Genotype and phenotype in patients with ACAN gene variants: Three cases and literature review.

OBJECTIVE: To characterize the phenotype spectrum, diagnosis, and response to growth-promoting therapy in patients with ACAN variants causing familial short stature. METHODS: Three families with ACAN variants causing short stature were reported. Similar cases in the literature were summarized, and the genotype and phenotype were analyzed. RESULTS: Three novel heterozygous variants, c.757+1G>A, (splicing), c.6229delG, p.(Asp2078Tfs*1), and c.6679C>T, p.(Gln2227*) in the ACAN gene were identified. A total of 314 individuals with heterozygous variants from 105 families and 8 individuals with homozygous variants from 4 families were confirmed to have ACAN variants from literature and our 3 cases. Including our 3 cases, the variants reported comprised 33 frameshift, 39 missense, 23 nonsense, 5 splicing, 4 deletion, and 1 translocation variants. Variation points are scattered throughout the gene, while exons 12, 15, and 10 were most common (25/105, 11/105, and 10/105, respectively). Some identical variants existing in different families could be hot variants, c.532A>T, p.(Asn178Tyr), c.1411C>T, p.(Gln471*), c.1608C>A, p.(Tyr536*), c.2026+1G>A, (splicing), and c.7276G>T, p.(Glu2426*). Short stature, early-onset osteoarthritis, brachydactyly, midfacial hypoplasia, and early growth cessation were the common phenotypic features. The 48 children who received rhGH (and GnRHa) treatment had a significant height improvement compared with before (-2.18 ± 1.06 SD vs. -2.69 ± 0.95 SD, p < 0.001). The heights of children who received rhGH (and GnRHa) treatment were significantly improved compared with those of untreated adults (-2.20 ± 1.10 SD vs. -3.24 ± 1.14 SD, p < 0.001). CONCLUSION: Our study achieves a new understanding of the phenotypic spectrum, diagnosis, and management of individuals with ACAN variants. No clear genotype-phenotype relationship of patients with ACAN variants was found. Gene sequencing is necessary to diagnose ACAN variants that cause short stature. In general, appropriate rhGH and/or GnRHa therapy can improve the adult height of affected pediatric patients caused by ACAN variants.

Validation of the RBP-9801 oscillometric blood pressure monitor in the general population according to the association for the Advancement of Medical Instrumentation/European Society of Hypertension/ International Organization for Standardization Universal Standard.

The aim of this study was to evaluate the accuracy of the single upper-arm cuff oscillometric blood pressure (BP) monitor RBP-9801 developed for office and home BP measurement in the general population according to the Association for the Advancement of Medical Instrumentation/European Society of Hypertension/International Organization for Standardization (AAMI/ESH/ISO) Universal Standard (ISO 81060-2:2018). Subjects were recruited to fulfil the age, gender, BP and cuff distribution criteria of the AAMI/ESH/ISO Universal Standard in general population using the same arm sequential BP measurement method. A total of 105 subjects were recruited and 85 were analyzed. For validation criterion 1, the mean ± SD of the differences between the test device and reference BP readings was 2.3 ± 6.4/3.1 ± 5.8 mmHg (systolic/diastolic). For criterion 2, the SD of the mean BP differences between the test device and reference BP per subject was 5.24/5.03 mmHg (systolic/diastolic). The conclusion is that the RBP-9801 oscillometric device for office and home BP measurement fulfilled all the requirements of the AAMI/ESH/ISO Universal Standard (ISO 81060-2:2018) in the general population and can be recommended for clinic and self-use at home.

High-throughput sequencing and fatty acid profile analyses of the Black Amur bream (Megalobrama terminalis) reveal variation in dietary niche associated with geographic segregation.

