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Background: In Japan, where infertility treatment is now covered by insurance, appropriate protocols for patients with diminished ovarian reserve (DOR) based on treatment outcomes and cost-effectiveness must be selected. Therefore, this study aims to provide information on the outcomes and cost-effectiveness of conventional ovarian stimulation and mild stimulation for patients with DOR in Japan. Methods: Data from 66 women who underwent first oocyte retrieval at Showa University Hospital between May 2019 and November 2023 were analyzed. Results: The clomiphene citrate (CC) group used significantly fewer gonadotropins and incurred lower costs than the conventional ovarian stimulation group while achieving comparable clinical outcomes, including cumulative live birth rates. Conclusions: CC-based minimal stimulation is a cost-effective alternative to conventional ovarian stimulation for patients with low ovarian reserve without compromising clinical efficacy. Further randomized controlled trials are required to confirm these findings and optimize protocols for this population.

Spinal muscular atrophy (SMA) is a progressive neuromuscular disorder caused by mutations in SMN1, with disease severity influenced by the number of SMN2 copies. Although SMA is one of the most common autosomal recessive disorders, molecular diagnosis still presents challenges. We present a case series illustrating the variable clinical presentations and diagnostic complexities of spinal muscular atrophy (SMA). Case 1 highlights the importance of multiplex ligation-dependent probe amplification (MLPA) and sequencing for detecting heterozygous deletions and novel variants. Case 2 highlights the limitations of neonatal screening, in which a heterozygous deletion was overlooked. Case 3 demonstrates the need for thorough clinical examination and relevant genetic testing in patients with dual diagnoses, in this case Down syndrome and SMA. In cases 4, 5, and 6, the pseudodominant inheritance pattern is examined in a familial context, highlighting the need for thorough genetic analysis. The presented case series emphasizes the diagnostic challenges and the crucial role of various molecular techniques in the accurate diagnosis and management of SMA.

Castleman disease (CD) is a rare lymphoproliferative disease known as angiofollicular lymph node hyperplasia, firstly reported in 1954. It mainly occurs in adults, presenting with a wide range of clinical manifestations, including paraneoplastic pemphigus (PNP). PNP is a rare and often life-threatening autoimmune disorder characterized by painful blisters and erosions on the skin and mucous membranes. In children, PNP is often linked to Castleman disease, as evidenced in case reports. So far, less than 30 pediatric cases have been reported, with the pathogenesis remaining unclear and treatment approaches varied. Here, we present a pediatric case initially suspected as Behçet's disease due to persistent oral ulcers and conjunctivitis, and undergone a sudden aggravation of clinical features following an allergic reaction. New involvement of skin rashes and imaging findings prompted the final diagnosis as PNP linked to Unicentral Castleman disease (UCD).Through detailing the progression of clinical features and diagnostic work, we aim to arise the awareness of physicians and put emphasize on early recognition and multidisciplinary management, which can improve patient outcomes.

Understanding the psychological antecedents of socioeconomic status (SES) on pro-environmental behavior is crucial for effectively encouraging individuals from different socioeconomic backgrounds to address environmental issues. Previous research has separately examined the influence of SES and social observation on pro-environmental behavior. However, little is known about whether social observation moderates the influence of SES on pro-environmental behavior, and the underlying neurophysiological mechanisms remain uncharacterized. Using event-related potential (ERPs), we adopted the green purchase paradigm and manipulated subjective SES, to examine whether the influence of SES on pro-environmental behavior is moderated by social observation. The behavioral results revealed that individuals of high SES tended to purchase more eco-friendly products under the observable condition than those in the non-observable condition. The ERP results revealed that participants with high SES exhibited more negative N2 and N400 amplitude during environmental decisions in the non-observable condition than in the observable condition, indicating that high SES individuals experience less cognitive conflict during environmental decisions, which may reflect the attenuated cost–benefit trade-off due to reputational incentives in the presence of observers. Additionally, individuals with high SES exhibited greater reputational motivation when observed, as indicated by larger P3 amplitude. However, these differences were not observed among individuals with low SES. These findings suggest that SES is associated with distinct psychological and behavioral differences in pro-environmental behavior, moderated by social observation, evident across both the early and later stages of environmental decisions in the brain.

