Development of a core outcome set for cutaneous squamous cell carcinoma trials: identification of core domains and outcomes.

BACKGROUND: The lack of uniformity in the outcomes reported in clinical studies of the treatment of cutaneous squamous cell carcinoma (cSCC) complicates efforts to compare treatment effectiveness across trials. OBJECTIVES: To develop a core outcome set (COS), a minimum set of agreed-upon outcomes to be measured in all clinical trials of a given disease or outcome, for the treatment of cSCC. METHODS: One hundred and nine outcomes were identified via a systematic literature review and interviews with 28 stakeholders. After consolidation of this long list, 55 candidate outcomes were rated by 19 physician and 10 patient stakeholders, in two rounds of Delphi exercises. Outcomes scored 'critically important' (score of 7, 8 or 9) by ≥ 70% of patients and ≥ 70% of physicians were provisionally included. At the consensus meeting, after discussion and voting of 44 international experts and patients, the provisional list was reduced to a final core set, for which consensus was achieved among all meeting participants. RESULTS: A core set of seven outcomes was finalized at the consensus meeting: (i) serious or persistent adverse events, (ii) patient-reported quality of life, (iii) complete response, (iv) partial response, (v) recurrence-free survival, (vi) progression-free survival and (vii) disease-specific survival. CONCLUSIONS: In order to increase the comparability of results across trials and to reduce selective reporting bias, cSCC researchers should consider reporting these core outcomes. Further work needs to be performed to identify the measures that should be reported for each of these outcomes.

Real-time manifestation of strongly coupled spin and charge order parameters in stripe-ordered La(1.75)Sr(0.25)NiO(4) nickelate crystals using time-resolved resonant x-ray diffraction.

We investigate the order parameter dynamics of the stripe-ordered nickelate, La(1.75)Sr(0.25)NiO(4), using time-resolved resonant x-ray diffraction. In spite of distinct spin and charge energy scales, the two order parameters' amplitude dynamics are found to be linked together due to strong coupling. Additionally, the vector nature of the spin sector introduces a longer reorientation time scale which is absent in the charge sector. These findings demonstrate that the correlation linking the symmetry-broken states does not unbind during the nonequilibrium process, and the time scales are not necessarily associated with the characteristic energy scales of individual degrees of freedom.

Femtosecond dynamics of the collinear-to-spiral antiferromagnetic phase transition in CuO.

We report on the ultrafast dynamics of magnetic order in a single crystal of CuO at a temperature of 207 K in response to strong optical excitation using femtosecond resonant x-ray diffraction. In the experiment, a femtosecond laser pulse induces a sudden, nonequilibrium increase in magnetic disorder. After a short delay ranging from 400 fs to 2 ps, we observe changes in the relative intensity of the magnetic ordering diffraction peaks that indicate a shift from a collinear commensurate phase to a spiral incommensurate phase. These results indicate that the ultimate speed for this antiferromagnetic reorientation transition in CuO is limited by the long-wavelength magnetic excitation connecting the two phases.

Probing the out-of-plane distortion of single point defects in atomically thin hexagonal boron nitride at the picometer scale.

Crystalline systems often lower their energy by atom displacements from regular high-symmetry lattice sites. We demonstrate that such symmetry lowering distortions can be visualized by ultrahigh resolution transmission electron microscopy even at single point defects. Experimental investigation of structural distortions at the monovacancy defects in suspended bilayers of hexagonal boron nitride (h-BN) accompanied by first-principles calculations reveals a characteristic charge-induced pm symmetry configuration of boron vacancies. This symmetry breaking is caused by interlayer bond reconstruction across the bilayer h-BN at the negatively charged boron vacancy defects and results in local membrane bending at the defect site. This study confirms that boron vacancies are dominantly present in the h-BN membrane.

The electrophysiological effects of ouabain on sinus node and atrium in man.

