Unexpected discovery of renal mass in a patient with granulomatosis with polyangiitis: accidental or inevitable?

Granulomatosis with polyangiitis (GPA) is an uncommon disorder that mainly involves the upper and lower respiratory tract and kidney, presenting as sinusitis, saddle nose, otitis media, pulmonary nodule and cavity, rapidly progressive glomerulonephritis. It also affects skin, eye, heart, joint and nervous system. Renal involvement in GPA is commonly manifested as necrotising glomerulonephritis, while renal mass is very rare. We herein present two hospitalised cases with fever, pulmonary cavity and renal mass. Clinical course and examinations of the cases, from symptoms to diagnosis, will be discussed in detail, along with a relevant literature review of this unusual renal manifestation.

Mortality in patients admitted to hospital with heart failure in China: a nationwide Cardiovascular Association Database-Heart Failure Centre Registry cohort study.

BACKGROUND: China has the largest burden of heart failure worldwide. However, large-scale studies on heart failure mortality are scarce. We aimed to investigate mortality and identify risk factors for mortality among patients with heart failure in China. METHODS: This prospective cohort study used data from the China Cardiovascular Association (CCA) Database-Heart Failure Centre Registry, which were linked to the National Mortality Registration Information Management System by the Chinese Centre for Disease Control and Prevention. We included patients enrolled from Jan 1, 2017, to Dec 31, 2021, across 572 CCA Database-Heart Failure Centre certified hospitals in 31 provinces of mainland China. Eligible patients were aged 18 years or older (younger than 100 years) with a principal discharge diagnosis of heart failure based on Chinese heart failure guidelines. All-cause mortality at 30 days, 1 year, and 3 years for patients with heart failure were calculated and the causes of death were recorded. Multivariable analysis was used to analyse factors associated with all-cause mortality and cardiovascular mortality. This study was registered with the Chinese Clinical Trial Registry, ChiCTR2200066305. FINDINGS: Of the 327 477 patients in the registry, 230 637 eligible adults with heart failure were included in our analyses. Participant mean age was 69·3 years (SD 13·2), 94 693 (41·1%) participants were female, and 135 944 (58·9%) were male. The median follow-up time was 531 days (IQR 251-883). Post-discharge all-cause mortality of patients with heart failure at 30 days was 2·4% (95% CI 2·3-2·5), at 1 year was 13·7% (13·5-13·9), and at 3 years was 28·2% (27·7-28·6). Cardiovascular death accounted for 32 906 (71·5%) of 46 006 all-cause deaths. Patients with heart failure with reduced ejection fraction had the highest all-cause mortality. A lower guideline adherence score was independently associated with the increase of all-cause and cardiovascular mortality. INTERPRETATION: In China, mortality for patients with heart failure is still high, especially in patients with reduced ejection fraction. Our findings suggest that guideline-directed medical therapy needs to be improved. FUNDING: National High Level Hospital Clinical Research Funding, the Capital's Funds for Health Improvement and Research, and the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Impact of heart rate changes during hospitalization on outcome in heart failure with preserved ejection fraction.

