethnicity. Body mass index (BMI) was obtained from clinical records. Genetic risk was assessed via a validated polygenic score. Cox proportional hazards models were used to assess associations with PCa outcomes. RESULTS: After accounting for ancestry, family history, and genetic risk, smoking was associated with an increased risk of metastatic PCa (hazard ratio [HR], 1.83; 95% confidence interval [CI], 1.64-2.02; p < 10-16) and fatal PCa (HR, 2.73; 95% CI, 2.36-3.25; p < 10-16). Exercise was associated with a reduced risk of fatal PCa (HR, 0.86; 95% CI, 0.76-0.98; p = .03). Higher BMI was associated with a slightly reduced risk of fatal PCa, and diet score was not independently associated with any end point. Association with exercise was strongest among those who had nonmetastatic PCa at MVP enrollment. Absolute reductions in the risk of fatal PCa via lifestyle factors were greatest among men of African ancestry (1.7% for nonsmokers vs. 6.1% for smokers) or high genetic risk (1.4% for nonsmokers vs. 4.3% for smokers). CONCLUSIONS: Healthy lifestyle is minimally related to the overall risk of developing PCa but is associated with a substantially reduced risk of dying from PCa. In multivariable analyses, both exercise and not smoking remain independently associated with reduced metastatic and fatal PCa.

International comparison of availability for orphan drugs: focused on approved orphan drugs in South Korea.

Introduction: In this study, we aimed to comparatively analyse the indicators of availability to orphan drugs in South Korea, the United States of America, Europe Union, and Japan. Methods: For 169 drugs designated as orphan drugs in South Korea between 2012 and 2021, information on the drugs designated as orphan drugs from each jurisdiction was extracted by country. Then, the availability indicators (approval time, drug lag time, and designation gap) were analysed for the drugs approved in each jurisdiction. Results: The approval rate of drugs designated as orphan drugs were 11.22% and 6.31% in the USA and EU, respectively, which was lower than that of orphan drugs in South Korea and Japan. The highest number of approved drugs was in the USA (87 drugs), EU 27 drugs, Japan 22 drugs and Korea 21 drugs. Furthermore, the approval time significantly differed between South Korea and the other countries. South Korea had a significantly different drug lag time and designation gap compared with the USA and EU. Conclusion: Our findings show that to fundamentally improve the access to treatments for rare disease, a policy of regulatory science that can comprehensively support the early stages of research and development and commercialisation is needed.

Memristive Monte Carlo DropConnect crossbar array enabled by device and algorithm co-design.

Device and algorithm co-design aims to develop energy-efficient hardware that directly implements complex algorithms and optimizes algorithms to match the hardware's characteristics. Specifically, neuromorphic computing algorithms are constantly growing in complexity, necessitating an ongoing search for hardware implementations capable of handling these intricate algorithms. Here, we present a memristive Monte Carlo DropConnect (MC-DC) crossbar array developed through a hardware algorithm co-design approach. To implement the MC-DC neural network, stochastic switching and analog memory characteristics are required, and we achieved them using Ag-based diffusive selectors and Ru-based electrochemical metalization (ECM) memristors, respectively. The devices were integrated with a one-selector one-memristor (1S1M) structure, and their well-matched operating voltages and currents enabled stochastic readout and deterministic analog programming. With the integrated hardware, we successfully demonstrated the MC-DC operation. Additionally, the selector allowed for the control of switching polarity, and by understanding this hardware characteristic, we were able to modify the algorithm to fit it and further improve the network performance.

GLP-1 increases preingestive satiation via hypothalamic circuits in mice and humans.

GLP-1 receptor agonists (GLP-1RAs) are effective anti-obesity drugs. However, the precise central mechanisms of GLP-1RAs remain elusive. We administered GLP-1RAs to obese patients and observed heightened sense of preingestive satiation. Analysis of human and mouse brain samples pinpointed GLP-1R neurons in the dorsomedial hypothalamus (DMH) as candidates for encoding preingestive satiation. Optogenetic manipulation of DMHGLP-1R neurons caused satiation. Calcium imaging demonstrated that these neurons are actively involved in encoding preingestive satiation. GLP-1RA administration increased the activity of DMHGLP-1R neurons selectively during eating behavior. We further identified an intricate interplay between DMHGLP-1R neurons and arcuate NPY/AgRP neurons (ARCNPY/AgRP), to regulate food intake. Our findings reveal a hypothalamic mechanism through which GLP-1RAs control preingestive satiation, offering novel neural targets for obesity and metabolic diseases.

