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Recounts the author's visit to the epidemiologic landmark, the Broad Street Pump, in the British Isles. Information on John Snow; History of the Broad Street Pump; Efforts in locating the landmark.

Background: Surgical safety has advanced rapidly with evidence of improved patient outcomes through structural and process interventions. However, knowledge of how to apply these interventions successfully and sustainably at scale is often lacking. The 2019 Global Ministerial Patient Safety Summit called for a focus on implementation strategies to maintain momentum in patient safety improvements, especially in low- and middle-income settings. This study uses an implementation framework, knowledge to action, to examine a model of nationwide World Health Organization (WHO) Surgical Safety Checklist implementation in Cameroon. Cameroon is a lower-middle-income country, and based on data from high- and low-income countries, we hypothesized that more than 50% of participants would be using the checklist (penetration) in the correct manner (fidelity) 4 months postintervention., Methods: A collaboration of 3 stakeholders (Ministry of Health, academic institution, and nongovernmental organization) used a prospective observational design. Based on knowledge to action, there were 3 phases to the study implementation: problem identification (lack of routine checklist use in Cameroonian hospitals), multifaceted implementation strategy (3-day multidisciplinary training course, coaching, facilitated leadership engagement, and support networks), and outcome evaluation 4 months postintervention. Validated implementation outcomes were assessed. Primary outcomes were checklist use (penetration) and fidelity; secondary outcomes were perioperative teams' reactions, learning and behavior change; and tertiary outcomes were perioperative teams' acceptability of the checklist., Results: Three hundred and fifty-one operating room staff members from 25 hospitals received training. Median time to evaluation was 4.5 months (interquartile range [IQR]: 4.5-5.5, range 3-7); checklist use (penetration) increased from 20% (95% confidence interval [CI], 16-25) to 56% (95% CI, 49-63); fidelity for adherence to 6 basic safety processes was high: verification of patient identification was 91% (95% CI, 87-95); risk assessment for difficult intubation was 79% (95% CI, 73-85): risk assessment for blood loss was 88% (95% CI, 83-93) use of pulse oximetry was 93% (95% CI, 90-97); antibiotic administration was 95% (95% CI, 91-98); surgical counting was 89% (95% CI, 84-93); and fidelity for nontechnical skills measured by the WHO Behaviorally Anchored Rating Scale was 4.5 of 7 (95% CI, 3.5-5.4). Median scores for all secondary outcomes were 10/10, and 7 acceptability measures were consistently more than 70%., Conclusions: This study shows that a multifaceted implementation strategy is associated with successful checklist implementation in a lower-middle-income country such as Cameroon, and suggests that a theoretical framework can be used to practically drive nationwide scale-up of checklist use.

Background: Identification of people with hypertrophic cardiomyopathy (HCM) who are at risk of sudden cardiac death (SCD) and require a prophylactic implantable cardioverter defibrillator is challenging. In 2014, the European Society of Cardiology proposed a new risk stratification method based on a risk prediction model (HCM Risk-SCD) that estimates the 5-year risk of SCD. The aim was to externally validate the 2014 European Society of Cardiology recommendations in a geographically diverse cohort of patients recruited from the United States, Europe, the Middle East, and Asia., Methods: This was an observational, retrospective, longitudinal cohort study., Results: The cohort consisted of 3703 patients. Seventy three (2%) patients reached the SCD end point within 5 years of follow-up (5-year incidence, 2.4% [95% confidence interval {CI}, 1.9-3.0]). The validation study revealed a calibration slope of 1.02 (95% CI, 0.93-1.12), C-index of 0.70 (95% CI, 0.68-0.72), and D-statistic of 1.17 (95% CI, 1.05-1.29). In a complete case analysis (n= 2147; 44 SCD end points at 5 years), patients with a predicted 5-year risk of <4% (n=1524; 71%) had an observed 5-year SCD incidence of 1.4% (95% CI, 0.8-2.2); patients with a predicted risk of ≥6% (n=297; 14%) had an observed SCD incidence of 8.9% (95% CI, 5.96-13.1) at 5 years. For every 13 (297/23) implantable cardioverter defibrillator implantations in patients with an estimated 5-year SCD risk ≥6%, 1 patient can potentially be saved from SCD., Conclusions: This study confirms that the HCM Risk-SCD model provides accurate prognostic information that can be used to target implantable cardioverter defibrillator therapy in patients at the highest risk of SCD., (© 2017 American Heart Association, Inc.)

