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This region is like the Showtime Lakers of the 80s. Cardiology always packs the house by combining crowd pleasers like acute illness, therapeutic advances, and the weight of importance (1 in 4 deaths in the US is due to heart disease). This makes the Heart and Kidney Connection region a big draw. This region begins with a pair of novel therapies for heart failure, that try to break out of the loop diuretic prison we have been in for the last few decades. After that intro there are three match-ups that are just dripping with controversy:

1. The nature of cardiac mortality in ESRD: electrical versus plumbing
2. What should we do with sodium intake in acute and chronic heart failure
3. And the eternal question. If a drug works with intact kidneys, does it need to be re-vetted for dialysis patients?

Selection Committee member for the Heart and Kidney Connection Region:

Andrew House, MD

Dr. House is a Professor in the Faculty of Medicine at the Schulich School of Medicine & Dentistry, Western University, and is currently the Chair of the Western University Division of Nephrology, in London, Ontario. He completed his training in Physiology & Pharmacology at Western before his MD and specialist training at the University of Ottawa, and Masters in Epidemiology & Biostatistics at Western. In 2007 he completed a six-month sabbatical in Vicenza, Italy, where he developed an interest in Critical Care Nephrology and Cardiorenal Syndromes. He participated in the Acute Dialysis Quality Initiative (ADQI) consensus conferences on Cardio-Renal Syndromes held in Venice in 2008 and 2012.

Meet the Competitors for the Heart and Kidney Connection Region

Sacubitril in HF (PARADIGM-HF)
Tolvaptan in HF

Sudden Cardiac Death in ESRD
Acute Coronary Syndrome in ESRD

Hypertonic Saline in Acute CHF
Sodium Restriction for CHF

Statins in ESRD
Coumadin in ESRD

Sacubitril in HF (PARADIGM-HF) vs Tolvaptan in HF

This is a real show stopper. Two novel therapies going head to head in a grudge match. Sacubitril is a neprilysin inhibitor that is now coupled to a new partner (an ARB) hoping to shed a toxic past. The toxic past was a drug called omapatrilat which has combined ACE and neprilysin inhibitory effects that initially showed promise in heart failure but angioedema stole the show and proved too hazardous. The blockade of vasopressin receptors with tolvaptan continues to make appearances as a potential therapy in multiple arenas. How will tolvaptan hold up to an old renin-angiotensin system behemoth with shiny new neprilysin inhibition rims? This one will go down to the wire.

Sacubitril in HF (PARADIGM-HF)

The hype was palpable, like Kentucky in the John Calipari era. Will it be another group of one and dones or will this be a John Wooden UCLA dynasty? The PARADIGM Trial was reported at European Society of Cardiology Congress in Barcelona in 2014 and simultaneously published in the NEJM. This trial tested whether a neprilysin inhibitor coupled to valsartan provided more benefit than enalapril in patients with heart failure. First things first, what is neprilysin? And why should we block it? It is ubiquitously expressed but enriched in the renal proximal tubule, heart, lung, lymphocytes, and brain. Neprilysin is a circulating and membrane-bound metalloprotease that cleave peptides. In such, inactivates several peptide hormones including natriuretic peptides, vasoactive peptides (eg, endothelin 1, bradykinins, angiotensin II), neuropeptides (eg, substance P, enkephalins), and the beta-amyloid peptide amongst others. Some of these are “good” and others “bad”. So, the net effect of neprilysin inhibition is difficult to predict. The inhibition of neprilysin alone (in the form of candoxatril) was studied back in 1993 and reported in the journal Clinical Science. This showed no effect in blood pressure and a decrease in angiotensin II metabolism. This is why it is important to add neprilysin inhibition to either an ACEi or an ARB.

The results of the PARADIGM Trial were impressive, but not without controversy. This was a double-blind trial, with 8442 patients with class II, III, or IV heart failure and an ejection fraction of 40% or less to receive either LCZ696 (200 mg twice daily) or enalapril (10 mg twice daily). LCZ696 is a combination neprilysin inhibitor sacubitril and valsartan. The primary outcome was a composite of death from cardiovascular causes or hospitalization for heart failure. The trial was stopped early because of an overwhelming benefit with LCZ696.

