Factors associated with daptomycin consumption in French hospitals between 2019 and 2020: A nationwide surveillance study.

OBJECTIVES: This study aimed to investigate factors associated with daptomycin consumption in French healthcare facilities (HCF) between 2019 and 2020. METHODS: Antibiotic consumption expressed as number of defined daily doses (DDD) per 1,000 patient-days (PD) and antimicrobial resistance (AMR) expressed as incidence densities per 1,000PD were extracted each year from the nationwide surveillance network run by the SPARES project (Surveillance and Prevention of Antimicrobial RESistance in hospitals), collecting data at ward level among voluntary HCFs using standardized methodology and webtool. All HCF participating both in 2019 and 2020 were included. A multivariable linear regression was fitted. RESULTS: Among 622 HCFs, we analyzed daptomycin consumption and AMR data in 1,637 clinical wards. Incidence densities of methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-resistant coagulase-negative staphylococci (MRCNS) were the highest in intensive care unit wards (0.54 and 6.83 respectively in 2020). On the most adjusted model, the year 2020 was correlated with a higher daptomycin consumption (1.53; p = 0.01). A greater number of inpatient beds (0.01; p < 0.001), the presence of orthopedic surgery activity in the HCF (1.66; p < 0.02), MRSA (4.38; p < 0.001) and MRCNS (0.61; p < 0.001) incidence densities were associated with a higher daptomycin use. The final model explained 18% of the observed variance. CONCLUSIONS: This study showed that daptomycin consumption was correlated to MRSA and MRCNS incidence densities, to the year 2020 and to non-modifiable HCF-related factors. Prevention of coagulase-negative staphylococci infections should be considered by antimicrobial stewardship teams when daptomycin use is going up in HCF.

The PerPAIN trial: a pilot randomized controlled trial of personalized treatment allocation for chronic musculoskeletal pain-a protocol.

BACKGROUND: The therapy of chronic musculoskeletal pain (CMSP) is complex and the treatment results are often insufficient despite numerous therapeutic options. While individual patients respond very well to specific interventions, other patients show no improvement. Personalized treatment assignment offers a promising approach to improve response rates; however, there are no validated cross-disease allocation algorithms available for the treatment of chronic pain in validated personalized pain interventions. This trial aims to test the feasibility and safety of a personalized pain psychotherapy allocation with three different treatment modules and estimate initial signals of efficacy and utility of such an approach compared to non-personalized allocation. METHODS: This is a randomized, controlled assessor-blinded pilot trial with a multifactorial parallel arm design. CMSP patients (n = 105) will be randomly assigned 1:1 to personalized or non-personalized treatment based on a cluster assignment of the West Haven-Yale Multidimensional Pain Inventory (MPI). In the personalized assignment condition, patients with high levels of distress receive an emotional distress-tailored intervention, patients with pain-related interference receive an exposure/extinction-tailored treatment intervention and patients who adapt relatively well to the pain receive a low-level smartphone-based activity diary intervention. In the control arm, patients receive one of the two non-matching interventions. Effect sizes will be calculated for change in core pain outcome domains (pain intensity, physical and emotional functioning, stress experience, participant ratings of improvement and satisfaction) after intervention and at follow-up. Feasibility and safety outcomes will assess rates of recruitment, retention, adherence and adverse events. Additional data on neurobiological and psychological characteristics of the patients are collected to improve treatment allocation in future studies. CONCLUSION: Although the call for personalized treatment approaches is widely discussed, randomized controlled trials are lacking. As the personalization of treatment approaches is challenging, both allocation and intervention need to be dynamically coordinated. This study will test the feasibility and safety of a novel study design in order to provide a methodological framework for future multicentre RCTs for personalized pain psychotherapy. TRIAL REGISTRATION: German Clinical Trials Register, DRKS00022792 ( https://www.drks.de ). Prospectively registered on 04/06/2021.

