Access to New Clinic Appointments for Patients With Cancer.

Importance: Racial and ethnic disparities have been observed in the outpatient visit rates for specialist care, including cancer care; however, little is known about patients' experience at the critical step of attempting to access new clinic appointments for cancer care. Objective: To determine simulated English-speaking, Spanish-speaking, and Mandarin-speaking patient callers' ability to access new clinic appointments for 3 cancer types (colon, lung, and thyroid cancer) that disproportionately impact Hispanic and Asian populations. Design, Setting, and Participants: This cross-sectional audit study was conducted between November 2021 and March 2023 using 479 clinic telephone numbers that were provided by the hospital general information personnel at 143 hospitals located across 12 US states. Using standardized scripts, trained research personnel assigned to the roles of English-speaking, Spanish-speaking, and Mandarin-speaking patients called the telephone number for a clinic that treats colon, lung, or thyroid cancer to inquire about a new clinic appointment. Data analysis was conducted from June to September 2023. Main Outcomes and Measures: The primary outcome was whether the simulated patient caller was able to access cancer care (binary variable, yes or no), which was defined to include being provided with a clinic appointment date or scheduling information. Multivariable logistic regression analysis was performed to determine factors independently associated with simulated patient callers being able to access cancer care. Results: Of 985 total calls (399 English calls; 302 Spanish calls; 284 Mandarin calls), simulated patient callers accessed cancer care in 409 calls (41.5%). Differences were observed based on language type, with simulated English-speaking patient callers significantly more likely to access cancer care compared with simulated Spanish-speaking and Mandarin-speaking patient callers (English, 245 calls [61.4%]; Spanish, 110 calls [36.4%]; Mandarin, 54 calls [19.0%]; P < .001). A substantial number of calls ended due to linguistic barriers (291 of 586 Spanish or Mandarin calls [49.7%]) and workflow barriers (239 of 985 calls [24.3%]). Compared with English-speaking simulated patient callers, the odds of accessing cancer care were lower for Spanish-speaking simulated patient callers (adjusted odds ratio [aOR], 0.34; 95% CI, 0.25-0.46) and Mandarin-speaking simulated patient callers (aOR, 0.13; 95% CI, 0.09-0.19). Compared with contacting clinics affiliated with teaching hospitals, callers had lower odds of accessing cancer care when contacting clinics that were affiliated with nonteaching hospitals (aOR, 0.53; 95% CI, 0.40-0.70). Conclusions and Relevance: In this cross-sectional audit study, simulated patient callers encountered substantial barriers when attempting to access clinic appointments for cancer care. These findings suggest that interventions focused on mitigating these barriers are necessary to increase access to cancer care for all patients.

Analysis of bioactive compounds in cinnamon leaves and preparation of nanoemulsion and byproducts for improving Parkinson's disease in rats.

