Patient Care During Ramadan: A Narrative Review.

Ramadan is the Islamic holy month when Muslims around the world fast from dawn to sunset. This 30-day pattern of intermittent diurnal fasting can have a significant physiologic impact on the body. Importantly, oral intake is forbidden during this time, and many patients do not wish to take medications. From a clinical perspective, this potentially impacts healthcare delivery and chronic disease states. Despite these important changes, awareness of individual patient practices remains limited among healthcare providers in North America, which may worsen health disparities in Muslim patients. A fundamental understanding of the cultural and physiological implications of fasting during Ramadan can improve cultural competence and patient outcomes. In this paper, we review the physiologic changes during fasting, medical exemptions to fasting, and special considerations for the care of Muslim patients with chronic conditions who may fast during Ramadan.

Von Willebrand Factor and ADAMTS13 as Predictors of Adverse Outcomes in Patients With Nonvalvular Atrial Fibrillation.

BACKGROUND: Von Willebrand factor (VWF) elevation correlates with the left atrial blood stasis in nonvalvular atrial fibrillation (NVAF). However, the long-term impact of elevated VWF in patients with NVAF is not well established. METHODS: To assess the impact of VWF and a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13) in conjunction with echocardiographic measures of left atrium blood stasis on clinical outcomes, 414 NVAF prospectively recruited (October 4, 2007, to April 27, 2009) patients were followed for 3 years. VWF antigen, VWF activity, ADAMTS13 activity, and echocardiographic findings were assessed at baseline. Thromboembolism (TE) (stroke/transient ischemic attack (TIA)), myocardial infarction, or TE of other locations), major bleeding, clinically relevant nonmajor bleeding, and all-cause mortality were assessed by clinical follow-up, questionnaire, or telephone communication. RESULTS: Among 374 patients (mean age, 63.4 ± 12.7 years; 25% females) who had complete follow-up data, there were 33 TE in 32 patients (8.6%), 18 deaths (5.1%), and 33 bleeding events (21 major bleeding and 12 clinically relevant nonmajor bleeding) in 25 patients (6.7%). VWF antigen was predictive of TE in the univariate examination (hazard ratio [HR]: 1.007, 95% confidence interval [CI]: 1.002, 1.013, P = 0.011) but not in multivariate analysis. VWF was an independent predictor of all-cause mortality (HR: 1.011, 95% CI: 1.003, 1.020, P = 0.011) and a composite of TE and all-cause mortality (HR: 1.006, 95% CI: 1.001, 1.012, P = 0.039) in multivariate analysis. ADAMTS13 was not predictive of clinical outcomes in multivariate analysis. CONCLUSIONS: Among patients with NVAF, VWF is an independent predictor of poor outcomes including death and a composite of death and TE. As such, VWF measure may help identify high-risk patients and provide further stratification beyond CHA2DS2-VASc assessment.

CONTEXTE: Une élévation du facteur de Von Willebrand (FVW) concorde avec une stase sanguine dans l'oreillette gauche dans la fibrillation auriculaire non valvulaire (FANV). Les répercussions à long terme d'un taux élevé du FVW chez les patients présentant une FANV ne sont toutefois pas bien établies. MÉTHODOLOGIE: Pour évaluer les répercussions sur les résultats cliniques du FVW et d'une désintégrine et métalloprotéinase de motif type 1 (ADAMTS13) conjointement avec les mesures échocardiographiques de la stase sanguine dans l'oreillette gauche, 414 patients atteints de FANV ont été inscrits de façon prospective (du 4 octobre 2007 au 27 avril 2009) pour faire l'objet d'un suivi de 3 ans. L'antigène du FVW, l'activité du FVW, l'activité d'ADAMTS13, et les résultats de l'échocardiographie ont été évalués au départ. La thromboembolie (TE) (accident vasculaire cérébral/accident ischémique transitoire, infarctus du myocarde, ou TE survenant ailleurs), l'hémorragie majeure, l'hémorragie non majeure pertinente sur le plan clinique et la mortalité toutes causes ont été évaluées au suivi clinique, par questionnaire, ou lors d'un appel téléphonique. RÉSULTATS: Parmi les 374 patients (âge moyen : 63,4 ± 12,7 ans; 25 % de femmes) ayant participé au suivi jusqu'à sa fin, on a relevé 33 TE chez 32 patients (8,6 %), 18 décès (5,1 %) et 33 événements hémorragiques (21 hémorragies majeures et 12 hémorragies non majeures pertinentes sur le plan clinique) chez 25 patients (6,7 %). L'antigène du FW était prédictif d'une TE selon l'analyse univariée (risque relatif [RR] : 1,007; intervalle de confiance [IC] à 95 % : de 1,002 à 1,013; p = 0,011), mais non selon l'analyse multivariée. Le FVW était un facteur prédictif indépendant de la mortalité toutes causes (RR : 1,011; IC à 95 % : de 1,003 à 1,020; p = 0,011) et des événements regroupés de TE et de mortalité toutes causes (RR : 1,006; IC à 95 % : de 1,001 à 1,012; p = 0,039) dans l'analyse multivariée. La protéase ADAMTS13 ne constituait pas un facteur prédictif des résultats cliniques dans l'analyse multivariée. CONCLUSIONS: Parmi les patients présentant une FANV, le FVW était un facteur prédictif indépendant de résultats défavorables, notamment de décès et des événements regroupant les décès et la TE. La mesure du FVW pourrait donc aider à cibler les patients à risque élevé, et permettre une stratification au-delà de l'évaluation du score CHA2DS2-VASc.

