Does the nurse-led case management benefit rheumatoid arthritis patients in reducing distressing symptoms and C-reactive protein: a 2-year follow-up study in Taiwan.

Background: Rheumatoid arthritis (RA) is a chronic disease and may worsen over time. Today, nurse-led case management (NLCM) has been recommended to improve clinical outcomes for chronic disease patients, yet little is known regarding its impact on pain, fatigue, and C-reactive protein (CRP) among RA patients. We aimed to explore this issue among such groups via a two-group pre- and post-test approach. Methods: All subjects were recruited from one hospital in Taiwan from January 2017 to June 2018 and assigned to either a 6-month NLCM program in addition to usual care or to a control group that received usual care only. All of them were followed for 2 years. Outcomes of interests were compared at four time points: baseline, the third day after NLCM completion, and at 6 and 24 months after NLCM. Effects between them were tested using the generalized estimating equations (GEE) model after adjusting for differences at baseline. Results: A total of 50 patients in the NLCM group and 46 in the control group were recruited for data analysis. Results from the GEE model indicated that integrating NLCM into conventional care benefited patients in decreasing levels of pain and fatigue, as well as CRP value. These improvements were still observed for 2 years after NLCM. Conclusion: NLCM was shown to be helpful in lowering pain, fatigue, and CRP, which implies that NLCM may be a reference in the provision of tailored care for those affected by rheumatism.

Difficulties of Preoperative Diagnosis of Cribriform Morular Thyroid Carcinoma.

Background: Cribriform morular thyroid carcinoma has been recently renamed in the 2022 WHO classification as a thyroid tumor of uncertain histogenesis. The epidemiologic, pathological, and pathophysiological characteristics distinguish it from papillary thyroid carcinoma (PTC). Preoperative genetic testing plays a role in facilitating the differential diagnosis. Methods: This report presents a confirmed case of cribriform morular thyroid carcinoma. Initially, fine-needle aspiration cytology suggested a diagnosis of PTC. However, a genetic analysis did not reveal the typical mutations associated with follicular-cell-derived neoplasms. Results: A 31-year-old woman was found to have a thyroid nodule at the left lobe measuring 11.8 × 10.2 × 12.4 mm. Ultrasonography indicated a hypoechoic, solid nodule with regular margins. Cytology revealed a papillary structure of tall cells, leading to a PTC diagnosis. Nevertheless, the genetic analysis failed to detect mutations such as BRAF V600E, NRAS Q61R, NRAS Q61K, HRAS Q61R, or HRAS Q61K mutation or the fusion of CCDC6-RET, NCOA4-RET, PAX8-PPARG, ETV6-NTRK3, TPM3-NTRK1, IRF2BP2-NTRK1, or SQSTM1-NTRK1 in the aspirated follicular cells. The patient subsequently underwent total thyroidectomy with central lymph node dissection. Pathological examination revealed a cribriform pattern of spindle-shaped cells with morular areas. Immunohistochemical staining showed positive results for ß-catenin and TTF-1, except in the morular regions, and negative results for PAX8, thyroglobulin, and BRAF (clone VE1). The diagnosis was confirmed to be cribriform morular thyroid carcinoma. Conclusion: Significant cytological similarity exists between PTC and cribriform morular thyroid carcinoma. Preoperative genetic analysis is important to differentiate these two diseases. Cribriform morular thyroid carcinoma can be differentiated from common follicular-cell-derived tumors by the absence of typical mutations; the presence of nuclear and cytoplasmic expressions of ß-catenin; the presence of TTF-1, except in morular areas; and the absence of thyroglobulin.

Enhancing DSSCs and Photocatalytic Hydrogen Production with D-A1-A2-π-A Sensitizers Containing 10'H-Spiro[fluorene-9,9'-phenanthren]-10'-one and Benzo[c][1,2,5]thiadiazole.

