Effectiveness Associated With BNT162b2 Vaccine Against Emergency Department and Urgent Care Encounters for Delta and Omicron SARS-CoV-2 Infection Among Adolescents Aged 12 to 17 Years.

Importance: Data about the duration of protection of 2 and 3 doses of BNT162b2 in children and adolescents are needed to help inform recommendations for boosters in this age group. Objective: To evaluate vaccine effectiveness (VE) and durability associated with 2 doses of BNT162b2 against Delta- and Omicron-related emergency department (ED) and urgent care (UC) encounters among adolescents aged 12 to 17 years and to estimate VE associated with 3 doses against these same outcomes. Design, Setting, and Participants: This test-negative case-control study was conducted at Kaiser Permanente Southern California, an integrated health care system using electronic health records in the US. Participants included Kaiser Permanente Southern California members ages 12 to 17 years with an ED or UC encounter from November 1, 2021, through March 18, 2022, for acute respiratory infection who were tested for SARS-CoV-2 via a reverse transction-polymerase chain reaction test. Analyses were conducted from March 21 to June 22, 2022. Exposures: BNT162b2 vaccination status ascertained from electronic health records and state registry data. Main Outcomes and Measures: The main outcome was VE associated with BNT162b2 against ED and UC encounters related to Delta or Omicron variant SARS-CoV-2 infection. Results: Analyses were conducted among 3168 adolescents, including 1004 with ED visits and 2164 with UC visits. Median (IQR) age was 15 (13-16) years, and 1461 (46.1%) were boys. In adjusted analyses, VE associated with 2 doses of BNT162b2 against ED or UC encounters was highest within the first 2 months for both Delta (89% [95% CI, 69% to 96%]) and Omicron (73% [95% CI, 54% to 84%]) variants but waned to 49% (95% CI, 27% to 65%) for the Delta variant and 16% (95% CI, -7% to 34%) for the Omicron variant at 6 months and beyond. A third dose of BNT162b2 was associated with improved protection against the Omicron variant (87% [95% CI, 72% to 94%]) after a median (IQR) of 19 (9-32) days after dose 3. Conclusions and Relevance: These findings suggest that 2 doses of the BNT162b2 COVID-19 vaccine were associated with high levels of protection against ED and UC encounters related to the Delta and Omicron variants of SARS-CoV-2 in the first few months after vaccination. However, effectiveness waned over time, especially against Omicron. A third dose of BNT162b2 was associated with improved protection against Omicron beyond that seen initially after 2 doses, underscoring the importance of boosters for adolescents aged 12 to 17 years.

Durability of BNT162b2 vaccine against hospital and emergency department admissions due to the omicron and delta variants in a large health system in the USA: a test-negative case-control study.

BACKGROUND: The duration of protection against the omicron (B.1.1.529) variant for current COVID-19 vaccines is not well characterised. Vaccine-specific estimates are especially needed. We aimed to evaluate the effectiveness and durability of two and three doses of the BNT162b2 (Pfizer-BioNTech) mRNA vaccine against hospital and emergency department admissions due to the delta (B.1.617.2) and omicron variants. METHODS: In this case-control study with a test-negative design, we analysed electronic health records of members of Kaiser Permanente Southern California (KPSC), a large integrated health system in California, USA, from Dec 1, 2021, to Feb 6, 2022. Vaccine effectiveness was calculated in KPSC patients aged 18 years and older admitted to hospital or an emergency department (without a subsequent hospital admission) with a diagnosis of acute respiratory infection and tested for SARS-CoV-2 via PCR. Adjusted vaccine effectiveness was estimated with odds ratios from adjusted logistic regression models. This study is registered with ClinicalTrials.gov (NCT04848584). FINDINGS: Analyses were done for 11 123 hospital or emergency department admissions. In adjusted analyses, effectiveness of two doses of the BNT162b2 vaccine against the omicron variant was 41% (95% CI 21-55) against hospital admission and 31% (16-43) against emergency department admission at 9 months or longer after the second dose. After three doses, effectiveness of BNT162b2 against hospital admission due to the omicron variant was 85% (95% CI 80-89) at less than 3 months but fell to 55% (28-71) at 3 months or longer, although confidence intervals were wide for the latter estimate. Against emergency department admission, the effectiveness of three doses of BNT162b2 against the omicron variant was 77% (72-81) at less than 3 months but fell to 53% (36-66) at 3 months or longer. Trends in waning against SARS-CoV-2 outcomes due to the delta variant were generally similar, but with higher effectiveness estimates at each timepoint than those seen for the omicron variant. INTERPRETATION: Three doses of BNT162b2 conferred high protection against hospital and emergency department admission due to both the delta and omicron variants in the first 3 months after vaccination. However, 3 months after receipt of a third dose, waning was apparent against SARS-CoV-2 outcomes due to the omicron variant, including hospital admission. Additional doses of current, adapted, or novel COVD-19 vaccines might be needed to maintain high levels of protection against subsequent waves of SARS-CoV-2 caused by the omicron variant or future variants with similar escape potential. FUNDING: Pfizer.