AIMS: The benefits of lowering heart rate (HR) in heart failure (HF) with preserved ejection fraction (HFpEF) patients are still a matter of debate. This study aimed to investigate the relationship between changes in HR during hospitalization and cardiovascular (CV) events and all-cause death in hospitalized HFpEF patients. METHODS AND RESULTS: Hospitalized HF patients between January 2017 and December 2021 were consecutively enrolled in a national, multicentred, and prospective registry database, the China Cardiovascular Association Database-HF Center Registry. HF patients with a left ventricular ejection fraction of ≥50% were defined as HFpEF patients. The study analysed admission/discharge HR, change in HR during hospitalization (∆HR), and ∆HR ratio (∆HR/admission HR). The patients were categorized into three groups: no HR dropping group (ΔHR ratio > 0.0%), moderate HR dropping group (-15% < ΔHR ratio ≤ 0.0%), and excessive HR dropping group (ΔHR ratio ≤ -15%). All patients were followed up for 12 months. The primary endpoint was CV events (CV death or HF rehospitalization). The secondary endpoint was all-cause death. A total of 19 510 HFpEF patients (9750 males, mean age 71.9 ± 12.2 years) were included, with 4575 in the no HR dropping group, 8434 in the moderate HR dropping group, and 6501 in the excessive HR dropping group. Excessive HR dropping during hospitalization was significantly associated with an increased risk of CV events (17.1%) compared with the no HR dropping group (14.5%, P < 0.001) or the moderate HR dropping group (14.0%, P < 0.001), although all-cause mortality was similar among the three groups. After adjusting for multiple confounding factors, excessive HR dropping remained an independent predictor of increased CV event risk [hazard ratio 1.197, 95% confidence interval (CI) 1.078-1.328]. Subgroup analysis revealed that the prognostic impact of excessive HR dropping on increased CV event risk remained in the subgroups of older age, New York Heart Association class IV, ischaemic HF, higher left ventricular ejection fraction, absence of chronic kidney disease, and use of beta-blockers or ivabradine. Independent determinants associated with excessive HR dropping during admission included use of beta-blockers [odds ratio (OR) 1.683, 95% CI 1.558-1.819], lower discharge diastolic blood pressure (OR 0.988, 95% CI 0.985-0.991), no pacemaker (OR 0.501, 95% CI 0.416-0.603), coexisting atrial fibrillation or atrial flutter (OR 1.327, 95% CI 1.218-1.445), and use of digoxin (OR 1.340, 95% CI 1.213-1.480). CONCLUSIONS: In hospitalized HFpEF patients, excessive HR dropping during hospitalization is associated with an increased risk of CV death or HF rehospitalization. These findings highlight the importance of HR monitoring and avoiding excessively slowing down HR in hospitalized HFpEF patients to reduce the risk of CV events.

Unraveling Flow Effect on Capacitive Energy Extraction from Salinity Gradients.

The harvesting of salinity gradient energy through a capacitive double-layer expansion (CDLE) technique is directly associated with ion adsorption and desorption in electrodes. Herein, we show that energy extraction can be modulated by regulating ion adsorption/desorption through water flow. The flow effects on the output energy, capacitance, and energy density under practical conditions are systematically investigated from a theoretical perspective, upon which the optimal operating condition is identified for energy extraction. We demonstrate that the net charge accumulation displays a negative correlation with the water flow velocity and so does the surface charge density, and this causes a nontrivial variation in the magnitude of output energy when water flows are introduced. When high water flows are introduced in both the charging and discharging processes, the energy extraction can be significantly reduced by 47.69-49.32%. However, when a high flow is solely exerted in the discharging process, the energy extraction can be enhanced by 12.94-14.49% even at low operation voltages. This study not only offers a comprehensive understanding of the microscopic mechanisms of surface-engineered energy extraction with water flows but also provides a novel direction for energy extraction enhancement.

Comparison of AirSeal versus conventional insufflation system for retroperitoneal robot-assisted laparoscopic partial nephrectomy: a randomized controlled trial.

PURPOSE: AirSeal is a valve-less trocar insufflation system which is widely used in robotic urologic surgeries. More evidence is needed concerning the application and cost of AirSeal in retroperitoneal robot-assisted laparoscopic partial nephrectomy. METHODS: We conducted a randomized controlled trial enrolling 62 patients who underwent retroperitoneal robot-assisted laparoscopic partial nephrectomy from February 2022 to February 2023 in the Peking Union Medical College Hospital. Patients were randomly assigned into AirSeal insufflation (AIS) group and conventional insufflation (CIS) group. The primary outcome was the rate of subcutaneous emphysema (SCE). RESULTS: The SCE rate in the AIS group (12.9%) was significantly lower than that in the CIS group (35.5%) (P = 0.038). Lower maximum end-tidal carbon dioxide (CO2) (41 vs 45 mmHg, P = 0.011), PaCO2 at the end of the operation (40 vs 45 mmHg, P < 0.001), maximum tidal volume (512 vs 570 ml, P = 0.003), frequency of lens cleaning (3 vs 5, P < 0.001), pain score at 8 h (3 vs 4, P = 0.025), 12 h (2 vs 3, P = 0.029) postoperatively and at time of discharge (1 vs 2, P = 0.002) were observed in the AIS group, despite a higher hospitalization cost (68,197 vs 64658RMB, P < 0.001). Logistic regression analysis identified insufflation approach was the only influencing factor for the occurrence of SCE events. CONCLUSION: AirSeal insufflation system exhibited similar efficacy and improved safety for retroperitoneal robot-assisted laparoscopic partial nephrectomy than conventional insufflation system, despite an affordable increase of hospitalization costs.

Effectiveness and safety of ivabradine in Chinese patients with chronic heart failure: an observational study.