Novel D-A1-A2-π-A organic sensitizers (FZ-sensitizer), utilizing spiro[fluorene-9,9'-phenanthren]-10'-one (A1) and benzo[c][1,2,5]thiadiazole(A2) moiety as two auxiliary acceptors, are synthesized and applied in dye-sensitized solar cells (DSSCs) and hydrogen production. By incorporating a bulky A1 and A2 between the donor (D) and π-bridge moiety, structural modifications inhibit molecular aggregation, while the carbonyl group enhances the capture of Li+ ions, thereby delaying charge recombination. Furthermore, the extended π-conjugation broadens the light absorption range and enhances the power conversion efficiency (PCE) of FZ-2 under AM1.5 conditions, achieving up to 5.72%. Co-sensitization with N719 and FZ-2 shows PCE of 9.60% under one sun. Under TL84 indoor light conditions, the efficiency is 29.69% at 2500 lux. FZ-sensitizers also exhibit high efficiency in photocatalytic hydrogen production. The hydrogen production activities of FZ-2 are 9190 µmol/g (1 hour) and 76582 µmol/g (12 hours) respectively, while those of FZ-1 are 7430 µmol/g (1 hour) and 64004 µmol/g (12 hours), indicating that FZ-2 can inject charges into TiO2 more efficiently and utilize them for water splitting. Stability testing of photocatalytic water splitting after 12 hours shows a turnover number (TON) of 4249 for FZ-1 and 5378 for FZ-2.

Developing a Five-Minute Normative Database of Heart Rate Variability for Diagnosing Cardiac Autonomic Dysregulation for Patients with Major Depressive Disorder.

Heart rate variability (HRV) is related to cardiac vagal control and emotional regulation and an index for cardiac vagal control and cardiac autonomic activity. This study aimed to develop the Taiwan HRV normative database covering individuals aged 20 to 70 years and to assess its diagnosing validity in patients with major depressive disorder (MDD). A total of 311 healthy participants were in the HRV normative database and divided into five groups in 10-year age groups, and then the means and standard deviations of the HRV indices were calculated. We recruited 272 patients with MDD for cross-validation, compared their HRV indices with the normative database, and then converted them to Z-scores to explore the deviation of HRV in MDD patients from healthy groups. The results found a gradual decline in HRV indices with advancing age in the HC group, and females in the HC group exhibit higher cardiac vagal control and parasympathetic activity than males. Conversely, patients in the MDD group demonstrate lower HRV indices than those in the HC group, with their symptoms of depression and anxiety showing a negative correlation with HRV indices. The Taiwan HRV normative database has good psychometric characteristics of cross-validation.

The Accompanying Effect in Responses to Auditory Perturbations: Unconscious Vocal Adjustments to Unperturbed Parameters.

PURPOSE: The present study examined whether participants respond to unperturbed parameters while experiencing specific perturbations in auditory feedback. For instance, we aim to determine if speakers adjust voice loudness when only pitch is artificially altered in auditory feedback. This phenomenon is referred to as the "accompanying effect" in the present study. METHOD: Thirty native Mandarin speakers were asked to sustain the vowel /ɛ/ for 3 s while their auditory feedback underwent single shifts in one of the three distinct ways: pitch shift (±100 cents; coded as PT), loudness shift (±6 dB; coded as LD), or first formant (F1) shift (±100 Hz; coded as FM). Participants were instructed to ignore the perturbations in their auditory feedback. Response types were categorized based on pitch, loudness, and F1 for each individual trial, such as Popp_Lopp_Fopp indicating opposing responses in all three domains. RESULTS: The accompanying effect appeared 93% of the time. Bayesian Poisson regression models indicate that opposing responses in all three domains (Popp_Lopp_Fopp) were the most prevalent response type across the conditions (PT, LD, and FM). The more frequently used response types exhibited opposing responses and significantly larger response curves than the less frequently used response types. Following responses became more prevalent only when the perturbed stimuli were perceived as voices from someone else (external references), particularly in the FM condition. In terms of isotropy, loudness and F1 tended to change in the same direction rather than loudness and pitch. CONCLUSION: The presence of the accompanying effect suggests that the motor systems responsible for regulating pitch, loudness, and formants are not entirely independent but rather interconnected to some degree.

The effect of statin treatment on glucose homeostasis in prediabetic individuals: A prospective, randomized, controlled trial.

