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Abstract Serious blunt chest trauma usually induces hemothorax, pneumothorax, and rib fractures. More studies have claimed that early video-assisted thoracoscopic surgery with surgical stabilization of rib fractures (SSRF) results in a good prognosis in patients with major trauma. This study aimed to verify the outcomes in patients with chest trauma whether SSRF was performed. Consecutive patients who were treated in a medical center in Taiwan, for traumatic events between January 2015 and June 2020, were retrospectively reviewed. This study focused on patients with major trauma and thoracic injuries, and they were divided into groups based on whether they received SSRF. We used electrical impedance tomography (EIT) to evaluate the change of ventilation conditions. Different scores used for the evaluation of trauma severity were also compared in this study. Among the 8396 patients who were included, 1529 (18.21%) had major trauma with injury severity score > 16 and were admitted to the intensive care unit initially. A total of 596 patients with chest trauma were admitted, of whom 519 (87%) survived. Younger age and a lower trauma score (including injury severity scale, new injury severity score, trauma and injury severity score, and revised trauma score) account for better survival rates. Moreover, 74 patients received SSRF. They had a shorter intensive care unit (ICU) stay (5.24, p = 0.045) and better performance in electrical impedance tomography (23.46, p

Purpose: We aimed to explore the clinical outcomes and prognostic factors for PTCL-NOS patients in the real world. Methods: Clinical data were retrospectively collected from adult patients with PTCL-NOS treated at a single center in Taiwan. Results: 104 PTCL-NOS patients with a median age of 53.0 years were enrolled. Patients with the International Prognostic Index (IPI) or prognostic index for peripheral T-cell lymphoma (PIT) scores of zero had a longer overall survival (OS) and progression free survival (PFS), while patients with IPI or PIT scores ≥1 did poorly. For patients who are eligible for transplantation, the use of pralatrexate as salvage chemotherapy has shown better OS (2-year OS 83.3% vs. 24.4%, P = 0.011) compared to patients who did not. By multivariate analysis, age >60 years, male, B symptoms, ECOG >1, lung involvement, and thrombocytopenia were independent adverse factors for OS. Incorporating factors in multivariate analysis, we established a novel predictive index for PTCL-NOS which efficiently stratifies patients into low (0–1 factor), intermediate-1 (2 factors), intermediate-2 (3 factors), and high risk (4–6 factors) groups with 2-year OS rates of 81.5%, 32.9%, 8.8%, and 0%, respectively (P

Abstract Mammalian cells release a wealth of materials to their surroundings. Emerging data suggest these materials can even be mitochondria with perturbed morphology and aberrant function. These dysfunctional mitochondria are removed by migrating cells through membrane shedding. Neuronal cells, cardiomyocytes, and adipocytes send dysfunctional mitochondria into the extracellular space for nearby cells to degrade. Various studies also indicate that there is an interplay between intracellular mitochondrial degradation pathways and mitochondrial release in handling dysfunctional mitochondria. These observations, in aggregate, suggest that extracellular release plays a role in quality-controlling mammalian mitochondria. Future studies will help delineate the various types of molecular machinery mammalian cells use to release dysfunctional mitochondria. Through the studies, we will better understand how mammalian cells choose between intracellular degradation and extracellular release for the quality control of mitochondria.

Abstract Acute lung injury (ALI) is characterised by severe pulmonary inflammation, alveolar-capillary barrier disruption, and pulmonary oedema. Therefore, establishing effective therapeutic targets for ALI prevention is crucial. The present study reports a novel function of RNF128 in regulating LPS-induced ALI. Severe lung damage and increased immune cell infiltration were detected in RNF128-deficient mice. In vitro experiments revealed that RNF128 inhibits neutrophil activation by binding to myeloperoxidase (MPO) and reducing its levels and activity. Moreover, RNF128 regulates alveolar macrophage activation and neutrophil infiltration by interacting with TLR4, targeting it for degradation, and inhibiting NF-κB activation, hence decreasing pro-inflammatory cytokines. Our results demonstrate for the first time that RNF128 is a negative regulator of MPO and TLR4 in neutrophils and alveolar macrophages, respectively. However, AAV9-mediated RNF128 overexpression alleviated lung tissue damage and reduced inflammatory cell infiltration. Thus, RNF128 is a promising therapeutic candidate for pharmacological interventions in ALI.

Acute respiratory distress syndrome (ARDS) is a critical illness in critically unwell patients, characterized by refractory hypoxemia and shock. This study evaluates an early detection tool and investigates the relationship between hypoxia and circulatory shock in ARDS, to improve diagnostic precision and therapy customization. We used a porcine model, inducing ARDS with mechanical ventilation and intratracheal plus intravenous lipopolysaccharide (LPS) injection. Hemodynamic changes were monitored using an Acumen IQ sensor and a ForeSight Elite sensor connected to the HemoSphere platform. We evaluated tissue damage, inflammatory response, and hypoxia-inducible factor (HIF) alterations using enzyme-linked immunosorbent assay and immunohistochemistry. The results showed severe hypotension and increased heart rates post-LPS exposure, with a notable rise in the hypotension prediction index (HPI) during acute lung injury (p = 0.024). Tissue oxygen saturation dropped considerably in the right brain region. Interestingly, post-injury HIF-2α levels were lower at the end of the experiment. Our findings imply that the HPI can effectively predict ARDS-related hypotension. HIF expression levels may serve as possible markers of rapid ARDS progression. Further research should be conducted on the clinical value of this novel approach in critical care, as well as the relationship between the HIF pathway and ARDS-associated hypotension.

Background: Epidermal growth factor receptor (EGFR) gene mutation is a known predictor of the response to EGFR tyrosine kinase inhibitors. However, detecting EGFR mutations is a potential challenge because of the ground-glass opacity component, and its prognostic value for stage IA lung adenocarcinoma remains controversial. This study aimed to investigate the associations between EGFR mutation status, clinicopathological characteristics, and prognosis in surgically resected stage IA non-small cell lung cancer (NSCLC). Materials and Methods: We retrospectively examined the data of patients who underwent surgical resection for lung cancer between 2004 and 2014. The clinical data, imaging characteristics of nodules, surgical approaches, and outcomes were analyzed. Results: A total of 429 patients (female, n = 303; male, n = 126) with surgically resected stage IA NSCLC were analyzed and 343 were nonsmokers. The EGFR mutation rate was 48.3% (n = 207). Of the patients, 192 (44.8%) had stage IA1, 165 (38.5%) had stage IA2, and 72 (16.8%) had stage IA3 NSCLC. In the analysis of the correlations between clinicopathological features and EGFR status, older age (P = 0.032), nonsmoking history (P = 0.039), and pathological stage (P < 0.05) were related to EGFR mutation. Patients with stage IA2 NSCLC had a higher positive expression of EGFR than patients with stages IA1 and IA3. The 5-year overall survival rates and disease-free survival rates were better in the EGFR mutation group; however, the difference was not statistically significant. Conclusion: EGFR mutations are common in older and nonsmoking patients with stage IA NSCLC. Further separate analyses of EGFR gene mutations and pathological stage could improve the diagnostic performance and predict patients with unavailable EGFR gene testing who may benefit from targeted drug treatment.

