Disease Risk Index Research Articles

Roundtable Discussion on Milkfat, Dairy Foods, and Coronary Heart Disease Risk

A group of 12 research scientists participated in a roundtable discussion on the health implications of milkfat in balanced diets. Four subjects areas were addressed: contributions of dairy foods and other fat sources to diets in the United States; influence of individual fatty acids on coronary heart disease risk; dairy foods and coronary heart disease risk; and health implications of low fat diets. The purpose of the meeting was twofold. First, the researchers evaluated the impact of fatty acids, milkfat and dairy foods on coronary heart disease risk, based on currently available evidence. They met this objective by considering statements of "fact" that were accepted, modified or rejected upon discussion. Final statements are presented in this report. Second, the group identified research questions that must be addressed to better define the role of dietary fats (in general) and milkfat (in particular) in varied diets. Critical study design considerations were high-lighted. Participants agreed that standard-fat dairy foods can fit into diets meeting contemporary fat intake guidelines; the guiding principles of balance, variety and moderation were stressed. More research is needed to understand fully the impact on blood lipid profiles (and on other indicators of disease risk) of butter and other sources of milkfat in mixed-fat diets.

The use of prognostic models in allogeneic transplants: a perspective guide for clinicians and investigators

AbstractAllogeneic hematopoietic cell transplant (HCT) can cure many hematologic diseases, but it carries the potential risk of increased morbidity and mortality rates. Prognostic evaluation is a scientific entity at the core of care for potential recipients of HCT. It can improve the decision-making process of transplant vs no transplant, help choose the best transplant strategy and allows for future trials targeting patients’ intolerances to transplant; hence, it ultimately improves transplant outcomes. Prognostic models are key for appropriate actuarial outcome estimates, which have frequently been shown to be better than physicians’ subjective estimates. To make the most accurate prognostic evaluation for HCT, one should rely on >1 prognostic model. For relapse and relapse-related mortality risks, the refined disease risk index is currently the most informative model. It can be supplemented with disease-specific models that consider genetic mutations as predictors in addition to information on measurable residual disease. For nonrelapse mortality and HCT-related morbidity risks, the HCT-comorbidity index and Karnofsky performance status have proven to be the most reliable and most accepted by physicians. These can be supplemented with gait speed as a measure of frailty. Some other global prognostic models might add additional prognostic information. Physicians’ educated perceptions can then put this information into context, taking into consideration conditioning regimen and donor choices. The future of transplant mandates (1) clinical investigators specifically trained in prognostication, (2) increased reliance on geriatric assessment, (3) the use of novel biomarkers such as genetic variants, and (4) the successful application of novel statistical methods such as machine learning.

Stroke Risk Factor Profile in an Urban Population: A Community-Based Descriptive Study in Mojo Sub-District, Surabaya, Indonesia

Highlight: The stroke risk of the urban population in Mojo sub-district, Surabaya, was high (more than 10% risk for 36.3% of the population) . The risk factor for stroke is highly prevalent in Indonesia's urban communities, such as Surabaya. The Indonesian version of the Cardiovascular Disease Risk Index chart aids in determining stroke risk factors. The development of a stroke-spesific index chart has been done before but requires validation for the Indonesian population ABSTRACT Introduction: Stroke is still a major cardiovascular disease in Indonesia. Locally published data regarding stroke risk factors is still rarely reported. This condition complicates the regulation, policy-making, and community empowerment efforts to reduce modifiable stroke risk factors. Thus, a study is necessary to provide an overview of stroke risk factors and risks in cities in Indonesia, such as Surabaya. Objective: This study aimed to describe stroke risk factors in an urban Indonesian community, such as the Mojo sub-district in Surabaya. Methods: This was a descriptive study to describe stroke risk factors like age, gender, history of comorbidities, and history of cardiovascular disease, as well as patient clinical data like neurological symptoms, cardiovascular symptoms, anthropometry, vital signs, simple laboratory values, and cardiovascular risk categorization in the next ten years based on the Cardiovascular Disease Risk Index chart, Indonesian version. Results: In this study, 33 participants were included. Risk factors showed that many participants had histories of active smoking (18.2%), hypertension (45.5%), and diabetes (24.2%). One-third of the participants had a history of dyslipidemia. Based on the risk chart for cardiovascular disease, 36.3% of participants were at >10% risk of developing cardiovascular disease in the next ten years. Conclusion: The risk index of cardiovascular disease in the Mojo sub-district, Surabaya, was still high. A combination of government policies, public awareness improvement, and community empowerment are urgently required to manage these risk factors epidemiologically.

Effects of Static Magnetic Field (SMF) Exposure on Coronary Heart Disease (CHD) Risk Indicators

Dyslipidemia is a condition of abnormalities in blood lipids, such as increased LDL and decreased HDL. Exposure to intracellular static magnetic fields (SMFs) can affect membranes to modulate the number of Ca2+ ions, which can affect cell biological effects. Increasing the number of Ca2+ ions will affect the expression of genes that help reduce LDL levels as an indicator of CHD. This study aims to see whether the influence of SMFs can affect calcium levels, lipid profiles, SREBP-2 protein excretion, and LDLR gene expression, which affects the process of breaking down cholesterol. We used obese C57BL/6J male mice divided into standard and HFD feed groups. The HFD feed group was split into Obes0, Obes2, Obes7, Obes14, and Obes21 groups based on the day of exposure. The exposure was carried out with an intensity of Bmax = 2 mT for 1 h daily. After exposure to SMFs, there were changes in blood cholesterol and LDL levels, which tended to decrease in the Obes2 and Obes7 groups and increase in the Obes14 and Obes21 groups. In addition, the exposed group tended to have an increase in the expression of the LDLR gene, SREBP-2 protein, and calcium ion compared to the control. Although it managed to increase after exposure on days 14 and 21, there was a decrease in the expression of the LDLR gene and SREBP-2 protein; hence, the effect of SMF exposure can reduce the risk of CHD. However, research still needs to be done regarding the effective duration of exposure.

