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Anthony C Oganov, Timothy Y Chou, Paris M Hanson, Azin Abazari, Preston Kung, Sarah B Weissbart, Jacqueline N Lenoci, Robert A Honkanen Department of Ophthalmology, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY, 11974, USACorrespondence: Timothy Y Chou, Department of Ophthalmology, Renaissance School of Medicine, Stony Brook University, HSC L2, Rm 152, Stony Brook, NY, 11974, USA, Tel +1 631444-1131, Fax +631444-4089, Email timothy.chou@stonybrookmedicine.eduPurpose: The aim of the research was to evaluate the use of teleophthalmology at a university practice during the COVID-19 pandemic, specifically examining precision, effectiveness, and patient satisfaction.Patients and Methods: Telemedicine visits were offered to new and established patients requesting appointments with the Stony Brook University Department of Ophthalmology between March 30 and June 2, 2020. Records from these visits were reviewed for chief complaint, past medical and ocular history, diagnoses, treatment/management, and providers’ sub-specialty. Precision was determined by comparing agreement between diagnoses of the telemedicine visit with those of the subsequent in-person visit. The decision to follow up in person was made by the physician and patient. Diagnostic precision as well as progression, improvement, or stability of patients’ symptoms were determined by the physician’s assessment at follow-up visits. Post-telemedicine visit satisfaction surveys were sent to all patients.Results: Telemedicine visits were offered to 783 patients, 520 (66.4%) of whom accepted. Of these 520 patients, 409 (78.7%) were established and 105 (20.2%) had in-person, follow-up visits. Overall, the diagnostic precision of the follow-up visits was 89.5%. Precision differed significantly across ophthalmologic subspecialties. Of the patients who had in-person follow-up visits, 56.8% remained stable, 32.4% improved, and 10.8% worsened. Established patients presented with more extensive ocular histories/procedures and experienced a higher percentage of worsening symptoms/disease stage compared to new patients. Oculoplastics/orbit was the most prevalent diagnostic subspecialty that worsened. Surveys were sent to all patients completing telemedicine visits, 15.0% of whom responded. Overall satisfaction was 91.9%, although only 23.0% of respondents preferred telemedicine to an in-office visit.Conclusion: Telehealth provides high levels of precision and patient satisfaction for a wide range of ophthalmologic visits, although most patients still prefer in-office examinations. Employing teleophthalmology for follow-up and emergency care may provide patients with an effective alternative during pandemic situations and beyond.Plain Language Summary: Telemedicine involves integration of modern telecommunications technology into medical practice. Over the years, it has demonstrated greater and more widespread utility for different medical specialties, including ophthalmology.As a response to the recent COVID-19 pandemic, the Stony Brook University Department of Ophthalmology provided an option of telemedicine for patients in lieu of in-person eye examinations. In this paper, Stony Brook ophthalmologists report on their experience with teleophthalmology, particularly regarding its utilization, accuracy, effectiveness, precision, and acceptability. The authors examined the records of 520 patients who had telemedicine encounters between March 30 and June 2, 2020. Precision was determined by comparing the initial and final diagnoses of all patients who had an in-person follow-up appointment following a telemedicine visit. Of 105 patients that followed up, precision was determined to be 89.5%. Precision was compared across ophthalmologic subspecialties and found to be statistically similar (p> 0.05). Approximately a third of patients improved, while nearly 11% worsened. Established and oculoplastics patients were more significantly likely to worsen. Surverys were sent out to study patients to gauge their satisfaction with their telemedicine experience. Although satisfaction was nearly 92%, only 23% of patients preferred telemedicine to an in-person physician encounter. The authors conclude that teleophthalmology provides a high level of diagnostic precision and patient satisfaction; nevertheless, most patients prefer in-person physician encounters. Telemedicine may provide an effective alternative to in-person ophthalmology assessments, especially during a pandemic. There appears to be a lesser but potentially useful role for teleophthalmology in a non-pandemic setting.Keywords: Teleophthalmology, teleglaucoma, teleretina, telehealth, coronavirus

Timothy Y Chou, Bennett Y Hong Department of Ophthalmology, Stony Brook University, Stony Brook, NY, USA Abstract: Eye disease due to herpes simplex virus (HSV) is a leading cause of ocular morbidity and the number one infectious cause of unilateral corneal blindness in the developed parts of the globe. Recurrent keratitis can result in progressive corneal scarring, thinning, and vascularization. Antiviral agents employed against HSV have primarily been nucleoside analogs. Early generation drugs included idoxuridine, iododesoxycytidine, vidarabine, and trifluridine. While effective, they tended to have low bioavailability and measurable local cellular toxicity due to their nonselective mode of action. Acyclovir 0.3% ointment is a more selective agent, and had become a first-line topical drug for acute HSV keratitis in Europe and other places outside of the US. Ganciclovir 0.15% gel is the most recently approved topical treatment for herpes keratitis. Compared to acyclovir 0.3% ointment, ganciclovir 0.15% gel has been shown to be better tolerated and no less effective in several Phase II and III trials. Additionally, topical ganciclovir does not cause adverse systemic side effects and is therapeutic at lower concentrations. Based on safety, efficacy, and tolerability, ganciclovir 0.15% gel should now be considered a front-line topical drug in the treatment of dendritic herpes simplex epithelial keratitis. Topics of future investigation regarding other potential uses for ganciclovir gel may include the prophylaxis of recurrent HSV epithelial keratitis, treatment of other forms of ocular disease caused by herpesviruses and adenovirus, and ganciclovir gel as an adjunct to antitumor therapy. Keywords: antiviral, herpes, Virgan, Zirgan, ganciclovir, keratitis, HSV

Timothy Y Chou1, Sujata P Prabhu21Department of Ophthalmology, State University of New York Stony Brook, Stony Brook, NY, 2Shiley Eye Center, University of California San Diego, La Jolla, CA, USAAbstract: We describe the clinical course and successful treatment of two cases of methicillin-resistant Staphylococcus aureus (MRSA) keratitis. In case 1, MRSA keratitis occurred 5 days after cataract extraction, associated with endophthalmitis; in case 2, diagnosis was made 19 months after penetrating keratoplasty. Treatment in both cases consisted of topical fortified vancomycin and fortified bacitracin. A third topical antibiotic, polymyxin B-trimethoprim, was added to the therapeutic regimen in case 2, one month into the treatment. Oral doxycycline was prescribed to reduce collagenase activity and treat blepharitis. Mupirocin nasal ointment and skin antiseptics were used to decrease and eliminate potential MRSA colonization. Topical prednisolone acetate 1% was applied conservatively to mitigate inflammation in both cases. In case 2, topical cyclosporine A was also used for similar purposes. Keratitis may have worsened while on these immune-modulating drops, especially in case 2, and eradication of infection may have been slowed. Eventually both patients achieved full resolution of infection. Duration of keratitis was 3 and 1.5 months, respectively. Polyantimicrobial therapy is effective in eradicating MRSA-related postoperative keratitis. Topical fortified vancomycin and fortified bacitracin were used in both cases, with a third topical antibiotic, polymyxin B-trimethoprim, also required in case 2. Oral doxycycline, nasal mupirocin, and antiseptic soap may be useful adjuncts in management. Treatment time to achieve full resolution may be prolonged relative to other types of bacterial keratitis. Alterations in immune status may have lengthened the time of treatment. Our two patients were immune compromised and were also susceptible to endophthalmitis. It is possible that topical immune-modulating drops such as prednisolone acetate may potentiate MRSA infection, and if used, should be only done so with great caution.Keywords: cornea, infection, methicillin-resistant Staphylococcus aureus, cataract, keratoplasty, endophthalmitis

RATIONALE: Acute respiratory distress syndrome (ARDS), a serious inflammatory reaction to acute lung injury, is associated with high mortality rates. Decoy receptor (DcR) 3 is a soluble protein with immunomodulatory effects. Biomarkers that reliably predict outcomes in ARDS are not currently available. OBJECTIVES: Comparing DcR3 with the Acute Physiology and Chronic Health Evaluation (APACHE) II scores and three other plasma markers to explore the association of DcR3 and the clinical outcome in ARDS. METHODS: Eighty-eight patients with ARDS were studied. Baseline APACHE II scores and clinical data were recorded. Plasma levels of DcR3, soluble triggering receptor expressed on myeloid cells (sTREM)-1, tumor necrosis factor (TNF)-alpha, and IL-6 were measured on Day 1 and later time points, and correlated with the survival status on Day 28 after the onset of ARDS. For validation, 59 patients with ARDS from another medical center were studied. MEASUREMENTS AND MAIN RESULTS: Among the biomarkers evaluated, only DcR3 discriminated the survivors and nonsurvivors at all time points in the first week of ARDS. DcR3 independently associated with and best predicted the 28-day mortality of patients with ARDS. Plasma DcR3 levels most correlated to multiple-organ dysfunction and ventilator dependence. Compared with survivors, the nonsurvivors had higher DcR3 levels regardless of the APACHE II scores. Kaplan-Meier survival analysis showed higher mortality in patients with ARDS with higher DcR3 levels. The outcome prediction of patients with ARDS by plasma DcR3 levels was recapitulated by the validation cohort. CONCLUSIONS: High plasma DcR3 levels correlate with development of multiple-organ dysfunction and independently predict the 28-day mortality in patients with ARDS. [ABSTRACT FROM AUTHOR]