Background: Intravascular large B-cell lymphoma (IVLBCL) is a rare subtype of non-Hodgkin lymphoma with uncommon clinical presentations and poor prognosis. The purpose of this study is to report the clinical features and outcome of IVLBCL in a single institution of Taiwan. Methods: Ten patients with IVLBCL diagnosed from June 2006 to January 2018 were retrospectively reviewed. Results: The median age was 61 (range 39–88) years. The most common presentation was fever (90%), cytopenia (90%), and confusion (50%). For all patients, the median progression free survival (PFS) and overall survival (OS) were 12.6 (95% confidence interval [CI] 0.0–76.1) and 18.8 (95% CI 0–59.3) months, respectively. Six patients received rituximab combined chemotherapy, and the other one patient was treated with chemotherapy alone. Six of seven (85.7%) patients achieved complete response after chemotherapy. The median PFS and OS for six patients who completed treatment were not reached. Three-year PFS and OS rates were 80% and 75%, respectively. Conclusion: Our study showed that patients might achieve durable remission after rituximab-based chemotherapy. The outcome of IVLBCL patients may further improve if early diagnosis and prompt treatment were made.

Background: Signs of feeding intolerance are common in formula-fed infants. We evaluated the clinical response to a partially hydrolyzed 100% whey protein formula with high sn -2 palmitate and reduced lactose (FA) and to an alpha-lactalbumin-enriched whey-predominant intact protein formula with full lactose (FB) in healthy full-term infants with parent-reported signs of feeding intolerance. Methods: In a double-blind, parallel-group trial in 6 Asian study centers, exclusively formula-fed infants aged 30 to 90 days, whose parents reported fussiness-crying for ≥2 hours/day plus gassiness and/or stooling difficulty, and intended to switch formula, were randomly assigned to FA (n = 130) or FB (n = 129) for 14 days. Primary endpoint was daily duration of fussiness-crying. Secondary endpoints included gassiness, spitting-up, vomiting, sleep pattern, Infant Gastrointestinal Symptom Questionnaire (IGSQ) Index, infant temperament and maternal anxiety. Results: Mean ± SE minutes/day of fussiness-crying in the 256 analyzed infants (FA, n = 127 and FB, n = 129) substantially decreased from baseline to study end in FA (291 ± 14 to 140 ± 8; –52%, P

Background Alzheimer’s disease (AD) is a prevalent progressive neurodegenerative human disease whose cause remains unclear. Numerous initially highly hopeful anti-AD drugs based on the amyloid-β (Aβ) hypothesis of AD have failed recent late-phase tests. Natural aging (AG) is a high-risk factor for AD. Here, we aim to gain insights in AD that may lead to its novel therapeutic treatment through conducting meta-analyses of gene expression microarray data from AG and AD-affected brain. Methods Five sets of gene expression microarray data from different regions of AD (hereafter, ALZ when referring to data)-affected brain, and one set from AG, were analyzed by means of the application of the methods of differentially expressed genes and differentially co-expressed gene pairs for the identification of putatively disrupted biological pathways and associated abnormal molecular contents. Results Brain-region specificity among ALZ cases and AG-ALZ differences in gene expression and in KEGG pathway disruption were identified. Strong heterogeneity in AD signatures among the five brain regions was observed: HC/PC/SFG showed clear and pronounced AD signatures, MTG moderately so, and EC showed essentially none. There were stark differences between ALZ and AG. OXPHOS and Proteasome were the most disrupted pathways in HC/PC/SFG, while AG showed no OXPHOS disruption and relatively weak Proteasome disruption in AG. Metabolic related pathways including TCA cycle and Pyruvate metabolism were disrupted in ALZ but not in AG. Three pathogenic infection related pathways were disrupted in ALZ. Many cancer and signaling related pathways were shown to be disrupted AG but far less so in ALZ, and not at all in HC. We identified 54 “ALZ-only” differentially expressed genes, all down-regulated and which, when used to augment the gene list of the KEGG AD pathway, made it significantly more AD-specific.

Abstract Background Differences between staged bilateral total knee replacement (TKR) and simultaneous bilateral TKR have been investigated, but few studies have investigated differences in the functional improvements resulting from these methods. Therefore, this study investigates the different functional improvements between staged bilateral total knee TKR and simultaneous bilateral TKR. Methods Among 144 potential bilateral TKR patients who were included in this study, 93 (64.6%) patients selected unilateral TKR and 51 (35.4%) selected bilateral TKR. Functional improvements were assessed using the Western Ontario and McMaster University osteoarthritis index (WOMAC) and the Medical Outcomes Trust Short Form-36 (SF-36), and patients were interviewed pre-operatively and after 6 months. A generalized equation was used to test for differences in functional improvements. Results After TKR, pain, stiffness, function and total WOMAC scores were significantly reduced in both groups, with mean changes from − 26.6 to − 41.4 and from − 27.5 to − 42.2.The mean health change of SF-36 scores, physical component and mental component scores changed to 45.2 ± 18.2, 74.0 ± 15.4 and 77.0 ± 9.6, respectively, in Group 1 and 47.1 ± 17.1, 74.0 ± 15.2 and 75.5 ± 12.1, respectively, in Group 2. Unilateral and simultaneous bilateral TKR produce similar functional improvements, although current work status may be a novel impact factor. Conclusion No differences in functional improvements were identified between patients who selected unilateral versus bilateral TKR, indicating no recommendation for one procedure over the other.

Background: The theory of pulse diagnosis is to assess the physiological condition of the human body using radial pulse. However, pulses can vary markedly from person to person. Further, pulse diagnosis is difficult to learn and requires one-on-one teaching. Methods: To address this problem, we built a home-made pulse diagnoser and measured human pulses for studying the standardization of pulse diagnosis. Our pulse diagnoser was composed of a piezoelectric transducer, differential amplifier, data acquisition instrument, and a Matlab analysis program. The measured pulses were converted into electronic signals by a piezoelectric transducer and saved on a computer. The digitalized data were then refined and analyzed by fast Fourier transform for frequency analysis. Simulations were performed to assess the factors that affected the pulse, including phase shifts of reflected pulse waves (generate sub-peaks in pulses), inconsistent heart rates (deform pulse waves), the vessel stiffness (alter harmonic frequencies of the pulses), and the wave amplitudes (determined by the pulse strength). Results: By comparing a published report and our simulation findings, we characterized the pulse types and the effects of various factors, and then applied the findings to study actual pulses in patients. Three types of pulses were determined from the frequency spectrum—choppy pulse (Se mai) without apparent harmonic peaks, the harmonic frequencies of wiry pulse (Xian mai) that are non-integer multiples of the fundamental frequency, and surging pulse (Hong mai) that exhibit strong amplitudes in the spectrum of frequency. A normal pulse and a slippery pulse were differentiated by a phase shift, but not by assessing the frequency spectrum. Conclusion: These findings confirm that frequency domain analysis can avoid ambiguity arising in assessing the three types of pulses in the time domain. Further studies of other pulses in the frequency domain are required to develop a precise electronic pulse diagnoser.