Analysis of particulate matter-induced alteration of genes and related signaling pathways in the respiratory system.

Airborne particulate matter (PM) is a global environmental risk factor threatening human health and is a major cause of cardiovascular and respiratory disease-associated death. Current studies on PM exposure have been limited to large-scale cohort and epidemiological investigations, emphasizing the need for detailed individual-level studies to uncover specific differentially expressed genes and their associated signaling mechanisms. Herein, we revealed that PM exposure significantly upregulated inflammatory and immune responses, such as cytokine-mediated signaling pathways, complement system, and the activation and migration of immune cells in gene set enrichment analysis of our RNA sequencing (RNAseq) data. Remarkably, we discovered that the broad gene expression and signaling pathways mediated by macrophages were predominantly expressed in the respiratory system following PM exposure. Consistent with these observations, individual PMs, classified by aerodynamic size and origin, significantly promoted macrophage recruitment to the lungs in the mouse lung inflammation model. Additionally, we confirmed that RNAseq observations from the respiratory system were reproduced in murine bone marrow-derived macrophages and the alveolar macrophage cell line MH-S after individual PM exposure. Our findings demonstrated that PM exposure augmented broad inflammatory and immune responses in the respiratory system and suggested the reinforcement of global strategies for reducing particulate air pollution to prevent respiratory diseases and their exacerbation.

Exogenous GABA Enhances Copper Stress Resilience in Rice Plants via Antioxidant Defense Mechanisms, Gene Regulation, Mineral Uptake, and Copper Homeostasis.

The importance of gamma-aminobutyric acid (GABA) in plants has been highlighted due to its critical role in mitigating metal toxicity, specifically countering the inhibitory effects of copper stress on rice plants. This study involved pre-treating rice plants with 1 mM GABA for one week, followed by exposure to varying concentrations of copper at 50 µM, 100 µM, and 200 µM. Under copper stress, particularly at 100 µM and 200 µM, plant height, biomass, chlorophyll content, relative water content, mineral content, and antioxidant activity decreased significantly compared to control conditions. However, GABA treatment significantly alleviated the adverse effects of copper stress. It increased plant height by 13%, 18%, and 32%; plant biomass by 28%, 52%, and 60%; chlorophyll content by 12%, 30%, and 24%; and relative water content by 10%, 24%, and 26% in comparison to the C50, C100, and C200 treatments. Furthermore, GABA treatment effectively reduced electrolyte leakage by 11%, 34%, and 39%, and the concentration of reactive oxygen species, such as malondialdehyde (MDA), by 9%, 22%, and 27%, hydrogen peroxide (H2O2) by 12%, 38%, and 30%, and superoxide anion content by 8%, 33, and 39% in comparison to C50, C100, and C200 treatments. Additionally, GABA supplementation led to elevated levels of glutathione by 69% and 80%, superoxide dismutase by 22% and 125%, ascorbate peroxidase by 12% and 125%, and catalase by 75% and 100% in the C100+G and C200+G groups as compared to the C100 and C200 treatments. Similarly, GABA application upregulated the expression of GABA shunt pathway-related genes, including gamma-aminobutyric transaminase (OsGABA-T) by 38% and 80% and succinic semialdehyde dehydrogenase (OsSSADH) by 60% and 94% in the C100+G and C200+G groups, respectively, as compared to the C100 and C200 treatments. Conversely, the expression of gamma-aminobutyric acid dehydrogenase (OsGAD) was downregulated. GABA application reduced the absorption of Cu2+ by 54% and 47% in C100+G and C200+G groups as compared to C100, and C200 treatments. Moreover, GABA treatment enhanced the uptake of Ca2+ by 26% and 82%, Mg2+ by 12% and 67%, and K+ by 28% and 128% in the C100+G and C200+G groups as compared to C100, and C200 treatments. These findings underscore the pivotal role of GABA-induced enhancements in various physiological and molecular processes, such as plant growth, chlorophyll content, water content, antioxidant capacity, gene regulation, mineral uptake, and copper sequestration, in enhancing plant tolerance to copper stress. Such mechanistic insights offer promising implications for the advancement of safe and sustainable food production practices.

