Cardiac Pathological Conditions in Young Soldiers: Case Series
Between July 2006 and April 2007, four young healthy soldiers presented to our emergency department (ED) with serious cardiac pathological conditions. These cases represent morbid conditions in a patient population generally thought to be at low risk for serious cardiac events, particularly in the military, where individuals are screened before service for baseline fitness levels and a multitude of disqualifying medical conditions. We briefly review these disease processes, witii the intent of encouraging others in military medicine to maintain a high index of suspicion index of suspicion Medtalk A phrase broadly used to indicate how seriously a particular disease is being entertained as a diagnosis; as an example, there is a high IOS that rapid and unexplained weight loss in an elderly Pt is due to pancreas CA, and a low IOS that for cardiac conditions even in a relatively young healthy population. We present two unusual cases of myocardial infarction, a coronary artery aneurysm, and a case of smallpox vaccine-induced myocarditis/pericarditis.
A 19-year-old active duty male soldier presented to the ED complaining of severe midsternal chest pain. The pain had developed the previous night and persisted through the morning, worsening with inspiration and fitness training. The patient appeared physically fit and denied any previous episodes of chest pain during his frequent 7-mile runs. He noted shortness of breath Shortness of Breath Definition
Shortness of breath, or dyspnea, is a feeling of difficult or labored breathing that is out of proportion to the patient's level of physical activity. , intermittent bilateral hand numbness, and pain radiating into his neck. He had no significant medical history, no medication or supplement use, and no family history of cardiac disease. He denied alcohol or substance abuse but admitted to smoking tobacco. Initial vital signs were as follows: pulse rate, 92 beats per minute beats per minute Cardiac pacing The unit of measure for the frequency of heart depolarizations or contractions each minute–or pulse rate ; blood pressure (BP), 147/88 mm Hg; respiratory rate, 28 breaths per minute; oxygen saturation, 100% with room air; oral temperature, 98.8°F. The patient reported weight of 183 lb and height of 72 inches (calculated BMI BMI body mass index.
body mass index
Body mass index (BMI)
A measurement that has replaced weight as the preferred determinant of obesity. of 24.8 kg/m^sup 2^). His physical examination and chest X-ray results were unremarkable.
The initial electrocardiogram (ECG) demonstrated ST segment elevations, concerning for an inferior wall myocardial myocardial /myo·car·di·al/ (-kahr´de-al) pertaining to the muscular tissue of the heart.
pertaining to the muscular tissue of the heart (the myocardium). injury (Fig. 1), with no previous ECGs for comparison. The cardiology service was consulted, and the patient was treated in the ED with aspirin, nitroglycerin nitroglycerin (nī'trōglĭs`ərĭn), C3H5N3O9, colorless, oily, highly explosive liquid. It is the nitric acid triester of glycerol and is more correctly called glycerol trinitrate. , intravenously administered morphine, a heparin drip, and an eptifibatide (Integrilin; Schering-Plough, Kenilworth, New Jersey Kenilworth is a Borough in Union County, New Jersey, United States. As of the United States 2000 Census, the borough population was 7,675.
Kenilworth was incorporated as a borough by an Act of the New Jersey Legislature on May 13, 1907, from portions of ) infusion. A bedside echocardiogram ech·o·car·di·o·gram
A visual record produced by echocardiography.
A non-invasive ultrasound test that shows an image of the inside of the heart. did not demonstrate any wall motion abnormality. Pertinent initial laboratory values included a troponin I level of 0.03 ng/mL (normal level, <0.5 ng/mL) and a urine drug screen negative for illicit substances. The patient was taken immediately to the cardiac catheterization laboratory, where near-total occlusion of the distal left anterior descending coronary artery Left anterior descending coronary artery (LAD)
One of the heart's coronary artery branches from the left main coronary artery which supplies blood to the left ventricle.
Mentioned in: Cardiac Catheterization (LAD) was identified. Successful reperfusion was achieved with intracoronary thrombolysis with 10 mg of tenecteplase. An eccentric plaque in the proximal LAD was identified as the likely source of the thrombus, which embolized to the distal portion of the vessel that wrapped around the inferior portion of the heart. All other coronary arteries were angiographically normal.
The remaining hospital course was uneventful, and a transthoracic transthoracic /trans·tho·rac·ic/ (-thah-ras´ik) through the thoracic cavity or across the chest wall.