• The primary outcome had occurred in ~22% in the LCZ696 group compared to ~27% in the enalapril group.
• Death from any cause occurred in ~17% receiving LCZ696 and ~20% receiving enalapril.
• As compared with enalapril, LCZ696 also reduced the risk of hospitalization for heart failure by 21%.
• LCZ696 decreased the symptoms and physical limitations of heart failure.

In regard to side effects, the LCZ696 group had higher proportions of patients with hypotension and non serious angioedema but lower proportions with renal impairment, hyperkalemia, and cough than the enalapril group.

These results were viewed by the cardiovascular community with great enthusiasm. However, questions remain about why enalapril was used as the comparator and not valsartan.

But what about kidney disease? Well, as mentioned previously, neprilysin is highly expressed in the proximal tubule of the nephron. Hence, there is much interest in using inhibitors of neprilysin in CKD. A rat model of diabetes showed substantial improvement in both proteinuria and kidney damage with the use of omapatrilat compared to ACEi use. What about human data? In an analysis of patients in the PARAMOUNT trial (designed to look at heart failure with preserved ejection fraction (HFpEF) showed that treatment with LCZ696 for 36 weeks led to slightly better eGFR than valsartan. However, the LCZ696 had a small but statistically increase in urinary ACR. The UK Heart And Renal Protection III (UK HARP-III) trial will compare LCZ696 to irbesartan in a planned 360 patients with proteinuric CKD (urine ACR > 20 mg/mmol and eGFR 20-<60 mL/min/1.73 m²). The trial will investigate the short-term safety and efficacy of LCZ696 in CKD with a primary outcome being the difference between the two arms in change in measured GFR from baseline to 6 months. This class of medications could become a potential therapy to slow the progression of CKD. We still await definitive clinical trials. Team Sacubitril has a lot of promise and will likely make some serious noise in NephMadness.

Tolvaptan in HF

The antagonists of vasopressin (vaptans) have shown great versatility, from the treatment of hyponatremia to polycystic kidney disease to heart failure, provoking the question whether Team Tolvaptan in HF can be stopped. Why should we block vasopressin in heart failure? Well, increases in vasopressin has been shown to play a role in mediating water retention in HF. Therefore, the interruption of inappropriate activation of vasopressin could be of therapeutic benefit. The vaptans (or small molecule antagonists to the V₂ receptor) now give us the ability to treat disorders with increased vasopressin levels. Short-term treatment with vaptans leads to improved fluid balance, renal function, and electrolyte composition compared to loop diuretics.

The EVEREST trial, reported in JAMA in 2007, was a randomized, double-blind, placebo-controlled study in patients (~4100) acutely decompensated and admitted to the hospital with either tolvaptan or placebo. This is in direct contradistinction to the PARADIGM Trial in which “stable” outpatients were studied. You have to give the authors of the EVEREST trial credit for going after an extremely difficult patient population. There have been no definitive studies that have shown benefit in acutely decompensated heart failure. Unfortunately, no difference in HF morbidity or mortality was identified. A benefit with tolvaptan was seen in day 1 dyspnea scores and body weight. There was also improved serum sodium concentrations in patients with hyponatremia. However, these effects did not translate to hard outcomes. So, where do we stand? ClinicalTrials.org lists several trials in both acute and chronic HF. Maybe vasopressin antagonism therapy needs to be given chronically and not acutely to be effective in HF.

Sudden Cardiac Death in ESRD vs Acute Coronary Syndrome in ESRD

Two very important topics that contribute heavily to mortality and morbidity in patients with ESRD. Both overlap in their pathophysiology and take from the same playbook (think 4-corners offense and Dean Smith).

Sudden Cardiac Death in ESRD

This is the scourge of nephrology and will be a difficult concept to overtake in NephMadness. An alarming statistic to think that almost 1 in every 4 deaths among hemodialysis and peritoneal dialysis is from sudden cardiac death. Even worse, the risk of sudden cardiac death (SCD) increases substantially as kidney function declines (in the absence of ESRD). We need to understand why this is occurring so we can introduce interventions to help decrease this trend. To put it a different way–the risk of sudden cardiac death in this patient population is actually above and beyond the risk attributable to classical risk factors.

