Early ablation of newly diagnosed paroxysmal atrial fibrillation (NEWPaAF) versus newly diagnosed persistent atrial fibrillation (NEWPeAF): Comparison of patient populations and ablation outcomes.

INTRODUCTION: Little is known about very early atrial fibrillation (AF) ablation after first AF detection. METHODS: We evaluated patients with AF ablation <4 months from newly diagnosed paroxysmal AF (NEWPaAF) and newly diagnosed persistent AF (NEWPeAF). We compared the two patient populations and compared ablation outcomes to those undergoing later ablation. RESULTS: Ablation was done <4 months from AF diagnosis in 353 patients (135 = paroxysmal, 218 = persistent). Early ablation outcome was best for NEWPaAF versus NEWPeAF for initial (p = 0.030) but not final (p = 0.102) ablation. Despite recent AF diagnosis in both groups, they were clinically quite different. NEWPaAF patients were younger (64.3 ± 13.0 vs. 67.3 ± 10.9, p = 0.0020), failed fewer drugs (0.39 vs. 0.60, p = 0.007), had smaller LA size (4.12 ± 0.58 vs. 4.48 ± 0.59 cm, p < 0.0001), lower BMI (28.8 ± 5.0 vs. 30.3 ± 6.0, p = 0.016), and less CAD (3.7% vs. 11.5%, p = 0.007), cardiomyopathies (2.2% vs. 22.9%, p = 0.0001), hypertension (46.7% vs. 67.4%, p < 0.0001), diabetes (8.1% vs. 17.4%, p = 0.011) and sleep apnea (20.0% vs. 30.3%, p = 0.031). For NEWPaAF, early ablation AF-free outcome was no better than later ablation (p = 0.314). For NEWPeAF, AF-free outcomes were better for early ablation than later ablation (p < 0.0001). Delaying ablation allowed more strokes/TIAs in both AF types (paroxysmal p = 0.014, persistent p < 0.0001). CONCLUSIONS: Patients presenting for early ablation after newly diagnosed persistent AF have more pre-existing comorbidities and worse initial ablation outcomes than patients with NEWPaAF. For NEWPaAF, there was no advantage to early ablation, as long as the AF remained paroxysmal. For NEWPeAF, early ablation gave better outcomes than later ablation and they should undergo early ablation. For both AF types, waiting was associated with more neurologic events, suggesting all patients should consider earlier ablation.

Examining the effectiveness of place-based interventions to improve public health and reduce health inequalities: an umbrella review.

BACKGROUND: Locally delivered, place-based public health interventions are receiving increasing attention as a way of improving health and reducing inequalities. However, there is limited evidence on their effectiveness. This umbrella review synthesises systematic review evidence of the health and health inequalities impacts of locally delivered place-based interventions across three elements of place and health: the physical, social, and economic environments. METHODS: Systematic review methodology was used to identify recent published systematic reviews of the effectiveness of place-based interventions on health and health inequalities (PROGRESS+) in high-income countries. Nine databases were searched from 1st January 2008 to 1st March 2020. The quality of the included articles was determined using the Revised Assessment of Multiple Systematic Reviews tool (R-AMSTAR). RESULTS: Thirteen systematic reviews were identified - reporting 51 unique primary studies. Fifty of these studies reported on interventions that changed the physical environment and one reported on changes to the economic environment. Only one primary study reported cost-effectiveness data. No reviews were identified that assessed the impact of social interventions. Given heterogeneity and quality issues, we found tentative evidence that the provision of housing/home modifications, improving the public realm, parks and playgrounds, supermarkets, transport, cycle lanes, walking routes, and outdoor gyms - can all have positive impacts on health outcomes - particularly physical activity. However, as no studies reported an assessment of variation in PROGRESS+ factors, the effect of these interventions on health inequalities remains unclear. CONCLUSIONS: Place-based interventions can be effective at improving physical health, health behaviours and social determinants of health outcomes. High agentic interventions indicate greater improvements for those living in greater proximity to the intervention, which may suggest that in order for interventions to reduce inequalities, they should be implemented at a scale commensurate with the level of disadvantage. Future research needs to ensure equity data is collected, as this is severely lacking and impeding progress on identifying interventions that are effective in reducing health inequalities. TRIAL REGISTRATION: PROSPERO CRD42019158309.

Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes.