Measures of carbohydrate quality and their association with diet quality and cardiometabolic health outcomes in Singapore middle-aged and older adults

Background and aimsCarbohydrate quality may play a key role in cardiometabolic health and disease risk. This study aimed to assess the dietary carbohydrate quality of the free-living middle-aged and older adults in Singapore, and its association with overall diet quality and cardiometabolic health. Methods and resultsThis cross-sectional study examined the diet and cardiometabolic disease risk indicators of middle-aged and older adults in Singapore (n = 104). Dietary carbohydrate quality was assessed as the pass and fail rate of the population to four measures of carbohydrate quality: (i) dietary fiber recommended daily allowance (RDA), (ii) whole-grain recommendation, (iii) free sugar recommendation, and (iv) carbohydrate metrics. The association between each carbohydrate quality measure and diet quality, as well as cardiometabolic health, was assessed. Except for free sugar recommendation, the carbohydrate quality of the population was found to be poor with a low adherence (20–36%) to three measures. Subjects meeting these measures had generally higher intakes of fiber, protein, and most micronutrients compared with subjects who failed. Meeting different variants of the carbohydrate metrics was associated with 60% lower odds of pre-hypertensive blood pressure (p = 0.037; p = 0.047), and meeting the dietary fiber RDA was associated with lower waist circumference (p = 0.021). ConclusionAn improvement in carbohydrate quality is warranted among free-living middle-aged and older adults in Singapore. Not all measures of carbohydrate quality were equally effective in preserving overall diet quality; the carbohydrate metrics and dietary fiber RDA can be identified as effective measures in relation to cardiometabolic disease risk. Clinical trial registrationhttps://clinicaltrials.gov/ Clinical trial registrationNCT03554954, 13 Sept. 2018.

Adverse childhood experiences are associated with vascular changes in adolescents that are risk factors for future cardiovascular disease

BackgroundAdverse childhood experiences (ACEs), such as abuse, neglect, and household dysfunction, are associated with a higher risk of cardiovascular disease (CVD) and indicators of future CVD risk in adulthood, such as greater vascular stiffness. The impact of ACEs in adolescence is unclear, and understanding how ACEs relate to blood pressure (BP) and vascular function during early life is key for the development of prevention strategies to reduce CVD risk. We hypothesized that exposure to ACEs would be associated with changes in central hemodynamics such as increased vascular stiffness and higher BP during adolescence.MethodsThis pilot study enrolled 86 adolescents recruited from the Children’s of Alabama. A validated ACE questionnaire was employed, and ACEs were modeled both as a continuous variable and a categorical variable (ACE ≥ 1 vs. ACE = 0). The primary outcomes used are considered to be indicators of future cardio-renal disease risk: aortic augmentation index normalized to 75 bpm (Alx75, a surrogate for vascular stiffness), carotid-femoral PWV (m/s), and ambulatory BP patterns.ResultsAdolescents with ACE ≥ 1 had significantly higher Alx75 (ACE: 5.2% ± 2.2 compared to no ACE: − 1.4% ± 3.0; p = 0.043). PWV only reflected this trend when adjustments were made for the body mass index. Adolescents with ACEs showed no differences in ambulatory BP patterns during the 24-h, wake, or sleep periods compared to adolescents with no ACEs.ConclusionsACEs were associated with higher AIx75 in adolescence, which is a risk factor for future CVD. Adolescence could present an opportunity for early detections/interventions to mitigate adverse cardiovascular outcomes in adulthood.Graphical abstractA higher resolution version of the Graphical abstract is available as Supplementary information

GVHD relapse-free survival after peripheral blood hematopoietic cell transplantation for hematologic malignancies.

The preferred choice for hematopoietic cell transplantation (HCT) donors in India is a matched related donor (MRD) followed by a haploidentical (haplo) donor for patients with hematological malignancies. International data in the haplo-HCT setting is mainly using bone marrow as a source. Almost all HCTs in India use peripheral blood stem cells (PBSC), which increases the risk of graft-versus-host disease (GVHD). In this single-center prospective study from 2017 to 2021, we sought to compare these outcomes prospectively in adult patients with hematological malignancies. Patient, disease, donor, and HCT details were prospectively recorded. GVHD prophylaxis included cyclosporine + methotrexate in MRD-HCT and post-transplant cyclophosphamide (PTCy) based in haplo-HCT. The primary endpoint GVHD relapse-free survival (GRFS) was defined as the time post-HCT without any of the following events: grade III-IV acute GVHD, chronic GVHD requiring systemic immunosuppressive treatment, disease relapse, or death from any cause. A total of 41 MRD and 33 haplo-HCT recipients were included in the study. Both cohorts were matched for age, sex, diagnosis, disease risk index, donor age, sex and CMV mismatches, and CD34 counts. A lower proportion of MRD-HCT recipients than haplo-HCT received myeloablative conditioning (39% vs. 76%, p = 0.002). There was no difference in the cumulative incidence of grade III-IV acute GVHD (16% vs. 27%, p = 0.2) or moderate-to-severe chronic GVHD (58% vs. 71%, p = 0.5). The one-year GRFS was not significantly different (53% vs. 38%, p = 0.2), with median GRFS of 420 and 274 days. The relapse incidence (22% vs. 19%, p = 0.6) and non-relapse mortality (25% vs. 35%, p = 0.4) did not differ. There was no difference in overall survival at one year (60% vs. 52%, p = 0.3). Despite a higher proportion of myeloablative conditioning in the haplo-HCT cohort, all outcomes, including GRFS, were comparable to those of the MRD-HCT cohort. This should encourage patients without an MRD to undergo haplo-HCT.

Abstract B121: HLA-mismatched unrelated donor hematopoietic cell transplantation with post-transplant cyclophosphamide improves clinical outcomes for racial and ethnic minority patients with hematologic malignancies