BACKGROUND: This study aimed to evaluate the effects of rosuvastatin and pravastatin on glucose homeostasis and other biomarkers in individuals at high risk of developing diabetes. METHODS: This prospective, randomized, open-labeled, and controlled trial included prediabetic individuals with impaired fasting glucose and impaired glucose tolerance. The participants were randomized into three groups: rosuvastatin (10 mg), pravastatin (40 mg), or control. Biomarkers of diabetes and glucose and insulin responses to oral glucose tolerance tests were assessed at baseline and after 6 months of treatment. The primary outcomes were comparisons of glucose homeostasis and biomarkers of diabetes among groups at baseline and after 6 months of treatment. RESULTS: A total of 141 subjects with impaired fasting glucose (IFG) were screened and 41 participants were recruited. Twenty-two subjects were randomized to either the rosuvastatin or pravastatin group and 19 subjects were assigned to the control group. After 6 months of treatment, all groups had similar cholesterol and triglyceride levels. Likewise, HbA1c levels, glucose, and insulin excursions during oral glucose tolerance test, were similar among the three groups. However, compared to the other groups, the rosuvastatin group had higher homeostasis model assessment for insulin resistance (HOMA-IR) (insulin resistance) and a lower Matsuda index (insulin sensitivity). CONCLUSION: Among prediabetic individuals with IFG, rosuvastatin treatment was associated with increased insulin resistance and decreased insulin sensitivity compared to pravastatin and control groups. Further research is needed to elucidate the underlying mechanisms and clinical implications of these findings.

Neural mechanisms of resource allocation in working memory.

To mitigate capacity limits of working memory, people allocate resources according to an item's relevance. However, the neural mechanisms supporting such a critical operation remain unknown. Here, we developed computational neuroimaging methods to decode and demix neural responses associated with multiple items in working memory with different priorities. In striate and extrastriate cortex, the gain of neural responses tracked the priority of memoranda. Higher-priority memoranda were decoded with smaller error and lower uncertainty. Moreover, these neural differences predicted behavioral differences in memory prioritization. Remarkably, trialwise variability in the magnitude of delay activity in frontal cortex predicted differences in decoded precision between low and high-priority items in visual cortex. These results suggest a model in which feedback signals broadcast from frontal cortex sculpt the gain of memory representations in visual cortex according to behavioral relevance, thus, identifying a neural mechanism for resource allocation.

Molecular Diagnosis of Nasopharyngeal Carcinoma: Past and Future.

Nasopharyngeal carcinoma (NPC) is a malignant tumor originated from the nasopharynx epithelial cells and has been linked with Epstein-Barr virus (EBV) infection, dietary habits, environmental and genetic factors. It is a common malignancy in Southeast Asia, especially with gender preference among men. Due to its non-specific symptoms, NPC is often diagnosed at a late stage. Thus, the molecular diagnosis of NPC plays a crucial role in early detection, treatment selection, disease monitoring, and prognosis prediction. This review aims to provide a summary of the current state and the latest emerging molecular diagnostic techniques for NPC, including EBV-related biomarkers, gene mutations, liquid biopsy, and DNA methylation. Challenges and potential future directions of NPC molecular diagnosis will be discussed.

Mycoplasma genitalium infection and resistance-associated mutations to macrolides and fluoroquinolones among high-risk patients in Taiwan.

BACKGROUND: Mycoplasma genitalium is an emerging etiology of sexually transmitted infections (STIs) with increasing resistance to antimicrobials. Surveillance on the epidemiology of M. genitalium infection and antimicrobial resistance is warranted. METHODS: Between September 2021 and August 2023, people with HIV (PWH) and people without HIV (PWoH) at risk of STIs were screened for M. genitalium infection using a multiplex polymerase-chain-reaction assay of specimens collected from the rectum, urethra, oral cavity, and vagina. The prevalences of resistance-associated mutations (RAMs) of M. genitalium to fluoroquinolones, macrolides, and tetracycline were investigated. RESULTS: During the 2-year study period, 1021 participants were enrolled, including 531 PWH and 490 PWoH. Overall, 83 (8.1%) and 34 (7.6%) participants had M. genitalium infection at baseline and during follow-up, respectively, with the rectum being the most common site of detection (61.5%). With the first course of antimicrobial treatment, 27 of 63 (42.9%) participants with M. genitalium infection were cured during follow-up, including 24 of 58 (41.4%) who received doxycycline monotherapy. The prevalence of RAMs to macrolides, fluoroquinolones, and tetracyclines at baseline were 24.3%, 22.4%, and 7.9%, respectively. Though PWH had more M. genitalium infection (10.2% vs 5.9%, p = 0.01), a higher rate of RAMs to macrolides (41.0% vs 14.7%, p < 0.01) was found in PWoH. CONCLUSIONS: Among high-risk populations, the prevalence of M. genitalium infection was 8.1%. The overall genotypic resistance of M. genitalium to macrolides and fluoroquinolones was moderately high in Taiwan. Detection of M. genitalium infection and antimicrobial resistance is warranted to ensure resistance-guided antimicrobial treatments to be administered.