Lung cancer is a heterogeneous disease with varied outcomes. Molecular markers are eagerly investigated to predict a patient's treatment response or outcome. Previous studies used frozen biopsy tissues to identify crucial genes as prognostic markers. We explored the prognostic value of peripheral blood (PB) molecular signatures in patients with advanced non-small cell lung cancer (NSCLC). Methods: Peripheral blood mononuclear cell (PBMC) fractions from patients with advanced NSCLC were applied for RNA extraction, cDNA synthesis, and real-time polymerase chain reaction (PCR) for the expression profiling of eight genes: DUSP6, MMD, CPEB4, RNF4, STAT2, NF1, IRF4, and ZNF264. Proportional hazard (PH) models were constructed to evaluate the association of the eight expressing genes and multiple clinical factors [e.g., sex, smoking status, and Charlson comorbidity index (CCI)] with overall survival. Results: One hundred and forty-one patients with advanced NSCLC were enrolled. They included 109 (77.30%) patients with adenocarcinoma, 12 (8.51%) patients with squamous cell carcinoma, and 20 (14.18%) patients with other pathological lung cancer types. A PH model containing two significant survival-associated genes, CPEB4 and IRF4, could help in predicting the overall survival of patients with advanced stage NSCLC [hazard ratio (HR) = 0.48, p

In most patients, systemic anaplastic large cell lymphoma (sALCL) is an 18F-FDG-avid tumor. Both ALK-positive and ALK-negative tumors can be evaluated by PET scans as both tumor types uptake 18F-FDG in PET. The PET scan is also valuable in predicting prognosis during and after the treatment course. The evolution of 18F-FDG uptake in patients with sALCL has not been reported. For tumors lacking 18F-FDG uptake, there is a diagnostic pitfall of underestimating the cancer stage and misjudgment of metastases. In the present case, the PET scan results were negative at diagnosis but disseminated 18F-FDG avid lesions were found at relapse. Biopsy of bone marrow and lymph nodes revealed the pathological features were identical to the original tumor at the time of diagnosis. In the wake of such evolutional change, physicians dealing with sALCL should be cautious in interpretation of PET/CT scans.

Aim: We investigated outcomes of sublobar resection in patients with clinical early-stage nonsmall cell lung cancers. Patients and Methods: Patients who underwent surgical resection between January 2002 and June 2013 were reviewed. The clinical data, surgical approach, and outcome were analyzed with mean follow-up of 108 months. Results: Of 597 patients, 108 (18.1%) underwent sublobar resection. The 5-year overall survival (OS) and disease-free survival rate for this group were 76.2% and 70.3%, respectively, compared with 79.7% and 73.0% for those undergoing anatomic resection (P = 0.709 and 0.618). After stratifying for tumor size

ObjectivesThe purpose of this study was to examine the impact of epidermal growth factor receptor (EGFR) mutation status and tyrosine kinase inhibitors (TKIs) on the survival of brain metastases (BM) in patients with surgically resected non-small cell lung cancer (NSCLC).MethodsWe selected the patients who had developed metastatic NSCLC; analyzed the differences between brain metastases and other sites of metastases, including patient characteristics, EGFR status, and survival; and selected the patients who had BM for further investigation. We also compared the treatment effects of first-generation TKIs with those of second-/third-generation TKIs.ResultsA total of 785 cases of stage I-IIIa NSCLC were reviewed. Thirty-six (4.6%) patients were identified as having BM. Among them, 14 patients had a mutated EGFR status. No association between EGFR mutation and the incidence of BM was observed (p = 0.199). Patients with mutated EGFRs had significantly longer overall survival and post-recurrence survival than patients with wild-type EGFR mutation (p = 0.001 for both). However, there was no survival difference between patients with exon 19 and exon 21 mutations (p = 0.426). Furthermore, patients who received the second- and/or third-generation EGFR-TKIs had better survival than patients who only received first-generation EGFR-TKIs (p = 0.031). A multivariate analysis indicated that the next-generation TKIs (HR, 0.007; 95% CI, 0.000 to 0.556; p = 0.026) and a longer interval before BM development (HR, 0.848; 95% CI, 0.733 to 0.980; p = 0.025) were significant factors in longer survival.ConclusionsEGFR-TKIs were effective in treating NSCLC patients with BM after curative pulmonary surgery, especially in those patients harboring EGFR mutations. Furthermore, the second-/third-generation EGFR-TKIs showed more promising results than the first-generation EGFR-TKIs in treating those particular patients, though larger studies needed to further prove the results.

Background: Heart rate variability (HRV) had been promoted for longer than half a century to monitor the activity of autonomic nerve systems. Previous studies have not clarified the relationship between HRV and prehypertension (pre-HTN) status compared with the normal group. We aimed to figure out the optimal model or cutoff point for predicting the possible pre-HTN status. Patients and Methods: We retrospectively collected and reviewed 2586 Asian people who had joined annual physical examination in Tri-Service General Hospital at 2013. The patient profiles such as age, gender, body height, body weight, body weight index, waist circumferences, and serological biochemistry data were analyzed and correlated with HRV parameter. Results: A total number of 909 patients were enrolled in our study. The physical stress index (PSI) owed a small but most significant Spearman's relation coefficient (r = 0.118, P< 0.001) among the other HRV parameters. Statistical significant parameters exist between the normal blood pressure group and pre-HTN group other than gender factor. The measured blood pressure increased with elevated PSI level. A PSI level ≥58.4 has a significant β coefficient in each linear regression model for systolic blood pressure and diastolic blood pressure with a P< 0.001 for trend. Conclusion: The PSI level gains a positive correlation to elevated blood pressure. Our study emphasized that PSI is an efficient HRV parameter which represents higher risks for pre-HTN status and elevated blood pressure while the PSI level is >58.4. Early intervention to these participants may decrease cardiovascular events in the coming future.

OBJECTIVES:The beneficial application of three-dimensional (3D) printing for surgical stabilization of rib fractures (SSRF) has never been proposed in the literature before. The aim of this study was to verify patients' surgical outcomes when utilizing preoperative three-dimensional printing for SSRF. METHODS:We retrospectively reviewed the records of all consecutive patients who were treated at our hospital for SSRF from July 2015 to December 2017. The patients were divided into two groups according to whether or not 3D printing was utilized. RESULTS:Forty-eight patients who underwent SSRF at our hospital were enrolled. Of them, three patients underwent bilateral surgeries. The patients with application of preoperative 3D printing for SSRF had statistically significant associations with shorter operation time per fixed plate (p < 0.001), and a smaller incision length (p < 0.001). CONCLUSIONS:We present an useful technique involving 3D printing for promoting SSRF significantly with shorter operation time and an appropriate incision length.