Introduction: Cinnamomum osmophloeum Kanehira (C. osmophloeum), a broad-leaved tree species of Taiwan, contains phenolic acids, flavonoids, and phenylpropanoids such as cinnamaldehyde and cinnamic acid in leaves. Many reports have shown that the cinnamon leaf extract possesses anti-inflammatory, hypoglycemic, hypolipidemic and neuroprotective functions. This study aims to analyze bioactive compounds in C. osmophloeum (cinnamon leaves) by UPLC-MS/MS and prepare hydrosol, cinnamon leaf extract and cinnamon leaf nanoemulsion for comparison in improving Parkinson's disease (PD) in rats. Methods: After extraction and determination of total phenolic and total flavonoid contents, cinnamaldehyde and the other bioactive compounds were analyzed in cinnamon leaves and hydrosol by UPLC-MS/MS. Cinnamon leaf nanoemulsion was prepared by mixing a suitable proportion of cinnamon leaf extract, soybean oil, lecithin, Tween 80 and deionized water, followed by characterization of particle size and polydispersity index by dynamic light scattering analyzer, particle size and shape by transmission electron microscope, encapsulation efficiency, as well as storage and heating stability. Fifty-six male Sprague-Dawley rats aged 8 weeks were divided into seven groups with group 1 as control (sunflower oil) and group 2 as induction (2 mg/kg bw rotenone in sunflower oil plus 10 mL/kg bw saline), while the other groups including rotenone injection (2 mg/kg bw) followed by high-dose of 60 mg/kg bw (group 3) or low-dose of 20 mg/kg bw (group 4) for tube feeding of cinnamon leaf extract or cinnamon leaf nanoemulsion at the same doses (groups 5 and 6) every day for 5 weeks as well as group 7 with rotenone plus hydrosol containing 0.5 g cinnamon leaf powder at a dose of 10 mL/kg bw. Biochemical analysis of brain tissue (striatum and midbrain) was done to determine dopamine, α-synuclein, tyrosine hydroxylase, superoxide dismutase, catalase, glutathione peroxidase and malondialdehyde contents by using commercial kits, while catalepsy performed by bar test. Results and discussion: An extraction solvent of 80% ethanol was found to be the most optimal with a high yield of 15 bioactive compounds being obtained following UPLC analysis. A triple quadrupole tandem mass spectrometer with electrospray ionization mode was used for identification and quantitation, with cinnamaldehyde present at the highest amount (17985.2 µg/g). The cinnamon leaf nanoemulsion was successfully prepared with the mean particle size, zeta potential, polydispersity index and encapsulation efficiency being 30.1 nm, -43.1 mV, 0.149 and 91.6%, respectively. A high stability of cinnamon leaf nanoemulsion was shown over a 90-day storage period at 4 and heating at 100 for 2 h. Animal experiments revealed that the treatments of cinnamon leaf extract, nanoemulsion and hydrosol increased the dopamine contents from 17.08% to 49.39% and tyrosine hydroxylase levels from 17.07% to 25.59%, while reduced the α-synuclein levels from 17.56% to 15.95% in the striatum of rats. Additionally, in the midbrain of rats, an elevation of activities of superoxide dismutase (6.69-16.82%), catalase (8.56-16.94%), and glutathione peroxidase (2.09-16.94%) was shown, while the malondialdehyde content declined by 15.47-22.47%. Comparatively, the high-dose nanoemulsion exerted the most pronounced effect in improving PD in rats and may be a promising candidate for the development of health food or botanic drug.

Metabolic genes, a potential predictor of prognosis and immunogenicity of clear cell renal cell carcinoma.

Clear cell renal cell carcinoma (ccRCC) is the most common subtype of renal cell carcinoma (RCC). Many ccRCCs are diagnosed at an advanced stage due to the lack of early symptoms, with a high mortality rate and a poor prognosis. The occurrence and development of ccRCC are closely related to metabolic disorders. This study aims to explore the relationship between metabolic genes and prognosis, immune microenvironment, and tumor development of ccRCC. Using data from TCGA, GEO, and ArrayExpress, we successfully established a risk model (riskScore) based on 4 metabolic genes (MGs) that can accurately predict the prognosis and immune microenvironment of ccRCCs. In addition, we determined the role of PAFAH2 in suppressing tumor cell proliferation and migration in ccRCC in vitro. Our research may shed new light on ccRCC patients' prognosis and treatment management.

Risks of Topical Carbonic Anhydrase Inhibitors in Glaucoma Patients With Chronic Kidney Disease: A Nationwide Population-Based Study.

PURPOSE: To investigate the risks of metabolic acidosis and renal outcomes after topical carbonic anhydrase inhibitor (CAI) use in patients with both primary open-angle glaucoma (POAG) and advanced chronic kidney disease (CKD). DESIGN: Nationwide, population-based cohort study. METHODS: This study was conducted with population data from Taiwan's National Health Insurance (NHI) Research Database between January 2000 and June 2009. Patients with advanced CKD who were diagnosed with glaucoma (International Classification of Diseases, Ninth Revision [ICD-9] code 365) and had been receiving eye drops for glaucoma (including carbonic anhydrase inhibitors selected by NHI drug code) were enrolled. Using Kaplan-Meier methods, we compared the cumulative incidence of mortality, long-term dialysis, and cumulative incidence of metabolic acidosis over time between CAI users and CAI non-users. Primary outcomes comprised mortality, renal outcome (progression to hemodialysis), and metabolic acidosis. RESULTS: In this cohort, topical CAI users had a higher incidence of long-term dialysis than non-users (incidence = 1,216.85 vs 764.17 events per 100 patient-years; adjusted hazard ratio = 1.17, 95% CI = 1.01-1.37). Hospital admissions due to metabolic acidosis were higher in CAI users compared with non-users (incidence = 21.54 vs 11.87 events per 100 patient-years; adjusted hazard ratio = 1.89, 95% CI = 1.07-3.36). CONCLUSIONS: Topical CAIs may be associated with higher risks of long-term dialysis and metabolic acidosis in patients with POAG and pre-dialysis advanced CKD. Therefore, topical CAIs should be used with caution in advanced CKD patients.

