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This paper ascertains that the bilinear shock Hugoniot equation of state (EOS) can model the plasticizing process of the porous media like concrete material for high-velocity impact problems successfully. The negative slope of the bilinear Hugoniot for low particle velocity regime can simulate the process that the porosity of concrete may be compressed to form shock wave in concrete, through a series of numerical analyses over the investigation on the physical phenomena. The results of particle velocity for the concrete material are also discussed to be compared with those of non-porous aluminum alloy for 100 and 1000 m/s impact velocities. All the numerical simulations were carried out by applying the bilinear shock Hugoniot EOS to concrete which was linked to the binary object of a hydrocode: ANSYS Autodyn®[1−3] through a user’s subroutine.

Analogs and homologs of PDMP were synthesized, based on its structure (D-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol). This compound had previously been found to block the synthesis of GlcCer (glucosylceramide). Increasing the acyl chain length from 10 to 16 carbon atoms greatly enhanced the efficacy of the enzyme inhibitor, as did the use of a less polar cyclic amine, especially a pyrrolidine instead of a morpholine ring. Replacement of the phenyl ring by a chain corresponding to sphingosine also yielded a strongly inhibitory material. By using a chiral synthetic route, we showed that the isomers active against GlcCer synthase had the R,R-(D-threo)-configuration. However, strong inhibition of the growth of human cancer cells in plastico was produced by both the threo and erythro racemic compounds, showing involvement of an additional factor (beyond simple depletion of cell glycosphingolipids by blockage of GlcCer synthesis). The growth arresting effects could be correlated with increases in cellular ceramide and diglyceride levels. The aliphatic pyrrolidino compound was strongly inhibitory toward the glucosyltransferase and produced almost complete depletion of glycolipids, but did not inhibit growth or cause an accumulation of ceramide. Attempts were made to see whether the differences in growth effects could be attributed to the influence of the inhibitors on related enzymes (ceramide and sphingomyelin synthase and ceramidase and sphingomyelinase). While some stimulation of enzyme activity was noted, particularly at high inhibitor concentrations (50 microM), these findings did not explain the differing effects of the different inhibitors. The best inhibitors of GlcCer synthase compared favorably in efficacy with some cancer chemotherapeutic drugs in current use when tested with a battery of human cancer cells.

The observed dramatic decrease in September sea ice extent (SIE) has been widely discussed in the scientific literature. Though there is qualitative agreement between observations and ensemble members of the Third Coupled Model Intercomparison Project (CMIP3), it is concerning that the observed trend (1979–2010) is not captured by any ensemble member. The potential sources of this discrepancy include: observational uncertainty, physical model limitations and vigorous natural climate variability. The latter has received less attention and is difficult to assess using the relatively short observational sea ice records. In this study multi-centennial pre-industrial control simulations with five CMIP3 climate models are used to investigate the role that the Arctic oscillation (AO), the Atlantic multi-decadal oscillation (AMO) and the Atlantic meridional overturning circulation (AMOC) play in decadal sea ice variability. Further, we use the models to determine the impact that these sources of variability have had on SIE over both the era of satellite observation (1979–2010) and an extended observational record (1953–2010). There is little evidence of a relationship between the AO and SIE in the models. However, we find that both the AMO and AMOC indices are significantly correlated with SIE in all the models considered. Using sensitivity statistics derived from the models, assuming a linear relationship, we attribute 0.5–3.1%/decade of the 10.1%/decade decline in September SIE (1979–2010) to AMO driven variability.

Background and Objective: Human papillomavirus (HPV) is one of the common infectious and pathogenic agents, and some of its genotypes have the ability to cause malignant changes in the surface of mucous cells. By examining the prevalence of HPV in atypical squamous cells of undetermined significance (ASCUS) Pap smear according to the risk factors, we can make a more correct decision in choosing the evaluation method and directing the patient to report the ASCUS lesion. Therefore, the aim of this study is to investigate the types of human papillomavirus (HPV) in patients with ASCUS Pap smear. Methods: This cross-sectional study was conducted on 200 patients with ASCUS pap smear results and HPV test referred to the colposcopy clinic of Babol Ayatollah Rouhani Hospital during the last two years. Demographic information, history of obstetrics, history of OCP use, history of STD disease and high-risk behaviors, cervical treatments, HPV typing, Pap smear, colposcopy and cervical biopsy results were recorded and analyzed. Findings: The mean age of the patients was 33.83±8.09 years, and ASCUS pap smear showed 129 cases (64.5%) of high-risk papillomavirus, 16 cases (0.8%) of low-risk papillomavirus and 55 cases (27.5%) of both types. Cervical intraepithelial neoplasia grade 2 was in 18 cases (0.9%), cervical intraepithelial neoplasia grade 1 in 10 cases (0.5%) and cervical intraepithelial neoplasia grade 3 in 2 cases (0.1%). 17.1% of high-risk viruses caused cervical neoplasm. None of the low-risk viruses led to neoplasms and all of them were inflammatory. In both high-risk and low-risk cases, 14.5% neoplasm was seen. However, the relationship between the type of papillomavirus and the incidence of neoplasm was significant (p=0.058). Conclusion: Based on the results of this study, the ASCUS pap smear needs more detailed investigation such as colposcopy and cervical biopsy under the supervision of experts because it is associated with the high-risk HPV virus in many cases.

Oscillations in various structures of the solar atmosphere, such as transverse (kink) oscillations of coronal loops, can be used in seismology. Transvers kink oscillations of coronal loops are often accompanied by solar flares. Despite the intensive study of kink oscillations of coronal loops in recent years, the excitation mechanism of these oscillations are still not known. In this paper, we aim to clarify the excitation mechanisms of transverse oscillations of coronal loops. For this purpose, first 458 oscillation events were identified by the Atmospheric Imaging Assembly (AIA) onboard the Solar Dynamics Observatory (SDO) during its first ten years (2010–2019) with the use of the Helioviewer, JHelioviewer and Heliophysics Events Knowledgebase (HEK). Then, the association of these oscillation events with probable mechanism for exciting the kink oscillations such as flares, lower coronal eruptions and plasma ejections, and coronal mass ejections bursts were listed. Finally, about 138 suitable kink oscillations out of 485 oscillations with high-amplitude, long oscillation period and visible through the naked eye that were accompanied with other probable excitation mechanism of kink oscillations, were selected. This statistical analysis of the transverse oscillation coronal loops showed that that 102 of these 138 oscillation events (74 %) were associated with lower coronal eruptions or plasma ejections. About 38 oscillations out of 138 transverse oscillations (27.5%) were associated with coronal mass ejections/eruption. Also, 65 events (47 %) were associated with flares. The required speed of hypothetical drivers of transverse oscillations were calculated. The magnitude values of calculated speeds for shock wave of flares were found to be lower than 500±100 km/s in 87% of the cases. Also, the magnitude values of speeds for lower coronal mass eruption/ejection were obtained to be lower than 500±125 km/s in 94% of the cases. The magnitude values of these speeds are acceptable for lower coronal mass eruption/ejection. But, such low speeds do not favor the association of the oscillation excitation with a shock wave of flares, as usually assumed. Also, statistical analysis of start time and time difference of hypothetical drivers of transverse oscillations showed that there is no clear correlation between them. The results of this study indicated that shock wave of flares cannot be the main cause of transverse oscillations of coronal loops. So, this analysis shows that the most probable excitation mechanism of the kink oscillations of coronal loops are eruptions or plasma ejections rather than the blast shock waves ignited by flares. ‎