Background: Breast is an uncommon location of lymphoma involvement. The most common type of primary breast lymphoma (PBL) is diffuse large B-cell lymphoma (DLBCL). Rituximab is the widely used monoclonal antibody against CD20+ B-cell lymphoma, especially DLBCL. We aimed to analyze the clinical features, prognostic factors, and treatment outcome with or without rituximab in primary breast DLBCL. Methods: We retrospectively analyzed patients diagnosed with PBL from October 1987 to March 2012 in our hospital, excluding metastasis by whole-body computed tomography and bone marrow study. Results: Twenty-three patients were diagnosed with PBL. All were females. Eighteen patients were stage IE and five were stage IIE according to the Ann Arbor staging system. Two patients had lymphoma other than DLBCL. The median age of primary breast DLBCL patients was 48 years (range 27-79). Two were excluded from the analysis due to refusal or ineligibility for chemotherapy. No significant prognostic factor was found. Patients receiving chemotherapy with (RC) or without (C) rituximab were not significantly different in the 5-year overall survival (RC: 57.1%; C: 58.3%; p = 0.457) or progression-free survival (RC: 57.1%; C: 50.0%; p = 0.456). A high incidence of relapse in the central nervous system (CNS) (17.6%) was observed. Conclusions: In accordance with prior literature reports, our Taiwanese cohort of primary breast DLBCL seemed younger than those reported in Japan, Korea, and Western societies. Relapse in the CNS was not uncommon. The benefit of rituximab in addition to chemotherapy was not statistically significant. Treatment modality remained to be defined by further large-scale studies.

Myasthenia gravis (MG) is a disease affecting the acetylcholine receptor in the neuromuscular junction. Symptoms of MG are muscle weakness and fatigue. Video-assisted thoracoscopic extended thymectomy (VATS-ET) is well established in the treatment of MG if medical treatment is failed. In the recent decade, VATS under nonintubated anesthesia has been intensively researched and reported, which has been advocated to be a preferred alternative to the conventional intubated anesthesia for pulmonary nodules. However, cases with MG receiving nonintubated VATS-ET have rarely been reported. Here, we described a successful anesthesia of a 44-year-old woman with MG undergoing nonintubated VATS-ET.

Chest wall tumors can arise from a wide variety of benign and malignant etiologies, and therefore it can be challenging for clinicians to diagnose and manage them. Isolated metastatic squamous cell carcinoma from cervical cancer is extremely rare. We report a metastatic chest wall tumor from cervical cancer arising after 19 years of disease-free survival. Wide resection of the metastatic chest wall tumor, followed by a polypropylene mesh and free flap reconstruction with adequate coverage was successful. The patient continues to be a disease-free at 2 years.

Context: Thoracotomy is a common procedure. However, thoracotomy leads to lung atelectasis and deteriorates pulmonary gas exchange in operated side. Therefore, different positions with operated side lowermost or uppermost may lead to different gas exchange after thoracotomy. Besides, PEEP (positive end-expiratory pressure) influence lung atelectasis and should influence gas exchange. Aims: The purpose of this study was to determine the physiological changes in different positions after thoracotomy. In addition, we also studied the influence of PEEP to positional effects after thoracotomy. Materials and Methods: There were eight pigs in each group. Group I received left thoracotomy with zero end-expiratory pressure (ZEEP), and group II with PEEP; group III received right thoracotomy with ZEEP and group IV with PEEP. We changed positions to supine, LLD (left lateral decubitus) and RLD (right lateral decubitus) in random order after thoracotomy. Results: PaO 2 was decreased after thoracotomy and higher in RLD after left thoracotomy and in LLD after right thoracotomy. PaO 2 in groups II and IV was higher than in groups I and III if with the same position. In group I and III, PaCO 2 was increased after thoracotomy and was higher in LLD after left thoracotomy and in RLD after right thoracotomy. In groups II and IV, there were no PaCO 2 changes in different positions after thoracotomy. Lung compliance (C rs ) was decreased after thoracotomy in groups I and III and highest in RLD after left thoracotomy and in LLD after right thoracotomy. In groups II and IV, there were no changes in C rs regardless of the different positions. Conclusion: There were significant changes with regards to pulmonary gas exchange, hemodynamics and C rs after thoracotomy. The best position was non-operated lung lowermost Applying PEEP attenuates the positional effects.

Taiwan is only now beginning to offer palliative care to patients who do not have cancer. This study aimed to document the polysymptomatic presentation of illness in Taiwanese patients with late-stage nonmalignant disease and to evaluate the potential benefits of palliative care for these patients. The results may help to educate healthcare personnel regarding the need for and importance of palliative treatment as comprehensive, appropriate end-of-life care for patients with nonmalignant disease. Methods: We retrospectively analyzed 115 patients without cancer hospitalized in a community hospital in Taiwan: 61 had organic brain disease, 31 had chronic obstructive pulmonary disease, 17 had chronic renal failure, 14 had congestive heart failure, 12 had liver cirrhosis, and 20 had multiple illnesses. The median age was 81 years (interquartile range 69–86 years), and 51% of patients were enrolled from intensive care. Symptoms and their severity were analyzed. Patients' and their families' understanding of the diagnosis and prognosis and “Do Not Resuscitate” (DNR) consent were evaluated pre- and post-palliative care. Results: The four leading symptoms were fatigue (96%), fever (86%), cough (81%), and dyspnea (79%). No significant differences in symptom prevalence were found between different sexes, ages, performance statuses, ward locations, or underlying diseases, except for fewer episodes of dizziness, more frequent episodes of cough in patients older than 80 years, and more episodes of jaundice in ward service subjects. Only the presence of abdominal distension differed significantly between surviving and deceased patients (22.9% vs. 40.3%; p=0.004). After the start of palliative care, patients' DNR consent increased (105/115 before, 114/115 after). Patients' recognition of the diagnosis and prognosis increased from 13 to 64, respectively, with a simultaneous increase in family members' recognition (66 before, 114 after). Conclusion: Hospice care with good symptom control is warranted for patients with late-stage nonmalignant disease who need appropriate end-of-life care. Medical personnel need education in the importance of palliative care and the identification of patients who could benefit from it. In addition, patients should be informed of its availability.

Background: Cardiac power output (CPO) predicts outcomes in advanced heart failure (HF) and cardiogenic shock, but its role in early HF stages is unclear. This study assessed the prognostic value of CPO in coronary artery disease patients with asymptomatic left ventricular systolic dysfunction (ALVSD) at stage B HF. Methods: We conducted a retrospective analysis of coronary artery disease patients who underwent coronary and pulmonary artery catheterization between 2006 and 2016. Stage B HF with ALVSD was defined as left ventricular ejection fraction

