Epithelial-mesenchymal transition induced by tumor cell-intrinsic PD-L1 signaling predicts a poor response to immune checkpoint inhibitors in PD-L1-high lung cancer.

BACKGROUND: We investigated the role of tumor cell-intrinsic PD-L1 signaling in the epithelial-mesenchymal transition (EMT) in non-small-cell lung cancer (NSCLC) and the role of EMT as a predictive biomarker for immune checkpoint inhibitor (ICI) therapy. METHODS: PD-L1-overexpressing or PD-L1-knockdown NSCLC cells underwent RNA-seq and EMT phenotype assessment. Mouse lung cancer LLC cells were injected into nude mice. Two cohorts of patients with NSCLC undergoing ICI therapy were analyzed. RESULTS: RNA-seq showed that EMT pathways were enriched in PD-L1-high NSCLC cells. EMT was enhanced by PD-L1 in NSCLC cells, which was mediated by transforming growth factor-ß (TGFß). PD-L1 promoted the activation of p38-MAPK by binding to and inhibiting the protein phosphatase PPM1B, thereby increasing the TGFß production. Tumor growth and metastasis increased in nude mice injected with PD-L1-overexpressing LLC cells. In the ICI cohort, EMT signature was higher in patients with progressive disease than in those with responses, and EMT was significantly associated with poor survival in PD-L1-high NSCLC. In PD-L1-high NSCLC, EMT was associated with increased M2-macrophage and regulatory T-cell infiltrations and decreased cytotoxic T-cell infiltration. CONCLUSIONS: Tumor cell-intrinsic PD-L1 function contributes to NSCLC progression by promoting EMT. EMT may predict an unfavorable outcome after ICI therapy in PD-L1-high NSCLC.

National trends of allergic diseases and pandemic-related factors among individuals with obesity in South Korea: A nationwide representative serial study, 2005-2021.

Background: Although obesity is known to be related to allergic diseases, few studies have investigated the prevalence of allergic diseases in individuals with obesity, especially during the COVID-19 pandemic. Thus, this study aimed to analyze national trends of allergic diseases among individuals with obesity and sociodemographic factors. Methods: This study used data from the Korea National Health and Nutrition Examination Survey to examine the prevalence of allergic diseases among individuals with obesity in South Korea from 2005 to 2021. A nationally representative sample of 118,275 participants aged over 2 years or above was divided into six groups for analysis. This study used weighted multivariate regression analysis to examine the estimates of related factors. It assessed the weighted odds ratios or ß-coefficients for these factors across different categories, including age, sex, region of residence, education level, household income, and body mass index for the entire population. Results: All allergic diseases showed a general upward trend from 2005 to 2021, but each disease showed different prevalence trends when compared by age. Before the pandemic, those aged ≤39 years had an increasing trend for asthma and AD, but those aged ≥40 years had a decreasing trend. For asthma, ß-coefficients were 0.629 (95 % CI, 0.299 to 0.958) for 19-39 years, -0.245 (-0.450 to -0.040) for 40-59 years, and -0.668 (-1.024 to -0.313) for ≥60 years. For AD, ß-coefficients were 2.514 (1.258-3.769) in those aged 2-18 years, 0.630 (0.173-1.086) in those aged 19-39 years, -0.458 (-0.648 to -0.268) in those aged 40-59 years, and -0.253 (-0.454 to -0.052) in those aged ≥60 years. However, for both asthma and AD, there were no significant changes in prevalence during the pandemic. In the case of AR, trends were different from those of asthma and AD. Before the pandemic, AR showed an increasing trend in those aged ≤39 years and those aged ≥40 years: ß-coefficients were 3.067 (2.344-3.790) in 19-39 years, 2.051 (1.609-2.493) in 40-59 years, and 1.173 (0.820-1.526) in ≥60 years. During the pandemic, there was an increasing trend only among those aged 40-59, with no significant changes in other age groups: ß-coefficients were 1.438 (0.065-2.811) in 40-59 years. Conclusions: From 2005 to 2021, all allergic diseases (asthma, AD, and AR) increased overall, but with different age-related trends. No significant link was found between COVID-19 and allergic diseases, possibly due to preventive measures like mask-wearing and social distancing. Anxiety about accessing healthcare during the pandemic likely contributed to a decline in allergy diagnoses, highlighting the need for comprehensive strategies to manage and prevent allergic diseases.