Cluster binding studies with two anti-Thomsen-Friedenreich (anti-core-1, CD176, TF) antibodies: Evidence for a multiple TF epitope.

Antibodies to carbohydrate epitopes are often of the IgM isotype and require multiple binding for sufficient avidity. Therefore clusters of epitopes are preferred antigenic sites in these cases. We have examined the type of clusters recognized by two anti-Thomsen-Friedenreich (TF, core-1, CD176) IgM antibodies, NM-TF1 and NM-TF2, using several different sets of TF-carrying synthetic glycoconjugates in ELISA experiments. To our surprise, the single most important factor determining binding strength was a close vicinity of several TF glycans at distances of ≤1 nm. Considering the known dimensions of IgM antibodies, our data strongly suggest that a cluster of up to four TF moieties, presenting as a "multiple epitope", is required to attach to a single combining site in order to result in adequate binding strength. This effect can also be achieved by "surrogate-multiple epitopes" consisting of separate TF-carrying molecules in close vicinity. In addition, it was found that serine-linked TFs are stronger bound than threonine-linked TFs by both antibodies. This peculiar type of cluster recognition may contribute to improved avidity and explicit tumor specificity.

Visually induced analgesia during massage treatment in chronic back pain patients.

BACKGROUND: Previous findings suggest that watching sites of experimental and chronic pain can exert an analgesic effect. Our present study investigates whether watching one's back during massage increases the analgesic effect of this treatment in chronic back pain patients. METHODS: Twenty patients with chronic back pain were treated with a conventional massage therapy. During this treatment, patients received a real-time video feedback of their own back. Watching a neutral object, a video of another person of the same sex being massaged, a picture of the own back, and keeping one's eyes closed were used as controls. These conditions were presented in randomized order on five separate days. RESULTS: All conditions yielded significant decreases in habitual pain intensity. The effect of real-time video feedback of the own back on massage treatment was the strongest and differed significantly from the effect of watching a neutral object, but not from the other control conditions, which may have induced slight effects of their own. CONCLUSIONS: Repeated real-time video feedback may be useful during massage treatment of chronic pain. SIGNIFICANCE: This study shows that inducing visual induced analgesia during massage treatment can be helpful in alleviating chronic pain.

Watching your pain site reduces pain intensity in chronic back pain patients.

BACKGROUND: Chronic back pain (CBP) is a frequent debilitating and often treatment-resistant disorder. The awareness of one's own body seems to be essential in pain reduction through visual input. Visual feedback of the back reduces experimental pain perception in CBP at this site and watching the back during repeated lumbar spine movements reduces movement-evoked pain. In this study, we tested whether visual feedback alone can reduce habitual pain in CBP. METHODS: In a within-subject design, 19 CBP patients participated in an online visual feedback condition, watching one's own back. This was compared to several control conditions, such as watching a neutral object (book), a video of another person of the same sex, a picture of the own back, and keeping one's eyes closed in randomized order on five separate days. In each experimental session, participants rated habitual pain intensity and unpleasantness before and after the experimental manipulation. RESULTS: We present evidence that visual feedback by watching the site of chronic pain on a video screen alone is sufficient to reduce habitual chronic pain. No additional manipulation or movement was necessary. CONCLUSIONS: These results suggest that online video feedback may be helpful in alleviating chronic pain.

PDK1 controls upstream PI3K expression and PIP3 generation.

