Know the Warning Signs

2.6 CONTACT HOURS

Know the warning signs

By Jessica Gill, RN, CRNP, PhD Leorey N. Saligan, RN, CRNP, PhD Wendy A. Henderson, CRNP, MSN, PhD Sarah Szanton, ANP, MSN, PhD

osttraumatic stress disorder (PTSD) is an anxiety objective of this review is to provide rationale and tools disorder that commonly occurs in primary care for PTSD assessment and treatment in primary care settings, P patients. Patients with PTSD experience declines as well as a brief overview of physiologic changes in PTSD in physical and psychological health.Although these declines patients. are often observed by NPs and other primary care providers (PCPs), PTSD is not routinely assessed in primary care. ■ Incidence PTSD develops after exposure to a traumatic event and In the course of a lifetime, 90% of Americans experience a is associated with debilitating physical and psychological traumatic event from which most recover without experi- health declines. Symptoms of PTSD include re-experiencing encing PTSD.1,2 However, there are important characteris- the traumatic event through intrusive dreams or thoughts, tics that can increase the risk of PTSD. These include avoidance or arousal when the patient encounters stimuli assaultive trauma or trauma that occurs at an early age.11 that symbolize the event, numbing of feelings, and avoid- Rates for current PTSD in the general U.S. population range ance of thoughts, feelings, people, and activities that sym- from 2% to 4%.1,2,12 In primary care patients, rates for cur- bolize the event. PTSD has been recognized as an anxiety rent PTSD range from 8% to 30%.6,7 Women develop PTSD disorder that can impact any individual, resulting in lifetime at twice the rate of men.1,2,12 This vulnerability may be re- prevalence rates of 5% for men and 10% for women.1,2 Be- lated to an increased risk of experiencing assaultive events. cause people with PTSD suffer from multiple medical con- However, women are at a greater risk than men to develop ditions3,4 and a lower subjective health rating5, PTSD rates PTSD, independent of event type.1 in primary care settings are at least double the national rate.6,7 In addition, individuals with PTSD experience increased ■ Comorbid conditions medical care costs.8 More women with PTSD seek care for Individuals with PTSD may be more prominent in primary these symptoms in primary care settings compared with care settings due to greater use of outpatient services.8,13 In psychiatric settings.9 Although 8% to 30% of primary care addition, individuals with PTSD report at least one other patients present with PTSD, PCPs rarely assess for it.10 The medical condition when compared with traumatized and

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nontraumatized controls without PTSD, including chronic uals. If these patients are treated for medical complaints pain, diabetes, cardiovascular disease, autoimmune disor- without addressing the underlying psychological response ders, thyroid disorders, and gastrointestinal disorders.3-5,7 to trauma, the pattern of continued health visits without Therefore, PTSD is often associated with multiple medical symptom improvement is likely to continue. issues that may result in complex medical complaints, some of which may be treatment-resistant. Recognizing and treat- ■ Pathophysiology ing PTSD may help protect some patients from developing Patients with PTSD exhibit multiple alterations in biologic these health alterations. function, including the neurologic, endocrine, and immune Over 80% of individuals with PTSD have another psy- systems,all of which may contribute to health declines.Func- chiatric disorder.1,2,11 Common comorbid psychiatric disor- tioning of memory areas in the brain is altered, resulting in ders include major depressive disorder (MDD), generalized the development of many PTSD symptoms. Specific brain anxiety disorder, drug and alcohol abuse and dependence, areas implicated in PTSD include the amygdala, the hip- and obsessive compulsive disorder. MDD is well researched pocampus, and the prefrontal cortex (see Location of the in the primary care setting and healthcare providers are now amygdala and hippocampus). There is reduced volume of apt to recognize and intervene with MDD, however, its the hippocampus in adults and children with PTSD;15 comorbidity with PTSD may go undiagnosed. As an exam- however, return to normal hippocampal volume has been ple, one-third of depressed patients seen in primary care reported with treatment and symptom remission.16 Reduced who were previously assessed and not identified as having memory function has also been observed and related to PTSD were found to be positive for PTSD during a research functional alterations in brain activity in the amygdala, screening.10 In another recent study, only 11% of primary hippocampus, and other brain structures, indicating that care patients with current PTSD had a diagnosis of PTSD multiple neurologic alterations may be related to PTSD in their charts.14 Recognition and treatment of PTSD in symptoms.17 primary care settings may be the most effective way to The hypothalamic-pituitary-adrenal (HPA) axis pro- improve mental and physical health in traumatized individ- duces hormones in basal and stressed states that regulate immune, neural, and other bodily functions. Alterations in this complex Location of the amygdala and hippocampus set of hormonal feedback loops of the HPA axis alterations have been observed in PTSD patients.18 The hallmark of PTSD among combat veterans is low cortisol levels and a greater negative feedback system for cortisol as tested with pharmacologic and nonpharma- cologic stimulation, indicating alterations in HPA axis function. These findings were surprising considering patients with PTSD reported high levels of stress.18 Recent studies have reported con- trasting findings, suggesting that sex, duration of PTSD, and other factors may contribute to alterations in HPA axis function.19 However, independent

