Meaningful Endpoints for Idiopathic Pulmonary Fibrosis (IPF) Clinical Trials: Emphasis on 'Feels, Functions, Survives'. Report of a Collaborative Discussion in a Symposium with Direct Engagement from Representatives of Patients, Investigators, the National Institutes of Health, a Patient Advocacy Organization, and a Regulatory Agency.

Background: Idiopathic pulmonary fibrosis (IPF) carries significant mortality and unpredictable progression, with limited therapeutic options. Designing trials with patient-meaningful endpoints, enhancing the reliability and interpretability of results, and streamlining the regulatory approval process are of critical importance to advancing clinical care in IPF. Methods: A landmark in-person symposium in June 2023 assembled 43 participants from the US and internationally, including patients with IPF, investigators, and regulatory representatives, to discuss the immediate future of IPF clinical trial endpoints. Patient advocates were central to discussions, which evaluated endpoints according to regulatory standards and the FDA's 'feels, functions, survives' criteria. Results: Three themes emerged: 1) consensus on endpoints mirroring the lived experiences of patients with IPF; 2) consideration of replacing forced vital capacity (FVC) as the primary endpoint, potentially by composite endpoints that include 'feels, functions, survives' measures or FVC as components; 3) support for simplified, user-friendly patient-reported outcomes (PROs) as either components of primary composite endpoints or key secondary endpoints, supplemented by functional tests as secondary endpoints and novel biomarkers as supportive measures (FDA Guidance for Industry (Multiple Endpoints in Clinical Trials) available at: https://www.fda.gov/media/162416/download). Conclusions: This report, detailing the proceedings of this pivotal symposium, suggests a potential turning point in designing future IPF clinical trials more attuned to outcomes meaningful to patients, and documents the collective agreement across multidisciplinary stakeholders on the importance of anchoring IPF trial endpoints on real patient experiences-namely, how they feel, function, and survive. There is considerable optimism that clinical care in IPF will progress through trials focused on patient-centric insights, ultimately guiding transformative treatment strategies to enhance patients' quality of life and survival.

In vitro and in vivo anti-inflammatory activities of ethanolic extract of Sargassum confusum.

This study was to investigate the anti-inflammatory activity of ethanolic extract of Sargassum confusum (SCEE). LPS is recognized by TLR4 on the macrophage surface, which activates the NF-κB and MAPK signaling pathways, increasing the expression of inflammatory cytokine like interleukin-6 (IL-6), IL-1ß, and tumor necrosis factor (TNF)-α and inflammatory mediators such as nitric oxide (NO) and cyclooxygenase-2 (COX-2). The anti-inflammatory effect of SCEE (0, 1, 10, 50 µg/mL) was identified using LPS stimulated RAW 264.7 macrophages. As a result, it was confirmed that inflammatory factors were suppressed by inhibiting expression of COX-2 and iNOS without any cytotoxicity. In addition, phosphorylation of ERK, JNK and NF-κB p65, transcription factors, were inhibited by SCEE does-dependent manner. These results suggest that SCEE has an anti-inflammatory effect and can be used as a material for health functional foods to prevent inflammatory diseases.

A human-machine collaborative approach measures economic development using satellite imagery.

Machine learning approaches using satellite imagery are providing accessible ways to infer socioeconomic measures without visiting a region. However, many algorithms require integration of ground-truth data, while regional data are scarce or even absent in many countries. Here we present our human-machine collaborative model which predicts grid-level economic development using publicly available satellite imagery and lightweight subjective ranking annotation without any ground data. We applied the model to North Korea and produced fine-grained predictions of economic development for the nation where data is not readily available. Our model suggests substantial development in the country's capital and areas with state-led development projects in recent years. We showed the broad applicability of our model by examining five of the least developed countries in Asia, covering 400,000 grids. Our method can both yield highly granular economic information on hard-to-visit and low-resource regions and can potentially guide sustainable development programs.

Anti-Atopic Activities of Sargassum horneri Hot Water Extracts in 2,4-Dinitrochlorobezene-Induced Mouse Models.