This paper applies robust algorithms to control an active gait trainer for children with walking disabilities. Compared with traditional rehabilitation procedures, in which two or three trainers are required to assist the patient, a motor-driven mechanism was constructed to improve the efficiency of the procedures. First, a six-bar mechanism was designed and constructed to mimic the trajectory of children's ankles in walking. Second, system identification techniques were applied to obtain system transfer functions at different operating points by experiments. Third, robust control algorithms were used to design Hinfinity robust controllers for the system. Finally, the designed controllers were implemented to verify experimentally the system performance. From the results, the proposed robust control strategies are shown to be effective. [ABSTRACT FROM AUTHOR]

Ovarian clear cell carcinoma (OCCC) frequently develops resistance to platinum-based therapies, which is regarded as an aggressive subtype. However, metabolic changes in paclitaxel resistance remain unclear. Herein, we present the metabolic alternations of paclitaxel resistance in bioenergetic profiling in OCCC. Paclitaxel-resistant OCCC cells were developed and metabolically active with oxygen consumption rates (OCR) compared to parental cells. Metabolite profiling analysis revealed that paclitaxel-resistant OCCC cells reduced intracellular ATP and GTP influx rates, increasing the NADH/NAD+ ratio. We further demonstrated that paclitaxel-resistant OCCC cells led to characteristic alternations of metabolite levels in energy-requiring and energy-releasing steps of glycolysis and their corresponding glycolytic enzymes. Copy number alterations and RNA sequencing analysis demonstrated that ATP-binding cassette (ABC) transporters and solute carrier (SLC) transporter genes involved in glycolysis metabolism and molecular transport were enriched in paclitaxel-resistant OCCC cells. We first identified that Hexokinase 2 (HK2) expression is upregulated in paclitaxel-resistant OCCC cells to determine the quantity of glucose entering glycolysis. Utilizing proteolysis-targeting chimera (PROTAC) HK2 degraders, we also found that paclitaxel sensitivity, viability, and oxygen consumption rates under paclitaxel treatment were restored by HK2 degraders treatment, and decreased downstream expression of the ABC and SLC transporters was shown in OCCC cells. Taken together, these findings highlight the paclitaxel resistance in OCCC elucidates metabolic alternation, including ABC- and SLC- drug transporters, thereby affecting glycolysis metabolism in response to paclitaxel resistance, and HK2 may become a novel potential therapeutic target for paclitaxel resistance., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Lung cancer is the leading cause of cancer related deaths worldwide, although some patients with early-stage disease can be cured with surgical resection. Standardised reporting of all clinically relevant pathological parameters is essential for best patient care and is also important for ongoing data collection and refinement of important pathological features that impact patient prognosis, staging and clinical care. Using the established International Collaboration on Cancer Reporting (ICCR) procedure, a representative international expert panel of nine lung pathologists as well as an oncologist was convened. Essential core elements and suggested non-core elements were identified for inclusion in the resected lung cancer pathology data set based on predetermined levels of evidence as well as consensus expert opinion. A lung cancer histopathology reporting guide was developed that includes relevant clinical, macroscopic, microscopic and ancillary testing. Critical review and discussion of current evidence was incorporated into the new data set including changes from the 2021 World Health Organisation (WHO) Classification of Thoracic Tumours, fifth edition, new requirements for grading invasive non-mucinous adenocarcinomas, assessment of response to neoadjuvant therapy and requirements for molecular testing in early-stage resected lung carcinomas. This ICCR data set represents incorporation of all relevant parameters for histology reporting of lung cancer resection specimens. Routine use of this data set is recommended for all pathology reporting of resected lung cancer and it is freely available worldwide on the ICCR website (https://www.iccr-cancer.org/datasets/published-datasets/). Widespread implementation will help to ensure consistent and comprehensive pathology reporting and data collection essential for lung cancer patient care, clinical trials and other research., (© 2024 John Wiley & Sons Ltd.)

Introduction: Spread through air spaces (STAS) consists of lung cancer tumor cells that are identified beyond the edge of the main tumor in the surrounding alveolar parenchyma. It has been reported by meta-analyses to be an independent prognostic factor in the major histologic types of lung cancer, but its role in lung cancer staging is not established., Methods: To assess the clinical importance of STAS in lung cancer staging, we evaluated 4061 surgically resected pathologic stage I R0 NSCLC collected from around the world in the International Association for the Study of Lung Cancer database. We focused on whether STAS could be a useful additional histologic descriptor to supplement the existing ones of visceral pleural invasion (VPI) and lymphovascular invasion (LVI)., Results: STAS was found in 930 of 4061 of the pathologic stage I NSCLC (22.9%). Patients with tumors exhibiting STAS had a significantly worse recurrence-free and overall survival in both univariate and multivariable analyses involving cohorts consisting of all NSCLC, specific histologic types (adenocarcinoma and other NSCLC), and extent of resection (lobar and sublobar). Interestingly, STAS was independent of VPI in all of these analyses., Conclusions: These data support our recommendation to include STAS as a histologic descriptor for the Ninth Edition of the TNM Classification of Lung Cancer. Hopefully, gathering these data in the coming years will facilitate a thorough analysis to better understand the relative impact of STAS, LVI, and VPI on lung cancer staging for the Tenth Edition TNM Stage Classification., Competing Interests: Disclosure Dr. Donington reports receiving personal fees from Amgen, AstraZeneca, Bristol Myers Squibb, Merck & Co., Inc., and Genentech, Inc./F. Hoffmann-La Roche Ltd., outside the submitted work. Dr. Joubert reports grants from AstraZeneca, Roche, Merck and Biomark Signature Inc. and personal fees from AstraZeneca and Merck, outside the submitted work. Dr. Mino-Kenudson reports receiving personal fees from AstraZeneca, Pfizer, Repare, Sanofi, AbbVie, Daiichi Sankyo, Boehringer Ingelheim, and Elsevier, outside the submitted work. Dr. Nishimura reports receiving grants from IASLC, outside the submitted work. Dr. Nicholson reports receiving personal fees from Merck, Boehringer Ingelheim, Novartis, AstraZeneca, Bristol Myers Squibb, Roche, AbbVie, Oncologica, UpToDate, the European Society of Oncology, Liberum, Takeda UK, and Sanofi and grants and personal fees from Pfizer, outside the submitted work. Dr. Papotti reports receiving personal fees from Roche, Eli Lilly, AstraZeneca, and Pfizer, outside the submitted work. Dr. Ugalde Figueroa reports receiving personal fees from AstraZeneca, Bristol, Roche, Medtronic, and Johnson & Johnson, outside the submitted work. Dr. Van Schil reports receiving personal fees from AstraZeneca, Bristol Myers Squibb, Merck Sharp & Dohme, Roche, and Janssen, outside the submitted work; and serving as President of International Association for the Study of Lung Cancer and Treasurer of Belgian Association for Cardiothoracic Surgery. Dr. Yang reports being on advisory boards for AstraZeneca and Genentech. He has also received honorarium from AstraZeneca, outside the submitted work. Dr. Lievens reports financing from the EU ImmunoSABR project, personal fees from the UpLung project, Astra-Zeneca, outside the submitted work., (Copyright © 2024. Published by Elsevier Inc.)

Melanoma predominantly occurs in White individuals, which is associated with factors such as exposure to UV radiation and skin pigmentation. Despite its low incidence, melanoma is the primary cause of skin cancer-related death in Asia, typically in areas with low sun exposure. In our previous whole-exome sequencing study, we identified mutational signature 12 as the most prevalent variant in Asian patients, differing from the common UV-associated mutational signature 7 observed in White individuals. We also observed major differences between acral melanoma (AM) and nonacral melanoma (NAM) in terms of signatures 7, 21, and 22. Notably, few studies have investigated the genomic differences between AM and NAM in Asian individuals. Therefore, in this study, we conducted transcriptomic sequencing to examine the disparities in RNA expression between AM and NAM. Ribosomal RNA depletion was performed to enhance the detection of functionally relevant coding and noncoding transcripts. Ingenuity pathway analysis revealed significant differences in gene expression and regulatory pathways between AM and NAM. The results also indicate that the genes involved in cell cycle signaling or immune modulation and programmed cell death protein 1/programmed cell death 1 ligand 1 signaling were differentially expressed in NAM and AM. In addition, high CDK4 expression and cell cycle variability were observed in AM, with high immunogenicity in NAM. Overall, these findings provide further insights into the pathogenesis of melanoma and serve as a reference for future research on this major malignant disease., (© 2024 The Authors. The Journal of Dermatology published by John Wiley & Sons Australia, Ltd on behalf of Japanese Dermatological Association.)