Effectiveness of a third dose of BNT162b2 mRNA COVID-19 vaccine in a large US health system: A retrospective cohort study.

Background: Globally, recommendations are expanding for third (booster) doses of BNT162b2 (Pfizer-BioNTech). In the United States, as of November 19, 2021, boosters were recommended for all adults aged 18 years and older. We evaluated the effectiveness of a third dose of BNT162b2 among adults in a large US integrated health system. Methods: In this retrospective cohort study, we analyzed electronic health records from Kaiser Permanente Southern California between Dec 14, 2020 and Dec 5, 2021 to assess vaccine effectiveness (VE) of two and three doses of BNT162b2 against SARS-CoV-2 infections (without hospital admission) andCOVID-19-related hospital admission. VE was calculated using hazards ratios from adjusted Cox models. Findings: After only two doses, VE against infection declined from 85% (95% CI 83-86) during the first month to 49% (46-51) ≥ 7 months following vaccination. Overall VE against hospitalization was 90% (95% CI 86-92) within one month and did not wane, however, effectiveness against hospitalization appeared to wane among immunocompromised individuals but was not statistically significant (93% [72-98] at 1 month to 74% [45-88] after ≥ 7 months; p=0·490). Three-dose VE (median follow-up 1·3 months [SD 0·6]) was 88% (95% CI 86-89) against infection and 97% (95-98) against hospitalization. Effectiveness after three doses was higher than that seen one month after receiving only two doses for both outcomes. Relative VE of three doses compared to two (with at least six months after the second dose) was 75% (95% CI 71-78) against infections and 70% (48-83) against hospital admissions. Interpretation: These data support the benefit of broad BNT162b2 booster recommendations, as three doses confers comparable, if not better, protection against SARS-CoV-2 infections and hospital admission as was seen soon after receiving two doses. Funding: Pfizer Inc.

Effectiveness of mRNA BNT162b2 COVID-19 vaccine up to 6 months in a large integrated health system in the USA: a retrospective cohort study.

BACKGROUND: Vaccine effectiveness studies have not differentiated the effect of the delta (B.1.617.2) variant and potential waning immunity in observed reductions in effectiveness against SARS-CoV-2 infections. We aimed to evaluate overall and variant-specific effectiveness of BNT162b2 (tozinameran, Pfizer-BioNTech) against SARS-CoV-2 infections and COVID-19-related hospital admissions by time since vaccination among members of a large US health-care system. METHODS: In this retrospective cohort study, we analysed electronic health records of individuals (≥12 years) who were members of the health-care organisation Kaiser Permanente Southern California (CA, USA), to assess BNT162b2 vaccine effectiveness against SARS-CoV-2 infections and COVID-19-related hospital admissions for up to 6 months. Participants were required to have 1 year or more previous membership of the organisation. Outcomes comprised SARS-CoV-2 PCR-positive tests and COVID-19-related hospital admissions. Effectiveness calculations were based on hazard ratios from adjusted Cox models. This study was registered with ClinicalTrials.gov, NCT04848584. FINDINGS: Between Dec 14, 2020, and Aug 8, 2021, of 4 920 549 individuals assessed for eligibility, we included 3 436 957 (median age 45 years [IQR 29-61]; 1 799 395 [52·4%] female and 1 637 394 [47·6%] male). For fully vaccinated individuals, effectiveness against SARS-CoV-2 infections was 73% (95% CI 72-74) and against COVID-19-related hospital admissions was 90% (89-92). Effectiveness against infections declined from 88% (95% CI 86-89) during the first month after full vaccination to 47% (43-51) after 5 months. Among sequenced infections, vaccine effectiveness against infections of the delta variant was high during the first month after full vaccination (93% [95% CI 85-97]) but declined to 53% [39-65] after 4 months. Effectiveness against other (non-delta) variants the first month after full vaccination was also high at 97% (95% CI 95-99), but waned to 67% (45-80) at 4-5 months. Vaccine effectiveness against hospital admissions for infections with the delta variant for all ages was high overall (93% [95% CI 84-96]) up to 6 months. INTERPRETATION: Our results provide support for high effectiveness of BNT162b2 against hospital admissions up until around 6 months after being fully vaccinated, even in the face of widespread dissemination of the delta variant. Reduction in vaccine effectiveness against SARS-CoV-2 infections over time is probably primarily due to waning immunity with time rather than the delta variant escaping vaccine protection. FUNDING: Pfizer.