ObjectiveTo explore the clinical characteristics and treatment outcomes of children with central nervous system (CNS) involvement in eosinophilic granulomatosis with polyangiitis (EGPA).MethodsA child who presented with EGPA complicated by CNS involvement was admitted to our hospital in June 2023. The clinical features were analyzed retrospectively, and relevant literatures were reviewed to provide a comprehensive overview of this condition.ResultsA ten-year-old girl, who had a history of recurrent cough and asthma accompanied by peripheral blood eosinophilia for eight months, was admitted to our hospital. On admission, spotted papules were visible on her hands and feet, bilateral pulmonary rales were audible. The laboratory examination revealed that the proportion of eosinophils (EOS) exceeded 10% of white blood cells, the anti-neutrophil cytoplasmic antibody (MPO-ANCA) was positive, the immunoglobulin G level was 15.80g/L, and the immunoglobulin E level was greater than 2500.00IU/mL. The imaging examination showed multiple patchy and nodular high-density shadows in both lungs as well as sinusitis. Pulmonary function tests indicated moderate ventilation and diffusion dysfunction. Bone marrow cytology demonstrated a significant increase in the proportion of eosinophils. Skin pathology confirmed leukocytoclastic vasculitis. During the hospitalization, the child had a convulsion. The magnetic resonance imaging (MRI) scan of the brain showed multiple abnormal signal shadows in the bilateral cerebral cortex and the electroencephalogram (EEG) showed epileptic waves. Following the administration of methylprednisolone pulse therapy in combination with cyclophosphamide treatment, her cough and asthma resolved, the skin rash disappeared without any further convulsions. We found that only a young EGPA patient with CNS involvement had been previously reported. The previously reported case began with long-term fever, weight loss, and purpuric rash. Both patients responded well to treatment with glucocorticoids and cyclophosphamide, experiencing significant improvement in their clinical symptoms and normalization of their peripheral blood eosinophils.ConclusionThe diagnosis of EGPA in children can be challenging. When a child is affected by EGPA, it is essential to remain vigilant for signs of CNS involvement. The treatment with glucocorticoids and cyclophosphamide is effective in managing EGPA in children.

Understanding the psychological drivers of pro-environmental behavior across different socioeconomic statuses (SESs) is crucial for effectively addressing environmental challenges. To assist businesses and management departments in adequately identifying the psychological characteristics of target consumer groups from different SES backgrounds, our research manipulated subjective SES through three experimental studies to investigate the influence of subjective SES on pro-environmental behavior. Studies 1 and 2 adopted online experiments to examine the influence of subjective SES on pro-environmental behavior within the private sphere and the public sphere. Subsequently, Study 3 further investigated the psychological mechanisms through which subjective SES influences pro-environmental behavior. These results indicated that individuals from high SES backgrounds exhibit a greater propensity for green consumption behavior and contribute more financially to environmental organizations than those from low SES backgrounds. In addition, these studies further elucidated that the sense of control and life history strategy sequentially mediate the relationship. These findings provide empirical evidence for understanding whether and how subjective SES influences pro-environmental behavior, and enriching the theoretical framework of the relationship between subjective SES on pro-environmental behavior.

5‐Fluorouracil (5‐FU) is widely used for colorectal cancer (CRC) treatment; however, continuous treatment of CRC cells with 5‐FU can result in acquired resistance, and the underlying mechanism of 5‐FU resistance remains unclear. We previously established an acquired 5‐FU‐resistant CRC cell line, HCT116RF10, and examined its biological features and 5‐FU resistance mechanisms. In this study, we evaluated the 5‐FU sensitivity and cellular respiration dependency of HCT116RF10 cells and parental HCT116 cells under conditions of high‐ and low‐glucose concentrations. Both HCT116RF10 and parental HCT116 cells were more sensitive to 5‐FU under low‐glucose conditions compared with high‐glucose conditions. Interestingly, HCT116RF10 and parental HCT116 cells exhibited altered cellular respiration dependence for glycolysis and mitochondrial respiration under high‐ and low‐glucose conditions. Additionally, HCT116RF10 cells showed a markedly decreased ATP production rate compared with HCT116 cells under both high‐ and low‐glucose conditions. Importantly, glucose restriction significantly reduced the ATP production rate for both glycolysis and mitochondrial respiration in HCT116RF10 cells compared with HCT116 cells. The ATP production rates in HCT116RF10 and HCT116 cells were reduced by approximately 64% and 23%, respectively, under glucose restriction, suggesting that glucose restriction may be effective at enhancing 5‐FU chemotherapy. Overall, these findings shed light on 5‐FU resistance mechanisms, which may lead to improvements in anticancer treatment strategies.