What is the reason behind this? The pathophysiology of SCD has not been clearly established and this is why SCD represents a formidable foe. In the general population structural heart disease with reduced left ventricular ejection fraction is responsible for the majority of SCD events. However, this is not the case in CKD and ESRD. Coronary artery disease in general population consists of lipid-laden intimal atherosclerotic lesions. This pattern is not the case in CKD where diffuse multivessel arterial stiffening and calcification of the medial layers of the vessels predominates. In fact, Bleyer et al showed that ischemic cardiomyopathy with reduced ejection fraction was only present in less than 30% of patients on hemodialysis who died from SCD. Patients with CKD predominantly have HF with preserved ejection fraction (HFpEF) presumedly from left ventricular hypertrophy. MRI studies of patients on hemodialysis describe a diffuse pattern of myocardial fibrosis underlying left ventricular hypertrophy without a background of ischemic coronary artery disease. Multiple factors could be contributing to this in patients with CKD such as

• microvessel disease and capillary deficit (capillary/myocyte mismatch)
• disorders of mineral metabolism and secondary hyperparathyroidism
• repetitive myocardial injury from reduction in myocardial perfusion during dialysis
• dialysis-induced myocardial “stunning.”

These differences in pathophysiology may explain why the traditional risk factors fail at explaining the enhanced risk of SCD in dialysis patients.
What about arrhythmic triggers? This could be another factor besides just structural abnormalities leading to the increased risk of SCD in patients with ESRD. First, SCD occurs most frequently on hemodialysis days, especially on the first hemodialysis day after the long dialysis-free weekend for patients on a three times a week dialysis. This suggests that factors related to the hemodialysis procedure itself can potentially trigger a fatal arrhythmias. What are some of the factors:

• both hyperkalemia and hypokalemia (Pun et al)
• exposure to low potassium and calcium dialysate (Karnik et al)
• rapid ultrafiltration rate (Movilli et al)

Therefore, these findings suggest that shifts with varying amounts of potassium and calcium are critical risk factors for SCD in patients maintained on hemodialysis.

What can be done to prevent SCD in this vulnerable patient population? This is the ultimate question. There is no doubt that fatal ventricular arrhythmias can be prevented in patients with ischemic heart diseases and HF with reduced ejection fraction (HFrEF). But what about patients maintained on hemodialysis? Well, unfortunately all patients with advanced kidney disease were excluded from automatic internal cardiac defibrillator (AICD) trials such as MADIT-2 trial. However, a retrospective analysis of patients with reduced EF and ESRD in Michigan and Ottawa, Canada did show a mortality benefit with placement of an AICD for both primary and secondary prevention combined. A definitive randomized controlled trial looking at the primary prevention of SCD with AICD in ESRD has not been performed. A recently published matched cohort study in NDT utilizing data from the National Cardiovascular Data Registry’s ICD Registry did not detect a difference in overall mortality in AICDs as primary prevention for SCD. What about pharmacologic therapy in preventing SCD? A study by Cice et al in JACC linked beta-blockers to improved survival in patients on hemodialysis with dilated cardiomyopathy. However, a secondary analysis of the HEMO study published in AJKD did not find a difference in SCD in patients taking beta blockers compared to those who were not. In looking at the renin-angiotensin system blockers, multiple studies have failed to show a reduction in cardiovascular mortality in patients on dialysis (albeit they do show reduction in LV mass). Altogether, we still have much to learn about SCD in ESRD. It is clear that it will take different strategies to curtail SCD. Lastly, it will also be important to start including patients with CKD and ESRD in clinical trials so we can start to achieve a degree of evidence when seeing patients with what we think are risk factors for SCD.

Acute Coronary Syndrome in ESRD

This matchup couldn’t be more similar. Definitely a knock down drag out. Acute coronary syndrome, just as SCD, is just a completely different phenomenon in patients with diminished kidney function (CKD and ESRD) than in the general population. To be fair, the discrete ruptured plaque in an isolated stenotic vessel still occurs in this population but this is far less common than in the general population. The pathophysiology and thus the clinical presentation differ. Not to mention to risk of restenosis, bleeding, or the obligatory AKI event after contrast exposure in CKD. Acute coronary syndrome might need a name change to acute coronary syndrome^CKD.

First, let’s tackle the clinical presentation of acute coronary syndrome (ACS). Patients with diminished kidney function present differently than what is typically seen. To be fair, ACS represents a spectrum of syndromes from unstable angina (UA) to non-ST-elevation myocardial infarction (NSTEMI) to ST-elevation myocardial infarction (STEMI). So, how are they different?