Abstract Introduction: Racial and ethnic disparities exist in three areas related to hematopoietic cell transplantation (HCT): donor availability, access, and post-HCT outcomes. A significant barrier to access to HCT for patients (pts) of racial or ethnic minorities (REM) is the limited availability of fully matched donors (i.e., grafts matched at HLA-A, -B, -C, and -DRB1 loci) in volunteer registries. While mismatched unrelated donor (MMUD) grafts (i.e., <7/8 match) can be offered to pts without matched donors, MMUD HCT results in poor survival when traditional graft-versus-host disease (GVHD) prophylaxis (PPx) is used. GVHD PPx with post-transplantation cyclophosphamide (PTCy) is associated with favorable survival after haploidentical HCT, and promising outcomes have been reported in a prospective multicenter study utilizing PTCy in MMUD HCT. Herein, we analyzed the outcomes of an ethnically diverse cohort of pts who underwent MMUD HCT with PTCy at two large urban transplant centers. Objectives and Methods: Subjects receiving HCT from an MMUD from 2010-to 2020 at the University of Miami and Memorial Sloan-KetteringCancer Center were included. Pts were stratified by age, HCT indication, race/ethnicity, graft type, conditioning intensity, disease status, and degree of HLA mismatch. The primary study endpoint was one-year overall survival (OS). Secondary endpoints were event-free survival (EFS), non-relapse mortality (NRM), and cumulative incidence of acute and chronic GVHD. Results: A total of 82 pts were evaluated. The median age at HCT was 60 years (21-75), the most common indication for HCT was acute leukemia (51%), 41% of pts received an ablative conditioning regimen, and 50% received peripheral blood (PB) grafts. Forty-four percent identified as non-Hispanic white (NHW), and 56% identified as REM (Non-Hispanic Black: 30%; Hispanic: 64%; Asian/Pacific: 4.3%). The two groups (NHW vs. REM) were well-matched for leading HCT indication, disease-risk index, degree of mismatch, and disease status at HCT. REM pts were younger (median age at HCT 65 vs 56 years for NHW, p=0.001) and more likely to receive a PB graft (63% vs 40%, P = 0.04). One-year OS was 75%, EFS was 69%, and NRM was 16% for the entire cohort. Grade 3-4 acute GVHD at day 180 post-HCT was 15%, and one-year severe chronic GVHD was 9%. OS was comparable between 7/8-matched and highly-mismatched (<6/8) HCT recipients (75% vs. 76%, respectively; P >0.9). There were no differences in one-year OS (77% vs 74%, p = 0.9) and EFS (63% vs 72%, p = >0.9) between NHW and REM pts. Similarly, rates of acute (17% vs 13%, p = 0.5) and chronic GVHD (5.7% vs 11%, p = 0.5) were comparable between NHW and REM pts. Conclusion: PTCy resulted in encouraging clinical outcomes following MMUD HCT. Post-HCT OS, RFS, and GVHD rates were comparable between NHW and REM pts and those receiving 7/8 or highly mismatched grafts. Favorable post-HCT outcomes following MMUD with PTCy may increase HCT utilization and access for REM pts. Citation Format: Antonio M. Jimenez Jimenez, Sunil Iyer, Krishna Komanduri, Samantha Brown, Trent Wang, Stephanie Chinapen, Denise Pereira, Sean Devlin, Mark Goodman, Amer Beitinjaneh, Craig Sauter, Lazaros Lekakis, Miguel Angel Perales, Doris Ponce, Brian Shaffer. HLA-mismatched unrelated donor hematopoietic cell transplantation with post-transplant cyclophosphamide improves clinical outcomes for racial and ethnic minority patients with hematologic malignancies [abstract]. In: Proceedings of the 15th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2022 Sep 16-19; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr B121.

TREINAMENTO EM CIRCUITO REDUZ OS FATORES DE RISCO CARDIOMETABÓLICOS EM MULHERES

ABSTRACT Introduction Combined training is more effective than an isolated modality in reducing cardiometabolic risk indicators. Objective To evaluate the effect of circuit training volume on anthropometric and biochemical risk indicators for cardiometabolic diseases in overweight women. Methods Thirty-two participants underwent 24 weeks of circuit training with free weights combined with aerobic exercise. The training volume during the 24 weeks was used to distribute the women into moderate-volume physical activity (MVA), low-volume physical activity (LVA) and control (CON) groups. Anthropometric indices (body mass, body mass index (BMI), waist circumference (WC), waist-hip ratio (WHR)), blood glucose, insulin, insulin resistance (HOMA-IR), total cholesterol (TC), triglycerides, HDL-c, and LDL-c were evaluated at the beginning of the program and after 12 and 24 weeks. Results There was no interaction between training volume and time for any of the variables studied, but the intervention time influenced body mass (p=0.013) and BMI (p=0.012), and there was a tendency for participation time to reduce body mass (p=0.063) and BMI (p=0.062) after six months of intervention. The volume of the physical activity affected HDL-c (p=0.037), being significant (p=0.030) in the comparison between the MVA and CON groups. Additionally, there was a downward trend in HDL-c after six months of intervention (p=0.073), with a smaller reduction observed in the MVA group, indicating a protective role of moderate physical activity in the reduction of this lipid fraction. The association between physical activity volume and participation time resulted in a clinical improvement in total cholesterol (χ2 = 5.453, p = 0.02), with a higher probability of reaching clinically adequate values in the MVA group (OR = 0.126; 95%CI 0.019 - 0.827). Conclusion Training volume improved cardiometabolic risk factors in overweight women. Level of evidence II; Therapeutic Studies - Investigating the Results of Treatment.

The study of electrocardiographic changes in type II diabetes mellitus

Background: The predictions of the silent ischemia in the asymptomatic patients were done with the Electrocardiographic (ECG) abnormalities findings. The high risk of the cardiac morbidity and mortality was statistically associated with abnormal ECG findings. Aims and Objectives: To reduce patient mortality and morbidity, the current analysis was performed on diabetes patients to look for ECG alterations. Materials and Methods: A total of 100 people were used, 50 of whom had type-2 diabetes mellitus and 50 of whom were healthy, non-diabetic volunteers whose ages and sexes matched the patients with type-2 diabetes. The 12-lead ECG instrument was used to record the electrographic markings. For fasting blood sugar blood was collected after a minimum 8 h overnight fasting and for PP2BS blood was collected 2 h after lunch. Results: In people with type II diabetes mellitus, the P wave’s amplitude significantly decreased. When compared to controls, type II diabetics’ QRS complex duration was noticeably longer. When compared to controls, (type II DM) Type 2 diabetes mellitus sufferers had a significantly longer QT and QTC interval. When type II diabetics were compared to controls, the ST segment alterations were significantly different. When compared to controls, type II diabetes showed a considerable T-wave alteration. Conclusion: The ST segment deviation from the isoelectric line is a predictor of coronary events in an asymptomatic diabetic population. The incidence of sudden mortality due to cardiovascular disease in diabetics is reduced as a result of early detection of QT and QTC alterations, which are good indicators of cardiovascular disease risk in diabetics.