Pancreatic cancer is a highly lethal malignancy with few effective therapies. We performed exome sequencing and copy number analysis to define genomic aberrations in a prospectively accrued clinical cohort (n = 142) of early (stage I and II) sporadic pancreatic ductal adenocarcinoma. Detailed analysis of 99 informative tumours identified substantial heterogeneity with 2,016 non-silent mutations and 1,628 copy-number variations. We define 16 significantly mutated genes, reaffirming known mutations (KRAS, TP53, CDKN2A, SMAD4, MLL3, TGFBR2, ARID1A and SF3B1), and uncover novel mutated genes including additional genes involved in chromatin modification (EPC1 and ARID2), DNA damage repair (ATM) and other mechanisms (ZIM2, MAP2K4, NALCN, SLC16A4 and MAGEA6). Integrative analysis with in vitro functional data and animal models provided supportive evidence for potential roles for these genetic aberrations in carcinogenesis. Pathway-based analysis of recurrently mutated genes recapitulated clustering in core signalling pathways in pancreatic ductal adenocarcinoma, and identified new mutated genes in each pathway. We also identified frequent and diverse somatic aberrations in genes described traditionally as embryonic regulators of axon guidance, particularly SLIT/ROBO signalling, which was also evident in murine Sleeping Beauty transposon-mediated somatic mutagenesis models of pancreatic cancer, providing further supportive evidence for the potential involvement of axon guidance genes in pancreatic carcinogenesis.

Clinical and pathologic features of familial pancreatic cancer.

BACKGROUND: Inherited predisposition to pancreatic cancer contributes significantly to its incidence and presents an opportunity for the development of early detection strategies. The genetic basis of predisposition remains unexplained in a high proportion of patients with familial PC (FPC). METHODS: Clinicopathologic features were assessed in a cohort of 766 patients who had been diagnosed with pancreatic ductal adenocarcinoma (PC). Patients were classified with FPC if they had ≥1 affected first-degree relatives; otherwise, they were classified with sporadic PC (SPC). RESULTS: The prevalence of FPC in this cohort was 8.9%. In FPC families with an affected parent-child pair, 71% in the subsequent generation were 12.3 years younger at diagnosis. Patients with FPC had more first-degree relatives who had an extrapancreatic malignancy (EPM) (42.6% vs 21.2; P<.0001), particularly melanoma and endometrial cancer, but not a personal history of EPM. Patients with SPC were more likely to be active smokers, have higher cumulative tobacco exposure, and have fewer multifocal precursor lesions, but these were not associated with differences in survival. Long-standing diabetes mellitus (>2 years) was associated with poor survival in both groups. CONCLUSIONS: FPC represents 9% of PC, and the risk of malignancy in kindred does not appear to be confined to the pancreas. Patients with FPC have more precursor lesions and include fewer active smokers, but other clinicopathologic factors and outcome are similar to those in patients with SPC. Furthermore, some FPC kindreds may exhibit anticipation. A better understanding of the clinical features of PC will facilitate efforts to uncover novel susceptibility genes and the development of early detection strategies.

Comparison of CHADS2 and CHA2DS2-VASC anticoagulation recommendations: evaluation in a cohort of atrial fibrillation ablation patients.

AIMS: Atrial fibrillation (AF) is associated with a high incidence of strokes/thromboembolism. The CHADS2 score assigns points for several clinical variables to identify stroke risk. The CHA2DS2-VASC score uses the same variables but also incorporates age 65 to 74, female gender, and vascular disease in an effort to provide a more refined risk of stroke/thromboembolism. We aimed to examine oral anticoagulation (OAC) recommendations for a cohort of patients undergoing AF ablation depending upon whether thrombo-embolic risk was determined by the CHADS2 or CHA2DS2-VASC score. METHODS AND RESULTS: For 1411 patients we compared OAC recommendations for each of these risk stratification schemes to one of the three OAC strategies: (i) NO-OAC, (ii) CONSIDER-OAC, and (iii) DEFINITE-OAC. Compared with the CHADS2 score, the CHA2DS2-VASC score reduced NO-OAC from 40.3 to 21.8% and CONSIDER-OAC from 36.6 to 27.9% while increasing DEFINITE-OAC from 23.0 to 50.2% of patients. Age 65 to 74 and female gender accounted for 95.2% and vascular disease for only 4.8% of recommendations for more aggressive OAC using CHA2DS2-VASC. Most vascular disease occurred in patients with higher CHADS2 scores already recommended for DEFINITE-OAC (P < 0.0001). Reclassifying 30 females of age <65 with a CHA2DS2-VASC score of 1 to the NO-OAC group had minimal effect on the overall recommendations. CONCLUSION: Compared with the CHADS2 score, in our AF ablation population, the CHA2DS2-VASC score markedly increases the number of AF patients for whom OAC is recommended. It will be important to determine by randomized trials if this major paradigm shift to greater use of OAC using the CHA2DS2-VASC scoring improves patient outcomes.