Cardiomyopathies represent a wide and heterogeneous group of diseases wherein a genetic cause has been consistently identified.Dilated cardiomyopathy (DCM) is characterized by ventricular dilation and progressive systolic dysfunction, and it is the most common form of cardiomyopathy.Causative genetic mutations have been identified in more than 40 genes encoding proteins belonging to different cellular structures and pathways.A great diversity of pathways has been implied in the pathogenesis of DCM, depending on the affected genes and on the dislodged intracellular structures or mechanisms.This review describes the major genes and focus on the pathophysiologic mechanisms of DCM, with a special consideration of the most recent discoveries in the field.

Background: The differential diagnosis of left ventricular (LV) hypertrophy remains challenging in clinical practice, in particular, between hypertrophic cardiomyopathy (HCM) and increased LV wall thickness because of systemic hypertension. Diffuse myocardial disease is a characteristic feature in HCM, and an early manifestation of sarcomere-gene mutations in subexpressed family members (G+P- subjects). This study aimed to investigate whether detecting diffuse myocardial disease by T1 mapping can discriminate between HCM versus hypertensive heart disease as well as to detect genetically driven interstitial changes in the G+P- subjects., Methods and Results: Patients with diagnoses of HCM or hypertension (HCM, n=95; hypertension, n=69) and G+P- subjects (n=23) underwent a clinical cardiovascular magnetic resonance protocol (3 tesla) for cardiac volumes, function, and scar imaging. T1 mapping was performed before and >20 minutes after administration of 0.2 mmol/kg of gadobutrol. Native T1 and extracellular volume fraction were significantly higher in HCM compared with patients with hypertension (P<0.0001), including in subgroup comparisons of HCM subjects without evidence of late gadolinium enhancement, as well as of hypertensive patients LV wall thickness of >15 mm (P<0.0001). Compared with controls, native T1 was significantly higher in G+P- subjects (P<0.0001) and 65% of G+P- subjects had a native T1 value >2 SD above the mean of the normal range. Native T1 was an independent discriminator between HCM and hypertension, over and above extracellular volume fraction, LV wall thickness and indexed LV mass. Native T1 was also useful in separating G+P- subjects from controls., Conclusions: Native T1 may be applied to discriminate between HCM and hypertensive heart disease and detect early changes in G+P- subjects., (© 2015 American Heart Association, Inc.)

Background: A consistent feature of electrophysiological remodeling in heart failure is ventricular action potential duration (APD) prolongation. However, the effect of reverse remodeling on APD during cardiac resynchronization therapy (CRT) has not been determined in these patients. We hypothesized (1) that CRT may alter APD and (2) that the effect of CRT on APD may be different in patients who exhibit a good hemodynamic response to CRT compared with those with a poor response., Methods and Results: Left ventricular (LV) activation recovery intervals, as a surrogate for APD, were measured from the LV epicardium in 13 patients at day 0, 6 weeks, and 6 months after CRT implant. Responders to CRT were defined as those demonstrating a ≥15% reduction in LV end-systolic volume at 6 months. The responder group had a significant reduction in LV activation recovery interval (mean, -13±12 ms; median, -16 ms; interquartile range, -2 to -19 ms) during right ventricular pacing at 6 months (P<0.05). Conversely, the nonresponders showed a significant increase in activation recovery interval (mean, +22 ms±16; median, 17 ms; interquartile range, 8 to 35 ms; P<0.05). One patient in each group was on amiodarone., Conclusions: In patients with heart failure, LV epicardial APD (activation recovery interval) altered during CRT. The effect on APD was opposite in patients showing a good hemodynamic response compared with nonresponders. The findings may provide an explanation for the persistent high incidence of arrhythmias in some patients with CRT and the additional mortality benefit observed in responders of CRT.

