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Microelectronics  Division   Nanotechnology  &  Life-­‐Sciences   Division     Ins@tute  of  Bioengineering  -­‐  CLSE   Ins@tute  of  Electrical  Engineering  -­‐  LSI

 

Division  of  Clinical  Pharmacology   and  Toxicology      

Intelligent  Integrated  Systems  for  Personalized  Medicine  

ISyPeM  
C.  Guiducci  -­‐  ISyPeM  AM2013   1  

Microelectronics  Division   Nanotechnology  &  Life-­‐Sciences   Division     Ins@tute  of  Bioengineering  -­‐  CLSE   Ins@tute  of  Electrical  Engineering  -­‐  LSI  

Division  of  Clinical  Pharmacology   and  Toxicology      

Enable  and  extend  the  adjustment  of  the  drug  dosage  to  a   wider  disease  spectrum  through  the  development  of  so5ware   and  hardware  biomedical  engineering  solu@ons,   combining      bioanaly:cs,  molecular  biology,  pharmacology,  sensor   technology,  ICs,  nanotechnology  
C.  Guiducci  -­‐  ISyPeM  AM2013   2  

Variability  in  treatment  response  
IMATINIB Modern anticancer agent

Verena  Go)a  
C.  Guiducci  -­‐  ISyPeM  AM2013   3  

Variability  in  treatment  response  
2.4   Drug  Concentra:on  (μg/mL)   2.0   1.6   1.2   0.8   0.4   0.0   0   1  

Ima:nib  400  mg  qd  

Risk  of  adverse  effects    

Target  
T.  Buclin,  et  al.   “Who  is  in  charge  of   assessing  therapeu5c   drug  monitoring?  The   case  of  ima5nib”.     Lancet  Oncol.   2011;12(1):9-­‐11.    

800  mg  qd   Risk  of  inefficacy  
2   3  

Pa:ent  
10   11   12  

4   5   6   7   8   9   Treatment  dura:on  (days)  

C.  Guiducci  -­‐  ISyPeM  AM2013  

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Mo@va@on  and  aims  
§  Informa:on  and  Interpreta:on  
§  Missing  sta@s@cal  popula@on  data   §  Need  for  formal  and  accessible  models  of  interpreta@on  

§  Safety  

§  Integra@on  of  the  medical  protocol  in  a  semi-­‐autonomous   plaZorm  for  dose  adjustment  with  verifica@on  

§  Compa:bility/Suitability  

 

§  Acceptable  and  suitable  se]ng  for  in-­‐field  drug  measurement,   considering  disease,  frequency  of  monitoring,  treatment  toxicity,   costs     §  Need  for  stable  and  specific  molecular  assay  for  drug   measurement,  compa@ble  with  on  field  biosensors  
C.  Guiducci  -­‐  ISyPeM  AM2013   5  

LSI  

Missing  popula@on  data   Need  for  formal  and  accessible  models  of  interpreta@on    

INFORMATION/INTERPRETATION  

C.  Guiducci  -­‐  ISyPeM  AM2013  

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Meta-­‐data  analysis  
ð  to  summarize  mul@ple  studies  into  a  single  set  of   reference  parameters  
Verena  Goda   Nicolas  Widmer  

Range  of  expected  ima:nib  concentra:ons  
very  high/low,  un-­‐expected  

Therapeu5c  Drug  Monitoring,  2013  

rather  high/low  but  in  expected  range   50%   –    median   90%     predic@on   interval  

Clinical  Pharmacokine5cs,  2012  

C.  Guiducci  -­‐  ISyPeM  AM2013  

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the range, he amount ep to give increased

t of data designed al stromal tients and trial[20]), tients and sis, in the mpare the a general

Fig. 3. Comparison between Pharmacokinet Modeling and LS-SVM Methods based on 100% Utilization of the Patients Library, x-axis: Predicted Concentration Values, y -axis: Measured Concentration Values.