Across or through the thoracic cavity or chest wall. echocardiogram demonstrated preserved cardiac function. The soldier was discharged 2 days after presentation and began an outpatient regimen of aspirin, metoprolol metoprolol /met·o·pro·lol/ (met?ah-pro´lol) a cardioselective ß used in the form of the succinate and tartrate salts in the treatment of hypertension, chronic angina pectoris, and myocardial infarction. , simvastatin, lisinopril, and nitroglycerin.
A 39-year-old male firefighter was brought to the ED by emergency medical services An Emergency medical service (abbreviated to initialism "EMS" in many countries) is a service providing out-of-hospital acute care and transport to definitive care, to patients with illnesses and injuries which the patient believes constitutes a medical emergency. after a syncopal syn·co·pal
Of or relating to syncope. event that occurred during dinner. He experienced an episode of diaphoresis diaphoresis /di·a·pho·re·sis/ (-fah-re´sis) sweating, especially of a profuse type.
Perspiration, especially when copious and medically induced. and lightheadedness, followed by a witnessed loss of consciousness lasting ~10 seconds. The patient denied similar previous episodes, recent illness, and changes in activity. He described persistent lightheadedness but denied chest pain, pain in the jaw or upper extremities, shortness of breath, nausea, and palpitations. His medical history was significant for hyperlipidemia. Medications included simvastatin, Ibuprofen, and multivitamins. His social history was notable for occasional alcohol use but was negative for illicit substances, tobacco, and herbal supplements. There was no family history of coronary artery disease coronary artery disease, condition that results when the coronary arteries are narrowed or occluded, most commonly by atherosclerotic deposits of fibrous and fatty tissue. or sudden cardiac death Sudden Cardiac Death Definition
Sudden cardiac death (SCD) is an unexpected death due to heart problems, which occurs within one hour from the start of any cardiac-related symptoms. SCD is sometimes called cardiac arrest. . Initial vital signs were as follows: pulse rate, 74 beats per minute; BP, 135/83 mm Hg; respiratory rate, 18 breaths per minute; oxygen saturation, 100% on a rate of supplemental oxygen at 2 L/min through a nasal cannula; oral temperature, 95.1 °F. The physical examination and chest X-ray results were unremarkable.
The initial ECG was concerning for early repolarization repolarization /re·po·lar·iza·tion/ (re-po?ler-i-za´shun) the reestablishment of polarity, especially the return of cell membrane potential to resting potential after depolarization. versus an acute inferior wall myocardial injury (Fig. 2). The patient received aspirin, nitroglycerin, and metoprolol. He had one episode of profound bradycardia bradycardia: see arrhythmia. (to 30 beats per minute), lasting several minutes, without associated chest pain or dyspnea. This resolved after administration of a bolus of 500 mL of normal saline solution and Trendelenburg positioning. The cardiology service was consulted and heparin treatment was initiated in the ED. The initial troponin I level was 0.11 ng/mL, and the other laboratory values were normal. Over the next several hours, the patient's ECG findings evolved with increasing ST segment elevations consistent with an inferolateral wall myocardial injury (Fig. 3). Tenecteplase was administered at that time (~3 hours after symptom onset) with subsequent resolution of ECG abnormalities (Fig. 4). The troponin I level peaked at 93.48 ng/mL. Cardiac catheterization the following morning showed no regional wall motion abnormalities, a left ventricular ejection fraction of 65%, and 90% occlusion of the late proximal circumflex circumflex /cir·cum·flex/ (serk´um-fleks) curved like a bow.
1. Curving or bending around.
curved like a bow. coronary artery, which was treated with stenting. The patient began treatment with ß receptor blockers, aspirin, and Clopidogrel. The rest of the hospital course and outpatient follow-up care was uneventful.
A healthy 19-year-old active duty male soldier presented to the ED complaining of a sore throat accompanied by substernal chest pain and nausea for 1 hour. He reported being awakened from sleep by chest pain characterized as 9/10 severity, squeezing, pulling, and tightness associated with bilateral upper-extremity paresthesias Paresthesias
A prickly, tingling sensation.
