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Introduction: Fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) improve overall survival (OS) and progression-free survival (PFS) in patients with pancreatic cancer, compared with gemcitabine (GEM). However, whether PFS is a surrogate marker of OS in pancreatic cancer chemotherapy focusing on FOLFIRINOX or GEM plus nab-paclitaxel remains unknown. We aimed to verify whether PFS can be a surrogate marker of OS in prognosis prediction., Methods: This was an integrated analysis of the NAPOLEON study and retrospective cohort of the NAPOLEON-2 study-a multicenter observational study conducted in Japan, using real-world data. The primary and secondary endpoints were OS and PFS, respectively. The correlation between OS and PFS in first- and second-line treatments was assessed using Method of Moments estimation. An analysis was performed in patients with confirmed OS at the end of follow-up. The NAPOLEON-2 cohort included only patients who received 5-fluorouracil, leucovorin, and nanoliposomal irinotecan (NFF) as second-line treatment., Results: Among 479 patients, the correlation between PFS and OS from first- and second-line chemotherapies was calculated in 310 and 225 patients, respectively. The R-squared values for the correlation between PFS and OS from first- and second-line chemotherapies were 0.74 and 0.76, respectively. There was no statistically significant difference in first-line treatment between the FOLFIRINOX and gemcitabine plus nab-paclitaxel groups (P=0.92). Therefore, the FOLFIRINOX group may not have shown a stronger correlation than the NFF group., Conclusion: PFS can be a surrogate marker of OS in first- and second-line therapies. Appropriate prognostic estimation might contribute to proper treatment selection., (S. Karger AG, Basel.)

This study aims to investigate the influence of lumbar spine disorders on the development of asymmetric hallux valgus (HV). Data from the fifth survey of the Osteoarthritis/Osteoporosis Against Disability (ROAD) study, a nationwide prospective study in Japan, were analyzed. HV severity was categorized into 4 grades based on the radiographic HV angle, and asymmetric HV was defined as having at least one HV on either side, with a difference of two or more severity grades between the left and right. Controls were matched from both the Normal group (without HV on both sides) and the Symmetric group (HV on at least one side with a difference of one or less severity grades). Univariate analysis assessed lumbar conditions, and multinomial logistic regression analysis explored the association between lumbar spine disorders and asymmetric HV. Among 1997 participants, 27 had asymmetric HV. Univariate analysis revealed a higher incidence of L5 spondylolisthesis and scoliosis in the Asymmetric group. Multinomial logistic regression analysis revealed that scoliosis independently increased the likelihood of asymmetrical HV (Odds ratio [OR] = 3.586, 95%Confidence interval [CI] 1.111-11.582), but showed no significant impact on symmetrical HV (OR 0.910, 95% CI 0.355-2.334). Asymmetric HV is rare but may be associated with lumbar spine disorders, particularly scoliosis., (© 2024. The Author(s).)

A 61-year-old woman, hospitalized for a persistent cough and dyspnea, had no history of bronchial asthma, but was undergoing chemotherapy for methotrexate-related lymphoproliferative disorder due to rheumatoid arthritis. Her peripheral blood eosinophil count was significantly increased, and chest CT revealed left lower lobe atelectasis and high-attenuation mucus. Bronchoscopy revealed mucous plugs and pathological examination revealed numerous eosinophils and filamentous fungi. Allergic bronchopulmonary mycosis (ABPM) caused by Scedosporium apiospermum was diagnosed using culture and genetic analyses. Treatment with corticosteroids and antifungal drugs led to improvement. ABPM caused by S. apiospermum is extremely rare, emphasizing the importance of species identification., Competing Interests: The authors have no conflicts of interest to declare., (© 2024 The Authors.)

This study aimed to compare second-line treatment outcomes for patients with unresectable pancreatic cancer previously treated with gemcitabine plus nab-paclitaxel (GnP) therapy. We conducted an integrated analysis of two retrospective studies included 318 patients receiving nanoliposomal irinotecan + 5-fluorouracil/folinic acid (NFF) (n = 102), S-1 (n = 57), or FOLFIRINOX (n = 14) as second-line treatment. Median overall survival (OS) in the NFF group was 9.08 months, significantly better than S-1 (4.90 months, P = 0.002). FOLFIRINOX had a median OS of 4.77 months, not statistically different from NFF. Subgroup analyses of OS indicated NFF was generally superior, however, a statistical interaction was observed between the treatment regimen in serum Alb < 3.5 g/dL (P = 0.042) and serum CRP ≥ 0.3 mg/dL (P = 0.006). Median progression-free survival (PFS) was 2.93 months for NFF, significantly better than S-1 (2.53 months, P = 0.024), while FOLFIRINOX had a comparable PFS (3.04 months, P = 0.948). Multivariate analysis identified the serum CRP, serum CA19-9, duration of first-line GnP therapy, and use (yes/no) of S-1 for second-line treatment as independent predictors for OS. This study concludes that second-line NFF therapy demonstrated a more favorable OS compared to S-1 therapy, however, it is still important to consider the patient background characteristics while selecting the most appropriate treatment., (© 2024. The Author(s).)

