Novel use of dynamic MR hydrography to rule out esophageal perforation post atrial fibrillation ablation in a patient with anaphylaxis to gadolinium.

Esophageal thermal injury is one of the most devastating complications of atrial radiofrequency ablation, and its diagnosis can be challenging. In this report, we highlight the novel use of free water as a contrast material to better visualize the esophageal lumen in a patient with anaphylaxis to Iodinated contrast media and Gadolinium who recently underwent atrial fibrillation ablation. This becomes particularly handy in patients with contrast allergy, and further emphasizes the role of multimodality imaging.

Cardiovascular Testing in the United States during the COVID-19 Pandemic: Volume Recovery and Worldwide Comparison.

Purpose: To characterize the recovery of diagnostic cardiovascular procedure volumes in U.S. and non-U.S. facilities in the year following the initial COVID-19 outbreak. Materials and Methods: The International Atomic Energy Agency (IAEA) coordinated a worldwide study called the IAEA Noninvasive Cardiology Protocols Study of COVID-19 2 (INCAPS COVID 2), collecting data from 669 facilities in 107 countries, including 93 facilities in 34 U.S. states, to determine the impact of the pandemic on diagnostic cardiovascular procedure volumes. Participants reported volumes for each diagnostic imaging modality used at their facility for March 2019 (baseline), April 2020, and April 2021. This secondary analysis of INCAPS COVID 2 evaluated differences in changes in procedure volume between U.S. and non-U.S. facilities and among U.S. regions. Factors associated with return to prepandemic volumes in the United States were also analyzed in a multivariable regression analysis. Results: Reduction in procedure volumes in April 2020 compared with baseline was similar for U.S. and non-U.S. facilities (-66% vs -71%, P = .27). U.S. facilities reported greater return to baseline in April 2021 than did all non-U.S. facilities (4% vs -6%, P = .008), but there was no evidence of a difference when comparing U.S. facilities with non-U.S. high-income country (NUHIC) facilities (4% vs 0%, P = .18). U.S. regional differences in return to baseline were observed between the Midwest (11%), Northeast (9%), South (1%), and West (-7%, P = .03), but no studied factors were significant predictors of 2021 change from prepandemic baseline. Conclusion: The reductions in cardiac testing during the early pandemic have recovered within a year to prepandemic baselines in the United States and NUHICs, while procedure volumes remain depressed in lower-income countries.Keywords: SPECT, Cardiac, Epidemiology, Angiography, CT Angiography, CT, Echocardiography, SPECT/CT, MR Imaging, Radionuclide Studies, COVID-19, Cardiovascular Imaging, Diagnostic Cardiovascular Procedure, Cardiovascular Disease, Cardiac Testing Supplemental material is available for this article. © RSNA, 2023.

Mitral annular disjunction; how accurate are we? A cardiovascular MRI study defining risk.

Aims: Mitral Annular Disjunction (MAD) refers to embryologic fibrous separation between mitral annular ring and basal left ventricular myocardium. Since its original description, the role of MAD in arrhythmic mitral valve prolapse (MVP) has been the subject of active research. In this study we sought to assess prognostic and imaging characteristics of MVP patients with and without underlying MAD. Methods and results: Patients with posterior or bi-leaflet MVP were retrospectively identified via a review of all patients referred to our cardiac magnetic resonance (CMR) imaging laboratory from January 2015 to May 2022. MVP patients were further stratified by underlying MAD status. A total of 100 MVP patients undergoing CMR imaging (52 MVP patients with posterior MAD) were retrospectively identified with female comprising 55 % of the cohort. MVP patients with MAD were more likely to have an abnormal basal inferolateral/ papillary muscles LGE (51 % vs 21 %, p < 0.01). Posterior MAD longitudinal disjunction gap in 'mm' was a predictor of ventricular tachycardia (VT) [1.29, p = 0.01)]. Using ROC curve analysis, a disjunction gap of ≥ 4 mm was predictive of VT (AUC-0.71, p < 0.01), and incorporation of LGE in ROC model further improved AUC to 0.78 confirmed via Akaike information criterion (p < 0.01). Conclusion: Abnormal LGE involving basal inferolateral myocardium and papillary muscles may provide etiologic substrate for arrythmia in MVP patients.

A target definition based on electroanatomic maps for stereotactic arrhythmia radioablation.