In Taiwan, the use of radiocontrast medium for clinical image diagnosis recently surpassed one million times and the overall prevalence of radiocontrast hypersensitivity was ~7%. A microRNA (miRNA/miRs) is a small non-coding RNA molecule that mostly plays a suppressor role in cells. However, the roles of miRNA expression in radiocontrast-induced mast cells activation remains to be elucidated. The aim of the present study was to investigate the role of miRNA on radiocontrast-induced mast cell activation. Computed tomography radiocontrast, ultravist and mouse mast cell line, P815, were used in the present study. Cell viability was detected by CCK-8 experiment. Levels of histamine and β-hexosaminidase were measured by ELISA. miRNA expression was detected by miRNA sequencing and reverse transcription-quantitative PCR. The results showed that ultravist could increase histamine release and reduce intracellular β-hexosaminidase levels of mast cells. A total of 102 miRNAs could be significantly upregulated by ultravist stimulation. Selected candidate miRNAs for the validation included miR-19a-3p and miR-362-3p which were also increased expression following stimulation with ultravist. In conclusion, ultravist could induce mast cell activation through upregulation of miR-19a-3p and miR-362-3p. Thus, miR-19a-3p and miR-362-3p could be promising candidates for development as novel targets for preventing radiocontrast-induced allergy in the future., Competing Interests: The authors declare that they have no competing interests., (Copyright: © 2024 Chang et al.)

It is crucial to regulate N-methyl-D-aspartate (NMDA) function bivalently depending on the central nervous system (CNS) conditions. CNS disorders with NMDA hyperfunction are involved in the pathogenesis of neurotoxic and/or neurodegenerative disorders with elevated D-serine, one of the NMDA receptor co-agonists. On the contrary, NMDA-enhancing agents have been demonstrated to improve psychotic symptoms and cognition in CNS disorders with NMDA hypofunction. Serine racemase (SR), the enzyme regulating both D- and L-serine levels through both racemization (catalysis from L-serine to D-serine) and β-elimination (degradation of both D- and L-serine), emerges as a promising target for bidirectional regulation of NMDA function. In this study, we explored using dimethyl malonate (DMM), a pro-drug of the SR inhibitor malonate, to modulate NMDA activity in C57BL/6J male mice via intravenous administration. Unexpectedly, 400 mg/kg DMM significantly elevated, rather than decreased (as a racemization inhibitor), D-serine levels in the cerebral cortex and plasma. This outcome prompted us to investigate the regulatory effects of dodecagalloyl-α-D-xylose (α12G), a synthesized tannic acid analog, on SR activity. Our findings showed that α12G enhanced the racemization activity of human SR by about 8-fold. The simulated and fluorescent assay of binding affinity suggested a noncooperative binding close to the catalytic residues, Lys56 and Ser84. Moreover, α12G treatment can improve behaviors associated with major CNS disorders with NMDA hypofunction including hyperactivity, prepulse inhibition deficit, and memory impairment in animal models of positive symptoms and cognitive impairment of psychosis. In sum, our findings suggested α12G is a potential therapeutic for treating CNS disorders with NMDA hypofunction.

We investigated the effects of far-infrared radiation (FIR) lamp therapy on changes in muscle damage and performance parameters following six sets of 15-min Loughborough intermittent shuttle test (LIST), a simulated soccer match. Twenty-four elite female soccer players (20-24 y) were assigned into FIR or sham treatment group (n = 12/group). The participants received a 60-min FIR or sham treatment (30 min per muscle) over knee extensors (KE) and flexors (KF) at 2, 25, 49, 73, and 97 h post-LIST. Maximal voluntary isometric contraction (MVC) torque and muscle soreness of the KE and KF, plasma creatine kinase (CK) activity as muscle damage markers, and several performance parameters including countermovement jump (CMJ) and Yo-Yo intermittent recovery test level 1 (YYIR1) were measured before and 1, 24, 48, 72, 96, and 120 h post-LIST. Changes in the measures were compared between groups by a mixed-design two-way ANOVA. The running distance covered during LIST and changes in the measures at 1-h post-LIST (before the treatment) were similar (p = 0.118-0.371) between groups. Changes in muscle damage markers at 24-120 h post-LIST were smaller (p < 0.05, η 2  = 0.208-0.467) for the FIR (e.g., MVC-KE torque decrease at 48-h post-LIST: -1 ± 2%, peak KE soreness: 16 ± 10 mm, peak CK: 172 ± 42 IU/L) than sham group (-11 ± 9%, 33 ± 7 mm, 466 ± 220 IU/L, respectively). Performance parameters recovered faster (p < 0.05, η 2  = 0.142-0.308) to baseline for the FIR (e.g., decreases at 48-h post-LIST; CMJ: 0 ± 1%, YYIR1: 0 ± 1%) than sham group (-6 ± 2%, -9 ± 6%, respectively). These results suggest that the FIR lamp therapy was effective for enhancing recovery from a soccer match., (© 2024 The Authors. Scandinavian Journal of Medicine & Science In Sports published by John Wiley & Sons Ltd.)

Study Design: A systematic review and meta-analysis., Objective: To update the systematic review comparing the outcomes between surgical and non-surgical treatment for thoracolumbar burst fractures without neurological deficit., Methods: We registered a protocol in PROSPERO (ID: CRD42021291769) and searched Medline, Embase, Web of Science, and Google Scholar databases. Surgical and non-surgical treatments were compared in patients with thoracolumbar burst fractures without neurological deficits. Predefined outcomes at ≥6 months included pain (defined as a visual analog scale [VAS] of 0-100), functional outcomes (Oswestry Disability Index [ODI] of 0-50 and Roland-Morris Disability Questionnaire [RMDQ] of 0-24), and kyphotic angulation., Results: Nineteen studies involving 1056 patients were included in the analyses. For outcomes at ≥6 months, little to no difference was found in pain VAS score (mean difference, .95 [95% confidence interval {CI}, -6.02 to 7.92]; 827 participants; 15 studies; I 2 = 92%), ODI (mean difference, -1.40 [95% CI, -5.11 to 2.31]; 446 participants; 7 studies; I 2 = 79%), and RMDQ (mean difference, -.73 [95% CI, -5.13 to 3.66]; 216 participants; 5 studies; I 2 = 77%). The kyphotic angulation in the surgery group was 6.35° lower than that in the non-surgery group (mean difference, -6.56° [95% CI, -10.26° to -2.87°]; 527 participants; ten studies; I 2 = 86%). The trial sequential analysis indicated all outcomes reached adequate statistical power. The certainty of the evidence for all 4 outcomes was very low. For the analysis of minimally invasive procedures compared to traditional open surgeries, a statistically significant subgroup difference was found for VAS and ODI ( P < .01 and P < .04, respectively)., Conclusion: Surgical and non-surgical treatments showed little or no difference in outcomes at ≥6 months. This review provides a conclusion with adequate statistical power by including non-randomized studies. However, non-randomized studies also lowered the certainty of the evidence to a very low level., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Latent Low-Rank Representation (LatLRR) has emerged as a prominent approach for fusing visible and infrared images. In this approach, images are decomposed into three fundamental components: the base part, salient part, and sparse part. The aim is to blend the base and salient features to reconstruct images accurately. However, existing methods often focus more on combining the base and salient parts, neglecting the importance of the sparse component, whereas we advocate for the comprehensive inclusion of all three parts generated from LatLRR image decomposition into the image fusion process, a novel proposition introduced in this study. Moreover, the effective integration of Convolutional Neural Network (CNN) technology with LatLRR remains challenging, particularly after the inclusion of sparse parts. This study utilizes fusion strategies involving weighted average, summation, VGG19, and ResNet50 in various combinations to analyze the fusion performance following the introduction of sparse parts. The research findings show a significant enhancement in fusion performance achieved through the inclusion of sparse parts in the fusion process. The suggested fusion strategy involves employing deep learning techniques for fusing both base parts and sparse parts while utilizing a summation strategy for the fusion of salient parts. The findings improve the performance of LatLRR-based methods and offer valuable insights for enhancement, leading to advancements in the field of image fusion.

Among pediatric blood cancers, acute lymphoblastic leukemia (ALL) is the most common hematologic malignancy. Within ALL, T-cell acute lymphoblastic leukemia (T-ALL) accounts for 10 to 15% of all pediatric cases, and ~25% of adult cases. For T-ALL, its recurrence and relapse after treatment remain problematic. Therefore, it is necessary to develop new therapies for T-ALL. Recent studies suggested regulating energy metabolism is a novel approach to inhibit tumor growth, likely a promising treatment. Transketolase (TKT) is an important enzyme for modulating glucose metabolize in the pentose phosphate pathway (PPP). In this study, we treated T-ALL cells with different doses of niclosamide and primary T-ALL PBMCs were analyzed by RNA sequencing. T-ALL cells treated with niclosamide were analyzed with the Western blotting and TKT activity assay. Metabolism of T-ALL cells was evaluated by ATP assay and seahorse analyses. Lastly, we used a T-ALL xenograft murine model to determine effects of TKT knockdown on T-ALL tumor growth. Tumor samples were analyzed by H&E and IHC stainings. We found that niclosamide reduced T-ALL cell viability, and reduced expressions of TKT, Transketolase-Like Protein 1/2 (TKTL1/2) and transaldolase. In addition, niclosamide inhibited TKT enzyme activity, aerobic metabolism and glycolysis, finally leading to lower production of ATP. TKT knockdown inhibited tumor growth of xenograft T-ALL mice. Findings showed that niclosamide inhibits T-ALL cell growth by inhibiting TKT and energy metabolism., Competing Interests: None., (AJCR Copyright © 2024.)

