Spatial-temporal distribution characteristics of surface water pollutants and their potential sources in Ngari, China.

The Ngari region has many important rivers and is critical to water resource security and water resource continuity in China and even in adjoining Asian countries. However, the spatial distribution and monthly variation in local water quality have been poorly understood until recently. In this study, the spatial-temporal variations of 12 water quality parameters, including pH, dissolved oxygen (DO), permanganate index (IMn), chemical oxygen demand (COD), five-day biochemical oxygen demand (BOD5), ammonia nitrogen (NNH3), total nitrogen (Ntotal), total phosphorus (Ptotal), copper (Cu), fluoride (F), arsenic (As) and cadmium (Cd), were determined from samples collected monthly at 22 water cross-sectional sites in the Ngari region in 2020. The surface water pollution in the southern Ngari region was the most serious, and the water pollution level in winter was higher than that in the other seasons. As (0.0781 ~ 0.6154 mg/L) and F (1.05 ~ 4.64 mg/L) were the main exceedance factors derived from the recharge of high arsenic and fluoride geothermal water and weathering of As and F-bearing minerals. The hazard quotient and carcinogenic risk for As and F at the five contaminated sampling sites indicated potential health risks and even carcinogenicity to local populations. The hydrochemistry types of the lakes and rivers in the Ngari region were mainly chloride water and carbonate water. The results from this study can provide a scientific basis for the prevention and control of surface water pollution in the Ngari region and contribute to subsequent research on the ecology of water bodies.

Prognostic genome and transcriptome signatures in colorectal cancers.

Colorectal cancer is caused by a sequence of somatic genomic alterations affecting driver genes in core cancer pathways1. Here, to understand the functional and prognostic impact of cancer-causing somatic mutations, we analysed the whole genomes and transcriptomes of 1,063 primary colorectal cancers in a population-based cohort with long-term follow-up. From the 96 mutated driver genes, 9 were not previously implicated in colorectal cancer and 24 had not been linked to any cancer. Two distinct patterns of pathway co-mutations were observed, timing analyses identified nine early and three late driver gene mutations, and several signatures of colorectal-cancer-specific mutational processes were identified. Mutations in WNT, EGFR and TGFß pathway genes, the mitochondrial CYB gene and 3 regulatory elements along with 21 copy-number variations and the COSMIC SBS44 signature correlated with survival. Gene expression classification yielded five prognostic subtypes with distinct molecular features, in part explained by underlying genomic alterations. Microsatellite-instable tumours divided into two classes with different levels of hypoxia and infiltration of immune and stromal cells. To our knowledge, this study constitutes the largest integrated genome and transcriptome analysis of colorectal cancer, and interlinks mutations, gene expression and patient outcomes. The identification of prognostic mutations and expression subtypes can guide future efforts to individualize colorectal cancer therapy.

Prediabetes is associated with increased cardiac events in patients with cancer who are prescribed anthracyclines.