Drug  concentra@on  predic@on  
Data Library
Predic@ons   Clinical   Data   Training   Samples  

d to deterExample-

nds on the oice is to rameter ⇤
Fig. 4. Histogram of the Mean Absolute Difference in the Drug Concentration Predictions Among the four Approaches: (a) PK Model, (b) LS-SVM, (c) E-SVM Uniform, (d) E-SVM Discriminatory [bar unit = 200mcg/L]

Support Vector Machine

Nicolas  Widmer    

rformance meters and of C0 and y growing actice, our fold cross e original our experhe set of are used

6)

sest trained feature

cal to the value of ⌅. imated by set before

Histogram  of  the   difference  in  the  drug   of the testing patients. However, to make our system adaptive to each specific patient, we choose a specific concentra@on   value that for each data set. Practically, it performs as a predic@ons  among  the   filter to pass only the first M % closest training data. fd : decides theafeatures to be used in the training four   pproaches:   data samples and to perform the prediction of drug  (a)  P mAs odel,   (b)   LS-­‐ of using concentration asK   well. the main advantage SVM-based approaches, or removing one feature SVM,   (c)  Eadding xample-­‐ in building up the model is simpler than the classical based   SVM   Ufeatures niform,   (d)   pharmacokinetic method. The to be considered as training data are: {Amount of Dosage, Time of MeaExample-­‐based  SVM   suring, Gender, Age, Body Weight}, which correspond to {A, Discriminatory.   B, C, D, E} in Table I. Additionally, we also
compare the influence of using subsets of these features.

Wenqi  You,  Nicolas  Widmer,  Giovanni  De  Micheli,   'Example-­‐based  Support  Vector  Machine  for  Drug   Concentra@on  Analysis',  33rd  Annual  Interna@onal   Conference  of  the  IEEE  EMBS,  pp.153-­‐157.     Wenqi  You,  Nicolas  Widmer,  Giovanni  De  Micheli,   'Personalized  modeling  for  drug  concentra@on   predic@on  using  support  vector  machine',  4th   Interna@onal  Conference  on  Biomedical  Engineering   and  Informa@cs  (BMEI),  pp.  1523-­‐1527.     Wenqi  You;  Widmer,  N.;  De  Micheli,  G.,   "Personalized  modeling  for  drug  concentra@on   predic@on  using  Support  Vector  Machine,"   Biomedical  Engineering  and  Informa5cs  (BMEI),  2011   4th  Interna5onal  Conference  on  ,  vol.3,  no.,  pp. C.  Guiducci   -­‐  IO SyPeM   1505,1509,   15-­‐17   ct.  2011   AM2013  

Wenqi  You  

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Figure 3 shows the comparison of drug concentration predictions (x-axis) versus the measured concentration (y -axis)

Benchmarking  Therapeu@c  Drug   Monitoring  sonware  

Aline  Fuchs   Nicolas  Widmer   Chantal  Casajka   Thierry  Buclin    

Yann  Thoma  

C.  Guiducci  -­‐  ISyPeM  AM2013  

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www.ezeCHiel.ch  
§  Pa@ent  characteriza@on  derived  from  popula@on   data  and  observed  drug  concentra@on   §  Op@mize  posology    (Constraint  Sa@sfac@on   Problem  and  Gene@c  algorithms)    

Aline  Fuchs   Nicolas  Widmer   Chantal  Casajka   Thierry  Buclin    

Yann  Thoma   Carlos  Pena   Miguel  Barreto  

C.  Guiducci  -­‐  ISyPeM  AM2013  

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www.ezeCHiel.ch  
Dose  adjustment   sugges@ons  based  on   (a  combina@on  of:   Elimina@on,  Intake,  Number   of  compartments)   Validated  by  CHUV  with   Gentamicin  for  newborns  

C.  Guiducci  -­‐  ISyPeM  AM2013  

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LSI  

Integra@on  of  the  medical  protocol  in  a  semi-­‐autonomous  plaZorm  for   dose  adjustment    

