Disclosures: None Key Publications in Occupational & - - PDF document

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Key Publications in Occupational & Environmental Health: the Year in Review

Em Emerging and Re-Em Emerging Oc Occupational Disease 2018

Samuel M. Goldman, MD, MPH Associate Clinical Professor UCSF Division of Occupational & Environmental Medicine

Disclosures: None

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Clinical Infectious Diseases

Outbreak of Severe Histoplasmosis Among Tunnel Workers—Dominican Republic, 2015

Paige A. Armstrong,1 John D. Beard,2,a Luis Bonilla,3 Nelson Arboleda,3 Mark D. Lindsley,4 Sae-Rom Chae,5 Delia Castillo,6 Ramona Nuñez,6 Tom Chiller,4 Marie A. de Perio,7 Raquel Pimentel,6 and Snigdha Vallabhaneni4

1Epidemic Intelligence Service, Mycotic Diseases Branch, Division of Foodborne, Waterborne, and Environmental Diseases (DFWED), National Center for Emerging and Zoonotic Infectious

Diseases (NCEZID), Centers for Disease Control and Prevention (CDC), Atlanta, Georgia; 2Epidemic Intelligence Service, Industrywide Studies Branch, Division of Surveillance, Hazard Evaluations and Field Studies, National Institute for Occupational Safety and Health (NIOSH), Cincinnati, Ohio; 3Centers for Disease Control and Prevention, Santo Domingo, Dominican Republic; 4Mycotic Diseases Branch and 5Epidemic Intelligence Service, Global Water, DFWED, NCEZID, CDC, Atlanta, Georgia; 6Dirección General de Epidemiología, Santo Domingo, Dominican Republic; and 7Hazard Evaluations and Technical Assistance Branch, Division of Surveillance, Hazard Evaluations and Field Studies, NIOSH, Cincinnati, Ohio

M A J O R A R T I C L E

§On September 16, 2015, Dominican Republic Ministry of Health requested CDC investigation of an unknown severe febrile illness in tunnel workers

Background

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• Case definition:

‒ worked in tunnels to hydroelectric dam during July 30-Sept 2, 2015 ‒ fever and > 2 of: chills, night sweats, weakness, joint pain, cough, headache, malaise, dyspnea, myalgias, diarrhea, vomiting

• Case finding:

‒ Manual review of company payroll records ‒ Interviews with workers to identify any other workers

• Questionnaire:

‒ Interviews in Spanish ‒ Demographics, medical conditions ‒ Work history: days in tunnels, tasks, PPE

• Medical record review
• Cohort study to identify risk factors for severe disease (ICU admission)

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• Hydroelectric dam built in 1972
• 5 tunnels, 1-2 km long, 3m wide and tall, provide access for

inspection & maintenance

• No ventilation, hot, large bat colonies
• 1m deep bat guano, last cleaned 30 years ago

Tunnel Worker Characteristics (n = 36)

6

Characteristic

• No. (%)

Male sex 36 (100) Age, ya 18–32 18 (51) 33–62 17 (49) Asthma 5 (15) Current cigarette smoking 15 (43) Illicit drug use (noninjection) 12 (39) Type of work Shoveling/filling only 15 (43) Transporting wheelbarrow only 5 (14) Shoveling/filling and transporting wheelbarrow 11 (31) Supervising 3 (9) Other 1 (3) Tunnel of work Tunnel 1 only 10 (29) Tunnel 2 only 7 (20) Tunnels 1 and 2 18 (51) Median cumulative days worked in tunnels (range) 24 (1–25) Personal protective equipment use: surgical mask Never 16 (48) Sometimes 14 (42) Always 3 (9)

§ 36 men hired from local village by private company § PPE: knee-high rubber boots, hard hat, some had loose fitting paper masks § Filled wheelbarrows with bat guano, dumped at tunnel entrance § 3-4 hours work/morning due to heat § Began 30 July, stopped 2 Sept when several became ill

Distribution of Symptom Onset Dates

7 1 2 3 4 5 6 7 8

Cases Date of Symptom Onset

First patient admitted to local hospital First death Physician suggests histoplasmosis

• Leptospirosis initially suspected, but patients did not respond to penicillin
• Histoplasmosis suggested on 8 September, and all 19 hospitalized

workers were transferred from local to regional hospitals

Began work 30-Jul

Histoplasmosis infection

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• H. capsulatum most common pulmonary fungal infection

‒ occurs worldwide, especially throughout Americas & Caribbean; no prior reports in DR ‒ 500,000 annually in US, Ohio River valley ‒ 90% cases are self-limited and sub-clinical

• Dimorphic soil saprophyte often found in association with bird or bat

droppings (alkaline nitrogenous substrates)

• Occupations: farming, exposure to chicken coops or caves,

remodeling or demolition of old buildings, cutting down trees or clearing brush from sites in which blackbirds have roosted

• Exposure by inhalation of microconidia (asexual reproductive spores)
• Transforms into yeast phase in the body, incubation ~1-3 weeks
• Acute/subacute/chronic pulmonary forms; disseminated

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Histoplasma capsulatum

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Small, oval yeast cells (2-4 um) packed with macrophages. Giemsa’s stain. 1000 x In culture, produces hyaline, septate hyphae with microconidia. 400x

From: Carroll KC, et al. Jawetz, Melnick, & Adelberg’s Medical Microbiology, 27e

Diagnosis § Visualization of yeast in sputum § Culture takes up to 4 weeks § Antigen testing of both urine and serum ~40-80% sensitive § Antibody testing (immunodiffusion, complement fixation, EIA), may take up to 4-8 weeks § PCR not ready for prime time… Treatment

• None, if mild
• Acute: Amphotericin B + corticosteroids
• Chronic: itraconozole