Intranasal fentanyl spray versus intravenous opioids for the treatment of severe pain in patients with cancer in the emergency department setting: A randomized controlled trial.

OBJECTIVE: Intranasal fentanyl (INF) quickly and noninvasively relieves severe pain, whereas intravenous hydromorphone (IVH) reliably treats severe cancer pain but requires vascular access. The trial evaluated the efficacy of INF relative to IVH for treating cancer patients with severe pain in an emergency department (ED) setting. METHODS: We randomized 82 patients from a comprehensive cancer center ED to receive INF (n = 42) or IVH (n = 40). Eligible patients reported severe pain at randomization (≥7, scale: 0 "none" to 10 "worst pain"). We conducted non-inferiority comparisons (non-inferiority margin = 0.9) of pain change from treatment initiation (T0) to one hour later (T60). T0 pain ratings were unavailable; therefore, we estimated T0 pain by comparing 1) T60 ratings, assuming similar group T0 ratings; 2) pain change, estimating T0 pain = randomization ratings, and 3) pain change, with T0 pain = 10 (IVH group) or T0 pain = randomization rating (INF group). RESULTS: At T60, the upper 90% confidence limit (CL) of the mean log-transformed pain ratings for the INF group exceeded the mean IVH group rating by 0.16 points (>pain). Substituting randomization ratings for T0 pain, the lower 90% CL of mean pain change in the INF group extended 0.32 points below (

Focal Pulsed Field Ablation for Pulmonary Vein Isolation and Linear Atrial Lesions: A Preclinical Assessment of Safety and Durability.

BACKGROUND: A novel ablation and mapping system can toggle between delivering biphasic pulsed field (PF) and radiofrequency energy from a 9-mm lattice-tip catheter. We assessed the preclinical feasibility and safety of (1) focal PF-based thoracic vein isolation and linear ablation, (2) combined PF and radiofrequency focal ablation, and (3) PF delivered directly atop the esophagus. METHODS: Two cohorts of 6 swine were treated with pulsed fields at low dose (PFLD) and high dose (PFHD) and followed for 4 and 2 weeks, respectively, to isolate 25 thoracic veins and create 5 right atrial (PFLD), 6 mitral (PFHD), and 6 roof lines (radiofrequency+PFHD). Baseline and follow-up voltage mapping, venous potentials, ostial diameters, and phrenic nerve viability were assessed. PFHD and radiofrequency lesions were delivered in 4 and 1 swine from the inferior vena cava onto a forcefully deviated esophagus. All tissues were submitted for histopathology. RESULTS: Hundred percent of thoracic veins (25 of 25) were successfully isolated with 12.4±3.6 applications/vein with mean PF times of <90 seconds/vein. Durable isolation improved from 61.5% PFLD to 100% with PFHD (P=0.04), and all linear lesions were successfully completed without incurring venous stenoses or phrenic injury. PFHD sections had higher transmurality rates than PFLD (98.3% versus 88.1%; P=0.03) despite greater mean thickness (2.5 versus 1.3 mm; P<0.001). PF lesions demonstrated homogenous fibrosis without epicardial fat, nerve, or vessel involvement. In comparison, radiofrequency+PFHD sections revealed similar transmurality but expectedly more necrosis, inflammation, and epicardial fat, nerve, and vessel involvement. Significant ablation-related esophageal necrosis, inflammation, and fibrosis were seen in all radiofrequency sections, as compared with no PF sections. CONCLUSIONS: The lattice-tip catheter can deliver focal PF to durably isolate veins and create linear lesions with excellent transmurality and without complications. The PF lesions did not damage the phrenic nerve, vessels, and the esophagus.

