Simplified echocardiographic assessment of regional left ventricular wall motion pattern in patients with takotsubo and acute coronary syndrome: The Randomized Blinded Two-chamber Apical Kinesis Observation (TAKO) Study.

BACKGROUND: Differentiating Takotsubo cardiomyopathy (TTC) from acute coronary syndrome involving the left anterior descending coronary artery (LAD-ACS) is difficult due to left ventricular apical wall motion abnormality pattern in both and typically requires an invasive coronary angiography (ICA) study for diagnostic confirmation. OBJECTIVES: To identify differences in the regional wall motion abnormality (RWMA) pattern using a comprehensive comparative analysis of the transthoracic echocardiographic (TTE) findings in patients with TTC versus LAD-ACS. METHODS: This was a retrospective, randomized, blinded comparison study including a derivation cohort of 105 patients with TTC (N=52) or LAD-ACS (N=53) with concomitant TTE and ICA identified from our institutional database. A comprehensive echocardiographic wall motion analysis was performed (unblinded) to search for subtle differences in RWMA patterns by marking the exact locations of the end-systolic hinge points (HP) - defined as the intersection between the normal and abnormal regional myocardial thickening - in all apical views. The HP location relative to mitral annulus in each apical view was compared for symmetry and the apical 2-chamber (A2C) view was identified as having the most consistent, quantitative difference between TTC and LAD-ACS. This A2C quantitative model was then prospectively studied in a randomized, blinded, validation cohort of 30 subjects with either TTC or LAD-ACS by eight echocardiographic readers with all levels of clinical experience. RESULTS: In the unblinded derivation cohort, the A2C view showed that the ratio (1.02) and the absolute distance between the anterior HP (3.57 cm) and the inferior HP (3.53 cm) in TTC was significantly different than the ratio (0.761) and the absolute differences between the AHP (4.5 cm) and the IHP (5.93 cm) in LAD-ACS. An AHP: IHP of 0.96 for men and 0.84 for women was able to correctly categorize 84.8% of male and 91.7% of female patients. When applied to the validation cohort, the model showed fairly accurate results with a 74% prediction rate in diagnosing TTC in female patients. CONCLUSION: We propose a relatively simple 2-D TTE diagnostic tool emphasizing subtle differences in the RWMA pattern in the A2C view alone as a semi-quantitative imaging parameter to help differentiate TTC from LAD-ACS.

Disparities in metabolic dysfunction-associated steatotic liver disease and cardiometabolic conditions in low and lower middle-income countries: a systematic analysis from the global burden of disease study 2019.

OBJECTIVE: Metabolic dysfunction-associated steatotic liver disease (MASLD) and cardiometabolic conditions affect populations across economic strata. Nevertheless, there are limited epidemiological studies addressing these diseases in low (LICs) and lower-middle-income countries (lower MICs). Therefore, an analysis of the trend of MASLD and cardiometabolic conditions in these countries is necessary. METHODS: From 2000 to 2019, jointpoint regression analysis was employed to calculate the prevalence, mortality, and disability-adjusted life years (DALYs) for cardiometabolic conditions including MASLD, type 2 diabetes mellitus (T2DM), dyslipidemia (DLP), hypertension (HTN), obesity, peripheral artery disease (PAD), atrial fibrillation and flutter (AF/AFL), ischemic heart disease (IHD), stroke, and chronic kidney disease from HTN and T2DM, in LICs and lower MICs (according to the World Bank Classification 2019) using the Global Burden of Disease 2019 data. RESULTS: Among the eleven cardiometabolic conditions, MASLD (533.65 million), T2DM (162.96 million), and IHD (76.81 million) had the highest prevalence in LICs and Lower MICs in 2019. MASLD represented the largest proportion of global prevalence in these countries (43 %). From 2000 to 2019, mortality in LICs and lower MICs increased in all cardiometabolic conditions, with obesity-related mortality having the highest increase (+134 %). During this timeframe, there were increased age-standardized death rates (ASDR) from obesity, PAD, and AF/AFL. From all conditions, the DALYs-to-prevalence ratio was higher in LICs and lower MICs than the global average. CONCLUSION: The burden of MASLD and cardiometabolic conditions is increasing worldwide, with LICs and lower MICs experiencing higher (DALYs) disability per prevalence. As these conditions are preventable, counteracting these trends requires not only the modification of ongoing actions but also the strategizing of immediate interventions.

