Durability of thermal pulmonary vein isolation in persistent atrial fibrillation assessed by mandated repeat invasive study.

BACKGROUND: No study has assessed the durability of pulmonary vein isolation (PVI) with radiofrequency (RF) and cryoballoon (CB) in patients with persistent atrial fibrillation. These data are especially lacking for those with significantly diseased left atria (LA). OBJECTIVES: The goals of this study were to assess PVI durability in patients with significant LA disease and to compare reconnection rates between RF and CB. METHODS: Forty-four patients (mean age 63 years; 34 (77%) male; median time since atrial fibrillation diagnosis 22.5 months; median indexed LA volume 36 mL/m2) were randomized 1:1 to RF or CB PVI. A redo procedure using ultra-high-density electroanatomic mapping was mandated at 2 months, where PV reconnections were identified and reisolated. RESULTS: Thirty-eight patients underwent both procedures (CB n = 17; RF n = 21). Index RF procedures were longer (median 158 minutes vs 97 minutes; P < .001) but required less fluoroscopy (9.5 minutes vs 23 minutes; P < .001). At the index RF procedure, a median of 47% of LA myocardium had voltage < 0.5 mV, suggesting that half of the mapped LA comprised scar. PV reconnection was observed in 73 of 152 PVs (48.0%) and was more frequent with CB (58.8%) than with RF (39.3%) (P = .022). Reconnection of at least 1 PV was detected in >75% of patients. Significantly more ablation was required during the redo procedure to reisolate PVs in the CB arm (median 10.8 minutes vs 1.2 minutes; P < .001). CONCLUSION: PVI durability may be poor in those with significant LA scarring and dilatation, even with modern thermal ablation technologies. RF resulted in significantly better PVI durability than did CB in this complex population. TRIAL REGISTRATION: clinicaltrials.gov identifier: NCT04111731.

Inhibition of MER proto-oncogene tyrosine kinase by an antisense oligonucleotide enhances treatment efficacy of immunoradiotherapy.

BACKGROUND: The combination of radiotherapy and immunotherapy (immunoradiotherapy) has been increasingly used for treating a wide range of cancers. However, some tumors are resistant to immunoradiotherapy. We have previously shown that MER proto-oncogene tyrosine kinase (MerTK) expressed on macrophages mediates resistance to immunoradiotherapy. We therefore sought to develop therapeutics that can mitigate the negative impact of MerTK. We designed and developed a MerTK specific antisense oligonucleotide (ASO) and characterized its effects on eliciting an anti-tumor immune response in mice. METHODS: 344SQR cells were injected into the right legs on day 0 and the left legs on day 4 of 8-12 weeks old female 129sv/ev mice to establish primary and secondary tumors, respectively. Radiation at a dose of 12 Gy was given to the primary tumors on days 8, 9, and 10. Mice received either anti-PD-1, anti-CTLA-4 or/and MerTK ASO starting from day 1 post tumor implantation. The composition of the tumor microenvironment and the level of MerTK on macrophages in the tumor were evaluted by flow cytometry. The expression of immune-related genes was investigated with NanoString. Lastly, the impact of MerTK ASO on the structure of the eye was histologically evaluated. RESULTS: Remarkably, the addition of MerTK ASO to XRT+anti-PD1 and XRT+anti-CTLA4 profoundly slowed the growth of both primary and secondary tumors and significantly extended survival. The ASO significantly reduced the expression of MerTK in tumor-associated macrophages (TAMs), reprograming their phenotype from M2 to M1. In addition, MerTK ASO increased the percentage of Granzyme B+ CD8+ T cells in the secondary tumors when combined with XRT+anti-CTLA4. NanoString results demonstrated that the MerTK ASO favorably modulated immune-related genes for promoting antitumor immune response in secondary tumors. Importantly, histological analysis of eye tissues demonstrated that unlike small molecules, the MerTK ASO did not produce any detectable pathology in the eyes. CONCLUSIONS: The MerTK ASO can significantly downregulate the expression of MerTK on TAMs, thereby promoting antitumor immune response. The combination of MerTK ASO with immunoradiotherapy can safely and significantly slow tumor growth and improve survival.

Cryoballoon pulmonary vein isolation as first-line treatment of typical atrial flutter: long-term outcomes of the CRAFT trial.