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Level of medical care Inpatient hospitalization 28 (93) Intensive care unit 9 (30) Mechanical ventilation 6 (20) Deaths 3 (10) Symptoms Fever 25 (83) Cough 23 (77) Headache 21 (70) Generalized malaise 15 (50) Difficulty breathing 11 (37) Myalgias 11 (37) Diarrhea 8 (27) Diagnostics CXR 20 (67) Bilateral infiltrates, No. (%) of workers who had a CXR 17 (85) Interstitial consolidation, No. (%) of workers who had a CXR 14 (70) CT chest scan 12 (40) Bilateral infiltrates, No. (%) of workers who had a CT chest scan 11 (100) Interstitial consolidation, No. (%) of workers who had a CT chest scan 11 (100) Bronchoscopy 9 (30) BAL, No. (%) of workers who had a bronchoscopy 7 (100) Evidence of histoplasmosis on pathology, No. (%) of workers who had a BAL 2 (67) Bacterial culture consistent with ventilator–associated pneumonia, No. (%) of workers who had a BAL 6 (86) Laboratory Leukocytosis (WBC >12 × 109/L) 19 (68) AST or ALT >120 U/L 10 (36) HIV (type unknown) 0 (0) Leptospirosis (type unknown) 0 (0) Treatment Any antifungal 28 (93) Voriconazole, No. (%) of workers who had any antifungal 22 (79) Itraconazole, No. (%) of workers who had any antifungal 14 (50) Fluconazole, No. (%) of workers who had any antifungal 9 (33) Amphotericin B, No. (%) of workers who had any antifungal 8 (29) Days from symptom onset to first antifungal treatment, No. (%) of workers who had any antifungala 0–4 7 (29) 5–6 6 (25) 7–8 6 (25) 9–11 5 (21) Any corticosteroid 26 (87) Corticosteroids prior to antifungal treatment, No. (%) of workers who had any antifungal and any corticosteroid No 12 (48) Corticosteroids received on same day as antifungals 9 (36) Yes 4 (16)

Clinical Characteristics in those meeting case definition (n=30/36)

Lab analyses: Serum and/or urine collected 5-33 days after symptom onset. Antigen test positive in 53% serum, 45% urine Antibody (immunodiffusion) positive in 35%

Characteristics associated with developing Histoplasmosis (none significant)

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Characteristic Histoplasmosis Yes No Unadjusted Odds Ratio Age, ya 18–32 14 (48) 4 (67) 1.00 33–62 15 (52) 2 (33) 2.10 Asthma 4 (15) 1 (17) 0.87 Current cigarette smoking 12 (41) 3 (50) 0.71 Illicit drug use (noninjection) 9 (35) 3 (60) 0.37 Type of work Shoveling/filling only 13 (45) 2 (33) 1.00 Transporting wheelbarrow only 2 (7) 3 (50) 0.12 Shoveling/filling and transporting wheelbarrow 10 (34) 1 (17) 1.51 Supervising 3 (10) 0 (0) 0.49b Other 1 (3) 0 (0) 0.14b Tunnel of work Tunnel 1 only 10 (34) 0 (0) 3.39b Tunnel 2 only 5 (17) 2 (33) 0.72 Tunnels 1 and 2 14 (48) 4 (67) 1.00 Cumulative days worked in tunnels (per additional day worked) 1.04 Personal protective equipment use: surgical mask Never 13 (48) 3 (50) 1.00 Sometimes 11 (41) 3 (50) 0.85 Always 3 (11) 0 (0) 0.8b p=0.15

Characteristics associated with developing severe Histoplasmosis (ICU admission, n=9)

12 Characteristic ICU Admission Yes No Unadjusted Odds Ratio (Exact 95% CI) Exact P Value Age, ya 18–32 3 (33) 15 (58) 1.00 Reference Reference 33–62 6 (67) 11 (42) 2.65 (.45–20.07) .38 Asthma 0 (0) 5 (20) 0.41b (.00–2.52) .45 Current cigarette smoking 3 (33) 12 (46) 0.59 (.08–3.54) .79 Illicit drug use (noninjection) 1 (13) 11 (48) 0.16 (<.01–1.63) .17 Type of work Shoveling/filling only 5 (56) 10 (38) 1.00 Reference Reference Transporting wheelbarrow only 1 (11) 4 (15) 0.52 (.01–7 .42) >.99 Shoveling/filling and transporting wheelbarrow 2 (22) 9 (35) 0.46 (.04–3.73) .69 Supervising 1 (11) 2 (8) 1.00 (.01–23.97) >.99 Other 0 (0) 1 (4) 2.20b (.00–41.80) >.99 Tunnel of work Tunnel 1 only 4 (44) 6 (23) 3.18 (.40–28.95) .36 Tunnel 2 only 2 (22) 5 (19) 1.94 (.13–22.90) .87 Tunnels 1 and 2 3 (33) 15 (58) 1.00 Reference Reference Cumulative days worked in tunnels (per additional day worked) 1.18 (1.00–1.59) .06 Personal protective equipment use: surgical mask Never 4 (50) 12 (48) 1.00 Reference Reference Sometimes 3 (38) 11 (44) 0.82 (.10–6.14) >.99 Always 1 (13) 2 (8) 1.47 (.02–36.16) >.99 Days from symptom onset to first antifungal treatmentc,d 0–4 0 (0) 7 (47) 0.16a (.00–1.22) .13 5–6 4 (44) 2 (13) 1.89 (.12–37 .87) >.99 7–8 3 (33) 3 (20) 1.00 Reference Reference 9–11 2 (22) 3 (20) 0.69 (.03–12.15) >.99

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Conclusions

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• No prior history of Histo outbreaks in DR, likely unrecognized
• High proportion of hospitalization & death

‒ Delayed use of antifungals, and of Amphotericin B in particular ‒ Paucity of serologic or urine diagnostic capacity ‒ Probable high H. capsulatum inocula in tunnels

• Prevention

‒ Develop safety plan ‒ Moistening material prior to translocation ‒ PPE (N95 respirators at a minimum)