BACKGROUND: Prediabetes, which is a precedent of overt diabetes, is a known risk factor for adverse cardiovascular outcomes. Its impact on adverse cardiovascular outcomes in patients with cancer who are prescribed anthracycline-containing chemotherapy (ACT) is uncertain. The objective of this study was to evaluate the association of prediabetes with cardiovascular events in patients with cancer who are prescribed ACT. METHODS: The authors identified patients with cancer who received ACT from 2000 to 2019 from Clinical Data Analysis Reporting System of Hong Kong. Patients were divided into diabetes, prediabetes, and normoglycemia groups based on their baseline glycemic profile. The Primary outcome, a major adverse cardiovascular event (MACE), was the composite event of hospitalization for heart failure and cardiovascular death. RESULTS: Among 12,649 patients at baseline, 3997 had prediabetes, and 5622 had diabetes. Over median follow-up of 8.7 years, the incidence of MACE was 211 (7.0%) in the normoglycemia group, 358 (9.0%) in the prediabetes group, and 728 (12.9%) in the diabetes group. Compared with normoglycemia, prediabetes (adjusted hazard ratio [HR], 1.20; 95% confidence interval [CI], 1.01-1.43) and diabetes (adjusted HR, 1.46; 95% CI, 1.24-1.70) were associated with an increased risk of MACE. In the prediabetes group, 475 patients (18%) progressed to overt diabetes and exhibited a greater risk of MACE (adjusted HR, 1.76; 95% CI, 1.31-2.36) compared with patients who remained prediabetic. CONCLUSIONS: In patients with cancer who received ACT, those who had prediabetes at baseline and those who progressed to diabetes at follow-up had an increased risk of MACE. The optimization of cardiovascular risk factor management, including prediabetes, should be considered in patients with cancer who are treated before and during ACT to reduce cardiovascular risk. PLAIN LANGUAGE SUMMARY: Patients with cancer who have preexisting diabetes have a higher risk of cardiovascular events, and prediabetes is often overlooked. In this study of 12,649 patients with cancer identified in the Clinical Data Analysis Reporting System of Hong Kong who were receiving treatment with anthracycline drugs, prediabetes was correlated with increased deaths from cardiovascular disease and/or hospitalizations for heart failure. Patients who progressed from prediabetes to diabetes within 2 years had an increased risk of combined hospitalization for heart failure and death from cardiovascular disease. These findings indicate the importance of paying greater attention to cardiovascular risk factors, including how prediabetes is managed, in patients who have cancer and are receiving chemotherapy with anthracyclines, emphasizing the need for surveillance, follow-up strategies, and consideration of prediabetes management in cancer care.

Morphological and functional types of tricuspid regurgitation: prognostic value in patients undergoing tricuspid annuloplasty during left-sided valvular surgery.

BACKGROUND: The nonuniform benefit of tricuspid annuloplasty may be explained by the proportionality of tricuspid regurgitation (TR) severity to right ventricular (RV) area. The purpose of this study was to delineate distinct morphological phenotypes of functional TR and investigate their prognostic implications in patients undergoing tricuspid annuloplasty during left-sided valvular surgery. METHODS: The ratios of pre-procedural effective regurgitant orifice area (EROA) with right ventricular end-diastolic area (RVDA) were retrospectively assessed in 290 patients undergoing tricuspid annuloplasty. Based on optimal thresholds derived from penalized splines and maximally selected rank statistics, patients were stratified into proportionate (EROA/RVDA ratio ≤ 1.74) and disproportionate TR (EROA/RVDA ratio > 1.74). RESULTS: Overall, 59 (20%) and 231 (80%) patients had proportionate and disproportionate TR, respectively. Compared to those with proportionate TR, patients with disproportionate TR were older, had a higher prevalence of atrial fibrillation, lower pulmonary pressures, more impaired RV function, and larger tricuspid leaflet tenting area. Over a median follow-up of 4.1 years, 79 adverse events (47 heart failure hospitalizations and 32 deaths) occurred. Patients with disproportionate TR had higher rates of adverse events than those with proportionate TR (32% vs 10%; P = 0.001) and were independently associated with poor outcomes on multivariate analysis. TR proportionality outperformed guideline-based classification of TR severity in outcome prediction and provided incremental prognostic value to both the EuroSCORE II and STS score (incremental χ2 = 6.757 and 9.094 respectively; both P < 0.05). CONCLUSIONS: Disproportionate TR is strongly associated with adverse prognosis and may aid patient selection and risk stratification for tricuspid annuloplasty with left-sided valvular surgery.

A prediction model for in-hospital mortality in intensive care unit patients with metastatic cancer.

