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3 EPIDEMIOLOGY OF ADULT TRAUMATIC BRAIN INJURY
Pages 59-102

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From page 59...
... Scales and Scoring Systems Used to Describe Traumatic Brain Injury There are many classifications of TBI; for example, Knightly and Pulliam (1996) address the various components of TBI incurred in the military.
From page 60...
... Table 3.2 shows examples of TBI incidence studies conducted in the United States that used those measures. As can be seen there is no consistency in severity classification systems reflecting available clinical symptoms or evidence from neuroimaging.
From page 61...
... Even when ICD TBI codes were used in existing hospital electronic discharge files, the codes selected were not uniform. About half the incidence studies did not evaluate TBI severity.
From page 62...
... . Prevalence of Traumatic Brain Injury (Disability)
From page 63...
... attempted to estimate that number by using the US National Hospital Discharge Survey data to approximate incidence and then classified the data by TBI severity by applying the computer algorithm known as ICDMAP-90 developed by MacKenzie et al.
From page 64...
... may reflect the referral practice of the acute medical care treatment institutions involved. RISK FACTORS FOR TRAUMATIC BRAIN INJURY Several risk factors have been examined in connection with the incidence of TBI: age, sex, ethnicity, and socioeconomic status.
From page 65...
... (1989) reported in a TBI incidence study of San Diego County residents in 1981 that 49% of those who were tested for BAC had a BAC of 0.10% or higher (which is either an offense itself or presumptive evidence of driving under the influence)
From page 66...
... External Causes of Traumatic Brain Injury Only about half the 66 US and non-US studies reporting the incidence of TBI give details on the exposures that led to it. Data from those studies (Tables 3.11 and 3.12)
From page 67...
... RECURRENT TRAUMATIC BRAIN INJURY Researchers at the Mayo Clinic (Annegers et al., 1980) were among the first to measure the relative risk (RR)
From page 68...
... . TRAUMATIC BRAIN INJURY AND SHORT-TERM OUTCOMES One outcome of TBI is death.
From page 69...
... to account for the insensitivity of the scale to some changes in functional ability, especially in the moderate and severe categories. The large number of population-based TBI incidence studies might suggest the availability of much more information on the GOS as an early hospital-discharge tool, but only seven of the 66 studies (US and non-US)
From page 70...
... 70 TABLE 3.1 Glasgow Coma Scales and Glasgow Outcome Scales Glasgow Coma Scalea Glasgow Coma Scale-Extendedb Glasgow Outcome Scale Glasgow Outcome Scale-Extendedc Ability Assessed Points Memory Assessed Points Condition Points Condition Points Eye opening Amnesia Dead 1 Dead 1 Not open 1 >3 mo 0 Vegetative state 2 Vegetative state 2 To pain 2 31–90 days 1 Severely disabled 3 Lower severe disabled 3 To speech 3 8–30 days 2 Moderately disabled 4 Upper severe disabled 4 Spontaneous 4 1–7 days 3 Good recovery 5 Lower moderate disabled 5 Verbal response 3–24 h 4 Upper moderate disabled 6 Silence 1 0.5–3 h 5 Lower good recovery 7 Sounds 2 <30 min 6 Upper good recovery 8 Nonsense 3 No amnesia 7 Confused 4 Motor response to pain No response 1 Arm extension 2 Arm flexion 3 Withdrawal 4 Localizing 5 To command 6 a SOURCE: Jennett and Teasdale, 1981.
From page 71...
... Prehospital deaths from medical examiner = < 8; moderate = 9–11; mild = 12–15 Jagger et al., 1978 North Central Patients within defined service area with overnight stay, and Not reported 1984b Virginia documented head injuries Kraus et al., 1984 1981 San Diego Physician-diagnosed physical damage from acute mechanical energy Modified GCS: severe 8; moderate County, CA exchange resulting in concussion, hemorrhage, contusion, or = 9–11; plus hospital stay of 4–8 laceration of brain hours and brain surgery, or abnormal CT, or GCS 9–12; mild = all others, GCS 13–15 Whitman et al., 1979 to Inner city Any hospital discharge diagnosis of ICD-9-CM 800–804, 830, 850– (1) Fatal; (2)
From page 72...