Amygdala Brain stem and cerebellum of the direction of the observed alter- (beneath overlying cortex) removed and brain ation, any disruption in function of the rotated slightly HPA axis may result in the development Hippocampus of additional health conditions.20 (beneath overlying cortex) PTSD studies have reported evi- dence of increased inflammatory activ- Source: Bear MF, Connors BW, Parasido MA. Neuroscience - Exploring the Brain. 2nd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2001. ity in the immune system, including higher levels of stimulated and non-

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stimulated inflammatory cytokines,21-25 and a greater re- predictive of PTSD development, especially if events are on- sponse to antigens.26 These higher levels of inflammatory going (such as child abuse) or occurred in childhood.11 The activity have been linked to HPA axis abnormalities.21,25 A patient must have at least one symptom of re-experiencing chronically activated inflammatory response has been shown the trauma, three symptoms of avoidance or numbing re- to exert adverse reactions on many body systems. Specifically, lated to the traumatic event, and at least two symptoms of elevations of interleukin-6 (IL-6) have been associated with hyperarousal when reminded of the trauma (see Symptoms reports of chronic pain, arthritis, diabetes, cardiovascular of PTSD). These symptoms must have been present for at disease, and other medical conditions that have been associ- least 1 month, cause significant distress, and affect the pa- ated with PTSD.3,4,7,13 tient’s ability to function socially, occupationally, or domes- tically. If symptoms last for more than 3 months, a diagnosis ■ Development and progression of PTSD of chronic PTSD is established.27 To qualify for a PTSD diagnosis according to the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR), Common signs and symptoms the precipitating traumatic event must have occurred at least PCPs should assess for PTSD if the patient reports an ex- 3 months prior to assessment.27 If the precipitating event oc- perience of a traumatic event. State-mandated regulations curred less than 3 months prior, and the patient displays for reporting incidents of abuse should be followed. A pa- PTSD symptoms that cause distress, then the diagnosis of tient who divulges a recent event provides the PCP with an acute stress disorder may be appropriate. Traumatic events can be classified as an experienced event, a witnessed event, or an event that was learned of, and can range from being Symptoms of PTSD27 raped to learning that a family member or close friend was Re-experiencing symptoms (must have at least 1): injured (see Traumatic events). Assaultive events are most • Recurring memories of the event •Nightmares of the event • Intense fear, anxiety, or physical discomfort when Traumatic events27 patient is reminded of the event •Flashbacks; feeling or acting as if the event is Episodic assaultive violence: reoccurring while awake •Raped • Other sexual assault Avoidance of things that remind the patient of the event, and feelings of numbing (must have 3) • Shot or stabbed •Avoiding people, places, or things that remind the • Mugged or threatened with a weapon patient of the event •Badly beaten up •Avoiding thoughts or feelings that remind the patient of Repeated assaultive violence: the event • Combat exposure •Inability to recall certain things about the event • Intimate partner violence • Decreased activity in things previously enjoyed •Child physical abuse •Patient feels detached from other people; no one •Child sexual abuse understands • Sense of foreshortened future Other injury or shocking experience: • Restricted range of feelings •Serious car or motor vehicle accident • Any other kind of serious accident/injury Hyperarousal (must have 2) •Fire, hurricanes, or other natural disasters • Problems falling or staying asleep •Diagnosed with a life-threatening illness • Problems concentrating •A child diagnosed with a life-threatening illness •Irritability or outbursts of anger • Hypervigilance: The feeling of always having to be Witnessed events: ready to react. The patient may also report that he or •Saw someone get killed or seriously injured she is more attentive to sounds •Discovered a dead body •Exaggerated startle response: Sounds, being touched or surprised in any way can cause the patient to jump or Learned events of a close friend/relative: be startled. •Raped or sexually assaulted •Serious physical attack These symptoms must have been present for 1 month, cause significant distress or impaired •Seriously injured in a car or other accident functioning, and cannot be due to a medical condition • Unexpected death or use of drugs or alcohol.