First, patients with CKD are less likely to have:

• typical angina symptoms
• EKG changes (ST elevation or depression), Q waves, LBBB

Secondly, patients with CKD are more likely

• to be admitted with alternate diagnoses
• to have HF symptoms

Making the diagnosis of ACS becomes even more confusing when you factor in alterations seen in serum troponin levels. Troponin levels have become ubiquitous in the diagnosis of ACS. Troponin issues in CKD was a recent topic of #NephJC. Case in point: the mere presence of an slightly elevated serum troponin level portends to worse cardiovascular outcome in patients with advanced CKD or ESRD. The delta change (from baseline level) in troponin is more sensitive for AMI than the absolute level.

What is different in patients with CKD? Why this different presentation and accelerated phenotype? Several theories have emerged. Patients with CKD tend to have a higher burden of multivessel disease with complicated anatomy (longer and more tapered stenoses). The diseased vessels typically have more medial calcification (instead of intimal fibroatheromatous plaque). The traditional risk factors like LDL cholesterol, tobacco use, and family history are weaker associations in CKD despite the higher burden. Postulated pathophysiological reasons are

• chronic inflammation
• less nitric oxide availability
• chronic oxidative stress
• phosphate retention
• secondary hyperparathyroidism
• elevated FGF-23
• intravascular calcium phosphate crystallization
• uremia-related metabolic exposures

Even after the diagnosis is made the treatment of ACS in CKD remains a poorly studied area. Even worse are studies that show that patients with CKD receive suboptimal care than patients with normal kidney function (however, evidence from clinical trials are lacking to truly say these are “evidence based” as CKD is a typical exclusion criteria).

Just as with AICD trials for primary prevention of SCD, ACS treatment trials typically excluded patients with advanced kidney failure. For instance the NORDISTEMI trial (looking at percutaneous intervention (PCI) after thrombolysis) excluded patients with creatinine > 2.8 and the TACTIC-TIMI-18 Trial (looking at PCI in NSTEMI) excluded patients with a creatinine > 2.5. What are we to do? A systematic review published in 2009 reported that patients receiving an early invasive strategy for UA/NSTEMI fared better in CKD. What about coronary artery bypass grafting (CABG) in CKD/ESRD?  Only observational studies looking at PCI versus CABG have been performed in patients with advanced CKD or ESRD. A meta-analysis published in European Journal Internal Medicine in 2013 looking at 28 retrospective studies showed that patients with CKD fared better with CABG compared to PCI. However, this sort of analysis is fraught with problems. It is conceivable that only the “healthier” patients were referred for CABG thus leading to bias in these studies.

Where do we go from here? We need to start including patients with kidney failure in clinical trials for one. We need to start advocating that patients with diminished kidney function receive the same attention as any other patient. We also need to widen our differential diagnosis when seeing patients present with fatigue, shortness of breath and consider ACS. ACS versus SCD will be a tough matchup. Both are serious contenders to go far in NephMadness. However, we still have a lot to learn about each of them.

Sodium Restriction for CHF vs Hypertonic Saline in Acute CHF

Salt, or more specifically sodium, is central to this truly Hamlet of a match up! One has to really take a deep breath and relax before tackling this heavyweight battle. “To be or not to be” he said. Or more fittingly for this bout “to give or not to give!”

Hypertonic Saline in Acute CHF

For many decades sodium restriction has been central in the management of HF over the long term. However, in recent years high concentrations of saline has been used with high-dose loop diuretics for the treatment of acute decompensated failure.

The use of hypertonic fluids has been described as far back as 1919 when Penfield and colleagues described the use of hypertonic fluids in the resuscitation of experimental animals. More recently a number of small trials in the last decade or so have highlighted the potential benefit of using a low volume of hypertonic saline with furosemide for the treatment of acute decompensated HF. Experiments have shown that hypertonic saline can increase regional blood flow to the coronary and renal circulations and can increase cardiac contractility.

A recent meta-analysis looked at 10 randomized but small studies that compared hypertonic saline solution (HSS) and furosemide to furosemide alone. The interventions in each trial varied in terms of the volume of hypertonic saline or normal saline given and the dose of IV furosemide given. The HSS concentrations varied from 1.4% saline to 7.5% saline and the IV furosemide doses ranged from 40 mg daily to 1000 mg twice daily. Furthermore, some trials varied the tonicity of the hypertonic saline depending on baseline serum sodium using a higher percentage sodium solution in people with lower baseline serum sodium.

