The potential negative impact of antibiotic pack on antibiotic stewardship in primary care in Switzerland: a modelling study.

BACKGROUND: In Switzerland, oral antibiotics are dispensed in packs rather than by exact pill-count. We investigated whether available packs support compliance with recommended primary care treatment regimens for common infections in children and adults. METHODS: Hospital-based guidelines for oral community -based treatment of acute otitis media, sinusitis, tonsillopharyngitis, community-acquired pneumonia and afebrile urinary tract infection were identified in 2017 in an iterative process by contacting hospital pharmacists and infectious diseases specialists. Furthermore, newly available national guidelines published in 2019 were reviewed. Available pack sizes for recommended solid, dispersible and liquid antibiotic formulations were retrieved from the Swiss pharmaceutical register and compared with recommended regimens to determine optimal (no leftovers) and adequate (optimal +/- one dose) matches. RESULTS: A large variety of recommended regimens were identified. For adults, optimal and adequate packs were available for 25/70 (36%) and 8/70 (11%) regimens, respectively. Pack-regimen matching was better for WHO Watch (optimal: 15/24, 63%) than Access antibiotics (optimal: 7/39, 18%). For the four paediatric weight-examples and 42 regimens involving child-appropriate formulations, optimal and adequate packs were available for only 14/168 (8%) and 27/168 (16%), respectively. Matching was better for older children with higher body and for longer treatment courses > 7 days. CONCLUSIONS: Fixed antibiotic packs often do not match recommended treatment regimens, especially for children, potentially resulting in longer than necessary treatments and leftover doses in the community. As part of national stewardship, a move to an exact pill-count system, including for child-appropriate solid formulations, should be considered

Unambiguous state discrimination in quantum cryptography with weak coherent states

The use of linearly independent signal states in realistic implementations of quantum key distribution (QKD) enables an eavesdropper to perform unambiguous state discrimination. We explore quantitatively the limits for secure QKD imposed by this fact taking into account that the receiver can monitor to some extend the photon number statistics of the signals even with todays standard detection schemes. We compare our attack to the beamsplitting attack and show that security against beamsplitting attack does not necessarily imply security against the attack considered here.Comment: 10 pages, 6 figures, updated version with added discussion of beamsplitting attac

Photon tunneling through absorbing dielectric barriers

Using a recently developed formalism of quantization of radiation in the presence of absorbing dielectric bodies, the problem of photon tunneling through absorbing barriers is studied. The multilayer barriers are described in terms of multistep complex permittivities in the frequency domain which satisfy the Kramers--Kronig relations. From the resulting input--output relations it is shown that losses in the layers may considerably change the photon tunneling times observed in two-photon interference experiments. It is further shown that for sufficiently large numbers of layers interference fringes are observed that cannot be related to a single traversal time.Comment: 17 pages LaTeX, 9 figures (PS) include

Insights into the interactions between Replication Protein A and the ubiquitin ligase Rad18 from Saccharomyces cerevisiae.