AIMS: A therapeutic strategy for chronic heart failure (HF) is to lower resting heart rate (HR). Ivabradine is a well-known HR-lowering agent, but limited prospective data exist regarding its use in Chinese patients. This study aimed to evaluate the effectiveness and safety of ivabradine in Chinese patients with chronic HF. METHODS AND RESULTS: This multicentre, single-arm, prospective, observational study enrolled Chinese patients with chronic HF. The primary outcome was change from baseline in HR at 1 and 6 months, measured by pulse counting. Effectiveness was also evaluated using laboratory tests, the Kansas City Cardiomyopathy Questionnaire (KCCQ) clinical summary score (CSS) and overall summary score (OSS), and New York Heart Association (NYHA) class. Treatment-emergent adverse events (TEAEs) were assessed. A post hoc analysis examined the effectiveness and safety of ivabradine combined with an angiotensin receptor-neprilysin inhibitor (ARNI) or beta-blocker. A total of 1003 patients were enrolled [mean age 54.4 ± 15.0 years, 773 male (77.1%), mean baseline HR 88.5 ± 11.3 b.p.m., mean blood pressure 115.7/74.4 ± 17.2/12.3 mmHg, mean left ventricular ejection fraction 30.9 ± 7.6%, NYHA Classes III and IV in 48.8% and 22.0% of patients, respectively]. HR decreased by a mean of 12.9 and 16.1 b.p.m. after 1 and 6 months, respectively (both P < 0.001). At Month 6, improvements in the KCCQ CSS and OSS of ≥5 points were observed in 72.1% and 74.1% of patients, respectively (both P < 0.001). Left ventricular ejection fraction increased by 12.1 ± 11.6 (P < 0.001), and 66.7% of patients showed improvement in NYHA class (P < 0.001). At Month 6, the overall proportion of patients in NYHA Classes III and IV was reduced to 13.5% and 2.1%, respectively. Serum brain natriuretic peptide (BNP) and N-terminal pro-BNP changed by -331.9 ng/L (-1238.6, -134.0) and -1113.8 ng/L (-2202.0, -297.2), respectively (P < 0.001). HR reductions and improvements in NYHA and KCCQ scores with ivabradine were similar with and without use of ARNIs or beta-blockers. Of 498 TEAEs in 296 patients (29.5%), 73 TEAEs in 55 patients (5.5%) were considered related to ivabradine [most frequent sinus bradycardia (n = 7) and photopsia (n = 7)]. TEAEs were reported in a similar number of patients in ARNI and beta-blocker subgroups (21.9-35.6%). CONCLUSIONS: Ivabradine treatment reduced HR and improved cardiac function and health-related quality of life in Chinese patients with chronic HF. Benefits were seen irrespective of whether or not patients were also taking ARNIs or beta-blockers. Treatment was well tolerated with a similar profile to previous ivabradine studies.

Revascularization for Patients With Heart Failure With Preserved Ejection Fraction and Coronary Artery Disease.

Coronary artery disease (CAD) is one of the main causes of heart failure (HF) with preserved ejection fraction (HFpEF). The efficacy of revascularization therapy in patients with HFpEF and CAD, however, remains unclear. Patients who underwent coronary angiography from January 2017 to December 2019 were included in this retrospective study if they further satisfied the diagnosis of HFpEF (left ventricular ejection fraction ≥50% plus plasma N-terminal pro-BNP ≥125 pg/ml) and CAD (patients had a history of confirmed myocardial infarction or ≥50% stenosis in at least 1 epicardial coronary vessel). Clinical data, way of revascularization, and outcome events (unplanned repeated revascularization, HF readmission, cardiovascular death, readmission of cerebral hemorrhage/stroke or gastrointestinal bleeding, and all-cause death) were recorded and analyzed. A total of 1,111 patients were enrolled for the present analysis. Based on whether the revascularization was complete or not, the patients were divided into the complete revascularization group (n = 780) and the incomplete/no revascularization group (n = 331). All patients were followed up with a median of 355 days. The overall rates of unplanned repeated revascularization, HF readmission, and cardiovascular death were 6.6%, 5.0%, and 0.4%, respectively. Compared with incompletely/not revascularized patients, completely revascularized patients had a lower rate of unplanned repeated revascularization (10.9% vs 4.7%, p <0.001) and cardiovascular death (0.9% vs 0.1%, p = 0.048). However, HF readmission, readmission of cerebral hemorrhage/stroke or gastrointestinal bleeding, and noncardiac death were comparable between the 2 groups. The regression analysis showed that hyperlipidemia, previous myocardial infarction, in-stent restenosis, and way of revascularization were associated with the composite events of unplanned repeated revascularization, HF readmission, and cardiovascular death during the follow-up. Complete revascularization may reduce unplanned repeated revascularization and cardiovascular death for patients with HFpEF and CAD.