Clinical Efficacy of Application-Linked Stretching Ball as Digital Therapeutics in Plantar Fasciitis.

Background/Objectives: This study aimed to evaluate the efficacy of application-linked stretching ball instruments that record the rolling time and force of patients compared with a traditional simple stretching ball. Methods: Fourteen participants with plantar fasciitis were divided into a simple massage ball group (group A, n = 8) and an application-linked massage ball group (group B, n = 6). The application-linked massage ball sends information regarding the massages, such as the frequency and force of the massage on the foot, to the application on the patient's smartphone. All clinical outcomes were evaluated at the beginning of the study and 1-, 2-, and 3-month follow-up. The primary outcome measure was the Manchester-Oxford Foot Questionnaire (MOXFQ) score. Results: At the beginning of the study, the initial MOXFQ score was not significantly different between the two groups (p = 0.948). At each time point, the MOXFQ score of the whole population did not improve significantly compared to that of the initial state (p = 0.131). Generalized estimating equation modeling demonstrated that there was no significant difference in the improvement of the MOXFQ score between groups A and B during follow-up (p = 0.826). In addition, no group-by-time interactions were observed (p = 0.457). Conclusions: The efficacy of an application-linked massage ball for the treatment of plantar fasciitis was not as definite as that of a traditional simple stretching ball in patients whose symptoms persisted for at least six months. Future studies that include patients with acute plantar fasciitis are required.

Discrepancies in plantar pressure distribution between affected and unaffected sides in patients with plantar fasciitis.

PURPOSE: A fundamental understanding of plantar pressure distribution is important for prescribing an appropriate orthosis and applying nonoperative methods, such as stretching exercises, for the treatment of plantar fasciitis. Despite existing research on plantar pressure distribution, discrepancies between affected and unaffected sides in unilateral plantar fasciitis patients warrant further investigation. This study aimed to evaluate the plantar pressure distribution in patients with unilateral plantar fasciitis by comparing it with that on the contralateral unaffected side. METHODS: We retrospectively reviewed records from 20 consecutive patients diagnosed with unilateral plantar fasciitis, using the unaffected side as the control. The emed® pedobarographic system was used to measure the plantar pressure distribution during gait. The analysis was performed using a 4-mask configuration (toes, forefoot, midfoot, and hindfoot). RESULTS: Both sides showed no significant differences in radiographic parameters. The affected side showed a significantly higher contact area, maximum force, and force-time integrals in the midfoot. However, the unaffected side demonstrated significantly higher maximum force and force-time integrals in the hindfoot. There was no difference in the distribution of the peak pressure and pressure-time integrals between the two sides in all mask regions. The increased contact area and maximum force in the midfoot on the side with plantar fasciitis may result from heel pain-induced weight transfer from the hindfoot. CONCLUSION: The findings of this study provide a basic understanding of plantar pressure distribution in the treatment of plantar fasciitis and highlight the importance of considering inter-side differences when designing treatment interventions or orthotic devices.

Agent orange exposure and prostate cancer risk in the million veteran program.