Outcomes of Busulfan, Fludarabine, and 400 cGy Total Body Irradiation Compared With Busulfan and Fludarabine Reduced-Intensity Conditioning Regimens for Allogeneic Stem Cell Transplantation in Adult Patients With Hematologic Diseases: A Single-Center Experience

Reduced intensity conditioning (RIC) regimens decrease the risk for nonrelapse mortality (NRM) in adult patients undergoing allogeneic hematopoietic stem cell transplantation for hematologic malignancies but increase the risk for relapse. The aim of this study was to compare the outcomes of fludarabine-total body irradiation (TBI) with fludarabine among patients with hematologic diseases. This retrospective study of 137 patients with different hematologic malignancies compared the outcomes of 63 patients who received a conventional RIC regimen with 2 days of IV busulfan (3.2 mg/kg/d×2 days) and fludarabine with 74 patients who received the same regimen plus 400 cGy of fludarabine and busulfan (FB)-TBI divided in 2 doses over 1 day (200 cGy BID). Median follow-up was 4.62 years. The donors were either HLA-matched siblings (36%) or HLA-matched unrelated donors (64%). The FB-TBI showed trends toward improvement in progression-free survival (PFS) and overall survival (OS) over FB (5-year PFS rates 50% vs 34%, P=.06, and 5-year OS rate 53% vs 39%, P=.13). Acute graft-vs-host disease (aGVHD), relapse, and NRM were similar between the 2 groups. The 5-year cumulative incidence of chronic GVHD (cGVHD) was lower in the FB-TBI group compared with the FB group (29% vs 52%, P=.003). Multivariable analysis revealed that grade III-IV aGVHD was the only independent risk factor for worse OS (P=.001) in both groups. A high disease risk index was possibly associated with inferior OS (P=.07) in both groups. The FB-TBI is a safe and effective intensified RIC regimen for adult patients with hematologic malignancies. It predicted a lower risk for cGVHD and showed possibly improved PFS and OS compared with FB.

THE COMPARISON OF DUAL TASK TIME AMONG APOE CARRIERS AGAINST NON-APOE CARRIERS IN AGING ADULTS

Abstract No single variable has been identified as the sole factor for predicting an individuals’ declining health status. In order to predict mental or physical decline in older adults, researchers have designed tasks that include both a physical and mental or cognitive demand known as dual task (DT). The purpose of implementing dual task is to assess the possible changes in accuracy when a second task gets compounded with a given single task. Our study consists of males and females aged from 45 to 75 years who have risk factors for dementia. Each subject was randomly assigned to either a health coaching (HC), or health education (HE) control group. The HC group received coaching to address the lifestyle areas known to be linked to AD risk, such as diet, exercise, sleep, stress, cognitive training, and social interaction. Blood markers of each individual have been assessed to determine carrier status of Apolipoprotein E 4 (APOE4) due to the correlation between the allele and increased risk of Alzheimer’s. To be included in the study, the participants must have at least 2 positive risk factors for AD as determined by the Australian National University-Alzheimer Disease Risk Index (ANU-ADRI). Among non-APOE carriers, a 2x3 (group x time) mixed ANOVA revealed a significant interaction effect wherein the HC group improved DTC score more than the HE group from time 1 to time 3, F (2, 362) =1.253, P=0.017. No significant interaction was noted for APOE carriers.

Blood metabolite profiles linking dietary patterns with health-Toward precision nutrition.

Diet is one of the most important exposures that may affect health throughout life span. Investigations on dietary patterns rather than single food components are gaining in popularity because they take the complexity of the whole dietary context into account. Adherence to such dietary patterns can be measured by using metabolomics, which allows measurements of thousands of molecules simultaneously. Derived metabolite signatures of dietary patterns may reflect the consumption of specific groups of foods or their constituents originating from the dietary pattern per se, or the physiological response toward the food-derived metabolites, their interaction with endogenous metabolism, and exogenous factors such as gut microbiota. Here, we review and discuss blood metabolite fingerprints of healthy dietary patterns. The plasma concentration of several food-derived metabolites-such as betaines from whole grains and n-3 polyunsaturated fatty acids and furan fatty acids from fish-seems to consistently reflect the intake of common foods of several healthy dietary patterns. The metabolites reflecting shared features of different healthy food indices form biomarker panels for which specific, targeted assays could be developed. The specificity of such biomarker panels would need to be validated, and proof-of-concept feeding trials are needed to evaluate to what extent the panels may mediate the effects of dietary patterns on disease risk indicators or if they are merely food intake biomarkers. Metabolites mediating health effects may represent novel targets for precision prevention strategies of clinical relevance to be verified in future studies.

Post-Transplant Cyclophosphamide, Tacrolimus, and Mycophenolate Mofetil As the New Standard for Graft-Versus-Host Disease (GVHD) Prophylaxis in Reduced Intensity Conditioning: Results from Phase III BMT CTN 1703