Ablation for atrial fibrillation improves the outcomes in patients with heart failure with preserved ejection fraction.

AIMS: Patients with heart failure with preserved ejection fraction (HFpEF) and atrial fibrillation (AF) have worse clinical outcomes than those with sinus rhythm (SR). We aim to investigate whether maintaining SR in patients with HFpEF through a strategy such as AF ablation would improve outcomes. METHODS AND RESULTS: This is a cohort study that analysed 1034 patients (median age 69 [63-76] years, 46.2% [478/1034] female) with HFpEF and AF. Of these, 392 patients who underwent first-time AF ablation were assigned to the ablation group, and the remaining 642 patients, who received only medical therapy, were assigned to the no ablation group. The primary endpoint was a composite of all-cause death or rehospitalization for worsening heart failure. After a median follow-up of 39 months, the cumulative incidence of the primary endpoint was significantly lower in the ablation group compared to the no ablation group (adjusted hazard ratio [HR], 0.55 [95% CI, 0.37-0.82], P = 0.003) in the propensity score-matched model. Secondary endpoint analysis showed that the benefit of AF ablation was mainly driven by a reduction in rehospitalization for worsening heart failure (adjusted HR, 0.52 [95% CI, 0.34-0.80], P = 0.003). Patients in the ablation group showed a 33% relative decrease in atrial tachycardia/AF recurrence compared to the no ablation group (adjusted HR, 0.67 [95% CI, 0.54-0.84], P < 0.001). CONCLUSION: Among patients with HFpEF and AF, the strategy of AF ablation to maintain SR was associated with a lower risk of the composite outcome of all-cause death or rehospitalization for worsening heart failure.

Clinical outcomes by serum potassium levels for patients hospitalized for heart failure: Secondary analysis of data from the China National Heart Failure Registry.

BACKGROUND: Dyskalemia is a mortality risk factor in patients with heart failure (HF). HYPOTHESIS: We described the prevalence of dyskalemia, and clinical outcomes by serum potassium (sK) levels, in Chinese patients hospitalized for HF. METHODS: In this secondary analysis of the prospective China National Heart Failure Registry, adult patients hospitalized between January 1, 2013 and June 30, 2015 who had at least one baseline sK measurement were followed for up to 3 years after discharge. The use of renin-angiotensin-aldosterone system inhibitors at baseline and clinical outcomes during follow-up were compared among sK groups. RESULTS: Among 6950 patients, 5529 (79.6%) had normokalemia (sK >3.5-5.0 mmol/L), 1113 (16.0%) had hypokalemia (sK 0-3.5 mmol/L), and 308 (4.4%) had hyperkalemia (sK >5.0 mmol/L). Baseline characteristics that were most common in patients with hyperkalemia than those with hypo- and normokalemia included older age, HF with reduced ejection fraction, New York Heart Association Class III/IV status, hypertension, and chronic kidney disease. Use of angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) differed across sK groups (p = .0001); reported in 64.1%, 63.4%, and 54.5% of patients with hypo-, normo-, and hyperkalemia, respectively. Overall, 26.6%, 28.6%, and 36.0% of patients with hypo-, normo-, and hyperkalemia had rehospitalization for worsened HF, or cardiovascular mortality; p = .0057 for between-group comparison. CONCLUSIONS: Patients with hyperkalemia received ACEIs or ARBs for HF treatment at baseline less frequently than those with hypo- or normokalemia, and had worse prognoses. This warrants further investigation into effective hyperkalemia management in HF.

Targeting MAGI2-AS3-modulated Akt-dependent ATP-binding cassette transporters as a possible strategy to reverse temozolomide resistance in temozolomide-resistant glioblastoma cells.