Background: In Taiwan, lung cancers occur predominantly in never-smokers, of whom nearly 60% have stage IV disease at diagnosis. We aimed to assess the efficacy of low-dose CT (LDCT) screening among never-smokers, who had other risk factors for lung cancer., Methods: The Taiwan Lung Cancer Screening in Never-Smoker Trial (TALENT) was a nationwide, multicentre, prospective cohort study done at 17 tertiary medical centres in Taiwan. Eligible individuals had negative chest radiography, were aged 55-75 years, had never smoked or had smoked fewer than 10 pack-years and stopped smoking for more than 15 years (self-report), and had one of the following risk factors: a family history of lung cancer; passive smoke exposure; a history of pulmonary tuberculosis or chronic obstructive pulmonary disorders; a cooking index of 110 or higher; or cooking without using ventilation. Eligible participants underwent LDCT at baseline, then annually for 2 years, and then every 2 years up to 6 years thereafter, with follow-up assessments at each LDCT scan (ie, total follow-up of 8 years). A positive scan was defined as a solid or part-solid nodule larger than 6 mm in mean diameter or a pure ground-glass nodule larger than 5 mm in mean diameter. Lung cancer was diagnosed through invasive procedures, such as image-guided aspiration or biopsy or surgery. Here, we report the results of 1-year follow-up after LDCT screening at baseline. The primary outcome was lung cancer detection rate. The p value for detection rates was estimated by the χ 2 test. Univariate and multivariable logistic regression analyses were used to assess the association between lung cancer incidence and each risk factor. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of LDCT screening were also assessed. This study is registered with ClinicalTrials.gov, NCT02611570, and is ongoing., Findings: Between Dec 1, 2015, and July 31, 2019, 12 011 participants (8868 females) were enrolled, of whom 6009 had a family history of lung cancer. Among 12 011 LDCT scans done at baseline, 2094 (17·4%) were positive. Lung cancer was diagnosed in 318 (2·6%) of 12 011 participants (257 [2·1%] participants had invasive lung cancer and 61 [0·5%] had adenocarcinomas in situ). 317 of 318 participants had adenocarcinoma and 246 (77·4%) of 318 had stage I disease. The prevalence of invasive lung cancer was higher among participants with a family history of lung cancer (161 [2·7%] of 6009 participants) than in those without (96 [1·6%] of 6002 participants). In participants with a family history of lung cancer, the detection rate of invasive lung cancer increased significantly with age, whereas the detection rate of adenocarcinoma in situ remained stable. In multivariable analysis, female sex, a family history of lung cancer, and age older than 60 years were associated with an increased risk of lung cancer and invasive lung cancer; passive smoke exposure, cumulative exposure to cooking, cooking without ventilation, and a previous history of chronic lung diseases were not associated with lung cancer, even after stratification by family history of lung cancer. In participants with a family history of lung cancer, the higher the number of first-degree relatives affected, the higher the risk of lung cancer; participants whose mother or sibling had lung cancer were also at an increased risk. A positive LDCT scan had 92·1% sensitivity, 84·6% specificity, a PPV of 14·0%, and a NPV of 99·7% for lung cancer diagnosis., Interpretation: TALENT had a high invasive lung cancer detection rate at 1 year after baseline LDCT scan. Overdiagnosis could have occurred, especially in participants diagnosed with adenocarcinoma in situ. In individuals who do not smoke, our findings suggest that a family history of lung cancer among first-degree relatives significantly increases the risk of lung cancer as well as the rate of invasive lung cancer with increasing age. Further research on risk factors for lung cancer in this population is needed, particularly for those without a family history of lung cancer., Funding: Ministry of Health and Welfare of Taiwan., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Objectives: Molecular subtyping of small cell lung cancer (SCLC) tumors based on the expression of four transcription factors (ASCL1, NEUROD1, POU2F3, and YAP1) using immunohistochemical (IHC) staining has recently emerged as a proposed approach. This study was aimed to examine this subtyping method in Asian patients with SCLC and investigate its correlation with treatment efficacy., Materials and Methods: Seventy-two tumor samples from patients with SCLC, including de novo cases and those transformed from EGFR-mutant tumors, were analyzed. IHC staining was used to measure the expression of the four transcription factors and conventional SCLC markers. Subtypes were defined based on relative expression levels. The treatment response and outcome of patients receiving immune checkpoint inhibitors and chemotherapy were also reviewed., Results: ASCL1 was the most common subtype, observed in 55.2 % of the samples, followed by NEUROD1 (26.9 %) and POU2F3 (9 %). No tumor exhibited predominant YAP1 positivity, while 41.8 % of the samples demonstrated positivity for two subtype markers. Approximately 50 % of the patients experienced a subtype switch after disease progression. Patients with the ASCL1/NEUROD1 (SCLC-A/N) subtype had similar progression-free survival (PFS) compared to non-SCLC-A/N patients after treatment with immune checkpoint inhibitors plus chemotherapy. Transformed SCLC patients had significantly worse PFS than de novo SCLC patients after chemoimmunotherapy. (2.1 vs. 5.4 months, P = 0.023) CONCLUSIONS: This study revealed the challenges associated with using IHC alone for molecular subtyping, highlighting the frequent co-expression of subtypes and temporal changes following treatment. Further research is warranted to explore the prognostic and therapeutic implications of IHC subtyping in patients with SCLC., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Introduction: Morphologic and molecular data for staging of multifocal lung squamous cell carcinomas (LSCCs) are limited. In this study, whole exome sequencing (WES) was used as the gold standard to determine whether multifocal LSCC represented separate primary lung cancers (SPLCs) or intrapulmonary metastases (IPMs). Genomic profiles were compared with the comprehensive morphologic assessment., Methods: WES was performed on 20 tumor pairs of multifocal LSCC and matched normal lymph nodes using the Illumina NovaSeq6000 S4-Xp (Illumina, San Diego, CA). WES clonal and subclonal analysis data were compared with histologic assessment by 16 thoracic pathologists. In addition, the immune gene profiling of the study cases was characterized by the HTG EdgeSeq Precision Immuno-Oncology Panel., Results: By WES data, 11 cases were classified as SPLC and seven cases as IPM. Two cases were technically suboptimal. Analysis revealed marked genomic and immunogenic heterogeneity, but immune gene expression profiles highly correlated with mutation profiles. Tumors classified as IPM have a large number of shared mutations (ranging from 33.5% to 80.7%). The agreement between individual morphologic assessments for each case and WES was 58.3%. One case was unanimously interpreted morphologically as IPM and was in agreement with WES. In a further 17 cases, the number of pathologists whose morphologic interpretation was in agreement with WES ranged from two (one case) to 15 pathologists (one case) per case. Pathologists showed a fair interobserver agreement in the morphologic staging of multiple LSCCs, with an overall kappa of 0.232., Conclusions: Staging of multifocal LSCC based on morphologic assessment is unreliable. Comprehensive genomic analyses should be adopted for the staging of multifocal LSCC., (Copyright © 2023 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

The present study compared four different intervals between three simulated soccer matches for changes in muscle damage and performance parameters. Thirteen well-trained female university soccer players performed three bouts of 90-min Loughborough Intermittent Shuttle Test (LIST) with four different intervals between bouts; one (1d), two (2d), three (3d) and four days (4d), with >12-weeks between conditions in a counterbalanced order. Heart rate, blood lactate, rating of perceived exertion and distance covered in each LIST were measured. Changes in several muscle damage markers (e.g., maximal voluntary isometric torque of the knee extensors: MVC-KE, muscle soreness), performance parameters (e.g., Yo-Yo intermittent recovery test level 1: Yo-Yo IR1), and blood measures (e.g., osmolality, high sensitivity cardiac troponin T) before the first LIST, 1 h after each LIST, and one to five days after the third LIST were compared among the conditions. The total distance covered during the first two LISTs was not different among the conditions, but that during the third LIST was shorter (P < 0.05) for the 1d (9,416 ± 885 m) and 2d conditions (9,737 ± 246 m) than the 3d (10,052 ± 490 m) and 4d conditions (10,432 ± 538 m). Changes in all measures were smaller (P < 0.05) in the 3d and 4d conditions (e.g., the decrease in MVC-KE at one day after the third LIST was -13 ± 4% and -10 ± 3%, respectively) when compared with the 1d and 2d conditions (-20 ± 7%, -18 ± 5%). Performance parameters showed smaller (P < 0.05) changes in the 4d (e.g., the decrease in Yo-Yo IR1 at one day after the third LIST was -9 ± 3%) and 3d (-13 ± 6%) conditions when compared with the 1d (-19 ± 4%) and 2d (-20 ± 8%) conditions. These results suggest that muscle damage and fatigue accumulate when soccer matches are performed three consecutive days or every other day, but if more than three days are inserted between matches, this could be minimized., (© Journal of Sports Science and Medicine.)