DNA damage may lead to mutations and loss of genome integrity. Lesions encountered during replication cause the replication machinery to stall and, unless repaired or bypassed, can result in lethality of the cell. The DNA polymerase processivity clamp, PCNA (proliferating cell nuclear antigen), mediates either mutagenic damage bypass or error-free damage avoidance through its post-translational modification states. Mono-ubiquitylated PCNA stimulates the activity of translesion DNA polymerases, while poly-ubiquitylation of PCNA is a pre-requisite for error-free damage avoidance by a yet unknown mechanism. Recent findings in the laboratory suggested that Replication Protein A (RPA), an essential single-stranded (ss) DNA-binding protein, is required for induction of PCNA ubiquitylation upon DNA damage. Consequently, the aim of my thesis was to gain further insight into the mechanism by which RPA is involved in the up-stream signals that activate PCNA modification. The Rad18 protein from Saccharomyces cerevisiae (S. cerevisiae) is the ubiquitin ligase (E3) responsible for PCNA mono-ubiquitylation. The interactions of Rad18 with DNA and RPA, and the effects of this interaction on Rad18 binding to ssDNA, were studied in detail. Recombinant Rad18 was purified as a complex with its ubiquitin-conjugating enzyme, Rad6. Their stable association and ubiquitin conjugation activity was verified. Furthermore, basal levels of PCNA ubiquitylation were reconstituted in vitro. Yeast Rad18 was reported by others to bind preferentially to ssDNA over dsDNA. The intrinsic ssDNA-binding activity of the recombinant Rad18 protein was confirmed by pull-down assays using biotinylated oligonucleotides. Importantly, Rad18 is able to bind to ssDNA and to other ssDNA-containing structures, but also to forked-DNA consisting entirely of double-stranded (ds) DNA regions. Rad18 binding to DNA was demonstrated to be dependent on the ionic strength of the buffer. At low salt concentrations Rad18 was found to stably associate with ssDNA. At moderate to high salt concentrations, including in ionic strength conditions that could be considered physiological, Rad18 did not bind to ssDNA. Interestingly, binding to ssDNA at low ionic strength confers a stable association of Rad18 with the DNA for subsequent high ionic strength conditions. Taken together, these findings suggest that Rad18 binds to ssDNA at low salt concentrations with low affinity. Thereafter, a slow conformational change leads to an increased binding affinity that renders the ssDNA-bound Rad18 stable association with the ssDNA in high salt concentrations. Furthermore, these findings argue against the speculation that Rad18 can bind to sites of DNA damage in vivo by itself. In vitro experiments further demonstrated that the yeast Rad18-Rad6 complex interacts physically with RPA. The findings in this work support a mechanism through which both proteins bind directly to RPA. Further analysis of recombinant RPA subunits revealed that both Rfa2 and the DNA-binding domain of Rfa1 contribute independently to the specific interactions with the complex. Interestingly, the association between the Rad18-Rad6 complex and the DNA-binding domain of Rfa1 is stimulated by the presence of ssDNA. Furthermore, at physiological ionic strength, RPA recruits the Rad18-Rad6 complex to ssDNA. These findings support a model by which RPA-coated ssDNA recruits Rad18 to sites of DNA damage. Thus, ssDNA-bound RPA may provide the up-stream signal for the activation of the DNA damage tolerance pathway and for PCNA ubiquitylation. Although this has yet to be clarified, most likely the interactions of Rad18 with both RPA and DNA contribute to its localisation to stalled replication forks in vivo. Although the SAP domain of human Rad18 was reported to be both necessary and sufficient for its interactions with DNA, the results obtained in this work suggest that this function may not be conserved in yeast. Nevertheless, this domain is essential for the in vivo function of yeast Rad18. Although its effect may be indirect, the SAP domain appears to contribute to the correct conformation of the Rad18 protein and to facilitate the interaction of the E3 with PCNA, thereby allowing the ubiquitylation of the clamp

Unambiguous State Discrimination of Coherent States with Linear Optics: Application to Quantum Cryptography

We discuss several methods for unambiguous state discrimination of N symmetric coherent states using linear optics and photodetectors. One type of measurements is shown to be optimal in the limit of small photon numbers for any N. For the special case of N=4 this measurement can be fruitfully used by the receiving end (Bob) in an implementation of the BB84 quantum key distribution protocol using faint laser pulses. In particular, if Bob detects only a single photon the procedure is equivalent to the standard measurement that he would have to perform in a single-photon implementation of BB84, if he detects two photons Bob will unambiguously know the bit sent to him in 50% of the cases without having to exchange basis information, and if three photons are detected, Bob will know unambiguously which quantum state was sent.Comment: 5 RevTeX pages, 2 eps figure

Experimental Demonstration of Optimal Unambiguous State Discrimination

We present the first full demonstration of unambiguous state discrimination between non-orthogonal quantum states. Using a novel free space interferometer we have realised the optimum quantum measurement scheme for two non-orthogonal states of light, known as the Ivanovic-Dieks-Peres (IDP) measurement. We have for the first time gained access to all three possible outcomes of this measurement. All aspects of this generalised measurement scheme, including its superiority over a standard von Neumann measurement, have been demonstrated within 1.5% of the IDP predictions

Oscillator model for dissipative QED in an inhomogeneous dielectric

The Ullersma model for the damped harmonic oscillator is coupled to the quantised electromagnetic field. All material parameters and interaction strengths are allowed to depend on position. The ensuing Hamiltonian is expressed in terms of canonical fields, and diagonalised by performing a normal-mode expansion. The commutation relations of the diagonalising operators are in agreement with the canonical commutation relations. For the proof we replace all sums of normal modes by complex integrals with the help of the residue theorem. The same technique helps us to explicitly calculate the quantum evolution of all canonical and electromagnetic fields. We identify the dielectric constant and the Green function of the wave equation for the electric field. Both functions are meromorphic in the complex frequency plane. The solution of the extended Ullersma model is in keeping with well-known phenomenological rules for setting up quantum electrodynamics in an absorptive and spatially inhomogeneous dielectric. To establish this fundamental justification, we subject the reservoir of independent harmonic oscillators to a continuum limit. The resonant frequencies of the reservoir are smeared out over the real axis. Consequently, the poles of both the dielectric constant and the Green function unite to form a branch cut. Performing an analytic continuation beyond this branch cut, we find that the long-time behaviour of the quantised electric field is completely determined by the sources of the reservoir. Through a Riemann-Lebesgue argument we demonstrate that the field itself tends to zero, whereas its quantum fluctuations stay alive. We argue that the last feature may have important consequences for application of entanglement and related processes in quantum devices.Comment: 24 pages, 1 figur