Drug resistance is a major impediment to the successful treatment of glioma. This study aimed to elucidate the effects and mechanisms of the long noncoding RNA membrane-associated guanylate kinase inverted-2 antisense RNA 3 (MAGI2-AS3) on temozolomide (TMZ) resistance in glioma cells. MAGI2-AS3 expression in TMZ-resistant glioblastoma (GBM) cells was analyzed using the Gene Expression Omnibus data set GSE113510 and quantitative real-time PCR (qRT-PCR). Cell viability and TMZ half-maximal inhibitory concentration values were determined using the MTT assay. Apoptosis and cell cycle distribution were evaluated using flow cytometry. The expression of multidrug resistance 1 (MDR1), ATP-binding cassette superfamily G member 2 (ABCG2), protein kinase B (Akt), and phosphorylated Akt was detected using qRT-PCR and/or western blot analysis. MAGI2-AS3 was expressed at low levels in TMZ-resistant GBM cells relative to that in their parental cells. MAGI2-AS3 re-expression alleviated TMZ resistance in TMZ-resistant GBM cells. MAGI2-AS3 overexpression also accelerated TMZ-induced apoptosis and G2/M phase arrest. Mechanistically, MAGI2-AS3 overexpression reduced MDR1 and ABCG2 expression and inhibited the Akt pathway, whereas Akt overexpression abrogated the reduction in MDR1 and ABCG2 expression induced by MAGI2-AS3. Moreover, activation of the Akt pathway inhibited the effects of MAGI2-AS3 on TMZ resistance. MAGI2-AS3 inhibited tumor growth and enhanced the suppressive effect of TMZ on glioma tumorigenesis in vivo. In conclusion, MAGI2-AS3 reverses TMZ resistance in glioma cells by inactivating the Akt pathway.

Different expression and prognostic value of troponin in ischemic cardiomyopathy and non-ischemic dilated cardiomyopathy.

BACKGROUND: Early risk stratification of patients with ischemic cardiomyopathy (ICM) and non-ischemic dilated cardiomyopathy (NIDCM) may be beneficial for therapies. METHODS: We retrospectively enrolled all patients admitted for acute heart failure (HF) between January 2019 and December 2021 in Zhongshan Hospital Fudan University, dividing them according to etiology (ICM or NIDCM). Cardiac troponin T (TNT) concentration was compared between two groups. Risk factors for positive TNT and in-hospital all-cause mortality were investigated with regression analysis. RESULTS: A total of 1525 HF patients were enrolled, including 571 ICM and 954 NIDCM. The TNT positive patients were not different between the two groups (41.3% in ICM group vs. 37.8% in NIDCM group, P = 0.215). However, the TNT value in ICM group were significantly higher than that in NIDCM group (0.025 (0.015-0.053) vs. 0.020 (0.014-0.041), P = 0.001). NT-proBNP was independently associated with TNT in both ICM and NIDCM group. Although the in-hospital all-cause mortality did not show much difference between the two groups (1.1% vs. 1.9%, P = 0.204), the NIDCM diagnosis was associated with reduced risk of mortality after multiple adjustments (OR 0.169, 95% CI 0.040-0.718, P = 0.016). Other independent risk factors included the level of NT-proBNP (OR 8.260, 95% CI 3.168-21.533, P < 0.001), TNT (OR 8.118, 95% CI 3.205-20.562, P < 0.001), and anemia (OR 0.954, 95% CI 0.931-0.978, P < 0.001). The predictive value of TNT and NT-proBNP for all-cause mortality was similar. However, the best cutoff values of TNT for mortality were different between ICM and NIDCM groups, which were 0.113 ng/mL and 0.048 ng/mL, respectively. CONCLUSION: The TNT level was higher in ICM patient than that in NIDCM patients. TNT was an independent risk factor for in-hospital all-cause mortality for both ICM and NIDCM patients, although the best cutoff value was higher in ICM patients.

Study design and rationale of EXPLORER-CN: a phase III, randomised, double-blind, placebo-controlled clinical study to evaluate the efficacy and safety of mavacamten in Chinese adults with symptomatic obstructive hypertrophic cardiomyopathy.