Comparative profiling by data-independent acquisition mass spectrometry reveals featured plasma proteins in breast cancer: a pilot study.

Purpose: Breast cancer is known to be influenced by genetic and environmental factors, and several susceptibility genes have been discovered. Still, the majority of genetic contributors remain unknown. We aimed to analyze the plasma proteome of breast cancer patients in comparison to healthy individuals to identify differences in protein expression profiles and discover novel biomarkers. Methods: This pilot study was conducted using bioresources from Seoul National University Bundang Hospital's Human Bioresource Center. Serum samples from 10 breast cancer patients and 10 healthy controls were obtained. Liquid chromatography-mass spectrometry analysis was performed to identify differentially expressed proteins. Results: We identified 891 proteins; 805 were expressed in the breast cancer group and 882 in the control group. Gene set enrichment and differential expression analysis identified 30 upregulated and 100 downregulated proteins in breast cancer. Among these, 10 proteins were selected as potential biomarkers. Three proteins were upregulated in breast cancer patients, including cluster of differentiation 44, eukaryotic translation initiation factor 2-α kinase 3, and fibronectin 1. Seven proteins downregulated in breast cancer patients were also selected: glyceraldehyde-3-phosphate dehydrogenase, α-enolase, heat shock protein member 8, integrin-linked kinase, tissue inhibitor of metalloproteinases-1, vasodilator-stimulated phosphoprotein, and 14-3-3 protein gamma. All proteins had been previously reported to be related to tumor development and progression. Conclusion: The findings suggest that plasma proteome profiling can reveal potential diagnostic biomarkers for breast cancer and may contribute to early detection and personalized treatment strategies. A further validation study with a larger sample cohort of breast cancer patients is planned.

Heat Shock Response and Heat Shock Proteins: Current Understanding and Future Opportunities in Human Diseases.

The heat shock response is an evolutionarily conserved mechanism that protects cells or organisms from the harmful effects of various stressors such as heat, chemicals toxins, UV radiation, and oxidizing agents. The heat shock response triggers the expression of a specific set of genes and proteins known as heat shock genes/proteins or molecular chaperones, including HSP100, HSP90, HSP70, HSP60, and small HSPs. Heat shock proteins (HSPs) play a crucial role in thermotolerance and aiding in protecting cells from harmful insults of stressors. HSPs are involved in essential cellular functions such as protein folding, eliminating misfolded proteins, apoptosis, and modulating cell signaling. The stress response to various environmental insults has been extensively studied in organisms from prokaryotes to higher organisms. The responses of organisms to various environmental stressors rely on the intensity and threshold of the stress stimuli, which vary among organisms and cellular contexts. Studies on heat shock proteins have primarily focused on HSP70, HSP90, HSP60, small HSPs, and ubiquitin, along with their applications in human biology. The current review highlighted a comprehensive mechanism of heat shock response and explores the function of heat shock proteins in stress management, as well as their potential as therapeutic agents and diagnostic markers for various diseases.

Detrimental Roles of Hypoxia-Inducible Factor-1α in Severe Hypoxic Brain Diseases.

Hypoxia stabilizes hypoxia-inducible factors (HIFs), facilitating adaptation to hypoxic conditions. Appropriate hypoxia is pivotal for neurovascular regeneration and immune cell mobilization. However, in central nervous system (CNS) injury, prolonged and severe hypoxia harms the brain by triggering neurovascular inflammation, oxidative stress, glial activation, vascular damage, mitochondrial dysfunction, and cell death. Diminished hypoxia in the brain improves cognitive function in individuals with CNS injuries. This review discusses the current evidence regarding the contribution of severe hypoxia to CNS injuries, with an emphasis on HIF-1α-mediated pathways. During severe hypoxia in the CNS, HIF-1α facilitates inflammasome formation, mitochondrial dysfunction, and cell death. This review presents the molecular mechanisms by which HIF-1α is involved in the pathogenesis of CNS injuries, such as stroke, traumatic brain injury, and Alzheimer's disease. Deciphering the molecular mechanisms of HIF-1α will contribute to the development of therapeutic strategies for severe hypoxic brain diseases.