Background: Increased systemic inflammation has been linked to myocardial dysfunction and heart failure in patients with systemic lupus erythematosus (SLE). Accurate detection of early myocardial changes may be able to guide preventive intervention. We investigated whether multiparametric imaging by cardiovascular magnetic resonance can detect differences between controls and asymptomatic SLE patients., Methods and Results: A total of 33 SLE predominantly female patients (mean age, 40±9 years) underwent cardiovascular magnetic resonance for routine assessment of myocardial perfusion, function, and late gadolinium enhancement. T1 mapping was performed in single short-axis slice before and after 15 minutes of gadolinium administration. Twenty-one subjects with a low pretest probability and normal cardiovascular magnetic resonance served as a control group. Both groups had similar left ventricular volumes and mass and normal global systolic function. SLE patients had significantly reduced longitudinal strain (controls versus SLE, -20±2% versus -17±3%; P<0.01) and showed intramyocardial and pericardial late gadolinium enhancement. SLE patients had significantly increased native myocardial T1 (1056±27 versus 1152±46 milliseconds; P<0.001) and extracellular volume fraction (26±5% versus 30±6%; P=0.007) and reduced postcontrast myocardial T1 (454±53 versus 411±62 milliseconds; P=0.01). T1-derived indices were associated with longitudinal strain (r=0.37-0.47) but not with the presence of late gadolinium enhancement. Native myocardial T1 values showed the greatest concordance with the presence of clinical diagnosis of SLE., Conclusions: In patients with SLE and free of cardiac symptoms, there is evidence of subclinical perimyocardial impairment. We further demonstrate that T1 mapping may have potential to detect subclinical myocardial involvement in patients with SLE.

Background: Cardiac resynchronization therapy (CRT) using endocardial left ventricular (LV) pacing may be superior to conventional CRT. We studied the acute hemodynamic response to conventional CRT and LV pacing from different endocardial sites using a combined cardiac MRI and LV noncontact mapping (NCM) protocol to gain insights into the underlying mechanisms., Methods and Results: Fifteen patients (age, 63 ± 10 years; 12 men) awaiting CRT were studied in a combined x-ray and MRI laboratory. Delayed-enhancement cardiac magnetic resonance was performed to define areas of myocardial fibrosis. Patients underwent an electrophysiological study incorporating endocardial and epicardial LV pacing. Acute hemodynamic response was measured using a pressure wire within the LV cavity to derive LV dP/dt max. NCM was used to define areas of slow conduction. There was a significant improvement in all LV pacing modes versus baseline (P<0.001). LV endocardial CRT from the best endocardial site was superior to conventional CRT, with a 79.8 ± 49.0% versus 59.6 ± 49.5% increase in LV dP/dt max of from baseline (P<0.05). The hemodynamic benefits of pacing were greater when LV stimulation was performed outside of areas of slow conduction defined by NCM (P<0.001). Delayed-enhancement cardiac magnetic resonance was able to delineate zones of slow conduction seen with NCM in ischemic patients but was unreliable in nonischemic patients., Conclusions: Endocardial LV pacing appears superior to conventional CRT, although the optimal site varies between subjects and is influenced by pacing within areas of slow conduction. Delayed-enhancement cardiac magnetic resonance was a poor predictor of zones of slow conduction in nonischemic patients.

