Patient-Level Pooled Analysis of Endovascular Ultrasound Renal Denervation or a Sham Procedure 6 Months After Medication Escalation: The RADIANCE Clinical Trial Program.

BACKGROUND: The randomized, sham-controlled RADIANCE-HTN (A Study of the Recor Medical Paradise System in Clinical Hypertension) SOLO, RADIANCE-HTN TRIO, and RADIANCE II (A Study of the Recor Medical Paradise System in Stage II Hypertension) trials independently met their primary end point of a greater reduction in daytime ambulatory systolic blood pressure (SBP) 2 months after ultrasound renal denervation (uRDN) in patients with hypertension. To characterize the longer-term effectiveness and safety of uRDN versus sham at 6 months, after the blinded addition of antihypertensive treatments (AHTs), we pooled individual patient data across these 3 similarly designed trials. METHODS: Patients with mild to moderate hypertension who were not on AHT or with hypertension resistant to a standardized combination triple AHT were randomized to uRDN (n=293) versus sham (n=213); they were to remain off of added AHT throughout 2 months of follow-up unless specified blood pressure (BP) criteria were exceeded. In each trial, if monthly home BP was ≥135/85 mm Hg from 2 to 5 months, standardized AHT was sequentially added to target home BP <135/85 mm Hg under blinding to initial treatment assignment. Six-month outcomes included baseline- and AHT-adjusted change in daytime ambulatory, home, and office SBP; change in AHT; and safety. Linear mixed regression models using all BP measurements and change in AHT from baseline through 6 months were used. RESULTS: Patients (70% men) were 54.1±9.3 years of age with a baseline daytime ambulatory/home/office SBP of 150.5±9.8/151.0±12.4/155.5±14.4 mm Hg, respectively. From 2 to 6 months, BP decreased in both groups with AHT titration, but fewer uRDN patients were prescribed AHT (P=0.004), and fewer additional AHT were prescribed to uRDN patients versus sham patients (P=0.001). Whereas the unadjusted between-group difference in daytime ambulatory SBP was similar at 6 months, the baseline and medication-adjusted between-group difference at 6 months was -3.0 mm Hg (95% CI, -5.7, -0.2; P=0.033), in favor of uRDN+AHT. For home and office SBP, the adjusted between-group differences in favor of uRDN+AHT over 6 months were -5.4 mm Hg (-6.8, -4.0; P<0.001) and -5.2 mm Hg (-7.1, -3.3; P<0.001), respectively. There was no heterogeneity between trials. Safety outcomes were few and did not differ between groups. CONCLUSIONS: This individual patient-data analysis of 506 patients included in the RADIANCE trials demonstrates the maintenance of BP-lowering efficacy of uRDN versus sham at 6 months, with fewer added AHTs. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifiers: NCT02649426 and NCT03614260.

Endovascular Ultrasound Renal Denervation to Treat Hypertension: The RADIANCE II Randomized Clinical Trial.

Importance: Two initial sham-controlled trials demonstrated that ultrasound renal denervation decreases blood pressure (BP) in patients with mild to moderate hypertension and hypertension that is resistant to treatment. Objective: To study the efficacy and safety of ultrasound renal denervation without the confounding influence of antihypertensive medications in patients with hypertension. Design, Setting, and Participants: Sham-controlled, randomized clinical trial with patients and outcome assessors blinded to treatment assignment that was conducted between January 14, 2019, and March 25, 2022, at 37 centers in the US and 24 centers in Europe, with randomization stratified by center. Patients aged 18 years to 75 years with hypertension (seated office systolic BP [SBP] ≥140 mm Hg and diastolic BP [DBP] ≥90 mm Hg despite taking up to 2 antihypertensive medications) were eligible if they had an ambulatory SBP/DBP of 135/85 mm Hg or greater and an SBP/DBP less than 170/105 mm Hg after a 4-week washout of their medications. Patients with an estimated glomerular filtration rate of 40 mL/min/1.73 m2 or greater and with suitable renal artery anatomy were randomized 2:1 to undergo ultrasound renal denervation or a sham procedure. Patients were to abstain from antihypertensive medications until the 2-month follow-up unless prespecified BP criteria were exceeded and were associated with clinical symptoms. Interventions: Ultrasound renal denervation vs a sham procedure. Main Outcomes and Measures: The primary efficacy outcome was the mean change in daytime ambulatory SBP at 2 months. The primary safety composite outcome of major adverse events included death, kidney failure, and major embolic, vascular, cardiovascular, cerebrovascular, and hypertensive events at 30 days and renal artery stenosis greater than 70% detected at 6 months. The secondary outcomes included mean change in 24-hour ambulatory SBP, home SBP, office SBP, and all DBP parameters at 2 months. Results: Among 1038 eligible patients, 150 were randomized to ultrasound renal denervation and 74 to a sham procedure (mean age, 55 years [SD, 9.3 years]; 28.6% female; and 16.1% self-identified as Black or African American). The reduction in daytime ambulatory SBP was greater with ultrasound renal denervation (mean, -7.9 mm Hg [SD, 11.6 mm Hg]) vs the sham procedure (mean, -1.8 mm Hg [SD, 9.5 mm Hg]) (baseline-adjusted between-group difference, -6.3 mm Hg [95% CI, -9.3 to -3.2 mm Hg], P < .001), with a consistent effect of ultrasound renal denervation throughout the 24-hour circadian cycle. Among 7 secondary BP outcomes, 6 were significantly improved with ultrasound renal denervation vs the sham procedure. No major adverse events were reported in either group. Conclusions and Relevance: In patients with hypertension, ultrasound renal denervation reduced daytime ambulatory SBP at 2 months in the absence of antihypertensive medications vs a sham procedure without postprocedural major adverse events. Trial Registration: ClinicalTrials.gov Identifier: NCT03614260.

