TOF and QTOF Fundamentals March 2007 Page 1 Fundamentals of TOF and QTOF Dr. Patrick (Pat) Perkins...

TOF and QTOF Fundamentals

March 2007

Fundamentals of TOF and QTOF

Dr. Patrick (Pat) PerkinsR&D scientist

Agilent TechnologiesLife Sciences and Chemical AnalysisSanta Clara, CA


March 2007

Agenda

Time-of-Flight (TOF) Mass Spectrometry basics

• Mass measurement

• Sources of variability in the measurement

• Minimizing the variability in the measurement

Quadrupole Time-of-Flight (QTOF) MS

• Ion optics, collision cell design and performance


March 2007

Definitions Used With TOF

m/z—”mass-to-charge ratio”. The mass of an ion divided by its charge, the actual result produced by all mass spectrometers. For ions with a single charge (most small molecules), this is its isotopic molecular weight plus any adduct (proton, sodium,…). Proteins and peptide ions are in general multiply-charged, and therefore additional math (deconvolution) is used to determine their molecular weights.

oa—”orthogonal acceleration”. Ions are accelerated (“pulsed”) down the flight tube in a direction perpendicular to their entry into the TOF analyzer. This minimizes the effects of ion generation and transmission on the mass measurement.

ppm—”parts-per-million”, a measure of the error in the experimental mass assignment, compared to the known (or theoretical) value.

Resolution—a dimensionless value indicating the ability of the mass analyzer to separate (resolve) ions. Higher values mean better resolving power. Several definitions exist, but the most common is M/M, the m/z value of the ion divided by its peakwidth expressed in m/z units.

Transient—one packet of ions pulsed down the flight tube and detected. Data from many pulses, typically ~10,000, are summed to create a spectrum.


March 2007

Basic Ideal TOF Mass Spectrometer

KE = ½ m v2

v = d/t

t = m½ * d/(2KE)½ constant

Ideally, to measure the mass,

Measure the time and use

m = A * t2

Practically,

t = m½ * d/(2KE)½ + t0 2 constants

m = A * (t – t0)2

Detector

V

d

Vacuum


March 2007

Sources of Variability in Measurement (Deviations from Ideality)

Detector

V

d

Vacuum

???


March 2007

Sources of Variability in Measurement (Deviations from Ideality)

Ions don’t all start at the same plane in space relative to flight direction

Ions aren’t sitting still and have different velocities relative to flight direction

Temperature fluctuations change flight distance

Voltage pulse is not instantaneous or of invariant shape

Ions farther from voltage pulse element(s) obtain a higher velocity

Change in temperature/humidity alter pulse electronics

Poor vacuum scatters ions

Detector and/or method of detection alters arrival times

Inaccurate method(s) of locating the maximum of the mass peaks

Detector

V

d

Vacuum

???


March 2007

Minimizing the Variability in Measurement (Approximating Ideality)

• Orthogonal acceleration

• Reflectron

• Beam shaping/conditioning prior to pulsing

• Higher order focusing

• Temperature control

• Humidity control

• Analog-to-Digital Conversion (ADC) vs. Time-to-Digital Conversion (TDC)

• Calibration

• Reference mass addition

• Sophisticated algorithms to locate mass peak centroids


March 2007

Agilent TOF Schematic

Pulser Detector

Vacuum ~1*10-7 Torr

Internal support structure with low coefficient of thermal expansion

1 meter flight tube, 2 meter flight path

Reflectron (ion mirror) with self-compensating thermal design

Optics for beam shaping and conditioning

Flight acceleration orthogonal to ion introduction

Turbopumps


March 2007

A Time-of-Flight Scan

Pulser Detector

1. Pulse ions every 100 microseconds

2. Measure at detector each nanosecond (1 GHz)

3. 100,000 data points in each transient

4. Sum ~10000 transients into one scan (1 scan/second operation)

5. Produces spectra with excellent ion statistics

20 µsec – m/z 118

46 µsec – m/z 622

90 µsec – m/z 2421


March 2007

TOF Instruments: Excellent Mass Accuracy and High Resolution Simultaneously

Advantages of High Resolution and Mass Accuracy

• Excellent mass accuracy provides a high degree of confidence in compound identification

• High resolution allows distinguishing peaks separated by only small m/z values

• High resolution allows selective detection of desired (“targeted”) compounds in the presence of interferences


March 2007

Greater Resolution Does Not Necessarily Yield Better Mass Accuracy

A TOF MS at 10,000 resolution cannot resolve between an ion with one C13 isotope and one with one N15 isotope. FTMS at 100,000+ resolution can.