Mentioned in: Autoimmune Disorders , dyspnea, nausea, and diaphoresis. The patient denied previous similar episodes, a history of illicit drug use, and any antecedent illness. He had been in his usual state of health before this episode and denied any significant medical, surgical, or family history. He denied taking medications or herbal supplements but smoked tobacco and occasionally used alcohol. Initial vital signs were as follows: pulse rate, 45 beats per minute; BP, 130/80 mm Hg; respiratory rate, 16 breaths per minute; oxygen saturation, 98% with room air; oral temperature, 98.2°F. The physical examination and chest X-ray results were unremarkable.
The initial ECG (Fig. 5), compared with a previous ECG (Fig. 6), demonstrated ST segment changes concerning for early repolarization versus anterolateral anterolateral /an·tero·lat·er·al/ (an?ter-o-lat´er-al) situated anteriorly and to one side.
In front and away from the middle line. injury with associated hyperacute T waves. Soon after arrival, however, the patient began to have worsening chest pain. A repeat ECG was performed (Fig. 7), confirming an anterolateral myocardial injury. The cardiology service was consulted and treatment with aspirin, dolasetron (for nausea), morphine, and nitroglycerin infusion was initiated, witii minimal improvement in the patient's symptoms, ß receptor blockers were withheld because of bradycardia. Additional therapy initiated in the ED included Clopidogrel, heparin, and eptifibatide. A bedside transthoracic echocardiogram revealed severe hypokinesis/akinesis of the anterolateral wall of the myocardium myocardium /myo·car·di·um/ (-kahr´de-um) the middle and thickest layer of the heart wall, composed of cardiac muscle.
hibernating myocardium see myocardial hibernation, under . The patient was taken to the cardiac catheterization laboratory and was found to have a large aneurysm that involved the left circumflex artery, the first diagonal branch (Dl), and the proximal portion of the left main artery, with 100% thrombotic occlusion of the LAD and Dl (Fig. 8). The D1 territory was partially reperfused with angioplasty. The LAD remained occluded despite several attempts. The patient was transferred to the intensive care unit with an intra-aortic balloon pump intra-aortic balloon pump
A pump connected to a balloon device that is inserted into the descending aorta to provide temporary assistance to the heart in the management of left ventricular failure. and subsequently underwent emergency cardiothoracic surgery, during which a three- vessel bypass of the LAD, obtuse marginal coronary artery, and D1 was performed. Repeat cardiac catheterization 11 days after bypass showed the left main aneurysm with flow to the left circumflex artery and D1, a thrombosed thrombosed /throm·bosed/ (throm´bozd) affected with thrombosis.
2. Of, being, or characterizing a blood vessel that is the seat of thrombosis. proximal LAD with retrograde filling via a left internal mammary artery graft to the diagonal artery territory, and patent vein grafts to the left circumflex and obtuse marginal arteries. The ventriculogram showed akinesis to the anterior middle/distal wall and apex, with an ejection fraction of 35% to 40%. The patient was discharged with an outpatient regimen of lisinopril, metoprolol, warfarin, spironolactone spironolactone /spir·o·no·lac·tone/ (spi?rah-no-lak´ton) one of the spirolactones, an aldosterone inhibitor that blocks the aldosterone-dependent exchange of sodium and potassium in the distal tubule, thus increasing excretion of sodium , aspirin, Clopidogrel, and simvastatin. He later required automated implantable cardioverterdefibrillator placement because of his compromised cardiac function and was medically discharged from the military.
A 26-year-old healthy active duty male soldier presented to the ED complaining of a 1-day history of chest pain. His chest pain began at rest and was substernal, constant, nonradiating, of 5/10 severity, and worse with deep breaths and lying supine but improved witii sitting forward. For the previous 5 days, the patient had experienced sore throat, low-grade fevers, fatigue, myalgias, lightheadedness, nausea, and one episode of vomiting. Eleven days before presentation, the patient had received a smallpox vaccine intramuscularly and a live attenuated influenza vaccine intranasally administered. A review of systems was otherwise negative. The patient had no previous history of similar chest pain and denied stimulant or other recreational drug use Recreational drug use is the use of psychoactive drugs for recreational purposes rather than for work, medical or spiritual purposes, although the distinction is not always clear. . His medical, surgical, and family histories were unremarkable. His only coronary artery disease risk factor was smoking, and he had no pulmonary embolism risk factors. Initial vital signs were as follows: pulse rate, 98 beats per minute; BP, 112/78 mm Hg; respiratory rate, 18 breaths per minute; oxygen saturation, 98% with room air; oral temperature, 100.9°F. The physical examination and chest X-ray results were unremarkable.
