Ireneusz Grabowski

So Hirata

Victor F Lotrich

Ab initio DFT -the seamless connection between WFT and DFT

Keywords: optimized effective potential method, electron correlation, density functional theory optimized effective potential method, electron correlation, density functional theory, ab initio DFT

published or not. The documents may come

Introduction

The most powerful and popular contemporary many-electron theory methods used for calculating the electronic structure of atoms, molecules, and solids, originate from two main categories of quantum mechanical theories: the traditional ab initio theories directly grounded on the concept of the wave function (Wave Function Theories -WFT) and the density functional theory (DFT) essentially based on the concept that the electron density is fundamental. WFT provides methods in which we are able to control and predict the accuracy of the results. There is a the Taking into account n-fold excitations for n electrons defines the Full CC method which is equal to the FCI (CI -configuration interaction) method and is the best possible solution for the given basis set used in the calculations. Unfortunately as the inclusion of electron correlation effects is systematically improved the WFT methods become extremely expensive for larger systems, so, we still are limited to the systems with only few dozen of atoms. The computationally much cheaper DFT methods are the most widely used electronic structure methods and are routinely used for calculating ground state and dynamical properties of many-electron systems. Currently DFT seems to be the only practical method which can perform calculations on systems of hundreds and thousands of electrons. The huge reduction of the computational cost is due to the single-particle effective Hamiltonian in the Kohn-Sham [1,2](KS) implementation of DFT, compared to the two-particle

Hamiltonian in most WFT methods. In this method all unknown information is contained in the exchange-correlation (xc) functional E xc , which must be approximated in any practical implementation. Unfortunately DFT establishes the existence of E xc but does not provide the energy functional or even a prescription how to approximate it. Existing standard density-dependent approximations to the xc functionals, e.g. local-density LDA [2], generalized gradient approximations GGA [3][4][5], or hybrid functionals [6], despite their great popularity and success, suffer for many fundamental problems like lack of strict cancellation of self-interaction energies between Coulomb and exchange energies, incorrect asymptotic behaviour of the KS xc-potentials [7], missing the derivative discontinuity of the energy, qualitatively incorrect correlation potentials [8], and lack of the possibility of systematic improvement of existing functionals. KS-DFT cannot describe van der Waals interactions, there are problems with computation of response properties of molecular systems (polarization, excitation, etc.) , also activation barrier heights for a variety of chemical reactions are predicted incorrectly [9].

On one side we have excellent but unfortunately very expensive methods (WFT) which cannot routinely be applied to very large systems. On the other side KS DFT methods can be, but we have little confidence in the reliability of the results.

The main problems are not fundamental rather "technical" problems -approximations of the xc functionals and potentials in KS DFT. Since the beginning of KS DFT an enormous amount of effort has been invested in the search for realistic representations of the unknown exchange and correlation functionals (see e.g. the discussion in Ref. [START_REF] Perdew | Prescription for the design and selection of density functional approximations: More constraint satisfaction with fewer fitsJ[END_REF]), adding new rungs to the Jacob's Ladder [START_REF] Perdew | s Ladder of Density Functional Approximations for the Exchange-Correlation Energy[END_REF], and adding more and more empirical adjustable parameters in new xc functionals. The new xc functionals usually only correct existing ones and only partially solve some of their problems but do not really improve the reliability of the DFT methods.

So, the important questions are: can we make DFT methods as predictive as e.g. coupled cluster theory? Can we find a method capable of rigorously defining an xc functional and potential in the context of KS theory? And how can we effectively use our experience in WFT to help DFT to be more reliable?

One of the possible solutions to aforementioned problems is by exploiting orbitaldependent functionals and potentials in KS DFT. This step, from explicitly densitydependent xc functionals, to orbital-dependent ones can be viewed in some sense as analogous to the transition from the Thomas-Fermi equation to the KS equations. Therefore the KS DFT with orbital-dependent xc functionals can be called a third generation of DFT [START_REF] Engel | Orbital-dependent functional for the Exchange-Correlation Energy: A Third Generation of DFT[END_REF]. By using orbitals to define the xc orbital-dependent functionals we have much more flexibility in the construction of the functional.

It presents the possibility for using, almost directly, orbital-dependent expressions for the xc energy functionals from well known and established WFT methods. Hartree-Fock (HF) exchange energy functional

E OEP x [{φ p }] = - 1 2 N i,j (ij|ji), (1)
where two-electron integrals are defined as:

(pq|rs) = φ * p (r)φ q (r) 1 |r -r ′ | φ * r (r ′ )φ s (r ′ )drdr ′ . ( 2
)
and φ p (r) are the KS orbitals, which are the self-consistent solutions of the standard KS equation. Here and in the following we use the convention that i,j,k,l label occupied orbitals, a,b,c,d label virtual orbitals, and p,q,r,s label either. With this choice for the exchange functional there is no self interaction error in KS DFT, and we have precisely defined the dominant part of the xc energy functional. Unfortunately the corresponding KS exchange potential, which is by definition the functional derivative of E x with respect to the electron density, cannot be obtained directly as in the case of density-dependent functionals. Nonetheless the orbitaldependent exchange-only (x-only) approximation combined with the KS principles most naturally leads to the optimized effective potential (OEP) method of Talman and Shadwick [START_REF] Talman | [END_REF] following the original suggestion of Sharp and Horton [14]. In the KS DFT context, OEP is a rigorous exchange-only method in DFT akin to the HF method in ab initio WFT and it has been implemented using various modern algorithms for the ground state [15][16][17][18][19][20][21][22], and even for excited states [23].

Extensions of the x-only OEP to the correlation problem are not straightforward and have been the subject of substantial interest since the development of the xonly OEP method [18,[24][25][26][27]. The first fully self-consistent inclusion of correlation effects in the DFT OEP procedure used the second-order many-body perturbation theory (MBPT(2)) energy functional (OEP2-KS method [28]), where numerical results on a few atoms supported the methodology. Numerical results for a set of atoms and molecules, was presented by us in 2002 [28]. The proposed correlation potential has the correct overall shape as compared to quantum Monte-Carlo re- sults, especially for He-isoelectronic series, and is much better than the potentials obtained from the standard DFT calculations, which are frequently qualitatively wrong. However, we have also observed that, for larger systems, the depth of the correlation potentials may be significantly overestimated and correlation energies too negative. We have also found much slower convergence, or even divergence, of the iterative solutions of the self-consistent KS-OEP equation for the orbitals and potential [29] of the Be atom, where the quasi-degeneracy of the (1s) 2 (2s) 2 and (1s) 2 (2p) 2 configurations is present [30]. This baffling behaviour of the OEP2-KS method caused much confusion. Misunderstandings and failures to describe and solve this problem (see Refs. [31][32][33]), ending with the very pessimistic, but incorrect conclusion [31] " This failure basically excludes PT based orbital functionals for practical applications in DFT". Since then we have found [29] that the cause of this aforementioned problem of OEP2-KS is due to the choice of the zerothorder Hamiltonian H 0 , which, in this method, is the sum of eigenvalues of the KS equation, and which is not optimal although it is also made in Görling-Levy perturbation theory (GLPT) [25,34], and it appears to be a natural choice from the KS DFT point of view. A solution of this and other problems has been proposed by us [29] and consists of making a different choice of the unperturbed Hamiltonian to define the second-order OEP correlation functionals and potentials. Also in that paper [29], we have rederived the correlated OEP equation from a more general perspective, starting with the density condition [35] in conjunction with the CC energy functional. Defined this way the OEP exchange-only functional and OEP2-KS, OEP2-sc, OEP-ccpt2 [36] etc., correlation functionals constitute ab initio DFT a hierarchy of systematic approximations [37][38][39][40][41] converging to the exact solution of the Schrödinger equation in the correlation and basis set limit, just as does ab initio WFT. Independently other interesting algorithms which include correlation effects in the OEP method were proposed [42][43][44][45][46] which extend the applicability, and theoretical foundations of orbital-dependent functionals and potentials in DFT. This article is dedicated to a survey of the work done at QTP mainly on correlated OEP focusing on challenges, problems and applications. In the following we present a short theory of correlated OEP, a few important results and conclusions.

