Development of a core outcome set for basal cell carcinoma.

BACKGROUND: There is variation in the outcomes reported in clinical studies of basal cell carcinoma. This can prevent effective meta-analyses from answering important clinical questions. OBJECTIVE: To identify a recommended minimum set of core outcomes for basal cell carcinoma clinical trials. METHODS: Patient and professional Delphi process to cull a long list, culminating in a consensus meeting. To be provisionally accepted, outcomes needed to be deemed important (score, 7-9, with 9 being the maximum) by 70% of each stakeholder group. RESULTS: Two hundred thirty-five candidate outcomes identified via a systematic literature review and survey of key stakeholders were reduced to 74 that were rated by 100 health care professionals and patients in 2 Delphi rounds. Twenty-seven outcomes were provisionally accepted. The final core set of 5 agreed-upon outcomes after the consensus meeting included complete response; persistent or serious adverse events; recurrence-free survival; quality of life; and patient satisfaction, including cosmetic outcome. LIMITATIONS: English-speaking patients and professionals rated outcomes extracted from English language studies. CONCLUSION: A core outcome set for basal cell carcinoma has been developed. The use of relevant measures may improve the utility of clinical research and the quality of therapeutic guidance available to clinicians.

Core Outcome Set for Actinic Keratosis Clinical Trials.

Importance: Although various treatments have been found in clinical trials to be effective in treating actinic keratosis (AK), researchers often report different outcomes. Heterogeneous outcome reporting precludes the comparison of results across studies and impedes the synthesis of treatment effectiveness in systematic reviews. Objective: To establish an international core outcome set for all clinical studies on AK treatment using systematic literature review and a Delphi consensus process. Evidence Review: Survey study with a formal consensus process. The keywords actinic keratosis and treatment were searched in PubMed, Embase, CINAHL, and the Cochrane Library to identify English-language studies investigating AK treatments published between January 1, 1980, and July 13, 2015. Physician and patient stakeholders were nominated to participate in Delphi surveys by the Measurement of Priority Outcome Variables in Dermatologic Surgery Steering Committee members. All participants from the first round were invited to participate in the second round. Outcomes reported in randomized controlled clinical trials on AK treatment were rated via web-based e-Delphi consensus surveys. Stakeholders were asked to assess the relative importance of each outcome in 2 Delphi survey rounds. Outcomes were provisionally included, pending the final consensus conference, if at least 70% of patient or physician stakeholders rated the outcome as critically important in 1 or both Delphi rounds and the outcome received a mean score of 7.5 from either stakeholder group. Data analysis was performed from November 5, 2018, to February 27, 2019. Findings: A total of 516 outcomes were identified by reviewing the literature and surveying key stakeholder groups. After deduplication and combination of similar outcomes, 137 of the 516 outcomes were included in the Delphi surveys. Twenty-one physicians and 12 patients participated in round 1 of the eDelphi survey, with 17 physicians (81%) retained and 12 patients (100%) retained in round 2. Of the 137 candidate outcomes, 9 met a priori Delphi consensus criteria, and 6 were included in the final outcomes set after a consensus meeting: complete clearance of AKs, percentage of AKs cleared, severity of adverse events, patient perspective on effectiveness, patient-reported future treatment preference, and recurrence rate. It was recommended that treatment response be assessed at 2 to 4 months and recurrence at 6 to 12 months, with the AK rate of progression to cutaneous squamous cell carcinoma reported whenever long-term follow-up was possible. Conclusions and Relevance: Consensus was reached regarding a core outcome set for AK trials. Further research may help determine the specific outcome measures used to assess each of these outcomes.

Association of glucose homeostasis measures with heart rate variability among Hispanic/Latino adults without diabetes: the Hispanic Community Health Study/Study of Latinos (HCHS/SOL).