Prognostic impact of erythropoietin-stimulating agent use during front-line chemotherapy in patients with ovarian cancer: A Korean multicenter cohort study.

OBJECTIVE: To evaluate whether treatment with erythropoiesis-stimulating agents (ESAs) for chemotherapy-induced anemia affects progression-free survival (PFS) in patients receiving front-line chemotherapy following surgery for ovarian cancer (OC). METHODS: We retrospectively reviewed all consecutive patients who received front-line chemotherapy after surgery between 2013 and 2019 at six institutions. The patients were divided according to the use of ESAs during front-line chemotherapy. The primary endpoint was PFS. The secondary endpoint was the occurrence of thromboembolism. Propensity score matching (PSM) analysis was used to compare survival between matched cohorts. RESULTS: Overall, 2147 patients (433 receiving ESA and 1714 for no-ESA) were identified, with a median follow-up of 44.0 months. The ESA group showed a significantly higher proportion of stage III/IV disease (81.8% vs 61.1%; P < 0.001) and postoperative gross residual disease (32.3% vs 21.2%; P < 0.001) than the no-ESA group. In the multivariable Cox regression analysis, the use of ESAs did not affect PFS (adjusted hazard ratio, 1.03; 95% confidence interval [CI]: 0.89-1.20; P = 0.661). The incidence of thromboembolism was 10.2% in the ESA group and 4.6% in the no-ESA group (adjusted odds ratio, 6.58; 95% CI: 3.26-13.28; P < 0.001). When comparing the well-matched cohorts after PSM, PFS did not differ between the ESA (median PFS 23.5 months) and no-ESA groups (median PFS 22.2 months) (P = 0.540, log-rank test). CONCLUSIONS: The use of ESAs during front-line chemotherapy did not negatively affect PFS in patients with OC after surgery but increased the risk of thromboembolism.

Chemotherapy response score no longer predicts survival outcomes in high-grade serous ovarian cancer patients with BRCA mutation and/or maintenance therapy.

OBJECTIVE: We aimed to revalidate the chemotherapy response score (CRS) system as a prognostic factor for ovarian cancer patients with breast cancer gene (BRCA) mutations or those receiving frontline poly-ADP ribose polymerase (PARP) inhibitors or bevacizumab as maintenance therapy. METHODS: A retrospective analysis was performed using medical records of patients with high-grade serous carcinoma who received neoadjuvant chemotherapy followed by interval debulking surgery between January 2007 and December 2021 at 5 tertiary medical institutions in South Korea. At each hospital, pathologists independently assessed each slide of omental tissues obtained from surgery using the CRS system. Progression-free survival (PFS) and overall survival (OS) values were obtained using Kaplan-Meier analysis to evaluate the effect of BRCA mutation, maintenance therapy, and CRS on survival time. RESULTS: Of 466 patients, BRCA mutations were detected in 156 (33.5%) and 131 (28.1%) were treated with maintenance therapy; 98 (21.0%) and 42 (9.0%) were treated with PARP inhibitors or bevacizumab, respectively. Patients with CRS3 had significantly longer PFS than those with CRS1 or 2 (24.7 vs. 16.8 months, p<0.001). However, there was no significant difference in PFS improvement between CRS3 patients and those with CRS1 or 2 with BRCA mutation (22.0 vs. 19.3 months, p=0.193). Moreover, no significant PFS prolongation was observed in CRS3 patients compared to CRS1 or 2 patients treated with PARP inhibitors or bevacizumab (24.3 vs. 22.4 months, p=0.851; 27.5 vs. 15.7 months, p=0.347, respectively). CONCLUSION: CRS may not be a prognostic factor in patients with BRCA mutations and those receiving frontline maintenance therapy.

