8.1 Medicine II_Tropical Infectious Diseases, Dengue_2014A

December 2, 2017 | Author: Bhi-An Batobalonos | Category: Public Health, Infection, Bleeding, Virus, Shock (Circulatory)
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Let’s imagine it happened Getting Sick in the  Tropics (Tropical IDs) Part 1: Dengue OUTLINE: Part1: Overview A. Tropical infectious diseases III. B. 10 leading causes of morbidity Dengue A. Dengue virus B. Transmission of dengue virus by aedes aegypti C. Dengue infections D. Pathophysiology E. Course of illness F. Old WHO dengue classification G. Dengue case classification and levels of severity H. Diagnosis I. Tourniquet test J. Step-wise approach to management of dengue K. Group A L. Home care for dengue M. Admission criteria N. Group B O. Group C P. Effects of supportive treatments for DHF or DSS in children Q. Group C: emergency treatment R. Summary of blood transfusion treatment S. Discharge criteria T. Prognosis U. Prevention

Part 2: Typhoid fever A. Etiologic agents B. Enteric fever C. Complications and consequences D. Laboratory tests E. Antibiotic therapy F. Case course G. Prevention Malaria A. Etiologic agents B. Transmission cycle C. Laboratory tests D. Clinical features E. Major signs of severe malaria F. Other signs of severe malaria G. Drugs for susceptible plasmodium H. Drugs for MDR I. Drugs for severe or complicated P. falciparum malaria J. Primaquine K. Other issues

Rabies Yellow fever Dengue fever


APPROACH  Onset of Illness [2013B] o Cyclical, relapsing – plasmodium vivax (malaria) o Vague abdominal pain – enteric syndrome or typhoid fever o Calf muscle pain, abdominal pain, history of wading in flood water – leptospirosis o Same pattern of fever with a member of household, neighbourhood – dengue (but in the Philippines, dengue occurs all year round)

 Exposure o Season of the year – rainy – flood water – leptospirosis o Other sick household members or neighbors  Drug intake, including chemoprophylactic agents o o

TROPICAL INFECTIOUS DISEASES Parasites Malaria Taeniasis Amebiasis Echinococcosis Giardiasis Lymphatic Trypanosomia filariasis sis Loiasis Leishmaniasis Onchocerciasis Ascariasis Cryptosporidiosis Strongyloides Dracunculiasis Schistosomia Hookworm sis Trichinosis

Viruses HIV Measles Poliomyelitis Viral hepatitis Viral diarrhea

Fungi Histoplasmosis Sporotrichosis Cryptococcosis Coccidioidomycosis Blastomycosis

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605,471 539,701 487,302 398,538 349,609 114,714 31,331 23,773 23,207 23,090

Rate per 100,000 population 718.0 640.0 577.8 472.6 414.6 136.0 37.2 28.2 27.5 27.4

National Epidemiology Center, FHSIS, DOH, 2008


Bacteria Tuberculosi Campylobac s ter Leprosy Typhoid Cholera fever Tetanus Syphilis Plague Chlamydia Leptospiros Gonococcus is Anthrax Shigella Melioidosis

Number of cases

1. ALRI and Pneumonia 2. Acute Watery Diarrhea 3. Bronchitis/Bronchiolitis 4. Hypertension 5. Influenza 6. TB Respiratory 7. Diseases of the Heart 8. Dengue Fever 9. Malaria 10. Chickenpox

Part 3: Leptospirosis

 Many of the infections that we currently consider “tropical” were once endemic in the more temperate climates of developed countries o Successfully eradicated with a combination of public health, good sanitation and hygiene, and accessible medications  But many of these infections that we consider “tropical” are mainly found in developing countries, which is more a result of economics than it is of climate.