BACKGROUND: CRAFT was an international, multicentre, randomised controlled trial across 11 sites in the United UK and Switzerland. Given the evidence that pulmonary vein triggers may be responsible for atrial flutter (AFL) as well as atrial fibrillation (AF), we hypothesised that cryoballoon pulmonary vein isolation (PVI) would provide greater symptomatic arrhythmia reduction than cavotricuspid isthmus (CTI) ablation, whilst also reducing the subsequent burden of AF. Twelve-month outcomes were previously reported. In this study, we report the extended outcomes of the CRAFT study to 36 months. METHODS: Patients with typical AFL and no evidence of AF were randomised 1:1 to cryoballoon PVI or radiofrequency CTI. All patients received an implantable loop recorder (ILR) for continuous cardiac rhythm monitoring. The primary outcome was time-to-symptomatic arrhythmia recurrence > 30 s. Secondary outcomes included time-to-first-AF episode ≥ 2 min. The composite safety outcome included death, stroke and procedural complications. RESULTS: A total of 113 patients were randomised to cryoballoon PVI (n = 54) or radiofrequency CTI ablation (n = 59). Ninety-one patients reconsented for extended follow-up beyond 12 months. There was no difference in the primary outcome between arms, with the primary outcome occurring in 12 PVI vs 11 CTI patients (HR 0.97; 95% CI 0.43-2.20; p = 0.994). AF ≥ 2 min was significantly less frequent in the PVI arm, affecting 26 PVI vs 36 CTI patients (HR 0.48; 95% CI 0.29-0.79; p = 0.004). The composite safety outcome occurred in 5 PVI and 6 CTI patients (p = 0.755). CONCLUSION: Cryoballoon PVI shows similar efficacy to radiofrequency CTI ablation in reducing symptomatic arrhythmia recurrence in patients presenting with isolated typical AFL but significantly reduces the occurrence of subsequent AF.

Inhibition of STAT6 with Antisense Oligonucleotides Enhances the Systemic Antitumor Effects of Radiotherapy and Anti-PD-1 in Metastatic Non-Small Cell Lung Cancer.

Diverse factors contribute to the limited clinical response to radiotherapy (RT) and immunotherapy in metastatic non-small cell lung cancer (NSCLC), among which is the ability of these tumors to recruit a retinue of suppressive immune cells-such as M2 tumor-associated macrophages (TAM)-thereby establishing an immunosuppressive tumor microenvironment that contributes to tumor progression and radio resistance. M2 TAMs are activated by the STAT6 signaling pathway. Therefore, we targeted STAT6 using an antisense oligonucleotide (ASO) along with hypofractionated RT (hRT; 3 fractions of 12 Gy each) to primary tumors in three bilateral murine NSCLC models (Lewis lung carcinoma, 344SQ-parental, and anti-PD-1-resistant 344SQ lung adenocarcinomas). We found that STAT6 ASO plus hRT slowed growth of both primary and abscopal tumors, decreased lung metastases, and extended survival. Interrogating the mechanism of action showed reduced M2 macrophage tumor infiltration, enhanced TH1 polarization, improved T-cell and macrophage function, and decreased TGFß levels. The addition of anti-PD-1 further enhanced systemic antitumor responses. These results provide a preclinical rationale for the pursuit of an alternative therapeutic approach for patients with immune-resistant NSCLC.

Cryoballoon Pulmonary Vein Isolation as First-Line Treatment for Typical Atrial Flutter.

OBJECTIVE: We aimed to compare cryoballoon pulmonary vein isolation (PVI) with standard radiofrequency cavotricuspid isthmus (CTI) ablation as first-line treatment for typical atrial flutter (AFL). METHODS: Cryoballoon Pulmonary Vein Isolation as First-Line Treatment for Typical Atrial Flutter was an international, multicentre, open with blinded assessment trial. Patients with CTI-dependent AFL and no documented atrial fibrillation (AF) were randomised to either cryoballoon PVI alone or radiofrequency CTI ablation. Primary efficacy outcome was time to first recurrence of sustained (>30 s) symptomatic atrial arrhythmia (AF/AFL/atrial tachycardia) at 12 months as assessed by continuous monitoring with an implantable loop recorder. Primary safety outcome was a composite of death, stroke, tamponade requiring drainage, atrio-oesophageal fistula, pacemaker implantation, serious vascular complications or persistent phrenic nerve palsy. RESULTS: Trial recruitment was halted at 113 of the target 130 patients because of the SARS-CoV-2 pandemic (PVI, n=59; CTI ablation, n=54). Median age was 66 (IQR 61-71) years, with 98 (86.7%) men. At 12 months, the primary outcome occurred in 11 (18.6%) patients in the PVI group and 9 (16.7%) patients in the CTI group. There was no significant difference in the primary efficacy outcome between the groups (HR 1.11, 95% CI 0.46 to 2.67). AFL recurred in six (10.2%) patients in the PVI arm and one (1.9%) patient in the CTI arm (p=0.116). Time to occurrence of AF of ≥2 min was significantly reduced with cryoballoon PVI (HR 0.46, 95% CI 0.25 to 0.85). The composite safety outcome occurred in four patients in the PVI arm and three patients in the CTI arm (p=1.000). CONCLUSION: Cryoballoon PVI as first-line treatment for AFL is equally effective compared with standard CTI ablation for preventing recurrence of atrial arrhythmia and better at preventing new-onset AF. TRIAL REGISTRATION NUMBER: NCT03401099.