CRIF1 deficiency induces FOXP3LOW inflammatory non-suppressive regulatory T cells, thereby promoting antitumor immunity.

Recently identified human FOXP3lowCD45RA- inflammatory non-suppressive (INS) cells produce proinflammatory cytokines, exhibit reduced suppressiveness, and promote antitumor immunity unlike conventional regulatory T cells (Tregs). In spite of their implication in tumors, the mechanism for generation of FOXP3lowCD45RA- INS cells in vivo is unclear. We showed that the FOXP3lowCD45RA- cells in human tumors demonstrate attenuated expression of CRIF1, a vital mitochondrial regulator. Mice with CRIF1 deficiency in Tregs bore Foxp3lowINS-Tregs with mitochondrial dysfunction and metabolic reprograming. The enhanced glutaminolysis activated α-ketoglutarate-mTORC1 axis, which promoted proinflammatory cytokine expression by inducing EOMES and SATB1 expression. Moreover, chromatin openness of the regulatory regions of the Ifng and Il4 genes was increased, which facilitated EOMES/SATB1 binding. The increased α-ketoglutarate-derived 2-hydroxyglutarate down-regulated Foxp3 expression by methylating the Foxp3 gene regulatory regions. Furthermore, CRIF1 deficiency-induced Foxp3lowINS-Tregs suppressed tumor growth in an IFN-γ-dependent manner. Thus, CRIF1 deficiency-mediated mitochondrial dysfunction results in the induction of Foxp3lowINS-Tregs including FOXP3lowCD45RA- cells that promote antitumor immunity.

New Korean Guidelines for the Diagnosis and Management of Dry Eye Disease.

New Korean guidelines for the diagnosis and management of dry eye disease were developed based on literature reviews by the Korean Dry Eye Guideline Establishment Committee, a previous dry eye guideline by Korean Corneal Disease Study Group, a survey of Korean Dry Eye Society (KDES) members, and KDES consensus meetings. The new definition of dry eye was also proposed by KDES regular members. The new definition by the regular members of the KDES is as follows: "Dry eye is a disease of the ocular surface characterized by tear film abnormalities and ocular symptoms." The combination of ocular symptoms and an unstable tear film (tear breakup time <7 seconds) was considered as essential components for the diagnosis of dry eye. Schirmer test and ocular surface staining were considered adjunctive diagnostic criteria. The treatment guidelines consisted of a simplified stepwise approach according to aqueous deficiency dominant, evaporation dominant, and altered tear distribution subtypes. New Korean guidelines can be used as a simple, valid, and accessible tool for the diagnosis and management of dry eye disease in clinical practice.

Accuracy of preoperative T2 gallbladder tumor localization and the adequate surgical resection.

INTRODUCTION: The agreement between the radiologic and histopathologic tumor locations in T2 gallbladder cancer is critical. There is no consensus regarding the extent of curative resection by tumor locations. METHODS: Between January 2010 and December 2019, a consecutive series of 118 patients with pathological T2 gallbladder cancer who underwent surgery were retrospectively analyzed in terms of the accordance between radiologic and histopathologic tumor locations, the extents of hepatic resection and the numbers of harvested lymph nodes. Radical resection was defined as liver resection with harvesting of at least four lymph nodes. RESULTS: The accuracy of preoperative tumor localization was only 68%. After radical resection, the 5-year overall survival (OS) was 59.4%; after nonradical resection, the figure was 46.1% (p = 0.092). In subanalyses, the 5-year OS was marginally better for patients who underwent liver resection or from whom at least four lymph nodes were harvested than those who did not undergo liver resection or from whom three or fewer lymph nodes were harvested (58.2% vs. 39.4%, p = 0.072; 59.9% vs. 50.0%, p = 0.072, respectively). In patients with peritoneal side tumor, the 5-year OSs of those who did and did not undergo liver resection were 67% and 41.2%, respectively (p = 0.028). In multivariate analysis, perineural invasion and radical resection were independently prognostic of OS. CONCLUSION: The accuracy of preoperative tumor localization was 68%. Hepatic resection, lymph node dissection harvesting of at least four lymph nodes are required for curative resection for gallbladder cancer, regardless of tumor location.