In this research, a new algorithm is proposed to automatically extract the effective parameters on the radial velocity curves of the binary stars systems using the Wilson-Devnney (WD) 2007 code. In this regard, a binary star which has the proximity effect and its parameters are also announced by astronomers, is selected as the sample system. To avoid scattering of data and also to have more data point, the radial velocity curve of the sample binary stars is first made using the WD code. Then, the code output data is introduced to the proposed MATLAB algorithm to find the effective parameters on the radial velocity curve, including the eccentricity e, the product of a semi-major axis and orbital inclination asini, center of mass radial velocity VCM, the longitude of periastron ω, And surface parameters of stars such as surface potentials Ω, temperatures T, albude A, gravitational darkening coefficients g, and limb darkening coefficients x. After testing the algorithm on the sample binary stars system, the proposed algorithm is also exploited to analyze the radial velocity data of some other binary stars such as U Peg, AB And, and BD+422782. Comparison between the results obtained from the proposed approach and the results reported by other astronomers demonstrates the ability of the proposed approach in extracting the parameters effective on the radial velocity curves.

This research isolates, characterizes, and studies the computational and frequency calculations of emodin, extracted from the leaf extract of Pteridium acquilinum leaves using methanol. Vacuum liquid and tin layer Chromatography was used for the purification of the molecule. The (VLC purified), fraction was analyzed by Nuclear magnetic resonance (NMR) and the chemical structure of the compound isolated (anthraquinone), was confirmed by 1H & 13C-NMR analyses as emodin (C15H10O5). Computational and frequency studies have been done on the isolated molecule. Optimized geometry, IR frequencies, Bond distances (R) and angles (A), Dipole moments and other parameters have been computationally determined for the isolated molecule from quantum chemical calculations using the GAUSSIAN 09 retinue programs. Experimentally determined and computationally measured IR frequencies agree perfectly with each other. Computational studies can be used to predict unobserved chemical phenomena like design of new drugs and materials such as the positions of constituent atoms in relationship to their relative and absolute energies, electronic charge densities, dipoles, higher multiple moments, vibrational frequencies, relativity or other spectroscopic quantities and cross sections for collision with other molecules. This is the first time this anthraquinone, [emodin], with most of the parameters examined is reported from P. aquilinum.

Transversal oscillation of coronal loops that are interpreted as signatures of magneto hydrodynamics (MHD) waves are observed frequently in active region corona loops. The amplitude of this oscillation has been found to be strongly attenuated. The damping of transverse oscillation may be produced by the dissipation mechanism and the wake of the traveling disturbance. The damping of transversal loop oscillations with wake phenomena is not related to any dissipation mechanism. Also, these kinds of coronal loop oscillations are not related to the kink mode, although this mode can be occurred after the attenuation process by the energy of the wave packet deposited in the loop. In this paper the excitation and damping of transversal coronal loop oscillations with wake of traveling wave packet is discussed in detail, both theoretically and observationally. Here, the transversal coronal loop oscillations is modeled with a one dimensional simple line-tied. The dynamics of the loop and the coronal is governed by the Klein–Gordon differential equation. A localized disturbance that can be generated by nearby flare produces a perturbation that undergoes dispersion as it propagates toward the loop. As a consequence, the amplitudes of oscillates decay with time roughly t-1/2 at the external cutoff frequency. These observed data on 2016-Dec-4 by Atmospheric Imaging Assembly (AIA) onboard Solar Dynamic Observatory (SDO) observations data, consisting of 560 images with an interval of 24 seconds in the 171 A0 pass band is analyzed for evidence of excitation and damping of transverse oscillations of coronal loop that is situated near a flare. In this analyzed signatures of transverse oscillations that are damped rapidly were found, with periods in the range of P=18.5-23.85 minutes. Furthermore, oscillation of loop segments attenuate with time roughly as t-α that average values of α for 4 different loops change form 0.65-0.80. The magnitude values of α are in good agreement with theoretical prediction for damping of transverse loop oscillations by wake of the traveling wave packet that can be considered responsible for the rapid damping of the observed oscillations.

The aim of this descriptive and survey research was to determine the factors affecting the knowledge needs of Eucalyptus growers in Golestan Province. The data were collected using descriptive-correlation research and survey techniques. The study population consisted all of 300 Eucalyptus growers in Golestan province, out of which, 170 growers were randomly selected. Data was collected through a questionnaire which its content validity and reliability were confirmed by a pilot study using experts comments. The correlation test showed that there is a significant relationship between variables age, literacy level, history of agricultural activity, Eucalyptus cultivation background, wood crop cultivation area, visiting experts and people with experience in the field of wood growing, attendance in extension classes and programs, presence in collective visit programs from typical and model fields, number of hours listening to the radio during the day and knowledge needs of Eucalyptus growers in planting, growing and harvesting. Regression analysis results showed that Eucalyptus cultivation background, attendance in extension classes and programs, visiting experts and people with experience in the field of wood and wood crop cultivation area are the most important predictors for knowledge needs of Eucalyptus growers in the fields of planting, growing, and harvesting. This study recommended continuous use of practices such as extension classes and programs, collective visit programs from typical and model fields, visiting experts and people with experience in the field of wood growing, preparing and production the radio programs in wood grower training with the aim of response to their knowledge needs.