§ Largest case series of CTE § The first major study to apply standard clinicopathological and pathological criteria

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Clinicopathological Evaluation of Chronic Traumatic Encephalopathy in Players of American Football

Jesse Mez, MD, MS; Daniel H. Daneshvar, MD, PhD; Patrick T. Kiernan, BA; Bobak Abdolmohammadi, BA; Victor E. Alvarez, MD; Bertrand R. Huber, MD, PhD; Michael L. Alosco, PhD; Todd M. Solomon, PhD; Christopher J. Nowinski, PhD; Lisa McHale, EdS; Kerry A. Cormier, BA; Caroline A. Kubilus; Brett M. Martin, MS; Lauren Murphy, MBA; Christine M. Baugh, MPH; Phillip H. Montenigro, BA; Christine E. Chaisson, MPH; Yorghos Tripodis, PhD; Neil W. Kowall, MD; Jennifer Weuve, MPH, ScD; Michael D. McClean, ScD; Robert C. Cantu, MD; Lee E. Goldstein, MD, PhD; Douglas I. Katz, MD; Robert A. Stern, PhD; Thor D. Stein, MD, PhD; Ann C. McKee, MD

JAMA | Original Investigation

• JAMA. 2017;318(4):360-370. doi:10.1001/jama.2017.8334

Background: Chronic Traumatic Encephalopathy (CTE)

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• A progressive neurodegeneration associated with repetitive head

trauma and associated cognitive and behavioral syndrome

• Features noted in boxes in 1970s, football players in 2005 (Omalu et

al, Neurosurgery, 2005;57(1))

• Large series (n=68) reported in 2013 with proposed staging scheme

(McKee et al, Brain, 2013;136(1))

• Clinicopathological correlation developed 2014 (Mez et al, Alzheimers

Res Ther, 2015;7(1))

• Standardized pathological criteria developed 2015 by NINDS &

National Institute of Biomedical Imaging and Bioengineering (McKee et

al, Acta Neuropathol, 2016;131)

Study Recruitment

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• Brainbank created 2008 to study long-term effects of repetitive head

trauma through contact sports and military-related trauma

• Collaboration of VA Boston Healthcare System, Boston University,

Concussion Legacy Foundation (CLF)

• Inclusion criteria:

‒ Exposure to repetitive head trauma (e.g., contact sports, military service, or domestic violence) ‒ Playing American football was sufficient for inclusion § Beginning 2014, at least 2 years college-level play required ‒ Irrespective of clinical symptoms ‒ Postmortem interval < 72 hours

• Most donors’ kin approached the brainbank near the time of death

(81%), 9% referred by medical examiners, 6% “recruited” by CLF, 4% enrolled in brainbank registry during life

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Clinical Evaluation

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• Retrospective online surveys and semi-structured telephone interviews

with informants

• Researchers and informants blinded to neuropathological diagnosis
• Behavioral neurologist/neuropsychologist obtained detailed history re:

‒ timeline of cognition, behavior, mood, motor symptomatology ‒ additional diagnoses : substance use, sleep disorder, PTSD, AD, FTD, DLB, PD, CTE ‒ cause of death

• Demographic information included

‒ education, athletic history, military history, traumatic brain injury (TBI) including number of concussions

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100 μm A Stage I CTE 100 μm B Stage II CTE 100 μm 100 μm A Stage III CTE B Stage IV CTE

CTE pathological definition

§ At least 1 perivascular lesion of phosphorylated tau (ptau) aggregates in neurons, astrocytes, and cell processes around a small blood vessel, most commonly at depths of cortical sulci § 4 stages of severity: § Stage I: 1 or 2 isolated ptau epicenters, NFTs at depths of sulci § Stage II: 3 or more lesions in multiple cortical regions, NFTs along sulcal walls § Stage III: multiple lesions, superficial cortical NFTs, degeneration of amygdala, hippocampus § Stage IV: dense CTE lesions and NFTs throughout cortex, midbrain, brainstem

mild severe

Characteristics

• No. (%) of Brain Donorsb

Mild CTE (n = 44) Severe CTE (n = 133) Total (n = 177) Men 44 (100) 133 (100) 177 (100) Race White 35 (80) 105 (79) 140 (79) Black 8 (18) 27 (20) 35 (19) Pacific Islander 1 (1) 1 (1) Asian Other Unknown 1 (2) 1 (1) Age at death, median (IQR), y 44 (29-64) 71 (64-79) 67 (52-77) Cause of death Neurodegenerativec 7 (16) 62 (47) 69 (39) Cardiovascular disease 5 (11) 29 (22) 34 (19) Suicide 12 (27) 6 (5) 18 (10) Cancer 2 (5) 10 (8) 12 (7) Motor neuron disease 4 (9) 7 (5) 11 (6) Unintentional overdose 3 (7) 4 (3) 7 (4) Injury 2 (5) 3 (2) 5 (3) Other 9 (21) 12 (9) 21 (12)

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Demographic Characteristics Stratified by Neuropathological Severity

CTE diagnosed in 177/202 brains

20 Concussion count, median (IQR)d Definition provided (n = 99) 90 (22-150) 50.5 (12-163) 70 (12-150) No definition provided (n = 61) 2.5 (0-5) 8 (1-19) 5 (1-13) Age at first exposure to football, median (IQR), y 10 (8-14) 13 (10-14) 12 (10-14) Duration of play, mean (SD), y 13 (4.2) 15.8 (5.3) 15.1 (5.2) Highest level of play Youth High school 3 (7) 3 (2) College 21 (48) 27 (20) 48 (27) Semiprofessional 4 (9) 5 (4) 9 (5) Canadian Football League 1 (2) 6 (5) 7 (4) National Football League 15 (34) 95 (71) 110 (62) Primary position at highest level of play Offensive lineman 8 (18) 29 (22) 37 (21) Defensive lineman 8 (18) 27 (20) 35 (20) Running back 4 (9) 27 (20) 31 (18) Linebacker 12 (27) 14 (11) 26 (15) Defensive back 4 (9) 18 (14) 22 (12) Quarterback 2 (5) 11 (8) 13 (7) Tight end 1 (2) 6 (5) 7 (4) Wide receiver 3 (7) 1 (1) 4 (2) Kicker or punter 2 (5) 2 (1) Other special teams Military veteran 5 (11) 40 (30) 45 (25)