Behavioural activation for people in custody with depression: A protocol for a feasibility randomised controlled study.

People in custody are at high risk of developing depression. Accessing psychological treatments in a prison setting is a particular challenge, in part, due to difficulties accessing specialist mental health workers. Behavioural Activation (BA) may be helpful in improving health outcomes for people in custody experiencing depressive symptoms. The aim of this study is to establish the feasibility and acceptability of custodial health nurses delivering BA to improve depressive symptoms of people in custody. We will conduct a pilot randomised controlled trial with process observation examining the feasibility and acceptability of BA in treating people in custody with depressive symptoms. 60 people in custody presenting with depressive symptoms will be randomised to receive BA plus treatment as usual (TAU) or TAU provided by custodial health nurses. Eight custodial health nurses will be recruited, trained, and deliver BA. BA will be delivered twice a week for six weeks, with sessions lasting up to 30 minutes. Changes in depression and quality of life (QoL) will be assessed at baseline, 6 weeks, and 3 months post-intervention. Participants will be interviewed to understand feasibility and acceptability of BA in prison settings. The findings will inform the design of a randomised controlled trial to test the efficacy of BA for people in custody with depression. Findings will help determine whether BA for depression is suited to prison health care system and services. Improving depressive symptoms in people in custody has benefits beyond prison settings. The Central Adelaide Local Health Network Human Research Ethics Committee and University of South Australia Human Research Ethics Committee have approved the study. The trial results will be disseminated through peer-reviewed journals and scientific conferences and reported to local stakeholders and policy makers. If feasibility and acceptability is demonstrated, we will seek to progress to an effectiveness study. A potential strength of the trial model proposed, is in its scalability, with potential to increase the trial sites and locations. This trial has been prospectively registered with the Australian New Zealand Clinical Trials Registry (reference number: ACTRN12623000346673p). Trial registration ACTRN12623000346673p.

Cardiac troponin concentrations following exercise and the association with cardiovascular disease and outcomes: rationale and design of the prospective TREAT cohort study.

Exercise can produce transient elevations of cardiac troponin (cTn) concentrations, which may resemble the cTn release profile of myocardial infarction. Consequently, clinical interpretation of postexercise cTn elevations (ie, values above the 99th percentile upper reference limit) remains challenging and may cause clinical confusion. Therefore, insight into the physiological versus pathological nature of postexercise cTn concentrations is warranted. We aim to (1) establish resting and postexercise reference values for recreational athletes engaged in walking, cycling or running exercise; (2) compare the prevalence of (sub)clinical coronary artery disease in athletes with high versus low postexercise cTn concentrations and (3) determine the association between postexercise cTn concentrations and the incidence of major adverse cardiovascular events (MACE) and mortality during long-term follow-up. For this purpose, the prospective TRoponin concentrations following Exercise and the Association with cardiovascular ouTcomes (TREAT) observational cohort study was designed to recruit 1500 recreational athletes aged ≥40 to <70 years who will participate in Dutch walking, cycling and running events. Baseline and postexercise high-sensitivity cTnT and cTnI concentrations will be determined. The prevalence and magnitude of coronary atherosclerosis on computed tomography (eg, coronary artery calcium score, plaque type, stenosis degree and CT-derived fractional flow reserve) will be compared between n=100 athletes with high postexercise cTn concentrations vs n=50 age-matched, sex-matched and sport type-matched athletes with low postexercise cTn concentrations. The incidence of MACE and mortality will be assessed in the entire cohort up to 20 years follow-up. The TREAT study will advance our understanding of the clinical significance of exercise-induced cTn elevations in middle-aged and older recreational athletes. Trial registration number NCT06295081.

Cross-modal plasticity in children with cochlear implant: converging evidence from EEG and functional near-infrared spectroscopy.

Over the first years of life, the brain undergoes substantial organization in response to environmental stimulation. In a silent world, it may promote vision by (i) recruiting resources from the auditory cortex and (ii) making the visual cortex more efficient. It is unclear when such changes occur and how adaptive they are, questions that children with cochlear implants can help address. Here, we examined 7-18 years old children: 50 had cochlear implants, with delayed or age-appropriate language abilities, and 25 had typical hearing and language. High-density electroencephalography and functional near-infrared spectroscopy were used to evaluate cortical responses to a low-level visual task. Evidence for a 'weaker visual cortex response' and 'less synchronized or less inhibitory activity of auditory association areas' in the implanted children with language delays suggests that cross-modal reorganization can be maladaptive and does not necessarily strengthen the dominant visual sense.