T cell engagers (TCEs) are becoming an integral class of biological therapeutic owing to their highly potent ability to eradicate cancer cells. Nevertheless, the widespread utility of classical CD3-targeted TCEs has been limited by narrow therapeutic index (TI) linked to systemic CD4+ T cell activation and aberrant cytokine release. One attractive approach to circumvent the systemic activation of pan CD3+ T cells and reduce the risk of cytokine release syndrome is to redirect specific subsets of T cells. A promising strategy is the use of peptide-major histocompatibility class I bispecific antibodies (pMHC-IgGs), which have emerged as an intriguing modality of TCE, based on their ability to selectively redirect highly reactive viral-specific effector memory cytotoxic CD8+ T cells to eliminate cancer cells. However, the relatively low frequency of these effector memory cells in human peripheral blood mononuclear cells (PBMCs) may hamper their redirection as effector cells for clinical applications. To mitigate this potential limitation, we report here the generation of a pMHC-IgG derivative known as guided-pMHC-staging (GPS) carrying a covalent fusion of a monovalent interleukin-2 (IL-2) mutein (H16A, F42A). Using an anti-epidermal growth factor receptor (EGFR) arm as a proof-of-concept, tumor-associated antigen paired with a single-chain HLA-A *02:01/CMVpp65 pMHC fusion moiety, we demonstrate in vitro that the IL-2-armored GPS modality robustly expands CMVpp65-specific CD8+ effector memory T cells and induces potent cytotoxic activity against target cancer cells. Similar to GPS, IL-2-armored GPS molecules induce modulated T cell activation and reduced cytokine release profile compared to an analogous CD3-targeted TCE. In vivo we show that IL-2-armored GPS, but not the corresponding GPS, effectively expands grafted CMVpp65 CD8+ T cells from unstimulated human PBMCs in an NSG mouse model. Lastly, we demonstrate that the IL-2-armored GPS modality exhibits a favorable developability profile and monoclonal antibody-like pharmacokinetic properties in human neonatal Fc receptor transgenic mice. Overall, IL-2-armored GPS represents an attractive approach for treating cancer with the potential for inducing vaccine-like antiviral T cell expansion, immune cell redirection as a TCE, and significantly widened TI due to reduced cytokine release.

Background This study investigated drug–drug interactions in patients with atrial fibrillation taking both a direct oral anticoagulant (DOAC) and an antiarrhythmic drug. Methods and Results Using data from the National Health Insurance database (2012–2018), we identified 78 805 patients with atrial fibrillation on DOACs, with 24 142 taking amiodarone, 8631 taking propafenone, 2784 taking dronedarone, 297 taking flecainide, 177 taking sotalol, and 42 772 on DOACs alone. Patients with bradycardia, heart block, heart failure, mitral stenosis, prosthetic valves, or incomplete data were excluded. Propensity score matching compared those taking both DOACs and antiarrhythmic drugs with those on DOACs alone. There was an increased risk of major bleeding in patients concomitantly taking DOACs with amiodarone when compared with matched patients taking DOACs alone (hazard ratio [HR],1.13 [95% CI, 1.04–1.23]; P=0.0044), particularly in patients taking dabigatran (HR, 1.19 [95% CI, 1.03–1.38]; P=0.0175). No significant difference in bleeding risk was found for propafenone, dronedarone, flecainide, or sotalol. The small sample sizes in the flecainide and sotalol groups limit interpretation. Notably, intracranial bleeding risk was higher in patients on DOACs and amiodarone, regardless of age. Additionally, patients

BACKGROUND:Studies of angiotensin-converting enzyme insertion/deletion (ACE I/D) polymorphisms and the risks of knee osteoarthritis (OA) have yielded conflicting results. OBJECTIVE:To determine the association between ACE I/D and knee OA, we conducted a combined case-control study and meta-analysis. METHODS:For the case-control study, 447 knee OA cases and 423 healthy controls were recruited between March 2010 and July 2011. Knee OA cases were defined using the Kellgren-Lawrence grading system, and the ACE I/D genotype was determined using a standard polymerase chain reaction. The association between ACE I/D and knee OA was detected using allele, genotype, dominant, and recessive models. For the meta-analysis, PubMed and Embase databases were systematically searched for prospective observational studies published up until August 2015. Studies of ACE I/D and knee OA with sufficient data were selected. Pooled results were expressed as odds ratios (ORs) with corresponding 95% confidence intervals (CI) for the D versus I allele with regard to knee OA risk. RESULTS:We found no significant association between the D allele and knee OA [OR: 1.09 (95% CI: 0.76-1.89)] in the present case-control study, and the results of other genetic models were also nonsignificant. Five current studies were included, and there were a total of six study populations after including our case-control study (1165 cases and 1029 controls). In the meta-analysis, the allele model also yielded nonsignificant results [OR: 1.37 (95% CI: 0.95-1.99)] and a high heterogeneity (I2: 87.2%). CONCLUSIONS:The association between ACE I/D and knee OA tended to yield negative results. High heterogeneity suggests a complex, multifactorial mechanism, and an epistasis analysis of ACE I/D and knee OA should therefore be conducted.

Mesenchymal stem cells (MSCs) have gained attention as a promising therapeutic approach in both preclinical and clinical osteoarthritis (OA) settings. Various joint cell types, such as chondrocytes, synovial fibroblasts, osteoblasts, and tenocytes, can produce and release extracellular vesicles (EVs), which subsequently influence the biological activities of recipient cells. Recently, extracellular vesicles derived from mesenchymal stem cells (MSC-EVs) have shown the potential to modulate various physiological and pathological processes through the modulation of cellular differentiation, immune responses, and tissue repair. This review explores the roles and therapeutic potential of MSC-EVs in OA and rheumatoid arthritis, cardiovascular disease, age-related macular degeneration, Alzheimer's disease, and other degenerative diseases. Notably, we provide a comprehensive summary of exosome biogenesis, microRNA composition, mechanisms of intercellular transfer, and their evolving role in the highlight of exosome-based treatments in both preclinical and clinical avenues.

A method is described to screen fungal strains rapidly for overexpression of extracellular β-1,4-endoglucanase in the presence of high levels of sugar compounds. The semi-quantitative assay utilizes microplates in a 96-well format and an azurine dye covalently cross-linked (AZCL) chromogenic substrate. The digestion of AZCL-hydroxyethyl-β-1,4-endoglucanase results in the release of a blue dye directly proportional to the amount of enzyme activity present in the sample. Sample absorbance was read at 590 nm, and the enzyme activity was determined by reference to a standard curve. The results from the microplate diffusion assay were similar to the results derived from the Ostazin Brilliant Red-hydroxyethyl cellulose assay. The technique described allowed the rapid comparison and screening β-1,4-glucanase activity directly in spent fungal supernatant, from cultures grown in potato dextrose broth. The method could also be easily adapted for the screening of the presence of other activities such as β-1,3-glucanase activity by using either AZCL-β-glucan or AZCL-pachyman in place of the AZCL-hydroxyethyl-cellulose. This assay could be used to measure supernatant within an activity range of 0.1–2 U/mL.