A Study on the Application of Recombinant Factor C (rFC) Assay Using Biopharmaceuticals.

Gram-negative bacterial endotoxins can cause pathophysiological effects such as high fever when introduced into the bloodstream. Therefore, endotoxin testing is necessary when producing injectable pharmaceuticals. The pharmaceutical industry has widely used Limulus amebocyte lysate (LAL) to certify product quality. However, ethical concerns have been raised and the increasing scarcity of Limulus polyphemus necessitates the development of novel testing techniques. Recombinant factor C (rFC) was developed using genetic engineering techniques. The aim of this study was to investigate the validity of rFC testing and compare it with the LAL method. The specificity, linearity, accuracy, precision, and robustness of the rFC assay were evaluated. After validation, the rFC assay was found to be suitable for endotoxin detection. We compared the accuracy of the rFC and LAL assays using reference standard endotoxin. The rFC assay was as accurate as the LAL assay. We also compared the two assays using biopharmaceuticals. Greater interference occurred in some samples when the rFC assay was used than when the LAL assay was used. However, the rFC assay overcame the interference when the samples were diluted. Overall, we suggest that rFC can be applied to test biopharmaceuticals.

Suicide warning signs that are challenging to recognize: a psychological autopsy study of Korean adolescents.

BACKGROUND: In South Korea, the leading cause of youth death has been suicide for about 20 years. In this study, we conducted a multi-method psychological autopsy to identify the psychiatric diagnosis, developmental history, personality traits, family history, school life, warning signs of suicide, and risk factors related to suicide for the first time in Korea. METHODS: This was a postmortem, retrospective, and descriptive study of 36 adolescents who died by suicide between August 2015 and July 2021 in South Korea. We obtained qualitative and quantitative data from the Korean Psychological Autopsy of Adolescent, conducted by the Suicide and School Mental Health Institute, the official student mental health policy-focused research institute of the Korean Ministry of Education. RESULTS: The adolescents comprised equal percentage of girls and boys. Approximately half of the deaths (55.6%) occurred at home and most (72.2%) involved jumping from a height. Most of the adolescents (97.2%) had one major psychiatric disorder before death, with depressive disorder being the most prevalent (75%). They were at a high risk for internet addiction before death. The most common personality trait was avoidance (28.6%), followed by submissiveness (27.3%). Half of the parents reported that the adolescents were satisfied with their school life and the teachers observed that they had no behavioral problems. One year before death, seven (19.4%) adolescents injured themselves and five (13.9%) had attempted suicide. Most of the deceased (80.6%) had expressed suicide warning signs to their families within one year before death. Adolescents had a long experience of family-related adverse events. CONCLUSIONS: Most of the adolescents had mental health disorders and expressed suicidal intentions using verbal and nonverbal signs. However, it was challenging for families to recognize the risk signs because of adolescents' personality traits or a good school life. To prevent adolescent suicide, adolescents, parents, and teachers need to be educated to recognize signs of suicide warning signs and equipped to guide adolescents to appropriate care.

Efficacy of radiofrequency ablation for treatment of toxic thyroid nodules-a narrative review.