Fish dietary niche is a core focus, and it reflects the diversity of resources, habitats, or environments occupied by a species. However, whether geographic segregation among different populations triggers dietary diversification and concomitant fish niche shift remains unknown. In the present study, we selected the Black Amur bream (Megalobrama terminalis) is a migratory fish species that plays an important role in the material transfer and energy cycling of river ecosystems, inhabiting southern China drainage with multiple geographic populations. Here, we utilized the combined analyses of 18S rDNA high-throughput sequencing in fish gut contents and fatty acid (FA) in muscle tissues to evaluate potential spatial patterns of habitat and resource use for M. terminalis in three rivers of southern China. Our results showed that prey items of the Xijiang (XR) population (Pearl River) exhibited the highest species diversity and richness among the three geographic populations. Moreover, diet composition of M. terminalis was affected by spatial differences associated with geographic segregation. Analyses of FA biomarkers indicated that the highest levels of C16:0, C18:3n-3, and C18:2n-6c were found in Wanquan (WS) population (Wanquan River). The XR population exhibited a distinct FA profile characterized by higher amounts of arachidonic acid (ARA) and docosahexaenoic acid (DHA). The Moyang (MY) population (Moyang River) acted as the linkage between WS and XR populations and consisted of middle levels of saturated FAs (SFAs) and polyunsaturated FAs (PUFAs). The XR population displayed a greater FA niche width compared with WS population. Furthermore, we observed a close positive relationship between the niche width and α-diversity indices of dietary resources for FA proflies. Our study provides valued information to develop different conservation strategies among different populations and improve fisheries management for M. terminalis and other endemic species in local rivers.

Diabetes and high-glucose could upregulate the expression of receptor for activated C kinase 1 in retina.

BACKGROUND: Diabetic retinopathy (DR) is a major ocular complication of diabetes mellitus, leading to visual impairment. Retinal pigment epithelium (RPE) injury is a key component of the outer blood retinal barrier, and its damage is an important indicator of DR. Receptor for activated C kinase 1 (RACK1) activates protein kinase C-ε (PKC-ε) to promote the generation of reactive oxygen species (ROS) in RPE cells, leading to apoptosis. Therefore, we hypothesize that the activation of RACK1 under hypoxic/high-glucose conditions may promote RPE cell apoptosis by modulating PKC-ε/ROS, thereby disrupting the barrier effect of the outer blood retinal barrier and contributing to the progression of DR. AIM: To investigate the role and associated underlying mechanisms of RACK1 in the development of early DR. METHODS: In this study, Sprague-Dawley rats and adult RPE cell line-19 (ARPE-19) cells were used as in vivo and in vitro models, respectively, to explore the role of RACK1 in mediating PKC-ε in early DR. Furthermore, the impact of RACK1 on apoptosis and barrier function of RPE cells was also investigated in the former model. RESULTS: Streptozotocin-induced diabetic rats showed increased apoptosis and up-regulated expression of RACK1 and PKC-ε proteins in RPE cells following a prolonged modeling. Similarly, ARPE-19 cells exposed to high glucose and hypoxia displayed elevated mRNA and protein levels of RACK1 and PKC-ε, accompanied by an increases in ROS production, apoptosis rate, and monolayer permeability. However, silencing RACK1 significantly downregulated the expression of PKC-ε and ROS, reduced cell apoptosis and permeability, and protected barrier function. CONCLUSION: RACK1 plays a significant role in the development of early DR and might serve as a potential therapeutic target for DR by regulating RPE apoptosis and barrier function.

Gene variants and clinical characteristics of children with sitosterolemia.

OBJECTIVE: To enhance the detection, management and monitoring of Chinese children afflicted with sitosterolemia by examining the physical characteristics and genetic makeup of pediatric patients. METHODS: In this group, 26 children were diagnosed with sitosterolemia, 24 of whom underwent genetic analysis. Patient family medical history, physical symptoms, tests for liver function, lipid levels, standard blood tests, phytosterol levels, cardiac/carotid artery ultrasounds, fundus examinations, and treatment were collected. RESULTS: The majority (19, 73.1%) of the 26 patients exhibited xanthomas as the most prevalent manifestation. The second most common symptoms were joint pain (7, 26.9%) and stunted growth (4, 15.4%). Among the 24 (92.3%) patients whose genetics were analyzed, 16 (66.7%) harbored ABCG5 variants (type 2 sitosterolemia), and nearly one-third (8, 33.3%) harbored ABCG8 variants (type 1 sitosterolemia). Additionally, the most common pathogenic ABCG5 variant was c.1166G > A (p.Arg389His), which was found in 10 patients (66.7%). Further analysis did not indicate any significant differences in pathological traits among those carrying ABCG5 and ABCG8 variations (P > 0.05). Interestingly, there was a greater abundance of nonsense variations in ABCG5 than in ABCG8 (P = 0.09), and a greater frequency of splicing variations in ABCG8 than ABCG5 (P = 0.01). Following a change in diet or a combination of ezetimibe, the levels of cholesterol and low-density lipoprotein were markedly decreased compared to the levels reported before treatment. CONCLUSION: Sitosterolemia should be considered for individuals presenting with xanthomas and increased cholesterol levels. Phytosterol testing and genetic analysis are important for early detection. Managing one's diet and taking ezetimibe can well control blood lipids.