Electrophysiological studies were performed in 16 patients before and 30 min after intravenous administration of ouabain (0.1 mg/kg). P-A interval (mean+/-SEM) was 40+/-2.1 ms before and 44+/- 1.5 ms after ouabain (P less than 0.001). Atrial effective and functional refractory periods (ERP and FRP) were measured in all patients during sinus rhythm and during driving at equivalent paced rates in 12 patients. The mean atrial ERP and FRP during sinus rhythm were, respectively, 244+/-10.5 and 307+/-11.0 ms before and 253+/-9.7 and 318+/-11.4 ms after infusion of ouabain (NS). Mean atrial ERP and FRP during driving were, respectively, 231+/-15.3 and 264+/-14.9 ms before and 266+/-18.6 and 296+/-19.7 ms after ouabain (P less than 0.01 and P less than 0.01). Mean sinus cycle length and sinus recovery times were, respectively, 887+/-31.2 and 1,113+/-38.7 ms before and 905+/-38.2 and 1,008+/-30.7 ms after infusion of ouabain (NS and P less than 0.005). Calculated sinoatrial conduction times before and after ouabain were 90+/-6.8 and 110+/-8.5 ms, respectively (P less than 0.005). In summary, ouabain produced depression of intraatrial conduction as manifested by increase in P-A interval and atrial effective and functional refractory periods. Ouabain significantly increased calculated sinoatrial conduction time without significant effect on spontaneous sinus cycle length.

A 5-µm pitch charge-coupled device optimized for resonant inelastic soft X-ray scattering.

We have developed a charge-coupled device (CCD) with 5 µm × 45 µm pixels on high-resistivity silicon. The fully depleted 200 µm-thick silicon detector is back-illuminated through a 10 nm-thick in situ doped polysilicon window and is thus highly efficient for soft through >8 keV hard X-rays. The device described here is a 1.5 megapixel CCD with 2496 × 620 pixels. The pixel and camera geometry was optimized for Resonant Inelastic X-ray Scattering (RIXS) and is particularly advantageous for spectrometers with limited arm lengths. In this article, we describe the device architecture, construction and operation, and its performance during tests at the Advance Light Source (ALS) 8.0.1 RIXS beamline. The improved spectroscopic performance, when compared with a current standard commercial camera, is demonstrated with a ∼280 eV (CK) X-ray beam on a graphite sample. Readout noise is typically 3-6 electrons and the point spread function for soft CK X-rays in the 5 µm direction is 4.0 µm ± 0.2 µm. The measured quantum efficiency of the CCD is greater than 75% in the range from 200 eV to 1 keV.

A direct electron detector for time-resolved MeV electron microscopy.

The introduction of direct electron detectors enabled the structural biology revolution of cryogenic electron microscopy. Direct electron detectors are now expected to have a similarly dramatic impact on time-resolved MeV electron microscopy, particularly by enabling both spatial and temporal jitter correction. Here we report on the commissioning of a direct electron detector for time-resolved MeV electron microscopy. The direct electron detector demonstrated MeV single electron sensitivity and is capable of recording megapixel images at 180 Hz. The detector has a 15-bit dynamic range, better than 30-µm spatial resolution and less than 20 analogue-to-digital converter count RMS pixel noise. The unique capabilities of the direct electron detector and the data analysis required to take advantage of these capabilities are presented. The technical challenges associated with generating and processing large amounts of data are also discussed.

Clinical electrophysiology--a decade of progress.

During the past 14 years there have been major advances in the field of clinical electrophysiology. This progress is a result of a more extensive use of intracardiac electrode catheters with recordings from multiple sites in the right and left cardiac chambers, the introduction of programmed electrical stimulation techniques and the use of antiarrhythmic drugs for diagnostic and therapeutic purposes during acute electrophysiologic testing. This article examines the pioneering studies and the subsequent developments in the field of clinical electrophysiology. The specific topics that are reviewed include the sinus node and atrium, atrioventricular conduction, supraventricular tachycardia and ventricular tachycardia. The therapeutic implications of each topic are also discussed. Clinical electrophysiology in its initial stages was a descriptive technique, but has since become an important diagnostic and therapeutic tool. However, electrophysiologic testing is an intensive process, requiring specialized training and a substantial commitment of human and physical resources.