F

F

2. Orbital-dependent functionals in KS DFT, Optimized Effective Potential Method and ab initio DFT -theory and numerical results

Theory and implementation

In the KS implementation of DFT, the computed electron density, ρ(r)

= N i=1 |φ i (r)| 2
, is formed from the occupied KS orbitals φ i (r) which are the selfconsistent solutions of the KS equation [2]:

- 1 2 ∇ 2 + v s [ρ](r) φ p (r) = ε p φ p (r), (3)
with the local effective KS potential

v s [ρ](r) = v(r) + dr ′ ρ(r ′ ) |r -r ′ | + V xc [ρ](r), (4)
where

V xc [ρ](r) = δE xc [ρ] δρ(r) (5)
is the local xc potential formally defined as the functional derivative of the xc energy with respect to the electron density ρ(r). In the case of orbital-dependent xc functionals in KS DFT E xc [{φ p }] the common route to the obtain orbital-dependent form of xc OEP potentials is by using the chain rule for functional derivatives and first order perturbation theory [18,19,28,35]. But this seems not to be a very effective route to obtain explicit expressions for xc potentials, especially in the case when correlation is included and causes problems with extending correlation to higher orders effects.

In the following we will utilize the ideas of Bartlett et al. [29], where the density condition together with the CC methodology is employed to derive orbital- correlated OEP methods in an effective way. Thus, for the sake of completeness, we only briefly recall the basic ideas and notation employed, skipping the detailed diagrammatic and algebraic derivation [29,36,37,39] and focusing on the main steps and basics ideas of ab initio DFT.

By construction, the KS density is an exact density. This means that any corrections to the converged KS density introduced by changes in φ i (r) have to vanish [29,35,42];

ρ(r) = ρ KS (r) + δρ KS (r), (6)
and

δρ KS (r) = 0. ( 7
)
We use this condition to define a local exchange-correlation potential, instead of following the alternative derivative definition of the exchange-correlation potential V xc Eq.( 5). The density correction δρ KS (r) can be written using density matrix correction ∆γ qp from the CC theory [START_REF] Bartlett | Coupled-cluster Theory: An Overview of Recent Developments[END_REF] δρ KS (r) = p,q ϕ q (r)∆γ qp ϕ * p (r),

where

∆γ qp = 0|e T † {p † q}e T |0 / 0|e T † e T |0 = 0|[e T † {p † q}e T ] C |0 , ( 9
)
and T is the cluster operator [START_REF] Bartlett | Coupled-cluster Theory: An Overview of Recent Developments[END_REF][START_REF] Bartlett | Coupled-Cluster Approach to Molecular Structure and Spectra: A Step Toward Predictive Quantum ChemistryJ[END_REF][START_REF] Paldus | Coupled-cluster Theory: An Overview of Recent Developments[END_REF].

We separate the total Hamiltonian

H = i h(i) + i<j 1/r ij (10)
into the zeroth-order H 0 and a perturbation V where

H = H 0 + V, (11)
H 0 = i [ h(i) + u(i)], (12)
V = i<j 1/r ij - i u(i), (13)
and u = J + V xc is the one-particle potential which we determine in our approach. In the above, h(i) is the sum of the kinetic energy operator and the external potential and J is the Coulomb potential. Then we can expand the density corrections, Eq.( 8), from CC theory in orders of the perturbation V .

The density condition requirement at first order, δρ (1) (r) = 0, leads to the x-only OEP (OEPx) equation which defines local exchange potential V x [START_REF] Talman | [END_REF]29] by

a,i ϕ a (r 1 )ϕ * i (r 1 )[ a| K + V x |i /(ǫ i -ǫ a )] = 0, ( 14
)
and K is the non-local Hartree-Fock (HF) exchange potential. This OEP exchange potential V OEP

x corresponds to the x-only OEP functional E OEP

x , which has the form of usual HF exchange energy functional Eq.( 1) in terms of KS orbitals . In matrix form, as shown elsewhere [29,[START_REF] Ivanov | [END_REF] the x-only OEP equation which would define V X for a particular iteration can be written, XV

X = Y (1) (1)
where X is the matrix (auxiliary basis) representation of the density response function [19,28] To include correlation effects in ab initio DFT and introduce the correlation potential, we have to go to higher orders in perturbation theory. At the nextsecond-order, the density condition requires that the second-order correction to the KS density must vanish: δρ (2) (r) = 0. This directly results in the orbital-dependent OEP equations for the second-order correlation potential -the detailed derivation and the explicit form of the correlated OEP equations can be found elsewhere. Molecular Physics 9 [29,37,39] In a compact matrix form the relevant OEP equations become

XV (1+2) XC = Y (1) + Y (2) ( 16
)
where Y (2) arises from the correlation functional, MBPT2, and we understand

V (1+2) XC
to mean the combined potential through second order, which would then be used in an iterative, self-consistent scheme.

As was indicated elsewhere [29,36,40], the partitioning of the total Hamiltonian plays a prime role in determining the performance of the second-order correlated OEP functional. The zeroth-order Hamiltonian can be chosen in different ways.

The natural choice of H 0 in OEP DFT would seem to be a simple sum of KS oneparticle Hamiltonians,

H KS 0 = i [h(i) + v s (i)] = p ε KS p {p † p}.
This is the choice made by Görling-Levy [18], by Jiang and Engel [32], by Mori-Sanchez, et al. [31],

and by Rohr, et al. [33] and also by us: Grabowski et al. [28] in our first attempt to solve the OEP correlation problem (OEP2-KS method). However, as indicated above, this choice is a very poor one, which causes many problems in OEP2-KS calculations, and is not the one used to define ab initio DFT. [29,36,37,41,46] By removing the large diagonal contribution p| K + V xc |p from the perturbation and include it in the new H 0 .

H = p [ε KS p -p| K + V xc |p ]{p † p} H 0 = p f pp {p † p} - p =q p| K+ V xc |q {p † q}+ 1 4 p,q,r,s pq||rs {p † q † sr}+ 0|H|0 , (17)
and following the idea of generalized many body perturbation theory (GMBPT) [START_REF] Bartlett | Coupled-cluster Theory: An Overview of Recent Developments[END_REF], to reinstate orbital invariance of the MBPT(2) energy for rotations which mix occupied or virtual orbitals among themselves, we immediately define a more optimal partitioning of the Hamiltonian [29], the semi-canonical one. and f ab terms from the perturbation

V = ai f ai {a † i + i † a} + W, (18)
where f pq are the usual Fock matrix elements defined in terms of KS OEP spinorbitals

f pq = ε KS p δ pq -p| K + V xc |q . ( 19
)
Then H 0 becomes

H 0 = p f pp {p † p} + i =j f ij {i † j} + a =b f ab {a † b}. (20)
Defined in this way, the OEP2-sc method, has been found to be the most effective and stable second-order ab initio DFT method [29,37,40,41], in which all of the aforementioned problems of OEP2-KS were solved. A further generalization of ab initio DFT including higher then second-order terms was made by a change of H 0 in the OEP2-sc case to a form that has selected double excitation contributions along with single excitations [36,51]. The two-particle terms are those that correspond to operators that do not change the particle number of the diagrams that constitute the OEP functional (CCPT2). The new H 0 which defines OEP-ccpt2 method can be written as

H CCP T 0 = p f pp {p † p} + 1 4 a,b,c,d ab||cd {a † b † dc} + 1 4 i,j,k,l ij||kl {i † j † lk} (21) + a,b,i,j aj||bi {a † j † ib} + Φ KS |H|Φ KS (22)
The OEP equations Eq. ( 16) for V xc functional differs only in the form of Y (2) which arises from the correlation functional, and certainly depends on the choice of H 0 in our derivation.