Identification of thrombotic biomarkers in orthopedic surgery patients by plasma proteomics.

BACKGROUND: Due to the poor specificity of D-dimer, more accurate thrombus biomarkers are clinically needed to improve the diagnostic power of VTE. METHODS: The plasma samples were classified into low-risk group (n = 6) and high-risk group (n = 6) according to the Caprini Thrombosis Risk Assessment Scale score. Data-independent acquisition mass spectrometry (DIA-MS) was performed to identify the proteins in the 12 plasma samples. Bioinformatics analysis including volcano plot, heatmap, KEGG pathways and chord diagram analysis were drawn to analyze the significantly differentially expressed proteins (DEPs) between the two groups. Then, another 26 plasma samples were collected to verify the key proteins as potential biomarkers of VTE in orthopedic surgery patients. RESULTS: A total of 371 proteins were identified by DIA-MS in 12 plasma samples. Volcano plotting showed that there were 30 DEPs. KEGG pathway enrichment analysis revealed that the DEPs were majorly involved in the blood coagulation pathway. The chord diagram analysis demonstrated that proteins SAA1, VWF, FLNA, ACTB, VINC, F13B, F13A and IPSP in the DEPs were significantly related to blood coagulation. VWF and F13B were selected for validation experiments. ELISA test showed that, as compared with those in the low-risk group, the level of VWF in the high-risk sera was significantly increased. CONCLUSIONS: The level of VWF in the high-risk group of thrombosis after orthopedic surgery was significantly higher than that in the low-risk group of preoperative thrombosis, suggesting that VWF may be used as a potential thrombus biomarker in orthopedic surgery patients.

The conservation and diversity of the exons encoding the glycine and arginine rich domain of the fibrillarin gene in vertebrates, with special focus on reptiles and birds.

The nucleolar rRNA 2'-O-methyltransferase fibrillarin (FBL) contains a highly conserved methyltransferase domain at the C-terminus and a diverse glycine arginine-rich (GAR) domain at the N-terminus in eukaryotes. We found that a nine-exon configuration of fbl and exon 2-3 encoded GAR domain are conserved and specific in vertebrates. All internal exons except exon 2 and 3 are of the same lengths in different vertebrate lineages. The lengths of exon 2 and 3 vary in different vertebrate species but the ones with longer exon 2 usually have shorter exon 3 complementarily, limiting lengths of the GAR domain within a certain range. In tetrapods except for reptiles, exon 2 appears to be longer than exon 3. We specifically analyzed different lineages of reptiles for their GAR sequences and exon lengths. The lengths of exon 2 in reptiles are around 80-130-nt shorter and the lengths of exon 3 in reptiles are around 50-90 nt longer than those in other tetrapods, all in the GAR-coding regions. An FSPR sequence is present at the beginning of the GAR domain encoded by exon 2 in all vertebrates, and a specific FXSP/G element (X can be K, R, Q, N, and H) exist in the middle of GAR with phenylalanine as the 3rd exon 3-encoded amino acid residue starting from jawfish. Snakes, turtles, and songbirds contain shorter exon 2 compared with lizards, indicating continuous deletions in exon 2 and insertions/duplications in exon 3 in these lineages. Specifically, we confirmed the presence the fbl gene in chicken and validated the RNA expression. Our analyses of the GAR-encoding exons of fbl in vertebrates and reptiles should provide the basis for further evolutionary analyses of more GAR domain encoding proteins.

Identification and Characterization of Glycine- and Arginine-Rich Motifs in Proteins by a Novel GAR Motif Finder Program.