Early Psychological Impact of the COVID-19 Pandemic in Brazil: A National Survey.

BACKGROUND: Isolation measures used to contain epidemics generate social interaction restrictions and impose changes in routines of the public that increase negative psychological outcomes. Anxiety and depression are the most common symptoms. OBJECTIVE: To evaluate the mental health of the Brazilian population during the SARs-CoV-2 pandemic and its relationship with demographic and health characteristics. METHODS: Adults from all Brazilian States participated (n = 12,196; women: 69.8%, mean age = 35.2 years). The Depression, Anxiety and Stress Scale, and the Impact of Event Scale-revised were used (online survey). Data validity and reliability were verified by confirmatory factor analysis and ordinal alpha coefficient. The probability of presenting psychological symptoms was calculated by multiple logistic regression and odds ratio (OR) (0 = without symptoms, 1 = with mild, moderate, and severe levels of symptoms). RESULTS: High prevalence of depression (61.3%), anxiety (44.2%), stress (50.8%), and psychological impact (54.9%) due to the isolation experienced from the pandemic was found. Younger individuals (OR = 1.58-3.58), those that felt unsafe (OR = 1.75-2.92), with a previous diagnosis of mental health (OR = 1.72-2.64) and/or had general health problems before the pandemic (OR = 1.17-1.51), who noticed changes in their mental state due to the pandemic context (OR = 2.53-9.07), and excessively exposed to the news (OR = 1.19-2.18) were at increased risk of developing symptoms. Women (OR = 1.35-1.65) and those with lower economic status (OR = 1.38-2.69) were more likely to develop psychological symptoms. Lower educational levels increased the likelihood of depressive (OR = 1.03-1.34) and intrusive symptoms (OR = 1.09-1.51). Conclusions: The pandemic and related factors can have a high impact on the mental health of the population. Demographic characteristics can influence the occurrence of psychological symptoms.

Calf muscle pump function as a predictor of all-cause mortality.

Calf muscle pump (CMP) promotes venous return from the lower extremity and contributes to preload and cardiac output. Impaired CMP function may reflect a measure of frailty or cumulative disease burden or may impede cardiac function. The study objective was to test the hypothesis that impaired CMP negatively impacts survival. Consecutive adult patients who underwent venous strain gauge plethysmography at the Mayo Clinic Gonda Vascular Laboratory (January 1, 1998 - December 31, 2011) were assessed for overall survival. Patients with venous incompetence, venous obstruction or unilateral calf pump dysfunction were excluded. Risk of mortality was assessed with Cox proportional hazard ratios and after adjusting for Charlson Comorbidity Index variables. Over the study period, 2728 patients were included in the analysis. Compared to patients with normal CMP, those with impaired CMP were older (p < 0.001), predominantly female (p = 0.01) and had higher mean Charlson scores (p < 0.001). Patients with impaired CMP had a higher mortality rate at 5 (8.9% vs 2.4%), 10 (17.5% vs 5.9%), and 15 years (22.8% vs 8.3%) compared to those with normal CMP (p < 0.001 for each comparison). Of patients with heart failure, those with impaired CMP had worse survival at each 5-year increment compared to those with normal CMP (p < 0.05 at each increment). In conclusion, impaired CMP appears to be an independent predictor of poor outcomes after adjusting for variables within the Charlson Comorbidity Index. The association between impaired CMP, heart failure, and mortality may represent a negative impact on circulatory function or a surrogate measure of frailty.