We have to stress here that it is not necessary to solve the CC equations in our implementation of ab initio DFT. In our methodology, we use the CC theory

to properly define orbital-dependent exchange and correlation potentials in the context of KS DFT. All correlated OEP equations (OEP2-KS, OEP2-sc and OEP-ccpt2) for the potentials are solved fully self-consistently together with KS-DFT equations until final (usually 10 -9 ) convergence is achieved.

Our implementations of ab initio DFT are based on the linear combination of atomic orbital (LCAO) OEP method [19,20], which permits OEP calculations of atoms and molecules on an equal footing to the conventional molecular orbital or DFT calculations, i.e., with conventional Gaussian-type basis sets, but without any further approximations. The finite basis set implementation of OEP involves a projection method [19,[START_REF] Ivanov | [END_REF] for solving the required integral equation, and by construction all potentials are expanded in terms of auxiliary Gaussian functions. With these LCAO OEP methods, it is possible to extract local exchange and correlation potentials and other properties from the OEP calculations of atoms and molecules.

The local exchange-correlation potentials generated from the OEP method, can be plotted and may be used in developing accurate exchange and correlation potentials and functionals which can be systematically improved. [21,28,29,36]. Some computational difficulties in the LCAO OEP method have been found in routine calculations with exchange-only calculations [21,[START_REF] Ivanov | [END_REF], and with correlation included [36,39], were the manifestation of the well-known instability associated with the numerical solutions of Fredholm integral equation of the first kind. To obtain numerical solutions of reasonable accuracy for this class of equations, an appropriate choice of basis functions is crucial.

Numerical results

We have implemented various OEP methods defined above in the ACES II package [START_REF] Stanton | ACES 2 (Quantum Theory Project[END_REF] developed in Bartlett's group in QTP. Many testing calculations have been performed using all variants of OEP methods showing their properties, successes and failings (see the Refs. [28,29,36,37,40,41] and also the Conclusions).

Here we present another example, the comparison of fundamental DFT quantities -electron density and KS correlation potentials obtained in different WFT an DFT methods. This analysis helps us to get more insight into the links between the coverage of dynamic electron correlation effects defined in ab initio WFT, standard DFT and ab initio DFT.

We have performed similar kind of analysis before [START_REF] Jankowski | [END_REF][54][55], and here we present only few selected results obtained for the Neon atom. The Neon atom in its ground state is a perfect subject for this kind of analysis, because it has an almost ideal closed-shell structure and its correlation effects are classified as almost entirely dynamic. This allows us to avoid confusions at time of analysis with the presence of the non-dynamical correlation effects, which is often used as an explanation of failings of some methods. All calculations were performed with the uncontracted ROOS-ATZP basis set. [56] In order to make such a comparison of describing correlation effects by a different classes of various methods we have made the calculations using the main representative members of ab initio WFT methods: MP2, CCSD and CCSD(T), standard DFT methods SVWN5 [57,[START_REF] Slater | Quantum Theory of Molecules and Solids, Vol. 4: The Self-Consistent Field for Molecules and Solids[END_REF] from LDA class off functionals, and gradient corrected BLYP [6], and ab initio DFT methods OEP2-KS, OEP2-sc and OEP-ccpt2.

In Fig. tial [8]. To calculate the xc potentials form the MP2, CCSD and CCSD(T) densities, we employ the direct optimization technique of Wu and Yang [44]. Details of this procedure adopted to calculate xc KS potentials can be found elsewhere. [55] The resulting xc potential can be written

v xc ([ρ A ]; r) = t b t g t (r) + v 0 ([ρ A ]; r) -J([ρ A ]; r) (23)
where

J = ρ A (r ′ ) |r-r ′ | dr ′ is the Coulomb potential, v 0 (r)
is the Fermi-Amaldi potential [START_REF] Fermi | [END_REF] used to ensure the correct -1/r asymptotic behaviour of the resulting xc potential. The first term is an expansion in an auxiliary basis set of Gaussian functions g(r) and the coefficients {b t } are the only unknown parameters and are determined in our procedure [44,55]. In the following we perform calculations of v xc for a variety of ab initio WFT densities ρ A , where A = HF, MP2, CCSD or CCSD(T). In order to determine an approximate correlation potential, we calculate it by simply taking difference of the xc potential calculated in MP2, CCSD or CCSD(T) and x-only potential obtained in the same procedure from HF density, e.g. for the MP2 we have

v c ([ρ MP2 ]; r) = v xc ([ρ MP2 ]; r) -v xc ([ρ HF ]; r) (24)
Calculated this way correlation potentials are plotted together with the exact one and other KS potentials. As we can see in the Fig. 1., the ab initio WFT potentials are very close to the exact one and can be used as a reference correlation potentials in a comparison with DFT results. The standard density-dependent correlation potentials VWN and LYP are qualitatively incorrect, they have the wrong shape, magnitude and even the opposite sign to the exact results almost everywhere in the space. This fact is well known [8,28], but for some reason ignored by the DFT community. On the other side, the orbital-dependent correlation potentials calculated from initio DFT methods are very close to the exact results. Only the OEP2-KS correlation potential, as we indicated before, significantly overestimates the exact correlation potential, which is the result of the wrong choice of the H 0 in the definition of perturbation problem. But as we have shown elsewhere [29,36,37,40] it can be fixed by proper splitting of the total Hamiltonian. The improved OEP2-sc and OEP-ccpt2 are very close not only to the exact correlation potential, but they are also close to their ab initio WFT counterparts -correlation potentials calculated from MP2 and CCSD densities respectively. This shows the systematic improvement of the ab initio DFT methods mentioned above, which is reflected not only by e.g. the correlation and total energies but also by the KS correlation potentials, which are the very subtle correlation effect in the total xc potential.

In the following we include in our analysis of the behaviour of the correlated OEP methods also the electron density. The studies of the impact of electron correlation effects on the electron density are based on an analysis of graphical representations of difference radial-density distributions [START_REF] Jankowski | [END_REF]54] calculated between radial densities D(r) obtained from correlated method D XC (r) and x-only method D X (r),

δ XC/X (r) = D XC (r) -D X (r), (25)
where the radial charge densities are defined as

D A (r) = 4πr 2 ρ A (r), (26)
and ρ A (r) denotes the electron density at the distance r from the nucleus calculated by means of the method A. In the Fig. 2 we present a comparison of the plots which represent the response of the density on a correlation effects. We plot curves representing ab initio WFT difference radial density distributions: δ M P 2/HF (r)

δ CCSD/HF (r) and δ CCSD(T )/HF (r), together with the curves which represent impact on the density δ XC/X (r) of the correlation functionals C (C=VWN5,LYP, OEP2-KS, OEP2-sc, OEP-ccpt2) on the exchange functionals X (X=S, B88, and OEPX), all generated for the Ne atom. The curves δ M P 2/HF (r), δ CCSD/HF (r) and are our reference response density distribution curves. Going to the standard DFT results, we plot the response curves for δ SV W N 5/S (r), δ LY P/B88 (r), representing the impact of inclusion of the correlation functionals on the density distributions obtained at the X-only level. One can see in this figure that the plot obtained for the VWN5 and the LYP correlation functionals, do not show similarity with the δ M P 2/HF (r) and δ CCSD/HF (r) ones. This disagreement may be explained by the fact that the LYP and VWN5 correlation functionals do not represent any considerable dynamic correlation effects. [START_REF] Jankowski | [END_REF] A completely different situation takes place for the curves corresponding to the OEP2-KS, OEP2-sc and OEP2-ccpt2 functionals.