Glycine- and arginine-rich (GAR) motifs with different combinations of RG/RGG repeats are present in many proteins. The nucleolar rRNA 2'-O-methyltransferase fibrillarin (FBL) contains a conserved long N-terminal GAR domain with more than 10 RGG plus RG repeats separated by specific amino acids, mostly phenylanalines. We developed a GAR motif finder (GMF) program based on the features of the GAR domain of FBL. The G(0,3)-X(0,1)-R-G(1,2)-X(0,5)-G(0,2)-X(0,1)-R-G(1,2) pattern allows the accommodation of extra-long GAR motifs with continuous RG/RGG interrupted by polyglycine or other amino acids. The program has a graphic interface and can easily output the results as .csv and .txt files. We used GMF to show the characteristics of the long GAR domains in FBL and two other nucleolar proteins, nucleolin and GAR1. GMF analyses can illustrate the similarities and also differences between the long GAR domains in the three nucleolar proteins and motifs in other typical RG/RGG-repeat-containing proteins, specifically the FET family members FUS, EWS, and TAF15 in position, motif length, RG/RGG number, and amino acid composition. We also used GMF to analyze the human proteome and focused on the ones with at least 10 RGG plus RG repeats. We showed the classification of the long GAR motifs and their putative correlation with protein/RNA interactions and liquid-liquid phase separation. The GMF algorithm can facilitate further systematic analyses of the GAR motifs in proteins and proteomes.

Ocular surface reconstruction of Steven Johnson syndrome / toxic epidermal necrolysis affected eye - A case report.

Introduction: Toxic epidermal necrolysis (TEN), also known as Steven Johnson syndrome (SJS), is a devastating disease. Patients develop blindness and symblepharon despite multiple reconstructive surgeries. We report a case of SJS/TEN with ocular involvement where treatment with hyperbaric oxygen therapy (HBOT) resulted in a significant improvement in the visual acuity after surgery. Case presentation: A woman with SJS/TEN with severe ocular complication (SOC) had limbal stem cell deficiency and symblepharon of the superior and inferior fornix. Pannus grew over her cornea, reducing the vision to counting finger. The symblepharon produced shortening of the fornix, causing entropion. The in-turned eyelid caused her eyelashes to rub against the cornea, causing great damage to the ocular surface. Limbal stem cell deficiency led to the loss of normal corneal morphology and invasion of the pannus onto the central visual axis, resulting in poor vision. She experienced ocular inflammation for 3 months before transfer to our hospital for admission. Ophthalmic examination showed bilateral corneal opacity with conjunctivalization, and inferior and superior fornix shortening. Symblepharon-lysis with amniotic membrane transplantation was attempted but the outcome was poor, with recurrence of superior scaring and symblepharon. She finally underwent major reconstructive surgery with allogeneic limbal stem cell transplantation with her sister as the donor, autologous minor salivary gland transplantation, and oral buccal mucosa flap transplant. HBOT was given daily post-surgery for supporting the grafts and suppressing inflammation. After 17 HBOT sessions and 3 months of autoserum drops, her left eye vision increased from the initial counting finger to 0.4 due to the successful growth of the corneal epithelium from the donor corneal limbal cell line. When a scleral contact lens which vaulted over the corneal limbal area was fitted, her vision improved to 0.8 due to redressal of high order aberration and astigmatism from the cornea scar. Conclusion: After major reconstruction of the ocular surface with multiple cell type transplants, including limbal stem cells, minor salivary gland acinar cells, and oral mucosa cells, HBOT proved useful in supporting the graft uptake and oxygenation of the donor tissues, enabling fast recovery of the grafts and cell functioning, with eventual return of the working vision of the patient.

Valacyclovir-associated neurotoxicity among patients on hemodialysis and peritoneal dialysis: A nationwide population-based study.