The initial ECG showed ST segment elevation in an inferolateral distribution, with PR segment depression in lead II (Fig. 9), concerning for myocardial injury versus pericarditis Pericarditis Definition
Pericarditis is an inflammation of the two layers of the thin, sac-like membrane that surrounds the heart. This membrane is called the pericardium, so the term pericarditis means inflammation of the pericardium. . Laboratory testing was significant for a white blood cell count white blood cell count,
n a diagnostic clinical laboratory test to determine the number and types of leukocytes present in a measured sample of blood. Overall the normal number of leukocytes ranges from 5000 to 10,000/mm3. of 11.7 × 10^sup 3^ cells per µL (reference range, 3.7-10.0 × 10^sup 3^ cells per µL), a troponin I level of 6.54 ng/mL, and a C-reactive protein level of 26.9 mg/L (reference range, 0-8 mg/L). The patient was given aspirin, acetaminophen, and intravenous fluids. He was admitted to the cardiology service with a diagnosis of smallpox vaccine-associated myocarditis/ pericarditis.
During admission, the patient's subsequent ECGs showed anterior, lateral, and inferior ST segment elevation with PR segment depression. A transthoracic echocardiogram showed no pericardial effusion, no wall motion abnormalities, and an ejection fraction of 50% to 55%. Cardiac catheterization was subsequently performed and showed widely patent coronary arteries, an ejection fraction of 50%, and mild hypokinesis of the inferior wall base. The patient was discharged the next day on 1 month of light duty with no further medical therapy. Two weeks later, he was resuming his fitness training and was symptom-free at follow-up evaluation.
Although there may be a low prevalence of cardiac disease in young military patients, military health care officers must remain vigilant for serious cardiac pathological conditions. Sudden death in young military recruits is a rare event, occurring at a rate of ~13.0 deaths per 100,000 recruit-years. The most common cause of death on autopsy is structural cardiac abnormality (51% of cases), such as anomalous coronary artery from the sinus of Valsalva, myocarditis Myocarditis Definition
Myocarditis is an inflammatory disease of the heart muscle (myocardium) that can result from a variety of causes. While most cases are produced by a viral infection, an inflammation of the heart muscle may also be instigated by , or hypertrophic cardiomyopathy.1 Although our case series may not be representative of the majority of patients complaining of chest pain and near-syncope/syncope who present to general medical officers or military physicians, these cases demonstrate a variety of cardiac pathological conditions that may be encountered. The differential diagnosis for chest pain in a young, healthy, active duty soldier includes but is not limited to costochondritis, bronchitis, asthma, pneumonia, spontaneous pneumothorax, mediastinitis, gastroesophageal reflux or spasm, esophageal rupture, pulmonary embolus, pericarditis, myocarditis, aortic dissection, structural abnormalities such as coronary artery aneurysms, and acute coronary syndrome acute coronary syndrome
A sudden, severe coronary event that mimics a heart attack, such as unstable angina.
acute coronary syndrome .
The first case, involving a 19-year-old soldier with an inferior wall myocardial infarction, highlights the importance of a low threshold for the evaluation of myocardial injury, even in young athletic patients. According to the American Heart Association American Heart Association (AHA),
n.pr a national voluntary health agency that has the goal of increasing public and medical awareness of cardiovascular diseases and stroke, and thereby reducing the number of associated deaths and disabilities. , major risk factors for heart disease include male gender, increasing age, family history, smoking tobacco, hyperlipidemia, hypertension, diabetes mellitus, obesity, and physical inactivity, of which this patient had two factors. Other risk factors include clotting abnormalities, endothelial dysfunction, hyperuricemia hyperuricemia /hy·per·uri·ce·mia/ (-u?ri-se´me-ah) uricemia; an excess of uric acid in the blood.hyperurice´mic
An unusually high concentration of uric acid in the blood. , arterial intima-media thickening, infection, collagen vascular disease collagen vascular disease
See collagen disease. , calcification of major vessels and coronary vessels, thrombophilias, Kawasaki disease, and consumption of vasospastic stimulants such as cocaine.2,3 Infectious disorders such as cytomegalovirus, chlamydia, hepatitis A, and Helicobacter pylori, all of which lead to inflammation that leads to endothelial dysfunction, have been implicated in the pathogenesis of atherosclerotic disease.4 Paradoxical embolism via an atrial septal defect Atrial Septal Defect Definition
An atrial septal defect is an abnormal opening in the wall separating the left and right upper chambers (atria) of the heart. or patent foramen ovale patent foramen ovale PFO Cardiology An opening between the left and right atria which allows blood to bypass the lungs in utero; the FO normally closes shortly after birth, but remains open in up to 20%; a PFO is, in absence of other cardiac defects, is of no consequence has also been implicated for young patients with ST segment-elevation myocardial infarctions with a very low incidence.5 Although risk factors are important considerations in determining populations that may develop cardiac disease, they are poor predictors for determining individual cases of acute coronary syndrome in patients presenting with chest pain. The value of understanding varied pathophysiological features of cardiac disease to generate clinical suspicion for any patient, young or old, with symptoms of chest pain and ECG findings cannot be overemphasized.