SAFETY  

C.  Guiducci  -­‐  ISyPeM  AM2013  

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Formal  Modeling  of  Medical  Protocols  
 Formal  Modeling  in  Medicine:   –  Arden  (1989)   –  Asbru  (1998)   –  EON  (1996)   –  GLARE  (1997)   –  GLIF  (1998)   –  GUIDE  (1998)   –  Pres@ge  (1996)   –  PRODIGY  (1996)   –  PROforma  (1992  -­‐  2000)   –  SAGE  (2002)   –  Stepper  (2001  -­‐  2003)  

Do  not  allow  or  allow  only   par@ally:     § Safety  analysis   § Coordina@on  or  coopera@on   analysis   § Valida@on   § Real-­‐@me  analysis   § Synthesis  

LSI  

Alena  Simalatsar    

T1  =  P1 give_dose T1   ! ==  0  

Romain  Bornet  
calculate_dos e!

3

Timed  Automata   Model  Checker  

T3  =  P3

1
T1  <  P1 T2  <  P2 T3  <  P3

T2  =  P2 dose  =   T2   ==  0   new_dose  

2

A.  Simalatsar  et  al.,  ,  “Time  Aware  Formal  Representa@on  of  Medical   Guidelines:  Ima@nib  Case-­‐study”,  CODES+ISSS’12   A.    Simalatsar  et  al.,  “TAT-­‐based  Formal  Representa@on  of  Medical   C.  Guiducci  -­‐  ISyPeM  AM2013   Guidelines:  Ima@nib  Case-­‐study”,  EMBC’12  

Nicolas  Widmer  
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Embedded  plaZorm  with  dose   adjustment  in  real-­‐@me  
Serial  link   Alena  Simalatsar   Wenqi  You     Anna  Ferre]  

Drug   Concentra:on   measurement   and  processing  

Real-­‐:me  control   based  on  @med   automata   Dosage  adjustment   calcula@on  

Popula:on  data   update  +  SVM   training     Automa@c   interac@on  with   EzeCHiel  

Romain  Bornet   Yann  Thoma  

Chris@an  Enz   Alexandre  Corbaz  

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Towards  “companion  diagnos@cs”  
2.4  GHz  MBAN   or  MICS  400  MHz    

2.4  GHz  BT  LE    

badery  powered  nodes   remote  powered  nodes  

Wireless  body  area  network   Connec@ng  wearable  devices   and  a  smart  user  interface     On-­‐body  nodes  have  to   communicate  on  the  400MHz   MICS  band  or  the  upcoming   2.36-­‐2.4  GHz  MBAN  band     Ability  to  talk  on  Bluetooth   Low  Energy  (BT-­‐LE)  with  the   external  monitoring  unit      
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Aravind  Heragu    

A  Low-­‐Power  MEMS-­‐based  2.4-­‐GHz   Receiver    
§  0.18-­‐um  CMOS  process.   §  BAW  resonators   §  A  rejec:on  of  50-­‐dB   measured  at  15-­‐MHz  offset   from  the  center  frequency.   Can  tolerate  blocker  level  up   to  -­‐9.2-­‐dBm  with  8-­‐dB  margin.  