δ CCSD(T )/HF (
One can see in this figure that the plots obtained for the orbital-dependent OEP correlation functional very well, except OEP2-KS, resemble the MP2 and CCSD distributions. The OEP2-KS correlation response density curve significantly overestimates the reference WFT results, but still have qualitative good shape. It confirms the previous findings on the energy and correlation potential level and additionally supports the previous conclusions about problems with OEP2-KS method. [29,36] Using of the OEP2-sc and OEP-ccpt2 methods significantly improves the results.

OEP2-sc and OEP-ccpt2 curves are very close to the ab initio WFT reference ones.

The shape and magnitude are almost the same, and additionally, like in correlation potential case (see. Fig. 1.), the OEP2-sc curve is closer to the MP2 one, and curve generated from OEP-ccpt2 method approaches the CCSD result. This is very systematic behaviour of the correlated OEP results, visible on the density level, which confirms findings and conclusions from the energy-and correlation KS potentialanalysis. Improvement of the correlation KS-OEP functional, not only improves correlation energies, KS-potentials and other properties, but is also reflected in a systematic way on the electron density.

Conclusions

The use of systematically improvable, orbital-dependent approximations to the exact energy in DFT allows us to circumvent virtually all of the aforementioned shortcomings of the density-dependent functionals in KS DFT. There is no problem with the self interaction error, correlation potentials calculated in ab initio DFT provide the correct shape compared to those from reference quantum Monte Carlo calculations [28,29,36]. Exchange-only and exchange-correlation potentials are reasonable, and have the correct long-range behavior [21,28]. As a consequence, other calculated quantities are also reasonable, e.g. total and correlation energies calculated in correlated OEP methods are almost of CC accuracy [29,36]. Moreover ab initio DFT provides good ionization potentials and excitations energies [23,37,38]. We also have shown that the OEP2 method is capable of consistently recovering dispersion effects in weakly bounded dimers [41], which extends the applicability of ab initio DFT to areas which were inaccessible by standard DFT methods.

The different correlated OEP methods could be easily derived thanks to the ab initio DFT formalism of Bartlett et al. [29] based on the density condition and the CC functional. Our general approach also has important technical features: It eliminates the necessity of directly taking the cumbersome functional derivatives to arrive at the working equations to be implemented, giving us greater flexibility in defining new correlation potentials, even at infinite order. Indeed, it had been considered impossible to improve the approximations to exchange and/or correlation functionals in a systematic fashion until the concept and practical realisation of ab initio DFT was put forward capitalizing on the systematic orbital-dependent approximations to the exact energy in ab initio wave function theory (WFT). So, we are able to define a hierarchy of DFT methods (with orbital-dependent functionals) OEPx < OEP2-KS < ... < OEP2-sc < OEP-ccpt2 < ... which converge

to the right answer in the infinite and complete basis set limit as the correlation level is increased. This systematic improvement of the ab initio DFT methods is

reflected not only in total and correlation energies, ionization potentials, and excitation energies, but also in fundamental DFT quantities like electron density or correlation potentials. [START_REF] Jankowski | [END_REF]55] The derivation of ab initio DFT from CC theory and the KS density condition along with the numerical results, directly compared with their WFT counterparts (MP2 -OEP2-sc, CCSD -OEP-ccpt2) shows very systematic behaviour and clearly indicates the interconnections between these two independent types of theories DFT and WFT.

But certainly, "nothing is for free". We have to mention some negative aspects of using orbital-dependent functionals in DFT. First of all, xc functionals and potentials are orbital-dependent, so in the KS procedure we have to solve additional OEP equations, which are numerically demanding and in the LCAO-OEP implementation large uncontracted basis sets must be used in calculations to provide high quality of the solutions. Additionally our equations for correlated OEP are complicated (even if the ab initio DFT procedure helps significantly in their derivation) and numerically more demanding the standard density-dependent DFT -they scale as N it n 2 occ n 3 virt (at the OEP2 level). Also, the extension of our procedure to TD-DFT is possible but is extremely complicated especially at the correlated level [60].

But the price seems to be acceptable, because right now, even in DFT calculations, we are able to control and predict the accuracy level of the results, like in ab initio WFT, which makes DFT method much more reliable than before and brings a hope to the DFT world that there is a way to do DFT correctly, not only theoretically but also in practice.

  Lotrich and So Hirata well known hierarchy of converging, size extensive methods MBPT(2) < CCD < CCSD < CCSD(T) < CCSDT < ... < FCC. = FCI establishes the standards in ab initio WFT methods. MBPT(2) means second order many-body perturbation theory, CC -coupled cluster methods with S-single, D-double, T-triple excitations.

Figure 1 .

 1 Figure 1. Comparison of correlation potentials of the Neon atom obtained from the OEP2-KS, OEP2-sc, OEP-ccpt2 with the correlation potentials obtained from MP2, CCSD and CCSD(T), and from standard DFT: VWN5 and LYP and the exact correlation potential Ref. ([8]).

Figure 2 .

 2 Figure 2. Comparison of difference radial density distributions, δ M P 2/HF (r)δ CCSD/HF (r) and δ CCSD(T )/HF (r) with the impact on the density δ XC/X (r) of the correlation functionals C (C=VWN5, LYP, OEP2-KS, OEP2-sc, OEP-ccpt2) on the exchange functionals X (X=S, B88, and OEPX) generated for the Ne atom.

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  3.1. AcknowledgmentsThis work was supported by the Polish Committee for Scientific Research MNiSW under Grant no. N N204 560839. S. Hirata was supported by the U.S. National Science Foundation (CHE-0844448), the U.S. Department of Energy (DE-FG02-Francis and I.T. Consultant 04ER15621), and the Donors of the American Chemical Society Petroleum Research Fund (48440-AC6). S. Hirata is a Camille Dreyfus Teacher-Scholar. We appreciate many informative discussions with Dr. Ajith Perera and Dr. Igor Schweigert. And we would like to thank Rod Bartlett for his ideas, stimulation, "black board discussions", and for giving us opportunity to work together in Quantum Theory Project.

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Nick J Beeching
email: nbeeching@blueyonder.co.uk

Tom E Fletcher

David R Hill

Gail L Thomson

Travellers and viral haemorrhagic fevers: what are the risks?

Keywords:

Viral haemorrhagic fevers (VHF) are caused by zoonotic viral infections transmitted to humans directly or by ticks or mosquitoes. The overall risk to travellers is conservatively estimated at <1 in 1 million travel episodes to African countries where infection is present, and febrile patients returning from these countries are at least 1000 times more likely to have malaria than Lassa fever or another VHF. No cases have been reported in fellow travellers exposed to a travelling case and only one asymptomatic seroconversion (to Lassa) has been reported in over 2000 contacts following care of VHF cases in modern Western hospital settings. However, healthcare-associated transmission of infection has been a major problem in some endemic settings. The potential for healthcare-associated infection and the threats posed by unrecognized or new agents necessitate a high index of suspicion and a standardized risk assessment approach to febrile travellers. Travel-related hantavirus infections are increasingly being reported from Europe and the Americas. This article summarizes the epidemiology and reports of travel-related VHF cases in the past 40 years, together with strategies for their recognition, management and prevention.

A c c e p t e d M a n u s c r i p t

Introduction

Viral haemorrhagic fevers (VHF) rarely infect travellers but raise concern because of their potential for a dramatic clinical picture, high mortality, nosocomial transmission and risk to laboratory personnel. Historically, they have been major impediments to military campaigns over the centuries and remain endemic in much of the world, with emerging outbreaks in new locations and recent descriptions of new diseases. In response to travel-related cases of Lassa fever in the USA and the UK, and the importation of Marburg infection into Germany and the former Yugoslavia, proscriptive guidelines for the public health response to imported cases of suspected VHF and their clinical and laboratory management were developed in the 1970s [START_REF] Galbraith | Public health aspects of viral haemorrhagic fever in Britain[END_REF].