... 854.1 in any primary or secondary data fields Demonstrated intracranial traumatic lesions; (3) Focal abnormalities on neurological examination Diamond, 1996 1988 to Virginia All ED treated patients from Virginia Brain Injury Central Registry Severity not evaluated 1993 including hospital admitted ICD-9-CM codes 850–854.1, 800–804.9, 348.1, 900–900.9, 950–951.9 Gabella et al., 1990 to Colorado, Hospital discharge data for all state hospitals or healthcare providers No severity data reported 1997a 1993 Missouri, Oklahoma, Utah
From page 73...
... 1996; identified from US National Hospital Ambulatory Medical Care Survey Schootman et al., 1993 Iowa Hospital discharge data ICD-9 codes 800-801, 803-804, 850-854 No severity data reported 2000 [capture - recapture method] plus death certificates Langlois et al., 1997 14 US states State TBI surveillance projects.
From page 74...
... 74 Year(s) Reference of Data Location Case Definition and Data Source TBI Severity Criteria and Scoring Texas Department 1998 Texas Texas Trauma Registry and Bureau of Vital Statistics ICD-9 codes GCS used but not reported of Health, 2004 800–801, 803–804, 850–854 Rutland-Brown et 1995 to US Update from Langlois et al., 2003, see this for case ID See Langlois et al., 2003 al., 2006 2001 NOTE: AIS = Abbreviated Injury Scale, CA = California, CNS = central nervous system, CT = computed tomography, ED = emergency department, GCS = Glasgow Coma Scale, ICD = International Classification of Diseases, ICDA-8 = International Classification of Diseases, Eighth Revision, ICD-9-CM = International Classification of Diseases, Ninth Revision, Clinical Modification, ICDMAP = computer algorithm; ID = identification, ISS = Injury Severity Score, LOC = loss of consciousness, MN = Minnesota, PAS = Professional Activities Study, PTA = posttraumatic amnesia, TBI = traumatic brain injury, US = United States.
From page 75...
... 1986 China medical record followup Severity not evaluated Nestvold et al., 1974 Central Norway, Prospective identification by surgeons on duty case Survey ranked by length of PTA: None = 1, < 0.5 1988 Akershus County inclusion with neurological symptoms hr = 2, 0.5–6 hr = 3, 6–24 hr = 4, 1–2 days = 5, 3–7 (Oslo) days = 6, > 7 days = 7 Servadei et al., 1981 to Ravenna, Italy ED identification plus hospital admission and record GCS; 3–5, 6–8, 9-12, 13–15 1988 1982 review Badcock, 1984 South Australia Prospective study of all ED visits, hospital admissions and Length of PTA: none, < 5 min, 5–60 min, 1–24 1988 prehospital deaths hrs, 1–7 days, 1–4 wks, > 4 wks Tiret et al., 1986 Aquitaine, Prehospital deaths and hospital admissions survey by Severity by 3 classes based on PTA of coma > 6 1990 France medical staff using 180 possible head injury codes using hrs = severe, PTA 15 min to 6 hrs = moderate, AIS and ISS PTA, 15 min = mild Levi et al., 1984 to Northern Israel Prospective patient identification from referral to GCS used but not recorded 1990 1988 neurological service records Nell and Brown, 1986 Johannesburg, Inpatient admission with screening ICD-9 codes 800–804, GCS, mild = 13–15, moderate = 7–12 and severe = 1991 South Africa 850–854, 293, 294, 310, 870–873, 950–951, 958, 345, 3–6 347, 348, 253.9 75
From page 76...
... Hospitalized patients with intracranial lesions on Severe brain injury only GCS < 7, 7–9, 10–12, > 1992 Gallen, admission CT 12 Switzerland Vazquez- 1988 Cantabria, Spain Hospital admissions with objective neurological findings GCS, minor = 13–15, moderate 9–12, severe 3–8 Barquero et al., such as LOC, skull fracture 1992 Engberg, 1995 1988 Frederiksborg ED and hospital ICUs in 4 hospitals using hospital Severity by PTA: 24 hrs-7 days = severe, very County, Denmark records, Danish Hospital Register and National Register severe 7 days Chiu et al., 1988 to Taiwan Hospital admission with LOC, skull fracture, neurological GCS: mild = 13–5, moderate = 9–12 (or CT pos) , 1997 1994 deficit or CT intracranial hemorrhage severe 8 Hillier et al., 1987 South Australia All public and private hospitals with admission ICD-9 GCS: mild = 13–5, moderate = 9–12 (or CT pos)
From page 77...