Peri-procedural interrupted oral anticoagulation for atrial fibrillation ablation: comparison of aspirin, warfarin, dabigatran, and rivaroxaban.

AIMS: Atrial fibrillation ablation requires peri-procedural oral anticoagulation (OAC) to prevent thromboembolic events. There are several options for OAC. We evaluate peri-procedural AF ablation complications using a variety of peri-procedural OACs. METHODS AND RESULTS: We examined peri-procedural OAC and groin, bleeding, and thromboembolic complications for 2334 consecutive AF ablations using open irrigated-tip radiofrequency (RF) catheters. Pre-ablation OAC was warfarin in 1113 (47.7%), dabigatran 426 (18.3%), rivaroxaban 187 (8.0%), aspirin 472 (20.2%), and none 136 (5.8%). Oral anticoagulation was always interrupted and intraprocedural anticoagulation was unfractionated heparin (activated clotting time, ACT = 237 ± 26 s). Pre- and post-OAC drugs were the same for 1591 (68.2%) and were different for 743 (31.8%). Following ablation, 693 (29.7%) were treated with dabigatran and 291 (12.5%) were treated with rivaroxaban. There were no problems changing from one OAC pre-ablation to another post-ablation. Complications included 12 (0.51%) pericardial tamponades [no differences for dabigatran (P = 0.457) or rivaroxaban (P = 0.163) compared with warfarin], 12 (0.51%) groin complications [no differences for rivaroxaban (P = 0.709) and fewer for dabigatran (P = 0.041) compared with warfarin]. Only 5 of 2334 (0.21%) required blood transfusions. There were two strokes (0.086%) and no transient ischaemic attacks (TIAs) in the first 48 h post-ablation. Three additional strokes (0.13%), and two TIAs (0.086%) occurred from 48 h to 30 days. Only one stroke had a residual deficit. Compared with warfarin, the neurologic event rate was not different for dabigatran (P = 0.684) or rivaroxaban (P = 0.612). CONCLUSION: Using interrupted OAC, low target intraprocedural ACT, and irrigated-tip RF, the rate of peri-procedural groin, haemorrhagic, and thromboembolic complications was extremely low. There were only minimal differences between OACs. Low-risk patients may remain on aspirin/no OAC pre-ablation. There are no problems changing from one OAC pre-ablation to another post-ablation.

High proportion of rare and compound epidermal growth factor receptor mutations in an Australian population of non-squamous non-small-cell lung cancer.

BACKGROUND: Epidermal growth factor receptor (EGFR) mutation positivity in primary non-small-cell lung cancer (NSCLC) may confer increased sensitivity to EGFR tyrosine kinase inhibitor (TKI) therapy with improved progression-free survival over EGFR wild-type tumours. Some mutation subtypes may not confer such TKI sensitivity. The incidence of rare and compound subtypes in the Australian lung cancer population is not fully defined. AIMS: The aim of the study was to audit the incidence of EGFR mutation in serial cases of primary non-squamous NSCLC presenting to two multidisciplinary team meetings in metropolitan Sydney for incidence, type of mutation and phenotypic association with mutation positivity. METHODS: Serially presenting cases of primary non-squamous NSCLC were tested for EGFR mutation. The cases presented to either of two multidisciplinary team meetings in metropolitan Sydney and were referred for EGFR mutation testing on the basis of non-squamous NSCLC histopathology. Samples from the two sites were analysed for EGFR mutation at one of three different laboratories, each using a slightly different assay. Data on phenotypic characteristics, smoking history and clinicopathological features of the tumour were collected. RESULTS: There is a relatively high incidence of EGFR mutation in non-squamous NSCLC in a series of patients drawn from two metropolitan multidisciplinary team meetings in Sydney at a rate of 23.8%. A high proportion of rare and compound EGFR mutations were identified (6/32 mutation positive cases, 18.8%). CONCLUSIONS: The incidence of EGFR mutation may be higher in Australian populations than in other populations of predominantly European origin. Rare and compound EGFR mutations may occur and may have implications for treatment that differ from classically activating mutations.