Challenges and outcomes of the double kissing crush stenting technique: Insights from the PROGRESS-BIFURCATION registry.

BACKGROUND: Although the double kissing (DK) crush stenting technique can provide excellent outcomes in percutaneous coronary intervention (PCI) of bifurcation lesions, it can be challenging to perform. METHODS: We examined the clinical and angiographic characteristics, challenges encountered, and procedural outcomes of bifurcation PCI with DK crush in Prospective Global Registry of Percutaneous Coronary Intervention in Bifurcation Lesions (PROGRESS-BIFURCATION, NCT05100992). RESULTS: DK crush was used in 48 of 435 bifurcation lesions (11%). Technical success was 100%, procedural success was 96%, and the incidence of in-hospital major adverse cardiovascular events was 4%. Challenges while performing DK crush were encountered in 26 lesions (54%): (1) difficulty in side branch (SB) first rewiring (38%) that was overcome with the use of a new guidewire (30%) or a microcatheter (15%); (2) inability to deliver balloon to an SB for the first kiss (54%) that was overcome with the use of a smaller balloon (86%), rewiring (29%), microcatheter (14%), and increased support 7%; (3) difficulty in SB second rewiring (19%) that was overcome with the use of a new guidewire (80%) and/or microcatheter (60%). DK crush was more often performed in left main and proximal left anterior descending artery lesions (70% vs. 50%, p = 0.014). DK crush cases required more contrast (198 ± 84 ml vs. 163 ± 70 ml, p = 0.003), fluoroscopy time (35 ± 20 min vs. 25 ± 21 min, p = 0.004), and lasted longer (137 ± 69 min vs. 99 ± 66 min, p = 0.001) compared with non-DK crush techniques. CONCLUSIONS: While challenges are common when performing DK crush bifurcation stenting, success rates are high and complication rates are low.

Outcomes and challenges of the provisional stenting technique: Insights from the PROGRESS-BIFURCATION registry.

BACKGROUND: Provisional stenting is the most commonly used coronary bifurcation stenting strategy. METHODS: We examined the clinical and angiographic characteristics, challenges encountered, and procedural outcomes with the provisional bifurcation stenting strategy in the Prospective Global Registry of Percutaneous Coronary Intervention (PCI) in Bifurcation Lesions (PROGRESS-BIFURCATION, NCT05100992). RESULTS: Provisional stenting was used in 334 of 430 bifurcation interventions (78%). Technical success was lower (95% vs. 100%, p = 0.017) in provisional, but procedural success (90% vs. 95%, p = 0.095) and incidence of in-hospital major adverse cardiovascular events were similar (5% vs. 5%, p = 0.945) compared with two-stent strategies. Provisional was less often preferred in left main/left anterior descending involvement (47% vs. 73%, p < 0.001). Provisional stenting cases had smaller side branch (SB) diameter (2.4 ± 0.5 vs. 2.7 ± 0.6 mm, p < 0.001), shorter SB lesion length (5 [3-8] vs. 10 [5-10] mm, p < 0.001), less SB diameter stenosis (46 ± 35 vs. 81 ± 20%, p < 0.001), and were less likely to be Medina 1,1,1 (34% vs. 73%, p < 0.001). PCI challenges were less common (30% vs. 58%, p < 0.001) with provisional stenting: (1) rewiring difficulty (43%) that was overcome with use of a different wire (74%) or microcatheter (46%); (2) inability to deliver a stent (22%) or balloon (9%) that was overcome with use of a smaller balloon (88%), rewiring (25%), or increased support/microcatheter (25%). CONCLUSIONS: Provisional bifurcation stenting was more often performed in distal lesions with less SB involvement and had lower technical success, but similar procedural success and complications compared with two-stent strategies.