Background: This study is a retrospective record-based study involving all children aged less than five years admitted to Basrah General Hospital with acute gastroenteritis during study period 2008-2013. Objectives: To measure the prevalence of rotavirus infection and to relate the infection to selected epidemiological variables. Methods: All children less than five years old admitted to pediatric ward in Basrah General Hospital with acute gastroenteritis over the period 2008- 2013 were included. They were 942 in number. The data were collected through special form (diarrhea case report form). It included two parts, the first part about patient’s information and clinical information while the second one was about the laboratory information. Results: The overall prevalence of rotavirus infection among the study children was 43.7%. The highest prevalence rate was in 2009 (53.0%) and the lowest rate was in 2010 (33.6%). The infection increased in the colder months of the year. The infection was more among age group 6-12 months (58.7%) affecting males and females in similar degree and no statistical significance could be found. All the positive rotavirus cases complained from diarrhea (100%), vomiting (74.5%) and fever (70.1%). Conclusions: Rotavirus a common cause of acute gastroenteritis in children under five years old. The prevalence was higher in infant between 6-11 months. Key words: Rotavirus, Diarrhoea, gastroenteritis, infant

We developed a system to estimate the photovoltaic (PV) potential of urban buildings using a 3D city model at level of detail 2 (LOD2), considering an arrangement of solar panels. Although the PV potential estimation of buildings at the level of city districts prefers LOD2 data, many urban city districts with buildings capable of installing solar panels on façades do not have LOD2 data owing to the high production cost of LOD2 data. Therefore, we investigated the possibility of utilising LOD1 data instead of LOD2 data in the PV potential estimation of buildings at the level of city districts. We conducted an experiment in the investigation using 3D city model data from 24 city districts, which are most of the large cities with LOD2 data in Japan. The experiment results suggest that LOD1 would not be a substitute for LOD2 data in the PV potential estimation of building roofs. The cause of the inadaptability is that most roofs in LOD2 buildings have more small polygons than LOD1 building roofs. Roofs of a LOD2 building with many small polygons have fewer solar panels than roofs of a LOD1 building with a large polygon. On the contrary, the experiment results indicate that LOD1 may be a substitute directly for LOD2 in the PV potential estimation of building façades that are expected to be used as a mounting platform for solar panels in urban buildings from now on. The average of the relative differences in the calculated PV potential of building façades between using LOD1 data and using LOD2 data is approximately 10% in the experiment.

Abstract Background Although blood eosinophil count is recognized as a useful biomarker for the management of chronic obstructive pulmonary disease (COPD), the impact of eosinophils in COPD has not been fully elucidated. Here we aimed to investigate the relationships between the blood eosinophil count and various clinical parameters including lung structural changes. Methods Ninety-three COPD patients without concomitant asthma were prospectively enrolled in this study. Blood eosinophil count, serum IgE level, serum periostin level, and chest computed tomography (CT) scans were evaluated. Eosinophilic COPD was defined as COPD with a blood eosinophil count ≧ 300/µL. We examined the correlation between the blood eosinophil count and structural changes graded by chest CT, focusing specifically on thin airway wall (WT thin) and thick airway wall (WT thick) groups. In a separate cohort, the number of eosinophils in the peripheral lungs of COPD patients with low attenuation area (LAA) on chest CT was assessed using lung resection specimens. Results The mean blood eosinophil count was 212.1/µL, and 18 patients (19.3%) were categorized as having eosinophilic COPD. In the whole group analysis, the blood eosinophil count correlated only with blood white blood cells, blood basophils, C-reactive protein level, and sputum eosinophils. However, the blood eosinophil count positively correlated with the percentage of LAA and negatively correlated with the diffusing capacity for carbon monoxide in the WT thin group. Lung specimen data showed an increased number of eosinophils in the peripheral lungs of COPD patients with LAA on chest CT scans compared to normal controls. Conclusions Some COPD patients without concomitant asthma showed a phenotype of high blood eosinophils. Alveolar damage may be related to eosinophilic inflammation in patients with COPD without asthma and thickening of the central airway wall.

Abstract Nitrogen-containing compounds such as imides and amides have been reported as efficient materials that promote ammonia decomposition over nonnoble metal catalysts. However, these compounds decompose in an air atmosphere and become inactive, which leads to difficulty in handling. Here, we focused on perovskite oxynitrides as air-stable and efficient supports for ammonia decomposition catalysts. Ni-loaded oxynitrides exhibited 2.5–18 times greater catalytic activity than did the corresponding oxide-supported Ni catalysts, even without noticeable differences in the Ni particle size and surface area of the supports. The catalytic performance of the Ni-loaded oxynitrides is well correlated with the nitrogen desorption temperature during N2 temperature-programmed desorption, which suggests that the lattice nitrogen in the oxynitride support rather than the Ni surface is the active site for ammonia decomposition. Furthermore, NH3 temperature-programmed surface reactions and density functional theory (DFT) calculations revealed that NH3 molecules are preferentially adsorbed on the nitrogen vacancy sites on the support surface rather than on the Ni surface. Thus, the ammonia decomposition reaction is facilitated by a vacancy-mediated reaction mechanism.

Abstract Background Cognitive function plays a crucial role in human life, and its maintenance and improvement are essential in both young and older adults. Since cognitive decline can be associated with oral function decline, preventing the decline in both cognitive and oral functions is an urgent social issue. Several training methods to improve each function have been proposed. Previous studies have indicated that greater brain activity during training is associated with increased benefits for cognitive function. Although adding cognitive function elements to oral function training may promote the activation of brain activity during oral function training, the effects have not been validated. The main purpose of this study is to develop a novel training program that combines oral function training with cognitive training, which is expected to activate key brain regions involved in oral and cognitive functions, such as the left dorsolateral prefrontal cortex (DLPFC) and right medial prefrontal cortex (mPFC). Methods Four types of training programs combining oral and cognitive training: PaTaKaRa × calculation, lip exercise × N-back, tongue exercise × inhibition, and tongue exercise × memory, were developed. Each program had seven levels of difficulty [level 0 (no cognitive load) and level 6 (maximum difficulty)]. Twelve healthy young adults participated in the study and were instructed to perform all four programs. Brain activity in the left DLPFC and right mPFC were measured during each training session using two-channel near-infrared spectroscopy (NIRS). Results No significant brain activity was observed during training at level 0. Brain activity in the left DLPFC was significantly increased at levels 1 and 2 and in the left DLPFC and right mPFC at level 6 during PaTaKaRa × calculation training. Brain activity in the left DLPFC was significantly increased at level 6 during tongue exercise × inhibition training. Brain activity in the left DLPFC and right mPFC was significantly increased at level 6 during lip exercise × N-back training. Conclusion Oral function training did not significantly increase brain activity; nevertheless, oral function with cognitive training stimulated brain activity in the prefrontal cortex. Trial registration : UMIN-CTR. ID: UMIN000039678. date: 06/03/2020.