BACKGROUND: The US government considers veterans to have been exposed to Agent Orange if they served in Vietnam while the carcinogen was in use, and these veterans are often deemed at high risk of prostate cancer (PCa). Here, we assess whether presumed Agent Orange exposure is independently associated with increased risk of any metastatic or fatal PCa in a diverse Veteran cohort still alive in the modern era (at least 2011), when accounting for race/ethnicity, family history, and genetic risk. PATIENTS AND METHODS: Participants in the Million Veteran Program (MVP; enrollment began in 2011) who were on active duty during the Vietnam War era (August 1964-April 1975) were included (n = 301,470). Agent Orange exposure was determined using the US government definition. Genetic risk was assessed via a validated polygenic hazard score. Associations with age at diagnosis of any PCa, metastatic PCa, and death from PCa were assessed via Cox proportional hazards models. RESULTS AND INTERPRETATION: On univariable analysis, exposure to Agent Orange was not associated with increased PCa (hazard ratio [HR]: 1.02, 95% confidence interval [CI]: 1.00-1.04, p = 0.06), metastatic PCa (HR: 0.98, 95% CI: 0.91-1.05, p = 0.55), or fatal PCa (HR: 0.94, 95% CI: 0.79-1.09, p = 0.41). When accounting for race/ethnicity and family history, Agent Orange exposure was independently associated with slightly increased risk of PCa (HR: 1.06, 95% CI: 1.04-1.09, <10-6) but not with metastatic PCa (HR: 1.07, 95% CI: 0.98-1.15, p = 0.10) or PCa death (HR: 1.02, 95% CI: 0.83-1.23, p = 0.09). Similar results were found when accounting for genetic risk. Agent Orange exposure history may not improve modern PCa risk stratification.

Implementation of Guideline-Based HBV Reactivation Management in Patients with Chronic HBV Infections of HBsAg or Resolved HBV Infection Undergoing Immunosuppressive Therapy.

INTRODUCTION: Although patients with HBV have a risk of reactivation after immunosuppressive therapy (IST), the status of their risk management is unclear in Japan. This study aims to describe the proportion of patients who received preventive management of HBV reactivation during ISTs in patients with chronic HBV infection of HBsAg or resolved HBV infection. METHOD: A retrospective cohort study was conducted using the JMDC Japanese claims database from April 2011 to June 2021. Patients with HBV infections of HbsAg who received ISTs or patients who had resolved HBV infections who received ISTs were identified from the database and evaluated for appropriate management to prevent HBV reactivation. RESULTS: In total, 6242 eligible patients were identified. The proportions of patients with appropriate HBV reactivation management, stratified by the HBV reactivation risk level of IST, was 43.1% (276/641) for high-risk, 40.2% (223/555) for intermediate-risk and 14.9% (741/4965) for low-risk patients. When the evaluation period for the outcome calculation was shortened from 360 to 180 days, the proportion for high risk increased to 52.7%. The odds ratios of large hospitals for receiving appropriate management were 2.16 (95% CI 1.12-4.44) in the high-risk, 4.63 (95% CI 2.34-10.25) in the intermediate-risk and 3.60 (95% CI 3.07-4.24) in the low-risk patients. CONCLUSION: HBV reactivation management was tailored according to the reactivation risk associated with IST. However, adherence to HBV reactivation management guidelines was sub-optimal, even among high-risk patients. This is especially the case for ensuring smaller-sized medical institutions, highlighting the need for further educational activities.

The study assesses the implementation of guideline-based management of hepatitis B virus reactivation during immunosuppressive therapy in Japan. The appropriate management of hepatitis B virus treatment involves prophylactic nucleos(t)ide analog (NUC) therapy and regular monitoring of hepatitis B virus DNA. This study aims to assess the extent to which these management practices are implemented in a clinical setting in Japan using a retrospective cohort study using the Japanese Medical Claims Database. The analysis identified 6242 eligible patients and identified whether they received appropriate management to prevent hepatitis B virus reactivation based on the level of risk associated with their immunosuppressive therapy. Based on the guidelines, the proportions of patients receiving appropriate reactivation management were 43.1% for high-risk, 40.2% for intermediate-risk and 14.9% for low-risk immunosuppressive therapy patients. Shortening the evaluation period from 360 to 180 days showed an increase in the proportion of high-risk patients to 52.7%, which indicated the potential challenge for continued monitoring after immunosuppressive therapy administration. The study shows that large hospitals present higher odds of patients receiving appropriate management. Overall, adherence to hepatitis B virus reactivation management guidelines was suboptimal, especially in smaller medical institutions, emphasizing the need for additional educational activities.