Reverse electrical and structural remodeling of the left atrium occurs early after pulmonary vein isolation for persistent atrial fibrillation.

PURPOSE: Adverse left atrial (LA) remodeling is known to be associated with persistent atrial fibrillation (PeAF). The time course and pattern of reversal of LA remodeling following catheter ablation is poorly understood. We aimed to evaluate LA chamber volumes and dimensions, LA conduction velocities, and LA bipolar voltages at baseline and at 2 months after catheter ablation for PeAF. METHODS: Twenty-three patients with PeAF underwent detailed LA mapping during fixed rate atrial pacing using the CARTO3 navigation system prior to undergoing pulmonary vein isolation. All patients returned for protocol-mandated repeat electrophysiology study at 2 months, irrespective of symptoms or arrhythmia recurrence, during which all measurements were repeated using an identical mapping protocol. Patients then underwent daily ECG monitoring for 12 months. RESULTS: Nineteen out of twenty-three (83.6%) patients had durable PVI of all veins at repeat electrophysiology study, while 4 (17.4%) patients had late reconnection of a single vein each. In the blinded offline analysis, LA volume at follow-up was significantly lower as compared with baseline (55 ± 14 mL/m2 vs. 65 ± 15 mL/m2, P < 0.001). LA conduction velocities were significantly greater at 2 months (0.90 ± 0.13 m/s vs. 0.78 ± 0.13 m/s, P = 0.01). There was non-uniform regional LA voltage evolution, with a significant increase in bipolar voltages observed on the LA posterior wall (2.18 ± 0.85 mV vs. 1.83 ± 0.49 mV, P = 0.04), but not elsewhere. Individual variables of remodeling were not associated with AF recurrence. CONCLUSION: Significant structural and electrical reverse remodeling of the LA can be seen as early as 2 months following successful catheter ablation for PeAF.

Use of Ablation Index-Guided Ablation Results in High Rates of Durable Pulmonary Vein Isolation and Freedom From Arrhythmia in Persistent Atrial Fibrillation Patients: The PRAISE Study Results.

Background Catheter ablation for persistent atrial fibrillation (AF) is associated with less favorable outcomes than for paroxysmal AF. Substrate modification is often added to pulmonary vein isolation (PVI) to try to improve success rates. Recent studies have shown improved clinical outcomes with use of regional ablation index (AI) targets for PVI. We hypothesized that prospective use of AI-guided PVI in persistent AF patients would result in a low rate of PV reconnection at repeat electrophysiology study and that a high success rate can be achieved with durable PVI alone. Methods Forty consecutive patients with persistent AF underwent AI-guided PVI with target values of 550 for anterior and 400 for posterior left atrial regions, followed by a protocol-mandated repeat procedure after 2 months. Patients were monitored for atrial tachyarrhythmia recurrence via daily plus symptom-initiated ECG recordings for 12 months. Recurrence was defined as ≥30 seconds of any atrial tachyarrhythmia after a 3-month blanking period. Results PV reconnection was seen at repeat electrophysiology study in 22% of patients, affecting 7% of PVs. Ablation on the intervenous carina was required in 44% patients to achieve durable PVI. Atrial tachyarrhythmia recurrence was documented in 8 (20%) patients, only one of whom had PV reconnection at repeat study. At 12 months, 38/40 (95%) patients were in sinus rhythm, with 4 (10%) patients having started antiarrhythmic drugs. Higher body mass index and excess alcohol consumption were the only significant factors associated with atrial tachyarrhythmia recurrence. Conclusions Use of AI targets results in a high level of durable PVI. A good clinical outcome can be achieved in the great majority of persistent AF patients with AI-guided PVI alone. Clinical Trial Registration URL: https://www.clinicaltrials.gov . Unique identifier: NCT02628730.

Accuracy of left atrial bipolar voltages obtained by ConfiDENSE multielectrode mapping in patients with persistent atrial fibrillation.