... In hospital and prehospital deaths identified severe from hospital records or death certificates Masson et al., 1996 Aquitaine, France Persons admitted to anyone of 19 public hospitals with Severe TBI by GCS of < 9 for at least 24 hrs 2003 prolonged coma determined by LOC > 24 hrs or GCS of < 9 before sedation Kleiven et al., 1987 to Sweden National hospital discharge register using ICD codes 800– Severity not evaluated 2003 2000 804, 850–854, (ICD-9)
From page 78...
... Excludes prehospital deaths GCS: severe 9, moderate = 9–15 plus hospital 2001 Hualien County, in 2001 stay at least 48 hrs and had brain surgery or Taiwan abnormal CT scan, mild = all others Yates et al., 1997 to Royal Devon and ED database from one hospital. ICD codes used but not Based on ICD-10 but not defined 2008 2003 Exeter Hospital, stated UK Wu et al., 2008 2004 6 Providences of Hospital admitted patients with data from attending GCS: severe 9, moderate = 9–13, mild = 14, 15 Eastern China physician NOTE: AIS = Abbreviated Injury Scale, CHIRPP = Canadian Hospitals Injury Reporting and Prevention Program, CT = computed tomography, ED = emergency department, GCS = Glasgow Coma Scale, ICD = International Classification of Diseases, ICDMAP = computer algorithm, ICU = intensive care unit, ISS = Injury Severity Score, LOC = loss of consciousness, PTA = posttraumatic amnesia, TBI = traumatic brain injury, UK = United Kingdom.
From page 79...
... per year Comments Annegers et al., 1980 1965 to 1974 Olmstead County, MN 3,587 NS 193 Age adjusted to 1970 US population, rate averaged from men only and women only rates Fuortes et al., 1990 1984 to 1986 Iowa NS NS 159 in 1984 Hospital admissions only 133 in 1985 117 in 1986 Rimel, 1981 1977 to 1979 Central Virginia 1,330 NS NS Hospital patients and prehospital deaths Klauber et al., 1981 1978 San Diego, CA 5,055 NS 294 Includes some nonresidents, excludes a few external causes Cooper et al., 1983 1980 to 1981 Bronx, NY 1,209 NS 249 Rate based on sample, age adjusted to 1980 US population Jagger et al., 1984b 1978 North Central Virginia 735 354 208 Rate includes residents and nonresidents; no ED cases or prehospital deaths Kraus et al., 1984 1981 San Diego County, CA 3,358 1862 180 Population based, not age adjusted Whitman et al., 1984 1979 to 1980 Inner city Chicago and 782 213 331 Composite rate from data in publication, Evanston, IL average across race and gender Fife et al., 1986 1979 to 1980 Rhode Island 2,870 947 152 Hospital patients only Fife, 1987 1977 to 1981 US 307,000 226,545 136 Hospital patients only; 1.87 million 1.87 million 805 All injured patients MacKenzie et al., 1989a 1986 Maryland 5,838 NS 132 Hospital patients only MacKenzie et al., 1990 1979 to 1986 Maryland NS NS 114-134 Hospital patients only, range in rates Oklahoma State 1989 Oklahoma 3,672 NS 121 Hospital and fatal cases Department of Health, 1991 Schuster, 1994 1990 Massachusetts 27,819 6,016 10 Mortality rate 86 Hospital admissions 366 ED only Warren et al., 1995 1991 to 1993 Alaska 2,178 457 130 Hospital patients only Diamond, 1996 1988 to 1993 Virginia 46,680 NS NS Only age-specific rates reported Sosin et al., 1996 1991 US 1.54 million NS 618 Total rate 158 Hospitalized 79
From page 80...