Atopic dermatitis (AD) is a chronic inflammation associated with skin hypersensitivity caused by environmental factors. The objent of this study was to assess the hot water extracts of Sargassum horneri (SHHWE) on AD. AD was induced by spreading 2,4-dinitrochlorobenzene (DNCB) on the BALB/c mice. The efficacy of SHHWE was tested by observing the immunoglobulin E (IgE), cytokine, skin clinical severity score and cytokine secretions in concanavalin A (Con A)-stimulated splenocytes. The levels of interleukine (IL)-4, IL-5 and IgE, the pro-inflammatory cytokines that are closely related, were notably suppressed in a does-dependent manner by SHHWE, whereas the level of interferon γ (IFN-γ), the atopy-related Th1 cytokine inhibiting the production of Th2 cytokines, was increased. Therefore, these results show that SHHWE has a potent anti-inhibitory effect on AD and is highly valuable for cosmetic development.

Properties and anti-inflammatory effects of Sargassum muticum enzymatic extracts decomposed using crude enzyme from Shewanella oneidensis PKA1008.

This study was conducted to investigate the general properties of an enzymatic extract of Sargassum muticum (SM) produced using a crude enzyme from Shewanella oneidensis PKA 1008 and their anti-inflammatory activities. The SM was mixed with crude enzymes from S. oneidensis PKA 1008 (1:1 (v/v)) and incubated at 30 °C for 0, 3, 6, 12, 24, 48, and 60 h. S. oneidensis PKA 1008 crude enzyme showed the highest SM enzymatic extracts degradation ability when reacted with SM for 48 h. These evaluations demonstrated a 134.25% increase in reducing sugar content and a 14.90% reduction in viscosity at 48 h. The pH, lightness (L*) and yellowness (b*) of the SM enzymatic extracts decreased significantly with increasing reaction time. Moreover, the SM enzymatic extracts demonstrated significant anti-inflammatory activity. These results indicate that the crude enzyme from S. oneidensis PKA 1008 can be used to enhance the polysaccharide degradation of SM, and the resultant oligosaccharides may have an anti-inflammatory effect.

Effects of Gamma Irradiation on Inhibition of Urease Activity and Fishy Smell in Mackerel (Scomber japonicus) during Refrigerated Storage.

In this study, gamma-irradiated mackerel (Scomber japonicus) meat was stored in a refrigerator for 20 days to examine the physicochemical changes related to fishy smell. The effect of gamma irradiation on the inhibition of the activity of crude urease extracted from Vibrio parahaemolyticus was also evaluated. Increased levels of trimethylamine (TMA) and volatile basic nitrogen (VBN) content, which are the main components causing fishy smell, were significantly reduced by day 20 of storage after gamma irradiation, indicating that freshness was maintained during storage. The ammonia nitrogen contents of 3, 7, 10, and 20 kGy gamma-irradiated groups were significantly decreased by 6.5, 15.2, 17.4, and 23.9%, respectively, compared to non-irradiated groups on day 20 of storage. In addition, urease activity decreased in a gamma irradiation intensity-dependent manner. Volatile organic compounds (VOCs) were measured during the storage of gamma-irradiated mackerel meat. The contents of ethanol, 2-butanone, 3-methylbutanal, and trans-2-pentenal, which are known to cause off-flavors due to spoilage of fish, were significantly reduced by day 20 of storage. Therefore, gamma irradiation can be considered useful for inhibiting urease activity and reducing fishy smell during fish storage.

Effect of High Hydrostatic Pressure Treatment on Urease Activity and Inhibition of Fishy Smell in Mackerel (Scomber japonicus) during Storage.

In this study, the physicochemical changes related to fishy smell were determined by storing high hydrostatic pressure (HHP)-treated mackerel (Scomber japonicus) meat in a refrigerator for 20 days. The inhibition of crude urease activity from Vibrio parahaemolyticus using HHP treatment was also investigated. The mackerel meat storage experiment demonstrated that production of trimethylamine (TMA) and volatile basic nitrogen (VBN), the main components of fishy smell, was significantly reduced on the 20th day of storage after the HHP treatment compared to the untreated mackerels. The results demonstrated that the increased ammonia nitrogen rates in the 2000, 3000, and 4000 bar, HHP-treated groups decreased by 23.8%, 23.8%, and 31.0%, respectively, compared to the untreated groups. The enzyme activity of crude urease was significantly reduced in the HHP-treated group compared to that in the untreated group. Measurement of the volatile organic compounds (VOCs) in mackerel meat during storage indicated that the content of ethanol, 2-butanone, 3-methylbutanal, and trans-2-pentenal, which are known to cause off-flavor due to spoilage, were significantly reduced by HHP treatment. Collectively, our results suggested that HHP treatment would be useful for inhibiting the activity of urease, thereby reducing the fishy smells from fish and shellfish.