ABSTRACTClinical trials of combined IDO/PD1 blockade in metastatic melanoma (MM) failed to show additional clinical benefit compared to PD1-alone inhibition. We reasoned that a tryptophan-metabolizing pathway other than the kynurenine one is essential. We immunohistochemically stained tissues along the nevus-to-MM progression pathway for tryptophan-metabolizing enzymes (TMEs; TPH1, TPH2, TDO2, IDO1) and the tryptophan transporter, LAT1. We assessed tryptophan and glucose metabolism by performing baseline C11-labeled α-methyl tryptophan (C11-AMT) and fluorodeoxyglucose (FDG) PET imaging of tumor lesions in a prospective clinical trial of pembrolizumab in MM (clinicaltrials.gov, NCT03089606). We found higher protein expression of all TMEs and LAT1 in melanoma cells than tumor-infiltrating lymphocytes (TILs) within MM tumors (n = 68). Melanoma cell-specific TPH1 and LAT1 expressions were significantly anti-correlated with TIL presence in MM. High melanoma cell-specific LAT1 and low IDO1 expression were associated with worse overall survival (OS) in MM. Exploratory optimal cutpoint survival analysis of pretreatment ‘high’ vs. ‘low’ C11-AMT SUVmax of the hottest tumor lesion per patient revealed that the ‘low’ C11-AMT SUVmax was associated with longer progression-free survival in our clinical trial (n = 26). We saw no such trends with pretreatment FDG PET SUVmax. Treatment of melanoma cell lines with telotristat, a TPH1 inhibitor, increased IDO expression and kynurenine production in addition to suppression of serotonin production. High melanoma tryptophan metabolism is a poor predictor of pembrolizumab response and an adverse prognostic factor. Serotoninergic but not kynurenine pathway activation may be significant. Melanoma cells outcompete adjacent TILs, eventually depriving the latter of an essential amino acid.

Abstract 5‐Fluorouracil (5‐FU) is a cornerstone drug used to treat colorectal cancer (CRC). However, the prolonged exposure of CRC cells to 5‐FU results in acquired resistance. We have previously demonstrated that levels of the 5‐fluorodeoxyuridylate (FdUMP) covalent complex with thymidylate synthase (FdUMP‐TS) and free‐TS (native enzyme) are higher in 5‐FU‐resistant CRC cells than in the parental cell line (HCT116). Accordingly, resistant cells may have an efficient system for trapping and removing FdUMP‐TS, thus imparting resistance. In this study, using a model of 5‐FU‐resistant CRC cells generated by repeated exposure, the role of autophagy in the elimination of FdUMP‐TS in resistant cells was investigated. The resistant cells showed greater sensitivity to autophagy inhibitors than that of parental cells. Autophagy inhibition increased 5‐FU cytotoxicity more substantially in resistant cells than in parental cells. Furthermore, autophagy inhibition increased FdUMP‐TS protein accumulation in resistant cells. Our findings suggest that resistance to 5‐FU is mediated by autophagy as a system to eliminate FdUMP‐TS and may guide the use and optimization of combination therapies involving autophagy inhibitors.

Abstract Background To investigate the role of circNFIB in the alleviation of myocardial fibrosis by endogenous sulfur dioxide (SO2). Methods We stimulated cultured neonatal rat cardiac fibroblasts with transforming growth factor-β1 (TGF-β1) and developed an in vitro myocardial fibrosis model. Lentivirus vectors containing aspartate aminotransferase 1 (AAT1) cDNA were used to overexpress AAT1, and siRNA was used to silence circNFIB. The SO2, collagen, circNFIB, Wnt/β-catenin, and p38 MAPK pathways were examined in each group. Results In the in vitro TGF-β1-induced myocardial fibrosis model, endogenous SO2/AAT1 expression was significantly decreased, and collagen levels in the cell supernatant and type I and III collagen expression, as well as α-SMA expression, were all significantly increased. TGF-β1 also significantly reduced circNFIB expression. AAT1 overexpression significantly reduced myocardial fibrosis while significantly increasing circNFIB expression. Endogenous SO2 alleviated myocardial fibrosis after circNFIB expression was blocked. We discovered that circNFIB plays an important role in the alleviation of myocardial fibrosis by endogenous SO2 by inhibiting the Wnt/β-catenin and p38 MAPK pathways. Conclusion Endogenous SO2 promotes circNFIB expression, which inhibits the Wnt/β-catenin and p38 MAPK signaling pathways, consequently alleviating myocardial fibrosis.