INTRODUCTION: Hypertrophic cardiomyopathy (HCM) is a primary myocardial disease commonly caused by pathogenic genetic variants encoding sarcomere proteins. Mavacamten, a first-in-class allosteric inhibitor of cardiac-specific myosin, has demonstrated efficacy and safety in international clinical trials of patients with symptomatic obstructive HCM (oHCM) but clinical evidence for mavacamten in the Chinese population is lacking. METHODS AND ANALYSIS: EXPLORER-CN is a multicentre, phase III, randomised, double-blind, placebo-controlled registration trial to evaluate the efficacy and safety of mavacamten in Chinese adults with symptomatic oHCM. The study will enrol approximately 81 participants with symptomatic oHCM. Eligible participants are randomised 2:1 to receive once-daily, oral mavacamten (starting dose 2.5 mg/day), or matching placebo, for 30 weeks, followed by a long-term extension (LTE) period of 48 weeks with active treatment for all subjects. The mavacamten dose will be adjusted by pharmacokinetic (PK)/pharmacodynamic (PD) parameters during the double-blinded, placebo-controlled period and PD-only during the LTE period. The primary efficacy endpoint is change from baseline to week 30 in Valsalva left ventricular outflow tract (LVOT) peak gradient determined by Doppler echocardiography. Secondary efficacy endpoints are change in resting LVOT peak gradient, proportion of participants achieving a Valsalva LVOT peak gradient <30 or < 50 mm Hg, New York Heart Association functional class improvement, change in Kansas City Cardiomyopathy Questionnaire Clinical Summary Score, cardiac biomarkers and left ventricular mass index evaluated by cardiac magnetic resonance. LTE endpoints will characterise the long-term safety and efficacy of mavacamten. ETHICS AND DISSEMINATION: This clinical study has been approved by the Drug Clinical Trial Ethics Committee of the Chinese Academy of Medical Sciences & Peking Union Medical College Hospital (reference number: HS2021089). Written informed consent will be obtained from each participant. The results will be published in peer-reviewed journals and presented during national and international conferences. TRIAL REGISTRATION NUMBER: NCT05174416.

Whole exome sequencing reveal 83 novel Mendelian disorders carrier P/LP variants in Chinese adult patients.

Carrier screening can identify people at risk of conceiving pregnancies affected with inherited genetic disorders or who have a genetic disorder with late or variable onset. Carrier screening based on whole exome sequencing (WES) data can offer more comprehensive assessment than on-target carrier screening tests. A total of 224 Chinese adult patients WES data was analyzed, except positive variants associated with the patients' major complaint, 378 pathogenic (P) and "likely pathogenic" (LP) variants from 175 adult patients were identified. Whole exome-wide frequency of carriers for Mendelian disorders in Chinese adult patients was about 78.13% in this study, which was lower than the previously reported carrier frequency in healthy population. Contrary to expectations, the number of P or LP variants did not increase with larger chromosome size or decrease with smaller chromosome size. Totally 83 novel P or LP variants were identified which could further expand the carrier variants spectrum of the Chinese population. GJB2: NM_004004.6:c.299_300delAT:p.His100fs*14 and C6:NM_000065.4:c.654T>A:p.Cys218* were found in two or more patients, which might be two underestimated carrier variants in Chinese population. We also found 9 late-onset or atypical symptoms autosomal/X-linked dominant Mendelian disorders causative genes, which were easily overlooked during pathogenicity analysis. These results can provide a strong basis for preventing and avoiding the prevalence rates of birth defects and reducing social and family burdens. By comparing with three different expanded carrier screening gene panels, we further confirmed carrier screening based on WES could offer more comprehensive assessment and WES was applicable for carrier screening.

Intronic position +9 and -9 are potentially splicing sites boundary from intronic variants analysis of whole exome sequencing data.

Whole exome sequencing (WES) can also detect some intronic variants, which may affect splicing and gene expression, but how to use these intronic variants, and the characteristics about them has not been reported. This study aims to reveal the characteristics of intronic variant in WES data, to further improve the clinical diagnostic value of WES. A total of 269 WES data was analyzed, 688,778 raw variants were called, among these 367,469 intronic variants were in intronic regions flanking exons which was upstream/downstream region of the exon (default is 200 bps). Contrary to expectation, the number of intronic variants with quality control (QC) passed was the lowest at the +2 and -2 positions but not at the +1 and -1 positions. The plausible explanation was that the former had the worst effect on trans-splicing, whereas the latter did not completely abolish splicing. And surprisingly, the number of intronic variants that passed QC was the highest at the +9 and -9 positions, indicating a potential splicing site boundary. The proportion of variants which could not pass QC filtering (false variants) in the intronic regions flanking exons generally accord with "S"-shaped curve. At +5 and -5 positions, the number of variants predicted damaging by software was most. This was also the position at which many pathogenic variants had been reported in recent years. Our study revealed the characteristics of intronic variant in WES data for the first time, we found the +9 and -9 positions might be a potentially splicing sites boundary and +5 and -5 positions were potentially important sites affecting splicing or gene expression, the +2 and -2 positions seem more important splicing site than +1 and -1 positions, and we found variants in intronic regions flanking exons over ± 50 bps may be unreliable. This result can help researchers find more useful variants and demonstrate that WES data is valuable for intronic variants analysis.