Objective: To determine whether individuals with a prior concussion exhibit biomechanical alterations in balance, gait and jump-landing tasks with and without cognitive demands that are associated with risk of lateral ankle sprain (LAS) and anterior cruciate ligament (ACL) injury., Design: Systematic review and meta-analysis., Data Sources: Five electronic databases (Web of Science, Scopus, PubMed, SPORTDiscus and CiNAHL) were searched in April 2023., Eligibility Criteria: Included studies involved (1) concussed participants, (2) outcome measures of spatiotemporal, kinematic or kinetic data and (3) a comparison or the data necessary to compare biomechanical variables between individuals with and without concussion history or before and after a concussion., Results: Twenty-seven studies were included involving 1544 participants (concussion group (n=757); non-concussion group (n=787)). Individuals with a recent concussion history (within 2 months) had decreased postural stability (g=0.34, 95% CI 0.20 to 0.49, p<0.001) and slower locomotion-related performance (g=0.26, 95% CI 0.11 to 0.41, p<0.001), both of which are associated with LAS injury risk. Furthermore, alterations in frontal plane kinetics (g=0.41, 95% CI 0.03 to 0.79, p=0.033) and sagittal plane kinematics (g=0.30, 95% CI 0.11 to 0.50, p=0.002) were observed in individuals approximately 2 years following concussion, both of which are associated with ACL injury risk. The moderator analyses indicated cognitive demands (ie, working memory, inhibitory control tasks) affected frontal plane kinematics (p=0.009), but not sagittal plane kinematics and locomotion-related performance, between the concussion and non-concussion groups., Conclusion: Following a recent concussion, individuals display decreased postural stability and slower locomotion-related performance, both of which are associated with LAS injury risk. Moreover, individuals within 2 years following a concussion also adopt a more erect landing posture with greater knee internal adduction moment, both of which are associated with ACL injury risk. While adding cognitive demands to jump-landing tasks affected frontal plane kinematics during landing, the altered movement patterns in locomotion and sagittal plane kinematics postconcussion persisted regardless of additional cognitive demands., Prospero Registration Number: CRD42021248916., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

The present study compared the ipsilateral repeated bout effect (IL-RBE) and contralateral repeated bout effect (CL-RBE) of the elbow flexors (EF) and knee flexors (KF) for the same interval between bouts to shed light on their mechanisms. Fifty-two healthy sedentary young (20-28 years) men were randomly assigned to the IL-EF, IL-KF, CL-EF, and CL-KF groups (n = 13/group). Thirty maximal eccentric contractions of the EF were performed in IL-EF and CL-EF, and 60 maximal eccentric contractions of the KF were performed in IL-KF and CL-KF, with a 2-week interval between bouts. Changes in muscle damage markers such as maximal voluntary contraction (MVC) torque, muscle soreness, and plasma creatine kinase activity, and proprioception measures before to 5 days post-exercise were compared between groups. Changes in all variables were greater (p < 0.05) after the first than second bout for all groups, and the changes were greater (p < 0.05) for the EF than KF. The changes in all variables after the second bout were greater (p < 0.05) for the CL than IL condition for both EF and KF. The magnitude of the average protective effect was similar between CL-EF (33%) and CL-KF (32%), but slightly greater (p < 0.05) for IL-EF (67%) than IL-KF (61%). These demonstrate that the magnitude of CL-RBE relative to IL-RBE was similar between the EF and KF (approximately 50%), regardless of the greater muscle damage for the EF than KF. It appears that the CL-RBE is more associated with neural adaptations at cerebrum, cerebellum, interhemispheric inhibition, and coricospinal tract, but the IL-RBE is induced by additional adaptations at muscles., (© 2023 The Authors. Scandinavian Journal of Medicine & Science In Sports published by John Wiley & Sons Ltd.)

Introduction: Pathologic response has been proposed as an early clinical trial end point of survival after neoadjuvant treatment in clinical trials of NSCLC. The International Association for the Study of Lung Cancer (IASLC) published recommendations for pathologic evaluation of resected lung cancers after neoadjuvant therapy. The aim of this study was to assess pathologic response interobserver reproducibility using IASLC criteria., Methods: An international panel of 11 pulmonary pathologists reviewed hematoxylin and eosin-stained slides from the lung tumors of resected NSCLC from 84 patients who received neoadjuvant immune checkpoint inhibitors in six clinical trials. Pathologic response was assessed for percent viable tumor, necrosis, and stroma. For each slide, tumor bed area was measured microscopically, and pre-embedded formulas calculated unweighted and weighted major pathologic response (MPR) averages to reflect variable tumor bed proportion., Results: Unanimous agreement among pathologists for MPR was observed in 68 patients (81%), and inter-rater agreement (IRA) was 0.84 (95% confidence interval [CI]: 0.76-0.92) and 0.86 (95% CI: 0.79-0.93) for unweighted and weighted averages, respectively. Overall, unweighted and weighted methods did not reveal significant differences in the classification of MPR. The highest concordance by both methods was observed for cases with more than 95% viable tumor (IRA = 0.98, 95% CI: 0.96-1) and 0% viable tumor (IRA = 0.94, 95% CI: 0.89-0.98). The most common reasons for discrepancies included interpretations of tumor bed, presence of prominent stromal inflammation, distinction between reactive and neoplastic pneumocytes, and assessment of invasive mucinous adenocarcinoma., Conclusions: Our study revealed excellent reliability in cases with no residual viable tumor and good reliability for MPR with the IASLC recommended less than or equal to 10% cutoff for viable tumor after neoadjuvant therapy., (Copyright © 2023. Published by Elsevier Inc.)

Novel therapeutics have significantly improved the survival and quality of life of patients with malignancies in this century. Versatile precision diagnostic data were used to formulate personalized therapeutic strategies for patients. However, the cost of extensive information depends on the consumption of the specimen, raising the challenges of effective specimen utilization, particularly in small biopsies. In this study, we proposed a tissue-processing cascaded protocol that obtains 3-dimensional (3D) protein expression spatial distribution and mutation analysis from an identical specimen. In order to reuse the thick section tissue evaluated after the 3D pathology technique, we designed a novel high-flatness agarose-embedded method that could improve tissue utilization rate by 1.52 fold, whereas it reduced the tissue-processing time by 80% compared with the traditional paraffin-embedding method. In animal studies, we demonstrated that the protocol would not affect the results of DNA mutation analysis. Furthermore, we explored the utility of this approach in non-small cell lung cancer because it is a compelling application for this innovation. We used 35 cases including 7 cases of biopsy specimens of non-small cell lung cancer to simulate future clinical application. The cascaded protocol consumed 150-μm thickness of formalin-fixed, paraffin-embedded specimens, providing 3D histologic and immunohistochemical information approximately 38 times that of the current paraffin-embedding protocol, and 3 rounds of DNA mutation analysis, offering both essential guidance for routine diagnostic evaluation and advanced information for precision medicine. Our designed integrated workflow provides an alternative way for pathological examination and paves the way for multidimensional tumor tissue assessment., (Copyright © 2023 United States & Canadian Academy of Pathology. Published by Elsevier Inc. All rights reserved.)

Psoriasis is a chronic autoimmune skin disease with a significant impact on quality of life and potential for severe comorbidities. Inflammation in the skin is induced by immune cells that overexpress pro-inflammatory cytokines, with the Th17 cell playing a crucial role. NLRP3 inflammasome activation is associated with inflammatory diseases and abnormal T cell differentiation. 3H-1,2-dithiole-3-thione (D3T), isolated from cruciferous vegetables, has anti-inflammatory effects and inhibits Th17 differentiation. This study aimed to investigate how D3T reduces skin inflammation and modulates Th17 cell differentiation by inhibiting NLRP3 inflammasome activation. In an imiquimod-induced psoriasis mouse model, D3T treatment demonstrated significant reductions in ear thickness, skin redness, and scaling compared to a control group. Our study also observed decreased expression of ki-67, NLRP3 inflammasome, and cleaved caspase-1 in skin samples, reduced levels of IL-6 and IL-17A in serum samples, and inhibition of Th17 differentiation after D3T application. D3T could also inhibit the expression of NLRP3, caspase-1, and IL-1β in TNF-α stimulated HaCaT cells. The mechanical study also revealed that D3T could inhibit NLRP3 inflammasome activation by inhibiting the JNK pathway in HaCaT cells. These results indicate that targeting NLRP3 inflammasome activation is a promising strategy in the treatment of psoriasis.