INTRODUCTION: The ConfiDENSE™ module (Carto3 v4) allows rapid annotation of endocardial electrograms acquired by multielectrode (ME) mapping. However, its accuracy in assessing atrial voltages is unknown. METHODS AND RESULTS: Two ConfiDENSE™ left atrial voltage maps were created during continuous pacing in 20 patients undergoing catheter ablation for persistent AF using a ME lasso catheter and a contact force (CF) sensing ablation catheter. The automated tissue proximity indicator (TPI) filter was then applied to the ME map to yield a TPI map. Reference maps (RM) were created offline by a blinded observer by manually assessing all points against fidelity criteria. Bipolar voltages and proportion of low voltage points (< 0.5 mV) derived from the ME, CF, and TPI maps were compared with those derived from the RM. Note that 853 ± 365 points, 252 ± 184 points, and 144 ± 73 were collected for ME, TPI, and CF maps, respectively, and 429 ± 153 points were included in the RM. Voltages with CF and TPI maps were similar to those with RM (1.57 ± 0.47 mV vs. 1.63 ± 0.31 mV, P = 0.57 and 1.50 ± 0.38 mV vs. 1.63 ± 0.31 mV, P = 0.07, respectively), whereas ME maps showed a significantly lower mean voltage (1.00 ± 0.22 mV, P < 0.001). As compared to RM maps (17 ± 8%), low voltage points were significantly overestimated by the ME maps (50 ± 9% (P < 0.001) and TPI maps (28 ± 13% (P < 0.001), but not by the CF maps (22 ± 14%, P = 0.17). CONCLUSION: Application of the TPI filter to ConfiDENSE maps significantly increases the quality of the voltage data, conserving a reasonable point density, but still overestimates low voltage points as compared to CF-sensing maps or maps reviewed manually.

Prospective use of Ablation Index targets improves clinical outcomes following ablation for atrial fibrillation.

AIMS: Late recovery of ablated tissue leading to reconnection of pulmonary veins remains common following radiofrequency catheter ablation for AF. Ablation Index (AI), a novel ablation quality marker, incorporates contact force (CF), time, and power in a weighted formula. We hypothesized that prospective use of our previously published derived AI targets would result in better outcomes when compared to CF-guided ablation. METHODS: Eighty-nine consecutive drug-refractory AF patients (49% paroxysmal) underwent AI-guided ablation (AI-group). AI targets were 550 for anterior/roof and 400 for posterior/inferior left atrial segments. Procedural and clinical outcomes of these patients were compared to 89 propensity-matched controls who underwent CF-guided ablation (CF-group). All 178 procedures were otherwise similar, and both groups were followed-up for 12 months. The last 25 patients from each group underwent analysis of all VisiTags™ for ablation duration, CF, Force-Time Integral, and impedance drop. RESULTS: First-pass pulmonary vein isolation (PVI) was more frequent in AI-group than in CF-group (173 [97%] vs. 149 [84%] circles, P < 0.001), and acute PV reconnection was lower (11 [6%] vs. 24 [13%] circles, P = 0.02). Mean PVI ablation time was similar (AI-group: 42 ± 9 vs. CF-group: 45 ± 14 minutes, P = 0.14). Median impedance drop for AI-group was significantly higher than in CF-group (13.7 [9-19] Ω vs. 8.8 [5.2-13] Ω, P < 0.001). Two major complications occurred in CF-group and none in AI-group. Atrial tachyarrhythmia recurrence was significantly lower in AI-group (15 of 89 [17%]) than in CF-group (33 of 89 [37%], P = 0.002). CONCLUSION: AI-guided ablation is associated with significant improvements in the incidence of acute PV reconnection and atrial tachyarrhythmia recurrence rate compared to CF-guided ablation, potentially due to creation of better quality lesions as suggested by greater impedance drop.

Pulmonary Vein Re-Isolation as a Routine Strategy Regardless of Symptoms: The PRESSURE Randomized Controlled Trial.