Abstract Background The relationship between inflammatory response, fish consumption, and mortality risk in older individuals is unclear. We investigated whether C-reactive protein (CRP) levels ≥ 0.1 mg/dL, fish intake, and inflammatory responses are associated with all-cause mortality risk in older adults. Methods This prospective cohort study included older adults aged 85–89 years from the Kawasaki Aging and Wellbeing Project, who did not require daily care. Cohort was recruited from March 2017 to December 2018 (follow-up ended on December 31, 2021). Dietary assessment was conducted using the Brief Self-Administered Diet History Questionnaire. Multivariate Cox proportional hazards regression was used to estimate the hazard ratio (HR) and 95% confidence interval (CI) for all-cause mortality in the CRP ≥ 0.1 mg/dL group; the CRP

Abstract Human mesenchymal stem cells (hMSCs) with extended lifespan and differentiation potential that can recapitulate in vivo characteristics could significantly contribute to basic research, drug development, and cell therapy. Specifically, they could ensure a stable supply of specific cellular resources, and possibly extracellular vesicles. Here, we established a technology for extending the lifespan while maintaining differentiation potential, termed “rejuvenation,” of hMSCs (rej-hMSCs) using nonintegrative and conditionally removable temperature-sensitive Sendai virus (SeV) vectors. Various immortalizing factors (i.e., Bmi-1, hTERT, SV40T, and/or HPV E6/E7) were first introduced by the SeV vector into the cells. A combination of three SeVs with Bmi-1, hTERT, or SV40T conferred markedly improved cell proliferation and cloning ability while maintaining differentiation potential and a normal karyotype. An extended lifespan was also demonstrated in other cell types. The rejuvenation of long-passaged or aged hMSCs was also confirmed. SeV vectors were rapidly removed as a function of cell doubling by increasing the temperature from 35 °C to 37 °C or higher, while proliferative ability was maintained. Following FACS sorting, the complete removal of SeV vectors was confirmed by qPCR analyses. Therefore, our cell rejuvenation technology could contribute to research and clinical applications by enabling the supply of modified cells without damaging host chromosomes.

Abstract On-demand underwater adhesives with excellent adhesive and gentle detachment properties enable stable connections to various biomedical devices and biointerfaces and avoid the risk of harmful tissue damage upon detachment. Herein, we present a Janus hydrogel adhesive that can reversibly switch its adhesion strength, which is controlled by temperature, using a thermoresponsive polymer and mussel-inspired molecules. This thermoswitchable adhesive (TSA) hydrogel displays both strong adhesion and gentle detachment with an over 1000-fold gap in underwater adhesion strength onto glass, titanium, aluminum, and Teflon substrates when exposed to temperatures above and below the lower critical solution temperature (LCST). The adhesion switch is possibly caused by the change in toughness of the TSA hydrogels with temperature because the Janus hydrogel possesses gradient crosslinked structures. Moreover, the lowermost surface is sufficiently soft to gently detach from the substrate below the LCST. The electrode-integrated hydrogel remains on human skin, and electrical signals are continuous over 10 min above the LCST. In contrast, commercially available hydrogel electrodes quickly swell and detach from the skin. The thermoswitchability of the TSA hydrogel, with its robust adhesion and gentle detachment, offers significant potential for biomedical applications characterized by minimally invasive procedures.

Abstract Persistent bacterial lung infections in children lead to significant morbidity and mortality due to antibiotic resistance. In this paper, we describe how phage therapy has shown remarkable efficacy in preclinical and clinical studies, demonstrating significant therapeutic benefits through various administration routes. Ongoing trials are evaluating its safety and effectiveness against different pathogens. Advancing phage therapy through systematic studies and international collaboration could provide a viable alternative to traditional antibiotics for persistent infections.

Background: Asthma is characterized by phenotypes of different clinical, demographic, and pathological characteristics. Identifying the profile of exhaled volatile organic compounds (VOCs) in asthma phenotypes may facilitate establishing biomarkers and understanding asthma background pathogenesis. This study aimed to identify exhaled VOCs that characterize severe asthma phenotypes among patients with asthma. Methods: This was a multicenter cross-sectional study of patients with severe asthma in Japan. Clinical data were obtained from medical records, and questionnaires were collected. Exhaled breath was sampled and subjected to thermal desorption gas chromatography-mass spectrometry (GC/MS). Results: Using the decision tree established in the previous nationwide asthma cohort study, 245 patients with asthma were divided into five phenotypes and subjected to exhaled VOC analysis with 50 healthy controls (HCs). GC/MS detected 243 VOCs in exhaled breath samples, and 142 frequently detected VOCs (50% of all samples) were used for statistical analyses. Cluster analysis assigning the groups with similar VOC profile patterns showed the highest similarities between phenotypes 3 and 4 (early-onset asthma phenotypes), followed by the similarities between phenotypes 1 and 2 (late-onset asthma phenotypes). Comparisons between phenotypes 1–5 and HC revealed 19 VOCs, in which only methanesulfonic anhydride showed p

Abstract We discuss the effects of electric fields along compact directions within (supersymmetric) gauge theory in ℝ 1 , 3 × T 2 × T 2 × T 2 $$ {\mathbb{R}}^{1,3}\times {\mathbbm{T}}^2\left(\times {\mathbbm{T}}^2\times {\mathbbm{T}}^2\right) $$ . The electric field along compact directions is equivalent to time-dependent homogeneous configuration of Wilson line moduli, which would be relevant to physics in the early universe. In particular, we consider models with and without background magnetic fluxes, which lead to completely different effects of the electric field due to the difference in the Kaluza-Klein (KK) level structure. We show that, in the case without magnetic fluxes, the deceleration of KK momenta may cause non-perturbative KK particle production dubbed as the KK Schwinger effect, whereas in the case with magnetic flux such KK particle production does not take place but flavor structure of low energy effective theory may be affected.

Abstract Background Severe acute cholecystitis (AC) is a challenging disease because it comprises coexisting systemic infections that lead to vital organ dysfunction. This study evaluated the optimal surgical timing and efficacy of preoperative percutaneous cholecystostomy (PC) for patients with severe AC. Methods Data of 142 patients who underwent cholecystectomy for severe AC between 2011 and 2021 were retrospectively collected from the multi-institutional database of the Hiroshima Surgical Study Group of Clinical Oncology. Patients were divided into the early cholecystectomy (EC) group (within 72 h of symptom onset) and delayed cholecystectomy (DC) group. They were also subdivided into the upfront cholecystectomy group and preoperative PC before cholecystectomy group. The diagnosis and severity of AC were graded according to the Tokyo Guidelines 2018. Clinicopathological variables and outcomes were compared. Results No significant differences in age, body mass index, American Society of Anesthesiologists (ASA) classification, and Charlson comorbidity index between the EC and DC groups were observed. Preoperative drainage was more commonly performed for the DC group than for the EC group. Local severe AC features were more commonly detected in the DC group than in the EC group. The postoperative outcomes of the EC and DC groups were comparable. Compared to the PC before cholecystectomy group, the upfront cholecystectomy group included more patients with ASA physical status ≥ 3 and more patients who used oral warfarin. Warfarin usage and cardiovascular dysfunction rates of the PC after cholecystectomy group were higher than those of the upfront cholecystectomy group. PC was associated with significantly less intraoperative bleeding and shorter hospital stays. Conclusions Patients who can tolerate general anesthesia are good candidates for EC. Patients who use warfarin and those with cardiovascular dysfunction are considered to be at high risk for postoperative complications; therefore, to prevent AC recurrence during the waiting period, PC before cholecystectomy during the same admission is more appropriate than upfront cholecystectomy for these patients.