A TOF MS delivers < 3 ppm mass accuracy, while FTMS is often not as good under the same sample conditions


March 2007

Why is Accurate Mass Useful?

Accurate masses give possible elemental compositions

1

10

100

1000

0.1 0.05 0.01 0.005 0.001 0.0005 0.0001

Error in Mass Accuracy (amu)

176

386

882

1347

1672

5687

Po

ssib

le f

orm

ula

s MW


March 2007

Accurate Mass in Small Molecules

Reserpine (C33H40N2O9) has a protonated ion at 609.28066

Single quad reports mass to +/- 0.1 = 165 ppm

Number of possible formulas using only C, H, O & N:

• 165 ppm (quad) 209

• 10 ppm 13

• 5 ppm 7

• 3 ppm 4

• 2 ppm 2

Accurate mass reduces risk of investing effort on the wrong molecule (drug discovery and development)


March 2007

Data Analysis – Mass Assignment

How much is 1 ppm?m/z = 118.08625

0

10000

20000

30000

40000

50000

60000

117.6 117.7 117.8 117.9 118 118.1 118.2 118.3 118.4 118.5 118.6

m/z

Ab

un

dan

ce

Note: ADC sampling rate is 1 GHz


March 2007



0

10000

20000

30000

40000

50000

60000

118.05 118.07 118.09 118.11 118.13 118.15

m/z

Ab

un

dan

ce



March 2007


0

10000

20000

30000

40000

50000

60000

118.072 118.077 118.082 118.087 118.092 118.097

m/z

Ab

un

dan

ce




March 2007

4 GHz ADC:What Is It?

• 4 GHz ADC for TOF and QTOF based on proprietary Agilent oscilloscope technology

– Resolution improved to • 9,000 @ 118 m/z

• 14,000 @ 322 m/z

• 16,000 @ 2722 m/z

– In-spectrum dynamic range of 4.5 decades (ten-fold increase)

– Extend mass range to 20,000 m/z

– Retrofit to existing systems

FPGAMasterAgilent

TALONADC

4GSPS8-BIT

4GSPSBUS

PULSEFrontend_A

Frontend_B

CONTROLBUS

CLOCKFPGASlave

2GSPSBUSDual Gain

Front End

SIGNAL

Real Time Signal Processing and Summing Memory

(32 staggered ADCs)

FASTDATAOUT


March 2007

4 GHz ADC Resolution Example: Two Compounds Nominally 195 m/z Separated By 0.036 Da

FIA, 2 scans/sec (6713 transients/scan)2 IRM averaged over five scans

Butyl paraben[M+H]+ 195.101571 m/z

Methyl 5-acetylsalicylate[M+H]+ 195.065185 m/z

O

O

OH

O

OH

OO5x10

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

1.1

1.2

1.3

1.4

1.5

1.6

1.7

1.8

1.9

2

2.1

2.2

2.3

2.4

2.5

2.6+ Scan (#7) MAS_BP_1GHz_tppOFF_dgOFF_1.d

195.088679

Counts vs. Mass-to-Charge (m/z)195 195.02 195.04 195.06 195.08 195.1 195.12 195.14 195.16 195.18 195.2