... per year Comments 307 ED only 153 No care Thurman et al., 1996 1990 to 1992 Utah 5,782 NS 106 Age adjusted rate to 1990 US population Gabella et al., 1997a 1990 to 1993 Colorado, Missouri, 13,978 13,687 103 Age adjusted rate to 1990 US population Oklahoma, Utah Gabella et al., 1997b 1991 to 1992 Colorado 7056 NS 101 Hospitalized and deaths, age adjusted to US Thurman and Guerrero, 1994 to 1995 US NS NS 98 Hospitalized patients only 1999 Jager et al., 2000 1992 to 1994 US 1.144 million NS 444 ED patients only Schootman et al., 2000 1993 Iowa 2,559 NS 91 Severe TBI rate based capture recapture; age adjusted rate to 1990 US population Guerrero et al., 2000 1995 to 1996 US 1.027 million NS 392 ED patients only Louisiana Office of 1996 to 1999 Louisiana 16,203 NS 90 Hospitalized patients and prehospital Public Health Injury and deaths Research Prevention Section, 2004 Langlois et al., 2003 1997 14 US states 62,771 NS 70 Live hospital discharges only Langlois et al., 2006 1995 to 2001 US 1.396 million NS 505 Total rate, age adjusted to 2000 US population 235 86 Hospitalized patients only 1.111 million 401 ED visits only Selassie et al., 2004 1996 to 2001 South Carolina 70,671 NS 68 Hospital patients only 220 ED patients only Texas Department of 1998 Texas 20,000 NS NS Hospitalized patients only Health, 2004 Rutland-Brown et al., 2003 US 1.565 million NS 538 Total 2006 421 ED visits only 100 Hospitalization NOTE: CA = California, ED = emergency department, IL = Illinois, MN = Minnesota, NS = not stated, NY = New York, TBI = traumatic brain injury, US = United States.
From page 81...
... per year Comments Jennett and MacMillan, 1974 England, Wales and NS NS 270 in Annual rates based on sample weeks, 1981 Scotland England and rates not age adjusted Wales 313 in Scotland Selecki et al., 1981 1977 New South Wales, 18,678 4,960 377 Hospital admissions only excludes Australia prehospitalized deaths Servadei et al., 1985 1981 to 1982 San Marino 327 23.5 468 Hospital admissions Wang et al., 1986 1982 Urban areas of China 35 63 56 Rates based on samples of households in city communities Nestvold et al., 1988 1974 Central Norway 488 350 236 Hospital admissions Badcock, 1988 1984 South Australia 1,698 NS 520 Includes ED visits, admissions and prehospital deaths Servadei et al., 1988 1984 Ravenna, Italy 644 172 372 Hospitalized cases only excludes ED treated and released Levi et al., 1990 1984 to 1988 Northern Israel 1,370 1,200 25 Rate in person-years Tiret et al., 1990 1986 Aquitaine, France 8,940 2,700 281 Hospital admissions and deaths Johansson et al., 1991 1984 to 1985 Northern Sweden 242 70 242 Ages 16-60 only, hospital admissions Nell and Brown, 1991 1986 Johannesburg, South 5,106 NS 316 Rate based on population estimates Africa Annoni et al., 1992 1987 St. Gallon Canton of 80 410 20 Rate based on sample of hospital Switzerland weeks of data collection Vazquez-Barquero et al., 1988 Cantabria, Spain 477 523 91 Hospital admissions only 1992 Engberg, 1995 1988 Frederiksborg County, NS 340 22.6 (7.1)
From page 82...
... per year Comments Ingebrigtsen et al., 1998 1993 Northern Norway 247 108 229 Hospital referred patients Tate et al., 1998 1988 New South Wales 1,259 NS 100 Hospital admitted patients excludes prehospital deaths Alaranta et al., 2000 1991 to 1995 Finland 24,497 5,100 95–100 Hospital discharge first-time TBI patients only, rate range over 5 years Engberg and Teasdale, 1979 to 1996 Denmark NS NS 265, 224, Hospitalized patients trend from 1979– 2001 157 1981, 1985–1987, 1991–1993, excludes prehospital deaths Firsching and Woischneck, 1996 Germany 279,000 82,000 350 Hospital admitted patients only 2001 Masson et al., 2001 1996 Aquitaine, France 497 2,800 17.3 Total AIS 4 and 5, Severe TBI (AIS4 = 7.2 AIS5 = 10.1) Pickett et al., 2001 1998 Kingston, Canada 760 176 431 Rate calculated from published data (115)
From page 83...