Identification and sex expression profiles of candidate chemosensory genes from Atherigona orientalis via the antennae and leg transcriptome analysis.

Atherigona orientalis Schiner (1868) is an acknowledged agricultural pest owing to its feeding habits and breeding locations. This insect is a tropical and subtropical pest in fruits and vegetables, in which >50 varieties of fruits and vegetables in 26 families, such as Capsicum annuum, Lycopersicon esculentum, and Cucumis melo have been attacked. Moreover, A. orientalis may also develop in rotten crops and feces or insect carcasses, which are also considered one kind of sanitary pest and medical insect. At present, the invasion ranges of A. orientalis are still increasing and more preventive and management measures are to be processed. To gain a better understanding of the molecular mechanisms involved in olfactory reception in A. orientalis, the transcriptome of male and female antennae and legs was systematically analyzed. In total, 131 chemosensory-related genes, including 63 odorant receptors (ORs), 20 gustatory receptors (GRs), 18 ionotropic receptors (IRs), 27 odorant binding proteins (OBPs), 1 chemosensory protein (CSP), and 2 sensory neuron membrane proteins (SNMPs), were identified. The analysis focused on obtaining expression information of candidate olfactory genes at the transcriptomic level by examining the differentially expressed genes (DEGs) in all samples. Totally, 41 DEGs were identified between male antennae (MA) and female antennae (FA), including 32 ORs, 5 OBPs, 1 IR, 2 GRs and 1 SNMP. In MA versus male legs (ML), 78 DEGs were identified (45 ORs, 18 OBPs, 6 GRs, 6 IRs, 1 CSP and 2 SNMPs). In FA and female legs (FL), 96 DEGs were identified (51 ORs, 21 OBPs, 9 GRs, 12 IRs, 1 CSP and 2 SNMPs). For ML and FL, 3 DEGs were identified, including 2 ORs and 1 SNMP. Our results supplement valuable insights for future research on the chemoreception mechanisms in A. orientalis.

An odorant receptor mediates the avoidance of Plutella xylostella against parasitoid.

BACKGROUND: Ecosystems are brimming with myriad compounds, including some at very low concentrations that are indispensable for insect survival and reproduction. Screening strategies for identifying active compounds are typically based on bioassay-guided approaches. RESULTS: Here, we selected two candidate odorant receptors from a major pest of cruciferous plants-the diamondback moth Plutella xylostella-as targets to screen for active semiochemicals. One of these ORs, PxylOR16, exhibited a specific, sensitive response to heptanal, with both larvae and adult P. xylostella displaying heptanal avoidance behavior. Gene knockout studies based on CRISPR/Cas9 experimentally confirmed that PxylOR16 mediates this avoidance. Intriguingly, rather than being involved in P. xylostella-host plant interaction, we discovered that P. xylostella recognizes heptanal from the cuticular volatiles of the parasitoid wasp Cotesia vestalis, possibly to avoid parasitization. CONCLUSIONS: Our study thus showcases how the deorphanization of odorant receptors can drive discoveries about their complex functions in mediating insect survival. We also demonstrate that the use of odorant receptors as a screening platform could be efficient in identifying new behavioral regulators for application in pest management.

Trimester-specific effect of maternal co-exposure to organophosphate esters and phthalates on preschooler cognitive development: The moderating role of gestational vitamin D status.