Background and Objective: Radiofrequency ablation (RFA) has been used in the treatment of benign thyroid nodules for the past 20 years. The adaptation of RFA to benign autonomously functioning thyroid nodules (AFTNs) has been introduced into clinical practice with variable efficacy and outcomes published in the literature. To better understand international practices, we performed a literature search to better elucidate the efficacy and outcomes in the treatment of AFTNs with RFA. Methods: Comprehensive literature searches were independently conducted by two investigators on PubMed, EMBASE, and Scopus in October of 2022 to identify articles reporting AFTN treated by RFA using the terms "RFA", "radiofrequency ablation", "thyroid nodule", "toxic nodules", and "autonomous functioning thyroid nodule". Papers were selected by relevance of the title or abstract, and the date of publication. Key Content and Findings: In patients with toxic nodules, studies have shown 50% remission rate one year after single session of RFA, up to 71% after second dose. Adverse events are generally limited to postoperative pain lasting less than one day, however there are reports of self-limited voice changes, and self-limited hypothyroidism. RFA has been shown to be safe with no reported instances of post-procedure hypothyroidism or hypocalcemia when compared to radioactive iodine (RAI) and surgery. Conclusions: RFA is an acceptable alternative to surgical resection for the treatment of AFTNs in selective patients, however more studies on long-term hyperthyroidism remission rates and nodule regrowth are necessary for further applications.

Feasibility of robotic cholecystectomy at an academic center with a young robotic surgery program: a retrospective cohort study with umbrella review.

Laparoscopic cholecystectomy (LC) has been standard of care for surgical treatment of benign gallbladder pathology for decades. With the advent of robotic surgical technology, robotic cholecystectomy (RC) has gained attention as an alternative to conventional laparoscopy. This study introduces a single-surgeon experience with laparoscopic versus robotic cholecystectomy and an umbrella systematic review of the outcomes of both approaches. A retrospective chart review was performed at a single institution on a prospectively maintained database of patients undergoing laparoscopic or robotic cholecystectomy for benign gallbladder pathology. An umbrella systematic review was conducted using PRISMA methodology. A total of 103 patients were identified; 61 patients underwent LC and 42 underwent RC. In the RC cohort, 17 cases were completed using a four-port technique while 25 were completed using a three-port technique. Patients undergoing RC were older compared to the LC group (44.78 vs 57.02 years old; p < 0.001) and exhibited lower body mass index (29.37 vs 32.37 kg/m2, p = 0.040). No statistically significant difference in operative time or need for postoperative ERCP was noted. Neither this series nor the umbrella systematic review revealed significant differences in conversion to open surgery or readmissions between the LC and RC cohorts. Three-port RC was associated with reduced operative time compared to four-port RC (101.28 vs 150.76 min; p < 0.001). Robotic cholecystectomy is feasible and safe at a young robotic surgery program in an academic center setting and comparable to laparoscopic cholecystectomy clinical outcomes.

Amygdala electrical stimulation for operant conditioning in rat navigation.

There have been several attempts to navigate the locomotion of animals by neuromodulation. The most common method is animal training with electrical brain stimulation for directional cues and rewards; the basic principle is to activate dopamine-mediated neural reward pathways such as the medial forebrain bundle (MFB) when the animal correctly follows the external commands. In this study, the amygdala, which is the brain region responsible for fear modulation, was targeted for punishment training. The brain regions of MFB, amygdala, and barrel cortex were electrically stimulated for reward, punishment, and directional cues, respectively. Electrical stimulation was applied to the amygdala of rats when they failed to follow directional commands. First, two different amygdala regions, i.e., basolateral amygdala (BLA) and central amygdala (CeA), were stimulated and compared in terms of behavior responses, success and correction rates for training, and gene expression for learning and memory. Then, the training was performed in three groups: group R (MFB stimulation for reward), group P (BLA stimulation for punishment), and group RP (both MFB and BLA stimulation for reward and punishment). In group P, after the training, RNA sequencing was conducted to detect gene expression and demonstrate the effect of punishment learning. Group P showed higher success rates than group R, and group RP exhibited the most effective locomotion control among the three groups. Gene expression results imply that BLA stimulation can be more effective as a punishment in the learning process than CeA stimulation. We developed a new method to navigate rat locomotion behaviors by applying amygdala stimulation.

Fetal Lung Interstitial Tumor: A Comprehensive Case Study with an Emphasis on Next-Generation Sequencing.