OBJECTIVES: The goal of this study was to determine whether a strategy of early re-isolation of pulmonary vein (PV) reconnection in all patients, regardless of symptoms, would reduce the recurrence of atrial fibrillation (AF) and improve quality of life. BACKGROUND: Lasting pulmonary vein isolation (PVI) remains elusive. PV reconnection is strongly linked to the recurrence of arrhythmia. METHODS: A total of 80 patients with paroxysmal AF were randomized 1:1 after contact force-guided PVI to receive either standard care or undergo a repeat electrophysiology study after 2 months regardless of symptoms (repeat study). At the initial procedure, PVI was demonstrated by entrance/exit block and adenosine administration after a minimum 20-min wait. At the repeat study, all sites of PV reconnection were re-ablated. Patients recorded electrocardiograms daily and whenever symptomatic for 12 months using a handheld monitor. Recurrence was defined as ≥30 s of atrial tachyarrhythmia (AT) after a 3-month blanking period. The Atrial Fibrillation Effect on Quality-of-Life Questionnaire was completed at baseline and at 6 and 12 months. RESULTS: All 40 patients randomized to repeat study attended for this after 62 ± 6 days, of whom 25 (62.5%) had reconnection of 41 (26%) PVs. There were no complications related to these procedures. Subjects recorded a total of 32,203 electrocardiograms (380 [335 to 447] per patient) during 12.6 (12.2 to 13.2) months of follow-up. AT recurrence was significantly lower for the repeat study group (17.5% vs. 42.5%; p = 0.03), as was AT burden (p = 0.03). Scores on the Atrial Fibrillation Effect on Quality-of-Life Questionnaire were higher in the repeat study group at 6 months (p < 0.001) and 12 months (p = 0.02). CONCLUSIONS: A strategy of routine repeat assessment with re-isolation of PV reconnection improved freedom from AT recurrence, AT burden, and quality of life compared with current standard care. (The Effect of Early Repeat Atrial Fibrillation [AF] on AF Recurrence [PRESSURE]; NCT01942408).

Reablated Sites of Acute Reconnection After Pulmonary Vein Isolation Do Not Predict Sites of Late Reconnection at Repeat Electrophysiology Study.

INTRODUCTION: Acute reconnection of pulmonary veins (PVs) is frequently seen in the waiting period following pulmonary vein isolation (PVI). There are concerns that reablation at these sites may not be durably effective due to tissue edema caused by the initial ablation. We aimed to prospectively study the relationship between acute and late reconnection. METHODS AND RESULTS: Wide-area circumferential PVI was performed in 40 paroxysmal AF patients. Spontaneous reconnection was assessed after a minimum 20-minute waiting period, with adenosine administered to unmask dormant reconnection. All sites of acute reconnection were ablated to reisolate the PV. All 40 patients then underwent repeat electrophysiology study after 2 months, regardless of symptoms, to identify late reconnection. Sites of acute and late reconnection were compared according to a 12-segment PVI model. Acute reconnection was seen in 28 (6%) PVI segments in 20 (50%) patients, affecting 24/160 (15%) PVs. All were successfully reisolated. At repeat electrophysiology study, 51 (11%) PVI segments were reconnected in 25 (62%) patients, affecting 41 (25%) PVs. The proportion of PVI segments with and without acute reconnection exhibiting late reconnection at repeat study was no different (14% vs. 10%, P = 0.524). There was also no difference in late reconnection between PVI circles or patients with and without acute reconnection. CONCLUSION: Most PVI segments that undergo further ablation for acute reconnection show persistent isolation at repeat electrophysiology study, and the rate of late reconnection for these segments is no different to that for segments that did not acutely reconnect. This implies that effective reablation is delivered at these sites.

Biatrial linear ablation in sustained nonpermanent AF: Results of the substrate modification with ablation and antiarrhythmic drugs in nonpermanent atrial fibrillation (SMAN-PAF) trial.

BACKGROUND: More advanced atrial fibrillation (AF) is associated with lower success rates after pulmonary vein isolation (PVI), and the optimal ablation strategy is uncertain. OBJECTIVES: To assess the impact of additional linear ablation (lines) compared to PVI alone. METHODS: In this multicenter randomized controlled trial, 122 patients (mean age 61.9 ± 10.5 years; left atrial diameter 43 ± 6 mm) with persistent AF (PeAF) or sustained (>12 hours) paroxysmal AF (SusPAF) with risk factors for atrial substrate were included and followed up for 12 months. Patients were randomized to PVI-only or PVI + lines (left atrial roof line, mitral isthmus line, and tricuspid isthmus line) group. Holter monitoring was performed at 3, 6, and 12 months and according to symptoms. The primary outcome was atrial tachyarrhythmia recurrence lasting ≥30 seconds. RESULTS: Baseline characteristics were comparable between groups; 61% had PeAF and 39% SusPAF. Successful PVI was achieved for 98% of pulmonary veins, and bidirectional block was obtained in 90% of lines. The primary end point occurred in 38% of the PVI + lines group and 32% of the PVI-only group (P = .50), which was consistent in both PeAF (36% vs 28%; P = .45) and SusPAF (42% vs 39%; P = .86). Compared with the PVI-only group, the PVI + lines group had higher procedure duration (209 ± 52 minutes vs 172 ± 44 minutes; P < .001), ablation time (4352 ± 1084 seconds vs 2503 ± 1061 seconds; P < .001), and radiation exposure (Dose-area product 3992 ± 6496 Gy·cm(2) vs 2106 ± 1679 Gy·cm(2); P = .03). Quality of life (disease-specific Atrial Fibrillation Effect on Quality of Life questionnaire and mental component scale of the Short Form 36 Health Survey) improved significantly during the study but did not differ between groups. CONCLUSION: Adding lines to wide antral PVI in substrate-based AF requires significantly more ablation, increases procedure duration and radiation dose, but provides no additional clinical benefit.