Tachycardia- and bradycardia-dependent atrioventricular block: observations regarding the mechanism of block.

A case of paroxysmal bradycardia- and tachycardia-dependent atrioventricular (AV) block is described in a patient with right bundle branch block. The His bundle recordings demonstrated the site of the AV block to be distal to the His bundle recording site (probably in the left bundle branch). Whereas AV block distal to the His bundle occurred at an atrial paced cycle length of 700 ms, intact ventriculoatrial (VA) conduction was present up to a ventricular paced cycle length of 400 ms. Resumption of AV conduction was dependent on a critical HH or RH (in case of escapes) interval. These findings suggest that the bradycardia-dependent block is related to a time-dependent decrease in the amplitude of the current intensity of the proximal segment during late diastole. Spontaneous diastolic depolarization during late diastole resulted in impaired anterograde (AV) conduction but facilitated retrograde (VA) conduction. These findings are consistent with experimental "in vitro" observation in the sucrose gap model of AV block.

Short PR interval and narrow QRS complex associated with pheochromocytoma: electrophysiologic observations.

A patient with a short (0.10 second) PR interval, narrow QRS complex and palpitation is described. Electrophysiologic studies demonstrated the presence of accelerated atrioventricular (AV) nodal conduction. Subsequently, a pheochromocytoma was found. Surgical removal of the tumor resulted in normalization of the PR interval. These findings suggest that the short PR interval and the accelerated AV nodal conduction were due to the effect of excess catecholamines on the AV conduction system.

Definition of the best prediction criteria of the time domain signal-averaged electrocardiogram for serious arrhythmic events in the postinfarction period. The Cardiac Arrhythmia Suppression Trial/Signal-Averaged Electrocardiogram (CAST/SAECG) Substudy Investigators.

OBJECTIVES: The goal of this study was to establish guidelines for the prognostic use of the time domain signal-averaged electrocardiogram (ECG) after myocardial infarction. BACKGROUND: Previous studies of the prognostic use of the signal-averaged ECG in postinfarction patients had one or more of the following limitations: a small study group, empiric definition of an abnormal recording and possible bias in the selection of high risk groups or classification of arrhythmic events, or both. To correct for these limitations, a substudy was conducted in conjunction with the Cardiac Arrhythmia Suppression Trial (CAST). METHODS: Ten centers recruited 1,211 patients with acute myocardial infarction without application of the ejection fraction or Holter criteria restrictions of the main CAST protocol. Several clinical variables, ventricular arrhythmias on the Holter recording, ejection fraction and six signal-averaged ECG variables were analyzed. Patients with bundle branch block were excluded from the analysis, and the remaining 1,158 were followed for up to 1 year after infarction. The classification of arrhythmic events was reviewed independently by the CAST Events Committee. RESULTS: During an average (+/- SD) follow-up of 10.3 +/- 3.2 months, 45 patients had a serious arrhythmic event (nonfatal ventricular tachycardia or sudden cardiac arrhythmic death). A Cox regression analysis with only the six signal-averaged ECG variables indicated that the filtered QRS duration at 40 Hz > or = 120 ms (QRSD-40 Hz) at a cutpoint > or = 120 ms was the most predictive criterion of arrhythmic events. In a regression analysis that included all clinical, Holter and ejection fraction variables, a QRSD-40 Hz > or = 120 ms was the most significant predictor (p < 0.0001). The positive, negative and total predictive accuracy and odds ratio for QRSD-40 Hz > or = 120 ms were 17%, 98%, 88% and 8.4, respectively, and improved to 32%, 97%, 94% and 16.7, respectively, after combination with ejection fraction < or = 40% and complex ventricular arrhythmias on the Holter recording. CONCLUSIONS: The signal-averaged ECG predicts serious arrhythmic events in the first year after infarction better than do clinical, ejection fraction and ventricular arrhythmia variables, and QRSD-40 Hz > or = 120 ms provides the best predictive criterion in this clinical setting.