Recent studies have revealed that people might experience a lessened sense of agency for negative consequences by claiming that they were obeying orders. However, little is known about the cognitive neural mechanism behind the reduced sense of agency when individuals are forced to inflict physical harm on others. This study adopted temporal estimation tasks to investigate the internal mechanism of voluntary action on the sense of agency and the moderating effect of outcome valence as measured by event-related potentials (ERPs). In the temporal estimation task, participants were asked to make trade-offs of monetary gains for themselves against painful electric stimuli experienced by strangers, subjectively estimated the perceptual temporal interval between keypress actions (i.e., free or coercive actions) and consequent outcomes (i.e., positive or negative tones) and rated the feeling of control. The results showed that perceived temporal interval was shorter for positive tones compared with negative tones in the coercive condition, and induced more negative N1 and N300 amplitudes, which indicated that the implicit sense of agency was higher. However, the explicit sense of agency was stronger in the free condition than in the coercive condition, which was not influenced by outcome valence. We discuss the implications of utilizing positive feedback and free choice as significant strategies for those experiencing the abnormal sense of agency.

Although healthcare professionals are on the “frontline” of providing effective and quality healthcare delivery, they face several occupational risks when giving care, particularly during a global health crisis. This study examines healthcare workers’ compliance with COVID-19 safety protocols and identifies factors associated with their perceived risk of COVID-19. Between October and December 2020, this cross-sectional survey utilized online and paper-type questionnaires in data collection. Non-probability sampling techniques were used in selecting clinical and non-clinical healthcare workers in various health facilities within 4 regions of Ghana. Logistic regression analysis was performed to identify the factors associated with the perceived risk of COVID-19. The results showed that healthcare workers are highly compliant with hand hygiene practices and wearing PPE. The category of health professional, number of working years, type of health facility, region of work, frequency of COVID-19 test, and compliance with hand hygiene practices were significantly associated with healthcare workers’ perception of risk of COVID-19 at P

In order to compare the change trend of fermented garlic broth by different strains in the fermentation process, the chemical and physical index of total phenol, titratable acid, methanol, ethanol, and hydroxyl radical scavenging capacity during the fermentation process were determined, then the types and content of organic acid was analyzed by high performance liquid chromatography. The taste of fermented garlic broth at different fermentation time was analyzed by electronic tongue. The results showed that the total phenols and titratable acids of fermented garlic broth prepared by different strains (Saccharomyces cerevisiae and Lactobacillus plantarum) showed an upward trend during the fermentation process. The content of six organic acids (tartaric acid, malic acid, lactic acid, acetic acid, citric acid, succinic acid) was measured in fermented garlic broth, among which the content of malic acid and lactic acid was relatively high. The taste response value of fermented garlic broth prepared by Lactobacillus plantarum had a large change in the early stage of fermentation. The value of sourness response rapidly increased to 9.21±0.03 after 4 days of fermentation, and the value of saltiness response rapidly decreased to −21.11±0.01 after 4 days of fermentation. The scavenging capacity hydroxyl radicals and the content of methanol, ethanol showed a trend that firstly increasing and then keeping in a steady state. The hydroxyl radical scavenging ability for fermented garlic solution was 99.88%±0.05% after 80 days of fementation by Lactobacillus plantarum. The ethanol content produced by Saccharomyces cerevisiae fermentation was higher, while the content of methanol produced by fermentation of Lactobacillus plantarum was higher. Considering the comprehensive evaluation of the effects of strains on the quality of fermented garlic broth, Lactobacillus plantarum was more suitable for garlic fermentation than Saccharomyces cerevisiae, methanol content was within the safe range. This research would provide a theoretical study for the research and development of garlic fermentation products.