The largest study (Paterna 2011) compared:

• furosemide 250 mg IV with 150 ml of hypertonic saline twice a day
  • – moderate sodium restriction (~ 2.7 g/d) with
• furosemide 250 mg IV without hypertonic saline
  • – low sodium intake (~1.8 g/d).

The hypertonic saline group had an increase in diuresis and serum sodium levels, reduction in hospitalization time (3.5 vs 5.5 days), lower rate in readmissions (~19% vs ~34%) and lower mortality (~13% vs ~24%). This study also reported a survival benefit for the groups that received the hypertonic saline.

The aforementioned meta-analysis also concluded that hypertonic saline improves weight loss, preserved renal function, and decreased length of hospitalization, mortality, and HF rehospitalization. Of note, the Paterna 2011 study was by far the largest trial and may have driven much of the meta-analysis results. Furthermore, sodium restriction (included in the Paterna 2011 study) is a separate intervention. It is therefore hard to say a short course of hypertonic saline alone leads to improved long-term survival.

Overall, hypertonic saline for the treatment of acute decompensated HF is very promising. A large well-conducted randomized clinical trial needs to be performed to assess the long-term benefits of hypertonic saline treatment.

Sodium Restriction for CHF

The US Department of Agriculture and the Department of Health and Human Services recommend a 2300 mg daily intake of sodium for the general population (2010). Sodium restriction has been the mainstay of treatment for those with hypertension, CKD, and HF. Although there are now many pharmacological and device therapies with proven benefit in HF patients, there is inconsistent evidence supporting the use of sodium restriction in HF management. An Institute of Medicine assessment of the evidence report in JAMA Internal Medicine last year (2014) states there is evidence for potential harm in restricting sodium intake to less than 2.3 g/d in patients with congestive HF. Guidelines for sodium restriction are largely based on expert opinion and the available data is likely flawed by patient non-adherence to restrictive diets and inconsistent self-reporting of sodium intake.

The 2013 AHA/ACC guidelines for HF management suggest a sodium restriction of less than 3 g/d for heart failure stages C+D. This is based on opinion due to the fact that sodium consumption in the general population in the US is over 4 g/d.

Lennie et al showed sodium intake of less than 3 g/d was associated with better outcomes in HF class 3+4. This was an observational study that also reported sodium restriction to below 3 g/d in HF class 1+2 was associated increase hospital visits and mortality. This is contrary to the observational study by Arcand et al that showed sodium intake greater than 2.3 g/d in HF class 1+2 patients was associated with more hospitalizations compared to lower intake.

There are more examples in the literature of contradictory findings with regard to sodium intake and outcomes in HF patients. Most studies include other interventions such as water restriction and various pharmacological treatments. Not all patients enrolled in older trials received current standard to care such as ACE inhibition or beta blockade. Another flaw in this literature is predominance of white patients making it hard to generalize these findings to the total US HF population. Furthermore, there has been no large study investigating the effects of sodium restriction on patients with heart failure and preserved ejection fraction.

In summary it seems that the medical community has little to no evidence to guide the short- or long-term management of sodium balance in heart failure patients. Both the administration of HSS and sodium restriction are cheap interventions with the potential to impact the many millions of patients with heart failure in all parts of the world.

Statins in ESRD vs Coumadin in ESRD

Statins in ESRD

Both the ACC/AHA and KDIGO came out with new recommendations regarding lipid management in late 2013. The ACC/AHA guidelines made no specific recommendations regarding lipid management in ESRD patients. The KDIGO guidelines for lipid management are based on three RCTs:

4D (Die Deutsche Diabetes Dialyse Studie). 4D consisted of 1233 patients on hemodialysis that were treated for 4 weeks with atorvastatin 20 mg or placebo and followed for 4 years.

• LDL was reduced to a greater extent in the statin group.
• no difference in the primary endpoint of cardiac death, non-fatal MI and fatal and non-fatal stroke: the RR was 0.92 (95% CI, 0.77-1.1; p=0.37).
• Atorvastatin did have an effect on fatal stroke (RR, 2.02; 95% CI, 1.05-3.93; p=0.04).
• Overall there was no effect on the primary end points or total mortality.