Aravind  Heragu   Chris@an  Enz  

A.  Heragu,  et  al,  A  Concurrent  Quadrature  Sub-­‐Sampling  Mixer  for  Mul@band  Receivers,  European  Conference  on  Circuit  Theory  and  Design  (ECCTD  09),  2009,  "Best   Paper"  award   A.Heragu,  et  al.  ,  A  Mul@band  Concurrent  Sampling  Based  RF  Front  End  for  Biotelemetry  Applica@ons,  IEEE  Symposium  on  Circuits  and  Systems  (ISCAS  2010).   A.  Heragu,  et  al.  ,  A  MEMS  based  2.4-­‐GHz  Sub-­‐Sampling  RF  Frontend  for  Advanced  Healthcare  Applica@ons,  IEEE  Radio-­‐Frequency  Integra@on  Technology  2011.   A.  Heragu,  et  al.  ,A  Low  Power  2.4-­‐GHz  Front-­‐end  with  MEMS  La]ce  based  Channel  Filtering  at  RF,  IEEE  Symposium  on  Circuits  and  Systems  (ISCAS  2012).   A.Heragu,  et  al.    ,  A  2.4-­‐GHz  MEMS  based  Sub-­‐Sampling  Receiver  Front-­‐end  with  Low  Power  Channel  Selec@on  Filtering  at  RF,  IEEE  Interna@onal  Symposium  on  Radio   Frequency  Integrated  Circuits  (RFIC  2012).   A.Heragu,  et  al.  ,  A  2.4-­‐GHz  MEMS-­‐Based  PLL-­‐Free  Mul:-­‐Channel  Receiver  with  Channel  Filtering  at  RF,  European  Solid  State  Circuits  Conference  (ESSCIRC  2012).   A.  Heragu,  et  al.  ,  The  design  of  ultra-­‐low-­‐power  MEMS-­‐based  radio  for  WSN  and  WBAN,  22nd  workshop  on  Advances  in  Analog  Circuit  Design,  April,  2013.   A.  Heragu,  et  al.  ,  A  Low  Power  BAW  resonator  based  2.4-­‐GHz  Receiver  with  Bandwidth  Tunable  Channel  Selec:on  Filter  at  RF,  accepted  for  publica@on  in  the   Journal  of  Solid  State  Circuits  (JSSC)  –  publica@on  expected  in  the  June,  2013  issue.   A.Heraguet  al.  ,  A  2.4-­‐GHz  MEMS-­‐Based  PLL-­‐Free  Mul:-­‐Channel  Receiver  with  Channel  Filtering  at  RF,  solicited  and  accepted  for  publica@on  in  the  Journal  of  Solid   State  Circuits  (JSSC)  special  issue  (ESSCIRC)  –  publica@on  expected  in  the  July,  2013  special  issue.     C.  Guiducci  -­‐  ISyPeM  AM2013   16  

Acceptable  and  suitable  se]ng  for  drug  measurement,  with  respect  to  the   disease,  frequency  of  monitoring,  treatment  toxicity,  costs       Need  for  stable  and  specific  molecular  assays  for  drug  measurement,   compa@ble  with  in-­‐field  biosensors  

COMPATIBILITY/SUITABILITY    
C.  Guiducci  -­‐  ISyPeM  AM2013   17  

Candidate  treatments  for  therapeu@c   drug  monitoring  
Modern anticancer agents IMATINIB 1000 ng/ml 493.60 Da Immunosuppressant TACROLIMUS 10 ng/ml 804.02 Da

Antiretrovirals EFAVIRENZ 2000 ng/ml 315.70 Da

Antibiotics TOBRAMYCIN 1000 ng/ml 467.5 Da

C.  Guiducci  -­‐  ISyPeM  AM2013  

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Configura@on  and  se]ng  for  drug   measurement  on  pa@ent  
Blood  sampling   Drug  concentra:on  measurement  

hdp://e-­‐sante.futura-­‐sciences.com

Abbod  "Architect  ci8200"

MD’s cabinet or hospital

Central clinical facilities
C.  Guiducci  -­‐  ISyPeM  AM2013  

cleic acids

Detection through low-density microarray
The In-Check microarray module is used to detect the amplified labeled DNA sequences through hybridization on a low-density microarray composed of 126 spots.

erature sensor the In-Check PCR and cooling cycles t PCR.

eck PCR module is driven by the emperature control CS). This allows fast ammable temperature ether with ent random access for tests simultaneously.

The microarray module is fluidically connected to the PCR module and is thermally driven by the temperature control system. After hybridization, the microarray module is read by the In-Check optical reader (OR) in a few seconds.

Configura@on  and  se]ng  for  drug   measurement  on  pa@ent  
The microarray module includes a set of control probes at fixed positions, as well as specific probes located according to customer requirements.

In-Check system

Bench-­‐top  stand-­‐alone   analy:cal  system  

Hand-­‐held  device  for  self  sampling  

CR and hybridization tion does not require y simplifies the typical

The In-Check system is extremely userfriendly and allows unskilled operators to perform all steps from sample to result.