4 GHz board, 1 GHz rate

6,100 FWHM resolution

5x10

0

0.2

0.4

0.6

0.8

1

1.2

1.4

1.6

1.8

2

2.2

2.4

2.6

2.8

3

3.2

3.4+ Scan (#7) MAS_BP_4GHz_tppOFF_dgOFF_1.d

195.100392

195.066356


4 GHz 8,900 FWHM resolution

5x10

0

0.10.2

0.3

0.4

0.50.6

0.7

0.8

0.91

1.1

1.2

1.31.4

1.5

1.6

1.71.8

1.9

22.1

2.2

2.3

2.42.5

2.6

2.7

2.8

+ Scan (#7) MAS_BP_4GHz_tppON_dgOFF_2.d

195.101392

195.065349


Error = + 0.8 ppm

Error = - 0.9 ppm

4 GHz, transient peak picking


0.036 Da

5x10

0

0.25

0.5

0.75

1

1.25

1.5

1.75

2

2.25

2.5

+ Scan (#7) MAS_BP_1GHz_tppOFF_dgOFF_1.d

195.088679

Counts vs. Mass-to-Charge (m/z)195 195.01 195.02 195.03 195.04 195.05 195.06 195.07 195.08 195.09 195.1 195.11 195.12 195.13 195.14 195.15 195.16 195.17 195.18 195.19 195.2

4 GHz board, 1 GHz rate


5x10

0

0.25

0.5

0.75

1

1.25

1.5

1.75

2

2.25

2.5

2.75

+ Scan (#7) MAS_BP_4GHz_tppON_dgOFF_2.d

195.101392

195.065349


Error = + 0.8 ppmError = - 0.9 ppm

4 GHz, high resolution mode 0.036 Da


5x10

0

0.5

1

1.5

2

2.5

3

+ Scan (#7) MAS_BP_4GHz_tppOFF_dgOFF_1.d

195.100392

195.066356


4 GHz 8,900 FWHM resolution


March 2007

Automatic Tuning and Calibration

Automated tuning done infrequently

Automated calibration done daily


March 2007

View of Calibration Results


March 2007

Inlets – Electrospray Ion SourceDual sprayer design for sample and mass reference compound

Reference Sprayer

Analytical Sprayer


March 2007

Automated Internal Reference Mass Correction

100 200 300 400 500 600 700 800 900 1000m/z, amu

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Re

l. Int. (%

)

279.091691

579.155974

121.050925 301.073403922.010400

Reference Masses


March 2007

Empirical Formula Confirmation Report

Formula input by submitter and system calculates monoisotopic mass

Extracted ion chromatogram covering specified adducts

Mass spectrum for major peak

Zoomed spectrum covering adduct range

Calculated mass error results


March 2007

Expanded View of Results


March 2007

TDC versus ADC

Time to Digital Conversion only measures time of arrival of first ion at a given m/z value

• More sample means more ions means earlier arrival

• Requires higher acquisition rate than ADC and peak intensity matching to accurately assign mass

• Reduced dynamic range

Analog to Digital Conversion (ADC) records time and number of ions arriving

• Sample concentration does not impact (maximum) arrival time

• Provides wider dynamic range


0

10000

20000

30000

40000

50000

60000

118.05 118.07 118.09 118.11 118.13 118.15

m/z

Abun

danc

e


March 2007

Dynamic Range Example for TOF Technology: 400x Difference in Abundance


March 2007Page 28

Precision of the Mass Measurement in TOF Depends on Number of Ions Sampled


March 2007Page 29

High Throughput Chemical Library AnalysisAnalysis of 140 real screening compounds under ultra-fast RRLC/TOF conditions (90s cycle time 1000 samples/day):

2 outliers not shown, 16 compounds could not be ionized by ESI+

-5.00

-4.00

-3.00

-2.00

-1.00

0.00

1.00

2.00

3.00

4.00

0 20 40 60 80 100 120 140

Err

or [p

pm]

Results from automated formula confirmation report – no manual interaction!

LC: Water/ACN(0.1%TFA), 5-100%B in 0.7min, 60°C, 1.5ml/minUV-Detection: 210 – 500 nm, 80Hz MS-Detection: 120-1200Da, 8Hz, Split 1:7.5 Injection: 1µl, online sample dilution by injector program (determined the cycle time!)


March 2007Page 30

High Throughput Chemical Library AnalysisMass error histogram of the analysis of 140 real screening compounds under ultra-fast LC conditions (90s cycle time 1000 samples/day):

2 outliers not shown, 16 compounds could not be ionized by ESI+

!