... per year Comments Chiu et al., 2007 2001 Taipei and Hualien 5,754, 2,634 218, 417 Excludes prehospital deaths County, Taiwan 1,474 353 Wu et al., 2008 2004 6 Provinces of Eastern 14,948 NS NS Hospital admitted cases China Yates et al., 2006 1997 to 2003 England NS 345 453 From an ED database including hospital admitted NOTE: AIS = Abbreviated Injury Scale, Co = county, ED = emergency department, ICD = International Classification of Diseases, PTA = posttraumatic amnesia, TBI = traumatic brain injury.
From page 84...
... 84 TABLE 3.6 US TBI Deaths and Mortality Rates Number of Reference Year(s) of Data Location Deaths Rate / 105 per year Comments Annegers et al., 1980 1965 to 1974 Olmsted County, Minnesota 446 Male: 32 Average rates per year Female: 9 Klauber et al., 1981 1978 San Diego County, California 381 22 Excludes gunshot deaths Cooper et al., 1983 1980 to 1981 Bronx, New York NS 28 50% from violence, 75% before hospital admission Kraus et al., 1984 1981 San Diego County, California 562 30 Includes inhospital and prehospital deaths Whitman et al., 1984 1979 to 1980 Inner city Chicago and 54 19 Evanston blacks Average rates per year Evanston, IL 11 Evanston whites 32 Inner city Fife et al., 1986 1979 to 1980 Rhode Island 248 26/year Rate derived from data in text Cowan et al., 1990 1990 Delaware 122 18 59% from motor vehicle crashes Sosin et al., 1996 1979 to 1986 US 39,416 per yr 17 Death certificate review, average over 8 yrs Sosin et al., 1996 1979 to 1992 US 52,000 25 in 1979 Average number of deaths per yr 19 in 1992 Thurman et al., 1996 1990 to 1992 Utah 1,067 20 Average rate per yr Gabella et al., 1997b 1991 to 1992 Colorado 1,312 18 in urban regions 34 in rural regions Gabella et al., 1997a 1990 to 1992 Colorado, Missouri, 3,172 23 Average rate per yr Oklahoma, Utah Thurman et al., 1999 1994 US 51,350 20 Data source is state TBI registry Adekoya et al., 2002 1989 to 1998 US 53,288 per yr 21 22 in 1989 19 in 1998 Langlois et al., 2006 1995 to 2001 US 49,900 per yr 18 Average rate over 7 years Rutland-Brown et al., 2003 US 51,000 18 2006 NOTE: IL = Illinois, TBI = traumatic brain injury, US = United States.
From page 85...
... (8, 2) Servadei et al., 2002a 1998 Romagna, Italy 225 18 Highest rates for 5–24 and 75+ Andersson et al., 2003 1992 to 1993 Western Sweden 5 4 Few coma patients Baldo et al., 2003 1996 to 2000 Northeast Italy NS 7 Average rate over 4 years Masson et al., 2003 1996 Aquitaine, France 128 5 Coma patients only, rate derived from text Santos et al., 2003 1994, 1996, Portugal 5,425 17 Highest rate for those age 20–29, 80+ 1997 85
From page 86...
... b Includes work and other. NOTE: NS = not stated, TBI = traumatic brain injury.
From page 87...
... Mild = 12–15 California Whitman et al., 1984 1979 to 1980 Innercity Chicago and 86 9 5 Severity criteria same as Annegers, see table 3 Evanston, IL Kraus et al., 1984 1981 San Diego County, 82 9 9 Using slightly modified GCS California Badcock, 1988 1984 South Australia 90 8 2 Based on PTA Tiret et al., 1990 1986 Aquitaine, France 80 11 9 Based on LOC and AIS Nell and Brown, 1986 Johannesburg 87 8 5 GCS moderate = 7–12, severe = 3–6 1991 Vazquez-Barquero et 1988 Cantabria, Spain 88 7 5 Based on GCS al., 1992 Thurman et al., 1996 1990 to 1992 Utah 39 42 19 Using the GCS Chiu et al., 1997 1988 to 1994 Taiwan 79 9 12 Based on GCS over 7 years Hillier et al., 1997 1987 South Australia 75 9 16 Based on GCS, ICDMAP, 82 3 15 PTA, respectively 82 9 9 Tate et al., 1998 1988 New South Wales 65 21 14 Based on PTA Thurman et al., 1999 1980 to 1995 US 78 16 6 1980–1981 (Used ICDMAP to create AIS 1994– 23 1995) Gururaj, 2002 1999 Bangalore, India 70 14 16 Based on GCS Servadei et al., 2002a 1998 Romagna, Italy 66 7 27 Mild = 14–15, Moderate = 9–13 Baldo et al., 2003 1991 to 2000 Northeast Italy 69 22 9 1996 63 16 21 2000; Used GCS Chiu et al., 2007 1991 vs.