Prediction Models Based on Regression and Artificial Neural Network for Moduli of Layers Constituted by Open-Graded Aggregates.

The impermeable cover in urban area has been growing due to rapid urbanization, which prevents stormwater from being naturally infiltrated into the ground. There is a higher chance of flooding in urban area covered with conventional concretes and asphalts. The permeable pavement is one of Low-Impact Development (LID) technologies that can reduce surface runoff and water pollution by allowing stormwater into pavement systems. Unlike traditional pavements, permeable pavement bases employ open-graded aggregates (OGAs) with highly uniform particle sizes. There is very little information on the engineering properties of compacted OGAs. In this study, the moduli of open-graded aggregates under various compaction energies are investigated based on the Plate Load Test (PLT) and Light-Weight Deflectometer (LWD). Artificial Neural Network (ANN) and Linear Regression (LR) models are employed for estimation of the moduli of the aggregates based on the material type and level of compaction. Overall, the moduli from PLT and LWD steeply increase until the number of roller passes reaches 4, and they gradually increase until the number of roller passes becomes 8. A set of simple linear equations are proposed to evaluate the moduli of open-graded aggregates from PLT and LWD based on the material type and the number of roller passes.

Immunopathogenesis of ANCA-Associated Vasculitis.

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis is an autoimmune disorder which affects small- and, to a lesser degree, medium-sized vessels. ANCA-associated vasculitis encompasses three disease phenotypes: granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA). This classification is largely based on clinical presentations and has several limitations. Recent research provided evidence that genetic background, risk of relapse, prognosis, and co-morbidities are more closely related to the ANCA serotype, proteinase 3 (PR3)-ANCA and myeloperoxidase (MPO)-ANCA, compared to the disease phenotypes GPA or MPA. This finding has been extended to the investigation of biomarkers predicting disease activity, which again more closely relate to the ANCA serotype. Discoveries related to the immunopathogenesis translated into clinical practice as targeted therapies are on the rise. This review will summarize the current understanding of the immunopathogenesis of ANCA-associated vasculitis and the interplay between ANCA serotype and proposed disease biomarkers and illustrate how the extending knowledge of the immunopathogenesis will likely translate into development of a personalized medicine approach in the management of ANCA-associated vasculitis.

Novel application of an optical inspection system to determine the freshness of Scomber japonicus (mackerel) stored at a low temperature.

This study evaluated the use of an optical inspection system (OIS) to determine the freshness of mackerel (Scomber japonicus). The correlations between the light reflection intensity (LRI) of mackerel eyes (determined using an OIS) and the volatile basic nitrogen content (VBN) and K-value were analyzed. After unloading at the harbor, the mackerel were stored at 4 °C for 9 days and the VBN, K-value, and LRI were determined at 3-day intervals. During storage, the LRI, VBN, and K-value all increased. Furthermore, the LRI was correlated with the K-value and VBN. Therefore, although the LRI cannot be applied as an absolute standard for evaluating freshness, the LRI using an OIS is a suitable nondestructive method for evaluating freshness for quality and risk management in the processing industry when handling large numbers of fish.

Characterization of Undaria pinnatifida Root Enzymatic Extracts Using Crude Enzyme from Shewanella oneidensis PKA 1008 and Its Anti-Inflammatory Effect.

This study investigated the characterization and functionality of Undaria pinnatifida root (UPT) extracts, degraded using a crude enzyme from Shewanella oneidensis PKA1008. To obtain the optimum degrading conditions, the UPT was mixed with alginate degrading enzymes from S. oneidensis PKA 1008 and was incubated at 30°C for 0, 3, 6, 12, 24, and 48 h. The alginate degrading ability of these enzymes was then evaluated by measuring the reducing sugar, viscosity, pH and chromaticity. Enzymatic extract at 24 h revealed the highest alginate degrading ability and the lowest pH value. As the incubation time increased, the lightness (L *) also decreased and was measured at its lowest value, 39.84, at 12 hours. The redness and yellowness increased gradually to 10.27 at 6 h and to 63.95 at 3 h, respectively. Moreover, the alginate oligosaccharides exhibited significant anti-inflammatory activity. These results indicate that a crude enzyme from S. oneidensis PKA 1008 can be used to enhance the polysaccharide degradation of UPT and the alginate oligosaccharides may also enhance the anti-inflammatory effect.