Nanoliposomal irinotecan with fluorouracil and folinic acid (NFF) is a standard regimen after gemcitabine-based therapy for patients with unresectable or recurrent pancreatic cancer. However, there are limited clinical data on its efficacy and safety in the real-world. We therefore initiated a retrospective and prospective observational study (NAPOLEON-2). The results of the retrospective part were reported herein. In this retrospective study, we evaluated 161 consecutive patients who received NFF as second-or-later-line regimen. The main endpoint was overall survival (OS), and the other endpoints were response rate, disease control rate, progression-free survival (PFS), dose intensity, and adverse events (AEs). The median age was 67 years (range, 38-85 years). The median OS and PFS were 8.1 and 3.4 months, respectively. The objective response and disease control rates were 5% and 52%, respectively. The median relative dose intensity was 81.6% for nanoliposomal irinotecan and 82.9% for fluorouracil. Grade 3 or 4 hematological and nonhematological AEs occurred in 47 and 42 patients, respectively. Common grade 3 or 4 AEs included neutropenia (24%), anorexia (12%), and leukocytopenia (12%). Subanalysis of patients treated with second-line and third-or-later-line demonstrated no statistical significant difference in OS (7.6 months vs. 9.1 months, respectively; hazard ratio, 0.92; 95% confidence interval, 0.64-1.35; p = 0.68). In conclusion, NFF has acceptable efficacy and safety profile even in real-world clinical settings. The prospective study is in progress to validate these findings., (© 2024. The Author(s).)

Background: Falls among the elderly are a major societal problem. While observations of medium-distance walking using inertial sensors identified potential fall predictors, classifying individuals at risk based on single gait cycles remains elusive. This challenge stems from individual variability and step-to-step fluctuations, making accurate classification difficult., Methods: We recruited 44 participants, equally divided into high and low fall-risk groups. A smartphone secured on their second sacral spinous process recorded data during indoor walking. Features were extracted at each gait cycle from a 6-dimensional time series (tri-axial angular velocity and tri-axial acceleration) and classified using the gradient boosting decision tree algorithm., Findings: Mean accuracy across five-fold cross-validation was 0.936. "Age" was the most influential individual feature, while features related to acceleration in the gait direction held the highest total relative importance when aggregated by axis (0.5365)., Interpretation: Combining acceleration, angular velocity data, and the gradient boosting decision tree algorithm enabled accurate fall risk classification in the elderly, previously challenging due to lack of discernible features. We reveal the first-ever identification of three-dimensional pelvic motion characteristics during single gait cycles in the high-risk group. This novel method, requiring only one gait cycle, is valuable for individuals with physical limitations hindering repetitive or long-distance walking or for use in spaces with limited walking areas. Additionally, utilizing readily available smartphones instead of dedicated equipment has potential to improve gait analysis accessibility., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Crude glycerol (CG) is a major byproduct of biodiesel production. Most of it cannot be utilized due to major impurities. The CG generally contains alkalis, which generate the residual salts in a series of its purification stages. This study aims to obtain the optimum process conditions and acid molar ratio to produce a higher potassium salt yield while improving the purity of glycerol by a simple acidification procedure. The CG was obtained from the transesterification of palm oil using a catalyst based on potassium carbonate. A phosphoric acid (85%) is utilized at various molar ratios and the process temperature is 60-80 °C. The strong acid was slowly added to the CG and heated for 30 minutes with a mixing speed of 250 rpm. The optimum acidification process occurred at a temperature of 70 °C with a molar crude glycerol ratio to phosphoric acid of 1 : 0.5. The glycerol purity was increased from 43.3% to 67.63% (w/w). It effectively obtains a potassium phosphate salt with a yield of 6.78%. The functional group infrared (IR) and X-ray fluorescence (XRF) spectra identified the salt residue as potassium dihydrogen phosphate (KH 2 PO 4 ). This is composed predominantly of potassium oxide (K 2 O) and phosphorus pentoxide (P 2 O 5 ), 50% and 47.9%, respectively., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Background: Rhabdomyosarcoma is the most common soft tissue sarcoma in children, but rare in adults. Para-meningeal rhabdomyosarcoma in head and neck (PM-HNRMS) is less applicable for surgery due to the anatomic reason. PM-HNRMS has a poor prognosis in children. However, its clinical outcomes remain unclear in adults due to the rarity. Further, there is almost no detailed data about salvage therapy., Methods: We retrospectively examined the adult patients with PM-HNRMS treated at institutions belonging to the Kyushu Medical Oncology Group from 2009 to 2022. We evaluated the overall survival (OS) and progression-free survival (PFS) of the patients who received a first-line therapy. We also reviewed the clinical outcomes of patients who progressed against a first-line therapy and received salvage therapy., Results: Total 11 patients of PM-HNRMS received a first-line therapy. The characteristics were as follows: median age: 38 years (range 25 - 63 years), histology (alveolar/spindle): 10/1, and risk group (intermediate/high): 7/4. As a first-line therapy, VAC and ARST0431-based regimen was performed in 10 and 1 patients, respectively. During a first-line therapy, definitive radiation for all lesions were performed in seven patients. The median PFS was 14.2 months (95%CI: 6.0 - 25.8 months): 17.1 months (95%CI: 6.0 - not reached (NR)) for patients with stage I-III and 8.5 months (95%CI: 5.2 - 25.8 months) for patients with stage IV. The 1-year and 3-year PFS rates were 54.5% and 11.3% for all patients. Median OS in all patients was 40.8 months (95%CI: 12.1 months-NR): 40.8 months (95%CI: 12.1 - NR) for patients with stage I-III and NR for patients with stage IV. The 5-year OS rate was 48.5% for all patients. Among seven patients who received salvage therapy, three are still alive, two of whom remain disease-free for over 4 years after completion of the last therapy. Those two patients received multi-modal therapy including local therapy for all detected lesions., Conclusion: The cure rate of adult PM-HNRMS is low in spite of a first-line therapy in this study. Salvage therapy might prolong the survival in patients who received the multi-modal therapy including local therapy for all detected lesions., (© 2023. The Author(s).)