Aim: To identify predictors for in-hospital mortality in patients with metastatic cancer in intensive care units (ICUs) and established a prediction model for in-hospital mortality in those patients. Methods: In this cohort study, the data of 2,462 patients with metastatic cancer in ICUs were extracted from the Medical Information Mart for Intensive Care III (MIMIC-III) database. Least absolute shrinkage and selection operator (LASSO) regression analysis was applied to identify the predictors for in-hospital mortality in metastatic cancer patients. Participants were randomly divided into the training set (n = 1,723) and the testing set (n = 739). Patients with metastatic cancer in ICUs from MIMIC-IV were used as the validation set (n = 1,726). The prediction model was constructed in the training set. The area under the curve (AUC), sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were employed for measuring the predictive performance of the model. The predictive performance of the model was validated in the testing set and external validation was performed in the validation set. Results: In total, 656 (26.65%) metastatic cancer patients were dead in hospital. Age, respiratory failure, the sequential organ failure assessment (SOFA) score, the Simplified Acute Physiology Score II (SAPS II) score, glucose, red cell distribution width (RDW) and lactate were predictors for the in-hospital mortality in patients with metastatic cancer in ICUs. The equation of the prediction model was ln(P/(1 + P)) = -5.9830 + 0.0174 × age + 1.3686 × respiratory failure + 0.0537 × SAPS II + 0.0312 × SOFA + 0.1278 × lactate - 0.0026 × glucose + 0.0772 × RDW. The AUCs of the prediction model was 0.797 (95% CI,0.776-0.825) in the training set, 0.778 (95% CI, 0.740-0.817) in the testing set and 0.811 (95% CI, 0.789-0.833) in the validation set. The predictive values of the model in lymphoma, myeloma, brain/spinal cord, lung, liver, peritoneum/pleura, enteroncus and other cancer populations were also assessed. Conclusion: The prediction model for in-hospital mortality in ICU patients with metastatic cancer exhibited good predictive ability, which might help identify patients with high risk of in-hospital death and provide timely interventions to those patients.

Prognostic value of right ventricular remodelling in patients undergoing concomitant aortic and mitral valve surgery.

AIMS: Long-term risk stratification and surgical timing remain suboptimal in concomitant aortic and mitral (double) valve surgery. This study sought to examine the predictors, changes, and prognostic implications of right ventricular (RV) remodelling in patients undergoing double-valve surgery. METHODS AND RESULTS: In 152 patients undergoing double-valve surgery, four RV remodelling patterns were characterized using transthoracic echocardiography: normal RV size and systolic function (Pattern 1); dilated RV (tricuspid annulus diameter >35 mm) with normal systolic function (Pattern 2); normal RV size with systolic dysfunction (percentage RV fractional area change <35%; Pattern 3); and dilated RV with systolic dysfunction (Pattern 4). The primary endpoint was the composite of heart failure hospitalization and all-cause mortality. Patterns 1, 2, 3, and 4 RV remodelling were present in 41, 20, 23, and 16% of patients, respectively. Patients with Stage 4 RV remodelling had worse renal function, higher EuroSCORE II, and impaired left ventricular ejection fraction. During a 3.7-year median follow up, 45 adverse events occurred. Patterns 3 and 4 RV remodelling were associated with significantly higher adverse event rates compared with Pattern 1 (37 and 75% vs. 11%, P < 0.01) and had incremental prognostic value when added to clinical parameters and EuroSCORE II (χ2 increased from 30 to 66, P < 0.01). At 1 year after surgery (n = 100), Patterns 3 and 4 RV remodelling had a higher risk of adverse events compared with Pattern 1. CONCLUSION: Right ventricular remodelling was strongly related to adverse outcomes and deserves consideration as part of the risk and decision-making algorithms in double-valve surgery.

Concomitant Hepatorenal Dysfunction and Malnutrition in Valvular Heart Surgery: Long-Term Prognostic Implications for Death and Heart Failure.

Background Strategies to improve long-term prediction of heart failure and death in valvular surgery are urgently needed because of an increasing number of procedures globally. This study sought to report the prevalence, changes, and prognostic implications of concomitant hepatorenal dysfunction and malnutrition in valvular surgery. Methods and Results In 909 patients undergoing valvular surgery, 3 groups were defined based on hepatorenal function (the modified model for end-stage liver disease excluding international normalized ratio score) and nutritional status (Controlling Nutritional Status score): normal hepatorenal function and nutrition (normal), hepatorenal dysfunction or malnutrition alone (mild), and concomitant hepatorenal dysfunction and malnutrition (severe). Overall, 32%, 46%, and 19% of patients were classified into normal, mild, and severe groups, respectively. Over a 4.1-year median follow-up, mild and severe groups incurred a higher risk of mortality (hazard ratio [HR], 3.17 [95% CI, 1.40-7.17] and HR, 9.30 [95% CI, 4.09-21.16], respectively), cardiovascular death (subdistribution HR, 3.29 [95% CI, 1.14-9.52] and subdistribution HR, 9.29 [95% CI, 3.09-27.99]), heart failure hospitalization (subdistribution HR, 2.11 [95% CI, 1.25-3.55] and subdistribution HR, 3.55 [95% CI, 2.04-6.16]), and adverse outcomes (HR, 2.11 [95% CI, 1.25-3.55] and HR, 3.55 [95% CI, 2.04-6.16]). Modified model for end-stage liver disease excluding international normalized ratio and controlling nutritional status scores improved the predictive ability of European System for Cardiac Operative Risk Evaluation (area under the curve: 0.80 versus 0.73, P<0.001) and Society of Thoracic Surgeons score (area under the curve: 0.79 versus 0.72, P=0.004) for all-cause mortality. One year following surgery (n=707), patients with persistent concomitant hepatorenal dysfunction and malnutrition (severe) experienced worse outcomes than those without. Conclusions Concomitant hepatorenal dysfunction and malnutrition was frequent and strongly linked to heart failure and mortality in valvular surgery.