Other drugs like steroids that may predispose them to have fungal infections Mefloquine (malaria chemoprophylaxis) causes psychiatric side effects if taken for more than 3 months [2013B]

 Suggestive objective signs: o o o o

Calf muscle tenderness  leptospirosis Petechial rashes  dengue Hepatosplenomegaly  malaria Hepatosplenomegaly, maculopapular rash  typhoid fever [2014B]

DENGUE     

Case # 1: 18 year old, female, student Continuous fever for 5 days, highest temperature at 40oC, with headache and muscle pains No cough, epigastric pain, vomiting Took erythromycin and paracetamol with no relief Consulted a physician two days ago

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CBC: Hgb=125; Hct=0.37; WBC=6.7, with 0.72 neutrophils; Platelet count = 205,000 o Advised to continue hydration and paracetamol, with next follow-up after 2 days, if fever remains persistent  Few hours PTA, with persistently high-grade fever, she had gum bleeding  On PE, appears ill-looking o T=39.6oC, HR=110/min, RR=22/min, BP=90/60 mmHg o No tonsillopharyngeal congestion or cervical lymphadenopathy o C/L and heart findings are unremarkable o Abdomen is flat, with slight direct epigastric tenderness; no hepatosplenomegaly o No rashes or edema on extremities o Tourniquet test is negative o

Question: What is the most likely cause of the patient’s fever? A. Virus B. Bacteria C. Parasite D. Fungus [2013B]  Does patient have sepsis? Yes  decreased blood pressure, tachycardia, fever  High grade fever: VIRAL o 10 diagnosis: viral o WBC is normal although typhoid fever may also present with normal WBC; see also the clinical history and physical exam o Fever is high grade at onset for viral; typhoid fever starts with low-grade fever

Complete Blood Count was requested:  Hgb=13.9, Hct=0.40, WBC=2.3 with neutrophils  Platelet count=70,000


Question: At this point, what interventions would you institute? A. Administer a broad-spectrum antibiotic B. Transfuse blood components, including whole blood and platelets C. Serial blood count determinations, to include hematocrit and platelet count D. Initiate intravenous hydration incorporated with parenteral multivitamins NOTE (2013B): Do not choose the answer with the vitamins because vitamins do not have any use in acute infection!


Hgb=13.8; Hct=0.40; WBC=2.6 with 63% neutrophils o Platelet count=40,000 Fever resolved Few petechial rashes noted on the lower extremities o

 

Question: At this point, what interventions would you institute? A. Administer a broad-spectrum antibiotic B. Transfuse blood components, including whole blood and platelets C. Serial blood count determinations, to include hematocrit and platelet count D. Initiate intravenous hydration incorporated with parenteral multivitamins NOTE (2013B): Continue serial blood count determinations because during this time, when patient is afebrile, hemoconcentration and increase in platelet count happen; resolution of petechial rashes.

Course:  During her stay, serial blood count determinations were continued o Increasing platelet count levels noted on subsequent days  No signs or episodes of bleeding reported  Increased number of petechial rashes observed on the extremities

Case # 1: Issues  Dengue infection o Pathophysiologic mechanisms and clinical manifestations o Risk factors for susceptibility to infection and its complications o Diagnosis o Therapeutic interventions

DENGUE VIRUS  Family: Flaviviridae  Genus: Flavivirus  Enveloped, single-stranded, positive sense RNA virus  Four serotypes: DENV -1, -2, -3, -4 o Serotype 1 – South America o Serotype 2 – most frequent strain causing severe dengue

o Serotype 4 – South Africa [2013B]  Vector: Aedes aegypti, Aedes albopictus


Course:  Repeat CBC the following day

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Homologous Antibodies form Non-infectious Complexes

Figure 1. [2013B]  Mosquito will first bite an infected man. During this time, there will be continuing growth and viremia in the mosquito and the mosquito will subsequently transfer it to a susceptible individual. The individual will develop viremia, and 1-2 weeks later, the patient will have fever, along with other non-specific signs and symptoms.  Mosquito is low-flying: 300m distance

Figure 2. Dengue 1 virus will attach to the neutralizing antibody. This leads to primary dengue infection.

Heterologous Complexes





Figure 3. Antibody Dependent Enhancement Increased circulation of viruses Increased probability of secondary infection [2013B]: Reinfection with a different strain or serotype. Immune antibody will be enhanced (non-neutralizing antibody to Dengue 1 virus to which the Dengue 2 virus will attach Increased probability of occurrence of virulent strains Increased probability of immune enhancement itself). [Harrison’s]: Previous infection with a heterologous dengue-virus serotype may result in production of non-protective anti-viral antibodies that bind to virion’s surface and through interaction w/ Fc receptor focus secondary dengue viruses on target cell, the result being enhanced infection. The host is also primed for a secondary antibody response when viral antigens are released and immune complexes lead to activation of the classic complement pathway, with consequent phlogistic effects. Cross-reactivity at the T cell level results in the release of physiologically active cytokines, including interferon γ and tumor necrosis factor α.