These have been reinforced in a recent European consensus statement [START_REF] Bossi | Bichat guidelines for the clinical management of haemorrhagic fever viruses and bioterrorism-related haemorrhagic fever viruses[END_REF][START_REF] Brouqui | Infection control in the management of highly pathogenic infectious diseases: consensus of the European Network of Infectious Disease[END_REF].

Several VHF agents have been weaponized and their continued potential for deliberate release has been emphasized [START_REF] Bossi | Bichat guidelines for the clinical management of haemorrhagic fever viruses and bioterrorism-related haemorrhagic fever viruses[END_REF][START_REF] Borio | Hemorrhagic fever viruses as biological weapons: medical and public health management[END_REF][START_REF] Kortpeter | Managing potential laboratory exposure due to Ebola virus by using a patient biocontainment care unit[END_REF].

The purpose of this review is to focus on the risks of acquiring a VHF during travel and to update lists of known importations of cases across national borders.

Epidemiological and clinical approaches to the management of returned travellers with fever are also discussed. Full clinical descriptions of each infection are beyond the scope of this article but can be accessed from recent reviews. Dengue [START_REF] Wilder-Smith | Severe dengue virus infection in travelers[END_REF][START_REF] Hochedez | Management of travelers with fever and exanthema, notably dengue and chikungunya infections[END_REF] is excluded from this review and only passing mention will be made of the many VHFs that have localized geographical niches and that have not been reported as being travel related.

Methods

We conducted reviews of the Medline/PubMed databases for the period 1966-2009, the online database Google Scholar and the ProMED database using the keywords A c c e p t e d M a n u s c r i p t 'travel', 'traveller' and 'imported' combined with the terms 'VHF' and 'viral haemorrhagic fever' and with each of the diseases being described. In addition we reviewed relevant sections of the websites of the US Centers for Disease Control and Protection (www.cdc.gov), Health Canada (www.hc-sc.gc.ca/index-eng.php), the UK Health Protection Agency (www.hpa.org.uk), the English National Travel Health Network and Centre (www.nathnac.org) and the World Health Organization (www.who.int/en). Standard textbooks of infectious diseases and travel medicine were consulted, together with appropriate reviews and recently published books about VHF [START_REF] Howard | Viral haemorrhagic fevers[END_REF][START_REF] Ergönul | Crimean-Congo hemorrhagic fever: A global perspective[END_REF] and infections in military settings [START_REF] Smallman-Raynor | War epidemics[END_REF].

We cross-correlated references from these sources, when possible including papers in all languages. We list the source references for each case of VHF reported to have crossed an international boundary and highlight key references for further reading on clinical and epidemiological management. Laboratory-acquired cases have not been tabulated, nor have infections arising as a result of animal importation.

Epidemiology

General features

The agents causing VHFs are RNA viruses in the families Arenaviridae, Bunyaviridae, Filoviridae and Flaviviridae. All are known or thought to be zoonoses, some associated with very specific hosts, vectors and locations, such as the South American arenaviruses, and some with a larger range of animal hosts and wider intercontinental distribution, such as Crimean-Congo haemorrhagic fever (CCHF).

Key epidemiological features of VHFs known to have affected international travellers are summarized in Table 1.

A c c e p t e d M a n u s c r i p t

[Table 1 here] The routes of transmission of VHF to man in nature can be categorized into three broad groups [START_REF] Solomon | Viral haemorrhagic fevers[END_REF]. The first includes infections that are only transmitted by arthropod vectors, such as yellow fever (YF) and most other flaviviruses, and are not usually spread from person to person. The second group includes agents spread to man by contact with uncooked meat, blood, urine, saliva and other secretions of animals, such as arenaviruses, hantaviruses and filoviruses. Contamination of foodstuffs or human habitation by rodent urine has been implicated in the spread of arenavirus and hantavirus infections, but the zoonotic transmission routes to man of filovirus infections remain less clear (see below). The third group, which includes the bunyaviruses causing CCHF and Rift Valley fever (RVF), may be spread by arthropod vectors or by body-fluid contact.

In general, the human populations at most risk in endemic areas are pastoralists, butchers, slaughterers and others who have close contact with animals, their products and their ticks; people living in housing with peri-domestic rodent infestation; and those with occupations that take them into areas with enzootic transmission, such as mining, engineering, forestry work, cane cutting and agricultural labourers. Traditional funeral practices and close domestic contact can also result in infection in these settings. Civil unrest, conflict and political changes leading to the displacement of populations and breakdown of public health systems have been implicated in epidemics of VHFs such as CCHF and Marburg. Changes in climate conditions leading to increases in rodent hosts favour the spread of hantavirus infections in Europe [START_REF] Heyman | Situation of hantavirus infections and haemorrhagic fever with renal syndrome in European countries as of December 2006[END_REF] and epidemics of RVF have followed heavy rains and consequent increases in mosquito vectors in Egypt and Kenya [START_REF] Howard | Viral haemorrhagic fevers[END_REF]. Similar A c c e p t e d M a n u s c r i p t conditions and alterations in land use may also account for some of the recent expansion of CCHF in South and Eastern Europe [START_REF] Maltezou | Crimean-Congo hemorrhagic fever in Europe: current situation calls for preparedness[END_REF].

Infection in endemic settings

Hospital-associated transmission of infection has been responsible for the amplification of local outbreaks of several VHFs in Africa, including Ebola, Marburg and Lassa. Poor infection control measures and the reuse of sharps has resulted in onward transmission of infection to patients and staff in these settings. Other risks to staff and visitors include close contact and subsequent contamination with body fluids of patients, and mucocutaneous exposure to blood, saliva and respiratory secretions, especially during resuscitation or procedures that create infectious aerosols. This includes splashes of blood and other fluids into the mouth or eyes.

Droplet spread of respiratory secretions may also play a small role.

In general, dramatic outbreaks of nosocomial infection within endemic areas have been terminated by the provision of adequate medical supplies and training staff in the proper use of personal protective equipment, together with enforcement of guidance about the safe handling of deceased patients [START_REF]Infection control for viral haemorrhagic fevers in the African health care setting[END_REF]. The risks of contact infection and nosocomial infection in high-income settings are discussed in more detail later in this review. Patients, expatriates and local healthcare staff sent to Europe or the USA for medical care are included in Tables 2 and3, which list individual cases of VHFs that have travelled internationally.

Infections in travellers

Other travellers whose occupations or leisure activities bring them into contact with settings at risk for VHF are at particular risk; this includes both international travellers and those who do not cross national borders. Camping, hiking and other rural Mass gatherings can increase the risk of any infection, and the annual Hajj pilgrimage is of theoretical concern because it is accompanied by massive importation of animals for slaughter [START_REF] Ahmed | Health risks at the Hajj[END_REF].

Lassa fever was the first VHF to be identified in a traveller and is the most common imported VHF, with 28 cases documented in the past 30 years (Table 2). At least nine were healthcare workers in Africa and most of the remainder had rural occupations, including aid workers and military personnel. These infections all occurred in West Africa, especially Nigeria and Sierra Leone, with the first reported case from Mali in 2009. In 2008 a novel Old World arenavirus, Lujo virus, caused the death of a Zambian resident and the paramedic who assisted in her transport to South Africa for medical care [START_REF] Paweska | Nosocomial outbreak of novel arenavirus infection, Southern Africa[END_REF]. Two nurses who attended the patients in South Africa also became infected, together with a hospital cleaner. Only the nurse who received ribavirin survived. The natural reservoir, geographical range and distribution of subclinical human infection with this new virus have yet to be determined, but the sequence of events is a reminder of the dangers of unrecognized illness due to VHFs.

[Table 2 here] Only a few cases of imported filovirus infection have been reported. Table 3 includes two patients who travelled within Kenya, illustrating the link between these infections in travellers to cave exploration and bat exposure, in addition to an outbreak of Marburg infection in miners exposed to bats [START_REF] Towner | Isolation of genetically diverse Marburg viruses from Egyptian fruit bats[END_REF]. Fruit bats have now been A c c e p t e d M a n u s c r i p t confirmed to carry Marburg and Ebola infections, although the mode of transmission to people has not been determined [START_REF] Swanepoel | Studies of reservoir hosts for Marburg virus[END_REF][START_REF] Leroy | Human Ebola outbreak resulting from direct exposure to fruit bats in Luebo, Democratic Republic of Congo, 2007[END_REF]. Other large non-human primates can also be infected, and some human filovirus infections have been epidemiologically linked with the local preparation or consumption of non-human primate 'bushmeat'.

[Table 3 here] Given the large geographical range of CCHF in Africa, Eastern Europe, the Middle East and central Asia as far as Xiang Xiang Province in China, it is surprising that more travel-related infections have not been reported. Most cases have involved proven or possible exposure to ticks, including crushing ticks with unprotected fingers (Table 3). The recent acquisition of a lethal infection by an American serviceman in Afghanistan emphasizes the need to consider CCHF in the differential diagnosis of fever from this area [START_REF]Crimean-Congo hemorrhagic fever, fatal -Germany ex Afghanistan[END_REF].

Similarly, few clinical cases of RVF have been reported in travellers until recently, apart from two cases returning to the West for expert care of ophthalmic complications of infection and a patient in whom RVF may have contributed to death due to acute hepatitis A (Table 3). Subclinical cases have been identified in peacekeeping and military personnel stationed in endemic areas [START_REF] Niklasson | Antibodies to Rift Valley fever in Swedish U.N. soldiers in Egypt and the Sinai[END_REF][START_REF] Durand | Rift Valley fever virus infection among French troops in Chad[END_REF].

Hantaviruses are found in most continents and caused epidemics of haemorrhagic fever with renal syndrome (HFRS) in civilians and troops during World War I and the Korean War [START_REF] Smallman-Raynor | War epidemics[END_REF]. Recent reports of infected travellers in Europe and Asia again include both military and civilian personnel (Table 3). The European forms of HFRS have been reported in peacekeepers in the Balkan region, and travel-related cases are being reported more often from Western Europe and Scandinavia, especially in campers. The need for reference laboratory testing was emphasized by a recent A c c e p t e d M a n u s c r i p t 'pseudo-importation' of hantavirus from Ecuador to Belgium, subsequently shown to have been acquired after return to Belgium [START_REF] Demeester | Hantavirus nephropathy as a pseudo-import from Ecuador[END_REF]. In the New World, several new infections leading to hantavirus pulmonary syndrome (HPS) have been recognized, and a few travel-related cases have been reported (Table 3).

Yellow fever (YF) was a major cause of death of early European travellers to West Africa and was taken to the Americas with the slave trade [START_REF] Smallman-Raynor | War epidemics[END_REF]. From the 17th to the end of the 19th century tens of thousands of British, French, Dutch and Spanish troops were killed by YF outbreaks in the Caribbean and Central American region, and importation of YF to the USA was a constant problem, with onward transmission by local populations of Aedes mosquitoes. Mosquito bite avoidance measures and vaccination have been available for almost a century, but ten imported cases have been reported in the last three decades, usually in tourists who had not been vaccinated (Table 4).

[Table 4 here]

Animal travel and VHFs

Animal movements have been implicated in the spread of CCHF in central Asia [START_REF] Burney | Nosocomial outbreak of a viral hemorrhagic fever caused by Crimean hemorrhagic fever-Congo virus in Pakistan, January 1976[END_REF] and the Arabian peninsula [START_REF] Khan | An outbreak of Crimean-Congo hemorrhagic fever in the United Arab Emirates, 1994-1995[END_REF][START_REF] El-Azazy | Crimean-Congo haemorrhagic fever virus infection in the Western Province of Saudi Arabia[END_REF], of RVF into Saudi Arabia and the Yemen [START_REF] Balkhy | Rift Valley fever: an uninvited zoonosis in the Arabian peninsula[END_REF] and possibly in the recent emergence of human infections with Alkhurmah virus, a novel flavivirus similar to Kyasanur Forest disease in western Saudi Arabia [START_REF] Madani | Alkhumra virus infection, a new viral haemorrhagic fever in Saudi Arabia[END_REF].

Clinical features

VHF are severe infections with high mortality rates in travellers (Tables 234), apart from Puumala virus forms of HFRS from Europe. Details of clinical features in endemic settings and in travellers are beyond the scope of this review but can be found in textbooks and the references cited. The onset of most infections is abrupt, often with severe malaise and headache in the early stages, sometimes resembling encephalitis. Severe infections often follow a biphasic course, with initial improvement followed by multisystem failure in the second week, including encephalopathy. Haemorrhagic features can be absent at presentation in a substantial minority of patients and are rarely seen in the northern European forms of HFRS, or in patients with HPS or RVF. A fine rash may be seen in the first week of filovirus infections, and pharyngitis and/or facial swelling in patients with Lassa fever.

Jaundice can be prominent in YF and RVF. Abdominal pain can be severe in patients with Ebola, Marburg or CCHF, and prostration is a prominent feature of Ebola. Ophthalmic problems can complicate RVF (retinitis) and Lassa (uveitis), which also causes deafness. Spontaneous abortion is a feature of Lassa, Ebola and CCHF.

The differential diagnosis is wide and includes respiratory infections in the early stages, as well as malaria, dengue and other arboviruses, enteric fever, viral hepatitis, leptospirosis, meningococcaemia, encephalitis and rickettsial infections. Treatment is largely supportive, including dedicated high-security intensive care [START_REF] Brouqui | Infection control in the management of highly pathogenic infectious diseases: consensus of the European Network of Infectious Disease[END_REF][START_REF] Kortpeter | Managing potential laboratory exposure due to Ebola virus by using a patient biocontainment care unit[END_REF]. Ribavirin (unlicensed for these purposes) has proven beneficial when given early in Lassa fever and is used for other arenavirus infections. It appears to be useful in CCHF in areas were mortality is high, although its role remains controversial [START_REF] Ergönül | Ribavirin in Crimean-Congo hemorrhagic fever: primum non nocere[END_REF]. It confers no benefit in filovirus infections.

Risks assessment and management of returned travellers

Healthcare settings

Risk assessment to inform the management of patients returning from overseas with febrile symptoms should assess the likelihood that their illness is because of VHF, the likelihood of the infection being transmitted to workers, and the seriousness of the outcome of such transmission. The risks of delaying diagnosis and treatment of other treatable infections such as malaria should also be incorporated in the risk assessment process.

Firstly, how common are these infections? The overall risk to travellers is conservatively estimated at <1 in 1 million travel episodes to African countries where infection is present. In the recent GeoSentinel review of returned travellers with febrile illness managed in specialist centres around the world, VHF was not diagnosed in 6957 patients, of whom 2559 had returned from sub-Saharan Africa A c c e p t e d M a n u s c r i p t [START_REF] Wilson | Fever in returned travelers: results from the GeoSentinel Surveillance Network[END_REF]. Malaria was the most common diagnosis, as it was in 14/23 (61%) of patients specifically screened for VHFs in London in the early 1980s [START_REF] Tilzey | Patients with suspected Lassa fever in London during 1984: problems in their management at St Thomas's Hospital[END_REF] and in 14/37 (38%) travellers with possible VHF risk more recently at the London Hospital for Tropical Diseases [START_REF] Woodrow | Early risk assessment for viral haemorrhagic fever: experience at the Hospital for Tropical Diseases, London, UK[END_REF]. Africa, especially West and central Africa, has been the origin of most imported cases of VHF but is also the most common origin for severe malaria imported to Europe and North America [START_REF] Wilson | Fever in returned travelers: results from the GeoSentinel Surveillance Network[END_REF] and there is a remote possibility that a traveller might have both. During the decade 2000-2009, four patients have imported VHFs to the UK (Tables 2 and3), compared with 17 109 cases of malaria [START_REF]Malaria: epidemiological data[END_REF], and 4061 cases of enteric fever notified 2000-8 (mostly imported) [START_REF]Gastrointestinal Pathogens at the Health Protection Agency Centre for Infections and supplied by the Travel and Migrant Health A c c e p t e d M a n u s c r i p t Section, Centre for Infections (personal communication[END_REF].

More detailed risk assessment of the returned traveller with a febrile illness, especially with a rash, jaundice or haemorrhagic manifestations that cannot otherwise be explained, should take into account the countries visited, the specific areas visited within the country, and activities that might have put them at risk, including rural work and leisure pursuits such as cave visits and mining; contacts with wild animals, especially bats, rodents or their excreta; and working in or attending a health facility as a patient. The incubation period is taken into account, as none of the transmissible VHFs in Africa have an incubation period longer than 21 days. If the onset of symptoms has occurred more than 21 days after leaving an endemic area, the risk of VHF can be excluded [START_REF] Bossi | Bichat guidelines for the clinical management of haemorrhagic fever viruses and bioterrorism-related haemorrhagic fever viruses[END_REF][START_REF] Woodrow | Early risk assessment for viral haemorrhagic fever: experience at the Hospital for Tropical Diseases, London, UK[END_REF]. Patients at medium or high epidemiological risk should be isolated and discussed with national clinical, laboratory and public health experts. Initial investigations beyond exclusion of malaria should be kept to a minimum. If malaria is excluded, hence increasing the possibility of a VHF causing the illness, the intensity of isolation can be escalated, according to local or national guidelines.

A c c e p t e d M a n u s c r i p t

Although regulations have been in force in the UK since 1976 [START_REF] Galbraith | Public health aspects of viral haemorrhagic fever in Britain[END_REF][START_REF]Management and control of viral haemorrhagic fevers[END_REF], they are rarely applied systematically, even in specialist units. A travel history is only obtained from about 10% of patients with fever attending busy emergency rooms in the north-west of England (unpublished audit), and only a minority of patients thought to have potentially transmissible infections are isolated in British emergency rooms [START_REF] Anathallee | Emergency departments (EDs) in the United Kingdom (UK) are not prepared for emerging biological threats and bioterrorism[END_REF]. A recent survey of 21 British infectious disease units revealed that written VHF protocols available in six units were only systematically followed in two units; eight others discussed VHF risks in unit guidelines, and seven had no written protocols [START_REF] Woodrow | Early risk assessment for viral haemorrhagic fever: experience at the Hospital for Tropical Diseases, London, UK[END_REF]. One concern voiced by specialists is that use of such protocols might increase the delay in diagnosing falciparum malaria, which can rapidly be fatal and should be treated immediately [START_REF] Lalloo | UK malaria treatment guidelines[END_REF][START_REF] Griffith | Treatment of malaria in the United States. A systematic review[END_REF]. However, an audit of delays in diagnosis made at the London Hospital for Tropical Diseases, where use of the VHF assessment protocol is embedded in daily practice, only showed an increase in time to laboratory diagnosis of malaria from a median 90 min (range 50-125) for patients not thought to be at VHF risk to 140 mins (101-225) for those assessed as having a possible VHF [START_REF] Woodrow | Early risk assessment for viral haemorrhagic fever: experience at the Hospital for Tropical Diseases, London, UK[END_REF].

The next issue is the risk to personnel attending the patient. In a review of contact tracing for nine patients admitted to Western facilities with Lassa fever, no clinical illness was seen in 1521 contacts, including fellow travellers and healthcare workers [START_REF] Haas | Imported Lassa fever in Germany: surveillance and management of contact persons[END_REF]. One German physician (who had received ribavirin prophylaxis) had an asymptomatic seroconversion after failing to use adequate barrier precautions, yielding an estimated transmission risk of 0.06% [START_REF] Haas | Imported Lassa fever in Germany: surveillance and management of contact persons[END_REF]. To this may be added 576 further healthcare contacts screened after recently imported cases of Lassa to the UK, with no secondary cases [START_REF] Crowcroft | The public health response to a case of Lassa fever in London in 2000[END_REF][START_REF] Kitching | A fatal case of Lassa fever in London, January 2009[END_REF][START_REF] Atkin | The first case of Lassa fever imported from Mali to the United Kingdom, February 2009[END_REF]. No clinical cases were found after surveillance of almost 400 contacts of Marburg [START_REF] Timen | Response to imported case of Marburg hemorrhagic fever, the Netherlands[END_REF][START_REF]Special Pathogens Branch. Outbreak Posting[END_REF], 74 contacts of Ebola [START_REF] Formenty | Human infection due to Ebola virus, subtype Côte d'Ivoire: clinical and biologic presentation[END_REF] or 245 contacts of CCHF [START_REF] Stuart | Suspected case of Crimean/Congo haemorrhagic fever in British traveller returning from Zimbabwe[END_REF][START_REF] Tarantola | Look back exercise with imported Crimean-Congo hemorrhagic fever, Senegal and France[END_REF] in recent travellers. Concern lingers, however, A c c e p t e d M a n u s c r i p t because of the theoretical risk of aerosol dispersion of some infections, reinforced by the apparent remote airborne spread of the Ebola-Reston virus to non-human primates, and transmission of asymptomatic infections to animal handlers. Several excellent reviews include further details about healthcare-associated risks and the specific precautions that are necessary to reduce them [START_REF] Galbraith | Public health aspects of viral haemorrhagic fever in Britain[END_REF][START_REF] Brouqui | Infection control in the management of highly pathogenic infectious diseases: consensus of the European Network of Infectious Disease[END_REF][START_REF] Borio | Hemorrhagic fever viruses as biological weapons: medical and public health management[END_REF][START_REF] Crowcroft | The public health response to a case of Lassa fever in London in 2000[END_REF][START_REF] Haas | Imported Lassa fever in Germany: surveillance and management of contact persons[END_REF][START_REF] Tarantola | Estimates and prevention of Crimean-Congo hemorrhagic fever risks for health care workers[END_REF][START_REF] Isaäcson | Viral hemorrhagic fever hazards for travelers in Africa[END_REF]121].

To summarize, a VHF should be considered in a traveller with fever ≥38°C that starts within 21 days of leaving a risk area, especially if they have any of the risk exposures detailed earlier, and a severe illness with haemorrhagic manifestations, rash or other features, such as jaundice, that are compatible with a VHF and cannot be explained by malaria or other conditions. Such patients should be isolated in a single room, preferably with negative pressure, and attendants and diagnostic sampling kept to a minimum. Healthcare workers should adopt precautions against contact with blood and secretions, including gloves, gowns and eye protection, and against droplet spread of infection. Care should be taken to avoid contamination during removal or safe disposal of personal protective equipment. Suspected cases should be discussed immediately with appropriate local public health personnel and national clinical experts, who will assist with determining the future epidemiological, diagnostic and clinical management of the patient and contacts. This might include transfer to a special isolation facility [START_REF] Brouqui | Infection control in the management of highly pathogenic infectious diseases: consensus of the European Network of Infectious Disease[END_REF][START_REF] Crowcroft | The public health response to a case of Lassa fever in London in 2000[END_REF].

Although no cases of transmission have been documented as a result of routine diagnostic laboratory processing of specimens from returned travellers, clinical laboratories should be warned that there is a known or potential VHF risk and diagnostic sampling kept to a minimum. The closed systems used in modern clinical haematology and biochemistry laboratories should be safe. Samples should be transported safely and handled in appropriate safety cabinets by adequately trained containment facilities. There is a high risk to mortuary personnel and undertakers. All contacts with patients or samples should be identified and categorized according to their exposure risk [START_REF] Brouqui | Infection control in the management of highly pathogenic infectious diseases: consensus of the European Network of Infectious Disease[END_REF][START_REF] Crowcroft | The public health response to a case of Lassa fever in London in 2000[END_REF][START_REF] Kitching | A fatal case of Lassa fever in London, January 2009[END_REF][START_REF] Atkin | The first case of Lassa fever imported from Mali to the United Kingdom, February 2009[END_REF][START_REF] Woodrow | Early risk assessment for viral haemorrhagic fever: experience at the Hospital for Tropical Diseases, London, UK[END_REF].

Risks for fellow travellers and family contacts

Outside endemic areas and settings, fellow travellers have never been known to contract a VHF from another infected traveller. In the past, heroic efforts have been made to trace fellow travellers across international boundaries, such as following the importation of Lassa fever to the USA, with no evidence of transmission in several hundred potential contacts [START_REF] Zweighaft | Lassa fever: response to an imported case[END_REF]. Within endemic areas, close family contact (excluding the preparation of bodies for burial) has been implicated in the transmission of most VHFs originating in Africa, but this has only been documented in Western settings for Marburg infection transmitted sexually to a female spouse, and in South America for Argentinean haemorrhagic fever [START_REF] Borio | Hemorrhagic fever viruses as biological weapons: medical and public health management[END_REF] and Andes HPS virus [122]. Sexual transmission of other viruses, particularly Lassa, Ebola, CCHF, other arenaviruses and hantaviruses remains undocumented, but both Lassa and Ebola have been detected in semen 3 months after infection [START_REF] Borio | Hemorrhagic fever viruses as biological weapons: medical and public health management[END_REF][START_REF] Howard | Viral haemorrhagic fevers[END_REF]. Campers and others travelling or working in rural areas should avoid contact with rodents or their excreta and should wear masks if it is essential to sweep out habitations infested by rodents in any area where Lassa or other arenaviruses or hantaviruses are prevalent. In light of current knowledge, contact with fruit bats or their habitations, such as caves in Africa, should also be avoided.

Prevention for travellers

Immunization

The only approved vaccine against a VHF in travellers is for YF, although unlicensed or restricted vaccines have been used for RVF and in some areas against HFRS agents. YF vaccination may be required under international health regulations by individual countries as a condition of entry, and/or recommended to prevent acquiring YF. Unfortunately, the information provided by tour companies and travel agents to travellers visiting YF risk areas may not accurately discuss the risk and A c c e p t e d M a n u s c r i p t requirements for vaccination. Of the 10 imported cases reported in the last 30 years, only one had been immunized (Table 4).

Although the risk of YF infection in travellers to West Africa has been estimated to be higher than that in travellers to endemic areas of South America [START_REF] Monath | Prevention of yellow fever in persons traveling to the tropics[END_REF], 4 of the 10 cases in Table 4 had been to the Americas. Recent expansion of YF transmission in South America, along with the recognition of rare but life-threatening adverse events following YF vaccine, especially in those aged 60 and older [START_REF] Lindsey | Adverse event reports following yellow fever vaccination[END_REF], emphasize the need to improve the definition of YF risk areas. Geographic mapping of risk based on review of human and non-human primate cases, YF serology, vegetation, altitude and vector distribution has been undertaken by a World Health Organization (WHO) working group. They will harmonize internationally accepted maps of risk areas published by WHO and the Centers for Disease Control and Prevention, with clearer definitions of level of risk and vaccination recommendations down to small geographical zones. These maps should be available by the end of 2010.

Conclusions

The risk of a traveller acquiring a VHF is extremely small, but the consequences for them and for those involved in their care are potentially devastating. Patients with an imported VHF often have contact with many healthcare personnel before their diagnosis is recognized, but no clinically significant cases of transmission to healthcare attendants have been recorded in modern Western hospital settings.

Nevertheless, it is important to take adequate travel histories from patients with fever and perform a more specific risk assessment for patients returning from areas endemic for a VHF. Management of suspected cases should follow national protocols. Travellers need to be informed about the health risks associated with their travel plans, and to take steps to reduce personal risk.

A

  c c e p t e d M a n u s c r i p t holiday pursuits may expose travellers to ticks and mosquitoes or to rodent urine, while occupations such as mining, geological field work and cave exploration can result in contact with animal hosts. Military and peacekeeping personnel on active duty in the field are at risk if they are exposed to rodents, ticks or mosquito vectors.

  The risk of animal importation to the West was exemplified by outbreaks of Marburg disease involving 31 people, including 6 secondary cases, in Frankfurt, Marburg and Belgrade in 1967 [103], traced to monkeys used to provide tissue for cell-culture lines. Asymptomatic seroconversions have occurred in animal handlers looking after macaque monkeys imported from the Philippines, resulting in transmission of a strain A c c e p t e d M a n u s c r i p tof Ebola within a primate facility in Reston, Virginia[START_REF] Jahrling | Preliminary report: isolation of Ebola virus from monkeys imported to USA[END_REF], and in pig handlers in the Philippines[START_REF] Barrette | Discovery of swine as a host for the Reston Ebolavirus[END_REF]. Imported rodent cell lines have been the source of hantavirus infections in laboratory workers in the UK[START_REF] Lloyd | Infection of laboratory workers with hantavirus acquired from immunocytomas propagated in laboratory rats[END_REF]. In the past, importation of infected mosquito vectors has been implicated in the transmission of YF, and this should be prevented by spraying aircraft that come from endemic areas [107].

  Most infections cause neutropenia, thrombocytopenia, proteinuria and raised transaminases, plus other laboratory abnormalities related to the infecting organism, such as renal failure with hantaviruses causing HFRS. Specific diagnosis largely rests on virus culture or rapid molecular tests; serological methods may help in acute cases, but are mainly useful in convalescence. Such tests should only be performed by prior arrangement with national reference centres[START_REF] Brouqui | Infection control in the management of highly pathogenic infectious diseases: consensus of the European Network of Infectious Disease[END_REF].

A

  c c e p t e d M a n u s c r i p t personnel. Apart from risks of direct exposure to blood and other fluids and tissues, there is a potential risk of aerosol dissemination. Specific virological tests should only be performed in designated laboratories by personnel trained to use biosafety level 4

6. 1 .

 1 GeneralMany resources are available to inform travellers about potential health risks at their destination and while travelling. Healthcare workers who plan to work in an area endemic for a VHF should familiarize themselves with local risks and appropriate A c c e p t e d M a n u s c r i p t protective measures. Travellers in areas with mosquito-borne VHFs such as YF and RVF should take precautions to reduce the risk of bites, predominantly by Aedes mosquitoes, which are daytime and dusk feeders. This includes wearing longsleeved shirts and long trousers, and using repellents. Tick bites can be minimized by tucking trousers into socks and impregnating clothes with permethrin, and by avoiding direct contact with animals such as sheep, cattle and goats. Travellers potentially exposed to ticks should inspect themselves regularly and remove any attached ticks carefully, avoiding crushing the tick or handling it with unprotected fingers. Ticks are more easily seen on pale-coloured clothing. In Africa, travellers should not handle or eat non-human primate-derived 'bushmeat' and should not handle or consume uncooked meat, blood or secretions (including unpasteurized milk) from animals in CCHF-or RVF-endemic areas.

Table 2

 2 Lassa fever in travellers, 1969-2009 a

	Year	Country of origin	Imported to	Age	Gender Profession Fatal Comment	Reference
				(years)
	1969	Nigeria	USA	52	F	Nurse	No		[17]
	1971	Sierra Leone	UK	NS	F	Nurse	No	Retrospective in	[18]
								1972
	1971	Sierra Leone	UK	NS	M	Physician	No	Retrospective in	[18]
								1972
	1972	Sierra Leone	UK	35	F	Nurse	No		[19]
	1974	Nigeria	Germany	33	M	Physician	No		[20]

Acknowledgment

We thank Jo Lawrence of the Travel and Migrant Health Section, Centre for Infections, Health Protection Agency, for supplying aggregated data on enteric fever notifications in the UK.

Funding: None.

Competing interests: None declared.

Ethical approval: Not required.