Fetal lung interstitial tumor (FLIT), which is characterized by immature interstitial cells resembling the fetal lung parenchyma of 20 to 24 weeks of gestation, is a rare respiratory neoplasm. This study presents the first reported FLIT in Korea. It also aims to refine the diagnostic method of FLIT and increase the accuracy of prognostic assessment by using next-generation sequencing to check for anaplastic lymphoma receptor tyrosine kinase (anaplastic lymphoma kinase) gene rearrangement. Although the initial prognosis for FLIT has been promising since its first report in 2010, certain pathological features are associated with poorer outcomes. Therefore, achieving an accurate diagnosis of FLIT is crucial for avoiding unnecessary treatments beyond surgical resection.

Clinicopathological implications of immunohistochemical expression of TBX21, CXCR3, GATA3, CCR4, and TCF1 in nodal follicular helper T-cell lymphoma and peripheral T-cell lymphoma, not otherwise specified.

BACKGROUND: The classification of nodal peripheral T-cell lymphoma (PTCL) has evolved according to histology, cell-of-origin, and genetic alterations. However, the comprehensive expression pattern of follicular helper T-cell (Tfh) markers, T-cell factor-1 (TCF1), and Th1- and Th2-like molecules in nodal PTCL is unclear. METHODS: Eighty-two cases of nodal PTCL were classified into 53 angioimmunoblastic T-cell lymphomas (AITLs)/nodal T-follicular helper cell lymphoma (nTFHL)-AI, 18 PTCLs-Tfh/nTFHL-not otherwise specified (NOS), and 11 PTCLs-NOS according to the revised 4th/5th World Health Organization classifications. Immunohistochemistry for TCF1, TBX21, CXCR3, GATA3, and CCR4 was performed. RESULTS: TCF1 was highly expressed in up to 68% of patients with nTFHL but also in 44% of patients with PTCL-NOS (p > .05). CXCR3 expression was higher in AITLs than in non-AITLs (p = .035), whereas GATA3 expression was higher in non-AITL than in AITL (p = .007) and in PTCL-Tfh compared to AITL (p = .010). Of the cases, 70% of AITL, 44% of PTCLTfh/ nTFHL-NOS, and 36% of PTCL-NOS were subclassified as the TBX21 subtype; and 15% of AITL, 38% of PTCL-Tfh/nTFHL-NOS, and 36% of PTCL-NOS were subclassified as the GATA3 subtype. The others were an unclassified subtype. CCR4 expression was associated with poor progression-free survival (PFS) in patients with PTCL-Tfh (p < .001) and nTFHL (p = .023). The GATA3 subtype showed poor overall survival in PTCL-NOS compared to TBX21 (p = .046) and tended to be associated with poor PFS in patients with non-AITL (p = .054). CONCLUSIONS: The TBX21 subtype was more prevalent than the GATA3 subtype in AITL. The GATA3 subtype was associated with poor prognosis in patients with non-AITL and PTCL-NOS.

General surgery textbooks and surgical disparities.

INTRODUCTION: Some academic textbooks have previously disseminated simplistic or even incorrect conceptions of race. Propagation of such ideas in General Surgery could contribute to gaps in quality of care received by minority patients. This study aims to determine whether General Surgery textbooks provide a thorough understanding of racial disparities. METHODS: General Surgery texts were drawn from Doody's list, an industry-standard list of textbooks for medical education. Technical guides, atlases, and books for non-General Surgery professionals were excluded. Passages mentioning medical differences amongst racial and ethnic groups were extracted. Six binary classifications were made, based on whether passages (a) described interventions to alleviate difference; (b) addressed environmental mediators of difference; (c) described the contribution of racism or discrimination; (d) used causal language to connect race to difference; (e) referred to known, heritable genetic mechanisms; and (f) directly provided a reference. Types of intervention were also extracted. A heuristic scale was calculated granting one point each for classifications a-c and losing one point for classification d. Three authors performed classifications, and raw agreement and Cohen's kappa were used to assess inter-rater reliability. RESULTS: Thirteen textbooks from Doody's list contained 511 passages discussing medical differences among racial/ethnic groups. Among passages, 25% discussed white people, 22% Black people/African Americans, 19% Asians, 9% Latinos, 4% Jewish/Ashkenazi people, 3% Native Americans, and 18% other. Fifteen passages (2.9%) used language indicating race was the cause of medical difference, and only two explicitly discussed racism or discrimination. Most passages (370, 72.3%) received a scale of 0. 120 (23.5%) received a scale of 1, eight (1.2%) received a scale of 2, and zero received a scale of 3. The mean passage scale was 0.24 and is not changing with time (regression coefficient -0.006/year, p = 0.538). Agreement was 91.2% across all categories and overall Kappa was 0.62. CONCLUSIONS: General Surgery textbooks do not provide readers with scientifically thorough understanding of health disparities. Teaching more comprehensive conceptions, including systemic causes and the role of racism, may prevent reflexive association of minority patients with poor outcomes. Future editions should include these details where disparities are discussed in an independent, comprehensive section.