Abstract. Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life-threatening conditions characterized by extensive detachment of the epidermis and mucous membranes. These severe disorders carry a high mortality rate, and their pathogenesis remains largely unclear. Furthermore, optimal therapeutic strategies for SJS/TEN remain a subject of ongoing debate. Early diagnosis of SJS/TEN is challenging, and reliable biomarkers for diagnosis or severity prediction have not been firmly established. Certain drugs, such as carbamazepine and allopurinol, have shown a strong association with specific human leukocyte antigen (HLA) types. Recently, the potential benefits of HLA screening prior to administering these drugs to reduce the incidence of SJS/TEN have been explored. Epidermal cell death in SJS/TEN lesions is caused by extensive apoptosis, primarily through the Fas–Fas ligand (FasL) and perforin/granzyme pathways. Our findings suggest that necroptosis, a form of programmed necrosis, also contributes to epidermal cell death. Annexin A1, released from monocytes, interacts with the formyl peptide receptor 1 to induce necroptosis. Several biomarkers, such as CC chemokine ligand (CCL)-27, interleukin-15, galectin-7, receptor-interacting protein kinases 3 (RIP3), and lipocalin-2, have been identified for diagnostic and prognostic purposes in SJS/TEN. Supportive care is recommended for treating SJS/TEN, but the efficacy of various therapeutic options–including systemic corticosteroids, intravenous immunoglobulin, cyclosporine, and tumor necrosis factor-α antagonists–remains controversial. Recent studies have investigated the potential benefits of tumor necrosis factor-α antagonists. In this review, we discuss recent advances in the understanding and management of SJS/TEN.

Abstract Lymphocytic myocarditis (LM) is primarily triggered by various factors including viral infections and subsequent immune responses. While rare, some patients with LM experience recurrence with a life‐threatening fulminant form. Although combining steroids and immunosuppressants, such as azathioprine and mycophenolate mofetil, has demonstrated favourable outcomes in patients with LM, their efficacy is limited to the chronic phase. Indeed, various immunosuppressants have been used for LM with fulminant manifestation; however, their evidence remains lacking. In our case series, two patients with LM experienced fulminant relapses during steroid tapering, and another presented persistent cardiac enzymes elevation despite steroid therapies. Consequently, we initiated calcineurin inhibitors alongside steroids, resulting in well‐controlled clinical courses without further recurrence of LM and significant adverse effects. Our cases suggest calcineurin inhibitors as therapeutic options for managing steroid‐resistant LM with fulminant relapse.

Trabectedin is an antineoplastic drug used to treat soft tissue sarcomas. Trabectedin is mainly infused from the central venous port (CVP) because trabectedin leakage causes serious skin and soft tissue complications. Characteristic sterile inflammation has recently been reported after infusion of trabectedin from the CVP. Here, we report a case of sterile inflammation along a tunneled catheter pathway after trabectedin infusion from the CVP, with residual postinflammatory changes even after CVP removal.A 57-year-old man with myxoid liposarcoma developed skin erythema, swelling, and induration along a tunneled catheter pathway of the CVP after 16 cycles of trabectedin infusion through the CVP. The patient was diagnosed with sterile inflammation because various tests were negative for infection. The CVP was removed because the increasing injection resistance made trabectedin infusion difficult. The catheter firmly adhered to the surrounding tissue during removal. The induration and pigmentation along the catheter persisted for 4 months after CVP removal.

Background: Tissue handling is one of the pivotal parts of surgical procedures. We aimed to elucidate the characteristics of experts' left-hand during laparoscopic tissue dissection. Methods: Participants performed tissue dissection around the porcine aorta. The grasping force/point of the grasping forceps were measured using custom-made sensor forceps, and the forceps location was also recorded by motion capture system (Mocap). According to the global operative assessment of laparoscopic skills (GOALS), two experts scored the recorded movies, and based on the mean scores, participants were divided into three groups: novice (

Fibrous dysplasia (FD) is a rare skeletal disorder characterized by the replacement of normal bone with fibrous connective tissue, leading to abnormal bone formation. This case report details the successful treatment of a 61-year-old woman with FD at the craniovertebral junction (CVJ). The patient, who had a history of intracranial meningioma and had already been diagnosed with FD, experienced worsening gait disturbance and muscle weakness following a fall. Imaging studies revealed extensive polyostotic FD lesions in the skull and cervical spine, along with a C2 odontoid fracture causing spinal cord compression. The patient underwent occipitocervical fixation and decompression surgery. Intraoperative O-arm navigation was used to ensure accurate screw placement and effective decompression. This procedure allowed for proper positioning of the C2 and C3 pedicle screws, resection of the hyperplastic occipital bone and C1 posterior arch, and placement of the occipital plate with avoiding the cyst components. At a 2-year follow-up, there were no signs of screw loosening, and the patient showed marked clinical improvement. This case emphasizes the importance of tailored surgical strategies and the use of advanced navigational technologies in managing complex FD cases, particularly those involving the CVJ. It also highlights the challenges of treating polyostotic FD, where complete resection is often unfeasible. The successful outcome in this case supports the use of decompressive surgery combined with stabilization to relieve symptoms and prevent further complications.

Abstract Background Although the percentage of the population with a high degree of obesity (body mass index [BMI] ≥ 35 kg/m2) is low in Japan, the prevalence of obesity-related diseases in patients with high-degree obesity is greater than that in patients with a BMI

Abstract Lung cancer remains the leading cause of cancer death. Treatment with immune checkpoint inhibitor (ICI) alone or combination with chemotherapy served as first-line therapy in non-small cell lung cancer (NSCLC). However, only 20–50% of NSCLC patients respond to ICI. Necroptosis, an inflammatory form of cell death plays an important role in the regulation of tumor immune microenvironment which may affect prognosis and ICI response but its clinical significance in NSCLC patients has remained largely unknown. Therefore, we aimed to analyze the correlation between key necroptotic proteins and necroptosis and clinical outcomes, the status of tumor-infiltrating immune cells, and response to ICI in NSCLC patients. The expression of receptor-interacting protein kinase 3 (RIPK3), mixed lineage kinase domain-like protein (MLKL) and phosphorylated MLKL (pMLKL) were immunolocalized in 125 surgically resected NSCLC patients and 23 NSCLC patients administered with ICI therapy. CD8 + and FOXp3 + T cells and CD163 + M2 macrophages were also immunolocalized. High RIPK3 status was positively correlated with survival of the patients and RIPK3 turned out an independent favorable prognostic factor of the patients. RIPK3 was negatively correlated with CD8 + T cells, while MLKL positively correlated with CD163 + M2 macrophages, suggesting the possible involvement of RIPK3 and MLKL in formulating immunosuppressive microenvironment. In addition, high RIPK3 status tended to be associated with clinical resistance to ICI therapy (P-value = 0.057). Furthermore, NSCLC cells-expressing RIPK3 suppressed T cells response to ICI therapy in vitro. Therefore, RIPK3 and MLKL could induce an immunosuppressive microenvironment, resulting in low response to ICI therapy in NSCLC.