Increased probability of DHF

DENGUE HEMORRHAGIC FEVER/DENGUE SHOCK SYNDROME [Harrison’s]  Occurs against a background of previous exposure to another dengue-virus serotype; second infection w/ a serotype of dengue virus diff. from primary infection  DHF w/ severe shock  Transient heterotypic protection after dengue virus infection is replaced within several weeks by potential for heterotypic infection resulting in typical DF or uncommonly, in enhanced disease (2o DHF/DSS). In rare instances, 1o dengue infections lead to HF syndrome


Heterologous Complexes Enter Monocytes, Where Virus Replicates


Figure 4. Macrophage/monocyte infection is central to pathogenesis of DF and origin of DHF/DSS [Harrison’s]. Heterologous complexes enter more monocytes, where virus replicates [2013B]. Infected

monocytes release vasoactive mediators, resulting in increased vascular permeability and hemorrhagic manifestations that characterize DHF and DSS. Remember: Secondary infections are more severe. Serotype 2 is the most frequent strain causing a more severe disease. [2013B]

PATHOPHYSIOLOGY CAPILLARY LEAK SYNDROME  Transient increased capillary permeability due to endothelial cell dysfunction – hemoconcentration  Widening of tight junctions  Cytokine release and complement activation

LEUKOPENIA, THROMBOCYTOPENIA AND HEMORRHAGIC DIASTHESIS  Direct viral bone marrow suppression  Platelet destruction (due to immune complex generation)  that’s why platelet concentrate is being transfused [2013B]

 Molecular mimicry between viral protein and coagulation factors.  Bleeding occurs primarily because of derangement in coagulation and not because of thrombocytopenia. [2013B]

Figure 6. Course of Illness

1. FEBRILE PHASE  Usually lasts 2-7 days  Monitoring for defervescence and warning signs are crucial to recognise the progression to the critical phase  Defervescence occurs on day 3-7 of illness o When the temperature drops to 37.5-38oC or less and remains below this level

2. CRITICAL PHASE  Around the time of defervescence, patients can either improve or deteriorate  Those who improve after defervescence have dengue without warning signs  Those who deteriorate will manifest warning signs: dengue with warning signs

Warning Signs  Warning signs are the result of a significant increase in capillary permeability  Marks the beginning of the critical phase Table. Warning Signs Clinical

Figure 5. Pathophysiology of DHF



     

Abdominal pain or tenderness Persistent vomiting Clinical fluid accumulation Mucosal bleed Lethargy, restlessness Liver enlargement >2cm Increase in HCT concurrent with rapid decrease in platelet count

 May deteriorate to severe dengue infection with signs of: o Severe plasma leakage leading to shock (dengue shock) ± respiratory distress JMA-1, JMA-2, Telma Amit Page | 4

o Severe bleeding and/or o Severe organ impairment  The period of clinically significant plasma leakage usually lasts 24 to 48 hours  give extensive hydration

3. RECOVERY PHASE  Gradual reabsorption of extravascular compartment fluid in the next 48-72 hours  General well-being improves, hemodynamic status stabilizes, diuresis ensues  Classical rash of “isles of white in the sea of red” = Herman’s rash  HCT stabilizes or may be lower due to the dilution effect of reabsorbed fluid  WBC usually starts to rise o Recovery of platelet count is typically later than that of WBC

SUMMARY OF CLINICAL PROBLEMS Febrile phase  Dehydration  High fever may cause neurological disturbance and seizures in children Critical Phase  Shock from plasma leakage  Severe hemorrhage  Organ impairment Recovery Phase  Hypervolemia (only if IV therapy has been excessive or has extended into this period)


Fever accompanied by nonspecific constitutional symptoms such as anorexia, vomiting, abdominal pain; the only hemorrhagic manifestation is a (+) tourniquet test and/or easy bruising