Background: Idiopathic dilated cardiomyopathy is a familial disorder in 25% to 50% of patients, but the genetic basis in the majority of cases remains unknown. Genes encoding desmosomal proteins, currently regarded as synonymous with another disorder, arrhythmogenic right ventricular cardiomyopathy, are known to cause left ventricular dysfunction, but their importance in unselected patients with unequivocal dilated cardiomyopathy is unknown. The objective of this study was to determine the prevalence of mutations in 5 desmosomal protein genes in patients with dilated cardiomyopathy., Methods and Results: We studied 100 unrelated patients with idiopathic dilated cardiomyopathy consecutively referred to a dedicated cardiomyopathy unit. Patients underwent clinical evaluation, ECG, echocardiography, exercise testing, 24-hour ambulatory ECG monitoring, and mutation screening of 5 genes implicated in arrhythmogenic right ventricular cardiomyopathy: plakoglobin, desmoplakin, plakophilin-2, desmoglein-2, and desmocollin-2. Of the 100 patients (mean age at evaluation, 46.8+/-13.8 years; range, 17.0 to 72.8 years; male sex, 63%), 5 were found to carry pathogenic desmosomal protein gene mutations. An additional 13 patients had sequence variants of uncertain pathogenic significance and were excluded from further comparative analysis. Patients harboring desmosomal gene mutations had a phenotype indistinguishable from the 82 noncarriers, with the exception of exercise-induced ventricular ectopy, which was more frequent in the desmosomal mutation carriers (P=0.033). None of the 5 carriers of desmosomal mutations fulfilled current diagnostic criteria for arrhythmogenic right ventricular cardiomyopathy, but 1 had fibrofatty change in the left ventricle at autopsy., Conclusions: Heart failure caused by a dilated, poorly contracting left ventricle and arrhythmogenic right ventricular cardiomyopathy have been considered distinct clinicopathologic entities. This study suggests that both clinical presentations can be caused by mutations in desmosomal protein genes.

We report a mother and son with an interstitial deletion of chromosome 2: del(2)(p21p22.2). Both have mildly dysmorphic facial features and learning difficulties. This phenotype contrasts with two previously described cases with a similar deletion that presented with cyclopia and alobar holoprosencephaly.

This study describes the outcomes of children treated with combinations of temozolomide and radiation therapy for various aggressive central nervous system malignancies. Their age at diagnosis ranged from 1 to 15 years. Patients with focal disease were treated with concomitant temozolomide (daily 75 mg/m) and three-dimensional conformal radiotherapy in a dose that ranged from 50 to 54 Gy, followed by temozolomide (200 mg/m/d x 5 days/month in three patients, 150 mg/m x 5 days/ month in one patient). Patients with disseminated disease were treated with craniospinal radiation (39.6 Gy) before conformal boost. One patient received temozolomide (200 mg/m x 5 days/month) before craniospinal radiation, and one patient received temozolomide (daily 95 mg/m) concomitant with craniospinal radiation and a radiosurgical boost, followed by temozolomide (200 mg/m x 5 days/month). Three patients achieved a partial response during treatment, with two of these patients dying of progressive disease after treatment. One patient has no evidence of disease. Three patients achieved stable disease, with one of these patients dying of progressive disease after treatment. Toxicities observed included low-grade neutropenia, thrombocytopenia, and lymphopenia. The combination of temozolomide and radiotherapy appears to be well tolerated in a variety of treatment schemas for aggressive pediatric central nervous system malignancies. This information is of particular use in designing future studies, given the recent positive results in a randomized study examining the use of temozolomide concomitant with radiation in the treatment of adult glioblastoma.

The two-electrode voltage-clamp technique was used to evaluate the effect of protein kinase C (PKC) activation on ion current flow in Xenopus laevis oocytes injected with cRNA coding for the human vanilloid receptor (VR1). In the presence of 30 nM phorbol-12,13-dibutyrate (PDBu), current evoked by an effective concentration (EC(30)) of capsaicin (CAP) was potentiated by 638+/-117% (n=8). PDBu exhibited an EC(50) of about 17+/-3 nM for this effect (n=8). Potentiation was not observed when VR1 expressing oocytes were exposed to both 30 nM PDBu and 1 microM staurosporine. In the presence of 300 nM PDBu, the EC(50) for CAP shifted from 899+/-78 to 139+/-2 1 nM (n=11 and 5, respectively). In the presence of 30 nM PDBu, the maximal current amplitude evoked by application of CAP increased by 86+/-21% (n=10), in a staurosporine sensitive manner. Application of 1 microM PDBu alone elicited a capsazepine sensitive current within 3 min of exposure. This effect was observed in the absence of previous exposure of the oocyte to CAP and was abolished in the presence of 1 microM staurosporine. No current was elicited during a 10 min application of 300 nM PDBu, the longest interval assessed. Prior to 30 nM PDBu exposure, no current was evoked at temperature ramps from room temperature (22-23 degrees C) up to 37 degrees C at pH 6.8, 7.0, or 7.4. Following PDBu treatment, VR1 mediated current was evoked at 26 degrees C at pH 7.0. Likewise, following 30 nM PDBu treatment, current was evoked by application of pH 6.8 alone and a further increase in current amplitude was evoked by heat at 24 degrees C in a staurosporine sensitive manner. These data provide direct evidence that PKC activation can increase VR1 current evoked by candidate physiological activators, pH and heat. This observation provides an empirical foundation for explaining some types of inflammatory pain in terms of PKC activation, small decreases in tissue pH levels, and small increases in skin temperature, all of which can accompany inflammatory conditions.