PURPOSE: Identifying the target region is critical for successfully treating ventricular tachycardia (VT) with single fraction stereotactic arrhythmia radioablation (STAR). We report the feasibility of target definition based on direct co-registration of electroanatomic maps (EAM) and radioablation planning images. MATERIALS AND METHODS: The EAM consists of 3D cardiac anatomy representation with electrical activity at endocardium and is acquired by a cardiac electrophysiologist (CEP) during electrophysiology study. The CEP generates an EAM using a 3D cardiac mapping system anticipating radioablation planning. Our in-house software read these non-DICOM EAMs, registered them to a planning image set, and converted them to DICOM structure files. The EAM based target volume was finalized based on a consensus of CEPs, radiation oncologists and medical physicists, then expanded to ITV and PTV. The simulation, planning, and treatment is performed with a standard STAR technique: a single fraction of 25 Gy using volumetric-modulated arc therapy or dynamic conformal arc therapy depending on the target shape. RESULTS: Seven patients with refractory VT were treated by defining the target based on registering EAMs on the planning images. Dice similarity indices between reference map and reference contours after registration were 0.814 ± 0.053 and 0.575 ± 0.199 for LV and LA/RV, respectively. CONCLUSIONS: The quality of the transferred EAMs on the MR/CT images was sufficient to localize the treatment region. Five of 7 patients demonstrated a dramatic reduction in VT events after 6 weeks. Longer follow-up is required to determine the true safety and efficacy of this therapy using EAM-based direct registration method.

Worsening tricuspid regurgitation associated with permanent pacemaker and implantable cardioverter-defibrillator implantation: A systematic review and meta-analysis of more than 66,000 subjects.

BACKGROUND: Worsening tricuspid regurgitation (TR) after either permanent pacemaker (PPM) or implantable cardioverter-defibrillator (ICD) implantation is an emerging clinical challenge. Early recognition of this entity is essential in guiding treatment. OBJECTIVE: This meta-analysis was designed to identify the overall incidence and patient-specific predictors of TR post-device implantation. METHODS: We searched electronic databases from inception to January 2023 for published studies that reported the incidence of TR worsening post-device implantation. The log odds ratio (OR) was used to summarize group differences. RESULTS: Our analysis included 29 studies with 66,590 participants. Patients who underwent device implantation (n = 1008) were significantly more likely to develop worsening TR than controls who did not undergo device implantation (n = 58,605) (OR 3.18; P < .01). In a total of 7777 patients, the pooled incidence of at least 1-grade worsening of TR post-device implantation was 24%. Worsening TR post-device implantation significantly increases mortality (hazard ratio 1.42; P = .02). Larger right atrial area (OR 1.11; P < .01) is significantly associated with an increased risk of worsening TR post-device implantation, while male patients are less likely to develop this complication than female patients (OR 0.74; P < .01). Importantly, there is no statistically significant difference between the type of implanted device (ICD vs PPM) and post-device implantation TR. Further, right ventricular dysfunction, pulmonary artery pressure, baseline mitral regurgitation, left ventricular ejection fraction, baseline atrial fibrillation, and age have no association with worsening TR post-device implantation. CONCLUSION: A substantial number of patients undergoing PPM or ICD implantation are at an increased risk of worsening TR. Importantly, in this largest review to date incorporating more than 66,000 subjects, worsening TR significantly increases mortality by greater than 140%, accordingly deserving more recognition and clinical attention in the current era.

The sine transform is the sine qua non of the pulmonary and systemic pressure relationship.