The Effect and Mechanism of Astragalus Polysaccharides on T Cells and Macrophages in Inhibiting Prostate Cancer.

BACKGROUND: The impact and underlying mechanisms of astragalus polysaccharide (APS) on prostate cancer, particularly its role in immunomodulation, remain inadequately elucidated. METHODS: This study employed the XTT assay for assessing proliferation in prostate cancer cells and macrophages. T cell proliferation was determined using the Carboxyfluorescein diacetate succinimidyl ester labeling assay. APS's effect on T cells and macrophages was scrutinized via flow cytometry, Western blot analysis, ELISA, quantitative PCR and cytokine membrane arrays. The effect of APS on interaction between PD-L1 and PD-1 was investigated by the PD-L1/PD-1 homogeneous assay. Additionally, the impact of conditioned medium from T cells and macrophages on PC-3 cell migration was explored through migration assays. RESULTS: It was observed that APS at concentrations of 1 and 5 mg/mL enhanced the proliferation of CD8+ T cells. At a concentration of 5 mg/mL, APS activated both CD4+ and CD8+ T cells, attenuated PD-L1 expression in prostate cancer cells stimulated with interferon gamma (IFN-γ) or oxaliplatin, and moderately decreased the population of PD-1+ CD4+ and PD-1+ CD8+ T cells. Furthermore, APS at this concentration impeded the interaction between PD-L1 and PD-1, inhibited the promotion of prostate cancer migration mediated by RAW 264.7 cells, THP-1 cells, CD4+ T cells, and CD8+ T cells, and initiated apoptosis in prostate cancer cells treated with conditioned medium from APS (5 mg/mL)-treated CD8+ T cells, RAW 264.7 cells, or THP-1 cells. CONCLUSION: The findings indicate a potential role of 5 mg/mL APS in modulating the PD-1/PD-L1 pathway and influencing the immune response, encompassing T cells and macrophages. Consequently, further in vivo research is recommended to assess the efficacy of APS.

Sexually transmitted coinfections among at-risk HIV-positive MSM: implications for optimal preemptive treatment.

Background: Concurrent sexually transmitted infections (STIs) are common in sexually active populations. We aimed to estimate the prevalence and coinfection rates of bacterial STIs among sexually active, HIV-positive men who have sex with men (MSM), and to assess the potential benefits of different combination treatment regimens in managing concurrent bacterial STIs. Methods: From September 2021 to September 2023, HIV-positive MSM underwent STI testing when they had symptoms suggestive of STIs or recently acquired hepatitis C virus (HCV) infection or early syphilis. The oral rinse, rectal swab, and urethral swab specimens were tested for Chlamydia trachomatis, Neisseria gonorrhoeae, Mycoplasma spp., Ureaplasma spp., and Trichomonas vaginalis with the use of multiplex real-time polymerase-chain-reaction assays. The estimated coinfection rates were used to evaluate the benefits of different combination treatment regimens for managing coinfections. Results: During the study period, 535 participants (median age, 37 years; and CD4 count, 615 cells/mm3) were enrolled. On their first visits, at least one bacterial pathogen was detected in 57.9% and concomitant bacterial infections were found in 32.9% of the participants. The most commonly identified pathogen was U. urealyticum (36.3%), followed by C. trachomatis (22.8%), and N. gonorrhoeae (19.8%). The factors associated with any bacterial STIs included older age (per 1-year increase, adjusted odds ratio [AOR], 0.97; 95% confidence interval [CI], 0.95-1.00), early syphilis (AOR, 1.87; 95% CI, 1.22-2.84), and having more than 5 sex partners in the preceding 3 months (AOR, 2.08, 95% CI, 1.07-4.06). A combination therapy of benzathine penicillin G with a 7-day course of doxycycline could simultaneously treat 27.1% of C. trachomatis coinfections in participants with early syphilis, while a combination therapy of ceftriaxone with doxycycline could simultaneously treat 40.6% of chlamydial coinfections in participants with gonorrhea. Conclusion: Bacterial STIs were prevalent and concomitant infections were not uncommon among sexually active, HIV-positive MSM, supporting regular screening for bacterial STIs. The effectiveness of preemptive use of doxycycline as combination therapy for concurrent STIs warrants more investigations.