In-­‐Check   PCR  and  microarray   on  chip    

Fabio  Spiga  
C.  Guiducci  -­‐  ISyPeM  AM2013   20  

Tobramycin  detec@on  based  on   Transmission  SPR  
CLSE   Giulia  Cappi   Fabio  Spiga   Enrico  Accastelli  

RNA  on   surface  

Tobramycin   200  µM   467  Da  

Buffer   NaCl   Buffer   dissocia@on   Surface   Return  to   regenera@on   RNA  baseline  

Nicolas  Widmer   Laurent  Decosterd  

G.  Cappi,  et.al,  “Peak  Shin  Measurement  of  Localized  Surface   Plasmon  Resonance  by  a  Portable  Electronic  System”,  Sensors   and  Actuators  B:  Chemical,  2012     G.  Cappi,  et  al.,  “A  portable  setup  for  molecular  detec@on   based  on  transmission  LSPR”.  MRS  Proceedings  from  IMRC   2012.    

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Exploring  integrated  low-­‐noise  signal   measurement  for  ultra  miniaturized   plaZorms  
CMOS  0.18µm  interface     Low  noise  front-­‐end  current   mode  amplifier     8  bit  asynchronous  A/D   converter  
CLSE   Anna  Ferre]   Yuksel  Temiz  

Viswa  Balasubramanian   Chris@an  Enz  
V.  Balasubramanian  al,  A  0.18µ  Low  Power  CMOS  Biosensor  Interface  –  To  be  submided  to  the  IEEE  Journal  of  Solid  State  Circuits  (JSSC).     V.  Balasubramanian,  et  al,  A  0.18µ  Biosensor  Front-­‐end  based  on  1/f  Noise,  Distor@on  Cancela@on  and  Chopper  Stabiliza@on  Techniques  –(TBioCAS)   journal.     V.  Balasubramanian,  et  al.,  Noise  Canceling  Chopper  Stabilized  Front-­‐End  for  Electrochemical  Biosensors  with  Improved  Dynamic  Range,  (ISCAS),  2012.        V.  Balasubramanian,  et.al.  ,  Analysis  of  Ultralow-­‐Power  Asynchronous  ADCs,  Presented  at  the  Special  Session  on  Ultralow-­‐Power  Sensor  Interfaces  for   Biomedical  Applica@ons,.  (ISCAS),  2010.  

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Robustness  and  scalability  of   integrated  sensor  features  
(a) (b)
Fig. 1. SEM images of a SiNR: (a) Top view, (b) Crosssection. When the width is comparable with the thickness, as in this case, we can call the structure a Silicon Nanowire (SiNW). The SiNRs are fabricated on Silicon-On-Insulator (SOI) wafers and defined by means of standard top-down CMOS compatible processes, such as Deep Ultraviolet (DUV) photolithography, e-beam lithography and Reactive Ion Etching (RIE) [1]. SEM pictures courtesy of CEA-LETI (Grenoble, France).

2 cm (a) 2 cm

(b)

Fig. 2. Exploded view of Ithe microfluidic LETI   E.Accastelli   t  a l.   EEE   NANO  setup. 2013   Fig. e 1. SEM images of a The SiNR: (a) Top view, (b) CEA,   Crossmicrochannels are realized with a chemical resistant section. is comparable with the double-coated tape, When patterned the by width laser micromachining. The height of the channels is defined thickness, as in this case, we can call the structure a by the thickness of the tape (~190 µm). A PMMA cap Silicon Nanowire is placed to seal the channels and host (SiNW). the inlets and The SiNRs are fabricated on outlets tubes. A sealing polymer is used to avoid fluid wafers and defined by means Silicon-On-Insulator (SOI) leakages from the inlets/outlets tubes.