Evaluation of immunoprotective effects of recombinant proteins and DNA vaccines derived from Eimeria tenella surface antigen 6 and 15 in vivo.

Coccidiosis is an intestinal parasitic disease that causes huge economic losses to the poultry industry globally. Eimeria tenella belonging to protozoon is the causative agent of cecal coccidiosis in chicken, and it causes enormous damage to poultry industry. The surface antigens (SAGs) of apicomplexan parasites have functions of attachment and invasion in host-parasite interaction. As a result of parasitic invasion, host immune response is triggered. However, the immunogenicity and potency of E. tenella surface antigen 6 and 15 (EtSAG 6 and 15), as vaccinal candidate antigen, remain largely unknown. Therefore, gene fragments of E. tenella EtSAG 6 and 15 were amplified and transformed to pET28a prokaryotic vector for recombinant protein expression. The pEGFP-N1 eukaryotic vectors with EtSAG 6 and 15 amplification fragments (pEGFP-N1-EtSAG 5 and 16) were transformed into 293 T cell line. The results of reverse transcription-polymerase chain reaction (RT-PCR) and western blot analysis revealed successful expressions of EtSAG 6 and 15 in Escherichia coli and 293 T cells. Subsequently, animal experiments of 49 cobb broilers were performed to evaluate immunoprotection of recombinant proteins and DNA vaccines derived from E. tenella EtSAG 5 and 16 with an immunizing dose of 100 µg, respectively. Chickens vaccinated with rEtSAG 6 protein, rEtSAG 15 protein, pEGFP-N1-EtSAG 6 plasmid, or pEGFP-N1-EtSAG 15 plasmid showed no significant increase in IFN-γor interleukin-4 (IL-4) level compared with control groups. Chickens vaccinated with protein rEtSAG 6, protein rEtSAG 15, pEGFP-N1-EtSAG 6 plasmid, or pEGFP-N1-EtSAG 15 exhibited higher weight gains, lower oocyst output, and lower mean lesion scores, compared with infection control group. Among the four immunized groups, plasmid EGFP-N1-EtSAG 6 (100 µg) group exhibited the highest anticoccidial index (ACI) value (150.20). Overall, plasmids EGFP-N1-EtSAG 6 and 15, as DNA vaccines, provided a more effective immunoprotection for chickens against E. tenella than protein rEtSAG 6 and protein rEtSAG 15 as subunit vaccines. EtSAG 6 and 15 are promising candidate antigen genes for developing coccidiosis vaccine.

Outcomes of intravascular brachytherapy for recurrent drug-eluting in-stent restenosis.

OBJECTIVES: To examine the outcomes of vascular brachytherapy (VBT) for recurrent drug-eluting stents (DES) in-stent restenosis (ISR). BACKGROUND: Recurrent DES-ISR can be challenging to treat. VBT has been used with encouraging results. METHODS: We report the long-term outcomes of patients with recurrent DES-ISR treated with VBT between January 2014 and September 2018 at a tertiary care institution. The main outcome was target lesion failure (TLF), defined as the composite of clinically driven target lesion revascularization (TLR), target lesion myocardial infarction (MI), and target lesion-related cardiac death. Cox proportional hazards analysis was performed to identify variables associated with recurrent TLF. RESULTS: During the study period, 116 patients (143 lesions) underwent VBT. Median follow-up was 24.7 (14.5-35.4) months. The incidence of TLR, target-lesion MI, and TLF was 18.9%, 5.6%,and 20.1% at 1 year, and 29.4%, 10.5%, and 32.9% at 2 years.Initial presentation with acute coronary syndrome (ACS) was independently associated with TLF (hazard ratio = 1.975, 95% CI [1.120, 3.485], p = .019). Lesions treated with intravascular ultrasound (IVUS) guidance had a lower incidence of TLR (14.3% vs. 39.6%, log-rank p = .038), and a trend toward lower incidence of TLF (19% vs. 42.6%, log-rank p = .086). CONCLUSIONS: VBT can improve the treatment of recurrent DES-ISR, but TLF occurs in approximately one in three patients at 2 years. Initial presentation with ACS was associated with higher TLF and the use of IVUS with a trend for lower incidence of TLF.

Temporal changes in patient characteristics and outcomes in ST-segment elevation myocardial infarction 2003-2018.