Impact of programmed cell death protein 1 inhibitor therapy on the survival of patients with advanced or recurrent uterine cancers: a meta-analysis.

Introduction: No prior meta-analysis has investigated the impact of programmed cell death protein 1 (PD-1) inhibitor therapy on survival outcomes in patients with advanced or recurrent uterine cancers (including both corpus and cervical cancers). Methods: A comprehensive search of PubMed and Embase databases was conducted, covering the past 10 years (up to August 2023) and encompassing all clinical research related to uterine cancer. Five randomized controlled trials and one cohort study met the inclusion criteria and were included in the meta-analysis. Data on patient demographics, clinical characteristics, treatment regimens, and survival outcomes were extracted. Hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS), as well as the relative risk of grade 3 or higher adverse events, were pooled using random-effects models. Results: Patients receiving PD-1 inhibitors had better OS (HR, 0.65, 95% CI, 0.59-0.72; P<.001) and PFS (HR, 0.59, 95% CI, 0.49-0.70; P<.001) than those receiving variable non-PD-1 inhibitor therapies among 3452 uterine cancer patients. The leave-one-out meta-analysis of the HR of OS showed no individual study impact on the estimation of the overall effect size. Subgroup analysis revealed better OS in the PD-1 inhibitors use than the controls in cervical cancer (HR, 0.68, 95% CI, 0.59-0.79), endometrial cancer (HR, 0.62, 95% CI, 0.54-0.72), and pembrolizumab use (HR, 0.66, 95% CI, 0.57-0.75) subgroups. Patients with advanced cervical cancer, who had CPS > 1, receiving PD-1 inhibitors have statistically significant benefits in OS compared to controls (HR, 0.65, 95% CI, 0.53-0.80). The pooled HR for overall survival was 0.71 (95% CI, 0.60-0.82; P<.001) in patients who received PD-1 inhibitors as compared to those who did not receive PD-1 inhibitors in proficient mismatch repair (MMR) endometrial cancer patients. However, in deficient MMR patients, the HR was 0.30 (95% CI, 0.13-0.70). The relative risk of grade 3 or higher adverse events was not higher in the PD-1 inhibitor group (relative risk, 1.12, 95% CI, 0.98-1.27). Conclusion: Survival was significantly better using PD-1 inhibitor therapy than variable non-PD-1 inhibitor chemotherapies among patients with advanced or recurrent uterine cancers.

The effect of craniocervical flexion and neck endurance exercises plus pulmonary rehabilitation on pulmonary function in spinal cord injury: a pilot single-blinded randomised controlled trial.

STUDY DESIGN: Randomised controlled trial with computerised allocation, assessor blinding and intention-to-treat analysis. OBJECTIVE: This study wanted to prove that cervicocranial flexion exercise (CCFE) and superficial neck flexor endurance training combined with common pulmonary rehabilitation is feasible for improving spinal cord injury people's pulmonary function. SETTING: Taoyuan General Hospital, Ministry of Health and Welfare: Department of Physiotherapy, Taiwan. METHOD: Thirteen individuals who had sustained spinal cord injury for less than a year were recruited and randomised assigned into two groups. The experimental group was assigned CCFEs and neck flexor endurance training plus normal cardiopulmonary rehabilitation. The control group was assigned general neck stretching exercises plus cardiopulmonary rehabilitation. Lung function parameters such as forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1), FEV1/FVC, peak expiratory flow rate (PEFR), inspiratory capacity (IC), dyspnoea, pain, and neck stiffness were recorded once a week as short-term outcome measure. RESULT: The experimental group showed significant time effects for FVC (pre-therapy: 80.4 ± 21.4, post-therapy: 86.9 ± 16.9, p = 0.021, 95% CI: 0.00-0.26) and PEFR (pre-therapy: 67.0 ± 33.4; post-therapy: 78.4 ± 26.9, p = 0.042, 95% CI: 0.00-0.22) after the therapy course. Furthermore, the experimental group showed significant time effects for BDI (experimental group: 6.3 ± 3.0; control group: 10.8 ± 1.6, p = 0.012, 95% CI: 0.00-0.21). CONCLUSION: The exercise regime for the experimental group could efficiently increase lung function due to the following three reasons: first, respiratory accessory muscle endurance increases through training. Second, posture becomes less kyphosis resulting increasing lung volume. Third, the ratio between superficial and deep neck flexor is more synchronised. IRB TRIAL REGISTRATION: TYGH108045. CLINICAL TRIAL REGISTRATION: NCT04500223.