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To determine if the patient has symptoms of PTSD, the Short screening scale for PTSD28,29 PCP can either question the patient about these symptoms or use a standard instrument. The Short Screening Scale, de- In your life, have you ever had any experience that wasso 28 29 frightening, horrible, or upsetting that, in the past month... veloped by Breslau et al. and evaluated by Kimerling et al., 1. you have avoided being reminded of this experience by is a 7-question tool designed specifically for PTSD diagnosis staying away from certain places, people, or activities? in the primary care setting (see Short screening scale for 2. you have lost interest in activities that were once PTSD). Patients respond with a “yes” or “no” to each ques- important or enjoyable? tion. A sum score of 6 or greater predicts a PTSD diagno- 3. you have begun to feel more isolated or distant from 29 other people? sis. Although this instrument predicts a PTSD diagnosis, it 4. you have found it hard to feel love or affection for does not provide information on all PTSD symptoms. In other people? contrast, the PTSD symptom scale developed by Foa et al.30 5. you have begun to feel that there was no point in can be filled out by the patient or PCP, and provides infor- planning for the future? mation on all PTSD symptoms to track response to treat- 6. you have had more trouble than usual falling asleep or staying asleep? ment. Both tools are valuable, however a clinical interview 7. you have become jumpy or get easily startled by to determine symptoms and develop a rapport with the ordinary noises or movements? patient is necessary.

Mandatory reporting of trauma opportunity to intervene early and possibly prevent PTSD Reporting current abuse is mandatory for child abuse and development. Commonly reported PTSD-related psycho- may be mandatory even if the patient is an adult. Each logical symptoms include irritability,anger,problems sleep- state has different regulations that need to be determined ing, inability to relate to others, and physical restlessness. and discussed with the patient prior to assessing trau- In addition, if the patient is not responding to pharmaco- matic events. Information can be obtained at the National logic treatment of depression or anxiety, an assessment of Domestic Violence Hotline: 1-800-799-SAFE and the Na- PTSD is advised. tional Child Abuse Hotline (1-800-4-A-CHILD), or a state department that provides services for children. Focused assessment Patients who have experienced a traumatic event may be ■ PTSD intervention guarded, defensive, and unwilling to talk about it at the Treating patients with PTSD in primary care can include first meeting. If PCPs create a supportive and trusting re- prescribing medication, referral for short-term individ- lationship, patients may be more likely to disclose their ual or group psychotherapy, or both. Referral to a psy- traumatic experience. A PCP asking about the patient’s chotherapist or psychiatrist is required if the patient traumatic experiences should acknowledge that this is a reports any suicidal or homicidal ideation, is in acute cri- life-altering experience. The patient may feel better un- sis, or requires more intense treatment than the primary derstood and more willing to provide information that care setting can provide. In addition, referral to a psychi- can help improve care. Ways in which traumatic events atrist is required if medication management is not suc- can be assessed include asking the following questions: cessful, if there are multiple psychiatric comorbidities, or 1.“At some point in life, most people experience something if the patient needs more intensive care due to disability that may be traumatic or stressful. Has something like this or safety risk.31 ever happened to you?” 2.“Have you ever witnessed an event that happened to an- Early intervention other person that made you feel frightened, shocked, or In patients who recently experienced a traumatic event, helpless?” recognizing symptoms and providing immediate treat- 3.“Have you ever been sexually, physically, or emotionally ment may prevent the development of PTSD. In addition harmed by another person?” to pharmacologic and psychological therapy, PCPs may Following any disclosure of a traumatic event, patients also take the following actions: educate PTSD patients may feel vulnerable and need reassurance and support. Pro- that their response is normal, provide information re- viding information on resources and treatment options may garding acute stress disorder and PTSD symptoms, en- give the patient hope. It is equally important to assess for courage patients to talk with supportive family and friends suicidal feelings in those who are distressed and provide about their symptoms, and provide emotional support immediate help and referral. and referral to support groups.32