Introduction: Controlling both GVHD and disease relapse is essential for allogeneic hematopoietic cell transplantation (alloHCT) success. For three decades, the standard GVHD prophylaxis strategy has been a calcineurin inhibitor such as tacrolimus (Tac) plus methotrexate (MTX). Although several approaches have been tried in recent years to improve upon Tac/MTX, intensifying immunosuppression frequently comes with an increased risk of serious infections or relapse and usually no effect on chronic GVHD even if acute GVHD is reduced. The Blood and Marrow Transplant Clinical Trials Network (BMT CTN) previously completed a phase II study comparing three novel GVHD prophylaxis regimens to contemporaneous controls receiving Tac/MTX (BMT CTN 1203) in order to determine the most promising novel GVHD prophylaxis approach with reduced intensity conditioning (RIC). The most promising GVHD prophylaxis regimen in BMT CTN 1203 was a 3-drug combination of post-transplant cyclophosphamide (PTCy), tacrolimus, and mycophenolate mofetil (PTCy/Tac/MMF). Here, we report the results of the randomized phase III study comparing outcomes of alloHCT in those randomized to receive PTCy/Tac/MMF versus standard Tac/MTX. Patients and Methods: Eligible adults (age 18+) with hematologic malignancies undergoing RIC alloHCT with an 6/6 matched related (N=128), 8/8 matched unrelated (N=288), or 7/8 single mismatch (N=15) peripheral blood stem cell donor, satisfactory organ function, and adequate performance status were randomized 1:1 to receive PTCy/Tac/MMF (N=214) or Tac/MTX (N=217), stratified by transplant center and Disease Risk Index (DRI). The primary endpoint of the study was GVHD/relapse or progression-free survival (GRFS), a time-to-event outcome defined as grade III-IV acute GVHD, chronic GVHD requiring systemic immune suppression, disease relapse or progression, or death by any cause. The primary hypothesis was that PTCy/Tac/MMF has a ≥15% higher GRFS at 1 year than Tac/MTX in the intent-to-treat population. Secondary endpoints included the incidence/severity of acute and chronic GVHD, engraftment/chimerism, relapse/progression, infections, and survival. Results: The 2 study arms were well balanced by patient sex, age, Karnofsky performance status, disease risk, comorbidities, donor match, conditioning regimen, and post-transplant maintenance therapy (Figure panel A). In the multivariate Cox regression model of the primary endpoint, the PTCy treatment group had a significantly lower hazard of GRFS than Tac/MTX (hazard ratio 0.641, 95% confidence interval [CI] 0.492 to 0.835, p=0.001). The adjusted 1-year GRFS rate was 52.7% (95% CI: 45.8%, 59.2%) for the PTCy arm and 34.9% (95% CI: 28.6%, 41.3%) for the control arm, Figure panel B). The lower proportion of GRFS events in the PTCy arm was due to a reduction in both acute and chronic GVHD. The Day 100 grade III-IV acute GVHD was 6.3% vs 14.7% (p=0.001), and chronic GVHD rate at 1 year was 21.9% vs 35.1% (p=0.005) for PTCy vs Tac/MTX, respectively. There was no difference in the relapse/progression rate at 1 year (20.8% vs 20.2%, p=0.9), or OS rate at 1 year post transplant (76.8% vs 72.6% , p=0.3), in PTCy vs Tac/MTX. The cumulative incidence of engraftment was lower for PTCy for neutrophils ≥ 500/mm3 by day +28 (90.3% vs 93.4%, p=0.03), platelets ≥ 50,000/mm3 by day +100 (79.5% vs 83.7%, p<0.001), and lymphocytes ≥ 1000/mm3 by 1 year (47.1% vs 63.2%, p<0.001). Grade 3 infection rates were similar between the arms (12.2% for PTCy vs 13.3%, p=0.8) but grade 2 infections were greater for PTCy (33.7% vs 23.5%, p=0.002). There was no difference in CMV reactivation between the treatment arms (7.3% for PTCy vs 7.1%, p=0.8). There was no significant difference in proportion of chimerism at day +100 (>95% donor in 68.6% for PTCy vs 67.8%, p=0.2) or secondary graft failure between the arms (2.9% for PTCy vs 0.9%, p=0.2). Conclusions: BMT CTN 1703 met its primary endpoint, demonstrating a higher 1-year GRFS with PTCy/Tac/MMF compared to Tac/MTX owing to significant improvements in GVHD risk without increased risk of relapse or death. PTCy/Tac/MMF, which has become standard of care for mismatched transplants, should also become the standard of care for GVHD prophylaxis from closely-matched donors receiving reduced intensity conditioning. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Validity of three risk prediction models for dementia or cognitive impairment in Australia.

no studies have compared the predictive validity of different dementia risk prediction models in Australia. (i) to investigate the predictive validity of the Australian National University-Alzheimer's Disease Risk Index (ANU-ADRI), LIfestyle for BRAin Health (LIBRA) Index and cardiovascular risk factors, ageing and dementia study (CAIDE) models for predicting probable dementia/cognitive impairment in an Australian cohort. (ii) To develop and assess the predictive validity of a new hybrid model combining variables from the three models. the Hunter Community Study (HCS) included 3,306 adults aged 55-85years with a median follow-up of 7.1years. Probable dementia/cognitive impairment was defined using Admitted Patient Data Collection, dispensing of cholinesterase inhibitors or memantine, or a cognitive test. Model validity was assessed by calibration and discrimination. A hybrid model was developed using deep neural network analysis, a machine learning method. 120 (3.6%) participants developed probable dementia/cognitive impairment. Mean calibration by ANU-ADRI, LIBRA, CAIDE and the hybrid model was 19, 0.5, 4.7 and 3.4%, respectively. The discrimination of the models was 0.65 (95% CI 0.60-0.70), 0.65 (95% CI 0.60-0.71), 0.54 (95% CI 0.49-0.58) and 0.80 (95% CI 0.78-0.83), respectively. ANU-ADRI and LIBRA were better dementia prediction tools than CAIDE for identification of high-risk individuals in this cohort. ANU-ADRI overestimated and LIBRA underestimated the risk. The new hybrid model had a higher predictive performance than the other models but it needs to be validated independently in longitudinal studies.

Sex differences on a digitally‐administered cognitive assessment battery in adults at‐risk for development of Alzheimer’s disease.

AbstractBackgroundSex differences in cognition have been well‐established among both healthy individuals and various clinical populations, including patients diagnosed with Alzheimer’s disease (AD). Specifically, females with AD experience greater cognitive impairment than men. However, cognitive sex differences among a population at‐risk for AD have not been elucidated. Therefore, the purpose of this study was to examine sex differences among at‐risk individuals using a digital cognitive assessment battery.MethodData collected are part of the ongoing Digital Cognitive Multi‐domain Alzheimer’s Risk Velocity Study investigating the effects of a 2‐year digital lifestyle intervention on individuals at‐risk for developing AD. Risk factors were determined via the Australian National University‐Alzheimer’s Disease Risk Index (ANU‐ADRI); two positive risk factors for AD (e.g.: history of diabetes, smoking, and/or traumatic brain injury) and no more than one protective factor (e.g.: high level of physical activity) were required for participation. Participants (age 45–75) completed six digital assessments measuring executive function, inhibition, processing speed, attention, associative learning, and associative memory. Independent sample t‐tests were used to analyze group differences (female vs male) in cognitive performance.ResultA significant difference between sexes exists for associative memory. Specifically, females had greater accuracy in recognizing previously presented images as compared to their male counterparts (Females = 0.3691 + 0.1072; Males = 0.3186 + 0.1115; p = .007; Cohen’s d = .465). While males and females did not differ in their time spent gazing at the novel image, females demonstrated a significantly better accuracy at identifying which image pairs they had seen previously compared to their male counterparts (Females = 0.3691 + 0.1072; Males = 0.3186 + 0.1115; p = .007; Cohen’s d = .465). No other differences in cognitive performance were observed.ConclusionThis study demonstrates that at‐risk women demonstrate a more accurate behavioral response during an associative memory task than their male counterparts. These results are counter to evidence suggesting females with AD experience greater cognitive impairment, indicating that other factors should be considered to understand the process of dementia‐related cognitive decline and cognitive impairment differences between sexes among patients with AD.