Assessment of therapeutic interventions in patients with pulmonary arterial hypertension (PAH) suffers from several commonly encountered limitations: (1) patient studies are often too small and short-term to provide definitive conclusions, (2) there is a lack of a universal set of metrics to adequately assess therapy and (3) while clinical treatments focus on management of symptoms, there remain many cases of early loss of life in a seemingly arbitrary distribution. Here we provide a unified approach to assess right and left pressure relationships in PAH and pulmonary hypertension (PH) patients by developing linear models informed by the observation of Suga and Sugawa that pressure generation in the ventricle (right or left) approximately follows a single lobe of a sinusoid. We sought to identify a set of cardiovascular variables that either linearly or via a sine transformation related to systolic pulmonary arterial pressure (PAPs) and systemic systolic blood pressure (SBP). Importantly, both right and left cardiovascular variables are included in each linear model. Using non-invasively obtained cardiovascular magnetic resonance (CMR) image metrics the approach was successfully applied to model PAPs in PAH patients with an r2 of 0.89 (p < 0.05) and SBP with an r2 of 0.74 (p < 0.05). Further, the approach clarified the relationships that exist between PAPs and SBP separately for PAH and PH patients, and these relationships were used to distinguish PAH vs. PH patients with good accuracy (68%, p < 0.05). An important feature of the linear models is that they demonstrate that right and left ventricular conditions interact to generate PAPs and SBP in PAH patients, even in the absence of left-sided disease. The models predicted a theoretical right ventricular pulsatile reserve that in PAH patients was shown to be predictive of the 6 min walk distance (r2 = 0.45, p < 0.05). The linear models indicate a physically plausible mode of interaction between right and left ventricles and provides a means of assessing right and left cardiac status as they relate to PAPs and SBP. The linear models have potential to allow assessment of the detailed physiologic effects of therapy in PAH and PH patients and may thus permit cross-over of knowledge between PH and PAH clinical trials.

Effectiveness of levosimendan and role of cardiac magnetic resonance in cardiogenic shock due to COVID-19 related lymphocytic myocarditis in the course of viral sepsis.

COVID-19 and sepsis pose great challenges to clinicians and growing evidence is demonstrating links between the two conditions. Both can be complicated by acute heart failure. The use of levosimendan in patients with ventricular dysfunction during COVID-19 infection and sepsis has very little evidence. A 46-year-old, hypertensive and obese patient was admitted for severe left ventricular failure and shock during sepsis following a COVID-19 infection. The patient was treated first with norepinephrine, which was partially effective, then with the addition of levosimendan as a continuous 24 hours infusion. Vital signs and echocardiographic systolic performance indices, such as FE, SVi, CI, dP/dT, TAPSE, and tricuspid S-wave velocity, as well as diastolic function, were recorded at access, 12 and 24 hours. After initiation of levosimendan, a rapid improvement in vital signs and systolic and diastolic performance indices was observed, not depending on changes in preload, afterload, and inflammatory status. Blood cultures were negative for the presence of bacteria, thus defining the picture of likely viral sepsis. Cardiac magnetic resonance was determinant, showing a picture of myocarditis sustained by immune processes rather than direct viral injury, which was confirmed by endomyocardial biopsy. In conclusion, this case highlights the efficacy of levosimendan in acute heart failure complicated by shock due to COVID-19-related myocarditis and concomitant sepsis and confirms cardiac magnetic resonance as the gold standard for the diagnosis of myocardial inflammatory disease. To the best of our knowledge, this is the first documented case of effective use of levosimendan in this context.

Prognostic role of pulmonary hemodynamics before transcatheter aortic valve replacement among patients with severe aortic stenosis.

BACKGROUND: Pulmonary hypertension (PH) frequently co-exists in patients with severe aortic stenosis (AS). In this study, we sought to identify the implications of invasive pulmonary hemodynamics on major adverse cardiac events (MACE), biventricular function and NYHA functional class after transcatheter aortic valve replacement (TAVR). METHODS: Invasive hemodynamics via right heart catheterization (RHC) were performed pre-TAVR. Patients were stratified per mean PA pressure (mPAP), diastolic pulmonary gradient (DPG) and pulmonary vascular resistance (PVR), and followed at 1-month and 1-year intervals up to 6 years. MACE outcomes included cardiovascular death and heart failure hospitalizations post-TAVR. RESULTS: Among 215 patients, Kaplan-Meir estimates demonstrated an increased 1-year risk of MACE from 8% among those without pre-TAVR PH to 27% among patients with pre-existing PH. Specifically, the MACE risk was 32% among PH patients with PVR ≥ 3WU (p = .04) and 53% among PH patients with DPG ≥ 7 mm Hg (p < .01). On univariate Cox regression, RV stroke work index (RVSWI) (HR,1.02; p = .02), and pulmonary hemodynamic index (PHI) (HR,1.27; p = .047) were identified as additional predictors of MACE post-TAVR. On multivariable Cox regression analysis, SvO2 (HR, 0.95; p = .01) and PVR (HR, 1.2; p = .04) were demonstrated as predictive of MACE post-TAVR. A significant improvement in LVEF (2-Factor ANOVA, p < .01) and RV fractional area change (RVFAC%) (p < .01) was noted as assessed at baseline, 1-month and 1-year follow up post-TAVR. There was a significant interaction between pre-TAVR PH status and time post procedure with respect to NYHA functional class (p = .03), that is, the manner and degree of change in NYHA class over time depended on pre-TAVR PH status. CONCLUSIONS: Defining invasive pulmonary hemodynamics, such as mPAP, PVR, and DPG among patients with severe AS undergoing TAVR has significant prognostic implications. Routine risk stratification by utilizing invasive hemodynamics can better identify patients who will have functional improvement and improved outcomes post-TAVR.