The present study investigated the effects of a far-infrared radiation (FIR) lamp therapy on changes in muscle damage and proprioception markers after maximal eccentric exercise of the elbow flexors (EF: Study 1) and the knee flexors (KF: Study 2) in comparison to a sham treatment condition. In each study, 24 healthy sedentary women were assigned to a FIR or a sham treatment group ( n  = 12/group). They performed 72 maximal EF eccentric contractions (Study 1) or 100 maximal KF eccentric contractions (Study 2) with their non-dominant limbs. They received a 30-min FIR (wavelength: 8-14 µm) or sham treatment at 1, 25, 49, 73 and 97 h post-exercise to the exercised muscles. Maximum voluntary isometric contraction (MVC) torque, muscle soreness, plasma creatine kinase activity, and proprioception assessed by position sense, joint reaction angle, and force match were measured before, and 0.5, 24, 48, 72, 96 and 120 h post-exercise. The outcome measures showed significant changes ( P  < 0.05) at 0.5-hour post-exercise (before treatment) similarly ( P  > 0.05) between the conditions in both studies. However, changes in all measures at 24-120 h post-exercise were smaller ( P  < 0.05) for the FIR than sham condition in both studies. For example, MVC torque returned to the baseline by 72 h post-exercise for the FIR condition in both studies, but was still 19 ± 6% (Study 1) or 17 ± 12% (Study 2) lower than the baseline at 120 h post-exercise for the sham condition. These results suggested that the FIR lamp therapy was effective for accelerating recovery from muscle damage.

The mindfulness-based intervention and psychological skills training are often used for maintaining the mental health or reducing undesirable mental states in athletes. However, their differences in acute effects on mental health and underlying neural mechanism are not well understood. Therefore, the purpose of the current study was to examine the differential effects of brief mindfulness induction (MI) and relaxation induction (RI) on state anxiety, affect and brain activation. Thirty-five track and field athletes were recruited for this study. Using a within-subjects crossover design, participants underwent three conditions that incorporated two 30-min experimental conditions (i.e., MI or RI) and a control condition. State anxiety and affect were assessed before and after intervention, and brain activation (i.e., theta, alpha bands) were recorded by electroencephalography (EEG) during each 30-min condition. Repeated measures analysis of variance revealed that MI and RI similarly reduced state anxiety and negative affect from pre-test to post-test compared to the control condition. In terms of positive affect, there were no significant differences among the three conditions across times. Furthermore, participants exhibited higher frontal theta power during the MI and RI than control condition, whereas no differences in alpha power were observed among conditions. The current study provides initial evidence from an electrophysiological perspective that brief MI and RI both improve the negative psychological states in individual sport athletes through similar neural mechanisms. Nevertheless, the moderating effects of training experiences and long-term interventions on mental state and EEG activity in athletes need further investigation in future studies., Competing Interests: Declaration of competing interest Given their roles as an Editorial Board Members, Hung T.-M. and Chang Y.-K. had no involvement in the peer-review of this article and had no access to information regarding its peer-review. All other authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Ltd.)

Background: Cell-free tumor DNA (ctDNA) obtained through liquid biopsy is useful for the molecular analysis of advanced non-small-cell lung cancer (NSCLC). Few studies have directly compared analysis platforms in terms of their diagnostic performance in analyzing ctDNA obtained from the cerebrospinal fluid (CSF) of patients with leptomeningeal metastasis (LM)., Methods: We prospectively analyzed patients with epidermal growth factor receptor (EGFR)-mutant NSCLC who were subjected to CSF analysis for suspected LM. To detect EGFR mutations, CSF ctDNA was analyzed using the cobas EGFR Mutation Test and droplet digital polymerase chain reaction (ddPCR). CSF samples from osimertinib-refractory patients with LM were also subjected to next-generation sequencing (NGS)., Results: Significantly higher rates of valid results (95.1% vs. 78%, respectively, p = 0.04) and EGFR common mutation detection (94.3% vs. 77.1%, respectively, p = 0.047) were obtained through ddPCR than through the cobas EGFR Mutation Test. The sensitivities of ddPCR and cobas were 94.3% and 75.6%, respectively. The concordance rate for EGFR mutation detection through ddPCR and the cobas EGFR Mutation Test was 75.6% and that for EGFR mutation detection in CSF and plasma ctDNA was 28.1%. In osimertinib-resistant CSF samples, all original EGFR mutations were detected through NGS. MET amplification and CCDC6-RET fusion were demonstrated in one patient each (9.1%)., Conclusions: The cobas EGFR Mutation Test, ddPCR, and NGS appear to be feasible methods for analyzing CSF ctDNA in patients with NSCLC and LM. In addition, NGS may provide comprehensive information regarding the mechanisms underlying osimertinib resistance., (© 2023 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

The present study investigated the effects of a 3-week immobilization (IM) on muscle damage induced by maximal eccentric exercise (MaxEC) to test the hypothesis that the IM would make muscles prone to muscle damage. Young healthy sedentary men were pseudo-randomly assigned to IM or control group (n = 12/group). Non-dominant arms of the IM group participants were immobilized at 90° elbow flexion by a cast for 21 days. All participants performed MaxEC consisting of five sets of six elbow flexor contractions by lowering a dumbbell set at 100% of pre-exercise maximal voluntary isometric contraction (MVC) strength of the non-dominant arm. This was performed at 2 days after the cast removal for the IM group. MVC torque, range of motion (ROM), muscle thickness (MT), muscle hardness, position sense (PS), and joint reaction angle (JRA) of the elbow flexors were measured at baseline, post-immobilization, and before, immediately after, and one to 5 days after MaxEC. The IM decreased MVC torque (-17 ± 2%), ROM (-2 ± 1%), MT (-7 ± 3%), and JRA (-12 ± 6%), and increased in muscle hardness (20 ± 6%) and PS (11 ± 2%) (p < 0.05). Changes in MVC (e.g., 2 days: -40 ± 5 vs. -30 ± 9%), ROM (2 days: -11 ± 2 vs. -9 ± 3%), muscle soreness (peak: 63 ± 22 vs. 48 ± 14 mm), plasma CK activity (peak: 7820 ± 4011 vs. 4980 ± 1363 IU/L), PS (maximal change: -23 ± 2 vs. -18 ± 3%), and JRA (maximal change: -37 ± 4 vs. -26 ± 3%) after MaxEC were greater (p < 0.05) for the IM than control group. These results supported the hypothesis and showed that the IM made the muscles more vulnerable to muscle damage induced by eccentric exercise., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Introduction: Circulating tumor cells (CTCs) and their proliferative ability in lung adenocarcinoma (LUAD) were not well-investigated. We developed a protocol combining an efficient viable CTC isolation and in-vitro cultivation for the CTC enumeration and proliferation to evaluate their clinical significance., Method: The peripheral blood of 124 treatment-naïve LUAD patients were processed by a CTC isolation microfluidics, DS platform, followed by in-vitro cultivation. LUAD-specific CTCs were defined by immunostaining of DAPI+/CD45-/(TTF1/CK7)+ and were enumerated upon isolation and after 7-day cultivation. The CTC proliferative ability was evaluated by both the cultured number and the culture index, a ratio of cultured CTC number to the initial CTC number in 2 mL of blood., Result: All but two LUAD patients (98.4%) were detected with at least one CTC per 2 mL of blood. Initial CTC numbers did not correlate with metastasis (75 ± 126 for non-metastatic, 87 ± 113 for metastatic groups; P = 0.203). In contrast, both the cultured CTC number (mean: 28, 104, and 185 in stage 0/I, II/III, and IV; P < 0.001), and the culture index (mean: 1.1, 1.7 and 9.3 in stage 0/I, II/III, and IV; P = 0.043) were significantly correlated with the stages. Overall survival analysis within the non-metastatic group (N = 53) showed poor prognosis for patients with elevated cultured counts (cutoff ≥ 30; P = 0.027)., Conclusion: We implemented a CTC assay in clinical LUAD patients with a high detection rate and cultivation capability. Cultured CTC count and proliferative ability, rather than the crude CTC numbers, highly associated with cancer prognosis., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Viral bronchiolitis presents a heterogeneous spectrum. In this study, we investigated the clinical characteristics and the cytokines/chemokines profiles among respiratory syncytial virus (RSV), rhinovirus (RV), and their dual infection in Taiwanese children with viral bronchiolitis., Method: This study was conducted between October 2014 and June 2017. Viral etiology was identified using a Luminex respiratory virus panel and blood cytokines were evaluated using a MILLIPLEX MAP Human Cytokine/Chemokine Panel. Cytokine/Chemokine expressions were compared by clinical severity, steroid treatment, and viral entities., Results: A total of 184 patients were evaluated; at least one respiratory virus was identified in 163 (88.6%) patients. RSV and RV were the two leading viral etiologies, with 25.5% and 17.3%, respectively. RV bronchiolitis has a comparable severity to RSV but is more common in children of an older age with a history of recurrent wheezing and blood eosinophilia. Decreased tumor necrosis factor-alpha (TNF-α) and interferon gamma (INF-γ) levels were correlated with clinical severity. Patients infected with RV exhibited higher levels of Interleukin (IL)-22, IL-23, IL-25, IL-31, and IL-33 (p < 0.05), whereas those with RSV had higher levels of TNF-α, INF-γ, and IL-10 (p < 0.05). Systemic steroid treatment was associated with higher expressions of IL-4, IL-8, IL-13, and MIP-1α levels (p < 0.05). Cluster analysis revealed a high correlation of IL-33 and IL-31(R 2  = 0.9731, p < 0.0001)., Conclusion: Different viral infections elicited the characteristic clinical presentation and immune profiles in bronchiolitis. Our findings also highlight the role of the IL-33/IL-31 axis in the immunopathogenesis of bronchiolitis., (Copyright © 2022. Published by Elsevier B.V.)