0

5

10

15

20

25

30-5

.0

-4.5

-4.0

-3.5

-3.0

-2.5

-2.0

-1.5

-1.0

-0.5

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

91% within ±2.0 ppm

ppm

n p

er

0.2

5p

pm

71% within ±1.0 ppm


March 2007Page 31

Mass Accuracy – EnvironmentalExtremes

Injecting every 15 minutes, from 11º - 36º C and 10 - 95 %Relative Humidity

Mass Accuracy

-5-4-3-2-1012345

0 50 100 150 200 250 300

Reserpine Injection

Mas

s E

rro

r, p

pm


March 2007Page 32

XIC of +TOF MS: 334.4 to 335.4 amu from Sample 18 (Blank Poultry+0.5ppb) of Nitrodfuransequence1.wiff Max. 2.0e5 cps.

0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5 6.0 6.5 7.0 7.5 8.0 8.5Time, min

0.0

5000.0

1.0e4

1.5e4

2.0e4

2.5e4

3.0e4

3.5e4

4.0e4

4.5e4

5.0e4

5.5e4

6.0e4

6.5e4

6.8e4

Inte

ns

ity, c

ps

123.06

123.05

NPAMOZ at Unit Mass Resolution 335.1352 -0.7+0.3 (similar to quadrupole)

???


March 2007Page 33

NPAMOZ 335.1352 +/- 0.1 (300 ppm)


0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5 6.0 6.5 7.0 7.5 8.0 8.5Time, min

0.0

2000.0

4000.0

6000.0

8000.0

1.0e4

1.2e4

1.4e4

1.6e4

1.8e4

2.0e4

2.2e4

2.4e4

2.6e4

2.8e4

3.0e4

3.2e4

3.4e4

Inte

ns

ity, c

ps

123.06

S/N = 70:1


March 2007Page 34


0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5 6.0 6.5 7.0 7.5 8.0 8.5Time, min

0

500

1000

1500

2000

2500

3000

3500

4000

4500

5000

5500

6000

6500

7000

7500

8000

8500

9000

Inte

ns

ity, c

ps

NPAMOZ 335.1352 +/- 100ppm (335.09939 - 335.16641)

S/N = 103:1


March 2007Page 35

NPAMOZ 335.1352 +/- 20ppm (335.1262 - 335.1396)


0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5 6.0 6.5 7.0 7.5 8.0Time, min

0

100

200

300

400

500

600

700

800

900

1000

1100

1200

1300

1400

1500

1600

1700

1800

1900

2000

2100

2200

2300

2400

2500

2600

2700

2800

2900

3000

3100

3200

Inte

ns

ity, c

ps

123.05

S/N = 214:1


March 2007Page 36

Why QTOF?

All the benefits of TOF

plus

accurate mass information on the substructure fragments produced by MS/MS

and

selectivity of accurate mass product ions

yields

even greater confidence in the confirmation of the structure

and

even better selectivity for quantitation


March 2007Page 37

The analysis of impurities in Amoxicillin by Q-TOF

NH

O

HNH2 N

O

SH

CH3

CH3

H COOH

H

OH OH

NH

NH

O

O

NH

S

CH3

CH3

H COOH

1 3

1 Amoxicillin, 3 Impurity: Amoxicillin penilloic acid

3x105.5

00.250.5

0.751

1.251.5

1.752

2.252.5

2.753

3.253.5

3.754

4.254.5

4.755

5.25

Abundance vs. Mass-to-Charge (m/z)100 110 120 130 140 150 160 170 180 190 200 210 220 230 240 250 260 270 280 290 300 310 320 330 340 350 360 370 380 390 400

+ Product Ion (10.969 min) (366.1127[z=1] -> **) Cal10ng-10V.d

160.04243.9 ppm for MS/MS

114.0367207.0783

366.1327-0.90 ppm for MS

247.1216

Degradation of Amoxicillin

160.0432

366.1325

Confirmation of the identity of the degradation product by accurate mass measurement in MS and MS/MS mode with subsequent empirical formula calculation

Optimization of collision energy for targeted Q-TOF MRM and calibration for quantitative analysis of degradation products


March 2007Page 38

Agilent QTOF Design Incorporates Cumulative Hardware Innovations

Ion opticsCommon with Q & QQQ

Flight tubeCommon with TOF

Octopole 1

DC Quad

Collision cellCommon with QQQ

Rough Pump

Turbo Turbo Turbo

Quad Mass Filter (Q1)