BACKGROUND: We sought to describe changes in demographic variables, process of care measures, and outcomes of patients treated in a regional ST-segment elevation myocardial infarction (STEMI) program over the last 15 years. METHODS: We describe demographic variables, process of care measures, and outcomes of patients treated in the program in various 5-year time periods: 2003-2007 (n = 1,821), 2008-2012 (n = 1,968), and 2013-2018 (n = 2,223). The primary outcome measures were in-hospital and 30-day mortality. RESULTS: Among 6,012 STEMI patients treated from 2003 to 2018 we observed a significant increase in mean age at presentation (62 ± 14 to 64 ± 13 years) and diabetes (14-22%, p < .01). The proportion of patients with cardiogenic shock (CS) and cardiac arrest (CA) pre-PCI increased significantly from 9.5% to 11.1% and 8.5% to 12.7% (p < .05), respectively. The median door-to-balloon (D2B) times decreased from 98 to 93 min and total ischemic time decreased from 202 to 185 min (all p < .05). Despite increased patient complexity, the proportion of nontransfer and transfer patients achieving D2B times consistent with guideline recommendations remained unchanged (for nontransfer patients 79-82%, p = .45 and for transfer patients 65-64%, p = .34). Among all STEMI patients, in-hospital mortality increased during the study period from 4.9 to 6.9% (p = .007) but remained stable (<2%) when CA and CS patients were excluded. CONCLUSIONS: Over the last 15 years, short-term STEMI mortality has increased despite improvements in care delivery metrics. Patients with CA and/or CS now represent 10% of STEMI patients and are responsible for 80% of deaths. Therefore, efforts to improve STEMI mortality, and metrics for assessing STEMI programs, should focus on these patients.

NHLBI-Sponsored Randomized Trial of Postconditioning During Primary Percutaneous Coronary Intervention for ST-Elevation Myocardial Infarction.

RATIONALE: Postconditioning at the time of primary percutaneous coronary intervention (PCI) for ST-segment-elevation myocardial infarction may reduce infarct size and improve myocardial salvage. However, clinical trials have shown inconsistent benefit. OBJECTIVE: We performed the first National Heart, Lung, and Blood Institute-sponsored trial of postconditioning in the United States using strict enrollment criteria to optimize the early benefits of postconditioning and assess its long-term effects on left ventricular (LV) function. METHODS AND RESULTS: We randomized 122 ST-segment-elevation myocardial infarction patients to postconditioning (4, 30 seconds PTCA [percutaneous transluminal coronary angioplasty] inflations/deflations)+PCI (n=65) versus routine PCI (n=57). All subjects had an occluded major epicardial artery (thrombolysis in myocardial infarction=0) with ischemic times between 1 and 6 hours with no evidence of preinfarction angina or collateral blood flow. Cardiac magnetic resonance imaging measured at 2 days post-PCI showed no difference between the postconditioning group and control in regards to infarct size (22.5±14.5 versus 24.0±18.5 g), myocardial salvage index (30.3±15.6% versus 31.5±23.6%), or mean LV ejection fraction. Magnetic resonance imaging at 12 months showed a significant recovery of LV ejection fraction in both groups (61.0±11.4% and 61.4±9.1%; P<0.01). Subjects randomized to postconditioning experienced more favorable remodeling over 1 year (LV end-diastolic volume =157±34 to 150±38 mL) compared with the control group (157±40 to 165±45 mL; P<0.03) and reduced microvascular obstruction ( P=0.05) on baseline magnetic resonance imaging and significantly less adverse LV remodeling compared with control subjects with microvascular obstruction ( P<0.05). No significant adverse events were associated with the postconditioning protocol and all patients but one (hemorrhagic stroke) survived through 1 year of follow-up. CONCLUSIONS: We found no early benefit of postconditioning on infarct size, myocardial salvage index, and LV function compared with routine PCI. However, postconditioning was associated with improved LV remodeling at 1 year of follow-up, especially in subjects with microvascular obstruction. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov . Unique identifier: NCT01324453.

Quantitative analysis of the synergistic effect of Au nanoparticles on SnO2-rGO nanocomposites for room temperature hydrogen sensing.

Hydrogen detection devices based on gold-tin oxide/reduced graphene oxide (Au-SnO2/rGO) nanohybrids were fabricated by combining a hydrothermal method with sputter coating. The gas sensing performance of the Au-SnO2/rGO sensor was investigated under different concentrations of hydrogen from 0.04% to 1% at room temperature, which indicated a notable sensitive response even for 0.04% hydrogen. The activation energies of hydrogen adsorption/desorption were extracted via Arrhenius analysis which revealed the acceleration effect of gold dopants. This acceleration led to a faster response and recovery during hydrogen sensing. The activation energy analysis provided a more comprehensive understanding on the gas sensing mechanism. A hydrogen detection handheld device is demonstrated by integrating the sensor chip with a portable digital meter for direct readout of test results.

Comparative effects of Tagetes patula L. extraction, mercapto-palygorskite immobilisation, and the combination thereof on Cd accumulation by wheat in Cd-contaminated soil.