Determination of ambient ethanol concentrations in aqueous environmental matrixes by two independent analyses.

A new method for the determination of ethanol in aqueous environmental matrixes at nanomolar concentrations is presented and compared to an existing method that has been optimized for low-level alcohol determinations. The new analysis is based upon oxidation of ethanol by the enzyme alcohol oxidase obtained from the yeast Hansenula sp. which quantitatively produces acetaldehyde after reaction for 120 min at 40 °C and pH 9.0. The acetaldehyde reacts with 2,4-dinitrophenylhydrazine forming a hydrazone that is separated from interfering substances and quantified by high-performance liquid chromatography (HPLC) with UV detection at 370 nm. Comparison of initial acetaldehyde concentration with that after enzymatic oxidation yields the ethanol concentration with a corresponding detection limit of 10 nM. Analytical results were verified by intercomparison with a completely independent technique utilizing a solid-phase microextraction (SPME) Carboxen/PDMS SPME fiber. A 12 mL aqueous phase sample was heated at 50 °C for 10 min prior to loading onto the SPME fiber. Extraction of ethanol was performed by introducing the fiber into the headspace above a pH 4.4 buffered sample containing 30% NaCl for 20 min. Samples were agitated during heating and extraction by magnetic stirring at a rate of 750 rpm. The fiber was thermally desorbed for 1 min at 230 °C in the injection port of a gas chromatograph equipped with a flame ionization detector (FID) set at 250 °C. The resulting ethanol detection limit is 19 nM. Results of an intercomparison study between the enzymatic and SPME analyses produced a trend line with a slope of unity demonstrating that methods produced statistically equivalent ethanol concentrations in several natural waters including rainwater, fresh surface waters, and sediment pore waters.

Very long term outcomes of atrial fibrillation ablation.

BACKGROUND: Little is known about the very long term durability of atrial fibrillation (AF) ablation. OBJECTIVE: The purpose of this study was to evaluate very long term AF ablation outcomes. METHODS: We followed 5200 patients undergoing 7145 ablation procedures. We evaluated outcomes after single and multiple ablation procedures for paroxysmal (PAF; 33.6%), persistent (PeAF; 56.4%), and long-standing (LsAF; 9.9%) AF. We compared 3 ablation eras by initial ablation catheter: early (101 patients) using solid big tip (SBT) catheters (October 2003 to December 2005), intermediate (2143 patients) using open irrigated tip (OIT) catheters (December 2005 to August 2016), and contemporary (2956 patients) using contact force (CF) catheters (March 2014 to December 2021). RESULTS: AF freedom at 5, 10, and 15 years was as follows: initial ablation: PAF 67.8%, 56.3%, 47.6%; PeAF 46.6%, 35.6%, 26.5%; and LsAF 30.4%, 18.0%, 3.4%; final ablation: PAF 80.3%, 72.6%, 62.5%; PeAF 60.1%, 50.2%, 42.5%; and LsAF 43.4%, 32.0%, 20.6%. For PAF and PeAF, CF ablation procedures were better than OIT ablation procedures (P < .0001) and both were better than SBT ablation procedures (P < .001). LsAF had no outcome improvement over the eras. The 8-year success rate after final ablation for CF, OIT, and SBT catheter eras was as follows: PAF 79.1%, 71.8%, 60.0%; PeAF 55.9%, 50.7%, 38.0%; and LsAF 42.7%, 36.2%, 31.8%. Highest AF recurrence was in the first 2 years, with a 2- to 15-year recurrence of 2%/yr. Success predictors after initial and final ablation procedures were younger age, smaller left atrium, shorter AF duration, male sex, less persistent AF, lower CHA2DS2-VASc score, fewer drugs failed, and more recent catheter era. CONCLUSION: After year 2, there is 2%/yr recurrence rate for all AF types. Ablation success is best in the CF catheter era, intermediate in the OIT era, and worst in the SBT era. Over the ablation eras, outcomes improved for PAF and PeAF but not for LsAF. We should follow patients indefinitely after ablation. We need an understanding of how to better ablate more persistent AF.