Background: The Ross operation has several theoretical advantages. However, concern exists regarding evolving pathology in the pulmonary homograft., Methods and Results: Consecutive patients (n=144; mean age 31 years, range 2 months to 64 years) undergoing the Ross operation were studied between 1993 and 2000. Echocardiographic examination of the pulmonary homograft was performed immediately after surgery, then at yearly intervals for a mean interval of 48 months. Fifteen patients (mean age 37 years) in whom echocardiography revealed peak pulmonary gradients >/=30 mm Hg (mean 46+/-18 mm Hg) underwent MRI with velocity mapping in a Picker 1.5-T magnet. No patient had more than mild pulmonary regurgitation. Four patients required reoperation for rapidly progressive pulmonary homograft stenosis; in all 4, there was macroscopic and microscopic evidence of a pronounced chronic adventitial reaction, with perivascular infiltration producing extrinsic compression. Freedom from any pulmonary homograft stenosis at 7-year follow-up was 79.7%, with instantaneous hazard falling to zero after 4 years. Freedom from reoperation at 7 years was 96.7%. In those studied with MRI, there was evidence of narrowing of the whole homograft or distal suture line in 14 of 15 patients, with obvious excess surrounding tissue in 11. Mean minimum diameter and peak velocity by MRI were 11+/-2 mm and 3.2+/-0.7 m/s, respectively. Multivariate analysis of patient-, surgery-, and homograft-related variables did not reveal any significant risk factors for development of neopulmonary stenosis., Conclusions: Pulmonary homograft stenosis after the Ross operation is clinically important and appears to represent an early postoperative inflammatory reaction to the pulmonary homograft that leads to extrinsic compression and/or shrinkage.

Background: After pulmonary autograft replacement of the aortic valve and root, the pulmonary artery (PA) wall is subjected to higher pressures. Concern exists that this may lead to structural and functional changes in the implanted autograft and subsequent aortic root dilatation and neoaortic regurgitation. We therefore assessed root dimensions and neoaortic regurgitation, morphological structure, and mechanical behavior in patients who underwent the Ross operation., Methods and Results: Seventy-four patients who were randomized to undergo aortic valve replacement with an aortic homograft or a pulmonary autograft were followed up echocardiographically for up to 4 years and had their aortic root dimensions measured at the level of the annulus, sinuses, and sinotubular junction. In a separate series of 18 patients who underwent pulmonary autograft surgery and 8 normal organ donors, samples from the PA and aorta were analyzed for medial wall thickness, distribution of the staining of collagen and elastin, and elastin fragmentation. Finally, stress-strain curves were obtained from samples of the PA and aorta from 9 patients who underwent pulmonary autograft surgery and from 1 patient in whom a 4-month-old autograft was explanted. No patient in either group had aortic dilatation at any level of >20% or more than mild aortic regurgitation at up to 4 years of follow-up. The aortic media was thicker in both autografts and normal donors (P:<0.01), and there was a trend for the PA media to be thicker in the autograft group. Elastic fiber in all aortas showed little or no variation, whereas in the PA, there was considerable variation in fragmentation. Patients with higher preoperative PA pressures tended to have lower fragmentation scores (chi(2) P:<0.01). The lower stiffness modulus, higher stiffness modulus, and maximum tensile strength of the aorta was 34% to 38% higher than that of the PA (P:<0.01); however, the 4-month-old autograft appeared to show adaptation in mechanical behavior., Conclusions: In our series of patients, there was no significant progressive dilatation of the aortic root. We demonstrated differences in the anatomic structure and mechanical behavior of the PA in vitro and highlighted histological and mechanical modes of adaptation.