AURORA Study (A Study to Evaluate the Use of Rosuvastatin in Subjects on Regular Dialysis: an Assessment of Survival and Cardiovascular Events). AURORA had similarly negative results, with 2776 patients on hemodialysis randomized to rosuvastatin 10 mg or placebo with 3.8 years of follow up.

• There was no effect on the primary end point or any component of the primary end point or on all-cause mortality.

SHARP (Study of Heart and Renal Protection). SHARP was the largest and most recent of these studies. This was a randomized trial that assigned 9270 participants aged 40 years or older with CKD to receive simvastatin 20 mg plus ezetimibe 10 mg daily or placebo, and followed them for 4.9 years. ~33% of the patients (n=3023) were receiving maintenance dialysis at randomization.

• This combination treatment did not significantly reduce the risk of primary endpoint in the dialysis subgroup in this study.

A meta-analysis of eighty trials including ~50,000 patients with CKD demonstrated the variable benefits of statin therapy in different CKD stages. Statins reduced all-cause mortality, cardiovascular mortality, and cardiovascular events in patients with CKD not on dialysis but had little or no effect on all-cause mortality (RR, 0.96; 95% CI, 0.88-1.04), cardiovascular mortality (RR, 0.94; 95% CI, 0.82-1.07), or cardiovascular events (RR, 0.95; 95% CI, 0.87-1.03) in persons receiving dialysis.

Overall, there is no evidence for the use of statins in ESRD patients and guidelines suggest not starting a statin on patients who had not already been on one prior to starting dialysis. These trials are disappointing given the huge cardiovascular comorbidity and risk that our patients carry and the large benefit of statins seen in the general population.

Coumadin in ESRD

The use of warfarin (coumadin) in patients with ESRD is unfortunately very common given the frequency of comorbid conditions such as valvular heart disease and thrombosis seen in this patient population. In many of these situations the use of warfarin is unavoidable. Controversy over the use of warfarin arises when considering its use on non-valvular atrial fibrillation (AF). Patients with ESRD are already at increased risk of bleeding and hemorrhagic stroke. Warfarin is a risk factor for vascular calcification through its actions on matrix Gla protein and vascular smooth muscle cell phenotype. Warfarin has also been shown to increase the risk of aortic valve calcification in the general population. We also know that there is greater variability of INR in patients on dialysis and warfarin compared to those on warfarin but not on dialysis. All these issues make the decision to use warfarin a difficult one. On the other hand we know that dialysis patients are at increased risk of ischemic stroke and have higher rates of atrial fibrillation than the general population.

There is little evidence to guide the use of warfarin in dialysis patients with AF and the data that does exist is contradictory.

• A Danish registry study found that the use of warfarin in dialysis patients at high risk for stroke or thromboembolism based on the CHA2DS2-VASc score was associated with significantly lower all-cause mortality.
• Chan et al examined the outcomes of 1671 incident dialysis patients with pre-existing AF treated with warfarin or not. In comparison with nonuse, warfarin use associated with a significantly increased risk for new stroke.
• Shah et al performed a retrospective cohort study of Canadian patients over 65 years of age admitted to hospital with AF. 1626 of these patients were on dialysis. 46% of these dialysis patients were prescribed warfarin. Warfarin use, compared to no warfarin use, was not associated with a lower risk for stroke but was associated with a 44% higher risk for bleeding (adjusted HR, 1.44, 95% CI, 1.13-1.85) after adjusting for potential confounders.

The CHADS2 score in patients on dialysis needs to be interpreted with caution. Two components of this score, hypertension and HF, do not independently predict stroke risk in dialysis patients. This tends to misclassify low stroke risk patients as being high risk. This study by Wizemann et al also demonstrated that warfarin use among patients with pre-existing AF was associated with elevated stroke risk in patients >75 years.

Overall, the data for warfarin use for dialysis patients with AF supports a cautious approach to its use and we probably should be prescribing warfarin less frequently than we do for these patients given the risks outlined above.
Both coumadin and statins may not affect long-term outcomes in ESRD patients. You decide which one of them deserves to move to the next round.

– Post written and edited by Drs. Matthew Sparks, Andrew Malone, and Andrew House.

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