Organophosphate esters (OPEs) and phthalate acid esters (PAEs) are prevalent endocrine-disrupting chemicals (EDCs). Humans are often exposed to OPEs and PAEs simultaneously through multiple routes. Given that fetal stage is a critical period for neurodevelopment, it is necessary to know whether gestational co-exposure to OPEs and PAEs affects fetal neurodevelopment. However, accessible epidemiological studies are limited. The present study included 2, 120 pregnant women from the Ma'anshan Birth Cohort (MABC) study. The concentrations of tris (2-chloroethyl) phosphate (TCEP), 6 OPE metabolites and 7 PAE metabolites were measured in the first, second and third trimester using ultra-performance liquid chromatography-tandem mass spectrometry (LC-MS). Cognitive development of preschooler was assessed based on the Wechsler Preschool and Primary Scale of Intelligence-Fourth Edition (WPPSI-IV) of the Chinese version. Generalized estimating equations (GEEs), restricted cubic spline (RCS) and generalized additive models (GAMs) were employed to explore the associations between individual OPE exposure and preschooler cognitive development. The quantile-based g-computation (QGC) method was used to estimate the joint effect of PAEs and OPEs exposure on cognitive development. GEEs revealed significant adverse associations between diphenyl phosphate (DPHP) (ß: -0.58, 95% CI: -1.14, -0.01), bis (2-butoxyethyl) phosphate(BBOEP) (ß: -0.44, 95% CI: -0.85, -0.02), bis(1-chloro-2-propyl) phosphate (BCIPP) (ß: -0.81, 95%CI: -1.43, -0.20) and full-scale intelligence quotient (FSIQ) in the first trimester; additionally, TCEP and bis(2-ethylhexyl) phosphate (BEHP) in the second trimester, as well as DPHP in the third trimester, were negatively associated with cognitive development. Through the QGC analyses, mixture exposure in the first trimester was negatively associated with FSIQ scores (ß: -1.70, 95% CI: -3.06, -0.34), mono-butyl phthalate (MBP), BCIPP, and DPHP might be the dominant contributors after controlling for other OPEs and PAEs congeners. Additionally, the effect of OPEs and PAEs mixture on cognitive development might be driven by vitamin D deficiency.

Fecal Microbiota Transplantation Repairs Radiation Enteritis Through Modulating the Gut Microbiota-Mediated Tryptophan Metabolism.

Radiation enteritis is a common complication of abdominal and pelvic radiotherapy. Several previous studies showed that fecal microbiota transplantation (FMT) could alleviate radiation enteritis. In this study, we investigated the efficacy of FMT in alleviating radiation enteritis and explored the mechanisms by multi-omics approaches. Briefly, C57BL/6J mice were subjected to 9 Gy irradiation to the localized abdominal field, and randomized received FMT from healthy donor mice or saline. H&E staining of harvested small intestine showed FMT decreased epithelial injury. Radiation-induced microbiota dysbiosis, characterized by a decrease in beneficial bacteria Lactobacillaceae and Lachnospiraceae, while these bacteria were restored by FMT. Fecal metabolomics analysis revealed that FMT modulated metabolic dysregulation. Two tryptophan pathway metabolites, indole-3-acetaldehyde and N-Acetyl-5-hydroxytryptamine were decreased after irradiation, whereas these metabolites showed a pronounced recovery in mice receiving FMT. Proteomics analysis of small intestine indicated that radiation enteritis triggered immune-inflammatory responses, which were potentially mitigated by FMT. In 21 patients receiving pelvic radiotherapy for cervical cancer, those who developed enteritis (n = 15) had higher abundance in Lachnospiraceae. Moreover, Indole-3-acetaldehyde was reduced after irradiation. These findings provide insights into the therapeutic effects of FMT in radiation enteritis and highlight Lachnospiraceae and the tryptophan metabolite, Indole-3-acetaldehyde may protect against radiation enteritis.

Association of Sex With Cardiovascular Outcomes in Heart Failure Patients With Obstructive or Central Sleep Apnea.