Introduction: During the COVID-19 crisis, researchers had to collect data remotely. Telephone surveys and interviews can quickly gather data from a distance without heavy expense. Although interviewer-administered telephone surveys (IATS) can accommodate the needs of international public health research, the literature on their use during infectious disease outbreaks is scarce. This scoping review aimed to map the characteristics of IATS during infectious disease outbreaks., Methods: IATS conducted principally during infectious disease outbreaks and answered by informants at least 18 years old were searched from PubMed and EBSCO. There was a manual addition of relevant documents identified during an initial search. Overall trends were reported using different groupings, including WHO regions, and study details were compared before and during the COVID-19 pandemic., Results: 70 IATS published between 2003 and 2022 were identified. 57.1% were conducted during the COVID-19 pandemic. Among 30 IATS conducted before the COVID-19 pandemic in the world, only 3.3% were carried out in low-income and middle-income countries (LMICs). This percentage of studies in LMICs out of all the IATS rose to 32.5% during the pandemic. The share of qualitative studies grew from 6.7% before the COVID-19 outbreak to 32.5% during the outbreak. IATS performed during the COVID-19 pandemic focused on more diverse, specific population groups, such as patients and healthcare professionals. Mobile phones are increasingly used for IATS over time., Conclusion: IATS are used globally with high frequency in the Western Pacific Region and high-income countries. Technical and financial challenges continue to exist, and assessments of inclusiveness and representativeness should be carefully conducted. A lack of details related to methods was observed, and this scoping review urges researchers using this data collection method in the future to specify how they executed IATS for better use and more efficient deployment., Competing Interests: Competing interests: CloudlyYours is a for-profit business, which provides data management solutions, including technological support for telephone surveys, with its expertise in digital transformation and development. SA, as a paid master of public health intern, conducted this scoping review with other authors to produce insights into telephone-based surveys, which CloudlyYours could use to determine areas of improvement. Therefore, the theme of this scoping review aligns with one type of service that CoudlyYours provides, telephone surveys., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Obesity is a risk factor for gastrointestinal malignancies and tumors. However, which factors either protect or predispose the gastrointestinal organs to high-fat diet (HFD)-induced neoplasia remains unclear. Here, we demonstrate that HFD impacts the stomach to a greater extent as compared to the colorectum, resulting in leptin receptor (LepR) signaling-mediated neoplasia in the tissues. HFD activated leptin signaling, which in turn, accelerates the pathogenesis in the gastric mucosa more than that in the colorectum along with ectopic TFF3 expression. Moreover, in the stomach, higher levels of phosphorylated epidermal growth factor receptor (EGFR) in addition to the activation of STAT3 and Akt were observed as compared to the colorectum. The mice with LepR deletion in the gastrointestinal epithelium exhibited a suppressed induction of leptin, TFF3, and phosphorylated EGFR in the stomach, whereas the levels in the colorectum were insignificant. In co-transfected COS-7 cells with LepR and EGFR plasmid DNA, leptin transactivated EGFR to accelerate TFF3 induction along with activation of STAT3, ERK1/2, Akt, and PI3K p85/p55. Furthermore, TFF3 could bind to EGFR but did not transactivate LepR. Leptin-induced TFF3 induction was markedly suppressed by inhibitors of PI3K (LY294002) and EGFR (Erlotinib). Together, these results suggest a novel role of LepR-mediated signaling in transactivating EGFR that leads to TFF3 expression via the PI3K-Akt pathway. Therefore, this study sheds light on the identification of potentially new therapeutic targets for the treatment of pre-cancerous symptoms in stomach and colorectum., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Human immunodeficiency virus type-1 (HIV-1) protease is essential for viral propagation, and its inhibitors are key anti-HIV-1 drug candidates. In this study, we discovered a novel HIV-1 protease inhibitor (compound 16 ) with potent antiviral activity and oral bioavailability using a structure-based drug design approach via X-ray crystal structure analysis and improved metabolic stability, starting from hit macrocyclic peptides identified by mRNA display against HIV-1 protease. We found that the improvement of the proteolytic stability of macrocyclic peptides by introducing a methyl group to the α-position of amino acid is crucial to exhibit strong antiviral activity. In addition, macrocyclic peptides, which have moderate metabolic stability and solubility in solutions containing taurocholic acid, exhibited desirable plasma total clearance and oral bioavailability. These approaches may contribute to the successful discovery and development of orally bioavailable peptide drugs., Competing Interests: The authors declare no competing financial interest., (© 2022 American Chemical Society.)