Formulation and evaluation of cyclodextrin complexes for improved anticancer activity of repurposed drug: Niclosamide.

Niclosamide, previously used as an anthelmintic drug is currently being repurposed for its anticancer activity. Niclosamide is a brick like biopharmaceutical classification system (BCS) class II drug with poor aqueous solubility and dissolution consequently leading to low bioavailability. By considering the physicochemical properties and geometry of niclosamide, inclusion complex with cyclodextrin was prepared by freeze drying method and characterized using FT-IR, DSC, PXRD, and 1HNMR. In silico molecular modeling study was performed to study the possible interactions between niclosamide and cyclodextrin. The anticancer activity of niclosamide formulation was evaluated through in vitro cell cytotoxicity study using various cancer cell lines. The potential of niclosamide complex for improvement of the bioavailability was evaluated in male BALB/c mice. In vitro cytotoxicity studies indicated significantly higher cytotoxicity at lower concentrations and the pharmacokinetic studies showed significant improvement in Cmax and Tmax of niclosamide from cyclodextrin complex in comparison to pure niclosamide alone.

Process evaluation of the midwifery initiated oral health-dental service program: perceptions of pregnant women.

BACKGROUND: Pregnant women in Australia seldom seek dental care and are unaware of its importance. To address these gaps the midwifery-initiated oral health dental service (MIOH-DS) program was comprehensive trialled and found effective. The aim of this study was to undertake a process evaluation of the MIOH-DS using the perspectives of pregnant women who participated in the trial. METHODS: A qualitative research design was utilized, whereby content analysis was undertaken on data from 11 semi-structured interviews with women who participated in the program. RESULTS: All participants were receptive of the MIOH-DS intervention, and found it to be an acceptable intervention that met their needs, and encouraged future positive oral health practices and health-seeking behaviours. They expressed that midwives were an appropriate professional to conduct oral health assessments, education and referrals to affordable dental services. Although some participants were initially apprehensive towards receiving treatment during pregnancy, dental staff members were able to appropriately educate and reassure them during treatment. CONCLUSIONS: The MIOH-DS represents a promising and acceptable intervention strategy for pregnant women to promote their oral health. Findings merit further investigation on whether positive outcomes achieved can be sustained when implemented in other national or international settings similar to the study setting.

First report on the pharmacokinetic profile of nimbolide, a novel anticancer agent in oral and intravenous administrated rats by LC/MS method.

Nimbolide is a novel, natural compound with promising potential as a drug candidate for anticancer activity. It is isolated from the Indian traditional medicinal plant Azadirachta indica popularly known as neem. The present study was undertaken to explore the oral bioavailability and pharmacokinetic characteristics of nimbolide in rats using the LC/QTOF/MS method. A simple protein precipitation method using acetonitrile was employed for extracting nimbolide from rat plasma. The chromatographic separation of nimbolide and the internal standard (regorafenib) was attained on an Aquity BEH C18 column (100 × 2.1 mm, 2.7 µm), using ACN and 0.1% of formic acid in water as mobile phase components in a gradient elution mode at a flow rate of 0.45 mL/min over a short run time of 4 min. A mass detection was carried out using target ions of [M + H]+ at m/z 467.2074 for nimbolide and m/z 483.0847 for the internal standard. The LC/MS method was validated and all the parameters were found well within the specified limits. The calibration curve was constructed in the range of 1-1000 ng/mL. The method shows good accuracy (91.66-97.12%) and precision (intra 2.21-6.92% CV and inter-day 2.56-4.62% CV). This developed LC/MS method was effectively applied to the pharmacokinetic study of nimbolide upon oral and intravenous administration in rats. In concordance with its physicochemical properties and high lipophilicity, we found that it shows poor oral absorption at different doses (10, 30 and 50 mg/kg). As expected, higher plasma levels were observed upon intravenous (10 mg/kg) administration. This method can be extended for evaluation of drug interaction and drug metabolism in rats as well as in humans. Moreover, our rapid and sensitive method may cater the need to accelerate the preclinical formulation development and lead optimization for future drug development of this potent anticancer agent. Further, our oral bioavailability studies demonstrated that nimbolide possesses poor oral absorption, which could be the probable reason for the delay in therapeutic translation of this promising agent for clinical use.