Phytoextraction and in situ immobilisation are two of the most commonly used remediation techniques for Cd-contaminated farmland. In theory, phytoextraction followed by immobilisation can reduce the total Cd and available Cd contents of the soil, making it suitable for the remediation of heavily Cd-contaminated alkaline soil. However, the real remediation efficiency is uncertain, and it is also unknown whether phytoextraction affects subsequent wheat Cd accumulation. In this study, two seasonal pot experiments were conducted to determine the effects of S,S-ethylenediamine disuccinic acid (EDDS)-assisted Tagetes patula L. (T. patula) extraction, mercapto-palygorskite (MPAL) immobilisation, and the combination thereof on subsequent Cd accumulation in wheat. EDDS application significantly increased the Cd content in the subsequent-soil solution, but the EDDS-activated Cd could not be absorbed by wheat roots. T. patula extraction decreased the subsequent soil pH value by 0.1-0.2 pH units, increased the available Cd content by 0.19 mg/kg, but had no effect on subsequent wheat Cd accumulation. The Cd absorption capacity of wheat roots and the Cd translocation capacity of wheat stems to grains of high-Cd wheat were higher than that of low-Cd wheat cultivar. The application of MPAL had no effect on soil pH value, but significantly decreased soil available Cd and exchangeable Cd contents by 17.78-36.76% and 21.13-52.63%; it also increased the Fe/Mn oxide-bound Cd fraction by 14.02-64.00%. MPAL application decreased the wheat grain Cd concentrations from 0.51 to 0.13 mg/kg (high-Cd wheat) and 0.35 to 0.05 mg/kg (low-Cd wheat), but had no negative effect on Fe, Mn, Cu, and Zn elements. Compared with the single MPAL application treatments, the combination treatments had no inhibition effect on Cd accumulation in wheat. MPAL is an efficient amendment, and considering the remediation efficiency, stability, and time of these methods, the combination of MPAL application with a low-Cd accumulation wheat cultivar represents a suitable proposal to ensure the safe production of wheat in Cd-contaminated alkaline soil.

Six-Month Results of Treatment-Blinded Medication Titration for Hypertension Control After Randomization to Endovascular Ultrasound Renal Denervation or a Sham Procedure in the RADIANCE-HTN SOLO Trial.

BACKGROUND: The multicenter, international, randomized, blinded, sham-controlled RADIANCE-HTN SOLO trial (A Study of the ReCor Medical Paradise System in Clinical Hypertension) demonstrated a 6.3 mm Hg greater reduction in daytime ambulatory systolic blood pressure (BP) at 2 months by endovascular ultrasound renal denervation (RDN) compared with a sham procedure among patients not treated with antihypertensive medications. We report 6-month results after the addition of a recommended standardized stepped-care antihypertensive treatment to the randomized endovascular procedure under continued blinding to initial treatment. METHODS: Patients with a daytime ambulatory BP ≥135/85 mm Hg and <170/105 mm Hg after a 4-week discontinuation of up to 2 antihypertensive medications, and a suitable renal artery anatomy, were randomized to RDN (n=74) or sham (n=72). Patients were to remain off antihypertensive medications throughout the first 2 months of follow-up unless safety BP criteria were exceeded. Between 2 and 5 months, if monthly measured home BP was ≥135/85 mm Hg, a standardized stepped-care antihypertensive treatment was recommended consisting of the sequential addition of amlodipine (5 mg/d), a standard dose of an angiotensin-converting enzyme inhibitor/angiotensin receptor blocker, and hydrochlorothiazide (12.5 mg/d), followed by the sequential uptitration of hydrochlorothiazide (25 mg/d) and amlodipine (10 mg/d). Outcomes included the 6-month (1) change in daytime ambulatory systolic BP adjusted for medications and baseline systolic BP, (2) medication burden, and (3) safety. RESULTS: A total of 69/74 RDN patients and 71/72 sham patients completed the 6-month ambulatory BP measurement. At 6 months, 65.2% of patients in the RDN group were treated with the standardized stepped-care antihypertensive treatment versus 84.5% in the sham group (P=0.008), and the average number of antihypertensive medications and defined daily dose were less in the RDN group than in the sham group (0.9±0.9 versus 1.3±0.9, P=0.010 and 1.4±1.5 versus 2.0±1.8, P=0.018; respectively). Despite less intensive standardized stepped-care antihypertensive treatment, RDN reduced daytime ambulatory systolic BP to a greater extent than sham (-18.1±12.2 versus -15.6±13.2 mm Hg, respectively; difference adjusted for baseline BP and number of medications: -4.3 mm Hg, 95% confidence interval, -7.9 to -0.6, P=0.024). There were no major adverse events in either group through 6 months. CONCLUSIONS: The BP-lowering effect of endovascular ultrasound RDN was maintained at 6 months with less prescribed antihypertensive medications compared with a sham control. CLINICAL TRIAL REGISTRATION: URL: https://www. CLINICALTRIALS: gov. Unique identifier: NCT02649426.