Resolution of acute lower extremity deep vein thrombosis with rivaroxaban compared to warfarin.

Thrombosis resolution is an important component of treatment for deep vein thrombosis (DVT) and multiple anticoagulants are now available. It is unknown whether rivaroxaban contributes to a higher degree of thrombus resolution compared to conventional anticoagulation with warfarin. Our objective was to compare thrombus resolution for rivaroxaban versus warfarin treated patients with acute lower extremity DVT. Consecutive patients treated for proximal or distal lower extremity DVT with rivaroxaban were identified from the Mayo Thrombophilia Clinic Anticoagulants Registry (November 2015-June 2016) and compared to patients treated with warfarin. Ultrasonography/Doppler images were analyzed by two independent radiologists blinded to anticoagulant and using a standardized assessment algorithm. A total of 111 patients with DVT were studied. Sixty-three rivaroxaban treated patients were compared to 48 warfarin treated patients over a median follow up of 92 and 97 days, respectively. Percentage of patients with total or partial resolution of thrombosis was similar in rivaroxaban and warfarin treated groups (95.2% vs. 91.7%, p = 0.46, respectively); also the proportion of patients with total thrombus resolution was not significantly different (38.1% vs. 29.2%, p = 0.42, respectively). There was no significant difference in the proportion of patients with no thrombus resolution between rivaroxaban and warfarin treated groups either (4.8% vs. 2.1%, p = 0.63). Thrombus propagation with warfarin therapy was observed in 6.3% of patients treated with warfarin and in none of the patients from the rivaroxaban group (p = 0.08). Resolution of acute lower extremity DVT in patients treated with rivaroxaban is similar to those treated with warfarin.

Apixaban and Rivaroxaban in Patients With Acute Venous Thromboembolism.

OBJECTIVE: To compare the clinical efficacy and safety of apixaban with those of rivaroxaban for the treatment of acute venous thromboembolism (VTE). PATIENTS AND METHODS: Consecutive patients enrolled in the Mayo Thrombophilia Clinic Registry (between March 1, 2013, and January 30, 2018) and treated with apixaban or rivaroxaban for acute VTE were followed forward in time. The primary efficacy outcome was VTE recurrence. The primary safety outcome was major bleeding; the second safety outcome was clinically relevant nonmajor bleeding (CRNMB); and the third was a composite of major bleeding or CRNMB. RESULTS: Within the group of 1696 patients with VTE enrolled, 600 (38%) were treated either with apixaban (n=302, 50%) or rivaroxaban (n=298, 50%) within the first 14 days of VTE diagnosis and who completed at least 3 months of therapy or had a study event. Recurrent VTE was diagnosed in 7 patients (2.3%) treated with apixaban and in 6 (2%) treated with rivaroxaban (adjusted hazard ratio [aHR], 1.4; 95% CI, 0.5-3.8). Major bleeding occurred in 11 patients (3.6%) receiving apixaban and in 9 patients (3.0%) receiving rivaroxaban (aHR, 1.2; 95% CI, 0.5-3.2). Clinically relevant nonmajor bleeding was diagnosed in 7 patients (2.3%) receiving apixaban and in 20 (6.7%) receiving rivaroxaban (aHR, 0.4; 95% CI, 0.2-0.9). The rates of composite major bleeding or CRNMB were similar (aHR, 0.6; 95% CI, 0.3-1.2). Most study events occurred in patients with cancer. CONCLUSION: In the setting of a standardized, guideline-directed, patient-oriented clinical practice, the efficacy and safety of apixaban and rivaroxaban for the treatment of acute VTE were comparable.

Updates in venous thromboembolism management: evidence published in 2017.