Whether valacyclovir-associated neurotoxicity (VAN) occurs more frequently in patients with end-stage renal disease (ESRD) on dialysis is unknown. This is the first population-based study to examine the risk of VAN associated with ESRD patients on dialysis. Among 2,284,800 patients diagnosed as having herpes zoster from 2002 to 2016, patients with ESRD on dialysis and individuals with normal renal function were enrolled in this study. Following propensity score matching, we compared the risk of altered mental status between valacyclovir users and non-users in the ESRD and normal renal function cohorts over a 30-day follow-up period. In the ESRD cohort, the incidence of altered mental status was 1.68 and 0.52 per 1,000 person-day in valacyclovir users and non-users, respectively, with an adjusted hazard ratio (HR) of 3.22 (95% confidence interval [CI]: 2.04-4.99, P < 0.001). The incidence of altered mental status of valacyclovir users on hemodialysis (HD) and peritoneal dialysis (PD) was higher than that of non-users. The adjusted HR was 3.20 (95% CI: 1.98-5.15, P < 0.001) for those on HD and 3.44 (95% CI: 1.13-10.49, P = 0.030) for those with PD. However, altered mental status was not observed in patients on HD receiving ≤500 mg of valacyclovir three times per week or in those on PD receiving ≤500 mg of valacyclovir per day. The findings demonstrate that adjusting the valacyclovir dosage and monitoring VAN in patients with HD and PD who have herpes zoster is crucial.

Is there a need for individualized adjustment of electrode belt position during EIT-guided titration of positive end-expiratory pressure?

Objective. The aim of the present study was to evaluate the variation of tidal volume-to-impedance ratio (VT/ZT) during positive end-expiratory pressure (PEEP) titration with electrical impedance tomography (EIT) measurement.Approach. Forty-two patients with acute respiratory distress syndrome were retrospectively analyzed. An incremental and subsequently a decremental PEEP trial were performed with steps of 2 cm H2O and duration of 2 min per step during volume-controlled ventilation with decelerating flow. EIT measurement was conducted in the 5th intercostal space andVTwas recorded simultaneously. The variation ofVT/ZT(RatioV) was defined as the changes in percentage to average ratio per cm H2O PEEP change. A z-score > 1 was considered as a significant variation and an implication that the measurement plane was inadequate.Main results. TheRatioVof 42 patients was 1.29 ± 0.80%·cm H2O-1. A z-score of 1 corresponded to the variation of 2.09%·cm H2O-1. Seven patients (16.7%) had a z-score > 1 and showed either positive or negative correlation between the volume-to-impedance ratio and PEEP.Significance. Electrode placement at 5th intercostal space might not be ideal for every individual during EIT measurement. Evaluation of volume-to-impedance ratio variation is necessary for patients undergoing maneuvers with wide alteration in absolute lung volume.

Aging is associated with slower renal progression in patients with chronic kidney disease.

Objectives: Chronic kidney disease (CKD) is prevalent among the elderly. However, little is known about how the clinical course of CKD vary with age. The purpose of this study was to examine the impact of aging on the risk of end-stage kidney disease (ESKD) in patients with moderate to advanced CKD. Materials and Methods: A total of 454 patients with stages 3-5 CKD were prospectively followed for a median of 5.1 years. The primary outcome was ESKD needing chronic dialysis therapy or preemptive kidney transplantation. The secondary outcome was a composite of ESKD or all-cause mortality. Results: The mean age of the patients was 65 ± 13 years. 65.4% were men, 44.9% had diabetes mellitus, and 22.7% had cardiovascular disease. Overall, 142 participants progressed to ESKD and 63 participants died. Compared with young patients (age <65 years, n = 205), elderly patients (age ≥65 years, n = 249) were associated with a significantly decreased risk of ESKD in Cox proportional hazards models adjusted for sex, smoking history, diabetes mellitus, cardiovascular disease, systolic blood pressure, estimated glomerular filtration rate, urine protein: Creatinine ratio, use of renin-angiotensin-aldosterone blocker, hemoglobin, phosphate, interleukin-6, body mass index, and N-terminal pro-brain natriuretic peptide (hazard ratio [HR]: 0.66; 95% confidence interval [CI]: 0.45, 0.96; P = 0.028). The results remained statistically significant when death as a competing risk was taken into account (subdistribution HR: 0.65; 95% CI: 0.45, 0.95, P = 0.026). Notably, elderly did not predict a higher risk for the composite outcome (HR: 0.94; 95% CI: 0.67, 1.32; P = 0.723). Conclusion: Elderly confers a decreased risk of ESKD in Taiwanese patients with moderate to advanced CKD. Our findings suggest that age is an important effect modifier for CKD progression.

Ultrasound and elastography role in pre- and post-operative evaluation of median neuropathy in patients with carpal tunnel syndrome.