Feasibility, safety and effectiveness of robot-assisted retroperitoneal partial adrenalectomy with a new robotic surgical system: A prospective clinical study.

Objectives: To evaluate the feasibility, safety and efficacy of the newly developed KD-SR-01® robotic system for retroperitoneal partial adrenalectomy. Subjects and Methods: We prospectively enrolled patients with benign adrenal mass undergoing KD-SR-01® robot-assisted partial adrenalectomy in our institution from November 2020 to May 2022. Surgeries were performed via a retroperitoneal approach using the KD-SR-01® robotic system. The baseline, perioperative and short-term follow-up data were prospectively collected. A descriptive statistical analysis was performed. Results: A total of 23 patients were enrolled, including nine (39.1%) patients with hormone-active tumors. All patients received partial adrenalectomy via the retroperitoneal approach without conversions to other procedures. The median operative time was 86.5 min [interquartile range (IQR), 60.0-112.5] and the median estimated blood loss was 50 ml (range, 20-400). Three (13.0%) patients developed Clavien-Dindo grade I-II postoperative complications. The median postoperative stay was 4.0 days (IQR, 3.0-5.0). All surgical margins were negative. The short-term follow-up demonstrated complete or partial clinical and biochemical success as well as absence of imaging recurrence in all patients with hormone-active tumors. Conclusions: Initial results illustrate that the KD-SR-01® robotic system is safe, feasible and effective for the surgical management of benign adrenal tumors.

Effectiveness and safety of Shexiang Baoxin Pill (MUSKARDIA) in patients with stable coronary artery disease and concomitant diabetes mellitus: a subgroup analysis of a randomized clinical trial.

BACKGROUND: Preliminary studies have indicated that Shexiang Baoxin Pill (MUSKARDIA) has a coronary artery dilation effect and increases the coronary blood flow, relieving the symptoms of angina. This study aimed to evaluate the benefit of MUSKARDIA on patients with stable coronary artery disease (CAD) and diabetes mellitus (DM). METHODS: This was a subgroup analysis of a multicenter, randomized, placebo-controlled phase IV trial. CAD patients with a medical history of DM or baseline fasting blood glucose (FBG) ≥7.0 mmol/L were grouped according to the treatment (standard therapy plus MUSKARDIA or placebo). The primary outcome was major adverse cardiovascular events (MACEs), which was the composite outcome of cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke. The secondary outcome was the composite outcome of all-cause death, non-fatal myocardial infarction, non-fatal stroke, hospitalization for unstable angina or heart failure, and coronary angioplasty. RESULTS: MACEs occurred in 2.6% (9/340) and 4.8% (18/376) of patients in the MUSKARDIA and placebo groups, respectively ( P  = 0.192). Secondary composite outcome was significantly less frequent with MUSKARDIA than with placebo (15.3% [52/340] vs . 22.6% [85/376], P  = 0.017). Risk of MACEs (hazard ratio [HR] = 0.69, 95% confidence interval [CI]: 0.31-1.57) was comparable between two groups. In patients with uncontrolled DM (≥4 measurements of FBG ≥7 mmol/L in five times of follow-up), the risk of secondary outcome was significantly lower with MUSKARDIA (5/83, 6.0%) than with placebo (15/91, 16.5%) (HR = 0.35, 95%CI: 0.13-0.95). CONCLUSION: As an add-on to standard therapy, MUSKARDIA shows a trend of reduced MACEs in patients with stable CAD and DM. Furthermore, MUSKARDIA may reduce the frequency of all-cause death, hospitalization, and coronary angioplasty in this population, especially in those with uncontrolled DM. TRIAL REGISTRATION: ChiCTR.org.cn, ChiCTR-TRC-12003513.

Shexiang Baoxin Pill (MUSKARDIA) reduces major adverse cardiovascular events in women with stable coronary artery disease: A subgroup analysis of a phase IV randomized clinical trial.