Venous thromboembolism (VTE) management is rapidly evolving and staying up-to-date is challenging. We identified the most practice-informing articles published in 2017 relevant to the nonspecialist provider managing VTE. We performed a systematic search of the literature (Appendix A), limiting the search to a publication date of 2017. Two reviewers screened the 2735 resulting abstracts to identify high-quality, clinically relevant publications related to VTE management. One-hundred and six full-text articles were considered for inclusion. The five authors used a modified Delphi method to reach consensus on inclusion of seven articles for in-depth appraisal, following predetermined criteria of clinical relevance to nonspecialist providers, potential for practice change, and strength of the evidence.

Efficacy and safety of rivaroxaban compared to enoxaparin in treatment of cancer-associated venous thromboembolism.

BACKGROUND: Low molecular weight heparin (LMWH) is the guideline-endorsed treatment for cancer-associated venous thromboembolism (cVTE). Study objectives were to compare the efficacy and safety of rivaroxaban and enoxaparin in cVTE. METHODS: Using a cohort study design, consecutive patients with cVTE (3/1/2013-7/31/2016), enrolled in the Mayo Thrombophilia Clinic Direct Oral Anticoagulants Registry, were compared to contemporary cancer patients receiving enoxaparin. The cumulative incidence of venous thromboembolism (VTE) recurrence, major and clinically relevant non-major bleeding, and survival were assessed at 3 and 12 months. RESULTS: Ninety-eight patients received rivaroxaban (51% female, mean age 63 ± 12 years) and 168 enoxaparin (34.5% female, mean age 62 ± 15 years). The most common cancers included gastrointestinal/pancreatic, genitourinary and hematologic cancers. More than half of patients had pulmonary emboli at presentation. More than half had metastases, and two-thirds were receiving chemotherapy. At 3 months, there were no differences in VTE recurrence (rivaroxaban 1.0% vs enoxaparin 4.2%; P = .15), major bleeding (rivaroxaban 5.1% vs enoxaparin 3.6%; P = .55), or all-cause mortality (rivaroxaban 4.1% vs enoxaparin 8.9%; P = .14). At 12 months, these outcomes did not differ by treatment strategy. CONCLUSION: The results of this "real-world" experience with cVTE suggest that rivaroxaban may offer a safe and effective alternative to LMWH.

Testicular vein thrombosis: Incidence of recurrent venous thromboembolism and survival.

PURPOSE: Testicular vein thrombosis (TVT) etiology, recurrence, and survival were compared with lower extremity deep vein thrombosis (DVT) in order to determine whether treatment guidelines for DVT could be applied to TVT. PATIENTS AND METHODS: An inception cohort of patients with confirmed TVT (January 1995-October 2015) was compared to a control group of patients with lower extremity DVT matched by age, gender, and diagnosis date. RESULTS: Thirty-nine men with TVT were identified; 15 (38%) with isolated TVT. Left testicular vein was affected in 77% patients; there were no cases of bilateral TVT. Cancer was over twofold more common in TVT patients (59% vs 28%, P = .01). Most cancers (78%) involved organs in proximity to the testicular vein. Although TVT patients were less frequently treated with anticoagulants (49% vs 97%, P = .0001), recurrence rates were similar to DVT group (TVT 4.2 vs DVT 1.1 per 100 patient-years, P = .11). Despite higher cancer prevalence, survival rates were similar between groups (31% vs 28%; P = .34). Major bleeding events were rare (one patient per group). CONCLUSIONS: Identifying TVT should prompt a search for a regional malignancy. Despite the high cancer prevalence and low utilization of anticoagulants, recurrent venous thrombosis and mortality rates are similar to DVT patients.

Ovarian Vein Thrombosis: Incidence of Recurrent Venous Thromboembolism and Survival.