The PI3K/PDK1/Akt signaling axis is centrally involved in cellular homeostasis and controls cell growth and proliferation. Due to its key function as regulator of cell survival and metabolism, the dysregulation of this pathway is manifested in several human pathologies including cancers and immunological diseases. Thus, current therapeutic strategies target the components of this signaling cascade. In recent years, numerous feedback loops have been identified that attenuate PI3K/PDK1/Akt-dependent signaling. Here, we report the identification of an additional level of feedback regulation that depends on the negative transcriptional control of phosphatidylinositol 3-kinase (PI3K) class IA subunits. Genetic deletion of 3-phosphoinositide-dependent protein kinase 1 (PDK1) or the pharmacological inhibition of its downstream effectors, that is, Akt and mammalian target of rapamycin (mTOR), relieves this suppression and leads to the upregulation of PI3K subunits, resulting in enhanced generation of phosphatidylinositol-3,4,5-trisphosphate (PIP3). Apparently, this transcriptional induction is mediated by the concerted action of different transcription factor families, including the transcription factors cAMP-responsive element-binding protein and forkhead box O. Collectively, we propose that PDK1 functions as a cellular sensor that balances basal PIP3 generation at levels sufficient for survival but below a threshold being harmful to the cell. Our study suggests that the efficiency of therapies targeting the aberrantly activated PI3K/PDK1/Akt pathway might be increased by the parallel blockade of feedback circuits.

Effect of vildagliptin compared to glimepiride on postprandial proinsulin processing in the ß cell of patients with type 2 diabetes mellitus.

This study compared the effect of Glimepiride versus Vildagliptin on ß-cell function and the release of intact proinsulin (PI) in patients with type 2 diabetes mellitus. Patients on metformin monotherapy were randomized to add on treatment with Vildagliptin or Glimepiride. A standardized test meal was given at baseline, after 12 and 24 weeks of treatment. Insulin, PI and blood glucose values were measured in the fasting state and postprandial for 300 min. Fasting PI levels significantly decreased in the Vildagliptin group. The area under the curve for the postprandial release of PI decreased during Vildagliptin and increased during Glimepiride treatment. The proinsulin to insulin ratio declined in the Vildagliptin group, whereas it did not change significantly in the Glimepiride group. Addition of Vildagliptin to ongoing Metformin treatment reconstitutes the disproportionality of the proinsulin to insulin secretion from the ß cell.

Observation of non-Markovian dynamics of a single quantum dot in a micropillar cavity.

We measure the detuning-dependent dynamics of a quasiresonantly excited single quantum dot coupled to a micropillar cavity. The system is modeled with the dissipative Jaynes-Cummings model where all experimental parameters are determined by explicit measurements. We observe non-Markovian dynamics when the quantum dot is tuned into resonance with the cavity leading to a nonexponential decay in time. Excellent agreement between experiment and theory is observed with no free parameters providing the first quantitative description of an all-solid-state cavity QED system based on quantum dot emitters.

Dephasing of triplet-sideband optical emission of a resonantly driven InAs/GaAs quantum dot inside a microcavity.

Detailed properties of resonance fluorescence from a single quantum dot in a micropillar cavity are investigated, with particular focus on emission coherence in the dependence on optical driving field power and detuning. A power-dependent series over a wide range reveals characteristic Mollow triplet spectra with large Rabi splittings of |Ω|≤15 GHz. In particular, the effect of dephasing in terms of systematic spectral broadening ∝Ω(2) of the Mollow sidebands is observed as a strong fingerprint of excitation-induced dephasing. Our results are in excellent agreement with predictions of a recently presented model on phonon-dressed quantum dot Mollow triplet emission in the cavity-QED regime.

Post-selected indistinguishable photons from the resonance fluorescence of a single quantum dot in a microcavity.

Applying continuous-wave pure resonant s-shell optical excitation of individual quantum dots in a high-quality micropillar cavity, we demonstrate the generation of post-selected indistinguishable photons in resonance fluorescence. Close to ideal visibility contrast of 90% is verified by polarization-dependent Hong-Ou-Mandel two-photon interference measurements. Furthermore, a strictly resonant continuous-wave excitation together with controlling the spontaneous emission lifetime of the single quantum dots via tunable emitter-mode coupling (Purcell) is proven as a versatile scheme to generate close to Fourier transform-limited (T2/(2T1)=0.91) single photons even at 80% of the emission saturation level.

Control of the strong light-matter interaction between an elongated In_{0.3}Ga_{0.7}As quantum dot and a micropillar cavity using external magnetic fields.

We have studied a strongly coupled quantum dot-micropillar cavity system subject to an external magnetic field. The large diamagnetic response of elongated In_{0.3}Ga_{0.7}As quantum dots is exploited to demonstrate magneto-optical resonance tuning in the strong coupling regime. Furthermore, the magnetic field provides an additional degree of freedom to in situ manipulate the coupling constant. A transition from strong coupling towards the critical coupling regime is attributed to a reduction of the quantum dot oscillator strength when the magnetic confinement becomes significant with regards to the exciton confinement above 3 T.

The role of optical excitation power on the emission spectra of a strongly coupled quantum dot-micropillar system.

A strongly coupled quantum dot-micropillar cavity system is studied under variation of the excitation power. The characteristic double peak spectral shape of the emission with a vacuum Rabi splitting of 85 microeV at low excitation transforms gradually into a single broad emission peak when the excitation power is increased. Modelling the experimental data by a recently published formalism [Laussy et al., Phys. Rev. Lett. 101, 083601 (2008)] yields a transition from strong coupling towards weak coupling which is mainly attributed to an excitation power driven decrease of the exciton-photon coupling constant.

[Is there a link between the mercury release of amalgam fillings and the results of psychological questionnaires?]. / Gibt es Zusammenhänge zwischen der Quecksilberbelastung durch Amalgamfüllungen und Ergebnissen testpsychoIogischer Fragebogen-Untersuchungen?

Amalgam as a dental filling material shows excellent material property. It is fast, easy and economical to implement. Evidence for the release of mercury (Hg) from amalgam fillings was given in a number of studies. Mercury release from amalgam dental fillings is often claimed to be a possible cause of unspecific chronic symptoms such as chronic fatigue, headache and migraine. The present study explored relationships between the mercury release from amalgam fillings and the results of psychological questionnaires. The urine of 126 men and women in the age range of 16 to 76 years was examined. 45 participants did not present any amalgam restorations. The mercury released into the urine was measured by using cold-vapour AAS. The results of the study show that chronic mercury exposure, in the low concentration range, is not linked with chronic subjective symptoms.

Single quantum dot controlled lasing effects in high-Q micropillar cavities.

Lasing effects based on individual quantum dots have been investigated in optically pumped high-Q micropillar cavities. We demonstrate a lowering of the threshold pump power from a off-resonance value of 37 microW to 18 microW when an individual quantum dot exciton is on-resonance with the cavity mode. Photon correlation studies below and above the laser threshold confirm the single dot influence. At resonance we observe antibunching with g((2))(0) = 0.36 at low excitation, which increases to 1 at about 1.5 times the threshold. In the off-resonant case, g((2))(0) is about 1 below and above threshold.

Photon statistics of semiconductor microcavity lasers.

We present measurements of first- and second-order coherence of quantum-dot micropillar lasers together with a semiconductor laser theory. Our results show a broad threshold region for the observed high-beta microcavities. The intensity jump is accompanied by both pronounced photon intensity fluctuations and strong coherence length changes. The investigations clearly visualize a smooth transition from spontaneous to predominantly stimulated emission which becomes harder to determine for high beta. In our theory, a microscopic approach is used to incorporate the semiconductor nature of quantum dots. The results are in agreement with the experimental intensity traces and the photon statistics measurements.

Coherent photonic coupling of semiconductor quantum dots.

We report a new type of coupling between quantum dot excitons mediated by the strong single-photon field in a high-finesse micropillar cavity. Coherent exciton coupling is observed for two dots with energy differences of the order of the exciton-photon coupling. The coherent coupling mode is characterized by an anticrossing with a particularly large line splitting of 250 microeV. Because of the different dispersion relations with temperature, the simultaneous photonic coupling of quantum dot excitons can be easily distinguished from cases of sequential strong coupling of two quantum dots.