Exposure Characteristics Stratified by CTE Severity

Characteristics

• No. (%) of Brain Donorsb

Mild CTE (n = 44) Severe CTE (n = 133) Total (n = 177) Men 44 (100) 133 (100) 177 (100)

% with severe CTE by level of play:

• Highschool 0%
• College 56%
• Semi-pro 56%
• CFL 86%
• NFL 86%

% with any CTE by level of play:

• Highschool 21%
• College 91%
• Semi-pro 64%
• CFL 88%
• NFL 99%

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21 Figure 3. Phosphorylated Tau Pathology for Each Brain Region by CTE Neuropathological Stage Frontal 1 2 3 4 Total CTE Stage Temporal Parietal Septal Insula Entorhinal Brain Region Amygdala Hippocampus Thalamus SI SN LC Cerebellum 1.1 1.6 2.2 2.8 2.2 0.6 1.4 2.1 2.7 2.1 0.2 1.3 1.6 2.6 1.8 0.4 1.2 2.0 2.7 2.0 0.3 1.1 2.1 2.8 2.1 0.6 1.4 2.6 2.8 2.3 0.4 1.1 2.3 2.8 2.1 0.1 0.7 2.1 2.4 1.8 0.3 0.9 1.4 2.2 1.5 0.5 1.3 2.3 2.7 2.1 0.6 1.0 1.8 2.5 1.8 0.9 2.0 2.5 2.5 2.3 0.2 0.3 0.6 0.3 2 3 1 Mean phosphorylated tau pathology 11 33 76 57 177

• No. of

Donors CTE indicates chronic traumatic encephalopathy; NFT: neurofibrillary tangle, SI: substantia innominata, SN: substantia nigra; LC: locus coeruleus. Cerebellum indicates dentate nucleus of the cerebellum. In each region, 0 = no NFTs (yellow); 1 = 1 NFT per 20× field (orange); 2 = 2 to 3 NFTs per 20× field (amber); and 3 = 4 NFTs per 20× field (red). The color scale is based on the distribution

• f all values, not by each individual stage. Values represent means of

phosphorylated tau pathology among participants in each stage.

Anatomical Distribution of p-tau Pathology Stratified by CTE Stage

CTE Stage

• No. of

Brain Donors Age at Death, Median (IQR), y 1 11 36 (25-56) 2 33 49 (29-65) 3 76 67 (57-78) 4 57 76 (69-82) Total 177 67 (53-78) Abbreviations: AA, amyloid angiopathy; Aß, am

22

Other Neuropathological Diagnoses, No. (%) Pure CTE,

• No. (%)

AD LBD FTLD TDP-43 FTLD-Tau MND 1 (9) 1 (9) 8 (73) 1 (3) 2 (6) 1 (3) 1 (3) 4 (12) 21 (64) 4 (5) 15 (20) 1 (1) 3 (4) 6 (8) 42 (55) 18 (32) 16 (28) 5 (9) 2 (4) 1 (2) 27 (47) 23 (13) 34 (19) 8 (5) 6 (3) 11 (6) 98 (55) terized by 1 or 2 perivascular CTE lesions at the depths of the cerebral sulci in the cerebr

Other Neuropathological Diagnoses Stratified by CTE Stage

§ AD = Alzheimer disease § LBD= Lewy body dementia (i.e. PD, DLB) § FTLD = frontotemporal lobar dementia (pathologic subtypes classified by inclusion composition) § MND= motor neuron disease

23

Clinical Features

• No. (%) of Brain Donors

Mild CTE Severe CTE Total Progressive course 23 (85) 84 (100) 107 (96) Cognitive symptomsb 23 (85) 80 (95) 103 (93) Memory 19 (73) 76 (92) 95 (86) Executive function 19 (73) 67 (81) 86 (79) Attention 18 (69) 67 (81) 85 (78) Language 10 (39) 54 (66) 64 (59) Visuospatial 7 (27) 44 (54) 51 (47) Fluctuating cognition 2 (8) 17 (21) 19 (18) Dementiab 9 (33) 71 (85) 80 (72) Behavioral or mood symptomsb 26 (96) 75 (89) 101 (91) Impulsivity 23 (89) 65 (80) 88 (82) Depressive symptoms 18 (67) 46 (56) 64 (59) Explosivity 18 (67) 38 (45) 56 (51) Apathy 13 (50) 43 (52) 56 (51) Anxiety 14 (52) 41 (50) 55 (51) Hopelessness 18 (69) 36 (46) 54 (52) Verbal violence 17 (63) 28 (34) 45 (41) Social inappropriateness 13 (48) 26 (32) 39 (36) Physical violence 14 (52) 23 (28) 37 (34) Paranoia 11 (41) 26 (31) 37 (34) Suicidality (ideation, attempts, or completions) 15 (56) 21 (25) 36 (33) Visual hallucinations 6 (23) 22 (27) 28 (26) Mania 6 (22) 3 (4) 9 (8) Posttraumatic stress disorder 3 (11) 9 (11) 12 (11) Posttraumatic stress disorder (exposure and symptoms consistent with) 3 (11) 9 (11) 12 (11) Substance use disorder 18 (67) 41 (49) 59 (53) Alcohol 13 (50) 31 (37) 44 (41) Anabolic steroid 4 (5) 4 (4) Other 14 (54) 23 (28) 37 (34) Motor symptomsb 13 (48) 63 (75) 76 (68) Gait instability 7 (26) 55 (66) 62 (56) Slowness 5 (19) 42 (50) 47 (42) Coordination difficulties 7 (26) 38 (45) 45 (41) Falls 4 (15) 39 (46) 43 (39) Tremor 5 (19) 33 (39) 38 (34) Dysphagia 3 (11) 14 (18) 17 (16) Dysarthria 5 (19) 10 (13) 15 (14) Headache 8 (30) 11 (14) 19 (18) Diagnoses in life Motor neuron disease 1 (4) 3 (4) 4 (4) Parkinson disease 1 (4) 5 (6) 6 (6) Alzheimer disease 1 (4) 21 (25) 22 (20) Obstructive sleep apnea (diagnosis or symptoms) 7 (27) 36 (46) 43 (41) Rapid eye movement sleep behavior disorder (diagnosis or symptoms) 7 (27) 23 (29) 30 (29)