Endovascular ultrasound renal denervation to treat hypertension (RADIANCE-HTN SOLO): a multicentre, international, single-blind, randomised, sham-controlled trial.

BACKGROUND: Early studies suggest that radiofrequency-based renal denervation reduces blood pressure in patients with moderate hypertension. We investigated whether an alternative technology using endovascular ultrasound renal denervation reduces ambulatory blood pressure in patients with hypertension in the absence of antihypertensive medications. METHODS: RADIANCE-HTN SOLO was a multicentre, international, single-blind, randomised, sham-controlled trial done at 21 centres in the USA and 18 in Europe. Patients with combined systolic-diastolic hypertension aged 18-75 years were eligible if they had ambulatory blood pressure greater than or equal to 135/85 mm Hg and less than 170/105 mm Hg after a 4-week discontinuation of up to two antihypertensive medications and had suitable renal artery anatomy. Patients were randomised (1:1) to undergo renal denervation with the Paradise system (ReCor Medical, Palo Alto, CA, USA) or a sham procedure consisting of renal angiography only. The randomisation sequence was computer generated and stratified by centres with randomised blocks of four or six and permutation of treatments within each block. Patients and outcome assessors were blinded to randomisation. The primary effectiveness endpoint was the change in daytime ambulatory systolic blood pressure at 2 months in the intention-to-treat population. Patients were to remain off antihypertensive medications throughout the 2 months of follow-up unless specified blood pressure criteria were exceeded. Major adverse events included all-cause mortality, renal failure, an embolic event with end-organ damage, renal artery or other major vascular complications requiring intervention, or admission to hospital for hypertensive crisis within 30 days and new renal artery stenosis within 6 months. This study is registered with ClinicalTrials.gov, number NCT02649426. FINDINGS: Between March 28, 2016, and Dec 28, 2017, 803 patients were screened for eligibility and 146 were randomised to undergo renal denervation (n=74) or a sham procedure (n=72). The reduction in daytime ambulatory systolic blood pressure was greater with renal denervation (-8·5 mm Hg, SD 9·3) than with the sham procedure (-2·2 mm Hg, SD 10·0; baseline-adjusted difference between groups: -6·3 mm Hg, 95% CI -9·4 to -3·1, p=0·0001). No major adverse events were reported in either group. INTERPRETATION: Compared with a sham procedure, endovascular ultrasound renal denervation reduced ambulatory blood pressure at 2 months in patients with combined systolic-diastolic hypertension in the absence of medications. FUNDING: ReCor Medical.

Multifunctional UV and Gas Sensors Based on Vertically Nanostructured Zinc Oxide: Volume Versus Surface Effect.

This article reports that it is possible to make multifunctional sensing devices with ZnO infiltrated polymers while the sensing interactions could occur throughout the polymer. As such, we find that infiltrated devices with SU-8 polymer can result in highly sensitive UV sensors. Mesh dielectric core devices were found to make sensitive gas sensors with a better than 5 ppm sensitivity for formaldehyde and NO2. A new type of p-n junction device is further demonstrated that is sensitive to UV illumination, thus making it an enhanced UV sensor. Sensing devices relying on volume interactions, such as light absorption, can significantly benefit from the infiltrated polymer. In contrast, devices that rely on surface interactions, such as gas sensors, do not gain performance in any significant way with or without the infiltrated polymer.

A novel approach for rapid high-throughput selection of recombinant functional rat monoclonal antibodies.

BACKGROUND: Most monoclonal antibodies against mouse antigens have been derived from rat spleen-mouse myeloma fusions, which are valuable tools for purposes ranging from general laboratory reagents to therapeutic drugs, and yet selecting and expressing them remains a time-consuming and inefficient process. Here, we report a novel approach for the rapid high-throughput selection and expression of recombinant functional rat monoclonal antibodies with different isotypes. RESULTS: We have developed a robust system for generating rat monoclonal antibodies through several processes involving simultaneously immunizing rats with three different antigens expressing in a mixed cell pools, preparing hybridoma cell pools, in vitro screening and subsequent cloning of the rearranged light and heavy chains into a single expression plasmid using a highly efficient assembly method, which can decrease the time and effort required by multiple immunizations and fusions, traditional clonal selection and expression methods. Using this system, we successfully selected several rat monoclonal antibodies with different IgG isotypes specifically targeting the mouse PD-1, LAG-3 or AFP protein from a single fusion. We applied these recombinant anti-PD-1 monoclonal antibodies (32D6) in immunotherapy for therapeutic purposes that produced the expected results. CONCLUSIONS: This method can be used to facilitate an increased throughput of the entire process from multiplex immunization to acquisition of functional rat monoclonal antibodies and facilitate their expression and feasibility using a single plasmid.