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■ Pharmacologic options pain, and insomnia. Medical causes for these symptoms have First-line treatment for PTSD is a serotonin reuptake in- been ruled out. She appears in your primary care office tear- hibitor (SSRI); however the FDA has only approved the ful and anxious. When you ask her if anything has changed SSRIs paroxetine (Paxil) and sertraline (Zoloft) for use in in her life, she reports that her husband has become increas- treating PTSD (see Psychotropic medication for the treatment ingly angry and explosive and has been hitting and pushing of PTSD). Non-SSRI antidepressants may also be effective her over the past year. She says that she does not feel safe in (such as venlafaxine, mirtazapine), although fewer studies her house. She describes nightmares about the abuse and have supported their use and efficacy.33 In addition, mood says that, on most nights, she feels “on edge and jumpy,”and stabilizers, antianxiety medications, adrenergics, and atypi- is unable to calm down. She also says she has insomnia, re- cal psychotics can be used to treat patients who do not reduced appetite, and feels that she is no longer a useful per- spond to antidepressants, and should be selected based on son, is depressed every day, and that she avoids family and the patient’s presenting symptoms. These medications can friends who want to talk about her relationship with her hus- also be used as an adjunct to antidepressants if the patient band. She denies suicidal feelings. reports incomplete reduction of symptoms following treat- Rose reports that she experienced depression about 5 ment with the antidepressant. A lower dose would then be years ago, and that the current anxiety and nightmares required if the medication is prescribed as an adjunct.34 started immediately after the physical abuse began. After Medication to promote nighttime sleeping may also be questioning her further regarding PTSD symptoms, you effective and includes zolpidem, zaleplon, and diphenhy- determine that she has PTSD and comorbid depression. dramine.35 Prescribing multiple psychotropic medications You prescribe paroxetine (Paxil) 20 mg per day, which is is often required, especially in patients who have chronic the medication that resolved her depression symptoms dur- PTSD, those who have not responded to previously pre- ing her previous episode. She is willing to see a trained ther- scribed medications, or have other psychiatric comorbidi- apist and to return to the clinic for medication management. ties. The following combinations have been recommended: In addition, you provide information about local resources 1. antidepressant + mood stabilizer for domestic violence shelters, support groups for abused 2. antidepressant (SSRI) + other class of antidepressant women, and hotline numbers to access 24 hours a day. Fur- 3. antidepressant + antipsychotic thermore, you advise Rose to keep this information in a place 4. antidepressant + sleeping medication where her husband will not find it. You encourage Rose to 5. antidepressant + short-term antianxiety medication.33-36 use all the resources available.

■ Psychological therapy Short-term supportive therapy Psychotropic medication for the treatment of PTSD may be available in a primary care Medication class Specific medications Symptom reductions setting. Some primary care offices have a counselor or therapist on- SSRIs • Sertraline • Overall PTSD symptoms (FDA-approved) • Paroxetine • Improved sleep site. If therapy is not available in • Comorbid depression the primary care office, referral to a trained therapist is advised. Dual serotonin • Venlafaxine • Overall PTSD symptoms Therapy using cognitive behav- and noradrenergic•Mirtazapine • Comorbid depression reuptake inhibitors ioral methods or exposure therapy, (off-label use) which is a specific psychological method used to treat PTSD,are the Mood stabilizers • Valproic acid • Overall PTSD symptoms most effective modalities. Psycho- and anticonvulsants • Lamotrigine • Mood lability (off-label use) • Topiramate logical therapy in conjunction with •Gabapentin medication results in higher remission and symptom reduction Atypical•Olanzapine • Psychotic symptoms rates than either method alone.33 antipsychotics • Risperidone that present with PTSD (off-label use) • PTSD symptoms when used as an adjunct ■ Case study 1 Rose is a 50-year-old patient who Antiadrenergics • Prazosin•Nightmares (off-label use) • Clonidine • Hyperarousal symptoms has had multiple appointments in • Propranolol the last month for headaches, back www.tnpj.com The Nurse Practitioner • July 2009 35 PTSD: Know the warning signs