Diadenosine tetraphosphate (Ap4A), a constituent of platelet dense granules, and its P1,P4-dithio and/or P2,P3-chloromethylene analogs, inhibit adenosine diphosphate (ADP)-induced platelet aggregation. We recently reported that these compounds antagonize both platelet ADP receptors, P2Y1 and P2Y12. The most active of those analogs, diadenosine 5',5″″-P1,P4-dithio-P2,P3-chloromethylenetetraphosphate, (compound 1), exists as a mixture of 4 stereoisomers.To separate the stereoisomers of compound 1 and determine their effects on platelet aggregation, platelet P2Y1 and P2Y12 receptor antagonism, and their metabolism in human plasma.We separated the 4 diastereomers of compound 1 by preparative reversed-phase chromatography, and studied their effect on ADP-induced platelet aggregation, P2Y1-mediated changes in cytosolic Ca2+, P2Y12-mediated changes in VASP phosphorylation, and metabolism in human plasma.The inhibition of ADP-induced human platelet aggregation and human platelet P2Y12 receptor, and stability in human plasma strongly depended on the stereo-configuration of the chiral P1- and P4-phosphorothioate groups, the SPSP diastereomer being the most potent inhibitor and completely resistant to degradation in plasma, and the RPRP diastereomer being the least potent inhibitor and with the lowest plasma stability. The inhibitory activity of SPRP diastereomers depended on the configuration of the pseudo-asymmetric carbon of the P2,P3-chloromethylene group, one of the configurations being significantly more active than the other. Their plasma stability did not differ significantly, being intermediate to that of the SPSP and the RPRP diastereomers.The presently-described stereoisomers have utility for structural, mechanistic, and drug development studies of dual antagonists of platelet P2Y1 and P2Y12 receptors.

Floods, one of the costliest, and most frequent hazards, are expected to worsen in the U.S. due to climate change. The real-time forecasting of flood inundations is extremely important for proactive decision-making to reduce damage. However, traditional forecasting methods face challenges in terms of implementation and scalability due to computational burdens and data availability issues. Current forecasting services in the U.S. largely rely on hydrodynamic modeling, limited to river reaches near in situ gauges and requiring extensive data for model setup and calibration. Here, we have successfully adapted the Forecasting Inundation Extents using REOF (FIER) analysis framework to produce forecasted water fraction maps in two U.S. flood-prone regions, specifically the Red River of the North Basin and the Upper Mississippi Alluvial Plain, utilizing Visible Infrared Imaging Radiometer Suite (VIIRS) optical imagery and the National Water Model. Comparing against historical VIIRS imagery for the same dates, FIER 1- to 8-day medium-range pseudo-forecasts show that about 70–80% of pixels exhibit absolute errors of less than 30%. Although originally developed utilizing Synthetic Aperture Radar (SAR) images, this study demonstrated FIER’s versatility and effectiveness in flood forecasting by demonstrating its successful adaptation with optical VIIRS imagery which provides daily water fraction product, offering more historical observations to be used as inputs for FIER during peak flood times, particularly in regions where flooding commonly happens in a short period rather than following a broad seasonal pattern.

Abstract Low-education women, a substantially older population, are subject to increased risks of metabolic syndrome and consequent cardiometabolic diseases; early detection and effective management were urgently needed. Ninety-nine women with metabolic syndrome, age 61 and education ≤ 6 years, from four community units were randomly assigned to either a self-management intervention (n = 51) or a control arm (n = 48). The intervention consisted of five dimensions, physical activity and diet modifications (daily exercise classes and two nutrition courses), goal setting, coaching and peer support, problem-solving, and self-monitoring. The control arm received an education leaflet. Assessments were performed at baseline, six months, and 18 months. Compared with the control, the intervention participants improved the overall rate of meeting the recommended servings for six health foods, including vegetables, dairy products, and nuts (except whole grains, fruits, and protein); the rate of meeting regular leisure-time physical activity; and criteria biomarkers—waist circumference, fasting blood glucose, high-density lipoprotein cholesterol (except blood pressure and triglycerides); as well as body weight and body mass index; consequently decreased the number of risk factors and rate of metabolic syndrome. In conclusion, the multidimensional self-management intervention improved physical activity, healthy eating, and metabolic syndrome risks among low-education women with metabolic syndrome.

This paper proposes a new driving structure of the thin-film transistor liquid crystal display (TFT-LCD) that can yield a high image quality with a reduction in the number of source driver ICs for use in narrow-bezel notebook displays with ultra-high definition (UHD) and a high frame rate. The proposed driving structure improves the pixel charging ratio by reducing the RC loadings of TFTs of de-multiplexers on data lines and extending the available row-line time for pixel charging. A new gate driver circuit that generates two output waveforms in a single stage is presented to reduce the cost and occupied layout area of gate driver ICs, enabling the realization of high-resolution displays with a narrow bezel. To verify the feasibility of the proposed driving structure, a 12.3-inch panel with UHD (3840 × 2160) and a frame rate of 120 Hz is fabricated. Experimental results demonstrate that the proposed driving structure yields a measured pixel charging ratio of more than 97.09% for a heavy loading pattern with a gray level of 255. Following an accelerated lifetime test, the measured waveforms of the proposed gate driver circuit are stable without any malfunction, demonstrating its high reliability. Therefore, the proposed driving structure and the gate driver circuit are highly suitable for use in UHD TFT-LCD notebook applications.

In this study, the extended-gate field-effect transistor (EGFET) with an on-chip sensing window under the TSMC $0.18{\mu }\text{m}$ 1P6M (one poly and six metals) CMOS process technology was fabricated as a biosensor. The sensing window was composed of six metal layers and functionalized with the ruthenium dioxide (RuO2) thin film and uricase for uric acid detection. The RuO2 thin film was deposited on the top metal layer of the sensing window using the radio frequency (RF) sputtering system. The silver probe was employed as a reference electrode to provide a voltage to the test solution with a micro-volume of $0.5 {\mu }\text{L}$ . The properties of the EGFET for uric acid detection were investigated through the semiconductor parameter analyzer. The EGFET had a voltage and the current sensitivity of 8.63 mV/(mg/dL) and 0.17 ( ${\mu }\text{A}$ ) $^{1/2}$ /(mg/dL), respectively. The device worked with a supply voltage lower than 1.8V. Based on the results, the fabrication of the miniaturized biosensor device was a success. Due to its advantages such as the use of low voltage and its simple fabrication process, it could help realize the development of a wearable biosensor.

Abstract Background Anxiety and depressive disorders, characterized by high incidence and functional impairments, are emotional disorders with shared etiological and maintenance mechanisms. Dialectical behavior therapy (DBT) is a promising approach for the transdiagnostic treatment of emotional disorders. Developing a brief DBT intervention can facilitate the adoption of evidence-based therapy. Methods This protocol is for a 3-year single-blinded, two-arm randomized controlled trial. Individuals with depressive or anxiety disorder will be randomly allocated to a modified DBT–informed transdiagnostic psychotherapy group or a treatment-as-usual group. The intervention group will receive DBT individual therapy for 15 weeks. Power analyses revealed that the cohort should include a minimum of 250 participants. Preintervention, postintervention, and follow-up (after 3 months) assessments will be conducted. Primary outcomes will be severities of depression and anxiety rated by blind assessors. Intent-to-treat and per-protocol analyses will be conducted using the hierarchical linear model. Effect sizes will be estimated using Cohen’s d. Result To the best of our knowledge, the proposed study will be the first randomized controlled trial to evaluate the efficacy of a modified DBT intervention in managing transdiagnostic emotional disorders in Chinese individuals. Conclusion This intervention is expected to improve clinical outcomes, daily functioning, and quality of life. The trial will enrich the empirical evidence for transdiagnostic interventions, facilitating the implementation of evidence-based therapy and reducing the high prevalence and challenges (e.g., disability) of emotional disorders in the Chinese population. Trial registration number NCT05989451