BACKGROUND: This study investigated the association of sex with cardiovascular outcomes in a prospective cohort of patients with heart failure (HF) with obstructive sleep apnea or central sleep apnea. METHODS AND RESULTS: Patients were screened for sleep apnea on admission using multichannel cardiopulmonary monitoring from May 2015 to July 2018. The primary outcome was a composite of cardiovascular death or unplanned hospitalization for worsening HF. Ultimately, 453 patients with HF with obstructive sleep apnea or central sleep apnea were included; 71 (15.7%) and 382 (84.3%) were women and men, respectively. During a median follow-up of 2.33 years, 248 (54.7%) patients experienced the primary outcome. In the overall population, after adjusting for potential confounders, women had an increased risk of the primary outcome (66.2% versus 52.6%; hazard ratio [HR], 1.47 [95% CI, 1.05-2.04]; P=0.024) and HF rehospitalization (62.0% versus 46.6%; HR, 1.55 [95% CI, 1.10-2.19]; P=0.013) compared with men but a comparable risk of cardiovascular death (21.1% versus 23.3%; HR, 0.78 [95% CI, 0.44-1.37]; P=0.383). Likewise, in patients with HF with obstructive sleep apnea, women had a higher risk of the primary outcome (81.8% versus 46.3%, HR, 2.37 [95% CI, 1.28-4.38]; P=0.006) and HF rehospitalization (81.8% versus 44.7%, HR, 2.46 [95% CI, 1.32-4.56], P=0.004). However, in patients with HF with central sleep apnea, there was no statistically significant difference between women and men. CONCLUSIONS: In hospitalized patients with HF, female sex was associated with an increased risk of the primary outcome and HF rehospitalization, especially in those with obstructive sleep apnea. Screening for sleep apnea should be emphasized to improve the prognosis. REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02664818.

Orthopedic manifestations in children with Prader-Willi syndrome.

BACKGROUND: Prader-Willi syndrome (PWS) is a rare genetic disease often associated with bone problems, mainly scoliosis and hip dysplasia (HD). This study aimed to analyze the clinical characteristics of orthopedic deformities in patients with PWS. METHODS: A retrospective study was conducted on 175 patients up to March 2023. The Cobb angle(CA) of the spine, the alpha angle of the hip joint, and the acetabular index (AI) were measured. This study aimed to evaluate the relationship between demographic parameters and bone deformities. RESULTS: Scoliosis was found in 66 patients (43.7%), including 52 (78.8%) with mild scoliosis, 10 (15.2%) with moderate scoliosis, and 4 (6.1%) with severe scoliosis. Only seven patients received orthopedic treatment (10.6%). The median age of scoliosis was 4.5 years old, and the prevalence of scoliosis increased rapidly at the age of 5 years and adolescence. The mean CA in this study increased gradually with age. HD was found in 47 patients (38.2%), and 6 patients received orthopedic treatment (12.7%). The median age at HD was 1.8 years old. The mean AI of the study population decreased with age. The prevalence of HD treated with recombinant human growth hormone (rhGH) was low. No significant differences were observed in sex, genotype, body mass index (BMI), obesity rate, or onset of scoliosis and HD. CONCLUSION: The prevalence of scoliosis and HD was higher in patients with PWS. The onset age and developmental trends of the different skeletal malformations were different. Early diagnosis and treatment are important for the prognosis and treatment of orthopedic diseases in patients with PWS.

Association between venous leg ulcers and chronic heart failure: A Mendelian randomization study.

An association between venous leg ulcers (VLU) and chronic heart failure (CHF) has been suggested by observational research. This study used Mendelian randomization (MR) methods to look into any possible bidirectional causal links between VLU and CHF. The 'TwoSampleMR' R package was employed for MR analyses. The association of VLU and CHF was assessed via methods of inverse variance weighted (IVW), weighted mode, MR Egger and weighted median. Results of IVW suggested no association between VLU and CHF (ß 0.008356; SE 0.01889; p = 0.6582). The weighted median estimator (ß -0.005777; SE 0.02059, p = 0.7791), MR-Egger (ß -0.08955; SE 0.04557; p = 0.07296) and weighted mode (ß -0.01202; SE 0.02467; p = 0.6341) showed consistent results. Conversely, evidence indicating that the presence of CHF increased the risk of VLU was lacking. In conclusion, there is no bidirectional causal relationship between VLU and CHF. Further studies are required to validate the findings of this study.

Validation of the Raycome model M2 ambulatory blood pressure monitor in the general population according to the Association for the Advancement of Medical Instrumentation/European Society of Hypertension/International Organization for Standardization Universal Standard (ISO 81060-2:2018).