Abstract Positive peritoneal washing cytology is an indicator of poor prognosis in patients with pancreatic ductal adenocarcinoma (PDAC); however, its sensitivity is relatively low. This study evaluated the performance of peptide nucleic acid (PNA)-directed PCR clamping as a molecular-based peritoneal washing cytology for sensitive detection of KRAS mutation in PDAC. Intraoperative peritoneal washing fluid (IPWF) obtained from patients with PDAC who underwent surgery was analyzed. PNA-directed PCR clamping was performed on DNA extracted from IPWF. Among 54 patients enrolled, threshold cycle (Ct) was significantly lower in patients with positive peritoneal washing cytology than in those with negative peritoneal washing cytology (P

Abstract In-home automated scoring systems are in high demand; however, the current systems are not widely adopted in clinical settings. Problems with electrode contact and restriction on measurable signals often result in unstable and inaccurate scoring for clinical use. To address these issues, we propose a method based on ensemble of small sleep stage scoring models with different input signal sets. By excluding models that employ problematic signals from the voting process, our method can mitigate the effects of electrode contact failure. Comparative experiments demonstrated that our method could reduce the impact of contact problems and improve scoring accuracy for epochs with problematic signals by 8.3 points, while also decreasing the deterioration in scoring accuracy from 7.9 to 0.3 points compared to typical methods. Additionally, we confirmed that assigning different input sets to small models did not diminish the advantages of the ensemble but instead increased its efficacy. The proposed model can improve overall scoring accuracy and minimize the effect of problematic signals simultaneously, making in-home sleep stage scoring systems more suitable for clinical practice.

Abstract Laser-driven neutron sources (LDNSs) can generate strong short-pulse neutron beams, which are valuable for scientific studies and engineering applications. Neutron resonance transmission analysis (NRTA) is a nondestructive technique used for determining the areal density of each nuclide in a material sample using pulsed thermal and epithermal neutrons. Herein, we report the first successful NRTA performed using an LDNS driven by the Laser for Fast Ignition Experiment at the Institute of Laser Engineering, Osaka University. The key challenge was achieving a well-resolved resonance transmission spectrum for material analysis using an LDNS with a limited number of laser shots in the presence of strong background noise. We addressed this by employing a time-gated $$^{6}{\textrm{Li}}$$ 6 Li -glass scintillation neutron detector to measure the transmission spectra, reducing the impact of electromagnetic noise and neutron and gamma-ray flashes. Output waveforms were recorded for each laser shot and analyzed offline using a counting method. This approach yielded a spectrum with distinct resonances, which were attributed to $$^{115}\,{\textrm{In}}$$ 115 In and $$^{109}{\textrm{Ag}}$$ 109 Ag , as confirmed through neutron transmission simulation. The spectrum was analyzed using the least-square nuclear-resonance fitting program, REFIT, demonstrating the possibility of using an LDNS for nondestructive areal-density material characterization.

Introduction: Erythema nodosum (EN) is the most common form of panniculitis. EN can be idiopathic or secondary to an underlying systemic disease, infection, drug use, or tumor. CD5-positive diffuse large B-cell lymphoma (CD5+ DLBCL) is a relapsed and refractory lymphoma, and further understanding of its pathology is required. We report a case of newly diagnosed CD5+ DLBCL with concomitant EN. Within the scope of our search, there were no reports of CD5+ DLBCL complicated with EN. Case Presentation: A 79-year-old woman experienced swelling, warmth, redness, and pain in both legs and a mass lesion on the right side of the back at almost the same time. The respective lesions were diagnosed as EN and CD5+ DLBCL by biopsy. With chemotherapy, the lymphoma and EN improved in parallel courses. The patient has completed scheduled chemotherapy, and there has been no recurrence of swelling in the legs or mass on the right side of the back. Discussion: The lymphoma and EN developed simultaneously and followed a parallel clinical course after chemotherapy, suggesting that EN was a paraneoplastic symptom of CD5+ DLBCL. Recognizing and treating underlying malignancies in patients presenting with EN is crucial.

Abstract Third-party punishment (TPP) is an altruistic behavior or sense willing to punish transgressors as a third party not directly involved in the transgression. TPP is observed worldwide, regardless of tradition and culture, and is essential for morality in human society. Moreover, even preverbal infants display TPP-like judgement, suggesting that TPP is evolutionarily conserved and innate. Thus, it is possible that non-human animals display TPP-like behavior, although TPP has been said to be human-specific. We investigated whether or not male mature Wistar rats displayed TPP-like behaviors when they witnessed deadly aggression by an unknown aggressive mouse toward another unknown victim mouse. Normally reared rats did not display TPP-like behaviors, but rats reared with extensive affectionate handling by human caretakers as beloved pets contacted the unknown aggressive mice in a gentle manner leading to reduced aggression toward the unknown victim mice, even when the aggressive mice fought back. Furthermore, the handled rats touched unknown rat pups that were drowning in water and anesthesia-induced comatose rats more frequently than control rats. These findings suggest a possibility that TPP is not in fact human-specific and innate but rather an acquired behavior that flourishes in affectionate circumstances.

Imaging technologies are used to observe the morphology and function of various organs in the body and have become indispensable in a multitude of fields, ranging from basic research to clinical medicine. The luminescence technology based on the luciferin–luciferase reaction has been used in many research fields as an imaging technique, enabling quantitative analysis and detection at high sensitivity. Specifically in gene therapy and cell therapy, it has been developed as an in vivo bioimaging technique mainly for small animal models because of its non-invasive and time-sequential analysis. Currently, translational research using this luminescence imaging technology in pigs for clinical applications is ongoing. In this review, we discuss the progress of these technologies and issues for their clinical application, focusing on pigs, by comparing conventional imaging techniques, including fluorescent probes, with luminescence imaging techniques.