Temporal trends and patterns of infective endocarditis in a Chinese population: A territory-wide study in Hong Kong (2002-2019).

Background: The characteristics of infective endocarditis (IE) in Asians are poorly understood. Therefore, we aim to describe the epidemiological trends and clinical features of IE in Hong Kong. Methods: All patients with incident IE from 2002-2019 in a territory-wide clinical database in Hong Kong were identified. We studied the age- and sex-adjusted and one-year mortality of IE between 2002 and 2019 and identified significant contributors to 1-year all-cause death using the attributable fraction. We used propensity score and inverse propensity of treatment weighting to study the association of surgery with mortality. Findings: A total of 5139 patients (60.4 ± 18.2years, 37% women) were included. The overall incidence of IE was 4.9 per 100,000 person-year, which did not change over time (P = 0.17). Patients in 2019 were older and more comorbid than those in 2002. The one-year crude mortality rate was 30% in 2002, which did not change significantly over time (P = 0.10). Between 2002 and 2019, the rate of surgery increased and was associated with a 51% risk reduction in 1-year all-cause mortality (Hazard Ratio 0.49 [0.28-0.87], P = 0.015). Advanced age (attributable fraction 19%) and comorbidities (attributable fraction 15%) were significant contributors to death. Interpretation: The incidence of IE in Hong Kong did not change between 2002 and 2019. Patients with IE in 2019 were older and had more comorbidities than those in 2002. Mortality of IE remains persistently high in Hong Kong. Together, these data can guide public health strategies to improve the outcomes of patients with IE. Funding: This work was supported by Sanming Project of Medicine in Shenzhen, China [No. SZSM201911020] and HKU-SZH Fund for Shenzhen Key Medical Discipline [No. SZXK2020081].

Prevalence and Prognostic Importance of Massive Tricuspid Regurgitation in Patients Undergoing Tricuspid Annuloplasty With Concomitant Left-Sided Valve Surgery: A Study on Rheumatic Valvular Heart Disease.

BACKGROUND: The presence of tricuspid regurgitation (TR) is very common in patients with concomitant left-sided valve disease. Recent studies have advocated an additional grading of massive TR that is beyond severe. The present study sought to characterize the spectrum of TR in patients undergoing tricuspid annuloplasty (TA) and to evaluate the prognostic value of TR severity for post-operative outcome following TA. METHODS: A total of 176 patients who underwent TA with combined left-sided valve surgery, secondary to rheumatic valvular heart disease, were prospectively evaluated. The severity of TR was quantified by effective regurgitant orifice area (EROA) using the proximal isovelocity surface area method. Patients were categorized as having non-massive TR (EROA < 0.6 cm2) or massive TR (EROA ≥ 0.6 cm2). Adverse outcome was defined as all-cause mortality or heart failure requiring hospital admission following TA. RESULTS: A total of 55 (31%) patients were considered to have massive TR. Patients with massive TR had a greater right ventricular dimension but a smaller left ventricular dimension compared with those with non-massive TR. After a median follow-up of 39 months, 35 adverse events occurred. Cox-regression analysis showed that both continuous EROA and dichotomized EROA (massive vs. non-massive TR) were independently associated with adverse events even after multivariable adjustment. Further, Harrell C index demonstrated that the addition of massive TR provided better discrimination ability of a prediction model to known prognosticators following TA. CONCLUSIONS: Massive TR is common and up to 31% of study population had massive TR. Massive TR was associated with adverse outcome in patients undergoing TA. Classification of the severity of TR by quantitative measures and identification of massive TR in patients with concomitant left-sided valve disease are essential when considering the optimal timing of corrective surgery.