Introduction: Since the eight edition of the Union for International Cancer Control and American Joint Committee on Cancer TNM classification system, the primary tumor pT stage is determined on the basis of presence and size of the invasive components. The aim of this study was to identify histologic features in tumors with lepidic growth pattern which may be used to establish criteria for distinguishing invasive from noninvasive areas., Methods: A Delphi approach was used with two rounds of blinded anonymized analysis of resected nonmucinous lung adenocarcinoma cases with presumed invasive and noninvasive components, followed by one round of reviewer de-anonymized and unblinded review of cases with known outcomes. A digital pathology platform was used for measuring total tumor size and invasive tumor size., Results: The mean coefficient of variation for measuring total tumor size and tumor invasive size was 6.9% (range: 1.7%-22.3%) and 54% (range: 14.7%-155%), respectively, with substantial variations in interpretation of the size and location of invasion among pathologists. Following the presentation of the results and further discussion among members at large of the International Association for the Study of Lung Cancer Pathology Committee, extensive epithelial proliferation (EEP) in areas of collapsed lepidic growth pattern is recognized as a feature likely to be associated with invasive growth. The EEP is characterized by multilayered luminal epithelial cell growth, usually with high-grade cytologic features in several alveolar spaces., Conclusions: Collapsed alveoli and transition zones with EEP were identified by the Delphi process as morphologic features that were a source of interobserver variability. Definition criteria for collapse and EEP are proposed to improve reproducibility of invasion measurement., (Copyright © 2022 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

As Taiwan heads steadily toward becoming a super-aged society, the impact of aging on society at large will become increasingly extensive and intense. Therefore, establishing an age-friendly environment in Taiwan is an important issue for the government. Feasible guidelines for age-friendly communities are necessary to ensure that appropriate social welfare measures are enacted to achieve the national goal of aging in place. The first draft of the guideline questionnaire was developed based on the World Health Organization Guidelines for Age-Friendly Cities, a literature review, and input from seven experts on aging. Three rounds of questionnaire surveys were then conducted to assess the correctness, appropriateness, and importance of the guidelines, with amendments, additions, and deletions made based on the experts' responses until they all expressed a high degree of satisfaction with all of the guidelines. The Taiwan Age-friendly Community Guidelines document discussed in this article includes 38 guidelines that address the eight facets of "outdoor spaces and buildings", "transportation", "housing", "social participation", "respect and social inclusion", "civil participation and employment", "communication and information", and "community support and health services". The guidelines document describes in detail the goals of age-friendly communities in specific and easy-to-understand terms. Moreover, it provides a reference for frontline personnel in the community to promote age-friendly environs.

Introduction: Anaplastic lymphoma kinase (ALK) fusion mutation is more common in younger and never-smoking lung cancer patients. The association of smoking and ALK-tyrosine kinase inhibitors (TKIs) on overall survival (OS) of treatment-naïve ALK-positive advanced lung adenocarcinoma remains unclear in real-world., Methods: This retrospective study evaluated all 33170 lung adenocarcinoma patients registered in the National Taiwan Cancer Registry from 2017 to 2019, of whom 9575 advanced stage patients had ALK mutation data., Results: Among the 9575 patients, 650 (6.8%) patients had ALK mutation with the median follow-up survival time 30.97 months (median age, 62 years; 125 [19.2%] were aged ≥75 years; 357 (54.9%) females; 179 (27.5) smokers, 461 (70.9%) never-smokers, 10 (1.5%) with unknown smoking status; and 544 (83.7%) with first-line ALK-TKI treatment). Overall, of 535 patients with known smoking status who received first-line ALK-TKI treatment, never-smokers and smokers had a median OS of 40.7 months (95% confidence interval (CI), 33.1-47.2 months) and 23.5 months (95% CI, 11.5-35.5 months) (P=0.015), respectively. Among never-smokers, those who received first-line ALK-TKI treatment had a median OS of 40.7 months (95% CI, 22.7-57.8 months), while those ALK-TKI not as first-line treatment had a median OS of 31.7 months (95% CI, 15.2-42.8 months) (P=0.23). In smokers, the median OS for these patients was 23.5 months (95% CI, 11.5-35.5 months) and 15.6 months (95% CI, 10.2-21.1 months) (P=0.026), respectively., Conclusions and Relevance: For patients with treatment-naïve advanced lung adenocarcinoma, the ALK test should be performed irrespective of smoking status and age. Smokers had shorter median OS than never-smokers among treatment-naïve-ALK-positive patients with first-line ALK-TKI treatment. Furthermore, smokers not receiving first-line ALK-TKI treatment had inferior OS. Further investigations for the first-line treatment of ALK-positive smoking advanced lung adenocarcinoma patients are needed., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Zheng, Ku, Chen, Chiang, Wang, Chen, Tsai, Huang, Yu, Chen, Chou, Lee, Wang, Liu, Hsia and Chang.)

In recent years, the concept of health has gradually fit into people's lives through the government's promotion. The indoor sports complex is becoming more and more popular, offering people the opportunity to engage in physical and recreational activities regardless of weather conditions. Psychological and social abundance is the key to improving happiness, and the most important thing is to treat and care for yourself. Many fitness venues have emerged to provide athletes with a wide range of choices. However, the advent of the COVID-19 pandemic, which is caused by a virus mainly transmitted through direct contact or air droplets, has had a severe impact on indoor gym users. Therefore, based on the Theory of Planned Behavior (TPB) and Health-Promoting Lifestyle (HPL), this research investigated athletes' behavioral intentions regarding sports halls and perceived risks as interfering variables. For data collection, we collected data samples from sports complexes athletes in Taiwan. A total of 263 responses were analyzed via SPSS 20.0 (IBM Corporation, New York, NY, USA) and AMOS 20.0 (IBM Corporation, New York, NY, USA) seis tests. The study's results indicate that health-promoting lifestyle cognition has a positive and significant effect on behavioral intention; athletes' attitudes, subjective norms, and perceived behavioral control significantly affects the behavioral intention of using the facilities in a sports complex. Athletes' risk perceptions have an interference effect between HPL, attitude, subjective norm, perceived behavioral control, and behavioral intentions of using the facilities in a sports complex. Sports venue managers can refer to the results of this project to develop marketing strategies and promoting.

The distinction between different separate primary lung cancers (SPLCs) and intrapulmonary metastases (IPMs) is a challenging but clinically significant issue. Histopathology-based classification is the current practice; however, it is subjective and affected by interobserver variability. Recently, next-generation sequencing (NGS) panels have been used in lung cancer diagnostics. This study aimed to investigate the value of large-scale NGS panels for distinguishing between SPLCs and IPMs. A total of 32 patients with 69 lung adenocarcinomas were included. Comprehensive histopathologic assessments of multiple pulmonary adenocarcinomas were performed independently by 3 pathologists. The consensus of histopathologic classification was determined by a majority vote. Genomic analysis was performed using an amplicon-based large-scale NGS panel, targeting single-nucleotide variants and short insertions and deletions in 409 genes. Tumor pairs were classified as SPLCs or IPMs according to a predefined molecular classification algorithm. Using NGS and our molecular classification algorithm, 97.6% of the tumor pairs can be unambiguously classified as SPLCs or IPMs. The molecular classification was predictive of postoperative clinical outcomes in terms of overall survival (P = .015) and recurrence-free interval (P = .0012). There was a moderate interobserver agreement regarding histopathologic classification (κ = 0.524 at the tumor pair level). The concordance between histopathologic and molecular classification was 100% in cases where pathologists reached a complete agreement but only 53.3% where they did not. This study showed that large-scale NGS panels are a powerful modality that can help distinguish SPLCs from IPMs in patients with multiple lung adenocarcinomas and objectively provide accurate risk stratification., (Copyright © 2022 United States & Canadian Academy of Pathology. Published by Elsevier Inc. All rights reserved.)