The use of dabigatran immediately after atrial fibrillation ablation.

INTRODUCTION: Atrial fibrillation (AF) ablation requires postprocedural anticoagulation to prevent thromboembolic events because of the ablation procedure itself or due to recurrent AF postprocedure. Dabigatran is a new anticoagulant and may be useful after AF ablation to prevent thromboembolic events. METHODS AND RESULTS: We evaluated 123 consecutive patients who were started on dabigatran after AF ablation. Patients were given enoxaparin 0.5 mg/kg at the end of the procedure, which was repeated 12 hours later and then discontinued. Dabigatran was started 22 hours postablation with drug dose based on renal function. Primary outcomes were thromboembolic events, bleeding complications, and side effects over a 30-day follow-up period. The preablation anticoagulant was warfarin in 56 (45.5%) patients, dabigatran in 34 (27.6%), and aspirin in 26 (21.1%). Seven (5.7%) patients were on no anticoagulant before ablation. The patients on dabigatran before ablation with normal renal function had the drug stopped 36 hours preablation. There were no preprocedural or intraprocedural thromboembolic episodes or bleeding. Three patients received dabigatran 75 mg bid and the rest 150 mg bid. There were no postablation strokes, transient ischemic attacks, or systemic thromboemboli in any patient. Three patients discontinued dabigatran and were changed to warfarin, 2 because of gastrointestinal side effects and 1 because of a diffuse rash. CONCLUSIONS: Dabigatran is safe and well tolerated after AF ablation. It did not cause bleeding complications and there were no thromboembolic events. Dabigatran appears to be an alternative to warfarin after AF ablation.

Prior antiarrhythmic drug use and the outcome of atrial fibrillation ablation.

AIMS: Atrial fibrillation (AF) ablation is generally performed after patients fail antiarrhythmic drug (AAD) therapy. Some patients have drug contraindications or choose to avoid a lifetime of drug therapy. Little is known about the impact of previous drug therapy on ablation outcomes. We evaluated AAD use before AF ablation and its impact on ablation outcomes. METHODS AND RESULTS: We evaluated freedom from AF after ablation and patients' clinical characteristics by number of AADs failed in 1125 patients undergoing 1504 ablations. We also evaluated reasons why some patients did not receive prior drug therapy. Cox multivariate analysis examined factors predicting ablation failure. Patients failing more drugs before ablation were older (P = 0.001), had a longer duration of AF (P = 0.0001), were more likely female (P = 0.037), had more repeat ablations (P = 0.045), and less paroxysmal AF (P = 0.003). For patients with either paroxysmal or persistent AF, the number of drugs failed predicted AF recurrence (P = 0.0001). Other factors predicting AF recurrence following final ablation included age (P = 0.004), left atrial size (P = 0.002), female gender (P = 0.0001), and persistent AF (P = 0.0001). The reason for not receiving prior drug therapy was medical in 21.5% and patient choice in 78.5%. Number of drugs failed did not influence ablation outcome for patients with long-standing persistent AF (P = 0.352). CONCLUSIONS: For paroxysmal and persistent AF patients undergoing ablation, those failing fewer AADs have different clinical characteristics than those who fail more drugs. Our study also suggests that the more drugs failed pre-ablation, the lower the freedom from AF post-procedure, possibly due to AF progression during drug trials.

Supraphysiologic temperature enhances cytotoxic effects of bupivacaine on bovine articular chondrocytes in an in vitro study.

PURPOSE: The purpose of this study was to determine the effects of temperature or 0.25% bupivacaine treatment in combination with supraphysiologic temperatures on chondrocyte viability. METHODS: Bovine articular chondrocytes in suspension culture were treated with phosphate-buffered saline solution at 20°C, 37°C, 40°C, 42°C, 45°C, 47°C, and 50°C for 15, 30, and 60 minutes or with phosphate-buffered saline solution at 37°C, 45°C, and 50°C for 30 and 60 minutes followed by 0.25% bupivacaine at 20°C for 60 minutes. Chondrocyte viability was analyzed by flow cytometry with the LIVE/DEAD Viability/Cytotoxicity Kit (Molecular Probes, Eugene, OR). Annexin V and ethidium double staining determined whether apoptosis or necrosis occurred. RESULTS: Temperatures from 20°C to 42°C did not cause chondrocyte death. Temperatures at or above 45°C caused significant chondrocyte death, particularly at 50°C for 60 minutes, compared with 37°C at 60 minutes (P < .01). When the chondrocytes were incubated at 50°C, subsequent exposure to bupivacaine significantly increased chondrocyte death compared with the saline solution-treated control group (P < .001). There were additive cytotoxic effects when bupivacaine was combined with supraphysiologic temperatures. It was also found that bupivacaine at supraphysiologic temperatures caused necrosis of articular chondrocytes. CONCLUSIONS: Temperatures at or above 45°C caused significant chondrocyte death. Bupivacaine treatment in the presence of 45°C and 50°C temperatures significantly increased necrosis of bovine articular chondrocytes in this in vitro study. CLINICAL RELEVANCE: Immediate intra-articular injection of bupivacaine after heat-generating procedures may cause damage to the cartilage because of the additive cytotoxic effects of bupivacaine and elevated temperature.