Long-term outcomes of great saphenous vein harvest techniques for infrainguinal arterial bypass in a Medicare-matched registry database.

OBJECTIVE: Long-term outcomes for harvesting techniques for great saphenous vein (GSV) and its impact on the outcomes of infrainguinal arterial bypass remains largely unknown. Endoscopic GSV harvesting (EVH) has emerged as a less invasive alternative to conventional open techniques. Using the Vascular Quality initiative Vascular Implant Surveillance & Interventional Outcomes Network (VQI-VISION) database, we compared the long-term outcomes of infrainguinal arterial bypass using open and endoscopic GSV harvest techniques. METHODS: Patients who underwent infrainguinal GSV bypass between 2010 and 2019 were identified in the VQI-VISION Medicare linked database. Long-term outcomes of major/minor amputations, and reinterventions up to 5 years of follow-up were compared between continuous incisions, skip incision, and EVH, with continuous incisions being the reference group. Secondary outcomes included 30- and 90-day readmission, in addition to surgical site infections and patency rates at 6 months to 2 years postoperatively. Survival analysis using Kaplan-Meier curves and Cox regression hazard models were utilized to compare outcomes between groups. To adjust for multiple comparisons between the study groups, a P value of 2.5% was considered significant. RESULTS: Among the 8915 patients included in the study, continuous and skip vein harvest techniques were used in 44.4% and 43.4% of cases each, whereas 12.3% underwent EVH. The utilization of EVH remained relatively stable at around 12% throughout the study period. Compared with GSV harvest using continuous incisions, EVH was associated with higher rates of reintervention at 1 year (46.5% vs 41.3%; adjusted hazard ratio [aHR], 1.22; 95% confidence interval [CI], 1.06-1.41; P = .01]. However, no significant difference was observed between EVH and continuous incisions, and between skip and continuous incisions in terms of long-term reintervention or major and minor amputations on adjusted analysis. Compared with continuous incision vein harvest, both EVH and skip incisions were associated with lower surgical site infection rates within the first 6 months post-bypass (aHR, 0.53; 95% CI, 0.35-0.82 and aHR, 0.68; 95% CI, 0.53-0.87, respectively). Loss of primary, primary-assisted, and secondary patency was higher after EVH compared with continuous incision vein harvest. Among surgeons performing EVH, comparable long-term outcomes were observed regardless of low (<4 cases/year), medium (4-7 cases/year), or high procedural volumes (>7 cases/year). CONCLUSIONS: Despite higher 1-year reintervention rates, EVH for infrainguinal arterial bypass is not associated with a significant difference in long-term reintervention or amputation rates compared with other harvesting techniques. These outcomes are not influenced by procedural volumes for EVH technique.

How multidisciplinary clinics may mitigate socioeconomic barriers to care for chronic limb-threatening ischemia.