A novel strategy for lead identification that we have dubbed the "Pocket-to-Lead" strategy is demonstrated using HIV-1 protease as a model target. Sometimes, it is difficult to obtain hit compounds because of the difficulties in satisfying the complex pharmacophoric features. In this study, a virtual fragment hit which does not match all of the pharmacophore features but has key interactions and vectors that could grow into remaining pharmacophore features was optimized in silico . The designed compound 9 demonstrated weak but evident inhibitory activity (IC 50 = 54 μM), and the design concept was proven by the co-crystal structure. Then, structure-based drug design promptly gave compound 14 (IC 50 = 0.0071 μM, EC 50 = 0.86 μM), an almost 10,000-fold improvement in activity from 9 . The structure of the designed molecules proved to be novel with high synthetic feasibility, indicating the usefulness of this strategy to tackle tough targets with complex pharmacophore.

Fuel contamination is a major issue that comes with the utilization of biodiesel. Microbial growth is one of the primary causes of contamination during fuel handling and storage. This work attempts to identify the types, shapes, and growth profiles of microorganisms on fuel samples. The morphology of microbial colonies is presented in order to analyze the potential of fuel contamination. The diesel, biodiesel, and blends are stored in stainless steel (SS) and glass tanks, where each is placed indoors and outdoors during the 90 days of storage time. The morphology of microbial colonies is observed through a microscope with a magnification of 1000× and the quantity is calculated by a digital colony counter. Microbial contamination in all samples is considered as high contamination where the Colony Forming Unit (CFU) is greater than 10 5 L -1 . Colony forms are far more assorted in blends than in pure diesel (B0) and neat biodiesel (B100). The transformation of microbial colonies accelerates after 60 days of storage time. The results reveal that the number of bacterial colonies that grow in B20 is higher and more varied, nevertheless, the contamination in B100 is significantly higher. This is indicated by a 1.5-fold rise in B20 acidity and a 2.5-fold increase in water content compared to the initial condition., Competing Interests: The authors declare no conflict of interest., (© 2022 The Author(s).)

Objective: Little is known regarding how home care is affected by extreme weather. In February 2018, Fukui City in Japan experienced unprecedented levels of snowfall. We examined snowfall impact on the provision of home care to elucidate whether patients incurred any harm., Methods: A retrospective observational study using clinical and administrative records from a clinic in Fukui City was conducted on 294 patients (mean age = 69.9 ± 27.7 years; women = 60.5%, median age = 81). The study period was from February 5 to February 18, 2018. We analysed the patients' characteristics, daily trend of planned/actual patient visits, emergency transportation situations, and local snow accumulation. We summarized the situation in the clinic., Results: There were 326 planned home visits, however only 121 (37%) occurred. Despite this, there were only 2 emergency transfers. Although the available clinical staff was limited, they managed to contact most patients via telephone and social networking services., Conclusion: Although the number of home visits dramatically decreased, the number of emergency transfers did not increase. This study therefore highlights the necessity for effective disaster preparation, such as assessment training, or use of telemedicine, and on-site decision-making to maintain home care during disasters.