Low-dose aspirin and incidence of lung carcinoma in patients with chronic obstructive pulmonary disease in Hong Kong: A cohort study.

BACKGROUND: Evidence suggests that chronic obstructive pulmonary disease (COPD) is associated with a higher risk of lung carcinoma. Using a territory-wide clinical electronic medical records system, we investigated the association between low-dose aspirin use (≤160 mg) among patients with COPD and incidence of lung carcinoma and the corresponding risk of bleeding. METHODS AND FINDINGS: This is a retrospective cohort study conducted utilizing Clinical Data Analysis Reporting System (CDARS), a territory-wide database developed by the Hong Kong Hospital Authority. Inverse probability of treatment weighting (IPTW) was used to balance baseline covariates between aspirin nonusers (35,049 patients) with new aspirin users (7,679 patients) among all eligible COPD patients from 2005 to 2018 attending any public hospitals. The median age of the cohort was 75.7 years (SD = 11.5), and 80.3% were male. Competing risk regression with Cox proportional hazards model were performed to estimate the subdistribution hazard ratio (SHR) of lung carcinoma with low-dose aspirin and the associated bleeding events. Of all eligible patients, 1,779 (4.2%, 1,526 and 253 among nonusers and users) were diagnosed with lung carcinoma over a median follow-up period of 2.6 years (interquartile range [IQR]: 1.4 to 4.8). Aspirin use was associated with a 25% lower risk of lung carcinoma (SHR = 0.75, 95% confidence interval [CI] 0.65 to 0.87, p = <0.001) and 26% decrease in lung carcinoma-related mortality (SHR = 0.74, 95% CI 0.64 to 0.86, p = <0.001). Subgroup analysis revealed that aspirin was beneficial for patients aged above or below 75 years, but was also beneficial among populations who were male, nondiabetic, and nonhypertensive. Aspirin use was not associated with an increased risk of upper gastrointestinal bleeding (UGIB) (SHR = 1.19, 95% CI 0.94 to 1.53, p = 0.16), but was associated with an increased risk of hemoptysis (SHR = 1.96, 95% CI 1.73 to 2.23, p < 0.001). The main limitations of the study were (i) that one group of patients may be more likely to seek additional medical attention, although this was partially mitigated by the use of propensity score analysis; and (ii) the observational nature of the study renders it unable to establish causality between aspirin use and lung carcinoma incidence. CONCLUSIONS: In this study, we observed that low-dose aspirin use was associated with a lower risk of lung carcinoma and lung carcinoma-related mortality among COPD patients. While aspirin was not associated with an increased risk of UGIB, the risk of hemoptysis was elevated.

Prognostic value and reversibility of liver stiffness in patients undergoing tricuspid annuloplasty.

BACKGROUND: Liver stiffness (LS) assessed by transient elastography is associated with adverse events in patients with heart failure. However, the predictive value of LS for adverse outcome is uncertain in patients undergoing tricuspid annuloplasty (TA). This study sought to evaluate the prognostic value and reversibility of LS in patients undergoing TA during left-sided valve surgery. METHODS AND RESULTS: A total of 158 patients who underwent TA were prospectively evaluated. Patients were divided into three groups according to tertile of LS. Adverse outcome was defined as heart failure that required hospital admission or all-cause mortality following TA. The median LS was 13.9 (inter-quartile range 8.1-22.3) kPa and independently correlated positively with tricuspid regurgitation (TR) severity, inferior vena cava diameter and negatively with tricuspid annular plane systolic excursion. During a median follow-up of 31 months, 49 adverse events occurred. Multivariable Cox regression analysis revealed that LS was an independent predictor of adverse events. Significant improvement in LS at 1-year post-TA (13.1-7.8 kPa, P < 0.01) was noted only in patients who had no adverse events, not in those who experienced heart failure (17.1-14.2 kPa, P = 0.87) and seems to be linked to an absence of TR recurrence. CONCLUSIONS: This study demonstrated that LS is predictive of adverse outcome and is reversible in patients undergoing TA without TR recurrence at 1 year. These findings suggest that assessing LS, an integrative correlate of right heart condition, may aid the pre-operative risk assessment of candidate for heart surgery including TA.