OBJECTIVE: Although multidisciplinary clinics improve outcomes in chronic limb-threatening ischemia (CLTI), their role in addressing socioeconomic disparities is unknown. Our institution treats patients with CLTI at both traditional general vascular clinics and a multidisciplinary Limb Preservation Program (LPP). The LPP is in a minority community, providing expedited care at a single facility by a consistent team. We compared outcomes within the LPP with our institution's traditional clinics and explored patients' perspectives on barriers to care to evaluate if the LPP might address them. METHODS: All patients undergoing index revascularization for CLTI from 2014 to 2023 at our institution were stratified by clinic type (LPP or traditional). We collected clinical and socioeconomic variables, including Area Deprivation Index (ADI). Patient characteristics were compared using χ2, Student t, or Mood median tests. Outcomes were compared using log-rank and multivariable Cox analysis. We also conducted semi-structured interviews to understand patient-perceived barriers. RESULTS: From 2014 to 2023, 983 limbs from 871 patients were revascularized; 19.5% of limbs were treated within the LPP. Compared with traditional clinic patients, more LPP patients were non-White (43.75% vs 27.43%; P < .0001), diabetic (82.29% vs 61.19%; P < .0001), dialysis-dependent (29.17% vs 13.40%; P < .0001), had ADI in the most deprived decile (29.38% vs 19.54%; P = .0061), resided closer to clinic (median 6.73 vs 28.84 miles; P = .0120), and had worse Wound, Ischemia, and foot Infection (WIfI) stage (P < .001). There were no differences in freedom from death, major adverse limb event (MALE), or patency loss. Within the most deprived subgroup (ADI >90), traditional clinic patients had earlier patency loss (P = .0108) compared with LPP patients. Multivariable analysis of the entire cohort demonstrated that increasing age, heart failure, dialysis, chronic obstructive pulmonary disease, and increasing WIfI stage were independently associated with earlier death, and male sex was associated with earlier MALE. Ten traditional clinic patients were interviewed via convenience sampling. Emerging themes included difficulty understanding their disease, high visit frequency, transportation barriers, distrust of the health care system, and patient-physician racial discordance. CONCLUSIONS: LPP patients had worse comorbidities and socioeconomic deprivation yet had similar outcomes to healthier, less deprived non-LPP patients. The multidisciplinary clinic's structure addresses several patient-perceived barriers. Its proximity to disadvantaged patients and ability to conduct multiple appointments at a single visit may address transportation and visit frequency barriers, and the consistent team may facilitate patient education and improve trust. Including these elements in a multidisciplinary clinic and locating it in an area of need may mitigate some negative impacts of socioeconomic deprivation on CLTI outcomes.

Mutations, substitutions, and selection: Linking mutagenic processes to cancer using evolutionary theory.

Cancers are the product of evolutionary events, where molecular variation occurs and accumulates in tissues and tumors. Sequencing of this molecular variation informs not only which variants are driving tumorigenesis, but also the mechanisms behind what is fueling mutagenesis. Both of these details are crucial for preventing premature deaths due to cancer, whether it is by targeting the variants driving the cancer phenotype or by measures to prevent exogenous mutations from contributing to somatic evolution. Here, we review tools to determine both molecular signatures and cancer drivers, and avenues by which these metrics may be linked.

Global epidemiology of alcohol-associated liver disease in adolescents and young adults.

BACKGROUND AND AIMS: The objective of the study was to analyse the prevalence, incidence, and death of alcohol-associated liver disease (ALD) among adolescents and young adults globally, continentally, and nationally, focusing on trends over time. METHODS: The study analysed data from the Global Burden of Disease (GBD) study between 2000 and 2019. It examined ALD's prevalence, incidence, and death in adolescents and young adults aged 15-29, segmented by region, nation, and sociodemographic index. The analysis utilised Joinpoint regression modelling to calculate the annual per cent change (APC) in the rate of these parameters over time. RESULTS: In 2019, there were 281,450 ALD prevalences, 18,930 incidences, and 3190 deaths among adolescents and young adults globally. From 2000 to 2019, the age-adjusted prevalence rate per 100,000 increased in the 25-29 age group (APC: +0.6%, p = 0.003), remained stable among ages 20-24 (p = 0.302) and ages 15-19 (p = 0.160). Prevalence increased significantly from age 15-19 to 20-24 (19-fold increase) and from age 20-24 to 25-29 (2.5-fold increase). ALD prevalence rates increased in all age groups in adolescents and young adults in Africa and the Eastern Mediterranean region. Around three-quarters of countries and territories experienced an increase in ALD incidence rates in young adults. CONCLUSION: Over two decades, the burden of ALD among adolescents and young adults has increased globally. The study emphasises the importance of public health policies aimed at reducing alcohol consumption and preventing ALD among younger populations.

Better source memory for remembered to-be-forgotten items than for remembered to-be-remembered items.

When participants study items one-by-one and are directed to either remember or forget the respective item directly after its presentation, retention of to-be-forgotten items is regularly worse than of to-be-remembered items. We tested whether this directed forgetting effect which is regularly observed for item memory generalizes to source memory. In three experiments, participants studied items in two different source colors (N = 101) or at two different source locations (N = 64; N = 81). Sources were manipulated orthogonally to item type (remember vs. forget). At test, we asked participants to recognize all studied items and also to identify their source. We used a multinomial processing tree model to disentangle item memory, source memory, and guessing. In all three experiments, we replicated the directed forgetting effect in item memory. Source memory for to-be-forgotten items that were recognized despite the intention to forget, however, tended to be even better than source memory for to-be-remembered items that were recognized. These results suggest that the directed forgetting effect does not simply translate from item to source memory. Rather source memory seems to be disproportionally increased in to-be-forgotten items that are remembered. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

[Risk management with regard to QT-prolonging drugs]. / Risicomanagement rond QT-verlengende geneesmiddelen.