Grade 2

Spontaneous bleeding in addition to manifestations of grade 1 patients, usually in the form of skin or other hemorrhages (mucocutaneous, GIT)

Grade 3 *

Circulatory failure manifested by a rapid, weak pulse and narrowing of pulse pressure or hypotension, with the presence of cold, clammy skin and restlessness

CRITERIA FOR DENGUE ± WARNING SIGNS  Probable dengue o Live in/travel to dengue endemic areas. Fever and 2 of the following criteria:  Nausea, vomiting  Rash  Aches and pains  Tourniquet test (+)  Leukopenia any warning sign  Laboratory-confirmed dengue o Important when no sign of plasma leakage  Warning signs* o Abdominal pain or tenderness o Persistent vomiting o Clinical fluid accumulation o Mucosal bleed o Lethargy, restlessness o Liver enlargement >2cm o Laboratory: increase in HCT concurrent with rapid decrease in platelet count *requiring strict intervention




Profound shock with undetectable blood pressure or pulse *Grades 3 and 4 DHF constitute DSS Note: Forget this table because this is no longer being used


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 Severe plasma leakage leading to: o Shock (DSS) o Fluid accumulation with respiratory distress  Severe bleeding as evaluated by clinicians  Severe organ involvement o Liver: AST or ALT ≥ 1000 o CNS: impaired consciousness o Heart and other organs

Grade 4 *

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Presence of enhancing and nonneutralizing antibodies – higher risk in secondary infections Age 12 years of age [Harrison’s]

Female sex – females affected > males [Harrison’s]

Race o Caucasians more often affected than Blacks

Nutritional status o Malnutrition is protective Sequence of infection o Serotype 1 followed by serotype 2 seems to

 Good sensitivity & specificity when used >5 days after onset of fever, false positives  Whole blood, serum, plasma

be more dangerous than serotype 4 followed by serotype 2 [Harrison’s]

Infecting serotype o Type 2 more dangerous serotypes





 Detects recent or past infection  Whole blood, serum, plasma  Acute sera 1-5days; convalescent after 15 days  4-fold rise in recent infections

than other

DIAGNOSIS 1. 2. 3. 4.


Signs and symptoms Virus isolation Serologic identification Molecular identification

Results in ≥7 days

 Inhibition of Hemagglutination = (+) result  Whole blood, serum, plasma  Acute sera on admission & convalescent after 7 days

Results in ≥7 days


Highly Suggestive One of the following: 1. IgM (+) in a single serum sample 2. IgG (+) in a single serum sample with a HI titer of ≥ 1280

Figure 7. Comparison of diagnostic tests according to their accessibility and confidence [2013B]  Isolation: best but not available  NSI DETECTION: detects dengue at onset of febrile phase in children o Highly sensitive for children, poorly accurate among adult patients



 Gold standard, serotype identification  Whole blood, serum, tissues  Results in 1-2 weeks

 Sensitivity of 80-100% (vs. virus isolation)  Tissues, whole blood, serum, plasma  Results in 1-2 days; equipment

Results: Sphygmomanometer method o Sensitivity of 41.6% o Specificity of 94.4% o Test differentiated poorly between dengue hemorrhagic fever (45% positive) and dengue fever (38% positive) Simple elastic tourniquet was less sensitive than sphygmomanometer cuff o Other evidence of bleeding was frequently present and the tourniquet test provided additional information to aid diagnosis in only 5% of cases

 Not useful in adults [2013B]  Detection of non-structural protein 1 in both primary and secondary dengue of all serotypes  Sensitivity 91.6% & specificity 100%  Specimen: serum

Results in 1 day


Confirmed One of the following: 1. PCR (+) 2. Virus culture (+) 3. IgM seroconversion in paired sera 4. IgG seroconversion in paired sera or four-fold IgG titer increase in paired sera

 

Figure 8. C.X.T. Phuong et.al. Evaluation of the tourniquet test in dengue infection. Tropical Medicine and International Health Vol. 7 No. 2 pp. 125-132 February 2002