Objectives: This prospective study aimed to determine the association between radiographic lumbar spinal stenosis (LSS) and the quality of life (QOL) in the general Japanese population., Methods: The severity of radiographic LSS was qualitatively graded on axial magnetic resonance images as follows: no stenosis, mild stenosis with ≤1/3 narrowing, moderate stenosis with a narrowing between 1/3 and 2/3, and severe stenosis with > 2/3 narrowing. Patients less than 40 years of age and those who had undergone previous lumbar spine surgery were excluded from the study. The Oswestry Disability Index (ODI), which includes 10 sections, was used to assess the QOL. One-way analysis of variance was performed to determine the statistical relationship between radiographic LSS and ODI. Further, logistic regression analysis adjusted for gender, age, and body mass index was performed to detect the relationship., Results: Complete data were available for 907 patients (300 men and 607 women; mean age, 67.3±12.4 years). The prevalence of severe, moderate, and non-mild/non-radiographic were 30%, 48%, and 22%, respectively. In addition, the mean values of ODI in each group were 12.9%, 13.1%, and 11.7%, respectively, and there was no statistically significant difference between the three groups in logistic analysis (P = 0.55). In addition, no significant differences in any section of the ODI were observed among the groups. However, severe radiographic LSS was associated with low back pain in the "severe" group as determined by logistic analysis adjusted for gender, age, and body mass index (odds ratio: 1.53, confidence interval: 1.13-2.07) compared with the non-severe group., Conclusion: In this general population study, severe radiographic LSS was associated with low back pain (LBP), but did not affect ODI., Competing Interests: The authors have declared that no competing interests exist.

Global agricultural trade, which increased at the end of 2020, has been described as "resilient" to the impacts of the COVID-19 coronavirus pandemic; however, the size and channels of its quantitative impacts are not clear. Using a reduced-form, gravity-based econometric model for monthly trade, we estimate the effects of COVID-19 incidence rates, policy restrictions imposed by governments to curb the outbreak, and the de facto reduction in human mobility/lockdown effect on global agricultural trade through the end of 2020. We find that while agricultural trade remained quite stable through the pandemic, the sector as a whole did not go unscathed. First, we estimate that COVID-19 reduced agricultural trade by the approximate range of 5 to 10 percent at the aggregate sector level; a quantified impact two to three times smaller in magnitude than our estimated impact on trade occurring in the non-agricultural sector. Second, we find sharp differences across individual commodities. In particular, we find that non-food items (hides and skins, ethanol, cotton, and other commodities), meat products including seafood, and higher value agri-food products were most severely impacted by the pandemic; however, the COVID-19 trade effect for the majority of food and bulk agricultural commodity sectors were found to be insignificant, or in a few cases, positive. Finally, we also examine the effects across low vs high income countries, the changing dynamics of the pandemic's effect on trade flows, and the effects along the extensive product margins of trade., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Purpose This study aimed to determine the influence of mandibular free-end partial edentulism and use of conventional or implant-supported removable dental prostheses in the partially edentulous area on the load exerted on the maxillary anterior teeth.Methods A jaw model with mandibular free-end missing teeth was used, and a distal extension, removable partial dental prosthesis was fabricated to replace the missing posterior teeth. Four experimental conditions were set up: 1) without prosthesis, 2) with a conventional removable partial dental prosthesis, 3) with an implant-supported removable partial dental prosthesis, and 4) with a complete dental arch. Strain gauges were attached to the root surface of the maxillary left central incisor, canine, first premolar, and first molar. The load exerted on them was calculated based on the calibration coefficient. An occlusal load of 49 N was applied, and the forces were compared using a Kruskal-Wallis test (P < 0.05). Results The load exerted on the maxillary anterior teeth increased significantly with no prosthesis, decreased significantly with a conventional removable partial dental prosthesis, and decreased even more significantly with an implant-supported removable partial dental prosthesis. Conclusions The burden on the maxillary anterior teeth decreased with the use of a removable partial dental prosthesis and decreased even further with the use of an implant-supported dental prosthesis. The use of an implant to support a distal extension removable partial dental prosthesis is potentially effective in preserving the remaining teeth and tissues by reducing excessive stress in patients with mandibular free-end partial edentulism.