Background: A previous phase IV trial revealed sex as a potential effect modifier of MUSKARDIA efficacy in stable coronary artery disease (CAD). Objective: To assess the clinical effect of MUSKARDIA as a supplemental treatment to optimal medical therapy (OMT) in stable CAD cases. Methods: This study was a subgroup analysis of a multicenter, randomized, double-blinded, placebo-controlled phase IV clinical study. Eligible individuals underwent randomization to the oral MUSKARDIA and placebo groups and were treated for 24 months. All participants received OMT according to existing guidelines. The primary composite outcome was the major adverse cardiovascular event (MACE), included cardiovascular death, non-fatal myocardial infarction (MI), or non-fatal stroke. The secondary composite outcome encompassed all-cause mortality, non-fatal MI, non-fatal stroke, hospitalization for unstable angina and/or heart failure, and undergoing coronary procedure/surgery during treatment. Safety signals, especially cardiovascular adverse events (AEs), were analyzed. Results: The female subgroup included 776 participants (384 and 392 in the MUSKARDIA and placebo groups, respectively). The occurrence of the primary composite outcome was lower in the MUSKARDIA group compared with placebo-treated individuals (HR = 0.27, 95%CI: 0.09-0.83; P = 0.02), but the secondary composite outcome showed no significant difference (HR = 0.77, 95%CI: 0.47-1.25; P = 0.29). The MUSKARDIA group had reduced incidence of cardiovascular AEs compared with placebo-treated cases (2.9% vs. 5.6%). Conclusion: As a supplemental treatment to OMT, 24-month administration of MUSKARDIA is effective and safe in female stable CAD cases. Clinical trial registration: [https://clinicaltrials.gov/], identifier [NCT01897805].

GeO2-doped ring-core photonic crystal fiber for supporting robust orbital angular momentum modes.

Orbital angular momentum (OAM)-mode-supported photonic crystal fibers (PCFs) have inspired intensive research in modern fiber optics due to the robust propagation and theoretically unlimited signal-carried channels. In this paper, a dual-cladding GeO2-doped ring-core PCF is designed, and a strategy for optimizing OAM mode properties is analyzed by structure parameters and GeO2-doping concentration. Numeric results show that high structural degrees of freedom are available to improve the effective refractive index separation (within the vector modes), chromatic dispersion, effective mode field area, nonlinear coefficient, and OAM mode purity in terms of inner cladding, outer cladding, and ring-core. In particular, the effective refractive index separation and chromatic dispersion can exhibit a high order magnitude of 10-3 and a low value in the broad band from 1.3 µm to 1.7 µm, respectively. In addition to structural optimization, doping high index material into the ring-core is another way to regulate the fiber performance by controlling the doping concentration. A systematic investigation shows that as the doping concentration increases, the effective refractive index separation and mode purity increase obviously, while the dispersion and mode field area gradually decrease. This flexible manipulation offers a method for customizing the optical properties of OAM-supported PCFs in communication and sensor systems.

Clinical characteristics and 1-year outcomes in hospitalized patients with heart failure with preserved ejection fraction: results from the China Cardiovascular Association Database-Heart Failure Center Registry.

AIM: We aimed to evaluate clinical characteristics and 1-year outcomes in hospitalized patients with heart failure with preserved ejection fraction (HFpEF) from China. Factors associated with outcomes (hospitalization for HF [HHF] and cardiovascular [CV] death) were assessed. METHOD AND RESULTS: Data were from the China Cardiovascular Association (CCA) Database-HF Center Registry. Between January 2017 and June 2021, 41 708 hospitalized HFpEF patients with 1-year follow-up from 481 CCA Database-HF Center certified secondary and tertiary hospitals across overall 31 provinces of mainland China were included in this study. Of study participants (mean age 72.2 years, 49.3% female), 18.2% had HHF in prior 1 year and 55.8% had New York Heart Association class III/IV. Median left ventricular ejection fraction was 59%. Ischaemia (26.6%), infection (14.4%) and arrhythmia (10.5%) were the three most common precipitating factors for index HHF. Nearly 67.4% had ≥3 comorbidities. Hypertension (65.2%), coronary heart disease (60.3%) and atrial fibrillation (41.2%) were the three most common comorbidities. Device and medication therapy non-compliance with current HF guideline recommendation was observed. The 1-year rate of clinical outcomes was 16.4%, the 1-year rate of HHF was 13.6% and CV death was 3.1%. Factors associated with clinical outcomes included HHF in prior 1 year, serum level of sodium <135 mmol/L and N-terminal pro-B-type natriuretic peptide >1800 pg/ml. CONCLUSION: Patients with HFpEF from China were characterized by high comorbid burden and high 1-year risk of HHF and CV death. Immediate efforts are needed to improve HFpEF management in China.