A Single-Center Randomized Trial of Intraoperative Zero-Balanced Ultrafiltration During Cardiopulmonary Bypass for Patients With Impaired Kidney Function Undergoing Cardiac Surgery.

OBJECTIVES: The authors investigated whether zero-balance ultrafiltration (Z-BUF) during bypass significantly improves clinical and cost outcomes or biomarkers of kidney injury for patients with preoperative kidney impairment (estimated glomerular filtration rate [eGFR]<60 mL/minute) undergoing cardiac surgery. DESIGN: A single-center randomized controlled trial recruited, patients between 2010 and 2013, with a 12-months follow-up. SETTING: Hospital. PARTICIPANTS: One hundred ninety-nine patients undergoing cardiac surgery with cardiopulmonary bypass (CPB). INTERVENTIONS: Patients were assigned randomly to receive zero-balance ultrafiltration (Z-BUF) or not, with stratification for degree of kidney dysfunction and diabetes. MEASUREMENTS AND MAIN RESULTS: The authors assessed clinical efficacy and kidney function biomarkers. Cumulative probability of discharge from the intensive care unit (ICU) was assessed by Kaplan-Meier plots and was found not to be significantly different between the two trial arms (p = 0.61). After adjusting for EuroSCORE, diabetes, eGFR, cardioplegia types and type of surgery in a Cox proportional hazard model, hazard ratios (HR) for ICU length of stay between the Z-BUF and no-Z-BUF groups was not significantly different: HR (95% CI): 0.89 (0.66, 1.20; p = 0.44). In contrast, significant reductions in postoperative chest infections and the composite of clinical endpoints (death, strokes, and myocardial infarctions) in the Z-BUF group were observed. In addition, Z-BUF significantly abrogated the rise in the kidney damage markers urinary NGAL/creatinine ratio, urea, creatinine and eGFR during CPB and adverse events risks. CONCLUSIONS: Z-BUF during bypass surgery is associated with significant reductions in morbidity and biomarkers of CPB-induced acute kidney injury soon after CPB, which are indicative of clearance of inflammatory/immune mediators from the circulation.

Recurrence of atrial tachyarrhythmia during the second month of the blanking period is associated with more extensive pulmonary vein reconnection at repeat electrophysiology study.

BACKGROUND: Current guidelines recommend a 3-month blanking period after pulmonary vein isolation (PVI) as early recurrence of atrial tachyarrhythmia (ERAT) may be due to transient proarrhythmic factors. However, studies have suggested that these factors resolve by 1 month. PV reconnection (PVrc) is strongly associated with postblanking AT recurrence in paroxysmal atrial fibrillation. We hypothesized that ERAT occurring beyond 4 weeks after PVI is associated with PVrc at repeat electrophysiology study. METHODS AND RESULTS: Forty patients with paroxysmal atrial fibrillation underwent mandatory repeat electrophysiology study 2 months after PVI, regardless of symptoms, to document the number of reconnected PVs. Antiarrhythmic drugs, including ß-blockers, were discontinued 4 weeks after PVI. Patients were instructed to record a 30-second ECG everyday between the 2 procedures using a portable monitor, with additional recordings for symptoms. ERAT was defined as ≥30 seconds of AT. Patients recorded a total of 3293 ECGs. Four (10%) patients had ERAT in the first 4 weeks (M1) only, 2 (5%) in month 2 (M2) only, and 11 (28%) in both. PVrc of 1 PV was identified in 12 (30%) patients and of >1 PV in 13 (32%) patients. ERAT in M2 was associated with PVrc, whereas M1 was not (11/13 [85%] versus 0/4 [0%]; P=0.006). M2 ERAT was strongly associated with PVrc of >1 PV (10/13 [77%] versus 3/27 [11%] without M2 ERAT; P<0.0001). CONCLUSIONS: ERAT occurring beyond 4 weeks after PVI is associated with PVrc and particularly of PVrc of >1 PV. ERAT confined to M1 is unrelated to underlying PVrc. The relationship between ERAT beyond 4 weeks after PVI and postblanking AT recurrence merits further investigation.