Association of serum uric acid with biventricular myocardial dysfunction in patients with type 2 diabetes mellitus.

BACKGROUND AND AIMS: Increased serum uric acid (SUA) is common in type 2 diabetes mellitus (T2DM) and is associated with left ventricular (LV) myocardial dysfunction. Nonetheless the association of SUA with right ventricular (RV) function in T2DM has not been studied. This study aimed to investigate the association of SUA with biventricular myocardial function in patients with T2DM. METHODS AND RESULTS: A total of 560 patients with T2DM were enrolled and divided into four groups according to sex-specific quartiles of SUA. Transthoracic echocardiography was performed and two-dimensional speckle tracking was used to measure biventricular myocardial strain, including LV global longitudinal strain (GLS), circumferential strain (CS), radial strain (RS), and RV free wall longitudinal strain (RV-FWLS). The absolute value of all biventricular strain parameters showed a stepwise decrease across SUA quartiles (all P < 0.01). In particular, LV assessment by GLS, CS and RS demonstrated that those in the 4th quartile were impaired compared with the other quartiles (all P < 0.05). Similarly, RV-FWLS of the 4th quartile was significantly impaired compared with the 1st and 2nd quartiles (all P < 0.05). The same reduction in biventricular strain across SUA quartiles was observed in patients with estimated glomerular filtration rate < or ≥60 ml/min/1.73 m2, and glycated hemoglobin < or ≥7.0% (all P < 0.05). Multivariable linear regression analysis demonstrated that higher quartile of SUA was independently associated with impaired biventricular myocardial strain (all P < 0.05). CONCLUSIONS: SUA was independently associated with biventricular myocardial dysfunction in asymptomatic T2DM patients, regardless of renal function or diabetic control.

Statin associated lower cancer risk and related mortality in patients with heart failure.

AIMS: Patients with heart failure (HF) have an increased risk of incident cancer. Data relating to the association of statin use with cancer risk and cancer-related mortality among patients with HF are sparse. METHODS AND RESULTS: Using a previously validated territory-wide clinical information registry, statin use was ascertained among all eligible patients with HF (n = 87 102) from 2003 to 2015. Inverse probability of treatment weighting was used to balance baseline covariates between statin nonusers (n = 50 926) with statin users (n = 36 176). Competing risk regression with Cox proportional-hazard models was performed to estimate the risk of cancer and cancer-related mortality associated with statin use. Of all eligible subjects, the mean age was 76.5 ± 12.8 years, and 47.8% was male. Over a median follow-up of 4.1 years (interquartile range: 1.6-6.8), 11 052 (12.7%) were diagnosed with cancer. Statin use (vs. none) was associated with a 16% lower risk of cancer incidence [multivariable adjusted subdistribution hazard ratio (SHR) = 0.84; 95% confidence interval (CI), 0.80-0.89]. This inverse association with risk of cancer was duration dependent; as compared with short-term statin use (3 months to <2 years), the adjusted SHR was 0.99 (95% CI, 0.87-1.13) for 2 to <4 years of use, 0.82 (95% CI, 0.70-0.97) for 4 to <6 years of use, and 0.78 (95% CI, 0.65-0.93) for ≥6 years of use. Ten-year cancer-related mortality was 3.8% among statin users and 5.2% among nonusers (absolute risk difference, -1.4 percentage points [95% CI, -1.6% to -1.2%]; adjusted SHR = 0.74; 95% CI, 0.67-0.81). CONCLUSION: Our study suggests that statin use is associated with a significantly lower risk of incident cancer and cancer-related mortality in HF, an association that appears to be duration dependent.

Noninvasive radiomics-based method for evaluating idiopathic central precocious puberty in girls.