LC-ESI-MS/MS evaluation of forced degradation behaviour of silodosin: In vitro anti cancer activity evaluation of silodosin and major degradation products.

Silodosin (SLD) a novel α1-adrenoceptor antagonist was subjected to forced degradation involving hydrolysis (acidic, alkaline and neutral), oxidative, photolysis and thermal stress, as per ICH specified conditions. The drug underwent significant degradation under hydrolytic (acidic, alkaline and neutral) and oxidative stress conditions whereas, it was found to be stable under other stress conditions. A rapid, precise, accurate and robust chromatographic method for the separation of the drug and its degradation products (DPs) was developed on a Fortis C18 analytical column (150×4.6mm, 5µm) using 0.1% formic acid and acetonitrile as a mobile phase in gradient elution mode at a flow rate of 1.0mL/min. A total of 5 (DP 1 to DP 5) hitherto unknown DPs were identified by LC-ESI-TOF-MS/MS experiments and accurate mass measurements. The most probable mechanisms for the formation of DPs have been proposed based on a comparison of the fragmentation of the [M+H]+ ions of silodosin and its DPs. The major DPs (DP 1 and DP 2) were isolated and evaluated for anticancer activity using PC3 (human prostate cancer) cell lines by MTT assay. The results revealed that silodosin, DP 1 and DP 2 have potential anticancer activity with IC50 values (µM) 72.74 (±4.51), 25.21 (±2.36), and, 114.07 (±11.90) respectively.

Termination of persistent atrial fibrillation during pulmonary vein isolation: insight from the MAGIC-AF trial.

AIMS: Controversy on the optimal ablation strategy for persistent atrial fibrillation (AF) exists with limited work evaluating a strategy of pulmonary vein isolation (PVI) alone when AF terminates during PVI. Thirty-five patients had AF termination during PVI in the Modified Ablation Guided by Ibutilide Use in Chronic Atrial Fibrillation (MAGIC-AF; ClinicalTrials.gov number: NCT01014741) study. The objective of the current study is to report the 1-year outcome after PVI alone in this unique patient group. METHODS AND RESULTS: The 1-year single procedure freedom from atrial arrhythmia off anti-arrhythmic drugs was reported for the 35 patients in the MAGIC-AF study with persistent AF termination during or upon completion of PVI. Freedom from recurrent atrial arrhythmia was achieved in 60% of patients where AF terminated during PVI. Cavotricuspid isthmus flutter was common when AF terminated to a macro re-entrant flutter during PVI, and responsible for 92% of all flutter circuits with AF termination. CONCLUSIONS: Persistent AF termination during PVI may identify a subgroup of patients who experience a similar long-term clinical outcome with PVI ablation alone when compared with other more extensive persistent AF ablation strategies. Pulmonary vein isolation alone may be an appropriate tactic in this subgroup of persistent AF patients.

The modified stepwise ablation guided by low-dose ibutilide in chronic atrial fibrillation trial (The MAGIC-AF Study).

AIMS: Complex fractionated atrial electrograms (CFAE) are targeted during persistent atrial fibrillation (AF) ablation. However, many CFAE sites are non-specific resulting in extensive ablation. Ibutilide has been shown to reduce left atrial surface area exhibiting CFAE. We hypothesized that ibutilide administration prior to CFAE ablation would identify sites critical for persistent AF maintenance allowing for improved procedural efficacy and long-term freedom from atrial arrhythmias. METHODS AND RESULTS: Two hundred patients undergoing a first-ever persistent AF catheter ablation procedure were randomly assigned to receive either 0.25 mg of intravenous ibutilide or saline placebo upon completion of pulmonary vein isolation. Complex fractionated atrial electrogram sites were then targeted with ablation. The primary efficacy endpoint was the 1-year single procedure freedom from atrial arrhythmia off anti-arrhythmic drugs. Similar procedural characteristics (procedure, fluoroscopy, and ablation times) were observed with both strategies despite a greater reduction in left atrial surface area with CFAE sites (8 vs. 1%, P < 0.0001) and AF termination during CFAE ablation with ibutilide compared with placebo (75 vs. 57%, P = 0.007). The primary efficacy endpoint was achieved in 56% of patients receiving ibutilide and 49% receiving placebo (P = 0.35). No significant differences in peri-procedural complications were observed in both groups. CONCLUSION: Despite a reduction in CFAE area and greater AF termination during CFAE ablation, procedural characteristics and clinical outcomes were unchanged when CFAE ablation was guided by ibutilide administration. CLINICAL TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov number: NCT01014741.