Heme oxygenase-1 is induced in peripheral blood mononuclear cells of patients with acute pancreatitis: a potential therapeutic target.

Heme oxygenase-1 (HO-1) induction by hemin or Panhematin protects against experimental pancreatitis. As a preclinical first step toward determining whether HO-1 upregulation is a viable target in acute pancreatitis (AP) patients, we tested the hypothesis that HO-1 expression in peripheral blood mononuclear cell (PBMC) subsets of hospitalized patients with mild AP is upregulated then normalizes upon recovery and that cells from AP patients have the potential to upregulate their HO-1 ex vivo if exposed to Panhematin. PBMCs were isolated on days 1 and 3 of hospitalization from the blood of 18 AP patients, and PMBC HO-1 levels were compared with PMBCs of 15 hospitalized controls (HC) and 7 volunteer healthy controls (VC). On day 1 of hospitalization, AP patients compared with VCs had higher HO-1 expression in monocytes and neutrophils. Notably, AP monocyte HO-1 levels decreased significantly upon recovery. Panhematin induced HO-1 in ex vivo cultured AP PBMCs more readily than in HC or VC PBMCs. Furthermore, PBMCs from acutely ill AP patients on day 1 were more responsive to HO-1 induction compared with day 3 upon recovery. Similarly, mouse splenocytes had enhanced HO-1 inducibility as their pancreatitis progressed from mild to severe. In conclusion, AP leads to reversible PBMC HO-1 upregulation that is associated with clinical improvement and involves primarily monocytes. Leukocytes from AP patients or mice with AP are primed for HO-1 induction by Panhematin, which suggests that Panhematin could offer a therapeutic benefit.

Examining how personalised care planning can help patients with long-term conditions.

This is the first article in a three-part series on personalised care planning for people with long-term conditions. This first article describes personalised care planning, its benefits for nurses and patients, and how nurses can adopt this approach in healthcare settings. It also examines how Department of Health policies and initiatives can help implementation.

Accuracy and reliability of physical signs in the diagnosis of pleural effusion.

Although pleural effusion is a common disorder among patients presenting with respiratory symptoms, there is limited evidence on the accuracy and reliability of symptoms and signs for the diagnosis of pleural effusion. In our study, conducted at a rural hospital in India, two physicians, blind to history and chest radiograph findings, and to each other's results, independently evaluated 278 patients (196 men), aged 12 and older, admitted with respiratory symptoms. We did a blind and independent comparison of physical signs (asymmetric chest expansion, vocal fremitus, percussion note, breath sounds, crackles, vocal resonance and auscultatory percussion) with the reference standard (chest radiograph). We measured diagnostic accuracy by computing sensitivity, specificity, and likelihood ratios (LRs), and inter-observer reliability by using kappa (kappa) statistic. We performed multivariate analysis to identify the clinical signs that independently predict pleural effusion. The prevalence of pleural effusion was 21% (57/278). The LRs of positive signs ranged from 1.48 to 8.14 and their 95% confidence intervals (CIs) excluded 1. Except for pleural rub, the LRs for negative signs ranged between 0.13 and 0.71. The interobserver agreement was excellent for chest expansion, vocal fremitus, percussion and breath sounds (kappa 0.84-0.89) and good for vocal resonance, crackles and auscultatory percussion (kappa 0.68-0.78). The independent predictors of pleural effusion were asymmetric chest expansion (odds ratio [OR] 5.22, 95% CI 2.06-13.23), and dull percussion note (OR 12.80, 95% CI 4.23-38.70). For the final multivariate model, the area under receiver operating characteristic curve (ROC curve) was 0.88. In conclusion, our data suggest that physical signs may be helpful to rule out but not rule in pleural effusion.

Clinical predictors of in-hospital mortality in patients with snake bite: a retrospective study from a rural hospital in central India.