Clinical Features Stratified by CTE Severity

Clinical Features

• No. (%) of Brain Donors

Mild CTE Severe CTE Total Progressive course 23 (85) 84 (100) 107 (96)

Conclusions

24

• Football associations

‒ Nearly all football players beyond highschool had CTE pathology ‒ CTE severity low in highschool footballers, intermediate in college, and high in professionals ‒ Possible gradient by player position (running backs, defensive backs > linemen) ‒ Unclear if symptomatic hits (concussions) more relevant ‒ Unclear if age at starting play relevant

• Pathologic associations

‒ Co-pathology common in severe CTE (b-amyloid, a-synuclein, TDP-43) ‒ Co-morbidity common in severe CTE (AD, PD, FTLD)

• Clinicopathologic associations

‒ Behavioral, mood, cognitive symptoms very common in mild or severe CTE ‒ Dementia and motor symptoms much more common in severe CTE

• Limitations:

‒ Cross sectional: unable to assess progression, but substantial evidence CTE is progressive ‒ *Self-referred sample: likely not representative of all football players

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Environmental Exposures to Lead, Mercury, and Cadmium and Hearing Loss in Adults and Adolescents: KNHANES 2010–2012

Yoon-Hyeong Choi1,2 and Sung Kyun Park3,4

1Department of Preventive Medicine, Gachon University College of Medicine, Incheon, Republic of Korea 2Gachon Advanced Institute for Health Sciences and Technology, Incheon, Republic of Korea 3Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor, Michigan, USA 4Department of Environmental Health Sciences, University of Michigan School of Public Health, Ann Arbor, Michigan, USA

Environ Health Perspect. 2017 Jun 8;125(6):067003. doi: 10.1289/EHP565.

§ Limited data regarding low-level metals exposures and auditory function

Background: Lead, Mercury, Cadmium & Hearing Loss

26

• Human studies (reviewed by Castellanos, Int. J. Environ. Res. Public Health 2016, 13)

‒ Pb: § Some threshold deficits in highly exposed occupational populations, inconsistent § Bone-lead dose-related association (Park et al, Hear Res, 2010;269) § cause of Beethoven’s deafness? (Stevens et al, Laryngoscope, 2013;123(11)) ‒ Hg: § hearing deficits/deafness in methylmercury poisonings (Minimata, Japan, Iraq) § reduced auditory evoked potentials in children with high levels § No association in NHANES (Shargorodsky, Arch. Otolaryngol. Head Neck Surg. 2011, 137) ‒ Cd: hearing loss in highest NHANES quartile, but no dose-response (Shargorodsky)

• Proposed mechanisms

‒ Oxidative stress: depletion of glutathione, cochlear lipid peroxidation ‒ Blood flow alterations

Methods

27

• KHANES: cross-sectional surveys modeled on NHANES: Health & behavior interview;

Health exam; Nutrition survey ‒ Representative population sampling since 1998

• Audiometric evaluations, blood metals, noise exposure information obtained 2010-2012
• 5,187 adults, 853 adolescents aged >12 with complete data (80% response rate)
• Audiometry: pure tone thresholds and averages (PTA) in sound-isolated room

‒ Speech-PTA: averages of 0.5, 1, 2, 4 kHz ‒ High-PTA: averages of 3, 4, 6 kHz ‒ Hearing loss defined as PTA >25 dB for adults, >15 dB for adolescents

• Blood metals (venous whole blood):

‒ Graphite furnace absorption spectrometry (lead, cadmium); gold amalgam (mercury) ‒ None of adult and 2 adolescents had levels below limit of detection for any metal

• Analytic covariates: age, sex, education, household income, smoking, BMI, diabetes,

hypertension, self-reported noise ‒ occupational noise: “Ever worked in places exposed to loud noise >3 months” ‒ non-occupational: “Ever exposed to loud noise outside of work (e.g., power tools or loud music)”

Associations of blood metals and hearing in adults

28 Table 3. Odds ratios (ORs) [95% confidence intervals (CIs)] of hearing loss (>25 dB) by blood lead, mercury, and cadmium levels in single-pollutant models in adults (n = 5,187). Variablesa Speech-frequency PTAb High-frequency PTAc

• No. hearing loss/No. participants

ORs (95% CIs)