New insights into the definition and meaning of proarrhythmia during initiation of antiarrhythmic drug therapy from the Cardiac Arrhythmia Suppression Trial and its pilot study. The CAST and CAPS Investigators.

OBJECTIVES: This study was undertaken to determine the characteristics of worsening ventricular arrhythmia during antiarrhythmic drug titration. BACKGROUND: Proarrhythmia is an evolving concept in cardiology. Its definition, incidence and clinical significance in various patient settings require refinement. METHODS: The impact of early proarrhythmia was analyzed in 3,840 patients in the Cardiac Arrhythmia Suppression Trial (CAST). RESULTS: Drug therapy did not affect the incidence of new, sustained but nonfatal ventricular tachycardia (placebo 0.5%, active drug 0.4%). Nevertheless, there was a threefold increase in arrhythmic death (placebo 0.5% vs. active drug 1.6%). The incidence of increased ventricular premature depolarizations was equivalent (3% to 5%) for the three study drugs and indistinguishable from that seen with placebo. Patients with increased ventricular premature depolarizations on the first drug tested had fewer at baseline (65 +/- 94 vs. 137 +/- 260 per hour; mean +/- SD) (p < 0.01). When increased ventricular premature depolarizations occurred with the first drug, they were much more likely also to be present with the second drug (for example, 42% vs. 5%, p < 0.001). Increased ventricular premature depolarizations during initiation of therapy independently predicted increased risk of subsequent arrhythmic death (independent relative risk 2.34, p = 0.0053) in the absence of continued antiarrhythmic drug therapy. CONCLUSIONS: The overall incidence of early worsening of arrhythmia in the present study was low. In the absence of placebo control, the incidence of proarrhythmia will be overestimated. Increased ventricular premature depolarizations had characteristics that suggest they often represent spontaneous variability rather than proarrhythmia. The main finding is that markedly increased ventricular premature depolarizations during drug titration predict long-term increased risk of arrhythmic death in this patient population despite absence of long-term antiarrhythmic drug therapy.

Portable electrocardiographic monitoring: performance in patients with short P-R intervals without delta waves.

Twenty-four-hour continuous protable tape-recorded electrocardiograms were obtained in 24 patients with short P-R intervals without delta waves. Atrial premature beats were noted in 15 patients (62%), paroxysmal supraventricular tachycardia (PSVT) in 5 (21%), ventricular premature beats in 14 (58%), and noticeable ventricular arrhythmia in 5 (21%). All episodes of PSVT reflected either unifocal or multifocal atrial ectopic firing. Atrioventricular nodal reentrant PSVT was not observed. Electrocardiographic correlation of symptoms with arrhythmias was not striking. In 21 of the patients, the P-R interval remained short constant through the 24-hour recording period. Patients with a short P-R interval without delta waves have frequent arrhythmias involving multiple areas of the conduction system. The presence of an accessory atrioventricular connection (James tract) would not explain the arrhythmias recorded in these patients.

Clinical predictors of electrophysiologic findings in patients with syncope of unknown origin.

Unexplained syncope is a common medical problem. Intracardiac electrophysiologic studies (EPS) have been used to uncover the underlying arrhythmic mechanisms. Electrophysiologic studies are especially helpful in the management of patients with inducible tachyarrhythmias, but is of limited usefulness in those with normal EPS findings. We investigated whether clinical and noninvasive laboratory variables can predict the results of EPS in 89 patients with unexplained syncope. The prevalence of inducible ventricular tachycardia (VT) was 15%; supraventricular tachycardia, 15%; bradyarrhythmias, 41%; and normal EPS, 29%. We used multivariate discriminant function analysis to predict the results of EPS. The variables selected for identification of patients with inducible VT by this analysis include New York Heart Association (NYHA) functional class, gender, digitalis use, nonsustained VT, and atrial fibrillation. Based on our statistical model, performing EPS on 45% of the patients with unexplained syncope would result in a 90% sensitivity in detecting patients with inducible VT. The variables selected for identification of patients with normal EPS findings include: New York Heart Association functional class, heart disease, digitalis use, and intraventricular conduction. Based on this model, it would require that all but 12% of patients with unexplained syncope be studied to achieve a 90% predictive accuracy for identification of patients with normal EPS. During follow-up, recurrence rates for the different EPS categories did not differ significantly. The five-year cumulative survival among the EPS groups were as follows: VT, 37% +/- 28%; SVT, 90% +/- 9%; bradyarrhythmias, 71% +/- 10%; and normal EPS, 96% +/- 4%. Survival of the VT group differed significantly from that of the normal group. In patients with unexplained syncope, EPS findings can be predicted from clinical and noninvasive laboratory data. Mortality during follow-up relates to EPS findings.