OBJECTIVE: To identify the risk of venous thromboembolism recurrence, major bleeding, and mortality in patients with ovarian vein thrombosis so as to better define optimal treatment strategies. METHODS: Patients with ovarian vein thrombosis (1990-2015) and age- and gender-matched patients with contemporary leg deep vein thrombosis (DVT) were assessed for differences in etiology, venous thromboembolism recurrence, and survival in a case-control study. RESULTS: Over the timeframe of this study, only 219 ovarian vein thrombosis cases were identified compared with 13,417 leg DVTs. Median duration of follow-up was 1.23 years (interquartile range 0.25-4.14). Pulmonary embolism was identified at presentation in 6% of patients with ovarian vein thrombosis and 16% of those with DVT (P=.001). Frequent causes of ovarian vein thrombosis included cancer, hormonal stimulation, surgery, and hospitalization. Cancer was twofold more frequent in patients with ovarian vein thrombosis (44% compared with 21%; P<.01). Despite being less frequently treated with anticoagulation (ovarian vein thrombosis 54% compared with DVT 98%, P<.001), venous thromboembolism recurrence rates were similar between groups (ovarian vein thrombosis 2.3 compared with DVT 1.8 per 100 patient-years, P=.49). A personal history of venous thromboembolism and preceding surgery was found to be an independent risk factor for venous thromboembolism recurrence among those treated with anticoagulation (hazard ratio 6.7, P=.04 and hazard ratio 13.6, P=.03, respectively). There was no significant difference in overall survival. CONCLUSION: Ovarian vein thrombosis is a rare thrombotic condition with an incidence 60-fold lower compared with leg DVT in our institution. The striking association with cancer adversely affects overall survival rates in patients with ovarian vein thrombosis. Venous thromboembolism recurrence rates argue for anticoagulation with a direct oral anticoagulant or vitamin K antagonist, particularly in those with a history of venous thromboembolism.

Updates in venous thromboembolism management: evidence published in 2016.

The management of venous thromboembolic disease (VTE) is rapidly evolving and staying updated on practice-changing evidence can be challenging. In an attempt to alleviate this daunting task, we sought to determine the most important practice-informing articles published in 2016 relevant to the non-specialist provider managing VTE. We performed a systematic search of the literature, limiting the search to a publication date of 2016 (see Supplementary Appendix). Two reviewers screened the 3819 resulting abstracts to identify high-quality, clinically relevant publications related to VTE management. Two hundred sixteen full-text articles were considered for inclusion. The five authors used a modified Delphi method to reach consensus on inclusion of 7 articles for in-depth appraisal, following predetermined criteria of clinical relevance to non-specialist providers, potential for practice change, and strength of the evidence.

Periprocedural Management of Chronically Anticoagulated Patients: A Practical Approach to Use of Novel Anticoagulants in Orthopedic Surgery.

Chronic anticoagulation is common in patients undergoing total joint arthroplasty (TJA). The newer novel oral anticoagulants dabigatran, rivaroxaban, and apixaban target individual factors in the clotting cascade (factors Xa, IIa). The stable pharmacokinetics of these medications provide improved efficacy and safety with equivalent or superior antithrombotic properties. There are no management guidelines for these newer anticoagulants in TJA. Understanding the pharmacokinetics, conventional laboratory tests, dosing, and reversal methods that can be used for coagulation hemostasis is crucial for surgeons who are deciding whether to operate now or later.

Effect of Continued Cardiac Resynchronization Therapy on Ventricular Arrhythmias After Left Ventricular Assist Device Implantation.

Cardiac resynchronization therapy (CRT) reduces ventricular arrhythmia (VA) burden in some patients with heart failure, but its effect after left ventricular assist device (LVAD) implantation is unknown. We compared VA burden in patients with CRT devices in situ who underwent LVAD implantation and continued CRT (n = 39) to those who had CRT turned off before discharge (n = 26). Implantable cardioverter-defibrillator (ICD) shocks were significantly reduced in patients with continued CRT (1.5 ± 2.7 shocks per patient vs 5.5 ± 9.3 with CRT off, p = 0.014). There was a nonsignificant reduction in cumulative VA episodes per patient with CRT continued at discharge (42 ± 105 VA per patient vs 82 ± 198 with CRT off, p = 0.29). On-treatment analysis by whether CRT was on or off identified a significantly lower burden of VA (17 ± 1 per patient-year CRT on vs 37 ± 1 per patient-year CRT off, p <0.0001) and ICD shocks (1.2 ± 0.3 per patient-year CRT on vs 1.7 ± 0.3 per patient-year CRT off, p = 0.018). In conclusion, continued CRT is associated with significantly reduced ICD shocks and VA burden after LVAD implantation.

Introducing routine HIV screening for patients on an internal medicine residency inpatient service: a quality improvement project.

