Electrostatic Trapping of N_{2} Molecules in High Rydberg States.

N_{2} molecules traveling in pulsed supersonic beams have been excited from their X ^{1}Σ_{g}^{+} ground electronic state to long-lived Rydberg states with principal quantum numbers between 39 and 48 using a resonance-enhanced two-color three-photon excitation scheme. The Rydberg states populated had static electric dipole moments exceeding 5000 D which allowed deceleration of the molecules to rest in the laboratory-fixed frame of reference and three-dimensional trapping using inhomogeneous electric fields. The trapped molecules were confined for up to 10 ms, with effective trap decay time constants increasing with principal quantum number, and ranging from 450 to 700 µs. These observations, and comparison with the results of similar measurements with He atoms, indicate that the decay dynamics of the trapped Rydberg N_{2} molecules are dominated by spontaneous emission and do not exhibit significant contributions from effects of intramolecular interactions that lead to non-radiative decay.

Precision Microwave Spectroscopy of the Positronium 2

We report the results of a new measurement of the positronium 2 ^{3}S_{1}→2 ^{3}P_{2} (ν_{2}) interval. Using a modified experimental arrangement we have significantly reduced the effects of microwave reflections, which in previous experiments resulted in shifts and asymmetric line shapes. With the improved apparatus we obtain an experimental value of ν_{2}=8627.94±0.95 MHz, which is within 1.3σ of the theoretical value 8626.71±0.08 MHz.

Effects of rotational excitation on decay rates of long-lived Rydberg states in NO.

Nitric oxide (NO) molecules in pulsed supersonic beams have been excited to long-lived Rydberg-Stark states in series converging to the lowest vibrational level in the ground electronic state of NO+ with rotational quantum numbers N+ = 2, 4, and 6. The molecules in these excited states were then guided, or decelerated and trapped in a chip-based Rydberg-Stark decelerator, and detected in situ by pulsed electric field ionization. Time constants, reflecting the decay of molecules in N+ = 2 Rydberg-Stark states, with principal quantum numbers n between 38 and 44, from the electrostatic traps were measured to be ∼300µs. Molecules in Rydberg-Stark states with N+ = 4 and 6, and the same range of values of n were too short-lived to be trapped, but their decay time constants could be determined from complementary sets of delayed pulsed electric field ionization measurements to be ∼100 and ∼25 µs, respectively.

Cutaneous manifestations induced by check point inhibitors in 120 melanoma patients-The European MelSkinTox study.

BACKGROUND: Checkpoint inhibitors provide an effective approach for the melanoma treatment. They prolong lymphocyte effects, which explains the cytotoxicity underlying immune-related adverse events (IrAEs). Cutaneous IrAEs affect nearly 40% of PD-1i and 50% of CTLA4i-treated patients. Severe cutaneous irAE do not often occur but could be life-threatening and may persist despite treatment discontinuation. METHODS: We aimed to investigate cutaneous IrAEs in a cohort of patients treated with ICI across Europe in an effort to characterize the reactions in a real-world, phase IV, post-marketing study using a follow-up questionnaire. Data since November 2016 until March 2021 were obtained from the Melskintox database, a European multicentric biobank dedicated to the follow-up of melanoma and cutaneous adverse events, supported by EADO. The dermatoses reported were pooled into four categories: inflammatory dermatosis, bullous diseases, drug-related eruptions and pigmentary diseases. RESULTS: Inflammatory benign dermatoses (n = 63) represented the most common group of reactions (52.5%), followed by drug-related eruptions (n = 24, 20%), pigmentary diseases (n = 23, 19.2%) and bullous diseases (n = 10, 8.3%). Grade II (n = 41, 34.2%) are represented by bullous pemphigoid, eczema, hypodermitis, lichenoid eruption, maculopapular rash, pruritus, psoriasis-like rash, urticarial eruption and vitiligo. Grade III (n = 18, 15.0%) are represented by bullous pemphigoid, lichenoid eruption and rashes. Grade IV (n = 2, 1.7%) is only represented by bullous disease. Most cutaneous IrAEs led to immunotherapy continuation (n = 95, 88.0%). CR is associated with more severe the cutaneous irAEs. We report an average time-to-onset of 208 days and some late-onset events. CONCLUSION: Our study has characterized the clinical spectrum of cutaneous irAEs, their timing and severity and their relationship with tumour response. Grade I-II cutaneous IrAE are easily managed allowing ongoing anticancer treatment. Severe late-onset cutaneous irAE are not uncommon. A dermatological follow-up helps mitigate the risk of life-threatening adverse events. These findings highlight the importance of oncodermatological involvement in management of patients with melanoma receiving immunotherapy.