• No. hearing loss/No. participants

ORs (95% CIs) Lead Per doubling of lead 1,124/5,187 1.15 (0.94, 1.41) 1,124/5,187 1.30 (1.08, 1.57) Lead quartile (mg/dL) Q 1 ð0:327–1:593Þ 170/1,296 1 (Reference) 276/1,296 1 (Reference) Q 2 ð1:594–2:146Þ 204/1,296 0.94 (0.65, 1.35) 420/1,296 1.13 (0.83, 1.53) Q 3 ð2:148–2:822Þ 330/1,298 1.29 (0.92, 1.78) 587/1,298 1.35 (1.00, 1.81) Q 4 ð2:823–26:507Þ 420/1,297 1.25 (0.87, 1.79) 810/1,297 1.70 (1.25, 2.31) p-Trend 0.066 <0:001 Mercury Per doubling of mercury 1,124/5,187 0.96 (0.84, 1.08) 1,124/5,187 0.98 (0.87, 1.09) Mercury quartile (lg=L) Q 1 ð0:363–2:378Þ 284/1,296 1 (Reference) 469/1,296 1 (Reference) Q 2 ð2:379–3:528Þ 250/1,297 0.84 (0.61, 1.17) 460/1,297 0.89 (0.68, 1.16) Q 3 ð3:529–5:369Þ 267/1,296 0.79 (0.58, 1.09) 524/1,296 0.83 (0.63, 1.08) Q 4 ð5:370–60:678Þ 323/1,298 0.84 (0.63, 1.12) 640/1,298 0.89 (0.68, 1.17) p-Trend 0.221 0.382 Cadmium Per doubling of cadmium 1,124/5,187 1.18 (1.00, 1.39) 1,124/5,187 1.25 (1.08, 1.44) Cadmium quartile (lg=L) Q 1 ð0:068–0:689Þ 140/1,293 1 (Reference) 289/1,293 1 (Reference) Q 2 ð0:690–1:033Þ 255/1,300 1.04 (0.73, 1.49) 489/1,300 1.10 (0.81, 1.49) Q 3 ð1:035–1:470Þ 340/1,299 1.22 (0.86, 1.72) 645/1,299 1.43 (1.06, 1.93) Q 4 ð1:471–6:422Þ 389/1,295 1.30 (0.88, 1.91) 670/1,295 1.47 (1.05, 2.05) p-Trend 0.117 0.007 Note: Models were adjusted for age, age2, sex, education, body mass index, cigarette smoke, current diagnosis of hypertension, current diagnosis of diabetes, occupational noise, rec- reational noise, and firearm noise. PTA, pure tone average.

aHearing loss was defined as pure tone average >25dB. bSpeech-frequency PTA at 0.5, 1, 2, and 4 kHz. cHigh-frequency PTA at 3, 4, and 6 kHz.

*2.56

*US 90th percentile, 2012

*3.35 *1.14

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29 Table 4. Odds ratios (ORs) [95% confidence intervals (CIs)] of hearing loss (>15 dB) by blood lead, mercury, and cadmium levels in single-pollutant models in adolescents (n = 853). Variablesa Speech-frequency PTAb High-frequency PTAc

• No. hearing loss/No. participants

ORs (95% CIs)

• No. hearing loss/No. participants

ORs (95% CIs) Lead Per doubling of lead 48/853 1.20 (0.48, 3.05) 95/853 1.26 (0.73, 2.16) Lead quartile (lg=dL) Q 1 ð0:260–0:975Þ 11/213 1 (Reference) 20/213 1 (Reference) Q 2 ð0:978–1:260Þ 12/213 1.17 (0.41, 3.32) 20/213 0.89 (0.39, 2.03) Q 3 ð1:261–1:557Þ 13/213 1.08 (0.38, 3.08) 31/213 1.88 (0.83, 4.25) Q 4 ð1:562–5:904Þ 12/214 1.24 (0.34, 4.49) 24/214 1.38 (0.63, 3.02) p-Trend 0.803 0.181 Mercury Per doubling of mercury 48/853 1.01 (0.53, 1.91) 95/853 0.73 (0.45, 1.20) Mercury quartile (lg=L) Q 1 ð0:555–1:488Þ 13/213 1 (Reference) 32/213 1 (Reference) Q 2 ð1:490–1:956Þ 10/213 1.00 (0.36, 2.75) 20/213 0.64 (0.30, 1.36) Q 3 ð1:960–2:683Þ 11/214 0.60 (0.21, 1.75) 17/214 0.34 (0.16, 0.74) Q 4 ð2:687–8:409Þ 14/213 1.20 (0.41, 3.54) 26/213 0.58 (0.27, 1.26) p-Trend 0.901 0.107 Cadmium Per doubling of cadmium 48/853 1.41 (0.93, 2.14) 95/853 1.54 (1.12, 2.11) Cadmium quartile (lg=L) Q 1 ð0:010–0:245Þ 12/214 1 (Reference) 20/214 1 (Reference) Q 2 ð0:246–0:341Þ 9/213 0.96 (0.33, 2.76) 17/213 1.06 (0.46, 2.46) Q 3 ð0:342–0:495Þ 9/213 0.93 (0.33, 2.66) 20/213 1.51 (0.68, 3.37) Q 4 ð0:496–2:067Þ 18/213 2.39 (0.98, 5.83) 38/213 3.03 (1.44, 6.40) p-Trend 0.083 0.003 Note: Models were adjusted for age, age2, sex, education, body mass index, cigarette smoke, recreational noise, and firearm noise. PTA, pure tone average.

aHearing loss was defined as PTA >15dB. bSpeech-frequency PTA at 0.5, 1, 2, and 4 kHz. cHigh-frequency PTA at 3, 4, and 6 kHz.