OBJECTIVE: Traditional approaches that involve measuring the height and volume of the pituitary by magnetic resonance imaging (MRI) are unreliable. We investigated the use of a more accurate method using texture analysis to evaluate idiopathic central precocious puberty (ICPP) by MRI. METHODS: In total, 352 texture features of the pituitary were extracted from 12 healthy girls and 18 girls with ICPP. A LASSO regression model and linear regression model were used to create the prediction model. Pearson's correlation analysis and receiver operating characteristic curves were used to evaluate the predictive performance. RESULTS: The radiomics score had a significant linear relationship with the luteinizing hormone concentration and the luteinizing hormone/follicle-stimulating hormone ratio. The radiomics score showed better predictive performance than traditional pituitary measurements. The area under the curve of the radiomics score, pituitary height, and variable combinations was 0.759 (95% confidence interval [CI], 0.583-0.936), 0.681 (95% CI, 0.483-0.878), and 0.829 (95% CI, 0.681-0.976), respectively. CONCLUSION: Combination of the radiomics score with pituitary height measurements allows for better evaluation of the pituitary during diagnostic imaging, indicating satisfactory potential for efficacy assessments.

Centyrin ligands for extrahepatic delivery of siRNA.

RNA interference (RNAi) offers the potential to treat disease at the earliest onset by selectively turning off the expression of target genes, such as intracellular oncogenes that drive cancer growth. However, the development of RNAi therapeutics as anti-cancer drugs has been limited by both a lack of efficient and target cell-specific delivery systems and the necessity to overcome numerous intracellular barriers, including serum/lysosomal instability, cell membrane impermeability, and limited endosomal escape. Here, we combine two technologies to achieve posttranscriptional gene silencing in tumor cells: Centyrins, alternative scaffold proteins binding plasma membrane receptors for targeted delivery, and small interfering RNAs (siRNAs), chemically modified for high metabolic stability and potency. An EGFR Centyrin known to internalize in EGFR-positive tumor cells was site-specifically conjugated to a beta-catenin (CTNNb1) siRNA and found to drive potent and specific target knockdown by free uptake in cell culture and in mice inoculated with A431 tumor xenografts (EGFR amplified). The generalizability of this approach was further demonstrated with Centyrins targeting multiple receptors (e.g., BCMA, PSMA, and EpCAM) and siRNAs targeting multiple genes (e.g., CD68, KLKb1, and SSB1). Moreover, by installing multiple conjugation handles, two different siRNAs were fused to a single Centyrin, and the conjugate was shown to simultaneously silence two different targets. Finally, by specifically pairing EpCAM-binding Centyrins that exhibited optimized internalization profiles, we present data showing that an EpCAM Centyrin CTNNb1 siRNA conjugate suppressed tumor cell growth of a colorectal cancer cell line containing an APC mutation but not cells with normal CTNNb1 signaling. Overall, these data demonstrate the potential of Centyrin-siRNA conjugates to target cancer cells and silence oncogenes, paving the way to a new class of anticancer drugs.

Prognostic Value of Tricuspid Valve Geometry and Leaflet Coaptation Status in Patients Undergoing Tricuspid Annuloplasty: A Three-Dimensional Echocardiography Study.

BACKGROUND: The advent of three-dimensional echocardiography (3DE) enables detailed evaluation of the tricuspid valve (TV) apparatus; nonetheless, the clinical value of preoperative 3DE is unknown in patients undergoing tricuspid annuloplasty (TA). The aim of this study was to evaluate the prognostic value of TV geometric parameters and leaflet coaptation status evaluated by 3DE in patients undergoing TA. METHODS: A total of 122 patients who underwent TA during left-sided heart valve surgery were prospectively evaluated. Detailed 3DE was performed before surgery. Adverse outcome was defined as the occurrence of heart failure requiring hospital admission or all-cause mortality following TA. RESULTS: A total of 33 adverse events (17 heart failures and 16 deaths) occurred during a median follow-up of 36 months. Tethering volume (hazard ratio = 1.32; 95% CI = 1.05-1.66; P = .01) and ratio of total leaflet length to closure length (hazard ratio = 1.07; 95% CI = 1.03-1.12; P < .01) were associated with adverse events after adjustment for age, sex, and tricuspid regurgitation vena contracta width. Receiver-operator characteristic curve analysis revealed that tethering volume (area under curve = 0.73) and ratio of total leaflet length to closure length (area under curve = 0.75) were most associated with adverse events at 1-year follow-up. The presence of either a large tethering volume or a low ratio of total leaflet length to closure length was predictive of an adverse outcome 1 year following TA. CONCLUSIONS: Our study suggests that 3DE-derived TV tethering volume and ratio of total leaflet length to closure length are important preoperative measures associated with adverse events in patients undergoing TA.