Abstract This study aimed to evaluate the effect of Astragalus polysaccharides (PG2) on reducing chemotherapy-induced fatigue (CIF) and toxicity, thereby encouraging compliance to chemotherapy. This was a randomized, placebo-controlled, phase 2 study. Patients with stage II/III early breast cancer planning to undergo adjuvant anthracycline-based chemotherapy were randomly assigned to receive PG2 500 mg or placebo on days 1, 3, and 8 every 21 days. The fatigue global score (FGS) was assessed using the brief fatigue inventory (BFI)-Taiwan. The Breast Cancer-Specific Module of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaires-Core30 evaluated the health-related quality of life during the first four cycles of adjuvant chemotherapy. Overall, 66 eligible patients were equally randomized into the PG2 and placebo groups between March 01, 2018, and March 09, 2021. The mean change in the FGS and fatigue intensity did not significantly differ between both groups. However, the FGS and fatigue intensity were less aggravated in the first four cycles in the premenopausal-PG2 group than in the placebo group. Our study concluded PG2 combined with adjuvant chemotherapy can reduce CIF, insomnia, the negative effect on future perspectives, and improve global health status, especially for premenopausal patients with breast cancer. Trial registration number: NCT03314805 registered on 19/10/2017.

Abstract We have developed and validated a highly specific, versatile antibody to the extracellular domain of human LGR5 (α-LGR5). α-LGR5 detects LGR5 overexpression in >90% of colorectal cancer (CRC), hepatocellular carcinoma (HCC) and pre-B-ALL tumour cells and was used to generate an Antibody-Drug Conjugate (α-LGR5-ADC), Bispecific T-cell Engager (α-LGR5-BiTE) and Chimeric Antigen Receptor (α-LGR5-CAR). α-LGR5-ADC was the most effective modality for targeting LGR5+ cancer cells in vitro and demonstrated potent anti-tumour efficacy in a murine model of human NALM6 pre-B-ALL driving tumour attrition to less than 1% of control treatment. α-LGR5-BiTE treatment was less effective in the pre-B-ALL cancer model yet promoted a twofold reduction in tumour burden. α-LGR5-CAR-T cells also showed specific and potent LGR5+ cancer cell killing in vitro and effective tumour targeting with a fourfold decrease in pre-B-ALL tumour burden relative to controls. Taken together, we show that α-LGR5 can not only be used as a research tool and a biomarker but also provides a versatile building block for a highly effective immune therapeutic portfolio targeting a range of LGR5-expressing cancer cells.

Abstract Soft-matter-based photonic crystals like blue-phase liquid crystals (BPLC) have potential applications in wide-ranging photonic and bio-chemical systems. To date, however, there are limitations in the fabrication of large monocrystalline BPLCs. Traditional crystal-growth process involves the transition from a high-temperature disordered phase to an ordered (blue) phase and is generally slow (takes hours) with limited achievable lattice structures, and efforts to improve molecular alignment through post-crystallization field application typically prove ineffective. Here we report a systematic study on the molecular self-assembly dynamics of BPLC starting from a highly ordered phase in which all molecules are unidirectionally aligned by a strong electric field. We have discovered that, near the high-temperature end of the blue phase, if the applied field strength is then switched to an intermediate level or simply turned off, large-area monocrystalline BPLCs of various symmetries (tetragonal, orthorhombic, cubic) can be formed in minutes. Subsequent temperature tuning of the single crystal at a fixed applied field allows access to different lattice parameters and the formation of never-before-seen monoclinic structures. The formed crystals remain stable upon field removal. The diversity of stable monocrystalline BPLCs with widely tunable crystalline symmetries, band structures, and optical dispersions will significantly improve and expand their application potentials.

Abstract Aims The PIONEER‐HF and PARAGLIDE‐HF trials aimed to determine the efficacy and safety of the in‐hospital initiation of sacubitril/valsartan in patients hospitalized for AHF. However, whether the inclusion and exclusion criteria of the trials apply to patients encountered in real‐world routine care is unclear. This study aimed to investigate the applicability of the PIONEER‐HF and PARAGLIDE‐HF trials to real‐world AHF patients. Methods and results We identified 28 293 AHF hospitalized patients between August 2008 to August 2017 from the Chang Gung Research Database and classified them into four groups based on left ventricular ejection fraction (LVEF) and trial criteria. Cox proportional hazards models were used to compare the risk of HF hospitalization and cardiovascular (CV) death. We defined PIONEER‐HF eligible (n = 3683) and non‐eligible (n = 3502) patients with an LVEF ≤40%, and PARAGLIDE‐HF eligible (n = 5191) and non‐eligible (n = 5832) patients with an LVEF >40%. Over a mean follow‐up of 3.5 years, the PIONEER‐HF non‐eligible and eligible groups exhibited similar rates of HF hospitalization and CV death (41.1% vs. 41.8%, adjusted hazard ratio [aHR]: 0.95; 95% CI: 0.88–1.04). No significant difference was found in the composite outcome between PARAGLIDE‐HF non‐eligible and eligible groups (36.7% vs. 38.6%; aHR: 0.97; 95% CI: 0.90–1.04). Conclusions Using trial criteria, only 31.3% of AHF patients were eligible for sacubitril–valsartan. Yet, non‐eligible patients demonstrated similar outcomes to eligible patients, indicating a need for further evaluation of sacubitril–valsartan benefits in non‐eligible AHF patients.

In the absence of in-situ data, satellite radar altimetry, critical for studies requiring water elevation data, faces challenges in outlier removal over reservoirs, influenced by surrounding land. We present JASTER (Jason Altimetry Stand-Alone Tool for Enhanced Research), an open-source, fully automated tool processing Jason-2/3 altimetry data for water elevation time series generation over a user-defined inland water body. JASTER uses two outlier removal approaches. The first method employs interquartile range (IQR)-based filtering and K-means clustering. The second method incorporates water occurrence (WO) and Digital Elevation Model (DEM)-derived elevation thresholds. The Hampel filter embedded in JASTER further removes non-physical peaks in the time series caused by signal noise. We validated JASTER’s capabilities using 44 Jason altimeter crossings over 37 water bodies in the US and Canada. We assessed the significance of applying water occurrence and elevation thresholds, and investigated how the Hampel filter parameters and satellite crossing lengths affect accuracy. In all case studies, the Hampel filter significantly increased the consistency between JASTER-derived water elevations and in-situ data. Moreover, the DEM + WO-based method outperformed the IQR-based outlier removal approach in some cases where the greater number of altimeter footprints belonged to land instead of water.