Collision CellLens 1 and 2

Octopole 2

Ion Pulser

Ion Mirror

Detector

Turbo


March 2007Page 39

Innovations in Front-End Ion Optics Deliver Better Sensitivity Across a Broad Mass Range

10X sensitivity advantage Key components contributing to sensitivity • Dielectric capillary • Small diameter octopole ion

guide • High frequency RF octopole• Lens 2 RF (transmission of

higher masses)• Hyperbolic post-filter and

quadrupole


March 2007Page 40

Innovations in Front-End Ion Optics Deliver Better Sensitivity Across a Broad Mass Range, cont.10X sensitivity advantage Lens 2 RF (transmission of higher masses) Hyperbolic post-filter and quadrupole


March 2007Page 41

1st Quadrupole

Beam shaper

HEXAPOLE RODS

Entrance lens Exit lens

Beam shaper

3rd Quadrupole

Agilent 6410 Collision Cell Position


March 2007Page 42

Collision Cell Design and Electrical Drive

Acceleration Potential

to 10 V

RF Voltage = 10-550 v

•Hexapole construction

•2R0 = 4.5 mm

•Length = 150 mm

•Experimental press. range = 0.1 – 20mTorr

•In coming ion energy range = 0 – 250eV

•Accelerating potential range = 0 – 10V

•RF Drive voltage range 10 – 550v


March 2007Page 43

Transmission Velocity (Latency) Results

Simulation Studies

• 3-D ion optics modeling (100-600sec)

Experimental Results

• Fast precursor ion selection (SRM)

• Linked scan latency

• Gated ion beam measurements


March 2007Page 44

3x10

00.2

0.40.60.8

11.21.41.6

1.82

2.2

2.42.62.8

Abundance vs. Acquisition Time (Min)0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 5.5 6 6.5 7 7.5 8 8.5 9

+EIC (281.0 m/z) MRM (309.0 m/z); from alprazolam 100 A Dwell with 200 pg OC -101505-28V_2uL.d

7.9291.396 6.3004.6653.0301 1

Dwell time evaluation 200 pg Alprazolam 100, 20, 5 ms dwell times

3x10

00.2

0.40.60.8

11.2

1.41.61.8

22.22.4

2.62.8



7.9163.025 4.6581.396 6.2981 1

3x10

0

0.25

0.5

0.75

1

1.25

1.5

1.75

2

2.25

2.5

2.75

3



7.9306.2894.664

3.0411.419

1 1

3x10

0

0.20.4

0.60.8

11.2

1.41.6

1.8

22.2

2.42.6

2.8

Abundance vs. Acquisition Time (Min)1.18 1.2 1.22 1.24 1.26 1.28 1.3 1.32 1.34 1.36 1.38 1.4 1.42 1.44 1.46 1.48 1.5 1.52 1.54 1.56 1.58 1.6 1.62 1.64 1.66 1.68


1.4191 1

Dwell 100 ms 20 ms 5 ms

Area 14860 13605 13202% RSD 0.61 0.74 2.25

5 ms dwell


March 2007Page 45

Beam Turn-off Characteristics

10

100

1000

10000

100000

-500 0 500 1000 1500 2000

microseconds

Arb

. Un

its .

mz922 mz118

Collision Cell Clearing Profile

0 V collision energy 5 V Applied Axial Potential

600 sec

350 sec


March 2007Page 46

Broad Mass Range Transmission and Transmission Efficiency – Why Hexapole?

Mass Range Transmission

0

0.2

0.4

0.6

0.8

1

1.2

0 500 1000 1500Mass (m/z)

Tran

smis

sion

.