Drug-induced QT prolongation increases the risk of Torsade de Pointes (TdP). Drug-induced QT prolongation is a complex and unpredictable system due to many uncertainties. Risk factors such as electrolyte disturbances, heart failure and genetics play an important role in estimating the effect on QT prolongation. Moreover, the degree of QT prolongation is not always directly related to the risk of TdP and the assessment of the QT-interval is variable depending on the type and timing of QT measurement. Therefore, the variation in QT measurement may be larger than the effect of certain drugs on the QT interval. Because of the potentially lethal risk, several measures are undertaken to reduce the risk of QT prolongation and TdP, while their effect and proportionality are unclear. We suggest we should be less stringent in certain settings when risk of TdP is extremely low given the limited availability of our resources.

Investigation of Fe-Ni Battery/Module for Grid Service Duty Cycles.

Iron-nickel (Fe-Ni) batteries are renowned for their durability and resilience against overcharging and operating temperatures. However, they encounter challenges in achieving widespread adoption for energy storage applications due to their low efficiency and the need for regular maintenance and electrolyte replacement, which adds to maintenance costs. This study evaluates and demonstrates the capabilities of Fe-Ni batteries for participating in grid energy storage applications. Stable performance was observed frequency regulation (FR) testing at 100% and 50% state of charge (SOC)s, while at 50% SOC, there was a 14% increase in efficiency compared to 100% SOC. Although 25% SOC achieved higher efficiency, limited cyclability was observed due to reaching the discharge cutoff voltage. Optimal SOC selection, battery monitoring, maintenance, and appropriate charging strategies of Fe-Ni batteries seem to be crucial for their FR applications. Fe-Ni batteries exhibit stable peak shaving (PS) results, indicating their suitability and reliability under various load conditions for PS testing. Extended cycling tests confirm their potential for long-term grid-scale energy storage, enhancing their appeal for PS and FR applications.

Systems biology dissection of PTSD and MDD across brain regions, cell types, and blood.

The molecular pathology of stress-related disorders remains elusive. Our brain multiregion, multiomic study of posttraumatic stress disorder (PTSD) and major depressive disorder (MDD) included the central nucleus of the amygdala, hippocampal dentate gyrus, and medial prefrontal cortex (mPFC). Genes and exons within the mPFC carried most disease signals replicated across two independent cohorts. Pathways pointed to immune function, neuronal and synaptic regulation, and stress hormones. Multiomic factor and gene network analyses provided the underlying genomic structure. Single nucleus RNA sequencing in dorsolateral PFC revealed dysregulated (stress-related) signals in neuronal and non-neuronal cell types. Analyses of brain-blood intersections in >50,000 UK Biobank participants were conducted along with fine-mapping of the results of PTSD and MDD genome-wide association studies to distinguish risk from disease processes. Our data suggest shared and distinct molecular pathology in both disorders and propose potential therapeutic targets and biomarkers.

PNPLA3 risk allele is associated with risk of hepatocellular carcinoma but not decompensation in compensated cirrhosis.