BACKGROUND: Reduced heart rate variability (HRV), a measure of cardiac autonomic function, is associated with an increased risk of cardiovascular disease (CVD) and mortality. Glucose homeostasis measures are associated with reduced cardiac autonomic function among those with diabetes, but inconsistent associations have been reported among those without diabetes. This study aimed to examine the association of glucose homeostasis measures with cardiac autonomic function among diverse Hispanic/Latino adults without diabetes. METHODS: The Hispanic community Health Study/Study of Latinos (HCHS/SOL; 2008-2011) used two-stage area probability sampling of households to enroll 16,415 self-identified Hispanics/Latinos aged 18-74 years from four USA communities. Resting, standard 12-lead electrocardiogram recordings were used to estimate the following ultrashort-term measures of HRV: RR interval (RR), standard deviation of all normal to normal RR (SDNN) and root mean square of successive differences in RR intervals (RMSSD). Multivariable regression analysis was used to estimate associations between glucose homeostasis measures with HRV using data from 11,994 adults without diabetes (mean age 39 years; 52 % women). RESULTS: Higher fasting glucose was associated with lower RR, SDNN, and RMSSD. Fasting insulin and the homeostasis model assessment of insulin resistance was negatively associated with RR, SDNN, and RMSSD, and the association was stronger among men compared with women. RMSSD was, on average, 26 % lower in men with higher fasting insulin and 29 % lower in men with lower insulin resistance; for women, the corresponding estimates were smaller at 4 and 9 %, respectively. Higher glycated hemoglobin was associated with lower RR, SDNN, and RMSSD in those with abdominal adiposity, defined by sex-specific cut-points for waist circumference, after adjusting for demographics and medication use. There were no associations between glycated hemoglobin and HRV measures among those without abdominal adiposity. CONCLUSIONS: Impairment in glucose homeostasis was associated with lower HRV in Hispanic/Latino adults without diabetes, most prominently in men and individuals with abdominal adiposity. These results suggest that reduced cardiac autonomic function is associated with metabolic impairments before onset of overt diabetes in certain subgroups, offering clues for the pathophysiologic processes involved as well as opportunity for identification of those at high risk before autonomic control is manifestly impaired.

Major and minor electrocardiographic abnormalities and their association with underlying cardiovascular disease and risk factors in Hispanics/Latinos (from the Hispanic Community Health Study/Study of Latinos).

The association of electrocardiographic (ECG) abnormalities with cardiovascular disease and risk factors has been extensively studied in whites and African-Americans. Comparable data have not been reported in Hispanics/Latinos. The Hispanic Community Health Study/Study of Latinos (HCHS/SOL) is a multicenter, community-based, prospective cohort study of men and women of diverse backgrounds aged 18 to 74 years who self-identified as Hispanic/Latinos. Participants (n = 16,415) enrolled from March 2008 to June 2011. We describe the prevalence of minor and major ECG abnormalities and examined their cross-sectional associations with cardiovascular disease and risk factors. The Minnesota code criteria were used to define minor and major ECG abnormalities. Previous cardiovascular disease and risk factors were based on data obtained at baseline examination. Significant differences in prevalent ECG findings were found between men and women. Major ECG abnormalities were present in 9.2% (95% confidence interval 8.3 to 10.1) of men and 6.6% (95% confidence interval 5.8 to 7.3) of women (p <0.0001). The odds of having major ECG abnormalities significantly increased with age, presence of ≥3 cardiovascular risk factors, and prevalent cardiovascular disease, in both men and women. Significant differences in major ECG abnormalities were found among the varying groups; Puerto Ricans and Dominicans had more major abnormalities compared with Mexican men and women. In conclusion, in a large cohort of Hispanic/Latino men and women, prevalence of major abnormalities was low, yet strong associations of major ECG abnormalities with cardiovascular disease and risk factors were observed in both men and women.

The ladder diagram (a 100+ year history).

The ladder diagram (also called a laddergram) remains a popular visual aid when graphically representing the mechanism of arrhythmia. It disentangles atrial and ventricular electrical activity and gives explicit representation to the sinoatrial and atrioventricular nodes. More than 100 years after the first published ladder diagrams, this report reviews their origins, development, and limitations. Ladderlike diagrams have existed since 1885, first applied to venous and arterial pulsation timing or waveform tracings and later in 1920 alongside electrocardiograms to explain the generation and propagation of electrical impulses in the heart. Two examples are presented in which the underlying mechanism of arrhythmia either was predicted by a ladder diagram and later confirmed by intracardiac recordings (atrioventricular nodal reentrant tachycardia) or underwent evolution of its ladder diagram depiction as the pathophysiology became better understood (atrial flutter). In general, the ladder diagram represents well abnormalities of impulse conduction but is less explicit with abnormalities of impulse formation. In conclusion, the surprising scarcity of major changes since the introduction of the ladder diagram testifies to its power to deal with a range of arrhythmogenic mechanisms that were unknown at the time of its development.