Left ventricle accessory antero-septal papillary muscle: an echocardiography and cardiac MRI case-series report.

Background. We studied by means of echocardiography and cardiac MRI (CMR) the occurrence of an accessory papillary muscle that unites mostly the left ventricle (LV) apex with the basal antero-septum in the immediate vicinity of left ventricle outflow tract (LVOT) in patients with and without hypertrophic cardiomyopathy (HOCM). Methods. We included all good quality echocardiography and CMR studies as reviewed by two cardiologists and assessed the occurrence of a contractile papillary muscle situated between the LV apex and antero-septum. Results. A contractile accessory papillary muscle situated between the LV apex and the anteroseptum was seen in 100% of HOCM patients and 62% of control patients (p=0.05) in the CMR images acquired from a total of 9 HOCM and 13 control patients. The same structure was observed in 241 patients representing 69.5% of all-comers echocardiography studies. The age was 69 ± 17 years on average in the echocardiography arm, patients harboring the antero-septal accessory muscle being older (71.6 + 15.7 years old vs 63.5 ± 18.1 for those without, p=0.0005). We exemplify this structure by parasternal long axis still echocardiography images and clips from 24 patients and CMR SSFP still images and a clip from two HOCM patients and one control. Conclusion. A contractile accessory papillary muscle was observed in more than half of the all-comer echocardiography studies, and in all HOCM patients in the CMR arm. Further research is needed to fully characterize the anatomical and physiological significance as well as the possible structural interventional consequences of this structure attaching in the immediate vicinity of the LVOT in HOCM and control patients.

Accordion sign in COVID 19 related acute myocarditis, an old sign for a novel context? A cardiac magnetic resonance case series report study.

INTRODUCTION: The COVID-19 pandemic is related to a higher incidence of myocarditis; we present a case series of seven patients, admitted with COVID-19 related acute myocarditis, evaluated with cardiac magnetic resonance imaging, showing an altered profile of the free wall of the right ventricle, no longer present after six months follow-up. MATERIALS AND METHODS: Seven patients have been evaluated for COVID-19 related acute myocarditis, all patients have been evaluated with cardiac magnetic resonance imaging both in the acute setting and after six months follow-up. RESULTS: In the acute phase, myocarditis was confirmed in keeping with the current diagnostic criteria. In five out of seven cases, the presence of a crinkling profile of the free wall of the right ventricle was observed; at six months follow up, remission in four out of the five cases and a significant reduction in the remaining case, of the previously described findings, was observed. CONCLUSIONS: Crinkling appearance in the profile of the free wall of the right ventricle, detectable with cardiac magnetic resonance imaging, might represent a morphological feature present in the acute setting of COVID-19 related myocarditis; several underlying physiopathological mechanisms are conceivable. Further studies are needed to confirm this correlation, define the underlying mechanisms and the prognostic implication related to it. This is the first report in the literature that has considered such findings to the best of our knowledge.

When it's neighbor's fault, a complicated ascending aortic aneurysm mimicking pulmonary embolism: A case report.

Thoracic aortic aneurysms represent a potentially life-threatening disease with increasing prevalence, probably related to the increasing mean age of the global population; the complications of thoracic aortic aneurysms can show multiple modes of presentation in the acute phase based on various factors, including the involvement of the structures with which the aneurysm is in close anatomical relationship. With this case report we want to show how it is possible that a complicated ascending aortic aneurysm can mimic an acute pulmonary embolism/acute cor pulmonale in the acute phase; the earliest possible differential diagnosis between pulmonary embolism and acute aortic disease is of crucial importance due to the opposite implications that the treatment of these two diseases have. .