Associations of blood metals and hearing in adolescents

*1.09

*US 90th percentile, 2012

*1.32 *0.34

Conclusions

30

• Adults: hearing loss is associated with blood levels of lead and cadmium
• Adolescents: hearing loss is associated with blood levels of cadmium
• No associations with mercury
• Study strengths

‒ Population-based, large ‒ Adjusted for numerous potential confounders ‒ Numerous sensitivity analyses (supplemental material), including adjusting for the other 2 metals, urinary cotinine, fish intake, cholesterol, age strata-specific

• Study weaknesses

‒ Limited ability to adjust for noise ‒ Interactions between noise and metals not tested ‒ Blood levels reflect relatively recent exposure ‒ Possible residual confounding

§ The first OP, tetraethylpyrophosphate (TEPP), was synthesized between 1801-1854 by one or more French chemists § Gerhard Schrader at I.G. Farbenindustrie synthesized the first commercially successful OP pesticide (E605, aka parathion) in 1944 § German government pursued 2 development tracks: less toxic OPs for agriculture, and more toxic OPs for warfare (Tabun, Sarin and Soman) § Hundreds of OPs commercialized, with usage peaking during 1970s § OPs comprised ~33% pesticide usage in US in 2012; higher proportion in developing nations because of low cost

31

CONTEMPORARY REVIEW

Organophosphorus Compounds at 80: Some Old and New Issues

Lucio G. Costa*,†,1

*Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, Washington 98105; and †Department of Medicine and Surgery, University of Parma, Parma 43100, Italy

Roosevelt, Suite 100, Seattle, WA 98105. Fax: (206) 685-4696. E-mail: lgcosta@uw.edu. TOXICOLOGICAL SCIENCES, 2017, 1–12 doi: 10.1093/toxsci/kfx266 Advance Access Publication Date: December 7, 2017 Contemporary Review

Background: OP Structure

32

• Most OP insecticides are phosphorothioates

(P=S bond)

• Do not directly inhibit AChE
• Bioactivated by CYP-mediated oxidative

desulfuration

• Most nerve agents have P=O bond and don’t

require activation

Nerve agents Carbamate

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33

The former Russian spy Sergei Skripal was deliberately poisoned with a nerve agent in a case that police are now treating as attempted murder, Scotland Yard’s assistant chief commissioner has confirmed this afternoon. …the police officer who was first to the spot where the pair were found in Salisbury on Sunday afternoon was now “seriously ill” in hospital. “The medical and chemical evidence and the effects on the victims point to a sophisticated nerve toxin. The best known are VX and sarin.”

The Guardian, March 7, 2018

OP Toxicity: Acute cholinergic toxicity

34

§ Acute cholinergic toxicity caused by inhibition of AChE

Normal hydrolysis of ACh by AChE at muscarinic & nicotinic synapses OP binds at serine site, leaving group

• hydrolyzed. Prevents

ACh binding Non-enzymatic “aging” takes hours to days: OP irreversibly bound after hydrolysis of second alkyl group Oxime rescue prevents aging

§ Cholinergic syndrome: sweating, salivation, bronchial secretion, bronchoconstriction, miosis, diarrhea, tremors, muscular twitching, dizziness, convulsions, coma…

OP-induced delayed polyneuropathy (OPIDP)

35

• Most common form of toxicity through 1940s, now rare
• Largest outbreak affected >30,000 U.S. early 1930s: “Jake

leg” (The New Yorker, 9/15/03)

• Outbreak first detected in Oklahoma City, by Ephraim

Goldfain, a Romanian emigrant and physician, who ran a clinic called the Reconstruction Hospital

• Jamaica Ginger patent medicine (70-90% EtOH) produced

by Harry Gross and Max Reisman, of Hub Products, shipped barrels of jake around the country.

• Newly formed NIH identified toxicant as tri-ortho-cresyl

phosphate (TOCP), added to interfere with prohibition-era testing

• Multi-isomer TCP produced as “Lindol” by Celluloid

Corporation

OP-induced delayed polyneuropathy (OPIDP)

36

§ Signs & symptoms: onset 2-3 weeks after exposure

• Tingling of hands & feet, sensory loss
• Progressive muscle weakness, flaccid paralysis distal

skeletal muscles of LE & UE

• Ataxia

§ A distal sensorimotor axonopathy

• Bilateral degeneration of distal axons and terminals
• Primarily affects larger myelinated central & peripheral

fibers § Mechanism:

• binding (and aging) of neuropathy target esterase (NTE)
• ? Temporary toxic gain of function
• NTE function fully recovered by the onset of signs

§ OPIDP classically associated with TOCP, but also some insecticide OPs (leptophos, chlorpyrifos, trichlorfon) § OPs are tested for OPIDP in hens prior to commercialization

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Non-ACHE targets of OPs

§ Neuropathy target esterase (OPIDP). Effect: toxic gain of function. § Acylpeptide hydrolase (APH). Function: metabolizes beta-endorphin, other small peptides. Effect: inhibition § Fatty acid amide hydrolase (FAAH). Function: hydrolyzes various endocannabinoids (and THC). Effect: potently inhibited § Lipases (especially in CNS). § Oxidative stress (independent of AChE inhibition)

• Microglial activation
• CNS cytokine elevations

§ Inhibition of axonal transport

37

End-point Chlorpyrifos Chlorpyrifos Oxon Lowest effective concentration Anterograde transport 100 nM 0.1 nM Retrograde transport 10 lM 10 nM AChE activity 10 lM 10 nM

Axonal transport was measured in rat cortical neurons. Adapted from Gao et al. (2017a).

Emerging/debated hypotheses of OP toxicity

38

§ Developmental neurotoxicity

• Increasing evidence of effects of exposure in utero or in early childhood
• Effects in rodent models noted only at levels sufficient to inhibit AChE
• Deficits in learning & memory associated with low levels (Eskenazi, 1999, EHP)

‒ ? Relationship with slowed axonal transport § Aerotoxic syndrome

• Airline crew complaints of ill health x 2 decades
• Concerns about air quality (engine contaminants, use of pesticides)
• Symptoms varied: respiratory irritation, GI, CNS (tremors, disorientation, memory)
• Air monitoring: toluene, carbon monoxide, tri-cresyl phosphate (TCP, from hydraulic fluids)

‒ Levels of TCP quite low, both in air and in personnel

• “Issues related to the eventual roles of OPs in the airotoxic syndrome remain emotionally charged and

scientifically weak” § Microbiome derangement

• Clear evidence of gut microbial changes in rodents fed small concentrations various OPs
• Recent human study found changes in human oral microbiome in farmworkers using OPs (Stanaway, 2017,

Appl Environ Microbiol)