Impact of de novo vesicoureteral reflux on transurethral surgery outcomes in pediatric patients with ureteroceles.

Purpose: We aimed to determine the impact of de novo vesicoureteral reflux (VUR) on postoperative urinary tract infection (UTI) and renal function in pediatric patients with ureteroceles. Materials and Methods: We retrospectively reviewed the medical records of 34 patients (36 renal units) with ureteroceles that were treated endoscopically. Perioperative radiologic and clinical data regarding de novo VUR, UTI, and renal function were analyzed. Logistic regression analysis was used to identify factors that predicted unfavorable surgical outcomes, such as primary surgical failure, postoperative UTI, and deterioration of renal function. Results: Of the 36 renal units, 22 had a duplex system (61.1%). Preoperative VUR was noted in 9 units (25.0%), including 3 units without renal duplication. Endoscopic surgery successfully decompressed the ureterocele and hydronephrosis in 28 units (77.8%). De novo VUR developed in 18 renal units (50.0%) postoperatively. The absence or presence of de novo VUR was not related to unfavorable surgical outcomes in univariate or multivariate analyses. Even after selection for the 28 renal units without preoperative VUR, the occurrence of de novo VUR had no predictive value for unfavorable surgical outcomes. Moreover, among the 14 renal units without renal duplication, de novo VUR had no predictive value for any of these adverse outcomes. Conclusions: After endoscopic ureterocele puncture, de novo VUR is not significantly associated with postoperative UTI or deterioration in renal function in the long term. It may not, therefore, be necessary to reconstruct lower urinary tract routinely to correct de novo VUR after endoscopic puncture of the ureterocele.

Plasma Zonulin Levels in Childhood Nephrotic Syndrome.

Objective: We conducted this study to test the hypothesis that plasma zonulin levels are elevated in pediatric patients with nephrotic syndrome compared to healthy controls. Study Design: Plasma zonulin levels were measured by ELISA in 114 children enrolled in the NEPTUNE study. Clinical and laboratory data were retrieved from the NEPTUNE database. Results: The median age of the patients was 10 (IQR = 5 to 14) years, 59 were male, 64 had minimal change disease, 47 focal segmental glomerulosclerosis, median eGFR was 96 (IQR = 80 to 114) ml/min/1.73 m2, and median urine protein:creatinine ratio was 0.5 (IQR = 0.1 to 3.4) (g:g). The plasma zonulin level was 14.2 ± 5.0 vs. 10.2 ± 2.5 ng/ml in healthy adults in a report using the same assay kit, P = 0.0025. These findings were confirmed in an independent cohort of children with nephrotic syndrome compared to healthy age-matched controls, P = 0.01. Zonulin concentrations did not differ in children with minimal change disease vs. focal segmental glomerulosclerosis, frequently relapsing vs. steroid-dependent vs. steroid-resistant clinical course, and were not influenced by the immunosuppressive treatment regimen. There was no relationship between plasma zonulin levels and the absolute or percentage change in proteinuria from enrollment until the time of the zonulin assay. Conclusion: Plasma zonulin levels are elevated in childhood nephrotic syndrome regardless of level of proteinuria or specific treatment. The cause of the high plasma zonulin levels and whether zonulin contributes to glomerular injury requires further study.

Anti-Inflammatory Effects of Grasshopper Ketone from Sargassum fulvellum Ethanol Extract on Lipopolysaccharide-Induced Inflammatory Responses in RAW 264.7 Cells.