After extensive evaluation of this 19-year-old patient, including a normal coronary angiogram an·gi·o·gram
An angiographic x-ray of blood vessels used in diagnosing pathological conditions of the cardiovascular system.//An x-ray of one or more blood vessels produced by angiography and used in diagnosing pathology in the cardiovascular , it was thought that he exhibited a component of endothetial dysfunction, which is one of two mechanisms involved in an entity called cardiac syndrome X. Cardiac syndrome X, which is distinctly different from metabolic syndrome X, is characterized by coronary microvascular dysfunction such as abnormal dilatory Tending to cause a delay in judicial proceedings.
Dilatory tactics are methods by which the rules of procedure are used by a party to a lawsuit in an abusive manner to delay the progress of the proceedings. responses and/or increased vasoconstriction vasoconstriction /vaso·con·stric·tion/ (-kon-strik´shun) decrease in the caliber of blood vessels.vasoconstric´tive
n. and enhanced sensitivity to intracardiac pain (the "sensitive heart" syndrome).6-10 Ongoing studies are being performed to better elucidate the cellular mechanisms responsible for cardiac syndrome X and to establish treatment options.
Case 2, involving a 39-year-old, healthy, active, male firefighter with relatively few cardiac risk factors, highlights an atypical presentation of a ST segment-elevation myocardial infarction with syncope syncope
Effect of temporary impairment of blood circulation to a part of the body. It is often used as a synonym for fainting, which is loss of consciousness due to inadequate blood flow to the brain. and no chest pain. Whereas the other cases demonstrate severe cardiac pathological conditions in young patients with chest pain symptoms, this case was included to remind clinicians that myocardial injury is possible without the classic symptoms of chest pain/pressure or dyspnea, even in nondiabetic patients. This case also demonstrates the value of serial ECGs, especially when the initial ECG is nondiagnostic. One retrospective study of atypical presentations of acute coronary syndrome showed that 51.7% of 4,167 patients with confirmed unstable angina pectoris had no chest pain. The most frequent symptoms associated with atypical presentations were dyspnea (69.4%), nausea (37.7%), diaphoresis (25.2%), pain in the arms (11.5%), syncope (10.6%), epigastric epigastric adjective Referring to the body region between the costal margins and the subcostal plane pain (8.1%), shoulder pain (7.4%), and neck pain (5.9%).11 A review of >20,881 patients in the Global Registry of Acute Coronary Events in 95 hospitals from 14 countries identified 8.4% of patients with confirmed acute coronary syndrome with no evidence of chest pain on the chart and presenting symptoms similar to those in the former study. As might be expected, the hospital morbidity and mortality Morbidity and Mortality can refer to:
Case 3 demonstrates the devastating morbidity of a coronary artery aneurysm in a 19-year-old man. Coronary artery aneurysms may be congenital, may develop as a result of an underlying congenital coronary artery-pulmonary artery fistula or arteriovenous fistula, or may be formed through trauma, substance abuse (such as cocaine), or inflammatory processes such as periarteritis nodosa, Takayasu disease, or Kawasaki disease. Interestingly, the patient's mother reported mat the patient had a prolonged, highly febrile illness with unexplained rashes as a child, which resolved without medical intervention. In light of his coronary artery aneurysm and ischemia, it was suspected that the patient had experienced an undiagnosed case of Kawasaki disease as a child. Kawasaki disease is the most common cause of acquired coronary artery disease in childhood.13 Kawasaki disease is a febrile childhood illness that usually occurs between the ages of 6 months and 5 years and is characterized by a 5-day history of fever and four of the following: bilateral nonsuppurative conjunctivitis conjunctivitis (kənjəngtəvī`təs), inflammation or infection of the mucosal membrane that covers the eyeball and lines the eyelid, usually acute, caused by a virus or, less often, by a bacillus, an allergic reaction, or an , bright red, swollen, cracked lips, "strawberry" tongue, a polymorphous rash, extremity edema with subsequent desquamation desquamation /des·qua·ma·tion/ (des?kwah-ma´shun) the shedding of epithelial elements, chiefly of the skin, in scales or sheets.desquam´ative