Optimizing in vitro phage-ciprofloxacin combination formulation for respiratory therapy of multi-drug resistant Pseudomonas aeruginosa infections.

Respiratory infection caused by multi-drug resistant (MDR) Pseudomonas aeruginosa is challenging to treat. In this study, we investigate the optimal dose of anti-pseudomonas phage PEV31 (103, 105, and 108 PFU/mL) combined with ciprofloxacin (ranging from 1/8× MIC to 8× MIC) to treat the MDR P. aeruginosa strain FADD1-PA001 using time-kill studies. We determined the impact of phage growth kinetics in the presence of ciprofloxacin through one-step growth analysis. Single treatments with either phage PEV31 or ciprofloxacin (except at 8× MIC) showed limited bactericidal efficiency, with bacterial regrowth observed at 48 h. The most effective treatments were PEV31 at multiplicity of infection (MOI) of 0.1 and 100 combined with ciprofloxacin at concentrations above 1× MIC, resulting in a >4 log10 reduction in bacterial counts. While the burst size of phage PEV31 was decreased with increasing ciprofloxacin concentration, robust antimicrobial effects were still maintained in the combination treatment. Aerosol samples collected from vibrating mesh nebulization of the combination formulation at phage MOI of 100 with 2× MIC effectively inhibited bacterial density. In summary, our combination treatments eradicated in vitro bacterial growth and sustained antimicrobial effects for 48 h. These results indicated the potential application of nebulization-based strategies for the combination treatment against MDR lung infections.

Spectrally Stable Deep-Blue Light-Emitting Diodes Based on Layer-Transferred Single-Crystalline Ruddlesden-Popper Halide Perovskites.

A novel approach to producing high-color-purity blue-light-emitting diodes based on single-crystalline Ruddlesden-Popper perovskites (RPPs) is reported. The utilization of a pure bromide composition eliminates any possibility of halide segregation, which can otherwise lead to undesired shifts in the emission wavelength or irreversible degradation of the spectral line width. Phase-pure PEA2MAPb2Br7 single crystals with a lateral size exceeding 1 cm2 can be synthesized using the inverse temperature crystallization method. To prepare RPP layers with a thickness of less than 50 nm, we employ a thinning process of the initially thick bulk crystals, followed by a dry-transfer process to place them onto a hole transport layer and an indium-tin-oxide-coated glass substrate. By utilizing polydimethylsiloxane as a handling layer, deformations of the bulk RPP crystal and exfoliated RPP layer, as well as the formation of defects such as pinholes, can be effectively suppressed. Subsequent depositions of an electron transport layer and a metal contact complete the fabrication of electroluminescence (EL) devices. The EL devices utilizing the single-crystalline RPP demonstrate excellent spectral stability across a broad range of the applied bias voltage spanning from 4.5 to 10 V, exhibiting a significantly narrow line width of 14 nm at an emission wavelength of 440 nm that can potentially cover 99.3% of the Rec. 2020 color gamut. The sharp EL emission spectrum can be effectively preserved, avoiding any broadening of the line width, by suppressing Joule heating throughout the device operation, in addition to the intrinsic stability of single-crystalline RPPs.