This study evaluated the anti-inflammatory potential of a grasshopper ketone (GK) isolated from the brown alga Sargassum fulvellum on lipopolysaccharide (LPS)-induced RAW 264.7 murine macrophage cell line. GK was isolated and purified from the n-hexane fraction and its structure was verified on the basis of NMR spectroscopic data. GK up to 100 µg/ml is not cytotoxic to RAW 264.7, and is an effective inhibitor of LPS-induced NO production in RAW 264.7 cells. The production of pro-inflammatory cytokines, including IL-6, IL-1ß, and TNF-α was found significantly reduced in 0.1-100 µg/ml dose ranges of GK treatment (p < 0.05). We confirmed the dose-dependent and significant inhibition of iNOS and COX-2 proteins expression. In addition, it has been shown that GK induces anti-inflammatory effects by inhibiting MAPKs (ERK, JNK, and p38) and NF-κB p65 phosphorylation. Our results show that the anti-inflammatory properties of GK may be due to the inhibition of the NF-κB and MAPKs pathways, which are associated with the attenuation of cytokine secretion.

Cognitive Function, Emotional and Behavioral Problems, and Temperament of Premature Children.

OBJECTIVES: We aimed to compare preterm, neurodevelopmentally disordered and healthy full-term children. METHODS: We enrolled 47 children who were born preterm, 40 neurodevelopmentally disordered children, and 80 healthy children as control participants, in order to assess the cognitive functioning and the risk of behavioral problems at the age of 5. Children were assessed using the Korean Wechsler Preschool and Primary Scale of Intelligence-4th edition (K-WPPSI-IV), the Child Behavior Checklist (CBCL), and the Temperament and Character Inventory (TCI). RESULTS: The mean K-WPPSI-IV score of the preterm group was 87.19±17.36, which was significantly higher than that of the neurodevelopmental disorder group (69.98±28.63; p<0.001) but lower than that of the control group (107.74±14.21; p<0.001). The cumulative CBCL scores of the preterm children were not significantly different from those of the control group. Additionally, the TCI scores for reward dependence of the preterm children were higher than those of the control group. CONCLUSION: The cognitive performance of preterm infants was lower than that of healthy full-term infants at the age of 5, and there was an association between slower growth and decreased cognitive ability.

Immune-enhancement effects of tuna cooking drip and its enzymatic hydrolysate in Balb/c mice.

Tuna cooking drip (TCD) is a protein rich by-product of canned tuna processing that is typically discarded. In this study, the immune-enhancing activities of TCD and its enzymatic hydrolysate (EH-TCD) were investigated by intraperitoneally administering Balb/c male mice with TCD and EH-TCD for 2 weeks. This administration resulted in an increase in the weight of the spleen and thymus (200-800 mg/kg) and enhanced the proliferation rates of splenocytes (200-800 mg/kg). TCD and EH-TCD significantly increased the production of immunostimulatory cytokines (interleukin-10 and interleukin-2). In addition, TCD and EH-TCD increased serum IgG1 and IgG2a levels in a concentration-dependent manner. Particularly, EH-TCD had a greater immune-enhancing effect than TCD. These results suggest that TCD and EH-TCD exert immune-enhancing effects through an IgG antibody response and T cell activation, and EH-TCD can be used as an immunostimulatory agent.

Determining Whether a Dosage-Specific and Individualized Home Exercise Program With Consults Reduces Fall Risk and Falls in Community-Dwelling Older Adults With Difficulty Walking: A Randomized Control Trial.