1.5E-7
Drain current (A)

Drain Current (A)

1.0E-7 5.0E-8 0.0E+0 -100 1000
2E-7 1E-7 0E+0 -100 3200

of standard top-down CMOS compatible processes, such as Deep Ultraviolet (DUV) photolithography, CLSE   e-beam 5E-7 lithography and Reactive Ion Etching (RIE) [1]. SEM Anna   Ferre]   pictures courtesy of CEA-LETI (Grenoble, France). 4E-7
3E-7

Enrico  Accastelli   Yuksel  Temiz  

Time (s)
Fig. 3. The drain current drift can be modeled by a stretched-exponential time dependence given by the equation above. The red dots show how well the model fit the experimental data (black line). (Inset) When the electrolyte is not polarized by means of proper REs, the drain  current  doesn’t  show predictable trend.

Drain current (A)

2100

3200

Current (A)

Y.  Temiz,   A.  Ferre],  Y.  Leblebici,  C.  Guiducci,  “A  Compara@ve  Study  on  Fabrica@on  Techniques  for   2E-7 1.5E-7 On-­‐Chip  Micro-­‐  electrodes”,  Lab  Chip,  2012,  12,  4920–4928     1E-7 Y.  Temiz,   M.  Zervas,  C.  Guiducci  and  Y.  Leblebici,  “A  CMOS  Compa@ble  Chip-­‐to-­‐Chip  3D  Integra@on   PlaZorm,”   2012  ,  Page(s):   555  –  560.     1E+0 1E-6 1E-3 C.  Guiducci,  Y.  1.0E-7 Temiz,  Y.  Leblebici,  E.  Accastelli,  A.  Ferre],  G.  Cappi,  E.  Bianchi,    "Integra@ng  Bio-­‐ Na2SO4 Ionic Strength (M) sensing  Func@ons   on  CMOS  Chips,"  Proc.  of  Asia  Pacific  Conference  on  Circuits  and  Systems   (APCCAS),   2010.  surface   Fig. 4. The charged of the gate oxide attracts a 2E-7 layer of counter-ions to maintain the overall charge Y.   Temiz,   E.  Accastelli   Y.  Leblebici   and  C .  Guiducci,  "Robust  Microelectrodes  Developed  for  Improved   neutrality,in   forming an Electrical Double Layer (EDL). of  Biomolecular   1E-7 Layers,"  Proc.  IEEE  Sensors,  2010.   23   Stability   Electrochemical   Characteriza@on   5.0E-8
Keeping constant the pH, the ionic strength of the solution affects the distribution of ions close to the SiNRs channel, thus affecting the capacitive coupling between the gate and the wire and its drain current as a

Fig. 2. Explod microchannels double-coated micromachinin by the thicknes is placed to se outlets tubes. A leakages from

5E-7 4E-7 3E-7

0E+0 -100 3200

1E-6

2E-7

Sample  prepara@on  for  drug  free-­‐ frac@on  
Molecular  transport  through  nanopores  membranes   Tuning  of  pore  diameter  for  size-­‐based  filtra@on  of  small  biomolecules  
1  nm   5  nm  
To  be  published   Montagne,  F.,  Blondiaux,   N.,  Bojko,  A.  &  Pugin,  R.   Molecular  transport   through  nanoporous  silicon   nitride  membranes   produced  from  self-­‐ assembling  block   copolymers.  Nanoscale  4,   5880–5886  (2012).  

Alexandre  Bojko   Gaelle  Andreada   Frank  Montaigne   Raphael  Pugin  

Laurent  Decosterd  

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Highly-­‐stable  DNA  molecular  probes   for  small  molecules  

CLSE   Fabio  Spiga   Anna  Ferre]  

Laurent  Decosterd   Nicolas  Widmer   unpublished  results  
C.  Guiducci  -­‐  ISyPeM  AM2013   25  

Microelectronics  Division   Nanotechnology  &  Life-­‐Sciences   Division     Ins@tute  of  Bioengineering  -­‐  CLSE   Ins@tute  of  Electrical  Engineering  -­‐  LSI  

Division  of  Clinical  Pharmacology   and  Toxicology      

ISyPeM    Drug  Dose  Adjustment  for  In-­‐field  Use  

C.  Guiducci  -­‐  ISyPeM  AM2013  

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Thank  you!  

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