When she returns to the clinic a week later, she reports symptoms, but overall feels that the medication has been no troubling adverse reactions from the medication, and helpful. depression symptom reduction, which you do not attribute to the medication, but to the hope that her situation can ■ An opportunity for improvement improve. She says, however, that she still feels nervous. You PTSD is a condition that impacts the physical and psy- encourage her to continue the medication and advise her chological health of those individuals who develop it. that if her PTSD symptoms are not better in 4 weeks, addi- PTSD is often underrecognized and undertreated, espe- tional medication can be considered. She continues med- cially in the primary care setting. Primary care patients ication management at your primary care clinic and sees may have rates of PTSD that are three times the national a psychotherapist. rate, and may be more likely to report their PTSD symptoms to their PCPs, as opposed to seeking a referral to a ■ Case study 2 psychiatric care provider. Thus, there is a great opportu- Roger is a 24-year-old male who presents at your primary nity for PCPs to improve the health of traumatized indi- care clinic with anxiety and anger. He reports that he has viduals by assessing for symptoms of PTSD and providing been using marijuana once or twice a week and over-the- early treatment for PTSD. By intervening and acknowl- counter sleeping medications to alleviate these symptoms. edging the impact of traumatic events on the psychologi- He is guarded and “just wants the right medicine.” You re- cal and physical health of individuals, PCPs may be able assure him that a comprehensive assessment and the proper to reduce the negative impact of PTSD in those who diagnosis will provide him with the best medication for the experience trauma. symptoms he is experiencing. Upon further questioning, he reports that he has “al- REFERENCE ways been negative.” He says that he experienced physical 1. Breslau N, Kessler RC, Chilcoat HD. Trauma and posttraumatic stress disorder in the community: the 1996 Detroit Area Survey of Trauma. Arch Gen abuse from his stepfather from the ages of 2 to 8, and the Psychiatry. 1998; 55(7): 626-32. abuse ended when his stepfather and mother divorced. 2. Kessler RC, Sonnega A, Bromet E, et al. 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Butterfield MI, Becker M, Marx CE. Post-traumatic stress disorder in women: to help him sleep and venlafaxine (Effexor) that is increased current concepts and treatments. Curr Psychiatry Rep. 2002; 4(6): 474-86. over 1 week to a dose of 225 mg daily. He takes the medica- 10. Gerrity MS, Corson K, Dobscha SK. Screening for posttraumatic stress dis- tion for 4 weeks and reports some symptom reduction, but order in VA primary care patients with depression symptoms. J Gen Intern Med. 2007; 22(9): 1321-4. that he still is “jumpy,”anxious, and that he needs to avoid 11. Breslau N. The epidemiology of trauma, PTSD, and other posttrauma disor- people that remind him of the abuse. ders. Trauma Violence Abuse. 2009. Epub ahead of print. You prescribe topiramate (Topamax,an off-label med- 12. North CS. The Oklahoma City bombing study and methodological issues in longitudinal disaster mental health research. J Trauma Dissociation. 2005; ication for PTSD) and increase the dose as tolerated to 75 6(2): 27-35. mg twice daily. You also encourage him to begin psycho- 13. Dobie DJ, Kivlahan DR, Maycard C, et al. Posttraumatic stress disorder in fe- logical therapy. He says he will consider it, but does not male veterans: association with self-reported health problems and functional impairment. Arch Intern Med. 2004;164(4): 394-400. follow through. Roger receives some additional benefit 14. Liebschutz J, Saitz R, Brower V,et al. PTSD in urban primary care: high preva- from the topiramate, and over the next 2 months is able lence and low physician recognition. J Gen Intern Med. 2007; 22(6): 719-26. to initiate some friendships and starts taking classes at a 15. Wignall EL, Dickson JM, Vaughan P, et al. Smaller hippocampal volume in patients with recent-onset posttraumatic stress disorder. Biol Psychiatry. 2004; local college. He continues to experience some residual 56(11): 832-6.