Familial atrial tachyarrhythmia with short PR interval.

A family had an unusual and perhaps unique familial dysrhythmia. The proband had a short PR interval with normal QRS and chronic recurrent paroxysmal atrial tachycardia (Lown-Ganong-Levine syndrome). The arrhythmia produced left ventricular dysfunction. Both paroxysmal atrial tachycardia (PAT) and left ventricular dysfunction were reversed with administration of digoxin and propranolol hydrochloride. Three family members had paroxysmal or chronic atrial fibrillation, first diagnosed at a relatively young age (23 years, 38 years, and early 40s, respectively). Five additional family members had short PR intervals with normal QRS, and eight other family members had borderline short PR intervals. The mode of inheritance appeared to be autosomal dominant with varying expressivity. We have described a familial syndrome characterized by PAT or atrial fibrillation in its advanced form with short PR interval as a possible identifying trait. The future course of members with isolated short PR is unknown.

The automatic implantable cardioverter-defibrillator. Clinical experience, complications, and follow-up in 25 patients.

Twenty-five patients with recurrent ventricular tachyarrhythmias underwent implantation of an automatic implantable cardioverter-defibrillator. The mean length of follow-up was 11.9 +/- 10.8 months. Before the implantation, the patients had survived one or more cardiac arrests (mean, 1.7; range, 1 to 4) and episodes of syncope (mean, 2.2; range, 2 to 3) and had received 6.0 +/- 1.0 antiarrhythmic drug trials. The in-hospital complications included death (two patients), reoperation (one patient), intraoperative myocardial infarction (one patient), sensing-failure (one patient), infection (five patients), and pocket seroma (two patients). The posthospital complications included device failure (four patients), device deactivation (one patient), and inappropriate discharge (two patients). The device discharged appropriately in seven patients due to sustained ventricular tachycardia. During electrophysiologic measurements, the energy requirement for successful cardioversion-defibrillation was related to the type of ventricular arrhythmia induced (monomorphic or pleomorphic ventricular tachycardia or fibrillation). Ventricular tachycardia acceleration occurred in ten patients (40%). No significant changes were found in the size of the electrograms or in the cardioversion threshold during early and late follow-up measurements. Life table analysis showed a 12-month survival rate of 86% and an arrhythmic death survival rate of 100%. We confirm the improved rate of survival in this high-risk group of patients, despite significant complications.

Sudden death in patients with chronic bifascicular block.

Prospective follow-up studies of 277 patients with chronic bifascicular block showed that 30 patients developed sudden cardiac death (SCD). Cumulative one-, two-, and three-year SCD mortality was computed. The patients that developed SCD were compared with the remaining patients (209 alive and 38 dead). The groups were similar in regard to age, sex, AH, and HV intervals. The following were more frequent in the SCD group (P less than .05): angina, previous myocardial infarction, heart failure, cardiomegaly, left bundle-branch block, premature ventricular beats, and ventricular tachycardia. Ventricular fibrillation was the cause of death in four cases of SCD where terminal ECG documentation was available. We concluded that SCD is a major cause of mortality in patients with chronic bifascicular block. The association of SCD with coronary disease and ventricular dysrhythmia suggested ventricular fibrillation as a frequent mechanism.