Abstract Background Quantifying the informal caregiver burden is important for understanding the risk factors associated with caregiver overload and for evaluating the effectiveness of services provided in Long-term Care (LTC). Objective This study aimed to develop and validate a Caregiver Strain Index (CSI)-based score for quantifying the informal caregiver burden, while the original dataset did not fully cover evaluation items commonly included in international assessments. Subsequently, we utilized the CSI-based score to pinpoint key caregiver burden risk factors, examine the initial timing of LTC services adoption, and assess the impact of LTC services on reducing caregiver burden. Methods The study analyzed over 28,000 LTC cases in Southern Taiwan from August 2019 to December 2022. Through multiple regression analysis, we identified significant risk factors associated with caregiver burden and examined changes in this burden after utilizing various services. Survival analysis was employed to explore the relationship between adopting the first LTC services and varying levels of caregiver burden. Results We identified 126 significant risk factors for caregiver burden. The most critical factors included caregiving for other disabled family members or children under the age of three (β = 0.74, p

Background A mysterious skin rash (papular lesions) outbreak broke out for unknown reasons in Taiwan’s Pescadores Islands in mid-autumn 2021, causing much anxiety in the population already nervous about the ongoing COVID-19 epidemic. Objectives We conducted a field survey for possible culprit agents. Methods Skin samples were taken with rapid-glue adhesives from the affected skin. Electron microscopy from the skin samples as well as caterpillar seta was performed. Additional neurotransmitter analysis by mass spectrometry (MS) was conducted on the skin samples. Results A field survey found a large increase in caterpillars, Euproctis taiwana, in September 2021, the warmest September in recent years. Electron microscopy performed on superficial skin samples (3–6 cells thick) of affected and healthy skin (n = 5 and 3, respectively) and caterpillar setae revealed ultrastructural similarities between setae spurs (0.15–0.2 μm) and tiny pits (0.2 μm) on the affected skin as well as similar vegetative debris (0.75 μm) on both setae and affected skin. MS showed large increases in tyrosine, serine, and histamine, known mediators of arthropod insult. Conclusion The co-occurrence of E. taiwana population growth, excessive warming, and strong monsoon winds may lead to this unusual autumn outbreak in late September. The lifting of COVID-19-related travel restrictions against earlier that month probably exacerbated it.

Abstract Background Studies have demonstrated that exercise can mitigate the intensity of menstrual pain in primary dysmenorrhea, but the most effective type of exercise remains unclear. The objective of this systematic review and network meta-analysis was to evaluate the effectiveness of different exercise regimens in reducing pain associated with primary dysmenorrhoea. Methods Randomized controlled trials investigating the relationship between menstrual pain and exercise were selected from major electronic databases until February 2, 2024. The primary outcome was the effect of exercise on pain intensity measured by the mean difference on a 10-cm visual analogue scale at 4 and 8 weeks after intervention. The secondary outcome was the difference in risk of dropout at 8 weeks. The study protocol was registered as INPLASY202330050. Results This systematic review and network meta-analysis included 29 randomized controlled trials, which involved 1808 participants with primary dysmenorrhea. Exercise interventions included relaxation exercise, strength training, aerobic activity, yoga, mixed exercise, and the Kegel maneuver. Relaxation exercise was the most effective in reducing menstrual pain in 4 weeks (− 3.56; 95% confidence interval: − 5.03 to − 2.08). All exercise interventions were effective in reducing menstrual pain at 8 weeks, with reductions ranging from − 3.87 (95% CI − 5.51 to − 2.22) for relaxation exercise to − 2.75 (95% CI − 4.00 to − 1.51) for yoga, compared to the control group. Relaxation exercises were found to have a significantly lower dropout risk (− 0.11; 95% CI − 0.20 to 0.02), while none of the exercise types was associated with a higher dropout risk than the control group. Conclusion All exercise interventions were effective in reducing menstrual pain in primary dysmenorrhea after 8 weeks of intervention. However, relaxation exercise was found to be the most effective intervention at 4 and 8 weeks and had the lowest risk of dropout. Graphical Abstract

Background: To assess the quality change of our single-center pediatric colonoscopy after applying bundle for bowel preparation and general anesthesia and centralize the procedure using terminal ileum (TI) intubation rate as the main indicator. Methods: All elective colonoscopies performed for patients younger than 18 years old in MacKay Memorial Hospital from July 2015 through June 2020 (assigned to group 1, before bundle) and from August 2020 through July 2021 (assigned to group 2, after bundle) were retrospectively reviewed for demographic characteristics, indications, bowel preparation agent and cleansing level, diagnostic and therapeutic procedures, maximum intestinal level reached, and cecal intubation and total procedure time. Statistical analysis was done using P value

Summary: The CTLA-4 and PD-1 checkpoints control immune responses and are key targets in immunotherapy. Both pathways are connected via a cis interaction between CD80 and PD-L1, the ligands for CTLA-4 and PD-1, respectively. This cis interaction prevents PD-1-PD-L1 binding but is reversed by CTLA-4 trans-endocytosis of CD80. However, how CTLA-4 selectively removes CD80, but not PD-L1, is unclear. Here, we show CTLA-4-CD80 interactions are unimpeded by PD-L1 and that CTLA-4 binding with CD80 does not displace PD-L1 per se. Rather, both rigidity and bivalency of CTLA-4 molecules are required to orientate CD80 such that PD-L1 interactions are no longer permissible. Moreover, soluble CTLA-4 released PD-L1 only at specific expression levels of CD80 and PD-L1, whereas CTLA-4 trans-endocytosis released PD-L1 in all conditions. These data show that PD-L1 release from CD80 is driven by orientation and bivalent cross-linking of membrane proteins and that trans-endocytosis of CD80 efficiently promotes PD-L1 availability.

Abstract Introduction Recent evidence recommends the use of biologics in patients with severe uncontrolled type 2 chronic rhinosinusitis with nasal polyp (CRSwNP) owing to its propensity for recurrence after functional endoscopic sinus surgery (FESS). Among the type 2 biologics used for the treatment of nasal polyps, dupilumab (Dupi, anti‐IL‐4) exhibited superior efficacy and safety in indirect comparison studies. Objective This study aimed to evaluate the objective and subjective outcomes of patients with CRSwNP treated with and without adjuvant Dupi therapy after FESS. Methods Adult patients with type 2 CRSwNP who underwent FESS with adjuvant Dupi after surgery were enrolled. A matched control group without adjuvant Dupi therapy were recruited during the same period. All patients underwent nasal endoscopy and completed the sinonasal outcome test‐22 questionnaire evaluations at baseline and 3 months after surgery. Results A total of 10 patients who received postoperative adjuvant therapy with Dupi and 20 patients who underwent surgery only were included. Patients with add‐on Dupi therapy had significantly higher eosinophil cationic protein levels in the serum, eosinophil counts in peripheral blood, prevalence of asthma, and nasal polyp score at baseline. Both treatments were effective in reducing the patient's symptoms by SNOT‐22 at 3 months postoperatively. However, patients with adjuvant Dupi therapy exhibited significantly better endoscopic scores than those with surgery only (p = .022). Conclusion Surgery plays an important role in treating patients with CRSwNP, and adjuvant Dupi use may facilitate objective mucosal recovery postoperatively. Level of Evidence 4.