OBJECTIVE: To determine the association between selected admission risk factors and in-hospital mortality in patients admitted with venomous snake bite to a rural tertiary care hospital in central India. METHODS: Retrospective cohort study of patients aged 12 years or older admitted to a rural hospital in central India between January 2000 and December 2003 with venomous snake bites. The primary endpoint was in-hospital mortality. We used Cox proportional-hazards regression analysis to evaluate the association between risk factors (home-to-hospital distance, bite-to-hospital time, vomiting, neurotoxicity, urine albumin, serum creatinine concentration and whole-blood clotting time) and in-hospital mortality. RESULTS: Two hundred and seventy-seven patients [mean age 32 (SD 12) years; 188 men (68%)] were admitted with venomous snake bite, 29 patients (11%) died. The probability of survival at day 7 was 83%. Vomiting [hazard ratio 6.51 (95% CI 1.94-21.77), P < or = 0.002], neurotoxicity [hazard ratio 3.15 (95% CI 1.45-6.83), P = 0.004] and admission serum creatinine concentration [hazard ratio 1.35 (95% CI 1.17-1.56), P < or = 0.001] were associated with higher risk of death in the adjusted analysis. CONCLUSIONS: In our rural hospital setting, the overall mortality rate was 11 per 100 cases of snake bite. Vomiting, neurotoxicity and serum creatinine are significant predictors of mortality among inpatients with snake bite. These predictors can help clinicians assess prognosis of their patients more accurately and parsimoniously and also serve as useful signposts for clinical decision-making.

Provider assessment of eligibility for hepatitis C treatment in HIV-infected homeless and marginally housed persons.

PURPOSE: To characterize the group of providers delivering medical care to HIV and hepatitis C (HCV) co-infected homeless and marginally housed individuals in San Francisco and to assess factors affecting provider decisions to initiate HCV treatment in this population. SUBJECTS AND METHODS: The Research in Access to Care for the Homeless (REACH) cohort is a representative sample of HIV-infected homeless and marginally housed individuals identified from single room occupancy hotels, homeless shelters and free lunch programs in San Francisco. Primary care providers (PCP) for active, HIV/HCV co-infected REACH cohort participants were administered face-to-face, semi-structured interviews. REACH participants were administered quarterly face-to-face structured interviews. RESULTS: 52/62 (83.9%) providers were interviewed regarding 133/155 (85.8%) active, HIV/HCV co-infected patients. Providers classified 94/133 (70.7%) patients as ineligible for HCV treatment. The mean number of reasons for ineligibility was 3.2. Most frequent reasons for provider determination of ineligibility included likelihood of poor medication adherence, depression, active injection drug use and patient disinterest in treatment. In addition, structural barriers to treatment included poor access to testing, delays in evaluation by a gastroenterologist and exclusion from treatment of patients with comorbidities. CONCLUSIONS: While HCV infection is common, HCV treatment is rare in the HIV/HCV coinfected urban poor. On average, the PCP in this study are experienced and are familiar with this patient population. There are many reasons for providers classifying patients as ineligible for HCV treatment. While these reasons indicate that treatment is difficult given chaotic lifestyle and concurrent medical conditions of this population, they are not insurmountable barriers. New treatments and strategies are necessary to treat this population with high rates of hepatitis C infection.

A commercial line probe assay for the rapid detection of rifampicin resistance in Mycobacterium tuberculosis: a systematic review and meta-analysis.

BACKGROUND: Mycobacterium tuberculosis is a leading cause of death worldwide. In multi-drug resistant tuberculosis (MDR-TB) infectiousness is frequently prolonged, jeopardizing efforts to control TB. The conventional tuberculosis drug susceptibility tests are sensitive and specific, but they are not rapid. The INNO-LiPA Rif. TB (LiPA) is a commercial line probe assay designed to rapidly detect rifampicin resistance, a marker of MDR-TB. Although LiPA has shown promising results, its overall accuracy has not been systematically evaluated. METHODS: We did a systematic review and meta-analysis to evaluate the accuracy of LiPA for the detection of rifampicin-resistant tuberculosis among culture isolates and clinical specimens. We searched Medline, Embase, Web of Science, BIOSIS, and Google Scholar, and contacted authors, experts and the manufacturer. Fifteen studies met our inclusion criteria. Of these, 11 studies used culture isolates, one used clinical specimens, and three used both. We used a summary receiver operating characteristic (SROC) curve and Q* index to perform meta-analysis and summarize diagnostic accuracy. RESULTS: Twelve of 14 studies that applied LiPA to isolates had sensitivity greater than 95%, and 12 of 14 had specificity of 100%. The four studies that applied LiPA directly to clinical specimens had 100% specificity, and sensitivity that ranged between 80% and 100%. The SROC curve had an area of 0.99 and Q* of 0.97. CONCLUSION: LiPA is a highly sensitive and specific test for the detection of rifampicin resistance in culture isolates. The test appears to have relatively lower sensitivity when used directly on clinical specimens. More evidence is needed before LiPA can be used to detect MDR-TB among populations at risk in clinical practice.