Development and validation of diagnostic criteria for atrial flutter on the surface electrocardiogram.

BACKGROUND: There are no universally accepted ECG diagnostic criteria for atrial flutter (AFL), making its differentiation from "coarse" atrial fibrillation (AF) difficult. METHODS: To develop diagnostic criteria for AFL, we examined two sets of ECGs. Set 1 consisted of 100 ECGs (50 AF, AFL) with diagnoses confirmed by intracardiac recordings. Criteria evaluated were presence of F waves in the frontal plane leads, F waves in V(1), sawtooth F waves, rate, and regularity of ventricular response. Set 2 included 200 ECGs taken from the hospital database each of which had already been interpreted by a cardiologist as either AF (n = 100) or AFL (n = 100). Set 2 was blindly read by electrophysiologists whose consensus-diagnoses were compared to the diagnoses made by using the best criteria identified from the Set 1 data. RESULTS: The criteria of frontal plane F waves, regular or partially regular ventricular response, and their combination had sensitivities of 92%, 98%, and 90% and specificities of 100%, 78%, and 100% in Set 1 for the diagnosis of AFL. In Set 2, concordance of electrophysiologist and cardiologist diagnoses was only 84%. The criteria of frontal plane Fwaves, regular or partially regular ventricular response, and their combination resulted in concordances with the cardiologist diagnoses of 85%, 85%, and 82% and with the electrophysiologist-consensus diagnoses of 90%, 89%, and 94% (P < 0.001). CONCLUSIONS: The criteria of frontal plane F waves and regular or partially regular ventricular response aid in the proper diagnosis of AFL. Because management strategies may differ for AF and AFL, it is important to adopt a more rigorous diagnostic approach.

Neural substrate for atrial fibrillation: implications for targeted parasympathetic blockade in the posterior left atrium.

The parasympathetic (P) nervous system is thought to contribute significantly to focal atrial fibrillation (AF). Thus we hypothesized that P nerve fibers [and related muscarinic (M(2)) receptors] are preferentially located in the posterior left atrium (PLA) and that selective cholinergic blockade in the PLA can be successfully performed to alter vagal AF substrate. The PLA, pulmonary veins (PVs), and left atrial appendage (LAA) from six dogs were immunostained for sympathetic (S) nerves, P nerves, and M(2) receptors. Epicardial electrophysiological mapping was performed in seven additional dogs. The PLA was the most richly innervated, with nerve bundles containing P and S fibers (0.9 +/- 1, 3.2 +/- 2.5, and 0.17 +/- 0.3/cm(2) in the PV, PLA, and LAA, respectively, P < 0.001); nerve bundles were located in fibrofatty tissue as well as in surrounding myocardium. P fibers predominated over S fibers within bundles (P-to-S ratio = 4.4, 7.2, and 5.8 in PV, PLA, and LAA, respectively). M(2) distribution was also most pronounced in the PLA (17.8 +/- 8.3, 14.3 +/- 7.3, and 14.5 +/- 8 M(2)-stained cells/cm(2) in the PLA, PV, and LAA, respectively, P = 0.012). Left cervical vagal stimulation (VS) caused significant effective refractory period shortening in all regions, with easily inducible AF. Topical application of 1% tropicamide to the PLA significantly attenuated VS-induced effective refractory period shortening in the PLA, PV, and LAA and decreased AF inducibility by 92% (P < 0.001). We conclude that 1) P fibers and M(2) receptors are preferentially located in the PLA, suggesting an important role for this region in creation of vagal AF substrate and 2) targeted P blockade in the PLA is feasible and results in attenuation of vagal responses in the entire left atrium and, consequently, a change in AF substrate.

Pseudo Wellens T-waves in patients with suspected myocardial infarction: how cardiac magnetic resonance imaging can help the diagnosis.

Wellens' syndrome is characterized by symmetrically inverted T-waves in the precordial leads suggestive of impending myocardial infarction due to a critical proximal left anterior descending (LAD) stenosis. We describe three unusual cases of patients with such electrocardiographic abnormality in which coronary angiography ruled out the presence of critical coronary stenosis and cardiac magnetic resonance imaging excluded the presence of acute or chronic myocardial infarction.