Characteristics of ventricular tachycardia ablation in patients with continuous flow left ventricular assist devices.

BACKGROUND: Left ventricular assist devices (LVADs) are increasingly used as a bridge to cardiac transplantation or as destination therapy. Patients with LVADs are at high risk for ventricular arrhythmias. This study describes ventricular arrhythmia characteristics and ablation in patients implanted with a Heart Mate II device. METHODS AND RESULTS: All patients with a Heart Mate II device who underwent ventricular arrhythmia catheter ablation at 9 tertiary centers were included. Thirty-four patients (30 male, age 58±10 years) underwent 39 ablation procedures. The underlying cardiomyopathy pathogenesis was ischemic in 21 and nonischemic in 13 patients with a mean left ventricular ejection fraction of 17%±5% before LVAD implantation. One hundred and ten ventricular tachycardias (VTs; cycle lengths, 230-740 ms, arrhythmic storm n=28) and 2 ventricular fibrillation triggers were targeted (25 transseptal, 14 retrograde aortic approaches). Nine patients required VT ablation <1 month after LVAD implantation because of intractable VT. Only 10/110 (9%) of the targeted VTs were related to the Heart Mate II cannula. During follow-up, 7 patients were transplanted and 10 died. Of the remaining 17 patients, 13 were arrhythmia-free at 25±15 months. In 1 patient with VT recurrence, change of turbine speed from 9400 to 9000 rpm extinguished VT. CONCLUSIONS: Catheter ablation of VT among LVAD recipients is feasible and reasonably safe even soon after LVAD implantation. Intrinsic myocardial scar, rather than the apical cannula, seems to be the dominant substrate.

SAFETY PROFILE OF OCRIPLASMIN FOR SYMPTOMATIC VITREOMACULAR ADHESION: A Comprehensive Analysis of Premarketing and Postmarketing Experiences.

PURPOSE: After the recent approval of ocriplasmin by the Food and Drug Administration, postmarketing safety concerns have been raised by the vitreoretinal community. The American Society of Retina Specialists Therapeutic Surveillance Committee was commissioned to monitor postmarketing drug-related and device-related adverse events. The purpose of this report is to analyze the postmarketing safety experience in the context of available premarketing safety data. METHODS: Periodic aggregate safety reports consisting of premarketing, or clinical trial, data (n = 999 injections) and postmarketing reports through July 16, 2013 (n = 4,387 injections), were retrospectively analyzed by the TSC. The aggregate data were analyzed to classify adverse events, and the postmarketing safety data for each event type were compared with the premarketing data. RESULTS: Eight categories of adverse events were identified. Acute reduction in visual acuity attributable to either worsening of macular pathology or development of subretinal fluid, electroretinogram changes, dyschromatopsia, retinal tears and detachments, lens subluxation or phacodonesis, impaired pupillary reflex, and retinal vessel findings were reported in both the premarketing and postmarketing experiences. Ellipsoid zone (inner segment/outer segment) findings were only reported in the postmarketing experience. Rates of postmarketing reports were lower than in the premarketing data. Adverse events were generally transient, and characteristics of these adverse events were generally similar between the premarketing and postmarketing experience. CONCLUSION: Postmarket analyses are limited by significant underreporting, and in the case of ocriplasmin as a first in-class drug, they may not have captured safety events that have only more recently been identified. Nonetheless, postmarket analyses can identify the scope of potential safety events based on real-world experiences. Ocriplasmin administration should be guided by an appropriate and informed risk-benefit discussion with the patient. Ongoing active postmarket surveillance by all practitioners will continue to be critical to better understand this safety profile.