Circulating tumour markers can define patients with normal colons, benign polyps, and cancers.

BACKGROUND: Early diagnosis represents the best opportunity for cure of colorectal cancer. Current screening programmes use faecal occult blood testing for screening, which has limited sensitivity and poor specificity. METHODS: In this study we looked at a series of previously described diagnostic markers utilising circulating free DNA (cfDNA), with a preparation method allowing small DNA fragments to be isolated. The Circulating free DNA was isolated from samples obtained from 85 patients, including 35 patients without endoscopic abnormality, a group of 26 patients with benign colorectal adenomas, and 24 patients with colorectal carcinomas. In each case, polymerase chain reaction (PCR) was performed for Line1 79 bp, Line1 300 bp, Alu 115 bp, Alu 247 bp, and mitochondrial primers. In addition, carcinoembryonic antigen (CEA) was measured by ELISA. Each marker was analysed between normal, polyp, and cancer populations, and the best performing analysed in combination by logistic regression. RESULTS: The best model was able to discriminate normal from populations with adenoma or carcinoma using three DNA markers and CEA, showing an area under the receiver operator characteristic (ROC) curve of 0.855 with a positive predictive value of 81.1% for polyps and cancer diagnosis. CONCLUSION: These circulating markers in combination with other markers offer the prospect of a simple blood test as a possible secondary screen for colorectal cancers and polyps in patients with positive faecal occult blood tests.

Long-term results of atrial fibrillation ablation: the importance of all initial ablation failures undergoing a repeat ablation.

BACKGROUND: Ablation is more successful for patients with paroxysmal atrial fibrillation (AF1) than for those with persistent (AF2) or longstanding persistent AF (AF3). Many patients fail initial ablation and undergo repeat ablations. Little is known about repeat ablation procedure times, complications, and outcomes. METHODS: We evaluated Kaplan-Meier freedom from AF by AF type and sex for initial and repeat ablations and for final status of 843 patients undergoing 1122 ablations. We examined complications, procedure times and reasons why patients do not undergo repeat ablations. Cox multivariate analysis evaluated factors predicting ablation failure. RESULTS: Initial ablations were more successful in AF1 than AF2 or AF3 (P < .0001) patients. For each AF type, repeat ablations were more successful than initial ablations (P = .01 to <.001). Procedure times (139.1 ± 49.1 vs 135.3 ± 45.6 minutes, P = .248) and major complications (1.66% vs 2.87%, P = .216) were similar. Women had different clinical characteristics than men, similar initial and repeat ablation success rates but lower overall success because of fewer repeat ablations (57.8% vs 68.2%, P = .047) due to patient choice (P = .028). Patients with either successful initial ablations or undergoing repeat ablations had late AF recurrence rates of 0% to 1.5% a year. Age (P = .012), larger left atria (P = .002), female sex (P = .001), AF2 (P < .0001), AF3 (P = .003), and coronary disease (P = .003) predicted failure. CONCLUSIONS: Repeat ablations are more successful than initial ablations, have similar procedure times and complication rates, help determine final success rates, and may explain sex difference in success rates. For the best outcomes, patients should assume that a repeat ablation may be required to eliminate AF.

Zebrafish runx1 promoter-EGFP transgenics mark discrete sites of definitive blood progenitors.