From page 88...
... 88 Wu et al., 2008 2004 6 Provinces of Eastern 62 18 20 Used GCS China NOTE: AIS = Abbreviated Injury Scale, GCS = Glasgow Coma Scale, ICDMAP = computer algorithm, IL = Illinois, LOC = loss of consciousness, MN = Minnesota, PTA = posttraumatic amnesia.
From page 89...
... NOTE: ED = emergency department, NS = not stated.
From page 90...
... NOTE: NS = not stated, TBI = traumatic brain injury.
From page 91...
... NOTE: NS = not stated, TBI = traumatic brain injury.
From page 92...
... c Both races, nonfatal TBI. NOTE: Co = county, NS = not stated.
From page 93...
... TABLE 3.13 TBI In-Hospital Case Fatality Rates (CFR) from US Population-Based Studies Reference Location Source of Data and Study Population N = Sample Size CFR % Rimel, 1981 Central Virginia Hospital medical records N = 1330 7.0 Cooper et al., 1983 Bronx, New York Hospital medical and medical exam records N = 1209 24.9 Kraus et al., 1984 San Diego County, Hospital medical records and medical exam records N = 3358 5.2 California Whitman et al., 1984 Chicago area Hospital medical records and medical exam records N = 782 6.9 Jagger, 1984b North Central Virginia Hospital records N = 735 6.5 Fife et al., 1986 Rhode Island Hospital records N = 2870 4.9 MacKenzie et al., 1989a Maryland Hospital records N = 5838 4.4 Oklahoma State Department of Oklahoma Hospital/medical examiner records N = 3672 23 Health, 1991 Schuster, 1994 Massachusetts Hospital/medical examiner records N = 5778 10.1 Warren et al., 1995 Alaska Trauma registry N = 2178 5.6 Gabella et al., 1997b Colorado TBI surveillance N = 6863 7.6 Gabella et al., 1997a Colorado, Missouri, Hospital discharge data N = 11,611 6.9 Oklahoma, Utah Langlois et al., 2003 US 14 state TBI surveillance system N = 67,309 6.9 Rutland-Brown et al., 2006 US National Hospital Discharge Survey and Multiple Cause of Death tape N = 340,757 14.9 Langlois et al., 2006 US Same as Rutland-Brown, 2003 N = 284,900 17.5 NOTE: CFR = case fatality rate, TBI = traumatic brain injury.
From page 94...
... d From severity rates reported. NOTE: CFR = case fatality rates, TBI = traumatic brain injury.
From page 95...
... EPIDEMIOLOGY OF ADULT TRAUMATIC BRAIN INJURY 95 TABLE 3.15 Percent Distribution of GOS Outcome Categories at Hospital Discharge Rate for US and Non-US Studies Persistent Vegetative Reference Good Recovery Moderate Disability Severe Disability State Death Rimel, 1981 69 12 8 4 7 Kraus et al., 1984 90 3 1 0.5 6 Chiu et al., 1997 87 4 3 1 5 Masson et al., 2003 18 9 16 3 52 Langlois et al., 2003 74 10 6 0.6 NS Chiu et al., 1997 87 6 4 0.3 3 (Taipei City only) Wu et al., 2008 77 7 2 3 11 NOTE: GOS = Glasgow Outcome Score, NS = not stated.
From page 96...
... 2003. Epidemiology of traumatic brain injury: A population based study in western Sweden.
From page 97...
... 2006. Utility of Glasgow Coma Scale-Extended in symptom prediction following mild traumatic brain injury.
From page 98...
... 2003. Traumatic brain injury related hospital discharges.
From page 99...
... 2006. Traumatic Brain Injury in the United States: Emergency Department Visits, Hospitalizations, and Deaths.
From page 100...
... 2000. Use of the capture-recapture method to estimate severe traumatic brain injury rates.
From page 101...
... 1996. Surveillance of traumatic brain injuries in Utah.
From page 102...
... 2008. Epidemiology of traumatic brain injury in eastern China, 2004: A prospective large case study.


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