Quadrupole Hexapole Octopole

Variables include:

•Number of poles (i.e. quad, hex, octo)

•Inscribed diameter (R0)

•Drive Frequency

Evaluation included:

•Theoretical modeling

– Calculation, Simulations

•Experimental results


March 2007Page 47

Full Mass Range With Single Parameter Set on QTOF (m/z 100 – 3000), No Switching

5x10

0

0.2

0.4

0.6

0.8

1

1.2

1.4

1.6

1.8

2

2.2

2.4

2.6

2.8

3

3.2

3.4

3.6

3.8

4

Abundance vs. Mass-to-Charge (m/z)0 200 400 600 800 1000 1200 1400 1600 1800 2000 2200 2400 2600 2800 3000

+MS (0.317-0.384 min) TTI_after calib_IRM_MS2_1Hz.d (BP=436212) #2

391.28380

1221.99081

622.02836922.00964

223.20489

1521.97242

1821.95480

2121.93491

2421.91573

2721.89678


March 2007Page 48

Mass Accuracy in MS/MS ModeMS Calibration is Maintained over Broad Collision Energy

3x10

0

0.2

0.4

0.6

0.8

1

1.2

1.4

1.6

1.8

Abundance vs. Mass-to-Charge (m/z)0 200 400 600 800 1000 1200 1400 1600 1800 2000 2200 2400

+MS (0.075-0.249 min) MS/MS(2121.93311 m/z) MS2_on_IRM_2HZ.d (BP=1598) #6

229.92086

2121.93167

1477.927061789.92031

1165.92259853.92438541.92207

4.8

pp

m

1.3

pp

m

0.9

p

pm

1.6

pp

m 1.2

pp

m

3.2

pp

m

0.7

pp

mCE=150.5 eV @ 10 mTorr

3.4

pp

m

5.1

pp

m

3.8

pp

m

1.6

pp

m

3x10

0

1

2

3

4

5

6

7

Abundance vs. Mass-to-Charge (m/z)50 100 150 200 250 300 350 400 450 500 550 600 650 700 750 800 850 900 950 1000 1050

+MS (0.101-0.275 min) MS/MS(922.00983 m/z) MS2_on_IRM_2HZ.d (BP=7578) #6

922.00753789.98942

677.97608

229.92169 321.92867565.96291

453.94855

175.98726

1.2

pp

m

2.1

pp

m

1.4

pp

m

0.2

pp

m

0.4 ppm

0.7 ppm 2.5 ppmCE=66.5 eV @ 10 mTorr

2.6

pp

m 2.3

pp

m

2.6

pp

m

2.0

pp

m


March 2007Page 49

Internal Reference Mass Correction

Fundamentals: The header of each acquired spectrum has reference mass corrected “a” and “t0” coefficients. They are calculated based on the presence of user selectable ions in each MS spectrum. Running averaging is supported.

Extensions to MS/MS operation:

MS/MS (DDE): Survey scan coefficients are copied into the headers of the subsequent MS/MS spectra.

MS/MS (Manual/Targeted): MS scans are auto inserted into the specified MS/MS spectra acquisition cycle. The updated coefficients of these “background” generate MS spectra are copied into the headers of the subsequent MS/MS spectra.


March 2007Page 50

0 2 4 6 8 10 12 14 160

500

1000

1500

2000

2500

3000

3500

4000

4500

5000

550016.27

13.83

9.20 11.43

6.994.95

2.84

STD ESI: 0.25 mL/min flow Q1=256 (2.5 wide), CE=10v, 167 (0.1 wide) EIC

60 80 100 120 140 160 180 200 220 240 2600

50

100

150

200

250

300

350

400

450

499 167.0805

257.1350

168.0836179.0656

71.0826 117.0875 152.0602

MS/MS spectrum at 1 pg. Background subtracted

200 fg500 fg

1000 fg 2000 fg

Dilution Series of Diphenhydramine on Q-TOF


March 2007Page 51

Benchmarking - Small Molecule Sensitivity200 pg MDMA (3,4-methylenedioxymethamphetamine)

0.2 0.6 1.0 1.4 1.8Time, min

0

5.0e4

1.0e5

1.5e5

2.0e5

2.5e5

3.0e5

3.5e5

4.0e5

4.5e5

5.0e5

0.68

S/N = 230

! !

Agilent QTOF Breadboard

0.5 1.0 1.5 2.0 2.5 3.0Time, min

0

50

100

150

200

250

300

350

400

1.61

S/N = 10

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TOF and QTOF Fundamentals March 2007 Page 1 Fundamentals of TOF and QTOF Dr. Patrick (Pat) Perkins...

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