Adequate bed rest Adequate fluid intake (> 5 glasses for average-sized adult & accordingly in children) o Milk, fruit juice (caution with diabetic patient) and isotonic electrolyte solution (ORS) and barley / rice water / clear soup o Plain water alone may cause electrolyte imbalance  Take Paracetamol  Tepid sponging  Look for mosquito breeding places in and around the home and eliminate them

What Should Be AVOIDED? Step I: Overall Assessment  Aspirin, ibuprofen, NSAIDS(Aggravate gastritis 1.1. History 1.2.Physical examination or bleeding) 1.3.Investigation, including routine and dengue specific  If you are already taking these medications please laboratories Step II: Diagnosis, Assessment of Disease phase and Severity Step III: Management 3.1.Disease notification 3.2.Management decisions. Depending on the clinical manifestations and other circumstances, patients may: ̶ Be sent home (Group A); ̶ Be referred for in-hospital management (Group B); ̶ Require emergency treatment and urgent referral (Group C) Source: WHO Guidelines

consult your doctor Antibiotics are not necessary


 Any of the warning signs


Able to tolerate adequate volumes of oral fluids Pass urine at least once every 6 hours Do not have any of the warning signs, particularly when fever subsides Stable hematocrit No other co-existing conditions NOTE: Ambulatory patients should be reviewed daily for disease progression and development of warning signs until they are out of the critical period.


Should be reviewed daily with full blood count and HCT until they are out of the critical period What to monitor? o Disease progression  Defervescence  Rising HCT with concurrent rapid fall in WBC and platelet count o Development of warning signs

HOME CARE FOR DENGUE What Should Be DONE? JMA-1, JMA-2, Telma Amit Page | 7

 Dehydrated, unable to tolerate oral fluids  Postural hypotension  Profuse perspiration, fainting, prostration during defervescence

Spontaneous bleeding, independent of the platelet count

 Renal, hepatic, neurological or cardiac  Enlarged, tender liver, although not yet in shock

Chest pain or respiratory distress,

 Rising hematocrit

Pleural effusion, asymptomatic thickening

ascites, gallbladder

 Pregnancy  DM, HPM, peptic ulcer disease, hemolytic anemia  Overweight or obese (rapid venous access difficult in emergencies)  Infancy or old age

 Living alone  Living far from health facility  W/o reliable means of transport

 

GROUP B – REFERRED FOR IN-HOSPITAL MANAGEMENT DENGUE WITH WARNING SIGNS A. Obtain a reference HCT before fluid therapy B. Give only isotonic solutions such as 0.9% saline, Ringer's lactate, Hartmann's solution o 5-7 ml/ kg/hr for 1-2 hours o 3-5 ml/ kg/hr for 2-4 hr o 2-3 ml/kg/hr or less according to clinical response C. Reassess the clinical status and repeat the HCT D. HCT remains the same or rises minimally o Continue with the same rate (2-3 ml/kg/hr) for another 2-4 hours. E.Worsening of vital signs & rapid rise in HCT o Increase the rate to 5-10 ml/ kg/hour for 1-2 hours.  Reassess the clinical status, repeat HCT and review fluid infusion rates accordingly.  Give the minimum IVF required to maintain good perfusion and urine output of about 0.5 ml/ kg/hr.  IVFs are usually needed for 24-48 hrs.  Reduce IVF gradually when the rate of plasma leakage decreases towards the end of the critical phase. o Indicated by:  Adequate urine output and /or fluid intake  HCT decreases below the baseline value in a stable patient.

Monitoring by healthcare providers Normal maintenance fluid per hour can be calculated on the basis of the following formula* (equivalent to Holliday-Segar formula): o 4 mL/kg/h for first 10 kg body weight o + 2 mL/kg/h for next 10 kg body weight o + 1 mL/kg/h for subsequent kg body weight

GROUP C: WHO REQUIRES EMERGENCY TREATMENT AND URGENT REFERRAL? SEVERE DENGUE 1.Severe plasma leakage with shock and/or fluid accumulation with respiratory distress. 2.Severe bleeding as evaluated by clinician 3.Severe organ impairment  Severe liver involvement with AST ≥ 1000 or ALT ≥1000  Impaired consciousness with GCS < 15 or BCS 40-60mL/kg has been administered. o Persistent metabolic acidosis ± a normal systolic blood pressure