BACKGROUND AND PURPOSE: The development and implementation of effective interventions to prevent falls in older adults is a public health priority. The purpose of this study was to compare the efficacy of a new practice model, incorporating Shubert's evidence-based fall prevention recommendations, with the usual ambulatory physical therapy (PT) at Rusk Rehabilitation, to decrease fall risk among older adults living in the community. The hypotheses were (1) the proposed program would decrease participants' fall risk, (2) it would be more effective than our usual PT, and (3) the addition of 4 consults after discharge would improve compliance with a home exercise program. METHODS: This was a randomized controlled trial. Sixty-nine participants who were independent community dwellers, were 65 years or older, had difficulty walking or complaints of instability, and had 1 or more risk of falls were randomly assigned into a usual care group (UCG, n = 43) or an experimental group (EG, n = 26). Both groups received PT 2 times per week for 30 minutes for 10 to 32 visits. The UCG received the usual PT delivered at Rusk. The EG was instructed in a moderate- to high-intensity home exercise program designed after completing the mini-Balance Evaluation Systems Test to assist with exercise prescription. The EG was educated on performing a recommended dosage of exercise over 6 months using a diary. The EG received 4 additional 30-minute consults every 2 to 4 weeks postdischarge to reinforce compliance. Self-report of number of falls, number of minutes of exercise per week, and performance on outcome measures (Timed Up and Go, 5-times sit-to-stand, Berg Balance Scale, and Activity Balance Confidence Scale) were monitored at evaluation, 2, 4, and 6 months. RESULTS AND DISCUSSION: Thirty-five participants completed the study (UCG n = 22; EG n = 13). Both groups were similar at baseline on outcome measures and number of visits. Random effect model analyses demonstrated that both groups made significant reductions in fall risk over 6 months as identified by performance on outcome measures. However, the EG improved significantly more compared with the UCG over time (P < .05). Linear regression analyses showed that the EG exercised significantly more compared with the UCG at all times (P < .05). The EG exceeded the target of 115 min/wk of exercise (154 minutes, standard deviation [SD] 68.5; 170 minutes, SD 96.8; and 143 minutes, SD 68.5) at 2, 4, and 6 months, respectively. This study demonstrated that the experimental program is effective in decreasing fall risk in community-dwelling older adults and is more effective than our usual care. Moreover, it suggests that the overall experimental protocol may offer an effective strategy to foster adherence to an exercise program without the increasing number of visits. CONCLUSION: This study supports the efficacy of the experimental program in decreasing fall risk and being more effective than our usual care, as well as fostering greater compliance with an exercise regimen. It provides some preliminary evidence to support Shubert's recommendation on exercise prescription for fall prevention.

Mechanical and biological behavior of ultrafine-grained Ti alloy aneurysm clip processed using high-pressure torsion.

Severe plastic deformation (SPD) has recently been advanced as the main process for fabricating bulk ultrafine grained or nanocrystalline metallic materials, which present much higher strength and better bio-compatibility than coarse-grained counterparts. Medical devices, such as aneurysm clips and dental implants, require high mechanical and biological performance (e.g., stiffness, yield strength, fatigue resistance, and bio-compatibility). These requirements match well the characteristics of SPD-processed materials. Typical aneurysm clips are made of a commercial Ti-6Al-4V alloy, which has higher yield strength than Ti. In this work, Ti and Ti-6Al-4V workpieces were processed by high-pressure torsion (HPT) to enhance their mechanical properties. Tensile tests and hardness tests were performed to evaluate their mechanical properties, and their microstructure was investigated. The hardness and yield stress of the HPT-processed Ti are comparable to those of the initial Ti-6Al-4V due to significantly refined microstructure. Finite element analyses for evaluating the opening performance of a specific geometry of the YASARGIL aneurysm clip were carried out using mechanical properties of the initial and HPT-processed Ti and Ti-6Al-4V. These results indicate that SPD-processed Ti could be a good candidate to substitute for Ti-6Al-4V in aneurysm clips.

Anti-Inflammatory Activity of Pinus koraiensis Cone Bark Extracts Prepared by Micro-Wave Assisted Extraction.

In this study, we compared the anti-inflammatory activity of Pinus koraiensis cone bark extracts prepared by conventional extraction and microwave-assisted extraction (MAE). Water extracts and 50% ethanol extracts prepared using MAE were applied to RAW 264.7 cell at 5, 10, 25, and 50 µg/mL of concentrations, and tested for cytoxicity. The group treated with 50 µg/mL of 50% ethanol extracts showed toxicity. In order to investigate the inhibition of nitric oxide (NO) production in RAW 264.7 cells, extracts of water and ethanol were treated with 5, 10, and 25 µg/mL concentrations. The inhibitory activity of water and 50% ethanol extracts groups were determined as 40% and 60% at 25 µg/mL concentration, respectively. We found concentration dependent decreases on inducible NO synthase. The inhibitory effect against forming inflammatory cytokines, prostaglandin E2, tumor necrosis factor-α, interleukin (IL)-6, and IL-1ß, was also superior in the 25 µg/mL treated group than the control group. According to these results, the water extracts and 50% ethanol extracts both inhibited inflammatory mediators by reducing the inflammatory response. Therefore, The MAE extracts of P. koraiensis cone bark can be developed as a functional ingredient with anti-inflammatory activity.