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.

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.

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.

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.

Phase fluctuations and the absence of topological defects in a photo-excited charge-ordered nickelate.

The dynamics of an order parameter's amplitude and phase determines the collective behaviour of novel states emerging in complex materials. Time- and momentum-resolved pump-probe spectroscopy, by virtue of measuring material properties at atomic and electronic time scales out of equilibrium, can decouple entangled degrees of freedom by visualizing their corresponding dynamics in the time domain. Here we combine time-resolved femotosecond optical and resonant X-ray diffraction measurements on charge ordered La(1.75)Sr(0.25)NiO(4) to reveal unforeseen photoinduced phase fluctuations of the charge order parameter. Such fluctuations preserve long-range order without creating topological defects, distinct from thermal phase fluctuations near the critical temperature in equilibrium. Importantly, relaxation of the phase fluctuations is found to be an order of magnitude slower than that of the order parameter's amplitude fluctuations, and thus limits charge order recovery. This new aspect of phase fluctuations provides a more holistic view of the phase's importance in ordering phenomena of quantum matter.

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.

Development of a compact fast CCD camera and resonant soft x-ray scattering endstation for time-resolved pump-probe experiments.

The designs of a compact, fast CCD (cFCCD) camera, together with a resonant soft x-ray scattering endstation, are presented. The cFCCD camera consists of a highly parallel, custom, thick, high-resistivity CCD, readout by a custom 16-channel application specific integrated circuit to reach the maximum readout rate of 200 frames per second. The camera is mounted on a virtual-axis flip stage inside the RSXS chamber. When this flip stage is coupled to a differentially pumped rotary seal, the detector assembly can rotate about 100°/360° in the vertical/horizontal scattering planes. With a six-degrees-of-freedom cryogenic sample goniometer, this endstation has the capability to detect the superlattice reflections from the electronic orderings showing up in the lower hemisphere. The complete system has been tested at the Advanced Light Source, Lawrence Berkeley National Laboratory, and has been used in multiple experiments at the Linac Coherent Light Source, SLAC National Accelerator Laboratory.

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.

A fast, direct x-ray detection charge-coupled device.

A charge-coupled device (CCD) capable of 200 Mpixels/s readout has been designed and fabricated on thick, high-resistivity silicon. The CCDs, up to 600 microm thick, are fully depleted, ensuring good infrared to x-ray detection efficiency, together with a small point spread function. High readout speed, with good analog performance, is obtained by the use of a large number of parallel output ports. A set of companion 16-channel custom readout integrated circuits, capable of 15 bits of dynamic range, is used to read out the CCD. A gate array-controlled back end data acquisition system frames and transfers images, as well as provides the CCD clocks.

Detection of single atoms and buried defects in three dimensions by aberration-corrected electron microscope with 0.5-A information limit.

The ability of electron microscopes to analyze all the atoms in individual nanostructures is limited by lens aberrations. However, recent advances in aberration-correcting electron optics have led to greatly enhanced instrument performance and new techniques of electron microscopy. The development of an ultrastable electron microscope with aberration-correcting optics and a monochromated high-brightness source has significantly improved instrument resolution and contrast. In the present work, we report information transfer beyond 50 pm and show images of single gold atoms with a signal-to-noise ratio as large as 10. The instrument's new capabilities were exploited to detect a buried Sigma3 {112} grain boundary and observe the dynamic arrangements of single atoms and atom pairs with sub-angstrom resolution. These results mark an important step toward meeting the challenge of determining the three-dimensional atomic-scale structure of nanomaterials.

Changes in QT dispersion during adenosine infusion.

BACKGROUND: QT dispersion (QTd) measurement during treadmill stress testing has been to shown to improve the accuracy of exercise electrocardiogram (ECG) in the detection of significant coronary artery disease (CAD). HYPOTHESIS: The aim of this study was to determine whether adenosine-induced changes in QTd could predict significant CAD and to assess its efficacy as a diagnostic index in patients undergoing adenosine stress test. METHODS: QT interval measurements were made in 57 consecutive patients undergoing adenosine sestamibi stress test. Patients with an abnormal stress test underwent coronary angiography. Patients with significant disease by coronary angiography (> 70% stenosis) were classified as having CAD (Group 1), and those with normal stress images and/or normal coronaries by angiography were classified as having no CAD (Group 2). RESULTS: QT dispersion increased from 28.2 +/- 4.5 to 43.8 +/- 4.5 ms with a delta QTd of 15.53 +/- 3.68 in Group 1 (p = 0.001) and from 28.4 +/- 2.6 to 34.8 +/- 2.8 ms with a delta QTd of 6.58 +/- 2.21 ms in Group 2 (p = 0.006). Patients in Group 1 had a significantly higher increase in QTd (delta QTd) than the patients in Group 2 (p < 0.03). Addition of delta QTd (> 10 ms) to the ST depression during adenosine infusion would increase the sensitivity of the ECG from 23 to 65% and decrease the specificity from 91 to 70% for diagnosis of significant CAD. CONCLUSIONS: delta QTd is significantly more prolonged in patients with CAD during adenosine infusion. It increases the sensitivity of the stress ECG in diagnosis of CAD during adenosine infusion when used as an adjuvant index.

Refractory vasospasm with a malignant course.