The transcription factor Runx1 is essential for the development of definitive hematopoietic stem cells (HSCs) during vertebrate embryogenesis and is transcribed from 2 promoters, P1 and P2, generating 2 major Runx1 isoforms. We have created 2 stable runx1 promoter zebrafish-transgenic lines that provide insight into the roles of the P1 and P2 isoforms during the establishment of definitive hematopoiesis. The Tg(runx1P1:EGFP) line displays fluorescence in the posterior blood island, where definitive erythromyeloid progenitors develop. The Tg(runx1P2:EGFP) line marks definitive HSCs in the aorta-gonad-mesonephros, with enhanced green fluorescent protein-labeled cells later populating the pronephros and thymus. This suggests that a function of runx1 promoter switching is associated with the establishment of discrete definitive blood progenitor compartments. These runx1 promoter-transgenic lines are novel tools for the study of Runx1 regulation and function in normal and malignant hematopoiesis. The ability to visualize and isolate fluorescently labeled HSCs should contribute to further elucidating the complex regulation of HSC development.

Atrial fibrillation ablation: "perpetual motion" of open irrigated tip catheters at 50 W is safe and improves outcomes.

BACKGROUND: Point-by-point use of open irrigated tip catheters (OITCs) at 50 W increases atrial fibrillation (AF) ablation cure rates but also increases complications. We determined if constantly moving the OITC (perpetual motion) when using 50 W increases ablation cure rates without increasing complications. METHODS: We evaluated procedural data, complications, and individual procedure cure rates (IPCRs) for AF ablation using closed tip catheters (CTC) versus OITC at 40, 45, and 50 W in 1,122 ablations. We used "perpetual motion" to move the OITC at 50 W every 3-10 seconds. RESULTS: The OITC showed higher IPCR than CTC at 45 W (P = 0.012) and 50 W (P < 0.0005). For the OITC, IPCR increased from 44.6% to 60.7% as power increased from 40 to 50 W (P = 0.008). The OITC appeared superior to the CTC for all types of AF. For paroxysmal AF, increasing OITC power from 40 to 50 W provided no increase in IPCR (70.6% vs 71.2%, P = 0.827). For persistent AF, increasing power from 40 to 50 W increased IPCR from 34.5% to 59.5% (P = 0.001). Complications were similar for the CTC and the OITC at any power. The OITC at 50 W had shorter procedure, left atrial, and fluoroscopy times (P < 0.0005). CONCLUSIONS: Increasing OITC power from 40 to 50 W increases IPCR with no increase in complications as long as the 50 W setting is done using "perpetual motion." The OITC 50 W power setting results in shorter procedure and fluoroscopy times and should be considered for AF ablations.

Biomechanical Comparison of UCL Repair Using Suspensory Fixation Versus UCL Reconstruction.

BACKGROUND: Medial ulnar collateral ligament (mUCL) repair is growing in popularity as a treatment for younger athletes with mUCL tears. One of the most recent techniques utilizes a collagen-coated suture tape to augment the repair. The most popular repair technique uses a screw for proximal fixation in the humerus. We present an alternative technique that uses suspensory fixation in the proximal humerus. PURPOSE: To biomechanically compare elbow valgus stability and load to failure of a novel alternative repair technique with suspensory fixation to an mUCL reconstruction. STUDY DESIGN: Controlled laboratory study. METHODS: Eighteen fresh-frozen cadaveric elbows were dissected to expose the mUCL. Medial elbow stability was tested with the mUCL in an intact, deficient-either repaired or reconstructed-state. The repair technique used a suspensory fixation with suture augmentation, and the docking technique was used on all reconstructions. A 3-N·m valgus torque was applied to the elbow, and valgus rotation of the ulna was recorded via motion tracking cameras as the elbow was cycled through a full range of motion. After kinematic testing, specimens were loaded to failure at 70° of elbow flexion. RESULTS: Both ulnar collateral ligament reconstruction and repair restored valgus stability to levels that were not statistically different from intact at all angles of flexion. There was no significant difference in the ultimate torque to failure between repaired and reconstructed mUCLs. CONCLUSION: There was no significant difference in the valgus strength between the mUCL repair with suspensory fixation and the mUCL reconstruction. CLINICAL RELEVANCE: Suspensory fixation is an alternative method for proximal fixation in the mUCL without compromising the strength of the construct.

NRF2 as a therapeutic opportunity to impact in the molecular roadmap of ALS.