Criteria for the electrocardiographic diagnosis of atrial flutter improve diagnostic accuracy.

PURPOSE: We previously developed and validated diagnostic criteria for the differentiation of atrial flutter from atrial fibrillation. In this study we examine if the criteria (F waves in the frontal plane and a partially or completely regular ventricular response) can improve the diagnostic accuracy of internists. METHODS: Two groups of 10 internists (1 group given the criteria and 1 not) read a set of electrocardiograms (ECGs) selected from the hospital database with cardiologist-confirmed diagnoses of atrial fibrillation, atrial flutter, or "atrial fibrillation-flutter" (100 each). The final diagnoses of all ECGs were provided by a consensus of electrophysiologists. The criteria also were used to establish the criteria-based diagnoses. RESULTS: Of the 298 ECGs analyzed, the electrophysiologist diagnosis was atrial fibrillation in 71% and atrial flutter in 29%. The concordance of the internists' diagnoses with the electrophysiologist consensus diagnoses was 66+/-12% for those not given the criteria and 81+/-4% (P <.01) for those given the criteria. The concordance of the internists' diagnoses with the criteria based diagnoses was 66+/-12% for those not given the criteria and 83+/-4% (P <.01) for those given the criteria. CONCLUSIONS: The simple criteria of F waves in the frontal plane and a partially or completely regular ventricular response can be used to improve the differentiation of atrial flutter from atrial fibrillation based on the ECG.

Designation and distribution of events in the Multicenter UnSustained Tachycardia Trial (MUSTT).

Patients with coronary artery disease, depressed left ventricular ejection fraction, and nonsustained ventricular tachycardia (VT) have a high mortality rate due to arrhythmic (arrhythmic death/cardiac arrest) and other cardiac causes. The Multicenter UnSustained Tachycardia Trial (MUSTT) investigated whether electrophysiologic study (EPS) was helpful in choosing drug or defibrillator therapy in patients induced into sustained VT. The events committee attempted to categorize follow-up events in patients in MUSTT and to present a detailed breakdown of events. A derivative of the Hinkle-Thaler classification was used, incorporating lessons from other multicenter studies. The committee was blinded to results of EPS and implantable cardioverter-defibrillator (ICD) or other antiarrhythmic therapy status of patients. The primary end point was cardiac arrest or death from arrhythmia. Secondary end points were death from all causes, cardiac causes, and spontaneous sustained VT. Classifications were death and cardiac arrest. Each was similarly divided as arrhythmic with 14 subcategories, e.g., unwitnessed or related to EPS and nonarrhythmic with 10 subcategories, e.g., ischemia. Terminal VF in progressive heart failure was considered nonarrhythmic. Events were reviewed by 2 members. Disagreements were resolved by the 2 members or, if needed, by the full committee. Of the 2,202 patients in MUSTT, there were 902 deaths. Sustained VT requiring cardioversion occurred in 182 patients. An additional 94 patients had resuscitated cardiac arrests. Events occurred in 1,027 patients, and all were reviewed. The 3 leading events were deaths that were classed as sudden/unwitnessed (23% of 902), due to progressive heart failure (22%), or due to noncardiovascular causes (18%). Arrhythmic deaths or cardiac arrests were highest in inducible patients randomized to no antiarrhythmic therapy; next were inducible patients receiving an ICD; and lowest were in patients who were noninducible. In conclusion, the classification system provided a detailed breakdown of events in consistent categories, showing utility for event analysis and interpretation and development of therapeutic strategies. The classifications assigned by the committee were used in all MUSTT outcomes reports, thus affecting all reported outcomes and overall interpretations of the MUSTT.

Major and minor ECG abnormalities in asymptomatic women and risk of cardiovascular events and mortality.