Introduction: Carpal tunnel syndrome (CTS) is a common compression neuropathy of the median nerve in the wrist. Early diagnosis of CTS is essential for selecting treatment options and assessing prognosis. The current diagnosis of CTS is based on the patient's clinical symptoms, signs, and an electromyography (EMG) test. However, they have some limitations. Recently, ultrasound has been adopted as an adjunct diagnostic tool for electromyography (EMG). Ultrasound is a non-invasive and cost-effective technique. It provides a dynamic display of morphological changes in the median nerve and an assessment of CTS etiology such as tenosynovitis, mass compression, and tendon disease. This study aimed to investigate the value of conventional ultrasound and real-time shear wave elastography (SWE) in evaluation of median neuropathy in patients with carpal tunnel syndrome (CTS) before and after surgery. Methods: First, the Boston Carpal Tunnel Questionnaire (BCTQ) was administered to patients with CTS. All subjects were measured at three levels: the distal 1/3 of the forearm, the carpal tunnel inlet, and the distal carpal tunnel using conventional ultrasound and SWE. Median nerve parameters were examined in patients with CTS 1 week after surgery. Results: The cross-sectional area (CSA) and stiffness of the median nerve at the carpal tunnel inlet and distal carpal tunnel were significantly higher in patients with CTS than in healthy controls (p < 0.001). The CSA and stiffness of the median nerve at the carpal tunnel inlet were statistically significantly significantly between pre- and postoperative patients with CTS (p < 0.001). The CSA and stiffness of the nerve in patients with CTS had a positive correlation with electrophysiology severity. Conclusions and discussion: Conventional ultrasound and elastography are valuable in the diagnosis of CTS and are useful in the clinical assessment of patient's nerve recovery after operation.

Modular synthesis of 3-substituted isocoumarins via silver-catalyzed aerobic oxidation/6-endo heterocyclization of ortho-alkynylbenzaldehydes.

A method involving silver-catalyzed aerobic oxidation/6-endo heterocyclization of ortho-alkynylbenzaldehydes to yield 3-substituted isocoumarins is described. The developed protocol allows convenient access to a range of synthetically useful 3-substituted isocoumarins and related fused heterocyclolactones in good to high yields, using silver tetrafluoroborate as the catalyst, and atmospheric oxygen as the terminal oxidant and the source of endocyclic oxygen. Mechanistic studies suggest the involvement of a free-radical pathway.

CT-less electron radiotherapy simulation and planning with a consumer 3D camera.

PURPOSE: Electron radiation therapy dose distributions are affected by irregular body surface contours. This study investigates the feasibility of three-dimensional (3D) cameras to substitute for the treatment planning computerized tomography (CT) scan by capturing the body surfaces to be treated for accurate electron beam dosimetry. METHODS: Dosimetry was compared for six electron beam treatments to the nose, toe, eye, and scalp using full CT scan, CT scan with Hounsfield Unit (HU) overridden to water (mimic 3D camera cases), and flat-phantom techniques. Radiation dose was prescribed to a depth on the central axis per physician's order, and the monitor units (MUs) were calculated. The 3D camera spatial accuracy was evaluated by comparing the 3D surface of a head phantom captured by a 3D camera and that generated with the CT scan in the treatment planning system. A clinical case is presented, and MUs were calculated using the 3D camera body contour with HU overridden to water. RESULTS: Across six cases the average change in MUs between the full CT and the 3Dwater (CT scan with HU overridden to water) calculations was 1.3% with a standard deviation of 1.0%. The corresponding hotspots had a mean difference of 0.4% and a standard deviation of 1.9%. The 3D camera captured surface of a head phantom was found to have a 0.59 mm standard deviation from the surface derived from the CT scan. In-vivo dose measurements (213 ± 8 cGy) agreed with the 3D-camera planned dose of 209 ± 6 cGy, compared to 192 ± 6 cGy for the flat-phantom calculation (same MUs). CONCLUSIONS: Electron beam dosimetry is affected by irregular body surfaces. 3D cameras can capture irregular body contours which allow accurate dosimetry of electron beam treatment as an alternative to costly CT scans with no extra exposure to radiation. Tools and workflow for clinical implementation are provided.

Exosomal miR-107 antagonizes profibrotic phenotypes of pericytes by targeting a pathway involving HIF-1α/Notch1/PDGFRß/YAP1/Twist1 axis in vitro.