Garlic attenuates cardiac oxidative stress via activation of PI3K/AKT/Nrf2-Keap1 pathway in fructose-fed diabetic rat.

BACKGROUND: Cardiovascular complication due to diabetes has remained a major cause of death. There is an urgent need to intervene the cardiac complications in diabetes by nutritional or pharmacological agents. Thus the present study was designed to find out the effectiveness of garlic on cardiac complications in insulin-resistant diabetic rats. METHODS AND RESULTS: SD rats were fed high fructose (65%) diet alone or along with raw garlic homogenate (250 mg/kg/day) or nutrient-matched (65% corn starch) control diet for 8 weeks. Fructose-fed diabetic rats showed cardiac hypertrophy, increased NFkB activity and increased oxidative stress. Administration of garlic significantly decreased (p<0.05) cardiac hypertrophy, NFkB activity and oxidative stress. Although we did not observe any changes in myocardial catalase, GSH and GPx in diabetic heart, garlic administration showed significant (p<0.05) increase in all three antioxidant/enzymes levels. Increased endogenous antioxidant enzymes and gene expression in garlic treated diabetic heart are associated with higher protein expression of Nrf2. Increased myocardial H2S levels, activation of PI3K/Akt pathway and decreased Keap levels in fructose-fed heart after garlic administration might be responsible for higher Nrf2 levels. CONCLUSION: Our study demonstrates that raw garlic homogenate is effective in reducing cardiac hypertrophy and fructose-induced myocardial oxidative stress through PI3K/AKT/Nrf2-Keap1 dependent pathway.

Percutaneous hemodynamic support with Impella 2.5 during scar-related ventricular tachycardia ablation (PERMIT 1).

BACKGROUND: Percutaneous left ventricular assist devices (pLVADs) are increasingly being used to facilitate ablation of unstable ventricular tachycardia (VT), but the safety profile and hemodynamic benefits of these devices have not been described in a systematic, prospective manner. METHODS AND RESULTS: Twenty patients with scar VT underwent ablation with a pLVAD. Neuromonitoring using cerebral oximetry was performed to evaluate a cerebral desaturation threshold to guide the duration of activation/entrainment mapping. The efficacy of pLVAD support was tested in a controlled manner with simulated VT. Complete procedural success was achieved in 50% (n=8) of patients, who were initially inducible for sustained VT, and partial procedural success in 37% (n=6). Using a cerebral desaturation level of 55% as a lower safety limit to guide the duration of sustained VT, 3 patients (15%) developed mild acute kidney injury (all resolved), and 1 (5%) patient developed mild cognitive dysfunction. During fast simulated VT (300 ms), cerebral desaturation to ≤55% occurred in more than half (53%) of patients tested without pLVAD support, compared with only 5% with full pLVAD support (P=0.003). CONCLUSIONS: In a consecutive series of patients with severe left ventricular dysfunction, pLVAD-supported scar VT ablation was safe and feasible. During fast simulated VT, a miniaturized axial flow pump imparted a more favorable hemodynamic profile compared with pharmacological agents alone. Cerebral oximetry is a complimentary monitoring modality during scar VT ablation, and avoidance of cerebral desaturations below a threshold of 55% may safely guide the duration of mapping during unstable VT.

Areas with complex fractionated atrial electrograms recorded after pulmonary vein isolation represent normal voltage and conduction velocity in sinus rhythm.

AIMS: Although complex fractionated atrial electrograms (CFAEs) are purported to represent critical sites for atrial fibrillation (AF) perpetuation, the mechanism and the significance of CFAE in the genesis of AF remain poorly understood. This study evaluated the relationship between CFAE and areas of abnormal atrial tissue defined by low-voltage electrograms (LVE) and signal average of the P-wave (SAPW). METHODS AND RESULTS: Complex fractionated atrial electrogram maps were obtained after pulmonary vein isolation in 15 patients with persistent AF. Patients were then cardioverted and voltage/activation maps were acquired in normal sinus rhythm (NSR). Total left atrium (LA), CFAE and LVE areas were measured as % of total LA area (mean ± SD). Conduction velocities of normal, LVE and CFAE areas were also measured during NSR. Patients underwent signal averaged ECG of the P-wave in NSR within 24 h of the procedure. Complex fractionated atrial electrograms areas accounted for 33 ± 24% of total LA. In NSR, only 12 ± 10% of LA area had LVE. There was no anatomic correlation between CFAE sites and LVE; the area of overlap between CFAE and LVE was only 1.6 ± 1.5%. Conduction velocity was faster in CFAE areas (2.3 ± 1.4 m/s) than in normal voltage areas (1.3 ± 0.3 m/s), and LVE areas (1.1 ± 0.7 m/s, P = 0.06). A positive correlation was only found between LVE areas and SAPW duration (r = 0.7, P = 0.04). CONCLUSION: Areas of CFAEs correspond to areas of normal atrial voltage and normal conduction velocity during NSR. Complex fractionated atrial electrogram probably represents the response of normal healthy atrial tissue to rapid pulmonary vein activation.