1. , and cervical lymphadenopathy. Incomplete or atypical Kawasaki disease may exhibit fewer of the aforementioned characteristics but demonstrate complications of Kawasaki disease.14
Complications of Kawasaki disease include coronary abnormalities such as coronary artery aneurysms, coronary stenosis, myocarditis, pericarditis, and valvulitis valvulitis /val·vu·li·tis/ (val-vu-li´tis) inflammation of a valve, especially of a heart valve.
Inflammation of a valve, especially a cardiac valve. . In untreated patients, the incidence of coronary artery aneurysms is ~20% to 25%, with a mortality rate of ~2%. Approximately onethird of aneurysms larger than 8 mm become obstructed, leading to myocardial infarction, arrhythmias, or sudden death.15 Treatment is aimed at reducing the coronary inflammation and risk of thrombosis by using high-dose aspirin and intravenously administered immunoglobulin. Any delay in diagnosis, especially after 10 days, can increase the patient's likelihood of developing aneurysms.16 Although most cardiac sequelae sequelae Clinical medicine The consequences of a particular condition or therapeutic intervention occur in the first year after the viral illness, many delayed presentations have been reported. Tsuda et al.17 reported six cases involving patients 25 to 48 years of age with clinical features consistent with previous Kawasaki disease, all asymptomatic until presentation. Clinicians should be aware of the clinical sequelae of the disease and therefore consider Kawasaki disease for patients presenting with severe chest pain.
Case 4, involving a 19-year-old patient with myocarditis/ pericarditis, demonstrates a rare but known complication of smallpox vaccination. Childhood vaccination for smallpox had been routine in the United States until nearly worldwide eradication by 1971. In the wake of the September 11, 2001, terrorist attacks, the Department of Defense and the Department of Health and Human Services Noun 1. Department of Health and Human Services - the United States federal department that administers all federal programs dealing with health and welfare; created in 1979
Health and Human Services, HHS began administering the smallpox vaccine at the end of 2002. The U.S. Food and Drug Administration had approved a calf lymph-derived vaccinia strain (Dryvax; Wyeth Laboratories, Marietta, Pennsylvania). In 2003, between January and October, 38,885 vaccinations were administered with 100 serious adverse effects resulting in 2 permanent disabilities and 3 deaths.18 Among these, there were 21 cases of myocarditis and/or pericarditis (5 probable and 16 suspected), 10 cases of cardiac ischemia not anticipated on the basis of historical data,19 and 2 cases of delayed (2-3 months) dilated cardiomyopathy. The rates of probable or confirmed myocarditis/pericarditis in the two programs were similar (1.3 cases per 10,000 vaccinees in the Department of Health and Human Services program and 1.2 cases per 10,000 vaccinees in the Department of Defense program).20 The interval between vaccination and onset of cardiac symptoms was 7 to 14 days. Given that the smallpox vaccine is still being administered to members of the military, Department of Defense physicians should retain a high index of suspicion for these rare but potentially serious cardiac complications in postvaccination patients.
These cases highlight the fact that serious cardiac pathological conditions do occur in otherwise healthy, young soldiers. A careful history and physical examination are paramount. However, a high index of suspicion and a low threshold for performing basic diagnostic tests, such as a chest X-ray and ECG, with consideration of serial ECGs for ongoing symptoms, are encouraged when these potentially devastating conditions are being assessed. In each of these cases, the index of suspicion, as well as identification of abnormal ECGs, led to the diagnosis.
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