Tricuspid annular disjunction can be isolated and even arrhythmogenic. A cardiac magnetic resonance study.

Mitral annular disjunction is related to increased arrhythmogenic risk; in a certain percentage of cases, mitral annular disjunction is associated with tricuspid annular disjunction. While the prognostic implications of mitral annular disjunction have been well established, there is still little data to define this aspect regarding the tricuspid annular disjunction. We present a case of a patient admitted for life-threatening ventricular arrhythmias that occurred during endurance sporting activity, who was found to have isolated tricuspid annular disjunction, not associated with mitral annular disjunction. Based on several factors, including the morphology and axis of QRS of the ventricular arrhythmic activity, and its behavior, including the response to antiarrhythmic treatment, and in keeping with the finding of edema and late gadolinium enhancement at the basal segment of the right ventricle free wall on cardiac magnetic resonance imaging, a direct relation between tricuspid annular disjunction and ventricular arrhythmias was highly conceivable. Control after three months showed almost complete remission of the previously described and persistence of LGE at the level of the basal segment of the free wall of the right ventricle, so giving strength to the hypothesis of an event related to increased acute RV free wall stress, secondary to high-intensity physical activity, established on a framework of chronic wall stress, as represented by LGE, similarly to what happens for mitral valve prolapse. To the best of our knowledge, this is the first case of a legitimately conceivable direct relation between tricuspid annular disjunction and ventricular arrhythmias.

Reconsideration of the ECG in pericarditis; have we been led astray all these years?

Recently, new criteria for the diagnosis of pericarditis have been published. This paper has been thought to point out the limits in the new criteria specificity as well in the application of the new criteria for the diagnosis of pericarditis as recently demonstrated by studies based on cardiac magnetic resonance imaging. We report the case of A 18y old male with no significant past medical history who presented with complaints of chest pain typical for pericarditis, initially labeled as pericarditis; the patient was evaluated by electrocardiography, trans-thoracic echocardiography and cardiac magnetic resonance imaging; the condition, based on electrocardiogram and trans-thoracic echocardiography findings, was labeled as pericarditis in keeping with current diagnostic criteria. Cardiac magnetic resonance imaging demonstrated myocardial edema with no T2-defined pericardial inflammation on TIR/T2 imaging; late gadolinium enhancement imaging demonstrated multiple irregular, punctate, epicardial zones. The constellation of findings was consistent with acute myocarditis without pericardial involvement. In conclusion, limits in specificity of the newly published criteria for diagnosis of pericarditis, which add to the already demonstrated limits in sensitivity, subsist. Cardiac magnetic resonance imaging plays a unique role in the initial assessment of pericarditis; this is particularly important in the Covid-19 era in light of the increasing incidence of myocarditis and pericarditis; also, the case suggests that the combination of information between advanced echocardiography and cardiac magnetic resonance imaging may have an important diagnostic role in this setting. Additionally, we suggest that despite recent enthusiasm for colchicine, its role may be best defined in those with myocarditis, not pericarditis.

Estratificação da Insuficiência Cardíaca Clínica através do Mapa T1 Nativo: Experiência de um Serviço de Referência / Clinical Heart Failure Stratification Through Native T1 Mapping: Experience of a Referral Service

Resumo Fundamento: Fibrose cardíaca difusa é fator importante na avaliação prognóstica dos pacientes com disfunção ventricular. Mapeamento T1 nativo pela ressonância magnética cardíaca (RMC) apresenta elevada sensibilidade e é considerado preditor independente de mortalidade por todas as causas e desenvolvimento de insuficiência cardíaca (IC) nos pacientes com cardiomiopatia. Objetivos: Avaliar aplicabilidade da avaliação com mapa T1 nativo em pacientes com IC em um hospital de referência de cardiologia e sua associação com parâmetros estruturais e perfil funcional. Métodos: Estudo transversal com pacientes adultos com IC classes funcionais NYHA I e II, isquêmicos e não isquêmicos, acompanhados em hospital de referência, que realizaram RMC. Os valores de T1 nativo foram analisados em relação a parâmetros estruturais, comorbidades, etiologia e categorização da IC pela fração de ejeção do ventrículo esquerdo (FEVE). Análises foram realizadas com nível de significância de 5%. Resultados: Analisados 134 pacientes. Valores de T1 nativo elevados foram encontrados em pacientes com maior dilatação (1004,9 vs 1042,7ms, p=0,001), volume (1021,3 vs 1050,3ms, p<0,01) e disfunção ventricular (1010,1 vs 1053,4ms, p<0,001), mesmo quando analisados isoladamente os não isquêmicos. Pacientes classificados com IC com fração de ejeção reduzida apresentaram maiores valores T1 em relação aos com IC e fração de ejeção preservada (ICFEP) (992,7 vs 1054,1ms, p<0,001). Dos com ICFEP, 55,2% apresentavam T1 elevado. Conclusões: Mapeamento T1 por RMC é factível para avaliação da IC clínica. Houve associação direta entre maior valor nativo de T1 e menor fração de ejeção, maiores diâmetros e volumes do VE, independentemente da etiologia da IC.