OBJECTIVE: The aim of this study was to evaluate the accuracy of the Raycome model M2 oscillometric upper-arm blood pressure (BP) monitor developed for ambulatory BP measurement in the general population according to the Association for the Advancement of Medical Instrumentation/European Society of Hypertension/International Organization for Standardization (AAMI/ESH/ISO) Universal Standard (ISO 81060-2:2018) at rest and during dynamic exercise. METHOD: Subjects were recruited to fulfill the age, gender, BP and cuff distribution criteria of the AAMI/ESH/ISO Universal Standard in the general population using the same arm sequential BP measurement method. Three cuffs of the test device were used for arm circumference 18-22 cm (small), 22-32 cm (medium) and 32-42 cm (large). RESULTS: For the general validation study, 106 subjects were recruited and 85 were analyzed. For validation criterion 1, the mean ±â€…SD of the differences between the test device and reference BP readings was 0.5 ±â€…6.2/-0.2 ±â€…5.1 mmHg (systolic/diastolic). For criterion 2, the SD of the mean BP differences between the test device and reference BP per subject was 5.23/4.50 mmHg (systolic/diastolic). In the ambulatory validation study (N = 35), the mean difference was 0.4 ±â€…5.9/-1.1 ±â€…5.8 mmHg. The Raycome model M2 performed well against the standard in both the general and ambulatory validations and the Bland-Altman plots did not show any systematic variation in the error. CONCLUSION: These data show that the Raycome model M2 monitor meets the requirements of the AAMI/ESH/ISO Universal Standard (ISO 81060-2:2018) and in the ambulatory setting, indicating its suitability for measuring BP in the general population.

Nanozyme-based inulin@nanogold for adhesive and antibacterial agent with enhanced biosafety.

Nanozymes with oxidase or peroxidase-mimicking activity have emerged as a promising alternative for disinfecting resistant pathogens. However, further research and clinical applications of nanozymes are hampered by their low in vivo biosafety and biocompatibility. In this study, inulin-confined gold nanoparticles (IN@AuNP) are synthesized as an antibacterial agent via a straightforward in situ reduction of Au3+ ions by the hydroxyl groups in inulin. The IN@AuNP exhibits both peroxidase-mimicking and oxidase-mimicking catalytic activities, of which the maximum reaction velocity (Vmax) for H2O2 is 2.66 times higher than that of horseradish peroxidase. IN@AuNP can catalyze the production of reactive oxygen species (ROS), resulting in effective antibacterial behavior against both Gram-negative (Escherichia coli) and Gram-positive (Staphylococcus aureus) bacteria. Abundant hydroxyl groups retained in inulin endow the nanozyme with high adhesion to bacteria, reducing the distance between the captured bacteria and ROS, achieving an antibacterial ratio of 100 % within 1 h. Importantly, due to the natural biosafety and non-absorption of the dietary fiber inulin, as well as the inability of inulin-trapped AuNP to diffuse, the IN@AuNP exhibits high biosafety and biocompatibility under physiological conditions. This work is expected to open a new avenue for nanozymes with great clinical application value.

Association between red blood cell distribution width-to-albumin ratio and prognosis in non-ischaemic heart failure.

AIMS: Red blood cell distribution width-to-albumin ratio (RAR), an innovate biomarker of inflammation, can independently predict adverse cardiovascular outcomes. However, the association between RAR and prognosis in patients with non-ischaemic heart failure (NIHF) remains unclear. METHODS AND RESULTS: A total of 2077 NIHF patients admitted to the Heart Failure Care Unit, Fuwai Hospital, were consecutively enrolled from December 2006 to October 2017 in this retrospective study. The primary endpoint was a composite outcome of all-cause mortality and heart transplantation. The correlation between RAR and the composite outcome was assessed by the Kaplan-Meier survival analysis and the Cox regression analysis. Incremental predictive values and the clinical performance of RAR for all-cause mortality or heart transplantation were also assessed based on a 12-variable traditional risk model. The median follow-up time in this study was 1433 (1341, 1525) days. As the gender no longer satisfied the Cox proportional risk assumption after 1150 days, we set 1095 days as the follow-up time for analysis. A total of 500 patients reached the composite outcome. Multivariable Cox regression showed that per log2 increase of RAR was significantly associated with a 132.9% [hazard ratio 2.329, 95% confidence interval (CI) 1.677-3.237, P < 0.001] increased risk of all-cause mortality or heart transplantation. Better model discrimination [concordance index: 0.766 (95% CI 0.754-0.778) vs. 0.758 (95% CI 0.746-0.770), P < 0.001], calibration (Akaike information criterion: 1487.3 vs. 1495.74; Bayesian information criterion: 1566.25 vs. 1569.43; Brier score: 1569.43 vs. 1569.43; likelihood ratio test P < 0.001), and reclassification (integrated discrimination improvement: 1.35%, 95% CI 0.63-2.07%, P < 0.001; net reclassification improvement: 13.73%, 95% CI 2.05-27.18%, P = 0.034) were improved after adding RAR to the traditional model (P < 0.001 for all). A higher overall net benefit was also obtained in the threshold risk probability of 20-55%. CONCLUSIONS: High level of RAR was an independent risk factor of poor outcome in NIHF.