The standard treatment for patients in good general condition with limited-disease small cell lung cancer (LD-SCLC) is concurrent platinum/etoposide chemotherapy and thoracic radiotherapy (TRT). However, the efficacy and safety of chemoradiotherapy (CRT) in older patients with LD-SCLC has not been fully explored; moreover, the optimal treatment for this patient group remains unclear. This study aimed to investigate the feasibility and efficacy of CRT in older patients with LD-SCLC.

Abstract A dark matter model based on QCD-like SU(N c ) gauge theory with electroweakly interacting dark quarks is discussed. Assuming the dark quark mass m is smaller than the dynamical scale Λ d ~ 4πf d , the main component of the dark matter is the lightest G-parity odd dark pion associated with chiral symmetry breaking in the dark sector. We show that nonzero dark quark mass induces the universal mass contribution to both G-parity odd and even pions, and their masses tend to be degenerate. As a result, dark pion annihilation into heavier G-parity even dark pion also affects the dark matter relic abundance. Thus, our setup naturally accommodates forbidden dark matter scenario and realizes heavy dark matter whose mass is O $$ \mathcal{O} $$ (1–100) TeV, which is different from conventional electroweakly interacting dark matter such as minimal dark matter. We also discuss CP-violation from the θ-term in the dark gauge sector and find that the predicted size of the electron electric dipole moment can be as large as ∼ 10 −32 e cm.

Abstract To enhance and sustain movement accuracy, humans make corrections in subsequent trials based on previous errors. Trial-by-trial learning occurs unconsciously and has mostly been studied using reaching movements. Goal-directed projection movements, such as archery, have an inherent delay between releasing an object and observing an outcome (e.g. the arrival position of the object), and this delay may prevent trial-by-trial implicit learning. We aimed to investigate the learning in the projection movement and the impacts of the inherent delay. During the experiment, a joystick was flicked once to transport a cursor from the starting location to a target. To manipulate the length of the delay between the cursor release and outcome observation, the speed of the cursor movement was varied: a fast speed can lead to a short delay. We found trial-by-trial implicit learning under all speed conditions, and the error sensitivity was not significantly different across speed conditions. Furthermore, the error sensitivity depended on the target location, that is, the movement direction. The results indicate that trial-by-trial implicit learning occurred in goal-directed projection movement, despite the length of the inherent delay. Additionally, the degree of this learning was affected by the movement direction.

Abstract The onset and progression mechanisms of metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH) are being studied. We developed and analyzed a new mouse model of obesity by combining maternal Id-like molecule (Maid) and melanocortin-4 receptor (Mc4r) gene deletions. Four mice, each at 12 and 28 weeks of age, were analyzed for each genotype: Maid gene knockout, Mc4r gene knockout, combined Mc4r and Maid gene knockout, and Mc4r gene knockout with a high-fat diet. Mice with a combined deficiency of Mc4r and Maid gene showed significantly more severe obesity compared to all other genotypes, but no liver fibrosis or a decline in metabolic status were observed. In visceral white adipose tissue, Maid and Mc4r gene knockout mice had fewer CD11c-positive cells and lower mRNA expression of both inflammatory and anti-inflammatory cytokines. Furthermore, Maid and Mc4r gene knockout mice showed lower expression of adipocytokines in visceral white adipose tissue and uncoupling protein-1 in scapular brown adipose tissue. The expression of adipocytokines and uncoupling protein-1 is regulated by sympathetic nerve signaling that contribute severe obesity in Maid and Mc4r gene knockout mice. These mechanisms contribute hyperobesity in Maid and Mc4r gene knockout mice.

Abstract This single-arm multi-institutional prospective study aimed to evaluate the 10-year outcomes of sublobar resection for small-sized ground-glass opacity-dominant lung cancer. Among 73 patients prospectively enrolled from 13 institutions between November 2006 and April 2012, 53 ground-glass opacity-dominant lung cancer patients underwent sublobar resection with wedge resection as the first choice. The inclusion criteria were maximum tumor size of 8–20 mm; ≥ 80% ground-glass opacity ratio on high-resolution computed tomography; lower 18F-fluorodeoxyglucose accumulation than the mediastinum; intraoperative pathological diagnosis of adenocarcinoma in situ; and no cancer cells on intraoperative cut margins. The primary endpoint was a 10-year disease-specific survival. The 53 eligible patients had a mean tumor size of 14 ± 3.4 mm and a mean ground-glass opacity ratio of 95.9 ± 7.2%. Wedge resection and segmentectomy were performed in 39 and 14 patients, respectively. The final pathological diagnoses were adenocarcinoma in situ in 47 patients (88.7%) and adenocarcinoma with mixed subtype in 6 patients (11.3%). The 10-year disease-specific survival and overall survival were 100% and 96.2%, respectively, during a median follow-up period of 120 months (range, 37–162 months). Ground-glass opacity-dominant small lung cancer is cured by sublobar resection when patients are strictly selected by the inclusion criteria of this study.

Abstract Ryugu is the C-type asteroid from which material was brought to Earth by the Hayabusa2 mission. A number of individual grains and fine-grained samples analysed so far for noble gases have indicated that solar wind and planetary (known as P1) noble gases are present in Ryugu samples with concentrations higher than those observed in CIs, suggesting the former to be more primitive compared to the latter. Here we present results of analyses of three fine-grained samples from Ryugu, in one of which Xe concentration is an order of magnitude higher than determined so far in other samples from Ryugu. Isotopically, this Xe resembles P1, but with a much stronger isotopic fractionation relative to solar wind and significantly lower 36Ar/132Xe ratio than in P1. This previously unknown primordial noble gas component (here termed P7) provides clues to constrain how the solar composition was fractionated to form the planetary components.

Abstract The general principles of discrete, large self-assemblies composed of numerous components are not unveiled and the artificial formation of such entities is a challenging topic. In metal–organic cages, design strategies for tuning the coordination directions in multitopic ligands by the bend and twist angles were previously developed to solve this problem. In this study, the importance of remote geometric communications between components is emphasized, realizing several types of metal–organic assemblies based on dihedral angle control in multitopic ligands although they have the same coordination directions. Self-assembly of a tritopic ligand with dihedral angles θ = 36.5° and a cis-protected Pd(II) ion affords M9L6 and M12L8 cages as kinetic and thermodynamic products, respectively, whereas an M12L8 sheet is formed when θ = 90°. Geometric analyses of strains in the subcomponent rings reveals that remote geometric communications among neighboring multitopic ligands through coordination bonds are key for large assemblies.