A Light Harvesting Complex-Like Protein in Maintenance of Photosynthetic Components in Chlamydomonas.

Using a genetic approach, we have identified and characterized a novel protein, named Msf1 (Maintenance factor for photosystem I), that is required for the maintenance of specific components of the photosynthetic apparatus in the green alga Chlamydomonas reinhardtii Msf1 belongs to the superfamily of light-harvesting complex proteins with three transmembrane domains and consensus chlorophyll-binding sites. Loss of Msf1 leads to reduced accumulation of photosystem I and chlorophyll-binding proteins/complexes. Msf1is a component of a thylakoid complex containing key enzymes of the tetrapyrrole biosynthetic pathway, thus revealing a possible link between Msf1 and chlorophyll biosynthesis. Protein interaction assays and greening experiments demonstrate that Msf1 interacts with Copper target homolog1 (CHL27B) and accumulates concomitantly with chlorophyll in Chlamydomonas, implying that chlorophyll stabilizes Msf1. Contrary to other light-harvesting complex-like genes, the expression of Msf1 is not stimulated by high-light stress, but its protein level increases significantly under heat shock, iron and copper limitation, as well as in stationary cells. Based on these results, we propose that Msf1 is required for the maintenance of photosystem I and specific protein-chlorophyll complexes especially under certain stress conditions.

Impact of sleep deprivation on the outcomes of percutaneous coronary intervention.

OBJECTIVES: This study sought to compare the clinical outcomes of percutaneous coronary interventions (PCIs) performed by sleep deprived and non-sleep deprived operators. BACKGROUND: Interventional cardiologists are at risk for sleep deprivation as they often have to perform emergent procedures at night, but the effects of sleep deprivation on clinical outcomes have received limited study. METHODS: We examined the frequency, clinical characteristics, and outcomes of daytime PCIs performed by sleep deprived and non-sleep deprived operators at a tertiary medical center. Operators were considered sleep deprived when performing a daytime (7 am-11:59 pm) procedure preceded by a nighttime (12 am-6:59 am) procedure on the same date. RESULTS: Of the 12,680 daytime PCIs performed from 6/29/09 to 12/30/2016, 367 (2.9%) were performed by sleep deprived operators. Patients undergoing PCI performed by a sleep deprived operator were more likely to be younger, white, and to present with ST-elevation acute myocardial infarction (STEMI). The incidence of in-hospital death (1.1% vs. 1.3%, P = 1.0) and bleeding within 72 hr (3.9% vs. 2.9%, P = 0.29) were similar for procedures performed by sleep-deprived and non-sleep deprived operators. When the sleep deprived group was further stratified based on degree of sleep deprivation or length of sleep interruption, differences in mortality and total bleeding remained non-significant. CONCLUSIONS: In this large single center study, operator sleep deprivation did not appear to adversely impact PCI outcomes.

Meta-analysis of the impact of successful chronic total occlusion percutaneous coronary intervention on left ventricular systolic function and reverse remodeling.

BACKGROUND: We sought to examine the impact of coronary chronic total occlusion (CTO) percutaneous coronary intervention (PCI) on left ventricular (LV) function. METHODS: We performed a systematic review and meta-analysis of studies published between January 1980 and November 2017 on the impact of successful CTO PCI on LV function. RESULTS: A total of 34 observational studies including 2735 patients were included in the meta-analysis. Over a weighted mean follow-up of 7.9 months, successful CTO PCI was associated with an increase in LV ejection fraction by 3.8% (95%CI 3.0-4.7, P < 0.0001, I2 = 45%). In secondary analysis of 15 studies (1248 patients) that defined CTOs as occlusions of at least 3-month duration and reported follow-up of at least 3-months after the procedure, successful CTO PCI was associated with improvement in LV ejection fraction by 4.3% (95%CI [3.1, 5.6], P < 0.0001). In the 10 studies (502 patients) that reported LV end-systolic volume, successful CTO PCI was associated with a decrease in LV end-systolic volume by 4 mL, (95%CI -6.0 to -2.1, P < 0.0001, I2 = 0%). LV end-diastolic volume was reported in 9 studies with 403 patients and did not significantly change after successful CTO PCI (-2.3 mL, 95%CI -5.7 to 1.2 mL, P = 0.19, I2 = 0%). CONCLUSIONS: Successful CTO PCI is associated with a statistically significant improvement in LV ejection fraction and decrease in LV end-systolic volume, that may reflect a beneficial effect of CTO recanalization on LV remodeling. The clinical implications of these findings warrant further investigation.

Target identification by chromatographic co-elution: monitoring of drug-protein interactions without immobilization or chemical derivatization.