OPs and Neurodegeneration

39

132 In the sex- specifjc analysis, the PD incidences in the OP poisoning cohort were higher than those in the control cohort, and the risk of PD was higher for both women (adjusted IRR=1.47, 95% CI=1.27- 1.70) and men (adjusted IRR=1.32, 95% CI=1.20- 1.45). In the interactjon analysis, sex did not signifjcantly modify the associatjon between poi values for interactjon, .08). The age- specifjc analysis showed PD incidence increasing with age in both cohorts. However, the age- specifjc relatjve risk of PD was higher in the poisoning cohort than in the control cohort for all age

• groups. We stratjfy the urbanizatjon level by the populatjon density
• f the residentjal area into four levels, with level 1 as the most urban

ized region and level 4 as the least urbanized region. The urbanizatjon level- specifjc adjusted IRR of PD for the poisoning cohort relatjve to the control cohort was signifjcant for all urbanizatjon levels, except the second highest urbanizatjon level. Occupatjon- specifjc analysis showed that blue- collar workers in the poisoning cohort, compared with those in the control cohort, exhibited a higher risk of PD (adjusted IRR=1.59, 95% CI=1.44- 1.77). The comorbidity- specifjc risk and adjusted HR of PD for the poi soning cohort and the control cohort were signifjcant for both the subgroup without comorbidity (adjusted IRR=1.33, 95% CI=1.23- 1.45) and that with comorbidity (adjusted IRR=1.71, 95% CI=1.39- 2.11). The analysis was stratjfjed by the duratjon of follow- up; compared with the control cohort, the poisoning cohort exhibited a signifjcantly higher risk of developing PD in the fjrst 1 follow- up years (adjusted IRR=3.01, 95% CI=2.77- 3.26), in the 2- 3 follow- up years (adjusted IRR=1.27, 95% CI=1.15- 1.40), and in more than 5 follow- up years (ad justed IRR=1.39, 95% CI=1.26- 1.53). The multjvariable Cox proportjonal hazards regression analysis further evaluated the roles of sex, age, and baseline comorbiditjes in PD development (Table 3). The risk of PD exhibited a 10% incre ment per 1 year of age. Patjents whose occupatjon was not white collar had a higher risk of developing PD (adjusted IRR=1.30, 95% CI=1.20- 1.42). In the multjvariable model, patjents with depres sion had the highest risk (adjusted IRR=3.25, 95% CI=2.91- 3.64), followed by those with dementja (adjusted IRR=2.50, 95% CI=2.08- 3.01). Table 4 shows that the risk of PD increased with the severity of OP or CM poisoning. Patjents with a seven- day or longer hospital stay were considered to be in the high severity group; otherwise, they were considered as low severity. The high severity cases had an ad justed IRR of 1.53 (95% CI=1.37- 1.72); the low severity cases had an adjusted IRR of 1.19 (95% CI=1.09- 1.30). The poisoning cases with respiratory failure had an adjusted IRR of 1.63 (95% CI=1.43- 1.87); the cases without respiratory failure had an adjusted IRR of 1.21 (95% CI=1.11- 1.32). TABLE 1 Characteristjcs of patjents with organophosphate or carbamate poisoning and patjents without poisoning Organophosphate or carbamate

• value

(N=9128) No (N=36 466) n (%) n (%) 20- 49 3840 (42.1) 15 352 (42.1) 50- 75 4403 (48.2) 17 588 (48.2) ≥75 885 (9.70) 3526 (9.67) Mean (SD) 53.8 (16.3) 53.3 (16.4) Female 10 857 (29.8) 6411 (70.2) 25 609 (70.2) Urbanizatjon level 1 (highest) 10 184 (27.9) 10 853 (29.8) 1480 (16.2) 4 (lowest) 5034 (55.2) 9241 (25.3) Occupatjon White collar 2580 (28.3) 18 739 (51.4) Blue collar 5787 (63.4) Others 761 (8.34) 1500 (16.4) 176 (0.48) Stroke 1434 (3.93) Dementja 55 (0.60) Psychosis Chi- square test. The urbanizatjon level was categorized by the populatjon density of the residentjal area into four levels, with level 1 as the most urbanized region and level 4 as the least urbanized region. Other occupatjons included primarily retjred, unemployed, and low- income populatjons. FIGURE 2 Comparison of cumulative incidence of Parkinson’s disease between patients with and those without organophosphate

• r carbamate poisoning

§ Parkinson’s disease (PD)

• Data strongest for PD
• Acute, reversible parkinsonism has been reported
• Recent study found increased risk of PD after OP poisoning

(Chuang, 2017, Acta Neurol Scand)

• Several supportive epidemiologic studies
• Possible gene * OP interaction (paraoxonase-1, PON1)
• Proposed mechanisms: oxidative stress, neuroinflammation

§ Alzheimer’s disease (AD)/dementia/cognition

• Data generally weak and inconsistent for AD & OPs
• Recent study found accelerated cognitive decline associated

with estimated ambient OP exposure (Paul, et al, 2018, Environ Res)

• Gulf War veterans exposed to sarin have cognitive deficits

and reduced hippocampal volume (Chao 2017, JOEM) § ALS

• Limited evidence, though some resemblances with OPIDP

40

Questions?

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Question 1:

Which of the following statements about Histoplasma capsulatum is NOT true ? a) Most Histoplasmosis infections cause fulminant disease b)

• H. capsulatum is found throughout the Americas

c)

• H. capsulatum concentrates in bird and bat droppings

d) Intravenous Amphotericin B is the preferred treatment for severe disease

41

Question 2:

What percentage of NFL football players had pathological evidence of chronic traumatic encephalopathy? a) 20% b) 50% c) 75% d) 99%

42

Question 3:

Which of the following toxicities may be associated with

• rganophosphates?

a) acute cholinergic syndrome b) delayed polyneuropathy c) developmental neurotoxicity d) All of the above

43