Urinary cadmium concentration is associated with the severity and clinical outcomes of COVID-19: a bicenter observational cohort study.

BACKGROUND: Cadmium and nickel exposure can cause oxidative stress, induce inflammation, inhibit immune function, and therefore has significant impacts on the pathogenesis and severity of many diseases. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can also provoke oxidative stress and the dysregulation of inflammatory and immune responses. This study aimed to assess the potential associations of cadmium and nickel exposure with the severity and clinical outcomes of patients with coronavirus disease 2019 (COVID-19). METHODS: We performed a retrospective, observational, bicenter cohort analysis of patients with SARS-CoV-2 infection in Taiwan between June 2022 and July 2023. Cadmium and nickel concentrations in blood and urine were measured within 3 days of the diagnosis of acute SARS-CoV-2 infection, and the severity and clinical outcomes of patients with COVID-19 were analyzed. RESULTS: A total of 574 patients were analyzed and divided into a severe COVID-19 group (hospitalized patients) (n = 252; 43.9%), and non-severe COVID-19 group (n = 322; 56.1%). The overall in-hospital mortality rate was 11.8% (n = 68). The severe COVID-19 patients were older, had significantly more comorbidities, and significantly higher neutrophil/lymphocyte ratio, C-reactive protein, and interleukin-6 than the non-severe COVID-19 patients (all p < 0.05). Blood and urine cadmium and urine nickel concentrations were significantly higher in the severe COVID-19 patients than in the non-severe COVID-19 patients. Among the severe COVID-19 patients, those in higher urine cadmium/creatinine quartiles had a significantly higher risk of organ failure (i.e., higher APACHE II and SOFA scores), higher neutrophil/lymphocyte ratio, lower PaO2/FiO2 requiring higher invasive mechanical ventilation support, higher risk of acute respiratory distress syndrome, and higher 60-, 90-day, and all-cause hospital mortality (all p < 0.05). Multivariable logistic regression models revealed that urine cadmium/creatinine was independently associated with severe COVID-19 (adjusted OR 1.643 [95% CI 1.060-2.547], p = 0.026), and that a urine cadmium/creatinine value > 2.05 µg/g had the highest predictive value (adjusted OR 5.349, [95% CI 1.118-25.580], p = 0.036). CONCLUSIONS: Urine cadmium concentration in the early course of COVID-19 could predict the severity and clinical outcomes of patients and was independently associated with the risk of severe COVID-19.

Soluble tumor necrosis factor receptor type 1 is an alternative marker of urinary albumin-creatinine ratio and estimated glomerular filtration rate for predicting the decline of renal function in subjects with type 2 diabetes mellitus.

BACKGROUND: Urinary albumin-creatinine ratio (UACR) and estimated glomerular filtration rates (eGFR) help predict worsening diabetic kidney disease (DKD) but have their limitations. Soluble tumor necrosis factor receptor type 1 (sTNFR1) is a biomarker of DKD. The predictive abilities of sTNFR1 and UACR plus eGFR have not been compared. METHODS: This prospective cohort study included patients with type 2 diabetes (T2D) to identify the risk factors of worsening DKD. Renal events were defined as > 30 % loss in eGFR based on consecutive tests after 6 months. The associations of sTNFR1, UACR, and eGFR levels and the risks of renal events were tested using a Cox regression model and the area under the curve (AUC) was compared between sTNFR1 levels and UACR plus eGFR using receiver-operating characteristic (ROC) analysis. The accuracy of stratification was evaluated using Kaplan-Meier analysis. RESULTS: Levels of sTNFR1 and UACR were associated with risks of > 30 % decline in eGFR after adjusting for relevant factors. The association between sTNFR1 levels and renal outcomes was independent of UACR and eGFR at baseline. The AUC of sTNFR1 level was comparable with that of combined UACR and eGFR (0.73 vs. 0.71, respectively, p = 0.72) and the results persisted for quartile groups of sTNFR1 and risk categories of Kidney Disease: Improving Global Outcomes (KDIGO) (0.70 vs. 0.71, respectively, p = 0.84). Both stratifications by sTNFR1 levels and KDIGO were accurate. CONCLUSION: sTNFR1 could be an alternative marker for identifying patients with diabetes at risk of declining renal function.