Amyotrophic Lateral Sclerosis (ALS) is a devastating heterogeneous disease with still no convincing therapy. To identify the most strategically significant hallmarks for therapeutic intervention, we have performed a comprehensive transcriptomics analysis of dysregulated pathways, comparing datasets from ALS patients and healthy donors. We have identified crucial alterations in RNA metabolism, intracellular transport, vascular system, redox homeostasis, proteostasis and inflammatory responses. Interestingly, the transcription factor NRF2 (nuclear factor (erythroid-derived 2)-like 2) has significant effects in modulating these pathways. NRF2 has been classically considered as the master regulator of the antioxidant cellular response, although it is currently considered as a key component of the transduction machinery to maintain coordinated control of protein quality, inflammation, and redox homeostasis. Herein, we will summarize the data from NRF2 activators in ALS pre-clinical models as well as those that are being studied in clinical trials. As we will discuss, NRF2 is a promising target to build a coordinated transcriptional response to motor neuron injury, highlighting its therapeutic potential to combat ALS.

Internationally validated score to predict the outcome of non-paroxysmal atrial fibrillation ablation: the 'FLAME score'.

BACKGROUND: The clinical effectiveness of ablating non-paroxysmal atrial fibrillation (non-PAF) relies on proper patient selection. We developed and validated a scoring system to predict non-PAF ablation outcomes. METHODS: Data on 416 non-PAF ablations were analysed using binary logistic regression at a London centre. Identified preprocedural variables, which independently predicted freedom from atrial tachyarrhythmia. Twenty-one possible predictive variables and a model with c-statistic 0.751-explained outcome variation in London at mean follow-up 12±3 months. An additive point score (range 0-9) was developed-the FLAME score: female=1; long-lasting persistent atrial fibrillation=1; left atrial diameter in mm: 40 to <45 = 1, 45 to <50 = 2, 50 to <55=3, ≥55 =4; mitral regurgitation (MR) mild to moderate=1; extreme comorbidity=2. Extreme comorbidities include severe MR, moderate mitral stenosis, mitral replacement, hypertrophic cardiomyopathy or congenital heart disease. RESULTS: The FLAME score was applied to data (882 non-PAF ablations) at a Californian centre, and predicted the outcome of both single (p<0.0001) and multiple (p<0.0001) procedures. For first ablation (follow-up 2.1 years (median, IQR 1.0-4.1)), FLAME score: 0-1 predicts 62% success, 2-4 44% and ≥5 29% (Ptrend <0.0001). After the final ablation (mean procedures: 1.4±0.6, follow-up 1.8 years (median, IQR 0.8-3.6)), FLAME score: 0-1 predicts 81% success, 2-4 65% and ≥5 44% (Ptrend <0.0001). CONCLUSIONS: FLAME score is easily calculated, derived in London, and predicted single and multiple procedural outcomes for non-PAF ablations in California. In patients with a high score, even multiple procedures are usually ineffective.

PFOS dominates PFAS composition in ambient fine particulate matter (PM2.5) collected across North Carolina nearly 20 years after the end of its US production.

Contamination of drinking water by per- and polyfluoroalkyl substances (PFASs) emitted from manufacturing plants, fire-fighting foams, and urban waste streams has received considerable attention due to concerns over toxicity and environmental persistence; however, PFASs in ambient air remain poorly understood, especially in the United States (US). We measured PFAS concentrations in ambient fine particulate matter (PM2.5) at 5 locations across North Carolina over a 1 year period in 2019. Thirty-four PFASs, including perfluoroalkyl carboxylic, perfluoroalkane sulfonic, perfluoroalkyl ether carboxylic and sulfonic acids were analyzed by UHPLC/ESI-MS/MS. Quarterly averaged concentrations ranged from <0.004-14.1 pg m-3. Perfluorooctanoic acid (PFOA) and perfluorooctane sulfonic acid (PFOS) ranged from <0.18 to 14.1 pg m-3, comparable to previous PM2.5 measurements from Canada and Europe (<0.02-3.5 pg m-3). Concentrations above 1 pg m-3 were observed in July-September at Charlotte (14.1 pg m-3, PFOA), Wilmington (4.75 pg m-3, PFOS), and Research Triangle Park (1.37 pg m-3, PFOS). Notably, PM2.5 has a short atmospheric lifetime (<2 weeks), and thus, the presence of PFOS in these samples raises questions about their sources, since PFOS production was phased out in the US ∼20 years ago. This is the first US study to provide insights into ambient PFAS concentrations in PM2.5.