Reduced Post-Transplant Cyclophosphamide Dose Associated with Antithymocyte Globulin in Peripheral Blood Stem Cell Haploidentical Transplantation

INTRODUCTION Post-transplant cyclophosphamide (PT-Cy) has become the standard graft-versus-host disease (GVHD) prophylaxis for haploidentical hematopoietic cell transplantation (HCT) and has been increasingly used in allogeneic HCT with HLA-matched donors. However, PT-Cy is associated with significant toxicities and organ damage, especially in elderly patients. While toxicities may be correlated with the total cyclophosphamide dose, few studies have evaluated the safety and efficacy of different PT-Cy doses. We aimed to compare the outcomes with a reduced PT-Cy total dose of 70 mg/kg to those with PT-Cy at 100 mg/kg in elderly patients and patients with cardiac comorbidities undergoing haploidentical HCT. PATIENTS AND METHODS Inclusion criteria included: (1) age ≥ 65 years, or patients of any age with a history of cardiac events, (2) hematological malignancy, (3) haploidentical HCT, (4) peripheral blood stem cells, and (5) thiotepa-based conditioning regimen with antithymocyte globulin (ATG). Since 2015, our center policy has been PT-Cy at 100 mg/kg divided in 2 doses, to all patients. Starting from 2020, 40 patients have received PT-Cy at 35 mg/kg/day on day+3 and day+4 either because of older age or cardiac comorbidities. RESULTS Fifty-eight patients met the inclusion criteria. Median age was 68 years (range, 15-76) and 60% of patients were male. Median HCT-specific comorbidity index (HCT-CI) score was 2 (range, 0-5). Patients were transplanted for acute myeloid leukemia (n=37, 64%), myelodysplastic syndrome (n=11, 19%), lymphoma (n=8, 14%), or myeloproliferative neoplasm (n=2, 3%). Disease risk index was intermediate in 22 (38%) patients and high or very high in 36 (62%). Disease status at transplantation was complete remission in 18 patients (31%). Conditioning regimens were reduced intensity thiotepa-based (thiotepa - busulfan - fludarabine) in 25 (43%) patients or Flamsa-like sequential (thiotepa - etoposide - cyclophosphamide, followed by fludarabine - busulfan) in 33 (57%). GVHD prophylaxis included cyclosporin, mycophenolate mofetil, and ATG in all patients. Thirty-three patients received PT-Cy at 70 mg/kg and 25 at 100 mg/kg. There was no significant difference between the 2 groups (PT-Cy at 70 mg/kg versus 100 mg/kg) in terms of age, gender, HCT-CI score, cardiovascular risk factors, type of hematological disease, disease risk index, disease status, and type of conditioning regimen. The median follow-up was 17 months (interquartile range [IQR], 13-20) and 59 months (IQR, 51-66) in patients receiving PT-Cy at 70 mg/kg and 100 mg/kg, respectively. The cumulative incidences (CIs) of acute grade II-IV and grade III-IV GVHD were 18% and 0% with PT-Cy at 70 mg/kg compared to 17% and 5% with 100 mg/kg, respectively (p=0.94 for grade II-IV and p=0.87 for grade III-IV acute GVHD). The CI of chronic GVHD was 27% and 29% with PT-Cy at 70 mg/kg and 100 mg/kg, respectively (p=0.95). No significant difference was observed for moderate to severe chronic GVHD. Neutrophil recovery was significantly improved with 70 mg/kg compared to 100 mg/kg (median time of 16 versus 19 days, respectively, p=0.006). At days +30, +60, and +90 after HCT, 75%, 88% and 91% patients had a platelet count > 50 x 109/L with 70 mg/kg of PT-Cy, respectively, compared to 36%, 64%, and 64% with 100 mg/kg of PT-Cy, respectively (p=0.011). The CI of post-HCT bacteremia was 38% with PT-Cy at 70 mg/kg and 72% with 100 mg/kg (p=0.004). Other complications commonly associated with PT-Cy were also reduced with 70 mg/kg compared to 100 mg/kg of PT-Cy, such as BK-virus associated hemorrhagic cystitis (12% versus 28%) and left ventricular systolic dysfunction (9% versus 24%). At 2 years, CIs of non-relapse mortality were 18% and 33% (p=0.13), progression free-survival 65% and 46% (p=0.09), overall survival 68% and 52% (p=0.31), and GVHD-free, relapse-free survival 60% and 33% (p=0.04) with 70 mg/kg and 100 mg/kg of PT-Cy, respectively. CONCLUSIONS Reducing PT-Cy dose to 70 mg/kg is a safe and valid approach in elderly patients and patients with cardiac comorbidities underdoing haploidentical HCT with peripheral blood stem cells and low-dose ATG. Compared to 100 mg/kg, neutrophil and platelet recovery were improved, CIs of bacteremia, BK-virus associated hemorrhagic cystitis, and cardiac complications were reduced, the risk of acute and chronic GVHD was not increased, and GVHD-free, relapse-free survival was higher with PT-Cy at 70 mg/kg. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Influence of Conditioning Regimen Intensity on Outcomes Post-Allogeneic Transplantation for AML in Complete Morphological Remission