Age at lung cancer diagnosis in females versus males who never smoke by race and ethnicity.

BACKGROUND: We characterized age at diagnosis and estimated sex differences for lung cancer and its histological subtypes among individuals who never smoke. METHODS: We analyzed the distribution of age at lung cancer diagnosis in 33,793 individuals across 8 cohort studies and two national registries from East Asia, the United States (US) and the United Kingdom (UK). Student's t-tests were used to assess the study population differences (Δ years) in age at diagnosis comparing females and males who never smoke across subgroups defined by race/ethnicity, geographic location, and histological subtypes. RESULTS: We found that among Chinese individuals diagnosed with lung cancer who never smoke, females were diagnosed with lung cancer younger than males in the Taiwan Cancer Registry (n = 29,832) (Δ years = -2.2 (95% confidence interval (CI):-2.5, -1.9), in Shanghai (n = 1049) (Δ years = -1.6 (95% CI:-2.9, -0.3), and in Sutter Health and Kaiser Permanente Hawai'i in the US (n = 82) (Δ years = -11.3 (95% CI: -17.7, -4.9). While there was a suggestion of similar patterns in African American and non-Hispanic White individuals. the estimated differences were not consistent across studies and were not statistically significant. CONCLUSIONS: We found evidence of sex differences for age at lung cancer diagnosis among individuals who never smoke.

ASPM stabilizes the NOTCH intracellular domain 1 and promotes oncogenesis by blocking FBXW7 binding in hepatocellular carcinoma cells.

Notch signaling is aberrantly activated in approximately 30% of hepatocellular carcinoma (HCC), significantly contributing to tumorigenesis and disease progression. Expression of the major Notch receptor, NOTCH1, is upregulated in HCC cells and correlates with advanced disease stages, although the molecular mechanisms underlying its overexpression remain unclear. Here, we report that expression of the intracellular domain of NOTCH1 (NICD1) is upregulated in HCC cells due to antagonism between the E3-ubiquitin ligase F-box/WD repeat-containing protein 7 (FBXW7) and the large scaffold protein abnormal spindle-like microcephaly-associated protein (ASPM) isoform 1 (ASPM-i1). Mechanistically, FBXW7-mediated polyubiquitination and the subsequent proteasomal degradation of NICD1 are hampered by the interaction of NICD1 with ASPM-i1, thereby stabilizing NICD1 and rendering HCC cells responsive to stimulation by Notch ligands. Consistently, downregulating ASPM-i1 expression reduced the protein abundance of NICD1 but not its FBXW7-binding-deficient mutant. Reinforcing the oncogenic function of this regulatory module, the forced expression of NICD1 significantly restored the tumorigenic potential of ASPM-i1-deficient HCC cells. Echoing these findings, NICD1 was found to be strongly co-expressed with ASPM-i1 in cancer cells in human HCC tissues (P < 0.001). In conclusion, our study identifies a novel Notch signaling regulatory mechanism mediated by protein-protein interaction between NICD1, FBXW7, and ASPM-i1 in HCC cells, representing a targetable vulnerability in human HCC.

Cyclic increase in the ADAMTS1-L1CAM-EGFR axis promotes the EMT and cervical lymph node metastasis of oral squamous cell carcinoma.