Abstract Background: Diffuse cardiac fibrosis is an important factor in the prognostic assessment of patients with ventricular dysfunction. Cardiovascular magnetic resonance imaging (CMR) native T1 mapping is highly sensitive and considered an independent predictor of all-cause mortality and heart failure (HF) development in patients with cardiomyopathy. Objectives: To evaluate the feasibility of native T1 mapping assessment in patients with HF in a cardiology referral hospital and its association with structural parameters and functional profile. Methods: Cross-sectional study with adult patients with HF NYHA functional classes I and II, ischemic and non-ischemic, followed in a referral hospital, who underwent CMR. Native T1 values were analyzed for structural parameters, comorbidities, etiology, and categorization of HF by left ventricular ejection fraction (LVEF). Analyses were performed with a significance level of 5%. Results: Enrollment of 134 patients. Elevated native T1 values were found in patients with greater dilation (1004.9 vs 1042.7ms, p = 0.001), ventricular volumes (1021.3 vs 1050.3ms, p <0.01) and ventricular dysfunction (1010.1 vs 1053.4ms, p <0.001), also present when the non-ischemic group was analyzed separately. Patients classified as HF with reduced ejection fraction had higher T1 values than those with HF and preserved ejection fraction (HFPEF) (992.7 vs 1054.1ms, p <0.001). Of those with HFPEF, 55.2% had higher T1. Conclusions: CMR T1 mapping is feasible for clinical HF evaluation. There was a direct association between higher native T1 values and lower ejection fraction, and with larger LV diameters and volumes, regardless of the etiology of HF.

Propitious temporal changes in clinical outcomes after transcatheter compared to surgical aortic valve replacement; a meta-analysis of over 65,000 patients.

BACKGROUND: The treatment of symptomatic severe aortic stenosis (AS) has rapidly evolved over the past decade, in both transcatheter (TAVR) and surgical aortic valve replacement (SAVR), resulting in reported improved clinical outcomes. Operator experience and technical improvements have improved outcomes especially for patients undergoing TAVR. We sought to determine and compare 1-year outcomes using a contemporary meta-analysis. METHOD: We searched the Medline (MESH), Cochrane and Google scholar databases using keywords "AS", "atrial fibrillation" (AFib) and "stroke". We performed a meta-analysis to compare TAVR with SAVR populations for post-procedural stroke, all-cause and cardiovascular mortality at 1-year. RESULTS: A total of 23 studies met criteria for analysis with total population of 66,857 patients, of which 61,913 had TAVR and 4944 had SAVR. Temporal trends demonstrated overall improvement in outcome for both, TAVR and SAVR groups through the decade. Outcomes, in terms of stroke (3.1% vs. 5%), all-cause (12.4% vs. 10.3%) and cardiovascular mortality (7.2% vs. 6.2%) were similar at 1-year, in TAVR versus SAVR, respectively. CONCLUSION: Despite overall gradual improvement in both TAVR and SAVR outcomes over the decade, there is a statistical overlap in confidence intervals for all-cause, cardiovascular mortality and postprocedural stroke at 1-year. While 23 individual studies demonstrate considerable advantages of each technique in certain cohorts, integrating over 65,000 pts with our stratified surgical analysis suggests that TAVR is comparable to SAVR for low and intermediate risk population while superior to SAVR only in the highest-risk population for short and intermediate term outcomes. This has substantial socio-economic implications as we contemplate expanding our TAVR indications to low/intermediate risk populations.