Introduction: Acute myelogenous leukemia (AML) is a major indication for allogeneic hematopoietic cell transplantation (alloHCT). Myeloablative (MAC) regimens are preferred for their intensity, however, reduced intensity conditioning regimens (RIC) have been increasingly used to permit older patients and patients with comorbidities to undergo transplant. The literature is conflicting regarding the comparison of outcomes between RIC and MAC patients. While MAC regimens are associated with less relapse, non-relapse mortality (NRM) is higher. RIC regimens on the other hand, demonstrate less NRM but higher relapse rates. We sought to compare RIC vs MAC regimens at our centre for alloHCT of AML in complete remission (CR). Methods: We retrospectively analyzed the outcomes of 451 patients that underwent alloHCT for AML at the Princess Margaret Cancer Centre (PMCC) with either RIC or MAC using various donors between the years 2015-2020. Primary endpoint was 2-year overall survival (OS), secondary endpoints included cumulative incidence of relapse (CIR), cumulative NRM, and GVHD free/relapse free survival (GRFS). Conditioning regimen intensity was determined as defined by Bacigalupo et al (BBMT 2009). Of the total cohort 331 patients received RIC and 121 MAC. Among MAC regimens, 59% received FLU(4)Bu(4) (Fludarabine 140mg/m2 + Busulfan 12.8mg/m2). Among RIC patients 71% received Flu(4)Bu(2)TBI(200) (Fludarabine 140mg/m2+ Busulfan 6.4 mg/m2 + TBI 200cGy). Results: Median age at transplant was 48 years (range: 19-67) for MAC recipients and 61 (range: 18-75) for RIC recipients (p<0.001). Other patient characteristics are described in Table 1. For the entire cohort at 2 years, the incidence of NRM was 19.1% for MAC (95% CI: 12.4-26.8) and 22.5% for RIC (95% CI: 18.1-27.1) (p=0.44). Two-year CIR was 19.8% (95% CI: 12.9-27.8) for MAC recipients and 24.5% (95% CI: 20.0-29.4) for RIC recipients (p=0.15). Two-year OS was 61% and 53% for MAC and RIC, respectively (p=0.02). Acute GVHD occurred in 58.3% of MAC recipients versus 46.8% of RIC recipients. Chronic GVHD occurred in 43.3% of the MAC recipients versus 38% of the RIC recipients. At two years GRFS was 40.8% (95% CI: 35.4-46.1) for MAC and 33.7% (95% CI: 25.0-42.6) for RIC, p=0.30. When examining the Disease Risk Index (DRI) for the entire cohort, OS for high risk was 43.3% (95% CI: 32.5-53.5) vs 66.6% (95% CI: 61-71) and 64% (95% CI: 38-80) for intermediate risk and low risk respectively, p<0.001. A propensity score (PS) matched analysis was done matching patients for age, HLA matching (mismatched vs full match), DRI (low, intermediate, high risk) and in vivo T cell depletion (yes vs no). Two-year OS was 67% for the MAC recipients (95% CI: 57-76) and 66% for the RIC recipients (95% CI: 56-75), p=0.95 (Figure 1a). NRM for MAC was 22% (95% CI: 14-30) versus 14% (95% CI: 8-22) for RIC, p=0.19. CIR at 2 years was 18.5% for MAC (95% CI 11-27) and 24.3% for RIC (95% CI: 16-33), p=0.22. GRFS at 2 years was 36% (95% CI: 26.4-45.7) for MAC and 48.3% (95% CI: 38-58) for RIC recipients, p=0.17. In the subgroup analysis examining matched related donor (MRD) recipients in particular, the OS at 2 years was for MAC 83.6% (95% CI: 66.8-91.3) vs 57.3% (95% CI: 45.1-67.7) for RIC, p=0.006 (Figure 1b) Two-year NRM was 10.3% for MAC vs 23.4% for the RIC group, p=0.14. CIR at 2 years was 12.2% for MAC vs 23.4% for RIC in the MRD setting, p=0.11. Conclusions: Our study shows that in the MRD setting there is a statistically significant improved survival, especially in patients with low and intermediate DRI scores. In other donor settings, there is no significant difference in outcomes between patients that undergo alloHCT with MAC vs RIC regimens. MAC conditioning regimens should continue to be the preferred choice of intensity for patients that may tolerate it. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Sequential Use of Flamsa, FLAG, CLAG or TEC-Based Conditioning Regimen Followed By Allogeneic Hematopoietic Transplantation Results in Favorable Outcome for High Risk Acute Myeloid Leukemia, Myelodysplastic Syndrome and Myeloproliferative Neoplasia Patients: 15 Year Follow-up of the Multicenter Study in Singapore