PurposeThe Neglected Tropical Diseases programme since its implementation has improved the lives of many in the tropical and sub-tropical areas. Though witnessed many successes, the programme is continually facing challenges thus, preventing the attainment of various objectives. This study seeks to assess the challenges of implementation of the neglected tropical diseases programme in Ghana.Design/methodology/approachThe thematic analysis approach was used to analyze qualitative data collected from 18 key public health managers selected through purposive and snowballing procedures from the national, regional and district levels of Ghana Health Service. Data collection was done through in-depth interviews using semi-structured interview guides in line with the objective of the study.FindingsThe Neglected Tropical Diseases Programme though received funding from external sources, faces multiple challenges which cut across financial, human and capital resources to external control. Specifically, inadequate resources, dwindling volunteerism, poor social mobilization, weak governmental commitment and weak monitoring were major challenges to implementation. These factors work individually and in combination to impede effective implementation. Ensuring state ownership, re-structuring implementation approaches to include top-down and bottom-up approaches and building capacity in monitoring and evaluation are recommended in order to meet the programme objectives and ensure sustainability.OriginalityThis study forms part of an original study on Implementation of the NTDs programme in Ghana. Aside the key issues discussed, it presents first-hand information on major implementation challenges that are relevant to researchers, students, practitioners and the general public and will apply widely to vertically implemented programmes in Ghana.

Abstract Background The importance of health policy implementation cannot be overemphasized in contemporary public health. Neglected Tropical Diseases (NTDs) have negatively impacted society, affect quality of life and make the poor societies poorer. Several policies and strategies have been put in place across the world including the neglected tropical diseases programme in Ghana. Though chalked many successes, the programme continues to lag behind in the full attainment of various objectives. Several factors exist that determine how effective a programme is implemented. Identification of these factors on every programme is essential to determine where more programme resources need to be channelled. This study assessed the determinants of successful implementation of the neglected tropical diseases programme in Ghana. Methods A qualitative approach with the case study design was employed. Purposive and snowball sampling techniques were used to identify key programme officers at the national, regional and district levels of programme implementation. Eighteen (18) Key informant interviews were conducted at all the three levels of the Ghana Health Service NTDs programme. Data were thematically analysed and presented. Results Findings from the study revealed that determinants that influenced the successful implementation of the NTDs programme include donor support, education and training, partnerships, reliability of the health structure, integrative nature of the programme and management commitment. These determining factors cut across the inner settings of the implementing agency and the external environment. Conclusion Neglected tropical diseases continuously affect Ghanaians, especially the poor. It is important for both policy makers and implementers to identify the factors that ensure the success of the programme in the Ghanaian context. Though the factors are independently sufficient, they synergistically lead to improved programme implementation. Empowering all units involved (local to national level) and maximizing the enabling factors identified to would improve upon implementation and ensure sustainability.

ObjectiveThis study aimed to investigate the efficacy and safety of belimumab for treating children with refractory childhood-onset systemic lupus erythematosus (cSLE).MethodsTwenty-six cSLE patients who received belimumab treatment in our hospital from January 2020 to September 2021 (23 of them for more than 52 weeks) were enrolled in this study. Their clinical and laboratory data, assessment of disease activity, glucocorticoid dosage, and treatment-emergent adverse events (TEAEs) were retrieved for analysis. The paired samples t-test and the nonparametric test were used to compare the baseline and post-treatment data.ResultsThe mean age of onset was 10.3 ± 2.4 years old; the mean disease duration was 41.6 ± 37.4 months; the median Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) score was 10 (P25, P75: 3, 17); and the mean Physician’s Global Assessment (PGA) score at baseline was 1.9 ± 1.0. Compared with the baseline values, there was a significant decrease in the 24-h urine protein quantifications at 24 and 52 weeks of treatment (P

Primary Health Care (PHC), based on the Alma Ata declaration, calls for the movement of responsibility, resources, and control away from medical systems and curative measures toward health promotion. However, PHC implementation in practice appears to be heavily influenced by medical systems with its own attendant effects on the attainment of PHC goals. This study therefore examines the extent and effects of medical systems influence on PHC implementation in Ghana. The study uses the thematic framework approach to qualitative data analysis to analyze data collected from PHC managers through interviews. Ethical clearance for the study was obtained from the Noguchi Memorial Institute for Medical Research. Findings suggest that PHC in practice is tied to the apron-strings of medical systems. While this has catalyzed successes in disease control programs and other medicine-based interventions, it has swayed PHC from its intended shift toward health promotion. Community ownership, participation, and empowerment in PHC is therefore lost in the maze of medical systems which reserves power over PHC decision making and implementation to medical professionals while focusing attention on treatment and curative services. Ultimately, PHC has gradually metamorphosed into mini-clinics instead of the revolutionary community-driven promotive services espoused by Alma Ata with concomitant effects on the attainment of Universal Health Coverage. Further, findings show how gradually, the primary in PHC is being used as a descriptor of the first or basic level of hospital-based care instead of a first point of addressing existing health problems using preventive, promotive, and other community driven approaches. Without a reorientation of health systems, significant efforts and resources are channeled toward empowering health workers instead of local communities with significant effects on the long term sustainability of health efforts and the attainment of UHC. The study recommends further studies toward practical means of reducing the influence of medical systems.