Give 5-10 ml/kg of fresh packed red cells 10-20 ml/kg of fresh whole blood at

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In DHF/DSS patients with significant bleeding (hematemesis, hematochezia) 1. Fresh whole blood/whole blood is preferred but pRBC may be used as alternative. 2. Once DIC sets in, blood component therapy with cryoprecipitate, FFP, and platelet concentrate is recommended. Level of Evidence: Recommendation: A





Blood Component Therapy in DIC Type Packed red blood cells Platelets Fresh frozen plasma Cryoprecipitate

Amount or Volume 10-15 ml/kg 1 unit/10 kg 10-20 ml/kg 1-2 units/kg

What is the Role of Preventive Transfusion in DHF? Source: Santos JA. Evidence-Based Guidelines on Dengue Fever/DHF 2008

Preventive transfusion has no role in the treatment of DHF. o o


Source: Santos JA. Evidence-Based Guidelines on Dengue Fever/DHF 2008

Level of Evidence: Class 2 Grade of Recommendation: A


Source: Santos JA. Evidence-Based Guidelines on Dengue Fever/DHF 2008

No RCT’s or systematic reviews In DSS patients o FFP (Fresh Frozen Plasma) and PC (Plasma Concentrate) w/o sustained improvements in the coagulation status during plasma leakage phase of DHF/DSS o Those who were not transfused did not manifest severe bleeding when shock was adequately managed. o Improvement in platelet counts, PT and PTT after transfusions lasted < 5 hours. No difference in the frequency of bleeding was observed comparing patients who received

and those who did not receive platelet transfusion (Even in those with platelet count < 25,000/mm3) Studies on platelet levels in DF/DHF: platelet levels do not correlate directly with bleeding.

INTERVENTIONS WHICH ARE NOT RECOMMENDED IN DHF/DSS Source: Santos JA. Evidence-Based Guidelines on Dengue Fever/DHF 2008

Interven tion Steroids

Vitamin C Antihista mines Vitamin K Albumin

Systematic Reviews Use has not been shown to have any benefit in DSS (2 RCT’s : methylprednisolone & hydrocortisone vs. placebo) Not recommended No documented role in the management of DF/ DHF No role in the treatment of DHF No systematic review or published RCT’s on the effects of albumin in the treatment of DHF/DSS

Clinical  No fever for 24 – 48 hours  Improvement in clinical status (general well-being, appetite, haemodynamic status, urine output, no respiratory distress) Laborat  Increasing trend of platelet count (usually ory preceded by rising WBC)  Stable hematocrit without intravenous fluids

PROGNOSIS  Depends on prevention and early recognition and treatment of shock o CFR: 2.5-5% o

When shock sets in → 12-44%

PREVENTION  4S Campaign: o Search and destroy o Self-protection measures o Seek early consultation o Say “NO” to indiscriminate fogging  Key to control of both DF and DHF/DSS is the control of A. aegypti

 Live attenuated dengue vaccines are in late stages of development [Harrisons]

----------------------------------END-------------------------------------------References: 1. PDF of lec. 2. 2013B trans 3. Harrison’s Internal Medicine 4.WHO Guidelines on Dengue Management 2009


No clear guidelines on the role of transfusion of platelet concentrates and/or FFP o No prospective studies and consensus on platelet transfusion based on low platelet count w/ or w/o bleeding in dengue infection in adult population o No randomized prospective studies to show that administration of FFP or platelet concentrates have improved outcomes in dengue infection in adult patients Unclear when to start transfusion

Editor’s note: Sorry for very long trans! We tried to make it as short as possible na. If you want to read more about Dengue, download the pdf of WHO on dengue management.  Shoutout: HAPPY BIRTHDAY Jeaness! =)) Umaasa nagpaparinig na sana may libre. Hahaha =P



DISCHARGE CRITERIA NOTE: ALL of the following conditions must be present: Answers: (1) P. vivax & P.ovale; (2) Serotype 2; (3) Chloramphenicol

APPENDIX A: Algorithm for Fluid Management in Compensated Shock

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APPENDIX B: Algorithm for Fluid Management in Hypotensive Shock

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