Introduction: Allogeneic hematopoietic cell transplant (allo-HCT) is an effective consolidative treatment for patients with certain hematological malignancies and gives the best outcome when done in remission. However, patients with refractory acute myeloid leukemia (AML) or some myeloproliferative neoplasia (MPN) and myelodysplastic syndrome (MDS) deemed unable to achieve remission with standard induction are often excluded from allo-HCT with conventional conditioning regimen as pre-transplant remission could not be achieved. Recently, a sequential transplant approach, as developed by the Munich group, comprising of intensive cytoreductive chemotherapy FLAMSA (Fludarabine/Amsacrine/Cytarabine) to decrease leukemia cell burden shortly prior to conditioning regimen, has been successfully used for high-risk (HR) AML/MDS with promising results. Methods: We studied 72 patients (median age 51 years, range 17-68) with HR AML (n=57), as defined by refractory, relapsed disease, secondary leukemia, complete remission with adverse-risk cytogenetics according to ELN criteria, or high/very risk refined Disease Risk Index (DRI), MPN (n=3) and HR MDS (n=12) according to IPSS-R, undergoing allo-HCT using the sequential transplant approach in 2 transplant centers in Singapore between January 2009 and July 2022. The sequential transplant approach combined a cytoreductive chemotherapy, which consisted of either FLAMSA (n=21), FLAG [Fludarabine/Cytarabine/Granulocyte Colony Stimulating Factor (GCSF)] +/- Idarubicin (n=30), CLAG (Clofarabine +/- Cytarabine +/- GCSF) (n=18), or TEC (Thiotepa, Etoposide, Cyclophosphamide) (n=3) followed by reduced intensity (RIC) (n=61) or myeloablative (MAC) (n=11) conditioning regimen. All patients received peripheral blood stem cell from matched related donors (MRD) (n=36), mismatched related donors (MMRD) (n=7), matched unrelated donors (MUD) (n=21), or mismatched unrelated donors (MMURD) (n=8). Post-grafting immunosuppression consisted of calcineurin inhibitor and mycophenolate mofetil (MMF) in all patients. Thymoglobulin and post-transplant cyclophosphamide were added for GVHD prophylaxis for MUD/MMURD and MMRD transplant, respectively. One MMRD had selective ex vivo T-cell depleted transplant followed by MMF as GVHD prophylaxis. Results: The median time to neutrophil > 1000/μL was 11 days (range, 8-25). With a median follow-up duration of 51 months (range, 1-148), the Kaplan-Meier estimate of overall survival (OS) and leukemia-free survival (LFS) at 5 years were 42% (95% CI, 30-54) and 32% (95% CI 20-44), respectively. The cumulative incidence of relapse and non-relapse mortality (NRM) at 2 years were 47% (95% CI, 35-59) and 16% (95% CI, 9-26), respectively. Patients receiving FLAG, CLAG or TEC-based sequential regimen showed a trend towards lower NRM and relapse compared to FLAMSA-based regimen, although the difference was not statistically significant. This translated into a more favorable 5-year LFS (40% vs 13%, p=0.04), but no statistically significant difference in 5-year OS (42% vs 40%, p=0.56). Patients with refractory disease (n=49) were at higher risk of relapse compared to patients whom had achieved at least a partial remission prior to sequential allo-HCT (n=17) (2-year cumulative incidence of relapse: 59.0% vs 34.0%, p=0.02). This resulted in an inferior 5-year OS (31% vs 66%; p=0.02) and LFS (20% vs 75%, p<0.01). On multivariable analysis, only refined DRI showed significant impact on OS (p=0.01) and LFS (p=0.02) but had no significant impact on NRM and relapse. The 5-year OS for patients with intermediate/high risk and very high risk DRI were 51% and 21% (p<0.01), and the corresponding 5-year LFS were 42% and 10% (p<0.01), respectively (Figure 1 and Figure 2). Conclusions: Sequential transplant conditioning with FLAMSA, FLAG, CLAG or TEC-based cytoreductive regimen followed by allo-HCT is an effective strategy in overcoming the dismal prognosis of HR AML, MDS and MPN, including patients with high risk DRI, and enabling favorable long-term disease-free survival. More studies on effective strategies such as optimising the conditioning regimen intensity or post-transplant maintenance therapy with prophylactic donor lymphocyte infusion, are needed to further eliminate the risk of relapse, without increasing risk of treatment-related toxicity. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Haploidentical Transplant Using Selective Ex-Vivo Tcrαβ Depleting and Memory T Cell Add-Back Results in More Favorable Gvhd-Free /Relapse Free Survival (GRFS) As Compared to Post-Transplant Cyclophosphamide for Adults with Hematological Malignancies - a Comparative Analysis of 170 Patients in a Multicenter Study in Singapore

Background: Outcome after haploidentical (Haplo) hematopoietic cell transplantation (HCT) is encouraging and has become alternative option to treat patients with high-risk hematological malignancies without human leukocyte antigen (HLA) matched donor. Currently, ex-vivo T-cell depletion (TCD) and unmanipulated graft with post-transplant cyclophosphamide (PTCy) remain the most commonly employed graft-versus-host disease (GVHD) prophylaxis strategies in patients receiving Haplo-HCT. The aim of this study is to compare the clinical outcome of adult patients with hematological malignancies receiving Haplo-HCT using these two different GVHD prophylaxis strategies. Methods: We analysed 170 adults’ patients receiving haploidentical peripheral blood stem cell transplant for various hematological malignancies between Jan 2011 and July 2022, following myeloablative (MAC, n=21) or reduced intensity conditioning (RIC, N=149) regimen. 100 patients received Haplo-HCT with selective ex-vivo T cell (TCRαβ and CD45RA+) depleted grafts for GVHD prophylaxis (Haplo-TCD) (Koh LP et al. ASH 2018), whereas 70 patients received unmanipulated, T-cell-replete graft followed by PTCy (Haplo-PTCy), in combination with tacrolimus and mycophenolate mofetil for GVHD prophylaxis. Results: Median time to neutrophil recovery was 12 days (range, 8-25) and 18 days (range 13-29) for patients receiving Haplo-TCD and Haplo-PTCY, respectively (p<0.001). Primary graft failure was seen in 1 patient in each of the 2 groups. Cumulative incidence (C.I.) of non-relapse mortality (NRM) (22% vs 25%; p=0.508), relapse (22% vs 26%; p=0.561), day 180 grade 2-4 acute GVHD (aGVHD) (35% vs 33%; p=0.539), day 180 grade 3-4 aGVHD (11% vs 3%; p=0.508) were not significantly different between the Haplo-TCD and Haplo-PTCy cohorts. However, C.I. of chronic GVHD (cGVHD) at 2 years was significantly lower in Haplo-TCD as compared with Haplo-PTCy (4% vs 26%, P<0.001). At a median follow up of 19.7 months (range 0.3- 67.1) in surviving patients, the 2-year overall (OS), event-free (EFS), and GVHD-free/relapse-free (GRFS) survival were 62% vs 49% (p=0.083), 56% vs 42% (p=0.309) and 54% vs 31% (p=0.006) for Haplo-TCD and Haplo-PTCy, respectively. Multivariable analysis showed that disease risk index (DRI), HCT-Comorbidity Index (HCT-CI) and GVHD prophylaxis strategies were independent risk factors for OS, EFS and GRFS. In contrast, NRM was only influenced by HCT-CI (p=0.007), whereas relapse was only influenced by DRI (p=0.0001). Notably, Haplo-TCD was associated with significantly lower risk of cGVHD in multivariable analysis (HR 0.14; 95% CI 0.04-0.15; p=0.0011), and this translates into significantly more favorable GRFS as compared to Haplo-PTCy (Figure 1). We performed propensity scoring for matching and identified 54 patients in each cohort. With propensity score matching, the use haplo-TCD retained its significant prognostic impact with lower risk of cGVHD (HR 0.08; 95% CI 1-62; p=0.016), and resulting in more favorable 5 years GRFS (50% vs 30%; p=0.03) as compared to Haplo-PTCy recipients (Figure 2). There was no significant difference in OS, EFS, CI of relapse, NRM, acute GVHD 2-4 and 3-4 between the 2 groups. Conclusions: As compared to unmanipulated graft and PTCy, Haplo-HCT using ex-vivo TCRαβ and CD45RA+ depleted graft resulted in comparable outcome, with the additional advantage of earlier neutrophil engraftment, lower risk of cGVHD and more favorable GRFS. The difference in the post-transplant outcome with these two GVHD prophylaxis strategies warrants further investigation and confirmation in prospective controlled trials. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal