prompt_front: Now, answer the following question based on the text below, only give me the answer and do not output any other words.

Question: When was the paper published?

Read the following text and answer briefly.

Context 1: Paper Info

Title: Interpretable reduced-order modeling with time-scale separation Interpretable reduced-order modeling with time-scale separation
Publish Date: 7 March 2023
Author List: Sebastian Kaltenbach (from CSE-Lab, ETH Zurich, Harvard SEAS), Phaedon-Stelios Koutsourelakis (from CSE-Lab, ETH Zurich, Harvard SEAS), Petros Koumoutsakos (from CSE-Lab, ETH Zurich, Harvard SEAS), Harvard Seas (from CSE-Lab, ETH Zurich, Harvard SEAS)

Figure

FIG  5  Comparison between the phase-space of the reference solution (left) and the phase-space of the predictions
FIG  7  Comparison between predictions and reference solutions for a new initial condition fort = 1 25, 3 75, 7 5, 12 5, 20, 30  (from left to right and top to down) We note that with longer prediction time the uncertainty bounds increases Despite the chaotic nature of the KS equation, the predictive posterior mean is close to the reference solution for t ≤ 12 5

abstract

Partial Differential Equations (PDEs) with high dimensionality are commonly encountered in computational physics and engineering  However, finding solutions for these PDEs can be computationally expensive, making model-order reduction crucial  We propose such a data-driven scheme that automates the identification of the time-scales involved and, can produce stable predictions forward in time as well as under different initial conditions not included in the training data 
To this end, we combine a non-linear autoencoder architecture with a time-continuous model for the latent dynamics in the complex space  It readily allows for the inclusion of sparse and irregularly sampled training data  The learned, latent dynamics are interpretable and reveal the different temporal scales involved 
We show that this data-driven scheme can automatically learn the independent processes that decompose a system of linear ODEs along the eigenvectors of the system's matrix  Apart from this, we demonstrate the applicability of the proposed framework in a hidden Markov Model and the (discretized) Kuramoto-Shivashinsky (KS) equation 
Additionally, we propose a probabilistic version, which captures predictive uncertainties and further improves upon the results of the deterministic framework 

INTRODUCTION

High-fidelity simulations of critical phenomena such as ocean dynamics and epidemics have become essential for decision-making  They are based on physically-motivated PDEs expressing system dynamics that span multiple spatiotemporal scales and which necessitate cumbersome computations   In recent years there is increased attention to the development of data-driven models that can accelerate the solution of these PDEs as well as reveal salient, lower-dimensional features that control the long-term evolution 
In most cases, data-driven reduced-order models are not interpretable  In particular, models based on neural networks despite good predictive capabilities , they offer a black-box description of the system dynamics  A possible remedy is applying a symbolic regression to the learned neural network representation , but this adds additional computational cost due to the two-step procedure 
A number of frameworks such as SINDy allows to learn interpretable dynamics but it relies on the a-priori availability of lower-dimensional descriptors and of time-derivatives which can be very noisy for both simulation and experimental data  Other frameworks are tailored to specific problems such as molecular dynamics  
Here, we present a framework that only needs the value of the observables, and not their derivatives, as training data and is capable of identifying interpretable latent dynamics  The deployment of interpretable latent dynamics ensures that conservation of important properties of that are reflected in the reduced-order model  
The present method is related to approaches based on the Koopman-operator extended Dynamic Mode Decomposition (eDMD) but uses continuous complex-valued latent space dynamics and only requires one scalar variable per latent dimension to describe the latent space dynamics  Therefore we do not have to enforce any parametrizations on the Koopman matrix  
The time-continuous formulation moreover allows to incorporate sparse and irregularly sampled training data and fast generation of predictions after the training phase  By using a complex-valued latent space we can also incorporate harmonic effects and reduce the number of latent variables needed  Linear and non-linear autoencoders are used to map the observed, high-dimensional time-series to the lower-dimensional, latent representation and we identify simultaneously the autoencoder as well as the latent dynamics by optimizing a combined loss function 
Hence the to tasks of dimensionality reduction and discovery of the reduced dynamics are unified while other frameworks treat the two parts separately   Apart from using an architecture based on autoencoders to identify the latent space, projection-based methods could also be employed   We are also proposing a probabilistic version of our algorithm ) that makes use of probabilistic Slow Feature Analysis  
This allows for a latent representation that arart from being time-continuous, can quantify the predictive uncertainty and hierarchically decompose the dynamics into their pertinent scales while promoting the discovery of slow processes that control the system's evolution over long time horizons  The rest of the paper is structured as follows: We introduce the methodological framework as well as algorithmic details in section II 
Particular focus is paid on the interpretability of the inferred lower-dimensional dynamics  In section III we present three numerical illustrations, i e  a system of linear ODEs, a hidden Markov Model and the discretized KS-equation  We then present in section IV the probabilistic extension of the framework and apply it to the KS-equation 
We conclude with a summary and a short discussion about possible next steps  We introduce the autoencoders deployed in this work, followed by the interpretable latent space dynamic and discuss the training process  We consider data from high-dimensional time series x n ∈ R f with n = 1,    , T   We remark that the intervals between the different states do not need to be uniformly spaced 

Autoencoder

A core assumption of the method is that each high-dimensional state x n can be compressed to a lower-dimensional representation z n ∈ C c with c << f   We identify this lower-dimensional representation by an autoencoder consisiting of a parameterized encoder and decoder  The encoder maps the high-dimensional representation to the latent space as:
The latent space is complex-valued  The decoder reconstructs the high-dimensional representation based on the latent variables as: We denote the parameters of the encoder as well as the decoder by θ  As discussed later in Section II C, both set of parameters are optimized simultaneously during training and therefore there is no need for differentiating them 

Interpretable Latent Space Dynamics

We employ a propagator in the latent space to capture the reduced-order dynamics of the system  In contrast to other time-extended variational autoencoder frameworks, our representation uses complex valued latent variables  In addition the latent variables are treated independently  The latter feature enables us to have an interpretable latent dynamics as well as a model that is especially suitable for being trained in the Small Data regime due to the small number of required parameters 
This is in contrast to temporal propagators such as LSTMs   For each dimension i of the latent variable z we are using the following continuous ODE in the complex plane: By solving this ODE, we can define the operator: Interpretable reduced-order modeling with time-scale separation Here, λ is a vector containing all the individual λ's and ∆t n indicates the time-step between the latent states 
The symbol is used to indicate a component-wise multiplication  We remark that the latent variables and the parameter governing the temporal evolution are complex numbers and their role in describing the system dynamics is similar to that of an eigenvalue  The real part is associated with growth and decay whereas the imaginary part is representing the periodic component 
This approach has similarities with the Koopman-operator based methods and the extended dynamic mode decomposition   In contrast to the methods mentioned before we are using a continuous formulation in the latent space that allows us to incorporate scarce and irregularly sampled training data and directly rely on complex numbers in the latent space 

Training and Predictions

We optimize a loss function that combines both a reconstruction loss as well as a loss associated with the error of our learned propagator in the latent space: (5) We note that we could directly incorporate mini-batch training by only taking the summation over a subset of the N available training data 
For new predictions of unseen states, we use the encoder to generate a latent representations which is then advanced in time by the learned propagator  At a designated time step we are using the decoder to reconstruct the high-dimensional solution  We applied our algorithm to three systems  First, we show that the algorithm is capable of exactly reproducing the solution of a linear ODE and to identify its eigenvalues 
Afterwards we are applying the framework to a high-dimensional process generated by a complex latent dynamics, which is correctly identified  As a final test case, we are applying the algorithm to a Kuramoto Shivashinski (KS) equation  Interpretable reduced-order modeling with time-scale separation

Linear ODE

We are considering a two-dimensional ODE system for x = y 1 y 2 : Based on the obtained training data we run our algorithm using a linear encoder and decoder structure as well as two latent variables z  The loss function was optimized using the Adam algorithm   As we consider a linear ODE we can analytically compute the eigenvalues involved and compare it with the parameters λ identified by our algorithm 
We observe in Figure that the algorithm was able to recover the correct values, i e  the eigenvalues 7 and 3 of the given linear ODE  The system does not have a periodic component and the two imaginary parts correctly go to zero, whereas the real parts converge to the reference value  Moreover we are also able to identify for the linear mapping between our latent variables z and the training data a matrix consisting of a multiple of the eigenvectors (1,1) and (1,-1) and thus the correct solution 
This example was chosen to show that the algorithm is able to quickly identify the exact solution of a linear ODE in terms of its linearly independent components 

Hidden multiscale dynamics

We consider eight-dimensional synthetic time series data produced by an underlying twodimensional complex valued process  In particular, the data points x are generated by first solving for the temporal evolution for the two complex-valued processes p 1 and p 2 and than mapping to the eight-dimensional space by using a randomly sampled linear mapping W  
One of the two processes used to generate the data is chosen to be much slower than the other one and both processes have a periodic component  dp 2 dt = (−0 9 + 1 5i)p 2 (8) As training data we consider 40 time series with 150 data points each, obtained by simulating the described processes for a maximum of t = 15 s and then sampling from the obtained data points 
Hence the training data consists of: • 40 time-series • with each consisting 150 observations of the x at a uniform time-step ∆t = 0 0025 The autoencoder obtained consists of one linear layer for both the decoder as well as the encoder  The model is trained for 5000 iterations using the Adam optimizer and a learning rate of 10 −3  
The results for the convergence of the parameters λ 1 and λ 2 can be found in Figure   We note that the process which is slower decaying and thus more responsible for the long-term evolution of the system has a higher convergence rate than the faster process  With the obtained parameters λ as well as the trained autoencoder, we compute predictions based on the last time step used for training, i e  we apply the encoder to obtain our latent representation and than use the latent dynamics to advance the latent representation in time 
Afterwards, we employ the decoder to reconstruct the full high-dimensional system  The results can be found in Figure and show very good agreement between predictions and reference data  This example shows that our model is successfully able to carry out dimensionality reduction and moreover indicates that the convergence rate between latent processes can be different 
The latter is relevant when training models as for accurate predictions all latent processes and their dynamics should be converged 

Kuramoto-Sivashinsky

Finally, we applied our algorithm to the KS equation and aim to identify a reduced-order model for the solution u(y, t): We employed periodic boundary conditions, µ = 1 and a domain size y ∈ [0, 22]  For this domain-size, the KS-equation exhibits a structurally stable chaotic attractor as discussed in The black lines divides the area for which training data was given from the area without raining data 
;   The equation is discretized in space using a discretization step of 22 64 resulting in a state vector x of dimension 64 and a nonlinear system of coupled ODEs  This is solved using a stiff fourth-order solver  We employed a non-linear encoder and decoder with four fully-connected layers each and ReLU-activation functions as well as Dropout Layers between the fully-connected layers 
We trained the model for 200000 iterations using Adam and a learning rate of 5 • 10 4 and assuming a five-dimensional latent space  We obtained the λ's in Figure   Four latent variables have λ's close to zero and thus a slow temporal dynamic that is responsible for the long-term evolution whereas one latent variable is quickly decaying 
Based on the obtained parameters, we do predictions based on an unseen initial condition not contained in the training data  We are able to reconstruct the correct phase space based on our predictions despite only using a very limited amount of training data  The results for the phase space can be seen in Figure  
Although the small-scale fluctuations in the temporal dynamics are not well captured, the model identifies the correct manifold which has a good accuracy compared to the reference solution  All phase-spaces were obtained by using a finite-difference operator on the data or predictions  These results are in accordance Interpretable reduced-order modeling with time-scale separation with whose LSTM-based temporal dynamic model was also able to find the correct phase space but not to track the actual dynamics for long-term predictions 
Our model is not able to account for noise in the temporal evolution and thus dealing with chaotic, small-scale fluctuations is challenging  We believe that a probabilistic version of our algorithm could be advantageous here  This section contains a fully probabilistic formulation for the deterministic model discussed before 
We replace the Autoencoder with a Variational Autoencoder and the ODE in the latent space with a SDE  The loss function which we optimize is the Evidence-Lower Bound (ELBO) 