Analysis of grain boundary dynamics using event detection and cumulative averaging.

To analyze extended time series of high resolution images, we have employed automated frame-by-frame comparisons that are able to detect dynamic changes in the structure of a grain boundary in Au. Using cumulative averaging of images between events allowed high resolution measurements of the atomic relaxation in the interface with sufficient accuracy for comparison with atomistic models. Cumulative averaging was also used to observe the structural rearrangement of atomic columns at a moving step in the grain boundary. The technique of analyzing changing features in high resolution images by averaging between incidents can be used to deconvolute stochastic events that occur at random intervals and on time scales well beyond that accessible to single-shot imaging.

Morphologic characteristics of nonsustained ventricular tachycardia detected during Holter monitoring associated with atherosclerotic coronary artery disease.

Nonsustained ventricular tachycardia (VT) is an important prognostic indicator of outcome in patients with organic heart disease. The morphologic features of nonsustained VT were examined by obtaining a derived 12-lead electrocardiogram (ECGD) from a 24-hour Holter recording in 22 patients with nonsustained VT associated with coronary artery disease. A total of 60 nonsustained VT episodes were recorded. Of these, 20 were uniform and 40 were multiform. The mean rate of uniform episodes was faster (140 +/- 32 vs 124 +/- 16 beats/min; p < 0.01) and the duration longer (5.3 +/- 2.0 vs 4.0 +/- 1.0 beats; p < 0.02) than the multiform episodes. The majority (87%) of multiform episodes had only 2 different QRS configurations on the ECGD. Four distinct patterns of QRS configurations were seen within individual multiform nonsustained VT runs: type I--the initial QRS complex has 1 morphology and all subsequent complexes have another configuration; type II--the initial and terminal QRS complex has similar configuration; type III--the first 2 QRS complexes have similar configuration and all subsequent complexes have another morphology; and type IV--the QRS complexes have alternating morphologic features. These 4 different patterns may be related to the mechanism of nonsustained VT (reentry versus automaticity). Patients with multiple episodes of nonsustained VT frequently had differing patterns and morphologic features between episodes. Further studies are needed to evaluate the clinical importance of these findings.

Determinants of arrhythmogenic ventricular activity detected on the body surface QRS in patients with coronary artery disease.

The prevalence of arrhythmogenic ventricular activity (AVA) was investigated in 166 patients with coronary artery disease. Thirty patients had documented ventricular tachycardia (VT)/ventricular fibrillation (VF). Bipolar X, Y, Z leads were signal-averaged and filtered with a 40-Hz, bidirectional, high-pass digital filter. The filtered QRS signals were analyzed for the amplitude of the last 40 and 50 ms; duration of low-amplitude potentials (less than 40 microV) in the terminal portion; and duration of the filtered QRS. A positive AVA test result was defined as the presence of 2 or more abnormal indexes. Of the 30 patients with VT/VF, 66% had positive AVA test results (AVA-positive patients). Of the 136 patients without VT/VF, 25% had positive AVA test results. The following univariate variables showed significant correlation with an AVA-positive test: age, previous myocardial infarction, previous VT/VF, left ventricular wall motion abnormalities and left ventricular ejection fraction. Multivariate stepwise discriminant function analysis revealed that the presence of previous myocardial infarction and history of sustained VT/VF were the only independent determinants of AVA. During electrophysiologic studies, sustained VT/VF could be induced in 77% of the AVA-positive patients (24 of 31) and in 30% of the AVA-negative patients (3 of 10). The survival probabilities for 6, 12 and 18 months of follow-up were 92%, 85% and 85% for the AVA-positive and 97%, 92% and 90% for the AVA-negative patients. Our findings support the concept that a positive AVA test result reflects areas of delayed ventricular activation. The areas of delayed ventricular activation are associated with previous myocardial injury and scar tissue and serve as an anatomic basis for reentry.(ABSTRACT TRUNCATED AT 250 WORDS)