Objective: To assess the association of sport specialization combined with sport-related concussion (SRC) history on depression and health-related quality of life (HRQoL) in a population of high school athletes., Design: Cross-sectional study., Setting: High schools., Participants: Two thousand four hundred fifty-three athletes through the State of Wisconsin., Independent Variables: Sport specialization and SRC history., Main Outcome Measures: Athletes completed questionnaires reporting their SRC history, sports participation (single-sport or multisport), Patient Health Questionnaire-9 (PHQ-9), and Pediatric Quality of Life 4.0 (PedsQL). We used multivariate binary logistic regression to assess the odds ratio (OR) for depressive symptoms based on SRC and sport participation history. Separate multilinear regression evaluated the association between the PedsQL, SRC, and sport participation history. The interaction of sport specialization and SRC history was explored in both regression models., Results: High school athletes who participated in single-sport activities had a greater odds of reporting higher severity of depressive symptoms on PHQ-9 scores (OR, 1.50; 95% CI, 1.11-2.02) and reduced PedsQL ( P < 0.001) compared with their multisport counterparts. There were no associations between SRC history and either PHQ-9 or PedsQL scores. Statistically significant interactions between sport specialization and SRC were not found among all models., Conclusion: Single-sport high school athletes reported a reduction in HRQoL measures along with higher depressive symptoms when compared with the multisport athletes. The SRC history did not have a lingering effect on depression or HRQoL in this study. These findings raise some interesting concerns regarding the quality of mental health in adolescent athletes solely focused on single-sport endeavors., Competing Interests: The authors report no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Although many machine learning methods have been widely used to predict PM2.5 concentrations, these single or hybrid methods still have some shortcomings. This study integrated the advantages of convolutional neural network (CNN) feature extraction and the regression ability of random forest (RF) to propose a novel CNN-RF ensemble framework for PM2.5 concentration modeling. The observational data from 13 monitoring stations in Kaohsiung in 2021 were selected for model training and testing. First, CNN was implemented to extract key meteorological and pollution data. Subsequently, the RF algorithm was employed to train the model with five input factors, namely the extracted features from the CNN and spatiotemporal factors, including the day of the year, the hour of the day, latitude, and longitude. Independent observations from two stations were used to evaluate the models. The findings demonstrated that the proposed CNN-RF model had better modeling capability compared with the independent CNN and RF models: the average improvements in root mean square error (RMSE) and mean absolute error (MAE) ranged from 8.10% to 11.11%, respectively. In addition, the proposed CNN-RF hybrid model has fewer excess residuals at thresholds of 10 μg/m 3 , 20 μg/m 3 , and 30 μg/m 3 . The results revealed that the proposed CNN-RF ensemble framework is a stable, reliable, and accurate method that can generate superior results compared with the single CNN and RF methods. The proposed method could be a valuable reference for readers and may inspire researchers to develop even more effective methods for air pollution modeling. This research has important implications for air pollution research, data analysis, model estimation, and machine learning.

Peroxisome proliferator-activated receptor γ (PPARγ) gene mutations in humans and mice lead to whole-body insulin resistance and partial lipodystrophy. It is unclear whether preserved fat depots in partial lipodystrophy are beneficial for whole-body metabolic homeostasis. We analyzed the insulin response and expression of metabolic genes in the preserved fat depots of Pparg C/- mice, a familial partial lipodystrophy type 3 (FPLD3) mouse model resulting from a 75% decrease in Pparg transcripts. Perigonadal fat of Pparg C/- mice in the basal state showed dramatic decreases in adipose tissue mass and insulin sensitivity, whereas inguinal fat showed compensatory increases. Preservation of inguinal fat metabolic ability and flexibility was reflected by the normal expression of metabolic genes in the basal or fasting/refeeding states. The high nutrient load further increased insulin sensitivity in inguinal fat, but the expression of metabolic genes became dysregulated. Inguinal fat removal resulted in further impairment of whole-body insulin sensitivity in Pparg C/- mice. Conversely, the compensatory increase in insulin sensitivity of the inguinal fat in Pparg C/- mice diminished as activation of PPARγ by its agonists restored insulin sensitivity and metabolic ability of perigonadal fat. Together, we demonstrated that inguinal fat of Pparg C/- mice plays a compensatory role in combating perigonadal fat abnormalities.

Background: The Greulich-Pyle (GP) and Tanner-Whitehouse 3 (TW3) methods are two common methods for assessing bone age (BA). The applicability of these methods for populations other than those in the United States and Europe has been questioned. Thus, this study tested the applicability of these methods for Taiwanese children., Methods: In total, 1476 radiographs (654 boys, 822 girls) were analyzed. A subset of 200 radiographs was evaluated to determine intrarater and interrater reliability and the time required to yield a BA assessment. BA was determined by two reviewers using the GP method and two of the TW3 methods (the Radial-Ulnar-Short bones [RUS] method and the carpals method [Carpal]). The GP and TW3 methods were directly compared using statistical techniques. A subgroup analysis by age was performed to compare BA and chronological age using a paired t test for each age group., Results: The average times required to yield an assessment using the GP and TW3-RUS methods were 0.79 ± 0.14 and 3.01 ± 0.84 min (p < 0.001), respectively. Both the intrarater and interrater correlation coefficients were higher for the GP method (0.993, 0.992) than the TW3-RUS (0.985, 0.984) and TW3-Carpal (0.981, 0.973) methods. The correlation coefficient for the GP and TW3-RUS methods was highest in the pubertal stage (0.898 for boys and 0.909 for girls). The mean absolute deviations for the GP and TW3-RUS methods in the pubertal stage were 0.468 years (boys) and 0.496 years (girls). Both the GP and TW3-Carpal methods underestimated BA for boys in the prepubertal stage. Both the GP and TW3-RUS methods overestimated BA for girls in the pubertal and postpubertal stages., Conclusion: The GP and TW3-RUS methods exhibit strong agreement in the pubertal and postpubertal stages for both sexes. With appropriate adjustments based on Taiwanese data, both methods are applicable to our children., Competing Interests: Conflicts of interest: The authors declare that they have no conflicts of interest related to the subject matter or materials discussed in this article., (Copyright © 2023, the Chinese Medical Association.)

Micronodular thymoma with lymphoid stroma is a rare thymic neoplasm characterized by discrete nodules of epithelial tumor cells separated by abundant lymphoid stroma. The genetic features of micronodular thymoma with lymphoid stroma remain largely unexplored. Owing to the interference of abundant intratumoral, nonneoplastic lymphoid cells, a highly sensitive approach is necessary to study genetic changes in these tumors. In this study, we used a highly sensitive next-generation sequencing assay using the molecular barcoding Ion AmpliSeq HD technology to study the most commonly mutated genes in thymomas, including GTF2I, HRAS, NRAS, KRAS, and TP53. A total of 12 cases of micronodular thymomas with lymphoid stroma were tested, and 2 cases also had areas of type A thymoma in their tumor bed. Two micronodular thymic carcinomas with lymphoid stroma, a histological mimic of micronodular thymoma, were also included for comparison. Recurrent p.L424H mutations in GTF2I were found in all the cases of micronodular thymoma with lymphoid stroma but not in the cases of micronodular thymic carcinomas. In addition, 3 cases of micronodular thymoma with lymphoid stroma also had concomitant HRAS and/or KRAS mutations. Our study showed that p.L424H mutations in GTF2I is a constant genetic feature of micronodular thymoma with lymphoid stroma. This finding strongly suggests that micronodular thymoma with lymphoid stroma is closely related to type A and AB thymomas because they all share p.L424H mutations in GTF2I., (Copyright © 2022 United States & Canadian Academy of Pathology. Published by Elsevier Inc. All rights reserved.)

PD-L1 immunohistochemistry has been approved as a diagnostic assay for immunotherapy. However, an international comparison across multiple cancers is lacking. This study aimed to assess the performance of PD-L1 diagnostic assays in non-small cell lung cancer (NSCLC), head and neck squamous cell cancer (HNSCC) and urothelial cancer (UC). The excisional specimens of NSCLC, HNSCC and UC were assayed by Ventana SP263 and scored at three sites in each country, including Australia, Brazil, Korea, Mexico, Russia and Taiwan. All slides were rotated to two other sites for interobserver scoring. The same cohort of NSCLC was assessed with Dako 22C3 pharmDx PD-L1 for comparison. The PD-L1 immunopositivity was scored according to the approved PD-L1 scoring algorithms which were the percentage of PD-L1-expressing tumour cell (TC) and tumour proportion score (TPS) by Ventana SP263 and Dako 22C3 staining, respectively. In NSCLC, the comparison demonstrated the comparability of the SP263 and 22C3 assays (cut-off of 1%, κ=0.71; 25%, κ=0.75; 50%, κ=0.81). The interobserver comparisons showed moderate to almost perfect agreement for SP263 in TC staining at 25% cut-off (NSCLC, κ=0.72 to 0.86; HNSCC, κ=0.60 to 0.82; UC, κ=0.68 to 0.91) and at 50% cut-off for NSCLC (κ=0.64 to 0.90). Regarding the immune cell (IC) scoring in UC, there was a lower correlation (concordance correlation coefficient=0.10 to 0.68) and poor to substantial agreements at the 1%, 5%, 10% and 25% cut-offs (κ= -0.04 to 0.76). The interchangeability of SP263 and 22C3 in NSCLC might be acceptable, especially at the 50% cut-off. In HNSCC, the performance of SP263 is comparable across five countries. In UC, there was low concordance of IC staining, which may affect treatment decisions. Overall, the study showed the reliability and reproducibility of SP263 in NSCLC, HNSCC and UC., (Copyright © 2022 Royal College of Pathologists of Australasia. Published by Elsevier B.V. All rights reserved.)