Model Structure

We postulate the following relations for our probabilistic model using an Ornstein-Uhlenbeck (OU) for each dimension i of the latent space and a Wiener process W t in the latent space: We again assume that the latent variables z t are complex-valued and a priori independent  Complex variables were chosen as their evolution includes a harmonic components which are observed in many physical systems 
We assume an initial conditions z 0,i ∼ CN (0, σ 2 0,i )  The total parameters associated with the latent space dynamics of our model are thus {σ 2 0,i , σ 2 i , λ i } c i=1 and will be denoted by θ together with all parameters responsible for the decoder mapping G (see next section)  These parameters along with the state variables z t have to be inferred from the data x t  
Based on probabilistic Slow Feature Analysis (SFA) , we set σ 2 i = 2; (λ j ) and σ 2 0,i = 1  As a consequence, a priori, the latent dynamics are stationary  A derivation and reasoning for this choice can be found in Appendix A  Hence the only independent parameters are the λ i , the imaginary part of which can account for periodic effects in the latent dynamics 

Variational Autoencoder

We employ a variational autoencoder to account for a probabilistic mappings from the lower-dimensional representation z n to the high-dimensional system x n   In particular we are employing a probabilistic decoder The encoder is used to infer the state variables z based on the given data and thus defined in the inference and learning section 

Inference and Learning

Given the probabilistic relations , our goal is to infer the latent variables z 0:T as well as all model parameters θ  We follow a hybrid Bayesian approach in which the posterior of the state variables is approximated using amortized Variational Inference and Maximum-A-Posteriori (MAP) point-estimates for θ are computed 
The application of Bayes' rule for each data sequence x 0:T leads to the following posterior: where p(θ) denotes the prior on the model parameters  In the context of variational inference, we use the following factorization of the approximate posterior i e  we infer only the mean µ and variance σ for each state variable based on the given data points 
This conditional density used for inference is the encoder-counterpart to the probabilistic decoder defined in the section before  It can be readily shown that the optimal parameter values are found by maximizing the Evidence Lower Bound (ELBO) F(q φ (z 0:T ), θ) which is derived in Appendix B  We compute Monte Carlo estimates of the gradient of the ELBO with respect to φ and θ with the help of the reparametrization trick and carry out stochastic optimization with the ADAM algorithm  

Results for the probabilistic extension

We applied our probabilistic version to the KS-equation  We used the same settings as for the deterministic approach but considered up to 10 complex latent variables  The obtained λ's are in Figure   The probabilistic model allows us to quantify the uncertainty in predictions  In Figure predictions for various time-steps and the respective uncertainty bounds are shown for an unseen initial condition 
Due to the chaotic nature of the KS-equation and the small amount of training data, the underlying linear dynamic of our model is only able to capture the full dynamics for a limited time horizon  Fortunately, due to the probabilistic approach the model is capable of capturing chaotic fluctuations with increasingly wide uncertainty bounds 
We also computed the phase space representation for the KS-equation based on the predictions obtained by our model and compare it with the reference solution  The probabilistic model identifies the correct manifold with a better accuracy than the deterministic model  As some of the small-scale fluctuations are accounted as noise, the resulting manifold is more concentrated at the origin and the obtained values are slightly smaller than the reference manifold although their shape is very similar 
Context 2: By purchasing now, you agree to the following terms  You authorize Agency Spotter to store and charge your payment method on file  Your paid account will renew automatically, unless you terminate it, or you notify Customer Service by email ([email protected]) of your decision to terminate your paid account  You must cancel your subscription before it renews in order to avoid billing of subscription fees for the renewal form to your credit card 
Should You object to any of the Terms or any subsequent modifications thereto, or become dissatisfied with the Site in any way, Your only recourse is to immediately discontinue use of the Site  Agency Spotter has the right, but is not obligated, to strictly enforce the Terms through self-help, community moderation, active investigation, litigation and prosecution 
(b) Agency Spotter will use commercially reasonable efforts to make the Services available on a 24 hours a day, 7 days a week, and 365 days a year basis, subject to Section 23 below and to downtime for maintenance purposes 
(c) Agency Spotter may from time to time modify the Services and add, change, or delete features of the Services in its sole discretion, without notice to you  Your continued use of the Service after any such changes to the Service constitutes your acceptance of these changes  Agency Spotter will use commercially reasonable efforts to post information on the Site regarding material changes to the Services 
(d) The contents of the Site, such as text, graphics, images, logos, user interfaces, visual interfaces, photographs, button icons, software, trademarks, sounds, music, artwork and computer code, and other Agency Spotter content (collectively, “Agency Spotter Content”), are protected under both United States and foreign copyright, trademark and other laws  All Agency Spotter Content is the property of Agency Spotter or its content suppliers or clients  The compilation (meaning the collection, arrangement and assembly) of all content on the Site is the exclusive property of Agency Spotter and is protected by United States and foreign copyright, trademark, and other laws  Unauthorized use of the Agency Spotter Content may violate these laws, and is strictly prohibited  You must retain all copyright, trademark, service mark and other proprietary notices contained in the original Agency Spotter Content on any authorized copy You make of the Agency Spotter Content 
(e) You agree not to sell or modify the Agency Spotter Content or reproduce, display, publicly perform, distribute, or otherwise use the Agency Spotter Content in any way for any public or commercial purpose, in connection with products or services that are not those of the Site, in any other manner that is likely to cause confusion among consumers, that disparages or discredits Agency Spotter or its licensors, that dilutes the strength of Agency Spotter’s or its licensor’s property, or that otherwise infringes Agency Spotter’s or its licensor’s intellectual property rights  You further agree to in no other way misuse Agency Spotter Content that appears on this Site  Any code that Agency Spotter creates to generate or display any Agency Spotter Content or the pages making up the Website is also protected by Agency Spotter’s copyright and You may not copy or adapt such code 
2  Site Restrictions  You may not use the Site in order to transmit, post, distribute, store or destroy material, including without limitation, the Agency Spotter Content, (a) in violation of any applicable law or regulation, (b) in a manner that will infringe the copyright, trademark, trade secret or other intellectual property rights of others or violate the privacy, publicity or other personal rights of others, (c) that is defamatory, obscene, threatening, abusive or hateful, or (d) that is in furtherance of criminal, fraudulent, or other unlawful activity  You are also prohibited from violating or attempting to violate the security of the Site and Services, including without limitation, the following activities: (a) accessing or attempting to access data not intended for You or logging into a server or account which You are not authorized to access; (b) attempting to probe, scan or test the vulnerability of a system or network or to breach security or authentication measures without proper authorization; (c) attempting to interfere with service to any other user of the Site or Services, host or network, including, without limitation, via means of submitting a virus to the Website, overloading, “flooding”, “spamming”, “mailbombing” or “crashing”; or (d) forging any TCP/IP packet header or any part of the header information in any e-mail or newsgroup posting  Violations of system or network security may result in civil and/or criminal liability 
3  Specific Prohibited Uses  The Agency Spotter Content and other features of the Site may be used only for lawful purposes  Agency Spotter specifically prohibits any other use of the Site, and You agree not to do any of the following: (a) use the Site for any purpose other than as a platform for connecting businesses and agencies, including but not limited to using the information in the Website to sell or promote any products or services; (b) post or submit to the Website any incomplete, false or inaccurate biographical information or information which is not Your own; (c) post on the Website any franchise, pyramid scheme or “club membership”; (d) send unsolicited mail or e-mail, make unsolicited phone calls or send unsolicited faxes regarding promotions and/or advertising of products or services to any other user(s) of the Website; (e) delete or revise any material posted by any other person or entity; (f) take any action that imposes an unreasonable or disproportionately large load on the Website’s infrastructure; (g) notwithstanding anything to the contrary contained herein, use or attempt to use any engine, software, tool, agent or other automatic device, program, algorithm, methodology or mechanism (including without limitation browsers, spiders, robots, avatars or intelligent agents) to navigate or search the Website other than the search engine and search agents available from Agency Spotter on the Website and other than through generally available third party web browsers (e g , Internet Explorer, Firefox, Safari); (h) decipher, decompile, disassemble or reverse engineer any of the software comprising or in any way making up a part of the Website; or (i) aggregate, copy or duplicate in any manner any of the Agency Spotter Content or information available from the Website, without express written consent from Agency Spotter 
(a) Certain features or services offered on or through the Site to users or agencies may require you to open a user or agency account (“Agency Account”) (including setting up a user ID and password)  You are entirely responsible for maintaining the confidentiality of the information you hold for your account, including your password, and for any and all activity that occurs under your account until you close down your account or prove that your account security was compromised due to no fault of your own  To close your account, please email us at [email protected] You agree to notify Agency Spotter immediately of any unauthorized use of your account or password, or any other breach of security  You may be held liable for losses incurred by Agency Spotter or any other user of or visitor to the Site due to someone else using your Agency Spotter ID, password or account as a result of your failing to keep your account information secure and confidential  You may not use anyone else’s Agency Spotter ID, password or account at any time without the express permission and consent of the holder of that Agency Spotter ID, password or account  Agency Spotter cannot and will not be liable for any loss or damage arising from your failure to comply with these obligations  Agency Spotter may verify Agency Accounts to confirm that such accounts meet Agency Spotter’s minimum requirements to be an agency, as the same may be modified or amended from time to time, and may assign an administrator to such verified Agency Account 
(b) To eligible to use the Site and the Services, you must meet the following criteria and represent and warrant that you: (i) are at least 18 years of age; (ii) are not currently restricted from the Site or Services, and are not otherwise prohibited from having an Agency Spotter account, (iii) are not a competitor of Agency Spotter or are not using the Site or Services for reasons that are in competition with Agency Spotter, (iv) will only maintain one Agency Spotter account at any given time, (v) have full power and authority to enter into this Agreement and doing so will not violate any other agreement to which you are bound, (vi) will not violate any rights of Agency Spotter, including intellectual property rights such as copyright and trademark rights, and (vii) agree to provide at your cost all equipment, software and internet access necessary to use the Site or Services 
6  User Content and Submissions  You understand that all information, data, text, software, music, sound, photographs, graphics, video, advertisements, messages or other materials submitted, posted or displayed by You on or through the Website (“User Content”) is the sole responsibility of the person from which such User Content originated  Agency Spotter claims no ownership or control over any User Content  You or a third party licensor, as appropriate, retain all patent, trademark and copyright to any User Content You submit, post or display on or through Agency Spotter and You are responsible for protecting those rights, as appropriate  By submitting, posting or displaying User Content on or through Agency Spotter, You grant Agency Spotter a worldwide, non-exclusive, royalty-free license to reproduce, adapt, distribute and publish such User Content through Agency Spotter  In addition, by submitting, posting or displaying User Content which is intended to be available to the general public, You grant Agency Spotter a worldwide, non-exclusive, royalty-free license to reproduce, adapt, distribute and publish such User Content for the purpose of promoting Agency Spotter Services  Agency Spotter will discontinue this licensed use within a commercially reasonable period after such User Content is removed from the Site  Agency Spotter reserves the right to refuse to accept, post, display or transmit any User Content in its sole discretion 
You also represent and warrant that You have the right to grant, or that the holder of any rights has completely and effectively waived all such rights and validly and irrevocably granted to You the right to grant, the license stated above  If You post User Content in any public area of the Website, You also permit any user of the Website to access, display, view, store and reproduce such User Content for personal use  Subject to the foregoing, the owner of such User Content placed on the Website retains any and all rights that may exist in such User Content 
Agency Spotter does not represent or guarantee the truthfulness, accuracy, or reliability of User Content or endorse any opinions expressed by users of the Website  You acknowledge that any reliance on material posted by other users will be at Your own risk 
The following is a partial list of User Content that is prohibited on the Website  Prohibited Content includes, but is not limited to, Content that: is implicitly or explicitly offensive, such as User Content that engages in, endorses or promotes racism, bigotry, discrimination, hatred or physical harm of any kind against any group or individual; harasses, incites harassment or advocates harassment of any group or individual; involves the transmission of “junk mail”, “chain letters,” or unsolicited mass mailing or “spamming”; promotes or endorses false or misleading information or illegal activities or conduct that is abusive, threatening, obscene, defamatory or libelous; promotes or endorses an illegal or unauthorized copy of another person’s copyrighted work, such as providing or making available pirated computer programs or links to them, providing or making available information to circumvent manufacture-installed copy-protect devices, or providing or making available pirated music or other media or links to pirated music or other media files; contains restricted or password only access pages, or hidden pages or images; displays or links to pornographic, indecent or sexually explicit material of any kind; provides or links to material that exploits people under the age of 18 in a sexual, violent or other manner, or solicits personal information from anyone under 18; or provides instructional information about illegal activities or other activities prohibited by these Terms and Conditions, including without limitation, making or buying illegal weapons, violating someone’s privacy, providing or creating computer viruses or pirating any media; and/or solicits passwords or personal identifying information from other users 
It is your responsibility to keep your Agency Spotter profile information accurate and updated 
7  User-to-User Communications and Sharing (Agency Spotter Groups, Ratings, Reviews, Updates, Agency Pages, etc )  Agency Spotter offers various forums such as Agency Spotter Groups, Ratings, Reviews, and Updates, where you can post your observations and comments on designated topics  Agency Spotter also enables sharing of information by allowing users to post updates, including links to news articles and other information such as product recommendations, job opportunities, and other content to their profile and other parts of the Site, such as Agency Spotter Groups and Agency Pages  Agency Spotter members can create Agency Spotter Groups and Agency Pages for free; however, Agency Spotter may close or transfer Agency Spotter Groups or Agency Pages, or remove content from them if the content violates these Terms or others’ intellectual property rights  To create an Agency Spotter Agency Page, the Agency must be a company or legal entity that meets Agency Spotter’s minimum requirements for an Agency, and you must have the authority to create the Agency Page on behalf of the third party Agency 
For clarity, only DMCA Notices should go to the Copyright Agent; any other feedback, comments, requests for technical support, and other communications should be directed to: [email protected] You acknowledge that if you fail to comply with all of the requirements of this Section, your DMCA Notice may not be valid 
Upon receipt of a Notice, Agency Spotter will take whatever action, in its sole discretion, it deems appropriate, including removal of the challenged material from the Site and/or termination of the User’s account in appropriate circumstances  Please note that a Complainant may be liable for damages (including costs and attorneys’ fees) if he or she knowingly makes a material misrepresentation that content is infringing 
(i) If you have posted material subject to a DMCA Notice that allegedly infringes a copyright (the “Counterclaimant”), you may send Agency Spotter a written Counter Notice pursuant to Section 512(g), (ii) and 512(g), (iii) of the DMCA  When Agency Spotter receives a Counter Notice, it may, in its discretion, reinstate the material in question not less than ten (10) nor more than fourteen (14) days after receiving the Counter Notice unless Agency Spotter first receives notice from the Claimant that he or she has filed a legal action to restrain the allegedly infringing activity  Please note that Agency Spotter will send a copy of the Counter Notice to the address provided by the Claimant  A Counterclaimant may be liable for damages (including costs and attorneys’ fees) if he or she knowingly makes a material misrepresentation that that material or activity was removed or disabled by mistake or misidentification 
1  Identification of the material that has been removed or to which access has been disabled and the location at which the material appeared before it was removed or access to it was disabled 
2  A statement under penalty of perjury that you have a good faith belief that the material was removed or disabled as a result of mistake or misidentification of the material to be removed or disabled 
3  Your name, address, and telephone number, and a statement that you consent to the jurisdiction of Federal District Court for the judicial district in which the address is located, or if your address is outside of the United States, for any judicial district in which Agency Spotter may be found, and that you will accept service of process from the person who provided notification under subsection (c)(1)(C) of the DMCA or an agent of such person 
(c) AGENCY SPOTTER HAS NO OBLIGATION TO ADJUDICATE CLAIMS OF INFRINGEMENT – EACH USER’S AGREEMENT TO HOLD AGENCY SPOTTER HARMLESS FROM CLAIMS  Claimants, Counterclaimants, and users understand that Agency Spotter is not an intellectual property tribunal  While Agency Spotter may, in its discretion, use the information provided in a DMCA Notice and Counter Notice in order to decide how to respond to infringement claims, Agency Spotter is not responsible for determining the merits of such claims  If a Counterclaimant responds to a claim of infringement by providing a Counter Notice, the Counterclaimant agrees that if Agency Spotter restores or maintains the content, the Counterclaimant will defend and hold Agency Spotter harmless from any resulting claims of infringement against Agency Spotter 
10  Advertisements and Other Potential Sources Of Revenue  Some of the Services may now or in the future be supported by advertising revenue, pay-per-click mechanisms, or other funding, and the Site may display advertisements and promotions  These advertisements may be targeted to the content of information stored via the Site, queries made through the Services, or other criteria  The manner, mode and extent of advertising on the Site are subject to change without specific notice to you  In consideration for Agency Spotter granting you access to and use of the Site and the Services, you agree that the Agency Spotter may place such advertising on the Site and/or incorporate such advertisements into the Services 
11  DISCLAIMERS  THE SITE AND ITS CONTENT AND THE SERVICES ARE PROVIDED “AS IS” AND AGENCY SPOTTER MAKES NO REPRESENTATIONS OR WARRANTIES OF ANY KIND, EITHER EXPRESS OR IMPLIED, ABOUT THE IMAGES OR SITE INCLUDING, WITHOUT LIMITATION, WARRANTIES OF MERCHANTABILITY, FITNESS FOR A PARTICULAR PURPOSE, OR NON-INFRINGEMENT, TO THE FULLEST EXTENT PERMISSIBLE UNDER APPLICABLE LAW  AGENCY SPOTTER DOES NOT WARRANT THAT ACCESS TO THE SITE OR ITS CONTENTS OR THE SERVICES WILL BE UNINTERRUPTED OR ERROR-FREE, THAT DEFECTS WILL BE CORRECTED, OR THAT THIS SITE OR THE SERVERS THAT MAKE IT AVAILABLE ARE FREE OF VIRUSES OR OTHER HARMFUL COMPONENTS  AGENCY SPOTTER DOES NOT WARRANT OR MAKE ANY REPRESENTATIONS REGARDING THE USE OR THE RESULTS OF THE USE OF ANY CONTENT ON THE SITE IN TERMS OF ITS CORRECTNESS, ACCURACY, RELIABILITY, OR OTHERWISE  ACCORDINGLY, YOU ACKNOWLEDGE THAT YOUR USE OF THE SITE IS AT YOUR OWN RISK  YOU (AND NOT AGENCY SPOTTER) ASSUME THE ENTIRE COST OF ALL NECESSARY SERVICING, REPAIR, OR CORRECTION RESULTING FROM COMPUTER MALFUNCTION, VIRUSES OR THE LIKE  APPLICABLE LAW MAY NOT ALLOW THE EXCLUSION OF IMPLIED WARRANTIES, SO THE ABOVE EXCLUSION MAY NOT APPLY TO YOU 
12  Limitation on Liability  Neither Agency Spotter, nor its licensors, representatives, affiliates, employees, shareholders or directors (collectively, “Agency Spotter Affiliates”), shall be cumulatively responsible or liable for (a) any damages in excess of three (3) times the most recent monthly fee that you paid for a Premium Service, if any, or US $100, whichever amount is greater, or (b) any damages of any kind including, without limitation, lost business, profits or data (or the cost to recreate such data), direct, indirect, incidental, consequential, compensatory, exemplary, special or punitive damages that may result from Your access to or use of Website, the Agency Spotter Content, or the Services, or any content or other materials on, accessed through or downloaded from the Site  The allocations of liability in this Section represent the agreed and bargained-for understanding of the parties and the fees herein reflects such allocation  These limitations of liability will apply notwithstanding any failure of essential purpose of any limited remedy, whether your claim is based in contract, tort, statute or any other legal theory, and whether we knew or should have known about the possibility of such damages; provided, however, that this limitation of liability shall not apply if you have entered into a separate written agreement to purchase Premium Services with a separate Limitation of Liability provision that expressly supersedes this Section in relation to those Premium Services 
13  Indemnification  In the event that You use the Website, the Agency Spotter Content, or any portion thereof, in any manner not authorized by Agency Spotter, or if You otherwise infringe any intellectual property rights or any other rights relating to other users, You agree to indemnify and hold Agency Spotter, its subsidiaries, affiliates, licensors and representatives, harmless against any losses, expenses, costs or damages, including reasonable attorneys’ fees, incurred by them as a result of unauthorized use of the Website or the Agency Spotter Content and/or Your breach or alleged breach of these Terms and Conditions 
(a) You agree that Agency Spotter and its licensors own all intellectual property rights in and to the Services, the Site and related Software, including but not limited to the look and feel, structure, organization, design, algorithms, templates, data models, logic flow, text, graphics, logos, and screen displays associated therewith 
(b) You will not reverse engineer, decompile or disassemble the Software, or otherwise attempt to reconstruct or discover the source code for the Software  You further agree not to resell, lease, assign, distribute, time share or otherwise commercially exploit or make the Services available to any third party for such third party’s benefit 
(c) You may make a single copy of the Downloaded Software for backup purposes only; provided that any such copies contain the same proprietary rights notices that appear on the Downloaded Software  Agency Spotter reserves all rights in the Services and Software not expressly granted to you hereunder  As used herein, “Software” means Agency Spotter’s proprietary software used to deliver the Services, made available to you as part of the Site and/or Services, and all updates and associated documentation thereto made available as a part of the Site or Services pursuant to these Terms, including Downloadable Software  The term “Downloadable Software” means client software downloaded by you from the Site that augments your use of the Site and/or Services, including add-ins, sample code, APIs and ancillary programs 
(d) Agency Spotter shall have a perpetual, royalty-free, worldwide, and transferable license to use or incorporate into the Site and Services any suggestions, ideas, enhancements, feedback, or other information provided by you related to the Site or Services 
(e) Agency Spotter may derive and compile aggregated and/or analytical information from your usage of the Site and Services  Such aggregated data and metadata may be used for Agency Spotter’s own purposes without restriction, including, but not limited to, using such data in conjunction with data from other sources to improve Agency Spotter’s products and services and to create new products 
15  Third Party Software and Features; Agency Spotter Applications  (a) Agency Spotter may make software from third-party companies available to You  To download such software, You may be required to agree to the respective software licenses and/or warranties of such third-party software  Each software product is subject to the individual company’s terms and conditions, and the agreement will be between You and the respective company  This means that Agency Spotter does not guarantee that any software You download will be free of any contaminating or destructive code, such as viruses, worms or Trojan horses  Agency Spotter does not offer any warranty on any third-party software You download using the Site  Further, the Site and/or Service may contain features, functionality and information that are provided through or by third-party content, software, websites, and/or system (“Third Party Materials”)  Your use and access of these features and functionality are subject to the terms published or otherwise made available by the third-party providers of Third Party Materials  Agency Spotter has no responsibility for any Third-Party Materials, and you irrevocably waive any claim against Agency Spotter with respect to such Third-Party Materials
Context 3: Thalassaemia minor | definition of Thalassaemia minor by Medical dictionary
Thalassaemia minor | definition of Thalassaemia minor by Medical dictionary
https://medical-dictionary thefreedictionary com/Thalassaemia+minor
(redirected from Thalassaemia minor)
Related to Thalassaemia minor: thalassaemia major
Thalassemia describes a group of inherited disorders characterized by reduced or absent amounts of hemoglobin, the oxygen-carrying protein inside the red blood cells  There are two basic groups of thalassemia disorders: alpha thalassemia and beta thalassemia  These conditions cause varying degrees of anemia, which can range from insignificant to life threatening 
All types of thalassemias are considered quantitative diseases of hemoglobin, because the quantity of hemoglobin produced is reduced or absent  Usual adult hemoglobin is made up of three components: alpha globin, beta globin, and heme  Thalassemias are classified according to the globin that is affected, hence the names alpha and beta thalassemia  Although both classes of thalassemia affect the same protein, the alpha and beta thalassemias are distinct diseases that affect the body in different ways 
Beta thalassemia may be the most best-known type of thalassemia and is also called Cooley's anemia  It is caused by a change in the gene for the beta globin component of hemoglobin  Beta thalassemia causes variable anemia that can range from moderate to severe, depending in part on the exact genetic change underlying the disease  Beta thalassemia can be classified based on clinical symptoms  Beta thalassemia major usually causes severe anemia that can occur within months after birth  If left untreated, severe anemia can result in insufficient growth and development, as well as other common physical complications that can lead to a dramatically decreased life-expectancy  Fortunately, in developed countries beta thalassemia is usually identified by screening in the newborn period, before symptoms have developed  Children who are identified early can be started on ongoing blood transfusion therapy as needed  Although transfusion therapy prevents many of the complications of severe anemia, the body is unable to eliminate the excess iron contained in the transfused blood  Over time, the excess iron deposits in tissues and organs, resulting in damage and organ failure  Another medication must be administered to help the body eliminate the excess iron and prevent iron-over-load complications  Beta thalassemia intermedia describes the disease in individuals who have moderate anemia that only requires blood transfusions intermittently, if at all 
Alpha thalassemia is the result of changes in the genes for the alpha globin component of hemoglobin  There are two main types of alpha thalassemia disease: hemoglobin H disease and alpha thalassemia major  The two diseases are quite different from beta thalassemia as well as from one another  Individuals with hemoglobin H disease can experience events of hemolytic anemia—anemia caused by the rapid breakdown of the red blood cells  These events are thought to be triggered by various environmental causes, such as infection and/or exposure to certain chemicals  Hemoglobin H disease is in most cases milder than beta thalassemia  It does not generally require transfusion therapy  Alpha thalassemia major is a very serious disease that results in severe anemia that begins even before birth  Most affected babies do not survive to be born or die shortly after birth 
The thalassemias are among the most common genetic diseases worldwide  Both alpha and beta thalassemia have been described in individuals of almost every ancestry, but the conditions are more common among certain ethnic groups  Unaffected carriers of all types of thalassemia traits do not experience health problems  In fact, the thalassemia trait is protective against malaria, a disease caused by blood-borne parasites transmitted through mosquito bites  According to a widely accepted theory, most genetic changes—mutations—that cause thalassemia occurred multiple generations ago  Coincidentally, these mutations increased the likelihood that carriers would survive malaria infection  Survivors passed the mutation onto their offspring, and the trait became established throughout areas where malaria is common  As populations migrated, so did the thalassemia traits 
Beta thalassemia trait is seen most commonly in people with the following ancestry: Mediterranean (including North African, and particularly Italian and Greek), Middle Eastern, Indian, African, Chinese, and Southeast Asian (including Vietnamese, Laotian, Thai, Singaporean, Filipino, Cambodian, Malaysian, Burmese, and Indonesian)  Alpha-thalassemia trait is seen with increased frequency in the same ethnic groups  However, there are different types of alpha thalassemia traits within these populations  The frequency of hemoglobin H disease and alpha thalassemia major depends on the type of alpha thalassemia trait  The populations in which alpha thalassemia diseases are most common include Southeast Asians and Chinese (particularly Southern Chinese) 
It is difficult to obtain accurate prevalence figures for various types of thalassemia within different populations  This difficulty arises due to testing limitations in determining exact genetic diagnoses, as well as the fact that many studies have focused on small, biased hospital populations 
Two studies reflect prevalence figures that can be helpful counseling families and determining who to screen for beta thalassemia  Between the years of 1990 and 1996, the State of California screened more than 3 1 million infants born in the state for beta thalassemia  Approximately 1 in 114,000 infants had beta thalassemia major, with prevalence rates being highest among Asian Indians (about one in 4,000), Southeast Asians (about one in 10,000), and Middle Easterners (about one in 7,000)  Another type of beta thalassemia disease, E/beta thalassemia, was represented in approximately one in 110,000 births, all of which occurred in families of Southeast Asian ancestry  Among Southeast Asians, the prevalence of E/beta thalassemia was approximately one in 2,600 births  This is in keeping with the observation that hemoglobin E trait carrier rates are relatively high within the Southeast Asian population: 16% in a study of 768 immigrants to California, and up to 25% in some specific Southeast Asian populations such as Cambodians  While these California studies address some of the limitations of earlier population studies, the pattern observed in California is expected to be different in other areas of the United States and the world  For example, Italians are underrepresented in this population when compared to the population of the East Coast of the United States 
Determining prevalence figures for alpha thalassemia is even more difficult due to increased limitations in diagnostic testing  All types of alpha thalassemia disease are most common among people of Southeast Asian and Chinese descent, for reasons that become clearer with an understanding of the underlying genetics of alpha thalassemia  One study of 500 pregnant women in Northern Thailand estimated a frequency of one in 500 pregnancies affected by alpha thalassemia major, for example  Prevalence of alpha thalassemia disease is significantly lower in the United States primarily because of immigration patterns; although at least one state, California, has observed growing hemoglobin H disease incidence rates that are high enough to justify universal newborn screening for the condition 
Humans normally make several types of the oxygen-carrying protein hemoglobin  An individual's stage in development determines whether he or she makes primarily embryonic, fetal, or adult hemoglobins  All types of hemoglobin are made of three components: heme, alpha (or alpha-like) globin, and beta (or beta-like) globin  All types of thalassemia are caused by changes in either the alpha- or beta-globin gene  These changes cause little or no globin to be produced  The thalassemias are, therefore, considered quantitative hemoglobin diseases  All types of thalassemias are recessively inherited, meaning that a genetic change must be inherited from both the mother and the father  The severity of the disease is influenced by the exact thalassemia mutations inherited, as well as other genetic and environmental factors  There are rare exceptions, notably with beta thalassemia, where globin gene mutations exhibit a dominant pattern of inheritance in which only one gene needs to be altered in order to see disease expression  Scientists continue to study the causes  For instance, a new mutation for alpha-thalassemia was discovered for the first time among Iranian patients in 2004 
BETA-THALASSEMIA  Most individuals have two normal copies of the beta globin gene, which is located on chromosome 11 and makes the beta globin component of normal adult hemoglobin, hemoglobin A  There are approximately 100 genetic mutations that have been described that cause beta thalassemia, designated as either beta0 or beta + mutations  No beta globin is produced with a beta0 mutation, and only a small fraction of the normal amount of beta globin is produced with a beta + mutation 
When an individual has one normal beta globin gene and one with a beta thalassemia mutation, he or she is said to carry the beta thalassemia trait  Beta thalassemia trait, like other hemoglobin traits, is protective against malaria infection  Trait status is generally thought not to cause health problems, although some women with beta thalassemia trait may have an increased tendency toward anemia during pregnancy 
When two members of a couple carry the beta thalassemia trait, there is a 25% chance that each of their children will inherit beta thalassemia disease by inheriting two beta thalassemia mutations, one from each parent  The clinical severity of the beta thalassemia disease—whether an individual has beta thalassemia intermedia or beta thalassemia major—will depend largely on whether the mutations inherited are beta0 thalassemia or beta + thalassemia mutations  Two beta0 mutations generally lead to beta thalassemia major, and two beta+ thalassemia mutations generally lead to beta thalassemia intermedia  Inheritance of one beta0 and one beta + thalassemia mutation tends to be less predictable 
Although relatively uncommon, there are other thalassemia-like mutations that can affect the beta globin gene  Hemoglobin E is the result of a substitution of a single nucleotide  This change results in a structurally altered hemoglobin that is produced in decreased amounts  Therefore, hemoglobin E is unique in that it is both a quantitative (i e  thalassemia-like) and qualitative trait  When co-inherited with a beta thalassemia trait, it causes a disease that is almost indistinguishable from beta thalassemia disease  Large deletions around and including the beta globin gene can lead to delta/beta thalassemia or hereditary persistence of fetal hemoglobin (HPFH)  Interestingly, delta/beta thalassemia trait behaves very similarly to beta thalassemia trait in its clinical manifestations  However, HPFH trait does not tend to cause hemoglobin disease when co-inherited with a second thalassemia or other beta globin mutation 
ALPHA-THALASSEMIA  Most individuals have four normal copies of the alpha globin gene, two copies on each chromosome 16  These genes make the alpha globin component of normal adult hemoglobin, which is called hemoglobin A  Alpha globin is also a component of fetal hemoglobin and the other major adult hemoglobin called hemoglobin A2  Mutations of the alpha globin genes are usually deletions of the gene, resulting in absent production of alpha globin  Since there are four genes (instead of the usual two) to consider when looking at alpha globin gene inheritance, there are several alpha globin types that are possible 
Absence of one alpha globin gene leads to a condition known as silent alpha thalassemia trait  This condition causes no health problems and can be detected only by special genetic testing  Alpha thalassemia trait occurs when two alpha globin genes are missing  This can occur in two ways  The genes may be deleted from the same chromosome, causing the 'cis' type of alpha thalassemia trait  Alternately, they may be deleted from different chromosomes, causing the 'trans' type of alpha thalassemia trait  In both instances, there are no associated health problems, although the trait status may be detected by more routine blood screening 
Hemoglobin H disease results from the deletion of three alpha globin genes, such that there is only one functioning gene  Typically, this can occur when one parent carries the silent alpha thalassemia trait, and the other parent carries the 'cis' type of the alpha thalassemia trait  In this situation, there is a 25% chance for hemoglobin H disease in each of such a couple's children 
Hemoglobin H disease-like symptoms can also be a part of a unique condition called alpha thalassemia mental retardation syndrome  Alpha thalassemia mental retardation syndrome can be caused by a deletion of a significant amount of chromosome 16, affecting the alpha globin genes  This is usually not inherited, but rather occurs sporadically in the affected individual  Affected individuals have mild hemoglobin H disease, mild-to-moderate mental retardation, and characteristic facial features  This syndrome can also occur as a sex-linked form in which a mutation is inherited in a particular gene on the X-chromosome  This gene influences alpha globin production, as well as various other developmental processes  Individuals affected with this form of the syndrome tend to have more severe mental retardation, delayed development, nearly absent speech, characteristic facial features, and genital-urinary abnormalities  The remaining discussion will focus only on aspects of hemoglobin H disease 
Alpha thalassemia major results from the deletion of all four alpha globin genes, such that there are no functioning alpha globin genes  This can occur when both parents carry the 'cis' type of the alpha thalassemia trait  In this situation, there is a 25% chance for alpha thalassemia major in each of such a couple's children 
Beta thalassemia major is characterized by severe anemia that can begin months after birth  In the United States and other developed countries beta thalassemia is identified and treated early and effectively  Therefore, the following discussion of symptoms applies primarily to affected individuals in the past and unfortunately in some underdeveloped countries now  If untreated, beta thalassemia major can lead to severe lethargy, paleness, and delays in growth and development  The body attempts to compensate by producing more blood, which is made inside the bones in the marrow  However, this is ineffective without the needed genetic instructions to make enough functioning hemoglobin  Instead, obvious bone expansion and changes occur that cause characteristic facial and other changes in appearance, as well as increased risk of fractures  Severe anemia taxes other organs in the body—such as the heart, spleen, and liver—which must work harder than usual  This can lead to heart failure, as well as enlargement and other problems of the liver and spleen  When untreated, beta thalassemia major generally results in childhood death, usually due to heart failure  In 2004, the first known heart attack associated with beta thalassemia major was reported  Fortunately, in developed countries diagnosis is usually made early, often before symptoms have begun  This allows for treatment with blood transfusion therapy, which can prevent most of the complications of the severe anemia caused by beta thalassemia major  Individuals with beta thalassemia intermedia have a more moderate anemia that may only require treatment with transfusion intermittently, such as when infections occur and stress the body  As a person with beta thalassemia intermedia gets older, however, the need for blood transfusions may increase to the point that they are required on a regular basis  When this occurs their disease becomes more similar to beta thalassemia major  Other genetic and environmental factors can influence the course of the disease as well  For example, co-inheritance of one or two alpha thalassemia mutations can tend to ameliorate some of the symptoms of beta thalassemia disease, which result in part from an imbalance in the amount of alpha- and beta-globin present in the red blood cells 
Hemoglobin h disease
Absence of three alpha globin genes causes an imbalance of alpha and beta globin proteins in the red blood cells  The excess beta globin proteins tend to come together to form hemoglobin H, which is unable to release oxygen to the tissues  In addition, hemoglobin H tends to precipitate out in the cells, causing damage to the red blood cell membrane  When affected individuals are exposed to certain drugs and chemicals known to make the membrane more fragile, the cells are thought to become vulnerable to breakdown in large numbers, a complication called hemolytic anemia  Fever and infection are also considered to be triggers of hemolytic anemia in hemoglobin H disease  This can result in fatigue, paleness, and a yellow discoloration of the skin and whites of eyes called jaundice  Usually, the anemia is mild enough not to require treatment  Severe anemia events may require blood transfusion, however, and are usually accompanied by such other symptoms as dark feces or urine and abdominal or back pain  These events are uncommon in hemoglobin H disease, although they occur more frequently in a more serious type of hemoglobin H disease called hemoglobin H/Constant Spring disease  Individuals effected with this type of hemoglobin H disease are also more likely to have enlargement of and other problems with the spleen 
Alpha thalassemia major
Because alpha globin is a necessary component of all major hemoglobins and some minor hemoglobins, absence of all functioning alpha globin genes leads to serious medical consequences that begin even before birth  Affected fetuses develop severe anemia as early as the first trimester of pregnancy  The placenta, heart, liver, spleen, and adrenal glands may all become enlarged  Fluid can begin collecting throughout the body as early as the start of the second trimester, causing damage to developing tissues and organs  Growth retardation is also common  Affected fetuses usually miscarry or die shortly after birth  In addition, women carrying affected fetuses are at increased risk of developing complications of pregnancy and delivery  Up to 80% of such women develop toxemia, a disturbance of metabolism that can potentially lead to convulsions and coma  Other maternal complications include premature delivery and increased rates of delivery by cesarean section, as well as hemorrhage after delivery 
Thalassemia may be suspected if an individual shows signs that are suggestive of the disease  In all cases, however, laboratory diagnosis is essential to confirm the exact diagnosis and to allow for the provision of accurate genetic counseling about recurrence risks and testing options for parents and affected individuals  Screening is likewise recommended to determine trait status for individuals of high-risk ethnic groups 
The following tests are used to screen for thalassemia disease and/or trait:
hemoglobin electrophoresis with quantitative hemoglobin A2 and hemoglobin F
free erythrocyte-protoporphyrin (or ferritin or other studies of serum iron levels)
A complete blood count will identify low levels of hemoglobin, small red blood cells, and other red blood cell abnormalities that are characteristic of a thalassemia diagnosis  Since thalassemia trait can sometimes be difficult to distinguish from iron deficiency, tests to evaluate iron levels are important  A hemoglobin electrophoresis is a test that can help identify the types and quantities of hemoglobin made by an individual  This test uses an electric field applied across a slab of gel-like material  Hemoglobins migrate through this gel at various rates and to specific locations, depending on their size, shape, and electrical charge  Isoelectric focusing and high-performance liquid chromatography (HPLC) use similar principles to separate hemoglobins and can be used instead of or in various combinations with hemoglobin electrophoresis to determine the types and quantities of hemoglobin present  Hemoglobin electrophoresis results are usually within the normal range for all types of alpha thalassemia  However, hemoglobin A2 levels and sometimes hemoglobin F levels are elevated when beta thalassemia disease or trait is present  Hemoglobin electrophoresis can also detect structurally abnormal hemoglobins that may be co-inherited with a thalassemia trait to cause thalassemia disease (i e , hemoglobin E) or other types of hemoglobin disease (i e , sickle hemoglobin)  Sometimes DNA testing is needed in addition to the above screening tests  This can be performed to help confirm the diagnosis and establish the exact genetic type of thalassemia 
Diagnosis of thalassemia can occur under various circumstances and at various ages  Several states offer thalassemia screening as part of the usual battery of blood tests done for newborns  This allows for early identification and treatment  Thalassemia can be identified before birth through the use of prenatal diagnosis  Chorionic villus sampling (CVS) can be offered as early as 10 weeks of pregnancy and involves removing a sample of the placenta made by the baby and testing the cells  CVS carries a risk of causing a miscarriage that is between 0 5%-1%  Amniocentesis is generally offered between 15 and 22 weeks of pregnancy, but can sometimes be offered earlier  Two to three tablespoons of the fluid surrounding the baby is removed  This fluid contains fetal cells that can be tested  The risk of miscarriage associated with amniocentesis ranges from 0 33-0 5%  Pregnant woman and couples may choose prenatal testing in order to prepare for the birth of a baby that may have thalassemia  Alternately, knowing the diagnosis during pregnancy allows for the option of pregnancy termination  Preimplantation genetic diagnosis (PGD) is a relatively new technique that involves in-vitro fertilization followed by genetic testing of one cell from each developing embryo  Only the embryos unaffected by sickle cell disease are transferred back into the uterus  PGD is currently available on a research basis only and is relatively expensive 
Individuals with beta thalassemia major receive regular blood transfusions, usually on a monthly basis  This helps prevent severe anemia and allows for more normal growth and development  Transfusion therapy does have limitations, however  Individuals can develop reactions to certain proteins in the blood—called a transfusion reaction  This can make locating appropriately matched donor blood more difficult  Although blood supplies in the United States are very safe, particularly relative to the past and to other areas of the world, there remains an increased risk of exposure to such blood-borne infections as hepatitis  Additionally, the body is not able to get rid of the excess iron that accompanies each transfusion  An additional medication called desferoxamine is administered, usually five nights per week over a period of several hours, using an automatic pump that can be used during sleep or taken anywhere the person goes  This medication is able to bind to the excess iron, which can then be eliminated through urine  If desferoxamine is not used regularly or is unavailable, iron overload can develop and cause tissue damage and organ damage and failure  The heart, liver, and endocrine organs are particularly vulnerable  Desferoxamine itself may rarely produce allergic or toxic side effects, including hearing damage  Signs of desferoxamine toxicity are screened for and generally develop in individuals who overuse the medication when body iron levels are sufficiently low  Overall, however, transfusion and desferoxamine therapy have increased the life expectancy of individuals with the most severe types of beta thalassemia major to the 4th or 5th decade  This can be expected to improve with time and increased developments in treatment, as well as for those with more mild forms of the disease 
New treatments offer additional options for some individuals with beta thalassemia major  There are various medications that target the production of red blood cells (i e  erythropoeitin) or fetal hemoglobin (i e  hydroxyurea and butyrate)  Their effectiveness in ameliorating the severity of beta thalassemia is currently being investigated  Another promising new treatment is bone marrow transplantation, in which the bone marrow of an affected individual is replaced with the bone marrow of an unaffected donor  If successful, this treatment can provide a cure  However, there is an approximately 10-15% chance the procedure could be unsuccessful (i e  the thalassemia returns); result in complications (i e  graft-versus-host disease); or result in death  The risk for specific individuals depends on current health status, age, and other factors  Because of the risks involved and the fact that beta thalassemia is a treatable condition, transplant physicians require a brother or sister donor who has an identically matched tissue type, called HLA type  HLA type refers to the unique set of proteins present on each individual's cells, which allows the immune system to recognize "self" from "foreign " HLA type is genetically determined, so there is a 25% chance for two siblings to be a match  Transplant physicians and researchers are also investigating ways to improve the safety and effectiveness of bone marrow transplantation  Using newborn sibling umbilical cord blood—the blood from the placenta that is otherwise discarded after birth but contains cells that can go on to make bone marrow—seems to provide a safer and perhaps more effective source of donor cells  Donors and recipients may not have to be perfect HLA matches for a successful transplant using cord blood cells  Trials are also underway to determine the effectiveness of "partial transplants," in which a safer transplant procedure is used to replace only a percentage of the affected individual's bone marrow  Other possible treatments on the horizon may include gene therapy techniques aimed at increasing the amount of normal hemoglobin the body is able to make 
Hemoglobin H disease is a relatively mild form of thalassemia that may go unrecognized  It is not generally considered a condition that will reduce one's life expectancy  Education is an important part of managing the health of an individual with hemoglobin H disease  It is important to be able to recognize the signs of severe anemia that require medical attention  It is also important to be aware of the medications, chemicals, and other exposures to avoid due to the theoretical risk they pose of causing a severe anemia event  When severe anemia occurs, it is treated with blood transfusion therapy  For individuals with hemoglobin H disease, this is rarely required  For those with the hemoglobin H/Constant Spring form of the disease, the need for transfusions may be intermittent or ongoing, perhaps on a monthly basis and requiring desferoxamine treatment  Individuals with this more severe form of the disease may also have an increased chance of requiring removal of an enlarged and/or overactive spleen 
Anemia — A blood condition in which the level of hemoglobin or the number of red blood cells falls below normal values  Common symptoms include paleness, fatigue, and shortness of breath 
Bilirubin — A yellow pigment that is the end result of hemoglobin breakdown  This pigment is metabolized in the liver and excreted from the body through the bile  Bloodstream levels are normally low; however, extensive red cell destruction leads to excessive bilirubin formation and jaundice 
Bone marrow — A spongy tissue located in the hollow centers of certain bones, such as the skull and hip bones  Bone marrow is the site of blood cell generation 
Bone marrow transplantation — A medical procedure used to treat some diseases that arise from defective blood cell formation in the bone marrow  Healthy bone marrow is extracted from a donor to replace the marrow in an ailing individual  Proteins on the surface of bone marrow cells must be identical or very closely matched between a donor and the recipient 
Desferoxamine — The primary drug used in iron chelation therapy  It aids in counteracting the life-threatening buildup of iron in the body associated with long-term blood transfusions 
Globin — One of the component protein molecules found in hemoglobin  Normal adult hemoglobin has a pair each of alpha-globin and beta-globin molecules 
Heme — The iron-containing molecule in hemoglobin that serves as the site for oxygen binding 
Hemoglobin — Protein-iron compound in the blood that carries oxygen to the cells and carries carbon dioxide away from the cells 
Hemoglobin A — Normal adult hemoglobin that contains a heme molecule, two alpha-globin molecules, and two beta-globin molecules 
Hemoglobin electrophoresis — A laboratory test that separates molecules based on their size, shape, or electrical charge 
Hepatomegaly — An abnormally large liver 
HLA type — Refers to the unique set of proteins called human leukocyte antigens  These proteins are present on each individual's cell and allow the immune system to recognize 'self' from 'foreign'  HLA type is particularly important in organ and tissue transplantation 
Hydroxyurea — A drug that has been shown to induce production of fetal hemoglobin  Fetal hemoglobin has a pair of gamma-globin molecules in place of the typical beta-globins of adult hemoglobin  Higher-than-normal levels of fetal hemoglobin can ameliorate some of the symptoms of thalassemia 
Iron overload — A side effect of frequent blood transfusions in which the body accumulates abnormally high levels of iron  Iron deposits can form in organs, particularly the heart, and cause life-threatening damage 
Jaundice — Yellowing of the skin or eyes due to excess of bilirubin in the blood 
Mutation — A permanent change in the genetic material that may alter a trait or characteristic of an individual, or manifest as disease, and can be transmitted to offspring 
Placenta — The organ responsible for oxygen and nutrition exchange between a pregnant mother and her developing baby 
Red blood cell — Hemoglobin-containing blood cells that transport oxygen from the lungs to tissues  In the tissues, the red blood cells exchange their oxygen for carbon dioxide, which is brought back to the lungs to be exhaled 
Screening — Process through which carriers of a trait may be identified within a population 
Splenomegaly — Enlargement of the spleen 
Because alpha thalassemia major is most often a condition that is fatal in the prenatal or newborn period, treatment has previously been focused on identifying affected pregnancies in order to provide appropriate management to reduce potential maternal complications  Pregnancy termination provides one form of management  Increased prenatal surveillance and early treatment of maternal complications is an approach that is appropriate for mothers who wish to continue their pregnancy with the knowledge that the baby will most likely not survive  In recent years, there have been a handful of infants with this condition who have survived long-term  Most of these infants received experimental treatment including transfusions before birth, early delivery, and even bone marrow transplantation before birth, although the latter procedure has not yet been successful  For those infants that survive to delivery, there seems to be an increased risk of developmental problems and physical effects, particularly heart and genital malformations  Otherwise, their medical outlook is similar to a child with beta thalassemia major, with the important exception that ongoing, life-long blood transfusions begin right at birth 
As discussed above, the prognosis for individuals with the most serious types of thalassemia has improved drastically in the last several years following recent medical advances in transfusion, chemo-, and transplantation therapy  Advances continue and promise to improve the life expectancy and quality of life further for affected individuals 
"First Known Heart Attack Associated With Beta-thalassemia Major Reported " Heart Disease Weekly February 22, 2004: 10 
"Novel Alpha-thalassemia Mutations Identified " Hematology Week January 26, 2004: 19 
Children's Blood Foundation  333 East 38th St , Room 830, New York, NY 10016-2745  (212) 297-4336  cfg@nyh med cornell edu 
Cooley's Anemia Foundation, Inc  129-09 26th Ave  #203, Flushing, NY 11354  (800) 522-7222 or (718) 321-2873  http://www thalassemia org 
March of Dimes Birth Defects Foundation  1275 Mamaroneck Ave , White Plains, NY 10605  (888) 663-4637  resourcecenter@modimes org  http://www modimes org 
National Heart, Lung, and Blood Institute  PO Box 30105, Bethseda, MD 20824-0105  (301) 592-8573  nhlbiinfo@rover nhlbi nih gov  http://www nhlbi nih gov 
National Organization for Rare Disorders (NORD)  PO Box 8923, New Fairfield, CT 06812-8923  (203) 746-6518 or (800) 999-6673  Fax: (203) 746-6481  http://www rarediseases org 
Bojanowski J  "Alpha Thalassemia Major: The Possibility of Long-Term Survival " Pamphlet from the Northern California Comprehensive Thalassemia Center  (1999) 
Children's Hospital Oakland, Northern California Comprehensive Thalassemia Center website  http://www thalassemia com 
Cooley's Anemia Foundation, Inc  website  http://www thalassemia org/gohome html 
Joint Center for Sickle Cell and Thalassemic Disorders website  http://cancer mgh harvard edu/medOnc/sickle htm 
[thal″ah-se´me-ah]
a heterogeneous group of hereditary hemolytic anemias marked by a decreased rate of synthesis of one or more hemoglobin polypeptide chains, classified according to the chain involved (α, β, δ); the two major categories are α- and β-thalassemia 
α-thalassemia (alpha-thalassemia) that caused by diminished synthesis of alpha chains of hemoglobin  The homozygous form is incompatible with life, the stillborn infant displaying severe hydrops fetalis  The heterozygous form may be asymptomatic or marked by mild anemia 
β-thalassemia (beta-thalassemia) that caused by diminished synthesis of beta chains of hemoglobin  The homozygous form is called t  major and the heterozygous form is called t  minor 
thalassemia ma´jor the homozygous form of β-thalassemia, in which hemoglobin A is completely absent; it appears in the newborn period and is marked by hemolytic, hypochromic, microcytic anemia; hepatosplenomegaly; skeletal deformation; mongoloid facies; and cardiac enlargement 
thalassemia mi´nor the heterozygous form of β-thalassemia; it is usually asymptomatic, but there may be mild anemia 
sickle cell–thalassemia a hereditary anemia involving simultaneous heterozygosity for hemoglobin S and thalassemia 
thal·as·se·mi·a
, thalassanemia (thal'ă-sē'mē-ă, thă-las-ă-nē'mē-ă),
Any of a group of inherited disorders of hemoglobin metabolism in which there is impaired synthesis of one or more of the polypeptide chains of globin; several genetic types exist, and the corresponding clinical picture may vary from barely detectable hematologic abnormality to severe and fatal anemia 
[G  thalassa, the sea, + haima, blood]
/thal·as·se·mia/ (thal″ah-se´me-ah) a heterogeneous group of hereditary hemolytic anemias marked by a decreased rate of synthesis of one or more hemoglobin polypeptide chains, classified according to the chain involved (α, β, δ); the two major categories are α- and β-thalassemia 
α-thalassemia that caused by diminished synthesis of alpha chains of hemoglobin  The homozygous form is incompatible with life, the stillborn infant displaying severe hydrops fetalis  The heterozygous form may be asymptomatic or marked by mild anemia 
β-thalassemia that caused by diminished synthesis of beta chains of hemoglobin  The homozygous form is called t  major and the heterozygous form is called t  minor 
thalassemia ma´jor the homozygous form of &#x03B2;, in which hemoglobin A is completely absent; it appears in the newborn period and is marked by hemolytic, hypochromic, microcytic anemia, hepatosplenomegaly, skeletal deformation, mongoloid facies, and cardiac enlargement 
thalassemia mi´nor the heterozygous form of &#x03B2;, usually asymptomatic, although there is sometimes mild anemia 
(thăl′ə-sē′mē-ə)
An inherited form of anemia occurring chiefly among people of Mediterranean descent, caused by faulty synthesis of part of the hemoglobin molecule  Also called Mediterranean anemia 
thal′as·se′mic adj 
[thal′əsē′mē·ə]
Etymology: Gk, thalassa, sea, a + haima, without blood
production and hemolytic anemia characterized by microcytic, hypochromic red blood cells  Thalassemia is caused by inherited deficiency of alpha- or beta-globin synthesis  See also hemochromatosis, hemosiderosis 
Beta thalassemia, clinical thalassemia, Cooley's anemia, Mediterranean anemia, thalassemia major Hematology A group of genetic diseases by underproduction of hemoglobin due to mutations in the beta globin gene, which is more common in Mediterraneans Heredity Parents are carriers–heterozygotes; one in 4 children is homozygous for the mutation and thus has full-blown disease Clinical See Anemia  Cf Sickle cell anemia 
α-thalassemia
Hemoglobin Barts Hematology An inherited condition caused by a defect in the synthesis of the Hb α chain; Hb Barts hemoglobinopathy is characterized by the presence of 4 gamma chains; it is more common in southeast Asians; the most severe form of alpha thalassemia causes stillbirth due to hydrops fetalis Heredity Parents are carriers–heterozygotes; one in 4 children is homozygous for the mutation and thus has full-blown disease Clinical Pallor, fatiguability, FTT, fever, infections, diarrhea Management Transfusions
Thalassemia major Hematology A hemoglobinopathy caused by a defect in the synthesis of Hb β chain Clinical Pallor, fatigability, FTT, fever due to infections, diarrhea, bone deformities, hepatosplenomegaly Management Transfusions, but iron overload can damage the heart, liver, and endocrine systems, ergo iron chelation–early use of deferiprone, deferoxamine ↓ transfusion-related iron overload and may protect against DM, cardiac disease, early death
δ-thalassemia
Hematology A condition characterized by a defect of Hb A2–α2δ2; because Hb A2 comprises only 3% of the circulating Hb, even its complete absence; δ-thalassemia has little clinical or hematologic impact
γ-thalassemia
Hematology A condition characterized by a defect of gamma–γ Hb chains found in Hb F–α2γ2; because Hb F is present primarily in the fetus and newborns, it is rarely seen outside of the neonatal period, but may cause transient neonatal hemolytic anemia 
, thalassanemia (thal'ă-sē'mē-ă, -ă-să-nē'mē-ă)
Any of a group of inherited disorders of hemoglobin metabolism in which there is impaired synthesis of one or more of the polypeptide chains of globin; several genetic types exist, and the corresponding clinical picture may vary from barely detectable hematologic abnormality to severe and fatal anemia  People of Mediterranean, extraction are more often affected than others by this type of anemia 
Synonym(s): thalassaemia, thalassanaemia 
Any of a group of inherited disorders of hemoglobin metabolism with impaired synthesis of one or more polypeptide chains of globin; several genetic types exist 
<a href="https://medical-dictionary thefreedictionary com/Thalassaemia+minor">thalassemia</a>
Barts hemoglobin
beta hemoglobinopathy
beta-delta thalassemia
beta-thalassaemia
Bite Cell
black gallstone
I know of a couple, totally unrelated and unbeknownst to them, who are silent carriers of Thalassaemia minor 
Pakistan: Genetic factor: All in the genes
But, unfortunately, when one person with thalassaemia minor carrier happens to marry another with the same diagnosis, there is a strong possibility that their child would be thalassaemia major, as happened in the case of Taneja 
' My life depends upon a monthly blood transfusion '
0] thalassaemia demonstrates variable severity, ranging from a condition similar to [beta] thalassaemia minor to something approaching thalassaemia major 
A retrospective review of homozygous haemoglobin E patients
Thal, Alan P 
thalame
thalamencephalic
thalamencephalon
thalamic
thalamic fasciculus
thalamic nucleus
thalamic pain syndrome
thalamic peduncle
thalamic radiation
thalamo-
thalamocoele
thalamocortical
thalamocortical fibers
thalamogeniculate artery
thalamolenticular
thalamoperforating artery
thalamostriate radiation
thalamotuberal artery
Thalassaemia minor
thalassaemiaor Cooley's disease
thalassemic facies
thalasso-
Thalassobacter
Thalassobacter utilis
thalassoplankton
thalassoposia
thalidomide neuropathy
Thalidomider
thallium poisoning
Thalarctos
THALAS
Thalasaemia
Thalassaemia Association of Malaysia
thalassaemia major
Thalassaemias
thalassaemic
thalassanaemia
Thalassemia Action Group
Thalassemia Clinical Research Network
thalassemia syndrome



ground_truth: The paper was published on 7 March 2023.

prompt_front: Now, answer the following question based on the text below, only give me the answer and do not output any other words.

Question: Can someone sell or modify the Agency Spotter Content?

Read the following text and answer briefly.

Context 2: 
(b) Agency Spotter may also offer the Services through applications built using Agency Spotter’s platform (“Agency Spotter Applications”), including smart phone applications, “Share” and other similar buttons and other interactive plugins distributed on websites across the Internet  Agency Spotter Applications are distinct from Third-Party Materials and applications address in Section 14(a), above  If you use an Agency Spotter application or interact with a website that has deployed a plugin, you agree that information about you and your use of the Services, including, but not limited to, your device, your mobile carrier, your internet access provider, your physical location, and/or web pages containing Agency Spotter plugins that load in your browser may be communicated to us  You acknowledge that you are responsible for all charges and necessary permissions related to accessing Agency Spotter through your mobile access provider  You should therefore check with your provider to find out if the Services are available and the terms for these services for your specific mobile devices  Finally, by using any downloadable application to enable your use of the Services, you are explicitly confirming your acceptance of the terms of the End User License Agreement associated with the application provided at download or installation, or as may be updated from time to time 
16  International Use  Agency Spotter makes no representation that materials on this site are appropriate or available for use in locations outside the United States, and accessing them from territories where their contents are illegal is prohibited  Those who choose to access this site from other locations do so on their own initiative and are responsible for compliance with local laws 
17  Dispute Resolution  These Terms and any claim, cause of action or dispute (“claim”) arising out of or related to these Terms shall be governed by the laws of the State of Georgia, regardless of your country of origin or where you access Agency Spotter, and notwithstanding any conflicts of law principles and the United Nations Convention for the International Sale of Goods  You and Agency Spotter agree that all claims arising out of or related to these Terms must be resolved exclusively by a state or federal court located in Fulton County, Georgia, except as otherwise mutually agreed in writing by the parties or as described in the Arbitration option in Section 16(b), below  You and Agency Spotter agree to submit to the personal jurisdiction of the courts located within Fulton County, Georgia, for the purpose of litigating all such claims  Notwithstanding the foregoing, you agree that Agency Spotter shall still be allowed to seek injunctive remedies (or an equivalent type of urgent legal relief) in any jurisdiction 
18  Arbitration  You agree that any dispute, claim or controversy arising hereunder or relating in any way to the Terms, shall be settled by binding arbitration in Fulton County, Georgia, in accordance with the commercial arbitration rules of Judicial Arbitration and Mediation Services (“JAMS”)  The arbitrator shall issue a written decision specifying the basis for the award made  The party filing a claim or counterclaim in the arbitration proceeding shall pay the deposit(s) determined by JAMS with respect to such claim or counterclaim  All other costs associated with the arbitration and imposed by JAMS shall be paid as determined by the arbitrator(s) and, in absence of such determination, equally by each party to the arbitration  In addition, unless the arbitrator awards payment of reasonable attorney and other fees to a party, each party to the arbitration shall be responsible for its own attorneys’ fees and other professional fees incurred in connection with the arbitration  Determinations of the arbitrator will be final and binding upon the parties to the arbitration, and judgment upon the award rendered by the arbitrator may be entered in any court having jurisdiction, or application may be made to such court for a judicial acceptance of the award and an order of enforcement, as the case may be  The arbitrator shall apply the substantive law of the State of Georgia, without giving effect to its conflict of laws rules 
19  Export Control  You agree to comply with all relevant export laws and regulations, including, but not limited to, the U S  Export Administration Regulations and Executive Orders (“Export Controls”)  You warrant that you are not a person, company or destination restricted or prohibited by Export Controls (“Restricted Person”)  You will not, directly or indirectly, export, re-export, divert, or transfer the Site or Service or any related software, any portion thereof or any materials, items or technology relating to Agency Spotter’s business or related technical data or any direct product thereof to any Restricted Person, or otherwise to any end user and without obtaining the required authorizations from the appropriate governmental entities 
(a) These Terms will continue until terminated in accordance with this Section 
(b) You may cancel your legal agreement with Agency Spotter at any time by (i) notifying Agency Spotter in writing, (ii) ceasing to use the Services, and (iii) closing your accounts for all of the Services which you use, if we have made this option available to you  Your cancellation of the Services will not alter your obligation to pay all charges incurred prior to your effective date of termination 
Agency Spotter may terminate its legal agreement with you if, (i) you have breached any provision of the Terms (or have acted in manner which clearly shows that you do not intend to, or are unable to comply with the provisions of the Terms), or (ii) Agency Spotter is required to do so by law (for example, where the provision of the Services to you is, or becomes, unlawful), or (iii) Agency Spotter is transitioning to no longer providing the Services to users in the country in which you are resident or from which you use the service, or (iv) the provision of the Services to you by Agency Spotter is, in Agency Spotters’ opinion, no longer commercially viable 
(c) The terms provided in Sections 2, 3, 6, 11, 12, 13, 14, 17, 19, 20, 21 and 22 of these Terms shall survive any termination of these Terms 
21  Independent Contractors  The parties are and intend to be independent contractors with respect to the Services contemplated hereunder  You agree that neither you nor any of your employees or contractors shall be considered as having an employee status with Agency Spotter  No form of joint employer, joint venture, partnership, or similar relationship between the parties is intended or hereby created 
22  Assignment and Delegation  You may not assign or delegate any rights or obligations under these Terms  Any purported assignment or delegation shall be ineffective  We may freely assign or delegate all rights and obligations under these Terms, fully or partially, without notice to you  We may also substitute, by way of unilateral novation, effective upon notice to you, Agency Spotter Inc  for any third party that assumes our rights and obligations under these Terms 
The personally identifiable information we collect from you allows us to provide you with the Services and to enable users to navigate and enjoy using the Site  We will also use your personally identifiable information to develop, improve and advertise the Site and Services  We may also use your personally identifiable information for internal purposes such as auditing, data analysis and research to improve our Services and customer communications  We do not rent, sell or otherwise provide your personally identifiable information to third parties without your consent, except as described in this policy or as required by law 
When you register with us through the Site or Services and become a Registered User, or when you wish to contact another Registered User, we will ask you for personally identifiable information  This refers to information about you that can be used to contact or identify you (“Personally Identifiable Information“)  Personally Identifiable Information includes, but is not limited to, your name, phone numbers, email address, home postal address, business address, social media user names, employer/affiliated organization, reasons for accessing the Site, and intended usage of requested information, but does not include your credit card number or billing information  We may also use your email address or phone number (if provided by you) to contact you regarding changes to the Services; system maintenance and outage issues; account issues; or otherwise to troubleshoot problems  In order to process some of your transactions through the Site and Services, we may also ask for your credit card number and other billing information (“Billing Information“; and, together with Personally Identifiable Information, “Personal Information“) 
Information you provide to us also includes your account profile and your contributions to discussion groups and community features Agency Spotter may offer  Do not upload or insert any information to or into the Site or Services that you do not want to be shared or used in the manner described in this section 
In addition, when you use the Site, our servers automatically record certain information that your web browser sends whenever you visit any website  These server logs may include information such as your web request, Internet Protocol address, browser type, browser language, referring/exit pages and URLs, platform type, number of clicks, domain names, landing pages, pages viewed and the order of those pages, the amount of time spent on particular pages, the date and time of your request, and one or more cookies that may uniquely identify your browser 
Information from third party services and other websites 
Do not upload or insert any information to or into the Site or Services that you do not want to be shared or used in the manner described in this section 
Advertisements  Advertisers who present ads on the Site may use technological methods to measure the effectiveness of their ads and to personalize advertising content  You may use your browser cookie settings to limit or prevent the placement of cookies by advertising networks  Agency Spotter does not share personally identifiable information with advertisers unless we get your permission 
Links  When you click on links on Agency Spotter you may leave our site  We are not responsible for the privacy practices of other sites, and we encourage you to read their privacy statements 
If we are requested to disclose your information to a government agency or official, we will do so if we believe in good faith, after considering your privacy interests and other relevant factors, that such disclosure is necessary to: (i) conform to legal requirements or comply with a legal process with which we are involved; (ii) protect our rights or property or the rights or property of our affiliated companies; (iii) prevent a crime or protect national security; or (iv) protect the personal safety of Site users or the public  Because Agency Spotter is a United States limited liability company and information collected on our Site is stored in whole or in part in the United States, your information may be subject to U S  law 
We also reserve the right to disclose Personally Identifiable Information and/or other information about users that Agency Spotter believes, in good faith, is appropriate or necessary to enforce our agreements, take precautions against liability, investigate and defend itself against ay third-party claims or allegations, assist government enforcement agencies, protect the security or integrity of our Site or Services, and protect the rights, property or personal safety of Agency Spotter, our users and others 
Cookies allow us to (i) manage, present and keep track of temporary information, such as data you upload onto the Site for use with the Services; (ii) register you as a Registered User on the Site or in other various programs associated with the Site; (iii) remember you when you log in to the places on the Site that require you to be a Registered User of the Site; (iv) help us understand the size of our audience and traffic patterns; (v) collect and record information about what you viewed on the Site; and (vi) deliver specific information to you based on your interests 
When you access the Site, the Site automatically collects certain non-personally identifiable information through the use of electronic images known as web beacons (sometimes called single-pixel gifs) and log files  Such information may include your IP address, browser type, the date, time and duration of your access and usage of the Site and whether you opened emails You received from us 
This information is collected for all visits to the Site and then analyzed in the aggregate  This information is useful for, among other things, tracking the performance of our online advertising, such as online banner ads, and determining where to place future advertising on other websites 
Editing your profile  You may review and change or remove your personal information or the settings for your Agency Spotter account at any time by going to your account profile  You can edit your name, email address, password and other account information here  Please be aware that even after your request for a change is processed, Agency Spotter may, for a time, retain residual information about you in its backup and/or archival copies of its database 
Deactivating or deleting your account  If you want to stop using your account you may deactivate it or delete it  When you deactivate an account, no user will be able to see it, but it will not be deleted  We save your profile information in case you later decide to reactivate your account  Many users deactivate their accounts for temporary reasons and in doing so are asking us to maintain their information until they return to Agency Spotter  You will still have the ability to reactivate your account and restore your profile in its entirety  When you delete an account, it is permanently deleted from Agency Spotter  You should only delete your account if you are certain you never want to reactivate it  You may deactivate your account or delete your account within your account profile 
Limitations on removal  Even after you remove information from your profile or delete your account, copies of that information may remain viewable elsewhere to the extent it has been shared with others, it was otherwise distributed pursuant to your privacy settings, or it was copied or stored by other users  However, your name will no longer be associated with that information on Agency Spotter  (For example, if you post something to another user’s or Agency’s profile or Agency’s portfolio and then you delete your account, that post may remain, but be attributed to an “Anonymous Agency Spotter User ”) Additionally, we may retain certain information to prevent identity theft and other misconduct even if deletion has been requested  If you have given third party applications or websites access to your information, they may retain your information to the extent permitted under their terms of service or privacy policies  But they will no longer be able to access the information through our platform after you disconnect from them 
Default Settings  Because the mission of Agency Spotter is to connect businesses and agencies, enabling them to save time, be more productive and successful, we have established what we believe are reasonable default settings that we have found most agencies and professionals desire  Because Registered Users may use and interact with Agency Spotter in a variety of ways, and because those uses may change over time, we designed our settings to provide our users control over the information they share  We encourage our Registered Users to review their account settings and adjust them in accordance with their preferences 
Risks inherent in sharing information  Please be aware that no security measures are perfect or impenetrable, and no method of transmission over the Internet, or method of electronic storage, is 100% secure  We cannot control the actions of other users with whom you share your information  We cannot guarantee that only authorized persons will view your information  We cannot ensure that information you share on the Site or through the Services will not become publicly available  We are not responsible for third party circumvention of any privacy or security measures on Agency Spotter  You can reduce these risks by using common sense security practices such as choosing a strong password, using different passwords for different services, and using up to date antivirus software 
If you receive an unsolicited email that appears to be from us or one of our members that requests personal information (such as your credit card, login, or password), or that asks you to verify or confirm your account or other personal information by clicking on a link, that email was likely to have been sent by someone trying to unlawfully obtain your information, sometimes referred to as a “phisher” or “spoofer ” We do not ask for this type of information in an email  Do not provide the information or click on the link  Please contact us at [email protected] if you get an email like this  Notwithstanding the foregoing, after your initial account setup, we may send an email to your registered account address solely to confirm that we have the correct, valid email address for your account 
If You have concerns about your privacy in connection with your use of the Site or any general questions related thereto, please tell us by emailing us at [email protected] We will make every reasonable effort to address your concerns 
Thank You for supporting websites, such as ours  We take your privacy seriously by implementing written privacy policies, such as this one 