Predictive value of acute kidney injury for major adverse cardiovascular events following tricuspid annuloplasty: A comparison of three consensus criteria.

BACKGROUND: Tricuspid annuloplasty (TA) is increasingly being performed, but the clinical outcome is unsatisfactory. Acute kidney injury (AKI) is a common complication following cardiac surgery and predicts outcome. Nonetheless the occurrence rate and prognostic value of AKI after TA are unclear. METHODS: This study reviewed 339 consecutive patients (age 65±11 years; male 42%) who underwent TA. The incidence of AKI was defined according to risk/injury/failure/loss/end stage (RIFLE), acute kidney injury network (AKIN), and kidney disease improving global outcomes (KDIGO) criteria, respectively. Major adverse cardiovascular events (MACE) was defined as death, heart failure, stroke, and myocardial infarction (MI). The influence of AKI on MACE was evaluated as a short-term outcome and outcome beyond 30 days. RESULTS: The incidence of AKI, defined according to RIFLE, AKIN, and KDIGO was 57%, 52%, and 53%, respectively. MACE occurred in 94 cases (21 deaths, 63 heart failure requiring hospitalization, 7 stroke, and 3 MI). For short-term outcome, AKI defined by all three scoring systems was independently associated with MACE and death (p<0.01 for both), but not heart failure, stroke, or MI. For outcome beyond 30 days, AKI by all three criteria was associated with MACE and heart failure. Only AKI by AKIN and KDIGO, but not RIFLE, was independently associated with death. CONCLUSION: Our data suggest AKI affects over half of all patients who undergo TA, and has a major and long-lasting impact on survival, MACE, and heart failure. Use of AKIN and KDIGO is more useful than the RIFLE criteria when determining the prognostic value of AKI for mortality beyond 30 days.

BNP7787-mediated modulation of paclitaxel- and cisplatin-induced aberrant microtubule protein polymerization in vitro.

Taxane and platinum drugs are important agents in the treatment of cancer and have shown activity against a variety of tumors, including ovarian, breast, and lung cancer, either as single agents or in combination with other chemotherapy drugs. However, a serious and prevalent side effect of taxane (docetaxel and all formulations/derivatives of paclitaxel) and platinum (cisplatin, carboplatin, and oxaliplatin) agents is dose-limiting chemotherapy-induced peripheral neuropathy (CIPN). CIPN can result in treatment delays, dose modifications, and, in severe cases, discontinuation of chemotherapy. Consequently, effective treatments for CIPN are needed. Dimesna (BNP7787; Tavocept; disodium 2,2'-dithio-bis-ethanesulfonate) is an investigational drug that is undergoing international clinical development as a treatment that is coadministered with first-line taxane and platinum combination chemotherapy in patients with inoperable advanced primary adenocarcinoma of the lung. BNP7787 is currently being developed with the objective of increasing the survival of cancer patients receiving taxane- and/or cisplatin-based chemotherapy. Additional data indicate that BNP7787 may also protect against common and serious chemotherapy-induced toxicities, including chemotherapy-induced anemia, nausea, emesis, nephrotoxicity, and neuropathy, without interfering with antitumor activity of the chemotherapeutic agent(s). Studies herein show that BNP7787 prevents aberrant microtubule protein (MTP) polymerization that is caused by exposure of MTP to paclitaxel or cisplatin. BNP7787 modulates paclitaxel-induced hyperpolymerization of MTP in a dose-dependent manner, and mesna, an in vivo metabolite of BNP7787, protects against time-dependent cisplatin-induced inactivation of MTP. We propose that interactions between BNP7787 and MTP may play a role in BNP7787-mediated protection against CIPN.