The task of relation classification is an important pre-task in natural language processing tasks. Relation classification can provide a high-quality corpus for tasks such as machine translation, human–computer dialogue, and structured text generation. In the process of the digitalization of standards, identifying the entity relationship in the standard text is an important prerequisite for the formation of subsequent standard knowledge. Only by accurately labeling the relationship between entities can there be higher efficiency and accuracy in the subsequent formation of knowledge bases and knowledge maps. This study proposes a standard text relational classification model based on cascaded word vector attention and feature splicing. The model was compared and ablated on our labeled standard text Chinese dataset. At the same time, in order to prove the performance of the model, the above experiments were carried out on two general English datasets, SemEval-2010 Task 8 and KBP37. On standard text datasets and general datasets, the model proposed in this study achieved excellent results.

BackgroundAfrican Americans (AAs) have higher colorectal cancer (CRC) incidence and mortality rate than Caucasian Americans (CAs). Recent studies suggest that immune responses within CRCs contribute to the disparities. If racially distinct immune signatures are present in the early phases of carcinogenesis, they could be used to develop interventions to prevent or slow disease.MethodsWe selected a convenience sample of 95 patients (48 CAs, 47 AAs) with preinvasive colorectal adenomas from the surgical pathology laboratory at the Medical University of South Carolina. Using immunofluorescent-conjugated antibodies on tissue slides from the lesions, we quantified specific immune cell populations: mast cells (CD117+), Th17 cells (CD4+RORC+), and NK cell ligand (MICA/B) and inflammatory cytokines, including IL-6, IL-17A, and IFN-γ. We compared the mean density counts (MDCs) and density rate ratios (RR) and 95% CI of immune markers between AAs to CAs using negative binomial regression analysis. We adjusted our models for age, sex, clinicopathologic characteristics (histology, location, dysplasia), and batch.ResultsWe observed no racial differences in age or sex at the baseline endoscopic exam. AAs compared to CAs had a higher prevalence of proximal adenomas (66% vs. 40%) and a lower prevalence of rectal adenomas (11% vs. 23%) (p =0.04) but no other differences in pathologic characteristics. In age, sex, and batch adjusted models, AAs vs. CAs had lower RRs for cells labeled with IFNγ (RR 0.50 (95% CI 0.32-0.81); p=0.004) and NK cell ligand (RR 0.67 (0.43-1.04); p=0.07). In models adjusted for age, sex, and clinicopathologic variables, AAs had reduced RRs relative to CAs for CD4 (p=0.02), NK cell ligands (p=0.01), Th17 (p=0.005), mast cells (p=0.04) and IFN-γ (p< 0.0001).ConclusionsOverall, the lower RRs in AAs vs. CAs suggests reduced effector response capacity and an immunosuppressive (‘cold’) tumor environment. Our results also highlight the importance of colonic location of adenoma in influencing these differences; the reduced immune responses in AAs relative to CAs may indicate impaired immune surveillance in early carcinogenesis. Future studies are needed to understand the role of risk factors (such as obesity) in influencing differences in immune responses by race.