Microvascular pericytes have been demonstrated as an origin for myofibroblasts that produce excessive extracellular matrix (ECM) proteins such as α-smooth muscle actin (α-SMA) and type I collagen (ColIA1) and contribute to pulmonary fibrosis (PF). However, the signaling mechanism responsible for ECM production within pericytes is poorly understood. In this study, we examined exosomal miR-107 in the fibrotic phenotypes of pericytes and the pathogenesis of PF. Using RT-qPCR, MiR-107 level was compared between clinical or bleomycin-induced PF and normal pulmonary tissues. Exosomes were isolated from cultured microvascular endothelial cells (ECs) derived from either normal or PF tissues, characterized using dynamic light scattering, transmission electron microscopy, flow cytometry, Western blot, and immunofluorescence, and then applied to pericytes. The effects of exosomes or different fibrosis-related signaling molecules were examined by Western blot, and the potential regulations between the signaling molecules were identified using bioinformatic analysis and assessed by electrophoretic mobility shift assay, chromatin immunoprecipitation, luciferase assay, and RNA binding protein immunoprecipitation. MiR-107 was downregulated in clinical or experimental PF tissues and also in exosomes from PF-derived ECs. EC-derived exosomal miR-107 essentially controlled the miR-107 level and inhibited α-SMA and ColIA1 expression in pericytes. The antifibrosis effect of miR-107 was mediated through the suppression of a pathway involving HIF-1α/Notch1/PDGFRß/YAP1/Twist1, where miR-107 directly targeted HIF-1α mRNA, whereas the latter directly activated the transcriptions of both Notch1 and PDGFRß. Functionally, targeting miR-107 promoted and targeting HIF-1α abolished the fibrotic phenotypes of pericytes. Exosomal miR-107 produced by pulmonary vascular ECs may alleviate pericyte-induced fibrosis by inhibiting a signaling pathway involving HIF-1α/Notch1/PDGFRß/YAP1/Twist1.NEW & NOTEWORTHY This work reveals a novel mechanism by which pulmonary vascular endothelial cells, via regulating the transdifferentiation of microvascular pericytes into myofibroblasts, contribute to the pathogenesis of pulmonary fibrosis. Since targeting the formation of myofibroblasts may prevent the development and benefit the treatment of pulmonary fibrosis, this study provides not only mechanistic understanding but also promising therapeutic targets for pulmonary fibrosis.

[Management of androgenic diseases during the epidemic of COVID-19 pneumonia].

The novel coronavirus (COVID-19) pneumonia has been classified as a category B and dealt with as a category A infectious disease by the National Health Commission of China, and also as a public health emergency of international concern by the World Health Organization. During the epidemic, unnecessary visits to hospitals may increase the risk of infection among patients and clinicians. Therefore, it is particularly important to provide some scientific medical guidance for patients with male diseases, which is also a current imperative for andrology management. And it also deserves the attention of clinical researchers whether COVID-19 pneumonia and its clinical treatments currently used may affect the male reproductive system.

Low let-7d exosomes from pulmonary vascular endothelial cells drive lung pericyte fibrosis through the TGFßRI/FoxM1/Smad/ß-catenin pathway.

The pathogenesis of pulmonary fibrosis (PF) was mediated by the progressive deposition of excessive extracellular matrix, but little is known about the regulatory mechanisms of fibrogenesis by lung pericytes. The mouse PF model was established by treatment with bleomycin, followed by isolation of exosomes from mouse broncho-alveolar lavage fluids by the centrifuge method. Relative mRNA/microRNA levels and protein expression were assessed by qRT-PCR and Western blotting, respectively. The binding of let-7d with gene promoter was validated by dual-luciferase reporter assay. Protein interactions were verified via GST pull-down and co-immunoprecipitation. Nuclear retention of Smad3 was analysed by extraction of cytoplasmic and nuclear fraction of pericytes followed by Western blotting. Association of FoxM1 with gene promoter was detected by EMSA and ChIP-PCR methods. FoxM1 expression is significantly elevated in human lung fibroblasts of PF patients and mouse PF model. The expression of let-7d is repressed in exosomes derived from broncho-alveolar lavage fluids of PF mice. Let-7d or FoxM1 knockdown suppressed the expression of FoxM1, Smad3, ß-catenin, Col1A and α-SMA expression in mouse lung pericytes under TGF-ß1 treatment. FoxM1 overexpression elevated above gene expression in mouse lung pericytes under TGF-ß1 treatment. Let-7d directly targets TGFßRI to regulate FoxM1 and downstream gene expression in mouse lung pericytes. FoxM1 directly interacts with Smad3 proteins to promote Smad3 nuclear retention and binds with ß-catenin promoter sequence to promote fibrogenesis. Exosomes with low let-7d from pulmonary vascular endothelial cells drive lung pericyte fibrosis through activating the TGFßRI/FoxM1/Smad/ß-catenin signalling pathway.