Renal function modifies the association between hemoconcentration and outcomes in hospitalized heart failure patients.

Evidence-based management of decongestion is lacking in hospitalized heart failure (HHF) patients, especially in patients with impaired renal function. Hemoconcentration is an objective measure of decongestion that portends a favorable prognosis and guides management in HHF patients with preserved renal function. We aim to investigate whether it remains a prognosticator in patients with renal impairment, and to refine the identification of subpopulations who will benefit from hemoconcentration-guided therapy. HHF patients admitted to Heart Failure Center of Fuwai Hospital were consecutively included from December 2006 to June 2018. Patient characteristics were depicted. Relationships between in-hospital hemoconcentration, worsening renal function (WRF), and one-year all-cause mortality were investigated in the total population and compared between renal function groups using survival analysis and cubic splines, with a special focus on renal function-based interactions. The association was further validated in sensitivity analyses. Clinically relevant cut-offs and subpopulations were identified by subpopulation treatment effect pattern plots (STEPP) and subgroup analysis. 3661 participants (30.4% with impaired renal function) were included. Hemoconcentration, reflected by an in-hospital increase in hemoglobin, hematocrit, or a relative reduction in estimated plasma volume from baseline to discharge, was predictive of decreased one-year mortality in the total cohort despite its correlation with higher WRF incidence. The prognostic value of hemoconcentration differed in patients with impaired and preserved renal function. Hemoconcentration was related to a favorable prognosis in patients with preserved renal function (HR, 0.69; 95% CI, 0.53-0.90; P = 0.007), especially in young male patients with New York Heart Association functional class III-IV, reduced ejection fraction, and baseline eGFR > 75 mL/min/1.73m2. Contrarily, impaired renal function patients experienced a higher incidence of WRF, and hemoconcentration was no longer related to outcome (HR, 0.90; 95% CI, 0.64-1.26; P = 0.545), with findings consistent in all clinically relevant subgroups. In HHF patients, the prognostic value of hemoconcentration differs by renal function, and the clinical utility of hemoconcentration is contingent on preserved renal function.

DNI-MDCAP: improvement of causal MiRNA-disease association prediction based on deep network imputation.

BACKGROUND: MiRNAs are involved in the occurrence and development of many diseases. Extensive literature studies have demonstrated that miRNA-disease associations are stratified and encompass ~ 20% causal associations. Computational models that predict causal miRNA-disease associations provide effective guidance in identifying novel interpretations of disease mechanisms and potential therapeutic targets. Although several predictive models for miRNA-disease associations exist, it is still challenging to discriminate causal miRNA-disease associations from non-causal ones. Hence, there is a pressing need to develop an efficient prediction model for causal miRNA-disease association prediction. RESULTS: We developed DNI-MDCAP, an improved computational model that incorporated additional miRNA similarity metrics, deep graph embedding learning-based network imputation and semi-supervised learning framework. Through extensive predictive performance evaluation, including tenfold cross-validation and independent test, DNI-MDCAP showed excellent performance in identifying causal miRNA-disease associations, achieving an area under the receiver operating characteristic curve (AUROC) of 0.896 and 0.889, respectively. Regarding the challenge of discriminating causal miRNA-disease associations from non-causal ones, DNI-MDCAP exhibited superior predictive performance compared to existing models MDCAP and LE-MDCAP, reaching an AUROC of 0.870. Wilcoxon test also indicated significantly higher prediction scores for causal associations than for non-causal ones. Finally, the potential causal miRNA-disease associations predicted by DNI-MDCAP, exemplified by diabetic nephropathies and hsa-miR-193a, have been validated by recently published literature, further supporting the reliability of the prediction model. CONCLUSIONS: DNI-MDCAP is a dedicated tool to specifically distinguish causal miRNA-disease associations with substantially improved accuracy. DNI-MDCAP is freely accessible at http://www.rnanut.net/DNIMDCAP/ .