The matrix metalloprotease A disintegrin and metalloprotease with thrombospondin motifs 1 (ADAMTS1) was reported to be involved in tumor progression in several cancer types, but its contributions appear discrepant. At present, the role of ADAMTS1 in oral squamous cell carcinoma (SCC; OSCC) remains unclear. Herein, The Cancer Genome Atlas (TCGA) database showed that ADAMTS1 transcripts were downregulated in head and neck SCC (HNSCC) tissues compared to normal tissues, but ADAMTS1 levels were correlated with poorer prognoses of HNSCC patients. In vitro, we observed that ADAMTS1 expression levels were correlated with the invasive abilities of four OSCC cell lines, HSC-3, SCC9, HSC-3M, and SAS. Knockdown of ADAMTS1 in OSCC cells led to a decrease and its overexpression led to an increase in cell-invasive abilities in vitro as well as tumor growth and lymph node (LN) metastasis in OSCC xenografts. Mechanistic investigations showed that the cyclic increase in ADAMTS1-L1 cell adhesion molecule (L1CAM) axis-mediated epidermal growth factor receptor (EGFR) activation led to exacerbation of the invasive abilities of OSCC cells via inducing epithelial-mesenchymal transition (EMT) progression. Clinical analyses revealed that ADAMTS1, L1CAM, and EGFR levels were all correlated with worse prognoses of HNSCC patients, and patients with ADAMTS1high/L1CAMhigh or EGFRhigh tumors had the shortest overall and disease-specific survival times. As to therapeutic aspects, we discovered that an edible plant-derived flavonoid, apigenin (API), drastically inhibited expression of the ADAMTS1-L1CAM-EGFR axis and reduced the ADAMTS1-triggered invasion and LN metastasis of OSCC cells in vitro and in vivo. Most importantly, API treatment significantly prolonged survival rates of xenograft mice with OSCC. In summary, ADAMTS1 may be a useful biomarker for predicting OSCC progression, and API potentially retarded OSCC progression by targeting the ADAMTS1-L1CAM-EGFR signaling pathway.

Deep learning based automated left ventricle segmentation and flow quantification in 4D flow cardiac MRI.

BACKGROUND: 4D flow MRI enables assessment of cardiac function and intra-cardiac blood flow dynamics from a single acquisition. However, due to the poor contrast between the chambers and surrounding tissue, quantitative analysis relies on the segmentation derived from a registered cine MRI acquisition. This requires an additional acquisition and is prone to imperfect spatial and temporal inter-scan alignment. Therefore, in this work we developed and evaluated deep learning-based methods to segment the left ventricle (LV) from 4D flow MRI directly. METHODS: We compared five deep learning-based approaches with different network structures, data pre-processing and feature fusion methods. For the data pre-processing, the 4D flow MRI data was reformatted into a stack of short-axis view slices. Two feature fusion approaches were proposed to integrate the features from magnitude and velocity images. The networks were trained and evaluated on an in-house dataset of 101 subjects with 67,567 2D images and 3030 3D volumes. The performance was evaluated using various metrics including Dice, average surface distance (ASD), end-diastolic volume (EDV), end-systolic volume (ESV), LV ejection fraction (LVEF), LV blood flow kinetic energy (KE) and LV flow components. The Monte Carlo dropout method was used to assess the confidence and to describe the uncertainty area in the segmentation results. RESULTS: Among the five models, the model combining 2D U-Net with late fusion method operating on short-axis reformatted 4D flow volumes achieved the best results with Dice of 84.52% and ASD of 3.14 mm. The best averaged absolute and relative error between manual and automated segmentation for EDV, ESV, LVEF and KE was 19.93 ml (10.39%), 17.38 ml (22.22%), 7.37% (13.93%) and 0.07 mJ (5.61%), respectively. Flow component results derived from automated segmentation showed high correlation and small average error compared to results derived from manual segmentation. CONCLUSIONS: Deep learning-based methods can achieve accurate automated LV segmentation and subsequent quantification of volumetric and hemodynamic LV parameters from 4D flow MRI without requiring an additional cine MRI acquisition.

Multiplexed multicolor antiviral assay amenable for high-throughput research.

To curb viral epidemics and pandemics, antiviral drugs are needed with activity against entire genera or families of viruses. Here, we develop a cell-based multiplex antiviral assay for high-throughput screening against multiple viruses at once, as demonstrated by using three distantly related orthoflaviviruses: dengue, Japanese encephalitis and yellow fever virus. Each virus is tagged with a distinct fluorescent protein, enabling individual monitoring in cell culture through high-content imaging. Specific antisera and small-molecule inhibitors are employed to validate that multiplexing approach yields comparable inhibition profiles to single-virus infection assays. To facilitate downstream analysis, a kernel is developed to deconvolute and reduce the multidimensional quantitative data to three cartesian coordinates. The methodology is applicable to viruses from different families as exemplified by co-infections with chikungunya, parainfluenza and Bunyamwera viruses. The multiplex approach is expected to facilitate the discovery of broader-spectrum antivirals, as shown in a pilot screen of approximately 1200 drug-like small-molecules.