BACKGROUND: The PNPLA3-rs738409-G, TM6SF2-rs58542926-T, and HSD17B13-rs6834314-A polymorphisms have been associated with cirrhosis, hepatic decompensation, and HCC. However, whether they remain associated with HCC and decompensation in people who already have cirrhosis remains unclear, which limits the clinical utility of genetics in risk stratification as HCC is uncommon in the absence of cirrhosis. We aimed to characterize the effects of PNPLA3, TM6SF2, and HSD17B13 genotype on hepatic decompensation, HCC, and liver-related mortality or liver transplant in patients with baseline compensated cirrhosis. METHODS: We conducted a single-center retrospective study of patients in the Michigan Genomics Initiative who underwent genotyping. The primary predictors were PNPLA3, TM6SF2, and HSD17B13 genotypes. Primary outcomes were either hepatic decompensation, HCC, or liver-related mortality/transplant. We conducted competing risk Fine-Gray analyses on our cohort. RESULTS: We identified 732 patients with baseline compensated cirrhosis. During follow-up, 50% of patients developed decompensation, 13% developed HCC, 24% underwent liver transplant, and 27% died. PNPLA3-rs738409-G genotype was associated with risk of incident HCC: adjusted subhazard hazard ratio 2.42 (1.40-4.17), p=0.0015 for PNPLA3-rs738409-GG vs. PNPLA3-rs738409-CC genotype. The 5-year cumulative incidence of HCC was higher in PNPLA3-rs738409-GG carriers than PNPLA3-rs738409-CC/-CG carriers: 15.6% (9.0%-24.0%) vs. 7.4% (5.2%-10.0%), p<0.001. PNPLA3 genotype was not associated with decompensation or the combined outcome of liver-related mortality or liver transplant. TM6SF2 and HSD17B13 genotypes were not associated with decompensation or HCC. CONCLUSIONS: The PNPLA3-rs738409-G allele is associated with an increased risk of HCC among patients with baseline compensated cirrhosis. People with cirrhosis and PNPLA3-rs738409-GG genotype may warrant more intensive HCC surveillance.

Socio-economic association of alcohol use disorder and cardiovascular and alcohol-associated liver disease from 2010 to 2019.

BACKGROUNDS AND AIMS: Alcohol use leads to disabilities and deaths worldwide. It not only harms the liver but also causes alcohol use disorder (AUD) and heart disease. Additionally, alcohol consumption contributes to health disparities among different socio-economic groups. METHODS: We estimated global and regional trends in the burden of AUD, liver disease, and cardiovascular disease from alcohol using the methodology of the Global Burden of Disease study. RESULTS: In 2019, the highest disability-adjusted life years rate per 100,000 population was due to AUD (207.31 [95% Uncertainty interval (UI) 163.71-261.66]), followed by alcohol-associated liver disease (ALD) (133.31 [95% UI 112.68-156.17]). The prevalence rate decreased for AUD (APC [annual percentage change] -0.38%) and alcohol-induced cardiomyopathy (APC -1.85%) but increased for ALD (APC 0.44%) and liver cancer (APC 0.53%). Although the mortality rate for liver cancer from alcohol increased (APC 0.30%), mortality rates from other diseases decreased. Between 2010 and 2019, the burden of alcohol-associated complications increased in countries with low and low-middle sociodemographic index (SDI), contributing more significantly to the global burden. CONCLUSION: The global burden of AUD, liver, and cardiovascular disease has been high and increasing over the past decade, particularly for liver complications. Lower SDI countries are contributing more to this global burden. There is a pressing need for effective strategies to address this escalating burden.

French early nationwide idecabtagene vicleucel chimeric antigen receptor T-cell therapy experience in patients with relapsed/refractory multiple myeloma (FENIX): A real-world IFM study from the DESCAR-T registry.

Idecabtagene vicleucel (ide-cel), a chimeric antigen receptor T-cell therapy targeting B-cell maturation antigen (BCMA), received early access program (EAP) authorization in France in April 2021 for relapsed/refractory multiple myeloma (RRMM). We conducted a real-world registry-based multicentre observational study in 11 French hospitals to evaluate ide-cel outcomes. Data from 176 RRMM patients who underwent apheresis between June 2021 and November 2022 were collected from the French national DESCAR-T registry. Of these, 159 patients (90%) received ide-cel. Cytokine release syndrome occurred in 90% with 2% grade ≥3, and neurotoxicity occurred in 12% with 3% grade ≥3. Over the first 6 months, the best overall response and ≥complete response rates were 88% and 47% respectively. The median progression-free survival (PFS) from the ide-cel infusion was 12.5 months, the median overall survival (OS) was 20.8 months and the estimated OS rate at 12 months was 73.3%. Patients with extra-medullary disease (EMD) had impaired PFS (6.2 months vs. 14.8 months). On multivariable analysis, EMD and previous exposure to BCMA-targeted immunoconjugate or T-cell-redirecting GPRC5D bispecific antibody were associated with inferior PFS. Our study supports ide-cel's feasibility, safety and efficacy in real-life settings, emphasizing the importance of screening for EMD and considering prior treatments to optimize patient selection.