Long-Term Effects of Ketoanalogues on Mortality and Renal Outcomes in Advanced Chronic Kidney Disease Patients Receiving a Low-Protein Diet.

The effects of ketoanalogues (KA) supplementation on mortality and progression to dialysis in patients with pre-dialysis stage 5 chronic kidney disease (CKD) receiving a low-protein diet (LPD) remain ambiguous. From Taiwan's National Health Insurance Research Database during 1996-2011, 165 patients with pre-dialysis CKD on an LPD (0.6 g/kg/day) with KA supplementation were matched with 165 patients with pre-dialysis CKD on an LPD without KA supplementation. Of the 165 patients with advanced CKD receiving KA supplementation, 34 (20.6%) died, and 124 (75.2%) underwent long-term dialysis during the study period. There was no significant difference in mortality between the KA-user group and the KA-nonuser group (adjusted hazard ratio [HR], 1.41; 95% confidence interval [CI], 0.68-2.93; p = 0.355). KA supplementation significantly increased long-term dialysis risk (adjusted HR, 1.41; 95% CI, 1.04-1.90; p = 0.025) and combined outcome risk (defined as long-term dialysis and death; adjusted HR, 1.37; 95% CI, 1.02-1.83; p = 0.034). KA supplementation also increased long-term dialysis risk (adjusted HR, 1.49; 95% CI, 1.00-2.20; p = 0.048) in the subgroup of pre-dialysis patients with diabetes mellitus (DM), but not in those patients without DM. In conclusion, KA supplementation might increase long-term dialysis risk in patients with advanced CKD receiving an LPD, but it did not increase mortality.

Increased incidence, morbidity, and mortality in cirrhotic patients with hip fractures: A nationwide population-based study.

OBJECTIVES: Hip fractures mostly require surgical treatment and are associated with increased health-care costs and mortality rates. Patients with cirrhosis have low bone marrow density and inferior immune status which contribute to a higher fracture rate and higher surgical complication rate. This population-based study evaluated the prevalence, complication, and mortality rates due to hip fractures in cirrhotic patients. METHODS: Taiwan National Health Insurance Research Database data were used. The study group included 117,129 patients with hip fractures diagnosed from 2004 to 2010, including 4048 patients with cirrhosis. The overall prevalence, morbidity, and mortality rates of the cirrhosis group with hip fractures were compared with the rates of a general group with hip fractures. RESULTS: The cirrhosis group patients were younger than the general group patients (71.2 vs. 73.96 years, p < 0.001). The annual incidence of hip fractures in the cirrhosis and general groups was 46-54 and 7-7.5 per 10,000 person-years, respectively, with an incidence rate ratio of 6.95 (95% confidence interval 6.74-7.18). The rates of infection, urinary tract infection, and peptic ulcer disease were higher in the cirrhosis group (3.46% vs. 1.91%, 9.56% vs. 9.11%, and 8.05% vs. 3.55%, respectively; all p < 0.001). The mortality rate after hip fracture was also higher in the cirrhosis group than in the general group (within 3 months: 8.76-12.64% vs. 4.96-5.30% and within 1 year: 29.72-37.99% vs. 12.84-14.57%). Conclusion: Cirrhotic patients with hip fractures were relatively younger; had a seven times higher annual hip fracture incidence; had higher complication rates of infection, urinary tract infection, and peptic ulcer disease; and had two to three times higher a mortality rate at 3 months and 1 year. Clinicians should pay particular attention to the possibility of osteoporosis and hip fractures in patients with liver cirrhosis. LEVEL OF EVIDENCE: Level III, case-control study.