We present a patient with two rare disorders, recurrent vasospastic angina leading to cardiac transplant and acute aortic occlusion. The patient had recurrent episodes of coronary vasospasm presenting with unstable angina, acute myocardial infarction, and sudden cardiac death in spite of adequate therapy with nitrates and calcium-channel blockers. He went on to have a cardiac transplant. The patient later presented with acute aortic occlusion with concomitant renal and mesenteric artery spasm. The circumstances of the presentation raise the possibility of a generalized vasospastic predisposition that is responsible for both events. Smoking, the only known major risk factor other than atherosclerosis, was noted to be temporally related to both events in our patient.

Results of Stent Supported Percutaneous Transluminal Coronary Angioplasty in Octogenarians With Coronary Artery Disease.

Between January 1995 and July 1998, percutaneous transluminal coronary angioplasty was performed on 27 lesions in 24 octogenarians. Half of the patients were African American. Women comprised 67% of the study group. Patients with unstable angina and myocardial infarction constituted 54% of the cohort. Two-thirds of the patients (83%) had single vessel disease with predominant class A and B lesion complexity of the angioplasty site. Acute success rate was 92%. Stents were successfully placed in 11 subjects (46%). None had acute myocardial infarction, emergency coronary artery bypass surgery, or stroke as a complication of the procedure. One patient presenting with acute myocardial infarction complicated by cardiogenic shock, died. Significant bleeding complications requiring blood transfusions occurred in 17% of patients. Of the patients, 23 (96%) were discharged in a clinically stable condition. Follow up during a two year period was completed in 21 patients (88%). One patient died of cancer. Four subjects (19%) underwent repeat percutaneous transluminal coronary angioplasty. One other patient had recurrent chest pain requiring multiple hospitalizations. The remaining 16 patients (76%) remained free of recurrence of angina. We concluded that percutaneous transluminal coronary angioplasty with stent placement can be performed in octogenarians with a high rate of clinical and angiographic success with an acceptable range of morbidity and mortality, and favorable long term (two year) outcome. (c) 2000 by CVRR, Inc.

Electrocardiographic patterns of patients with echocardiographically determined biventricular hypertrophy.

The numerous criteria proposed for the electrocardiographic (ECG) diagnosis of biventricular hypertrophy (BVH) suffer from inadequate correlative data. We used two-dimensional (2D) echocardiography to identify BVH and analyzed the ECG patterns in these patients. The study group had 69 such patients with BVH and the control group had 22 patients with isolated left ventricular hypertrophy (LVH) demonstrated by 2D echocardiography. The electrocardiograms were analyzed for the presence of established criteria used in the diagnosis of LVH and right ventricular hypertrophy (RVH). Of the 69 patients in the study group, 17 (25%) had ECG findings of BVH, 25 (36%) had LVH, and 14 (20%) had RVH. An S wave in V5/V6 of >7 mm was most the frequent finding in the 17 patients with BVH on the electrocardiogram. The sensitivity of ECG criteria for BVH was 24.6%, specificity was 86.4%, and positive predictive value was 85%. This study reemphasizes the difficulty of ECG diagnosis of BVH. The electrocardiogram has a low sensitivity but satisfactory specificity and positive predictive accuracy for BVH.

Effect of long-term beta-blockade on aortic root compliance in patients with Marfan syndrome.

BACKGROUND: This study was undertaken to assess the effect of long-term beta-blockade on the aortic root stiffness index and distensibility in patients with Marfan syndrome. METHODS: Aortic root stiffness index and distensibility were calculated according to the formulas of Stefanadis and Hirai, respectively, with 2-dimensional guided M-mode echocardiogram before and after an average of 26 months of atenolol administration. RESULTS: Twenty-three asymptomatic patients were studied (11 men and 12 women, aged 31 +/- 14.2 years). The follow-up was 4 +/- 2.2 years. The dose of atenolol was individualized (mean 43.5 +/- 21.6 mg/d). Heart rate decreased from 79 +/- 9 beats/min to 64 +/- 9 beats/min (P =. 01), and systolic blood pressure decreased from 124 +/- 13 mm Hg to 114 +/- 2 mm Hg (P =.01). Distensibility increased from 1.85 +/- 0. 70 x 10(-6) cm2/dynes-1 to 2.21 +/- 0.76 x 10-6 cm2/dynes-1 (P =.02), and the stiffness index decreased from 9.68 +/- 3.78 to 8.85 +/- 3. 15 ( P =.2). Two groups of responses to treatment were identified. Compared with baseline values 15 (65%) patients who responded to treatment had increased distensibility and decreased stiffness index of the aortic root (P =.05). Eight patients (35%) who did not respond to treatment had no significant change. Body weight >91 kg and baseline end-diastolic aortic root diameter >40 mm were significantly associated with no response (P =.05). Two patients in the nonresponding group had echocardiographic progression of aortic insufficiency. CONCLUSIONS: There was a heterogeneous response in the aortic root elastic properties after long-term treatment with atenolol in asymptomatic patients with Marfan syndrome. Stiffness index and distensibility are more likely to respond when the baseline end-diastolic aortic root diameter is <40 mm.

Aortic dissection in a young corticosteroid-treated patient with systemic lupus erythematosus--a case report.

We report a rare case of acute aortic dissection in a young, corticosteroid-treated hypertensive patient with a long-standing history of systemic lupus erythematosus (SLE). A brief review of literature on aortic dissection in lupus erythematosus is presented. A low threshold for performing transesophageal echocardiography in the management of chest pain syndrome in SLE is emphasized.