Strong coupling in a single quantum dot-semiconductor microcavity system.

Cavity quantum electrodynamics, a central research field in optics and solid-state physics, addresses properties of atom-like emitters in cavities and can be divided into a weak and a strong coupling regime. For weak coupling, the spontaneous emission can be enhanced or reduced compared with its vacuum level by tuning discrete cavity modes in and out of resonance with the emitter. However, the most striking change of emission properties occurs when the conditions for strong coupling are fulfilled. In this case there is a change from the usual irreversible spontaneous emission to a reversible exchange of energy between the emitter and the cavity mode. This coherent coupling may provide a basis for future applications in quantum information processing or schemes for coherent control. Until now, strong coupling of individual two-level systems has been observed only for atoms in large cavities. Here we report the observation of strong coupling of a single two-level solid-state system with a photon, as realized by a single quantum dot in a semiconductor microcavity. The strong coupling is manifest in photoluminescence data that display anti-crossings between the quantum dot exciton and cavity-mode dispersion relations, characterized by a vacuum Rabi splitting of about 140 microeV.

Efficient elimination of chronic lymphocytic leukaemia B cells by autologous T cells with a bispecific anti-CD19/anti-CD3 single-chain antibody construct.

Recently, we have shown that a novel recombinant bispecific single-chain antibody construct (bscCD19 x CD3), induces highly efficacious lymphoma-directed cytotoxicity mediated by unstimulated peripheral T lymphocytes. Functional analysis of bscCD19 x CD3 has so far been exclusively performed with human B lymphoma cell lines and T cells from healthy donors. Here we analysed the properties of bscCD19 x CD3 using primary B cells and autologous T cells from healthy volunteers or patients with B-cell chronic lymphocytic leukaemia (B-CLL). We show that bscCD19 x CD3 induces T-cell-mediated depletion of nonmalignant B cells in all four cases and depletion of primary lymphoma cells in 22 out of 25 cases. This effect could be observed at low effector-to-target (E:T) ratios and in the majority of cases without additional activation of autologous T cells by IL-2. Even in samples derived from patients heavily pretreated with different chemotherapy regimens, strong cytotoxic effects of bscCD19 x CD3 could be observed. The addition of bscCD19 x CD3 to patients' cells resulted in an upregulation of activation-specific cell surface antigens on autologous T cells and elevated levels of CD95 on lymphoma B cells. Although anti-CD95 antibody CH-11 failed to induce apoptosis in lymphoma cells, we provide evidence that B-CLL cell depletion by bscCD3 x CD3 is mediated at least in part by apoptosis via the caspase pathway.

Efficiency of root torquing auxiliaries.

In an experimental typodont study simulating the third stage of Tip-Edge treatment, the effect of five torquing auxiliaries on upper four incisors was assessed using the method of laser reflection. The auxiliaries analysed were: (1) Two-Spurs 0.016", (2) Four-Spurs 0.016", (3) Reciprocal Lateral Torque 0.016", (4) Torque Bar 0.022x0.018", 20 degrees, and (5) Torque Bar 0.022x0.018, 30 degrees. When comparing the wires, the efficiency (amount and speed of root tipping) varied considerably: (1) The Two-Spurs wire was the most efficient auxiliary of the five tested and showed good torque effect on the central incisors. (2) The Four-Spurs wire acting on all four incisors was less efficient than the Two-Spurs wire. (3) The Reciprocal Lateral Torque wire exhibited good palatal root torque on the central incisors and labial root torque on the lateral incisors. (4) The Torque Bars (20 degrees and 30 degrees ) were the least efficient wires of the auxiliaries tested and showed only small torque effects on the central and lateral incisor teeth. In clinical work using the Tip-Edge technique, the Two-Spurs torquing auxiliary should be the wire of choice for an efficient palatal root torque of the upper central incisors.