CONTEXT: Data are sparse regarding the prevalence, incidence, and independent prognostic value of minor and/or major electrocardiographic (ECG) abnormalities in asymptomatic postmenopausal women. There is no information on the effect, if any, of hormonal treatment on the prognostic value of the ECG. OBJECTIVE: To examine association of minor and major baseline and incident ECG abnormalities with long-term cardiovascular morbidity and mortality. DESIGN, SETTING, AND PARTICIPANTS: Post-hoc analysis of the estrogen plus progestin component of the Women's Health Initiative study, a randomized controlled primary prevention trial of 14 749 postmenopausal asymptomatic women with intact uterus who received 1 daily tablet containing 0.625 mg of oral conjugated equine estrogen and 2.5 mg of medroxyprogesterone acetate or a matching placebo. Participants were enrolled from 1993 to 1998, and the estrogen plus progestin trial was stopped on July 7, 2002. MAIN OUTCOME MEASURES: The Novacode criteria were used to define minor, major, and incident ECG abnormalities. Cardiovascular end points included incident coronary heart disease (CHD) and cardiovascular disease (CVD) events. RESULTS: Among women with absent (n = 9744), minor (n = 4095), and major (n = 910) ECG abnormalities, there were 118, 91, and 37 incident CHD events, respectively. The incident annual CHD event rates per 10 000 women with absent, minor, or major ECG abnormalities were 21 (95% confidence interval [CI], 18-26), 40 (95% CI, 32-49), and 75 (95% CI, 54-104), respectively. After 3 years of follow-up, 5% of women who had normal ECG at baseline developed new ECG abnormalities with an annual CHD event rate of 85 (95% CI, 44-164) per 10 000 women. The adjusted hazard ratios for CHD events were 1.55 (95% CI, 1.14-2.11) for minor baseline, 3.01 (95% CI, 2.03-4.46) for major baseline, and 2.60 (95% CI, 1.08-6.27) for incident ECG abnormalities. There were no significant interactions between hormone treatment assignment and ECG abnormalities for risk prediction of cardiovascular end points. For prediction of CHD events, the addition of ECG findings to the Framingham risk score increased from 0.69 to 0.74 the area under the receiver operating characteristic curve. Similar findings were found for incident CVD events. CONCLUSIONS: Among asymptomatic postmenopausal women, clinically relevant baseline and incident ECG abnormalities are independently associated with increased risk of cardiovascular events and mortality, and the information is incremental to the established method of risk stratification. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00000611.

Do arrhythmia patients improve survival by participating in randomized clinical trials? Observations from the Cardiac Arrhythmia Suppression Trial (CAST)and the Antiarrhythmics Versus Implantable Defibrillators Trial (AVID).

It is debatable whether patients benefit directly from participation in a randomized clinical trial. We attempt to address this question for participants in the Cardiac Arrhythmia Suppression Trial (CAST) and the Antiarrhythmics Versus Implantable Defibrillators (AVID) studies. Survival rates were compared between eligible patients who enrolled in the trials and eligible patients who did not enroll, adjusting for baseline covariates. In CAST, despite that the active therapy was found to confer an almost threefold increased risk of death, survival was similar between the 3163 enrolled and the 1363 nonenrolled eligible patients. However, when patients were under study management, their risk of death was approximately 20% lower than when they left study management. In AVID, overall survival was similar between the 1016 enrolled and the 1246 nonenrolled eligible patients. However, mortality was substantially higher among patients not enrolled because the referring physician mandated the type of therapy. Overall these observational analyses suggest a net improvement in survival for the participants in these two trials.

Electrocardiografía de señal promediada de la onda P como determinante de riesgo para la fibrilación auricular / The signal averaged P wave: risk of atrial fibrillation

A la fecha el ECGSP de la onda P es todavía un método diagnóstico con costo relativamente alto y limitaciones técnicas. No existen datos objetivos que justifiquen su uso para predecir pacientes con riesgo de fibrilación auricular (FA) paroxística. No obstante, los resultados reportados son promisorios y deben estimular estudios más estandarizados incluyendo un mayor número de pacientes. El hallazgo de un predictor confiable beneficiaría a aquellos pacientes a quienes se les inicia tratamiento antiarrítmico con los conocidos efectos secundarios

Electrocardiografía de señal promediada de la onda P como determinante de riesgo para la fibrilación auricular / The signal averaged P wave: risk of atrial fibrillation

A la fecha el ECGSP de la onda P es todavía un método diagnóstico con costo relativamente alto y limitaciones técnicas. No existen datos objetivos que justifiquen su uso para predecir pacientes con riesgo de fibrilación auricular (FA) paroxística. No obstante, los resultados reportados son promisorios y deben estimular estudios más estandarizados incluyendo un mayor número de pacientes. El hallazgo de un predictor confiable beneficiaría a aquellos pacientes a quienes se les inicia tratamiento antiarrítmico con los conocidos efectos secundarios (AU)