Bioactive molecules typically mediate their biological effects through direct physical association with one or more cellular proteins. The detection of drug-target interactions is therefore essential for the characterization of compound mechanism of action and off-target effects, but generic label-free approaches for detecting binding events in biological mixtures have remained elusive. Here, we report a method termed target identification by chromatographic co-elution (TICC) for routinely monitoring the interaction of drugs with cellular proteins under nearly physiological conditions in vitro based on simple liquid chromatographic separations of cell-free lysates. Correlative proteomic analysis of drug-bound protein fractions by shotgun sequencing is then performed to identify candidate target(s). The method is highly reproducible, does not require immobilization or derivatization of drug or protein, and is applicable to diverse natural products and synthetic compounds. The capability of TICC to detect known drug-protein target physical interactions (K(d) range: micromolar to nanomolar) is demonstrated both qualitatively and quantitatively. We subsequently used TICC to uncover the sterol biosynthetic enzyme Erg6p as a novel putative anti-fungal target. Furthermore, TICC identified Asc1 and Dak1, a core 40 S ribosomal protein that represses gene expression, and dihydroxyacetone kinase involved in stress adaptation, respectively, as novel yeast targets of a dopamine receptor agonist.

Soil addition of MnSO4 reduces wheat Cd accumulation by simultaneously increasing labile Mn and decreasing labile Cd concentrations in calcareous soil: A two-year pot study.

Cadmium (Cd) pollution of wheat fields is a serious environmental and health problem that warrants attention. Manganese (Mn)-containing materials are considered effective for inhibiting Cd accumulation in Cd-contaminated acidic soils. However, information on the long-term remediation effects of Mn fertilizers on Cd accumulation in wheat and on the microbial community in calcareous soils remain limited. Here, a two-year pot experiment was conducted to assess the performance of 0.05-0.2% MnSO4 addition in Cd-contaminated calcareous soils (total Cd concentration: 3.65 mg/kg) on Cd accumulation in wheat as well as on the soil bacterial community. The formation of Mn oxides and transformation of exchangeable Cd to stable Cd fractions confirmed that the application of MnSO4 significantly decreased CaCl2-extractable Cd concentrations in soil (0-47.08%). In addition, MnSO4 addition improved the antagonistic effect of Cd and Mn ions in the wheat rhizosphere by increasing the available Mn concentration in the soil (1.04-3.52 times), thereby significantly reducing wheat Cd accumulation by 24.66-54.70%. Notably, the addition of MnSO4 did not affect the richness and diversity (P > 0.05) but altered the composition and function of bacterial communities, especially those involved in metabolism and genetic information processing. Importantly, the effects of MnSO4 on Cd immobilization in soil (10.66-47.08%) and the inhibition of Cd accumulation in wheat (12.13-54.30%) can last for two years after one addition. Furthermore, the maximum decrease in Cd concentration in grains was found in the low-Cd wheat cultivar, with values of 31.39-54.70% and 19.94-54.30% in the first and second years, respectively. Based on the present findings, the combination of MnSO4 with a low-Cd wheat cultivar is effective for the safe utilization of Cd-contaminated calcareous soils.

Heavy metal distribution in wheat plant components following foliar Cd application.

Atmospheric deposition of Cd, from anthropogenic activities, can be directly deposited onto and absorbed into wheat plants, yet, how foliar absorbed Cd is translocated in wheat plants is not well understood. A pot experiment investigated foliar Cd application on the accumulation and distribution of heavy metals in various wheat parts. Wheat was grown in a Cd/heavy metal contaminated soil, and from grain heading to the filling stage, 0, 10, 20, 30 and 40 mg kg-1 Cd solution was sprayed repeatedly on leaves (grain heads were covered). Foliar Cd application had no effect on grain yield and Cd concentration (3.01-3.51 mg kg-1 for all treatments), while increased flag leaf blade and sheath Cd concentrations by 1.06-2.77 and 0.00-0.66 times, respectively. Cadmium concentration in the center of the peduncle, from the 40 mg kg-1 Cd solution treatment, was 1.41 times that of the control (10.3 vs 7.30 mg kg-1). Foliar Cd application also increased Cd accumulation (concentration × mass) of the flag leaf blade and sheath. Rachis and grain Pb concentrations were reduced, while stem Pb concentration was increased by Cd application. Cadmium application negatively affected whole plant Ni accumulation and concentration of certain wheat parts; Ni absorption inhibition may have occurred in roots via the downward transport of Cd. Overall results implied that the predominant portion of foliar applied Cd was retained in leaves, while lesser portions migrated to peduncle or root and affected the absorption/distribution of other metals in wheat plants. These results are important for further discerning the mechanism of wheat grain Cd accumulation, especially when grain is raised in areas where atmospheric deposition of Cd (e.g., near smelting facilities) is an issue from an environmental and human health perspective.