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16. Vermetten EM Vythilingam, et al. Long-term treatment with paroxetine in- 28. Breslau N, Peterson EL, Kessler RC, et al. Short screening scale for DSM-IV creases verbal declarative memory and hippocampal volume in posttrau- posttraumatic stress disorder. Am J Psychiatry. 2000; 156(6): 908-11. matic stress disorder.” Biol Psychiatry. 2003; 54(7): 693-702. 29. Kimerling R, Ouimette P, Prins A, et al. Brief report: Utility of a short 17. Bremner JD. Functional neuroimaging in post-traumatic stress disorder. screening scale for DSM-IV PTSD in primary care. J Gen Intern Med. Expert Rev Neurother. 2007; 7(4): 393-405. 2006;21(1):65-7. 18. Yehuda R. Advances in understanding neuroendocrine alterations in PTSD 30. Foa EB, Cashman L, Jaycox L. The validation of a self-report measure of post- and their therapeutic implications. Ann N Y Acad Sci. 2006;1071: 137-66. traumatic stress disorder: the Posttraumatic Diagnostic Scale. Psychological 19. Meewisse ML, Reitsma JB, de Vries GJ, et al. Cortisol and post-traumatic Assessment. 1997; 9: 445-451. stress disorder in adults: systematic review and meta-analysis. Br J Psychia- 31. Nakell L. Adult post-traumatic stress disorder: screening and treating in pri- try. 2007; 191: 387-92. mary care. Prim Care. 2007;34(3): 593-610, vii. 20. Gill JM, Szanton SL, Page GG. Biological underpinnings of health alterations 32. Guess KF. Posttraumatic stress disorder: early detection is key. Nurse Pract. in women with PTSD: a sex disparity.” Biol Res Nurs. 2005; 7(1): 44-54. 2006;31(3): 26-7, 29-33; quiz 33-5. 21. Rohleder N, Joksimobvic L, Wolf JM, et al. Hypocortisolism and increased 33. Keane TM, Marshall AD, Taft CT. Posttraumatic stress disorder: etiology, epi- glucocorticoid sensitivity of pro-Inflammatory cytokine production in Bosn- demiology, and treatment outcome. Annl Rev Clin Psychol. 2006;2:161-97. ian war refugees with posttraumatic stress disorder. Biol Psychiatry. 2004; 34. Bobo WV, Warner CH Warner CM. The management of post traumatic 55(7): 745-51. stress disorder (PTSD) in the primary care setting.South Med J. 2007; 100(8): 22. Baker DG, Ekhator NN, Kasckow JW, et al. Plasma and cerebrospinal fluid 797-802. interleukin-6 concentrations in posttraumatic stress disorder. Neuroim- 35. Davis M, Barad M, Otto M, et al. Combining pharmacotherapy with cogni- munomodulation. 2001; 9(4): 209-17. tive behavioral therapy: traditional and new approaches. J Trauma Stress. 23. Woods AB, Page GG, O’Campo P,et al. The mediation effect of posttraumatic 2006; 19(5): 571-81. stress disorder symptoms on the relationship of intimate partner violence 36. National Academies of Medicine. I.0.M. Report. Post-traumatic stress disorder and IFN-gamma levels. Am J Community Psychol. 2005; 36(1-2): 159-75. (PTSD): Diagnosis and assessment; 2008. 24. Pervanidou P, Kolaitis G, Charitaki S, et al. Elevated morning serum interleukin (IL)-6 or evening salivary cortisol concentrations predict posttraumatic stress disorder in children and adolescents six months after a motor The authors have disclosed that they have no significant relationship or financial vehicle accident. Psychoneuroendocrinology. 2007; 32(8-10): 991-9. interest in any commercial companies that pertain to this educational activity. 25. Gill J, Vythilingam M, Page GG. Low cortisol, high DHEA, and high levels of stimulated TNF-alpha, and IL-6 in women with PTSD. J Trauma Stress. 2008; 21(6): 530-9. At the National Institutes of Health, National Institute of Nursing Research, 26. Altemus M, Dhabhar FS, Yang R. Immune function in PTSD. Ann N Y Acad Bethesda, Md., Dr. Jessica Gill is a clinical investigator, Dr. Leorey Saligan is a Sci. 2006; 1071: 167-83. nurse scientist, and Dr. Wendy Henderson is a staff scientist. Dr. Sarah Szanton 27. Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR). 4th ed. is an assistant professor at Johns Hopkins University School of Nursing, Balti- (2000). New York, NY: American Psychiatric Association. more, Md.

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