Abstract Background Tumor-associated neutrophils (TANs) constitute an abundant component among tumor-infiltrating immune cells and have recently emerged as a critical player in pancreatic ductal adenocarcinoma (PDAC) progression. This study aimed to elucidate the pro-tumor mechanisms of TAN and identify a novel target for effective immunotherapy against PDAC. Methods Microarray and cytokine array analyses were performed to identify the mechanisms underlying the function of TANs. Human and mouse TANs were obtained from differentiated HL-60 cells and orthotopically transplanted PDAC tumors, respectively. The interactions of TANs with cancer and cytotoxic T-cells were evaluated through in vitro co-culture and in vivo orthotopic or subcutaneous models. Single-cell transcriptomes from patients with PDAC were analyzed to validate the cellular findings. Results Increased neutrophil infiltration in the tumor microenvironment was associated with poor survival in patients with PDAC. TANs secreted abundant amounts of chemokine ligand 5 (CCL5), subsequently enhancing cancer cell migration and invasion. TANs subpopulations negatively correlated with cytotoxic CD8+ T-cell infiltration in PDAC and promoted T-cell dysfunction. TANs upregulated the membranous expression of Nectin2, which contributed to CD8+ T-cell exhaustion. Blocking Nectin2 improved CD8+ T-cell function and suppressed tumor progression in the mouse model. Single-cell analysis of human PDAC revealed two immunosuppressive TANs phenotypes: Nectin2+ TANs and OLR1+ TANs. Endoplasmic reticulum stress regulated the protumor activities in TANs. Conclusions TANs enhance PDAC progression by secreting CCL5 and upregulating Nectin2. Targeting the immune checkpoint Nectin2 could represent a novel strategy to enhance immunotherapy efficacy in PDAC.

Abstract Paleoclimate model simulations provide reference data to help interpret the geological record and offer a unique opportunity to evaluate the performance of current models under diverse boundary conditions. Here, we present a dataset of 35 climate model simulations of the warm early Eocene Climatic Optimum (EECO; ~ 50 million years ago) and corresponding preindustrial reference experiments. To streamline the use of the data, we apply standardised naming conventions and quality checks across eight modelling groups that have carried out coordinated simulations as part of the Deep-Time Model Intercomparison Project (DeepMIP). Gridded model fields can be downloaded from an online repository or accessed through a new web application that provides interactive data exploration. Local model data can be extracted in CSV format or visualised online for streamlined model-data comparisons. Additionally, processing and visualisation code templates may serve as a starting point for advanced analysis. The dataset and online platform aim to simplify accessing and handling complex data, prevent common processing issues, and facilitate the sharing of climate model data across disciplines.

Abstract The therapeutic potential of suppressing polypyrimidine tract-binding protein 1 (Ptbp1) messenger RNA by viral transduction in a post-stroke dementia mouse model has not yet been examined. In this study, 3 days after cerebral ischemia, we injected a viral vector cocktail containing adeno-associated virus (AAV)-pGFAP-mCherry and AAV-pGFAP-CasRx (control vector) or a cocktail of AAV-pGFAP-mCherry and AAV-pGFAP-CasRx-SgRNA-(Ptbp1) (1:5, 1.0 × 1011 viral genomes) into post-stroke mice via the tail vein. We observed new mCherry/NeuN double-positive neuron-like cells in the hippocampus 56 days after cerebral ischemia. A portion of mCherry/GFAP double-positive astrocyte-like glia could have been converted into new mCherry/NeuN double-positive neuron-like cells with morphological changes. The new neuronal cells integrated into the dentate gyrus and recognition memory was significantly ameliorated. These results demonstrated that the in vivo conversion of hippocampal astrocyte-like glia into functional new neurons by the suppression of Ptbp1 might be a therapeutic strategy for post-stroke dementia.

Abstract Background Early detection through screening dramatically improves lung cancer survival rates, including among war Veterans, who are at heightened risk. The effectiveness of low dose computed tomography scans in lung cancer screening (LCS) prompted the Veteran’s Affairs Lung Precision Oncology Program (VA LPOP) to increase screening rates. We aimed to develop an adaptive population health tool to determine adequate resource allocation for the program, with a specific focus on primary care providers, nurse navigators, and radiologists. Methods We developed a tool using C + + that uses inputs that represents the process of the VA LCS program in Ann Arbor, Michigan to calculate FTEs of human resource needs to screen a given population. Further, we performed a sensitivity analysis to understand how resource needs are impacted by changes in population, screening eligibility, and time allocated for the nurse navigators’ tasks. Results Using estimates from the VA LCS Program as demonstrative inputs, we determined that the greatest number of full-time equivalents required were for radiologists, followed by nurse navigators and then primary care providers, for a target population of 75,000. An increase in the population resulted in a linear increase of resource needs, with radiologists experiencing the greatest rate of increase, followed by nurse navigators and primary care providers. These resource requirements changed with primary care providers, nurse navigators and radiologists demonstrating the greatest increase when 1–20, 20–40 and > 40% of Veterans accepted to be screened respectively. Finally, when increasing the time allocated to check eligibility by the nurse navigator from zero to three minutes, there was a linear increase in the full-time equivalents required for the nurse navigator. Conclusion Variation of resource utilization demonstrated by our user facing tool emphasizes the importance of tailored strategies to accommodate specific population demographics and downstream work. We will continue to refine this tool by incorporating additional variability in system parameters, resource requirements following an abnormal test result, and resource distribution over time to reach steady state. While our tool is designed for a specific program in one center, it has wider applicability to other cancer screening programs.

Abstract Background Pembrolizumab plus cisplatin and 5-fluorouracil administered as first-line therapy for advanced esophageal cancer patients has shown a better objective response and survival than conventional chemotherapy with less severe hematological adverse events. The safety and efficacy of this regimen were evaluated in patients with T4b esophageal squamous cell carcinoma (ESCC). Methods Eight consecutive patients with T4b ESCC received this regimen according to KEYNOTE-590 as induction, and they were evaluated after 1–3 courses. The programmed death-ligand 1 (PD-L1) combined positive score (CPS) was also evaluated before chemotherapy. Efficacy for the primary lesion was evaluated by our original formula for the tumor reduction rate. Results The numbers of patients with partial response (PR), stable disease, and progressive disease (PD) were 5, 1, and 2, respectively. The tumor reduction rate ranged from 69 to 87% in PR patients, and all PR patients had relief from T4b. Two patients underwent conversion surgery with R0 resection. PD-L1 CPS was over 90 in 2 PR patients, but under 10 in 2 other PR patients. PD-L1 CPS was under 10 in PD patients. One patient had hyperprogression, resulting in an esophago-pulmonary fistula. Greater than grade 3 adverse events were bleeding gastric ulcer in one patient (12.5%), neutropenia without G-CSF in 3 patients (37.5%), and hypopotassemia in 1 patient (12.5%). No patient had febrile neutropenia. Conclusions Marked tumor reduction was confirmed in 62.5% of patients with pembrolizumab plus cisplatin and 5-fluorouracil with less adverse events. This regimen could be administered as induction chemotherapy for patients with T4b ESCC.