Acute electrical isolation is a necessary but insufficient endpoint for achieving durable PV isolation: the importance of closing the visual gap.

AIMS: Temporary, ablation-mediated effects such as oedema may cause reversible pulmonary vein (PV) isolation. To investigate this, point-by-point circumferential ablation was performed to achieve acute electrical PV isolation with an incomplete circumferential ablation line. Then, the impact of this intentional 'visual gap' (ViG) on the conduction properties of the ablation lesion set was assessed with adenosine and pacing manoeuvres. METHODS AND RESULTS: Twenty-eight patients undergoing ablation for paroxysmal (n= 20) or persistent atrial fibrillation (n= 8) were included. Pulmonary vein (PV) ablation was performed around ipsilateral vein pairs. Once acute isolation was achieved, ablation was halted and the presence and size of the ViG were calculated. The ViG electrophysiological properties were tested with pace capture along the ViG at 10 mA/2 ms, and assessment for dormant PV conduction with adenosine. Despite electrical isolation, a ViG was present in 75% (n= 42/56) of vein pairs (21 of 28 left PVs and 21 of 28 right PVs). There was no difference in the ViG size between the left and right PVs (22.1 ± 14.2 and 17.3 ± 11.3 mm, P > 0.05). Dormant PV connections were revealed by adenosine in more than a quarter (n= 12/42) of acutely isolated PV pairs, of which the majority were dependent on conduction through the ViG. CONCLUSIONS: Electrical PV isolation can usually be achieved without complete circumferential ablation. However, more than a quarter of these 'isolated' PVs exhibit dormant conduction-predominantly via the un-ablated 'ViGs' in the ablation lesion set. These findings support the hypothesis that reversible tissue injury contributes to PV isolation that may be acute but not necessarily durable.

The durability of pulmonary vein isolation using the visually guided laser balloon catheter: multicenter results of pulmonary vein remapping studies.

BACKGROUND: The visually guided laser ablation (VGLA) catheter is a compliant, variable-diameter balloon that delivers laser energy around the pulmonary vein (PV) ostium under real-time endoscopic visualization. While acute PV isolation has been shown to be feasible, limited data exist regarding the durability of isolation. OBJECTIVE: We sought to determine the durability of PV isolation following ablation using the balloon-based VGLA catheter. METHODS: The VGLA catheter was evaluated in patients with paroxysmal atrial fibrillation (3 sites, 10 operators). Following transseptal puncture, the VGLA catheter was advanced through a 12-F deflectable sheath and inflated at the target PV ostium. Under endoscopic guidance, the 30° aiming arc was maneuvered around the PV and laser energy was delivered to ablate tissue in a contiguous/overlapping manner. At ∼3 months, all patients returned for a PV remapping procedure. RESULTS: In 56 patients, 202 of 206 PVs (98%) were acutely isolated. At 105 ± 44 (mean ± SD) days, 52 patients returned for PV remapping at which time 162 of 189 PVs (86%) remained isolated and 32 of 52 patients (62%) had all PVs still isolated. On comparing the operators performing <10 vs ≥ 10 procedures, the durable PV isolation rate and the percentage of patients with all PVs isolated were found to be 73% vs 89% (P = .011) and 57% vs 66% (P = .746), respectively. After 2 procedures and 12.0 ± 1.9 months of follow-up, the drug-free rate of freedom from atrial fibrillation was 71.2%. CONCLUSIONS: In this multicenter, multioperator experience, VGLA resulted in a very high rate of durable PV isolation with a clinical efficacy similar to that of radiofrequency ablation.