Effect of mitotane in patients with ectopic adrenocorticotropic hormone syndrome caused by advanced pancreatic neuroendocrine tumors: a case series and review of the literature.

Ectopic adrenocorticotropic hormone syndrome (EAS) is a rare condition caused by pancreatic neuroendocrine tumors (p-NETs). The severe hypercortisolemia that characterizes EAS is associated with a poor prognosis and survival. Mitotane is the only adrenolytic drug approved by the Food and Drug Administration and is often used to treat adrenocortical carcinoma. Combination therapy with mitotane and other adrenal steroidogenesis inhibitors is common for patients with Cushing's syndrome (CS). Here, we describe three patients who developed EAS secondary to the liver metastasis of p-NETs. All three rapidly developed hypercortisolemia but no typical features of CS. They underwent anti-tumor and mitotane therapy, which rapidly reduced their blood cortisol concentrations and ameliorated their symptoms. Their hypercortisolemia was controlled long term using a low dose of mitotane. The principal adverse effects were a slight loss of appetite and occasional dizziness, and there were no severe adverse effects. Importantly, even when the tumor progressed, the patients' circulating cortisol concentrations remained within the normal range. In summary, the present case series suggests that mitotane could be used to treat hypercortisolemia in patients with EAS caused by advanced p-NETs, in the absence of significant adverse effects.

The effects of different doses of lanthanum-modified bentonite in combination with a submerged macrophyte (Vallisneria denseserrulata) on phosphorus inactivation and macrophyte growth: A mesocosm study.

The combination of chemical phosphorus (P) inactivation and submerged macrophyte transplantation has been widely used in lake restoration as it yields stronger effects than when applying either method alone. However, the dose effect of chemical materials on P inactivation when used in combination with submerged macrophytes and the influences of the chemicals used on the submerged macrophytes growth remain largely unknown. In this study, we investigated P inactivation in both the water column and the sediment, and the responses of submerged macrophytes to Lanthanum modified bentonite (LMB) in an outdoor mesocosm experiment where Vallisneria denseserrulata were transplanted into all mesocosms and LMB was added at four dosage levels, respectively: control (LMB-free), low dosage (570 g m-2), middle dosage (1140 g m-2), and high dosage (2280 g m-2). The results showed that the combination of LMB dosage and V. denseserrulata reduced TP in the water column by 32%-38% compared to V. denseserrulata alone, while no significant difference was observed among the three LMB treatments. Porewater soluble reactive P, two-dimensional diffusive gradient in thin films (DGT)-labile P concentrations, and P transformation in the 0-1 cm sediment layer exhibited similar trends along the LMB dosage gradient. Besides, LMB inhibited plant growth and reduced the uptake of mineral elements (i.e., calcium, manganese, iron, and magnesium) in a dosage-dependent manner with LMB. LMB may reduce plant growth by creating a P deficiency risk for new ramets and by interfering with the uptake of mineral elements. Considering both the dose effect of LMB on P inactivation and negative effect on macrophyte growth, we suggest a "small dosage, frequent application" method for LMB application to be used in lake restoration aiming to recover submerged macrophytes and clear water conditions.

The validation of new CHD1L inhibitors as a therapeutic strategy for cancer.

Chromodomain helicase DNA-binding protein 1 like (CHD1L) is an oncogene that promotes tumor progression, metastasis, and multidrug resistance. CHD1L expression is indicative of poor outcomes and low survival in cancer patients with various cancer types. Herein, we report a set of CHD1L inhibitors (CHD1Li) discovered from high-throughput screening and evaluated using enzyme inhibition, 3D tumor organoid cytotoxicity and mechanistic assays. The structurally distinct compounds 8-11 emerged as hits with promising bioactivity by targeting CHD1L. CHD1Li were further examined for their stability in human and mouse liver microsomes, which showed compounds 9 and 11 to be the most metabolically stable. Additionally, molecular modeling studies of CHD1Li with the target protein shed light on key pharmacophore features driving CHD1L binding. Taken together, these results expand the chemical space of CHD1Li as a potential targeted therapy for colorectal cancer and other cancers.