function P = PatientMonitoring(T,Y,VLhandle,dT)
%
% This function contains the implementation of routine patient monitoring
% (see von Kleist M, Menz S, Stocker H, Arasteh K, Huisinga W, Schuette S (2011) 
% "HIV Quasispecies Dynamics during Pro-active Treatment Switching: Impact on 
% Multi-Drug Resistance and Resistance Archiving in Latent Reservoirs", PlosOne)
%
%   Input arguments are:
%   
%       1st) Considered duration of simulation in days
%   
%       2nd) Initial state Y of the system
%   
%       3rd) Function handle to compute viral load from a state Y
%   
%       4th) Time intervals between monitorings in days
%
%
% Copyright (C) 2011, Free University Berlin
% Contact: vkleist@zedat.fu-berlin.de
%
% FOR ACADEMIC USE this program is free software; you can redistribute 
% it and/or modify it under the terms of the GNU General Public License
% as published by the Free Software Foundation; either version 2
% of the License, or (at your option) any later version.
% 
% This program is distributed in the hope that it will be useful,
% but WITHOUT ANY WARRANTY; without even the implied warranty of
% MERCHANTABILITY or FITNESS FOR A PARTICULAR PURPOSE.  See the
% GNU General Public License for more details. 
% 
% You should have received a copy of the GNU General Public License
% along with this program; if not, write to the Free Software
% Foundation, Inc., 59 Temple Place - Suite 330, Boston, MA  02111-1307,
% USA.


%%%%%%%%%% START %%%%%%%%%%


% set default values of patient-monitoring
dT_monitoring = dT;         % get time intervals between monitorings in days
if dT > T
    error('PatientMonitoring:argChk',...
        '\nMonitoring interval can not exceed duration of simulation.');
end
FirstLogDecline  = 100.0;	% neccessary log-decline in viral load [HIV mRNA/mL blood] after treatment initiation
VLDetectionLimit = 50.0;	% detection limit [HIV RNA/mL plasma]

SimulationEnd = T;
CheckUp       = 1;
CheckUpTimes  = dT_monitoring:dT_monitoring:T;
if CheckUpTimes(end) ~= T
    CheckUpTimes(end) = CheckUpTimes(end) + T;
end

prevVL     = VLhandle(Y);
VLfunction = VLhandle;


% event function of patient-monitoring
function [value,isterminal,direction] = patient_monitoring(t)
    value      = t - CheckUpTimes(CheckUp);
    isterminal = 1;
    direction  = 1;
end


% perform check up
function drugswitch = perform_checkup(y)
    
    drugswitch = false;
    
    % measure viral load
    VL = VLfunction(y);
    
    % later check up's
    if CheckUp > 1
        
        % infection successful suppressed
        if VL < VLDetectionLimit
            
            % shift remaining monitorings
            CheckUpTimes(CheckUp+1:end) = CheckUpTimes(CheckUp+1:end) + dT_monitoring;
        
        % failure
        elseif VL >= prevVL
        
            % switch drug combination
            drugswitch = true;
        end
    
    % first check up
    else
        
        % infection successful suppressed
        if VL < VLDetectionLimit
            
            % shift remaining monitorings
            CheckUpTimes(CheckUp+1:end) = CheckUpTimes(CheckUp+1:end) + dT_monitoring;
            
        % failure
        elseif VL >= prevVL/FirstLogDecline
            
            % switch drug combination
            drugswitch = true;
        end
    end
    
    prevVL  = VL;
    CheckUp = CheckUp+1;
end


% set monitoring parameters
function [] = set_dT_monitoring(dT)
    CheckUp       = 1;
    dT_monitoring = dT;
    CheckUpTimes  = dT:dT:SimulationEnd;
    if CheckUpTimes(end) ~= SimulationEnd
        CheckUpTimes(end) = CheckUpTimes(end) + SimulationEnd;
    end
end
function [] = set_first_logDecline(FLD)
    FirstLogDecline = FLD;
end
function [] = set_VL_detectionLimit(VLDL)
    VLDetectionLimit = VLDL;
end


% return functions of patient monitoring
P.patient_monitoring    = @patient_monitoring;
P.perform_checkup       = @perform_checkup;
P.set_dT_monitoring     = @set_dT_monitoring;
P.set_first_logDecline  = @set_first_logDecline;
P.set_VL_detectionLimit = @set_VL_detectionLimit;

end