BackgroundHigh tumor-infiltrating lymphocytes (TILs) and hemorrhage are important prognostic factors in patients who have undergone craniotomy for melanoma brain metastases (MBM) before 2011 at the University of Pittsburgh Medical Center (UPMC). We have investigated the prognostic or predictive role of these histopathologic factors in a more contemporary craniotomy cohort from the University of North Carolina at Chapel Hill (UNC-CH). We have also sought to understand better how various immune cell subsets, angiogenic factors, and blood vessels may be associated with clinical and radiographic features in MBM.MethodsBrain tumors from the UPMC and UNC-CH patient cohorts were (re)analyzed by standard histopathology, tumor tissue imaging, and gene expression profiling. Variables were associated with overall survival (OS) and radiographic features.ResultsThe patient subgroup with high TILs in craniotomy specimens and subsequent treatment with immune checkpoint inhibitors (ICIs, n=7) trended to have longer OS compared to the subgroup with high TILs and no treatment with ICIs (n=11, p=0.059). Bleeding was significantly associated with tumor volume before craniotomy, high melanoma-specific expression of basic fibroblast growth factor (bFGF), and high density of CD31+αSMA- blood vessels. Brain tumors with high versus low peritumoral edema before craniotomy had low (17%) versus high (41%) incidence of brisk TILs. Melanoma-specific expression of the vascular endothelial growth factor (VEGF) was comparable to VEGF expression by TILs and was not associated with any particular prognostic, radiographic, or histopathologic features. A gene signature associated with gamma delta (gd) T cells was significantly higher in intracranial than same-patient extracranial metastases and primary melanoma. However, gdT cell density in MBM was not prognostic.ConclusionsICIs may provide greater clinical benefit in patients with brisk TILs in MBM. Intratumoral hemorrhage in brain metastases, a significant clinical problem, is not merely associated with tumor volume but also with underlying biology. bFGF may be an essential pathway to target. VEGF, a factor principally associated with peritumoral edema, is not only produced by melanoma cells but also by TILs. Therefore, suppressing low-grade peritumoral edema using corticosteroids may harm TIL function in 41% of cases. Ongoing clinical trials targeting VEGF in MBM may predict a lack of unfavorable impacts on TIL density and/or intratumoral hemorrhage.

Abstract For inequality constrained optimization problem, we first propose a new smoothing method to the lower order exact penalty function, and then show that an approximate global solution of the original problem can be obtained by solving a global solution of a smooth lower order exact penalty problem. We propose an algorithm based on the smoothed lower order exact penalty function. The global convergence of the algorithm is proved under some mild conditions. Some numerical experiments show the efficiency of the proposed method.

Humans can recall various aspects of a characteristic sound as a whole when they see a visual shape stimulus that has been intimately associated with the sound. In subjects with audio-visual associative memory, auditory responses that code the associated sound may be induced in the auditory cortex in response to presentation of the associated visual shape stimulus. To test this possibility, mice were pre-exposed to a combination of an artificial sound mimicking a cat's "meow" and a visual shape stimulus of concentric circles or stars for more than two weeks, since such passive exposure is known to be sufficient for inducing audio-visual associative memory in mice. After the exposure, we anesthetized the mice, and presented them with the associated visual shape stimulus. We found that associative responses in the auditory cortex were induced in response to the visual stimulus. The associative auditory responses were observed when complex sounds such as "meow" were used for formation of audio-visual associative memory, but not when a pure tone was used. These results suggest that associative auditory responses in the auditory cortex represent the characteristics of the complex sound stimulus as a whole.

The study aims to assess site assessment of the performance of 18F-PBR-111 as a neuroinflammation marker in the cuprizone mouse model of multiple sclerosis (MS). 18F-PBR-111 PET imaging has not been well evaluated in multiple sclerosis applications both in preclinical and clinical research. This study will help establish the potential utility of 18F-PBR-111 PET in preclinical MS research and future animal and future human applications. 18F-PBR-111 PET/CT was conducted at 3.5 weeks (n = 7) and 5.0 weeks (n = 7) after cuprizone treatment or sham control (n = 3) in the mouse model. A subgroup of mice underwent autoradiography with cryosectioned brain tissue. T2 weighted MRI was performed to obtain the brain structural data of each mouse. 18F-PBR-111 uptake was assessed in multiple brain regions with PET and autoradiography images. The correlation between autoradiography and immunofluorescence staining of neuroinflammation (F4/80 and CD11b) was measured. Compared to control mice, significant 18F-PBR-111 uptake in the corpus callosum (p < 0.001), striatum (caudate and internal capsule, p < 0.001), and hippocampus (p < 0.05) was identified with PET images at both 3.5 weeks and 5.0 weeks, and validated with autoradiography. No significant uptake differences were detected between 3.5 weeks and 5.0 weeks assessing these regions as a whole, although there was a trend of increased uptake at 5.0 weeks compared to 3.5 weeks in the CC. High 18F-PBR-111 uptake regions correlated with microglial/macrophage locations by immunofluorescence staining with F4/80 and CD11b antibodies. 18F-PBR-111 uptake in anatomic locations correlated with activated microglia at histology in the cuprizone mouse model of MS suggests that 18F-PBR-111 has potential for in vivo evaluation of therapy response and potential for use in MS patients and animal studies.