The US Centers for Disease Control and Prevention (CDC) recommend human immunodeficiency virus (HIV) screening for all persons aged 13 to 64 years who present to a health care provider. We sought to improve adherence to the CDC guidelines on the Internal Medicine Resident Hospital Service. We surveyed residents about the CDC guidelines, sent email reminders, provided education, and engaged them in friendly competition. Credit for guideline adherence was awarded if an offer of HIV screening was documented at admission, if a screening test was performed, or if a notation in the resident sign out sheet indicated why screening was not performed. We examined HIV screening of a postintervention group of patients admitted between August 8, 2012, and June 30, 2013, and compared them to a preintervention group admitted between August 1, 2011, and June 30, 2012. Postintervention offers of HIV screening increased significantly (7.9% [44/559] vs 55.5% [300/541]; P<.001), as did documentation of residents' contemplation of screening (8.9% [50/559] vs 67.5% [365/541]; P<.001). A significantly higher proportion of HIV screening tests was ordered postintervention (7.7% [43/559] vs 44.4% [240/541]; P<.001). Monthly HIV screening documentation ranged from 0% (0/53) to 17% (9/53) preintervention, whereas it ranged from 30.6% (11/36) to 100% (62/62) postintervention. HIV screening adherence can be improved through resident education, friendly competition, and system reminders. Barriers to achieving sustained adherence to the CDC guidelines include a heterogeneous patient population and provider discomfort with the subject.

Efficacy and Safety of Rivaroxaban in Patients with Venous Thromboembolism and Active Malignancy: A Single-Center Registry.

OBJECTIVE: The purpose of this study is to evaluate the efficacy and safety of rivaroxaban in patients with venous thromboembolism and active malignancy, given the paucity of clinical data with the use of direct Xa inhibitors in this high-risk population. PATIENTS AND METHODS: Consecutive patients treated with rivaroxaban for deep vein thrombosis or pulmonary embolism, enrolled into Mayo Thrombophilia Clinic Direct Oral Anticoagulants Registry between March 1, 2013, and April 30, 2015, were followed prospectively to evaluate the efficacy and safety of this therapy. RESULTS: Of the 404 venous thromboembolism patients in the registry, 296 received rivaroxaban and had at least 3 months of follow-up. Of these, 118 (40%) had active malignancy (51% female, mean age 66 ± 10 years) and 178 had no cancer (47% female, mean age 55 ± 15 years). The 3 most common cancer locations were genitourinary (23.6%), gastrointestinal (20.3%), and lung (13.5%). There was no difference in venous thromboembolism recurrence between the malignant (3.3%) and the nonmalignant (2.8%) venous thromboembolism groups (P = .533). Borderline higher rates for major bleeding (P = .06) and nonmajor clinically relevant bleeding (P = .08) were observed in patients with cancer. CONCLUSIONS: The "real world" effectiveness and safety of rivaroxaban is similar for venous thromboembolism patients with and without active malignancy.

Ia diastolic dysfunction: an echocardiographic grade.

OBJECTIVE: To demonstrate that a distinct group of patients with Grade Ia diastolic dysfunction who do not conform to present ASE/ESE diastolic grading exists. METHOD AND RESULTS: Echocardiographic and demographic data of the Grade Ia diastolic dysfunction were extracted and compared with that of Grades I and II in 515 patients. The mean of age of the cohort was 75 ± 9 years and body mass index did not differ significantly between the 3 groups (P = 0.45). Measurements of left atrial volume index (28.58 ± 7 mL/m(2) in I, 33 ± 10 mL/m(2) in Ia, and 39 ± 12 mL/m(2) in II P < 0.001), isovolumic relaxation time (IVRT) (100 ± 17 msec in I, 103 ± 21 msec in Ia, and 79 ± 15 msec in II P < 0.001), deceleration time (248 ± 52 msec in I, 263 ± 58 msec in Ia, and 217 ± 57 msec in II P < 0.001), medial E/e' (10 ± 3 in I, 18 ± 5.00 in Ia, and 22 ± 8 in II), and lateral E/e' (8 ± 3 in I, 15 ± 6 in Ia, and 18 ± 9 in II P < 0.001) were significantly different in grade Ia compared with I and II. These findings remained significant even after adjusting for age, gender, diabetes, and smoking. CONCLUSION: Patients with echocardiographic characteristics of relaxation abnormality (E/A ratio of <0.8) and elevated filling pressures (septal E/e' ≥15, lateral E/e' ≥12, average E/e' ≥13) should be graded as a separate Grade Ia group.