ground_truth: No.

prompt_front: Now, answer the following question based on the text below, only give me the answer and do not output any other words.

Question: What are the symptoms of alpha thalassemia major?

Read the following text and answer briefly.

Context 4:  
No differences to the results presented here were found  
Initial perturbations on the particle density field are given by Eq ~\eqref{eq:inita},
where the perturbation amplitude $\triangle n/n_0$ was chosen between $10^{-3}$ and $20$ for blobs and $-10^0$ and $ -10^{-3}$ for depletions  
Due to computational reasons we show results only for $\triangle n/n_0\leq 20$  


For compressible flows we consider two different cases $\ell/R_0 = 10^{-2}$ and
$\ell /R_0 = 10^{-3}$  
 For incompressible flows Eq ~\eqref{eq:generala} and \eqref{eq:vorticity}
 can be normalized such that the blob radius is absent from the equations~\cite{Ott1978, Kube2012}  
 The simulations of incompressible flows can thus be used for both sizes  
The numerical code as well as input parameters and output data can be found 
in the supplemental dataset to this contribution~\cite{Data2017} 

\begin{figure}[htb]
    \includegraphics[width=\columnwidth]{com_blobs}
    \caption{
      The maximum radial COM velocities of blobs for compressible and incompressible flows are shown  
      The continuous lines show Eq ~\eqref{eq:vmax_theo} while the 
      dashed line shows the square root scaling Eq ~\eqref{eq:sqrt} with 
      $\mathcal Q = 0 32$ and $\mathcal R=0 85$ 
    }
    \label{fig:com_blobs}
\end{figure}
In Fig ~\ref{fig:com_blobs} we plot the maximum COM velocity for blobs 
with and without drift compression 
For incompressible flows blobs follow the square root scaling almost 
perfectly  Only at very large amplitudes velocities are slightly below
the predicted values  
For small amplitudes we observe that the compressible blobs follow
a linear scaling  When the amplitudes increase there is a transition to the
square root scaling at around $\triangle n/n_0 \simeq 0 5$ for 
$\ell/R_0=10^{-2}$ and $\triangle n/n_0 \simeq 0 05$ for $\ell/R_0=10^{-3}$, which is consistent with Eq ~\eqref{eq:vmax_theo} and Reference~\cite{Kube2016}  
In the transition regions the simulated velocities are slightly larger than the predicted ones from Eq ~\eqref{eq:vmax_theo} 
Beyond these amplitudes
the velocities of compressible and incompressible blobs align  

\begin{figure}[htb]
    \includegraphics[width=\columnwidth]{com_holes}
    \caption{
      The maximum radial COM velocities of depletions for compressible and incompressible flows are shown  
      The continuous lines show Eq ~\eqref{eq:vmax_theo} while the 
      dashed line shows the square root scaling Eq ~\eqref{eq:sqrt} with 
      $\mathcal Q = 0 32$ and $\mathcal R=0 85$ 
      Note that small amplitudes are on the right and amplitudes close to unity are on the left side 
  }
    \label{fig:com_depletions}
\end{figure}
In Fig ~\ref{fig:com_depletions} we show the maximum radial COM velocity 
for depletions instead of blobs 
For relative amplitudes below $|\triangle n|/n_0 \simeq 0 5$ (right of unity in the plot) the velocities
coincide with the corresponding blob velocities in Fig ~\ref{fig:com_blobs}  
 For amplitudes larger than $|\triangle n|/n_0\simeq 0 5$ the 
velocities follow the square root scaling 
We observe that for plasma depletions beyond $90$ percent the velocities 
in both systems reach a constant value that is very well predicted by the
square root scaling  

\begin{figure}[htb]
    \includegraphics[width=\columnwidth]{acc_blobs}
    \caption{
      Average acceleration of blobs for compressible and incompressible flows are shown 
      The continuous line shows the acceleration in Eq ~\eqref{eq:acceleration} 
      with $\mathcal Q=0 32$
      while the dashed line is a linear reference line, which corresponds to the Boussinesq approximation  
  }
    \label{fig:acc_blobs}
\end{figure}
In Fig ~\ref{fig:acc_blobs} we show the average acceleration of blobs 
for compressible and incompressible flows computed
by dividing the maximum velocity $\max V$ by the time  
to reach this velocity $t_{\max V}$  
We compare the simulation results
to the theoretical predictions Eq ~\eqref{eq:acceleration} of our model with and without inertia  
The results of the compressible and incompressible systems coincide and fit very
well to our theoretical values  
For amplitudes larger than unity the acceleration deviates significantly from the prediction with Boussinesq approximation 

\begin{figure}[htb]
    \includegraphics[width=\columnwidth]{acc_holes}
    \caption{
      Average acceleration of depletions for compressible and incompressible flows are shown 
      The continuous line shows the acceleration in Eq ~\eqref{eq:acceleration} 
      with $\mathcal Q=0 32$
      while the dashed line is a linear reference line, which corresponds to the Boussinesq approximation  
    }
    \label{fig:acc_depletions}
\end{figure}
In Fig ~\ref{fig:acc_depletions} we show the simulated acceleration of depletions in the
compressible and the incompressible systems  We compare the simulation results
to the theoretical predictions Eq ~\eqref{eq:acceleration} of our model with and without inertia 
Deviations from our theoretical prediction Eq ~\eqref{eq:acceleration} are visible for amplitudes smaller than $\triangle n/n_0 \simeq -0 5$ (left of unity in the plot)  The relative deviations are small at around $20$ percent  
As in Fig ~\ref{fig:com_depletions} the acceleration reaches a constant values
for plasma depletions of more than $90$ percent 
Comparing Fig ~\ref{fig:acc_depletions} to Fig ~\ref{fig:acc_blobs} the asymmetry between blobs and depletions becomes 
apparent  While the acceleration of blobs is reduced for large 
amplitudes compared to a linear dependence the acceleration 
of depletions is increased  In the language of our simple buoyancy 
model the inertia of depletions is reduced but increased for blobs  



In conclusion  
  we discuss the dynamics of seeded blobs and depletions in a 
  compressible and an incompressible system 
  With only two fit parameters our theoretical results reproduce the 
  numerical COM velocities and accelerations over five orders of magnitude 
  We derive the amplitude dependence of the acceleration of blobs and depletions from 
  the conservation laws of our systems in Eq ~\eqref{eq:acceleration}  
  From the same inequality a linear regime is derived in the compressible system for 
  ratios of amplitudes to sizes smaller than a critical value 
   In this regime 
  the blob and depletion velocity depends linearly on the initial amplitude and 
  is independent of size  The regime is absent from the system with incompressible flows 
  Our theoretical results are verified by numerical simulations for all 
  amplitudes that are relevant in magnetic fusion devices 
  Finally, we suggest a new empirical blob model that captures the detailed dynamics of more complicated models  
  The Boussinesq approximation is clarified as the absence of inertia and a thus altered acceleration of blobs and depletions 
  The maximum blob velocity is not altered by the Boussinesq approximation 

The authors were supported with financial subvention from the Research Council of Norway under grant
240510/F20  M W  and M H  were supported by the Austrian Science Fund (FWF) Y398   The computational
results presented have been achieved in part using the Vienna Scientific Cluster (VSC)  Part of this work was performed on the Abel Cluster, owned by the University of Oslo and the Norwegian metacenter
for High Performance Computing (NOTUR), and operated by the Department for Research Computing at USIT,
the University of Oslo IT-department 
This work has been carried out within the framework of the EUROfusion Consortium and has received funding from the Euratom research and training programme 2014-2018 under grant agreement No 633053  The views and opinions expressed herein do not necessarily reflect those of the European Commission 



ground_truth: Severe anemia that begins even before birth.