Interventions for basal cell carcinoma: abridged Cochrane systematic review and GRADE assessments.

BACKGROUND: Basal cell carcinoma (BCC) is the most common cancer affecting white-skinned individuals, and the worldwide incidence is increasing. Although rarely fatal, BCC is associated with significant morbidity and costs. OBJECTIVES: To assess the effects of interventions for primary BCC in immunocompetent adults. METHODS: We updated our searches of the following databases to November 2019: Cochrane Skin Group Specialised Register, CENTRAL, MEDLINE, Embase, CINAHL and LILACS. Certainty of evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation method. We used standard methodological procedures expected by Cochrane. RESULTS: We included 52 randomized controlled trials with 6990 participants (median age 65 years; range 20-95). Mean study duration was 13 months (range 6 weeks-10 years). Ninety-two per cent (n = 48/52) of studies exclusively included histologically low-risk BCC (nodular and superficial subtypes). The certainty of evidence was predominantly low or moderate for the outcomes of interest. Overall, surgical interventions have the lowest recurrence rates, and there may be slightly fewer recurrences with Mohs micrographic surgery over surgical excision for primary, facial BCC (high-risk histological subtype or located in the 'H-zone' or both) (low-certainty evidence). Nonsurgical treatments, when used for low-risk BCC, are less effective than surgical treatments, but recurrence rates are acceptable and cosmetic outcomes are probably superior. CONCLUSIONS: Surgical interventions have lower recurrence rates and remain the gold standard for high-risk BCC. Of the nonsurgical treatments, topical imiquimod has the best evidence to support its efficacy for low-risk BCC. Priorities for future research include agreement on core outcome measures and studies with longer follow-up.

Quantum-state-dependent decay rates of electrostatically trapped Rydberg NO molecules.

Nitric oxide (NO) molecules travelling in pulsed supersonic beams have been prepared in long-lived Rydberg-Stark states by resonance-enhanced two-colour two-photon excitation from the X 2Π1/2 (v'' = 0, J'' = 3/2) ground state, through the A 2Σ+ (v' = 0, N' = 0, J' = 1/2) intermediate state. These excited molecules were decelerated from 795 ms-1 to rest in the laboratory-fixed frame of reference, in the travelling electric traps of a transmission-line Rydberg-Stark decelerator. The decelerator was operated at 30 K to minimise effects of blackbody radiation on the molecules during deceleration and trapping. The molecules were electrostatically trapped for times of up to 1 ms, and detected in situ by pulsed electric field ionisation. Measurements of the rate of decay from the trap were performed for states with principal quantum numbers between n = 32 and 50, in Rydberg series converging to the N+= 0, 1, and 2 rotational states of NO+. For the range of Rydberg states studied, the measured decay times of between 200 µs and 400 µs were generally observed to reduce as the value of n was increased. For some particular values of n deviations from this trend were seen. These observations are interpreted, with the aid of numerical calculations, to arise as a result of contributions to the decay rates, on the order of 1 kHz, from rotational and vibrational channel interactions. These results shed new light on the role of weak intramolecular interactions on the slow decay of long-lived Rydberg states in NO.

Two dimensionless parameters and a mechanical analogue for the HKB model of motor coordination.

The widely cited Haken-Kelso-Bunz (HKB) model of motor coordination is used in an enormous range of applications. In this paper, we show analytically that the weakly damped, weakly coupled HKB model of two oscillators depends on only two dimensionless parameters; the ratio of the linear damping coefficient and the linear coupling coefficient and the ratio of the combined nonlinear damping coefficients and the combined nonlinear coupling coefficients. We illustrate our results with a mechanical analogue. We use our analytic results to predict behaviours in arbitrary parameter regimes and show how this led us to explain and extend recent numerical continuation results of the full HKB model. The key finding is that the HKB model contains a significant amount of behaviour in biologically relevant parameter regimes not yet observed in experiments or numerical simulations. This observation has implications for the development of virtual partner interaction and the human dynamic clamp, and potentially for the HKB model itself.

Assessment of the response of indigenous microflora and inoculated Bacillus licheniformis endospores in reconstituted skim milk to microwave and conventional heating systems by flow cytometry.

Heat treatment is one of the most widely used processing technologies in the dairy industry. Its primary purpose is to destroy microorganisms, both pathogenic and spoilage, to ensure the product is safe and has a reasonable shelf life. In this study microwave volumetric heating (MVH) was compared with a conventional tubular heat exchanger (THE), in terms of the effects of each at a range of temperatures (75°C, 85°C, 95°C, 105°C, 115°C, and 125°C) on indigenous microflora viability and the germination of inoculated Bacillus licheniformis endospores in reconstituted skim milk. To assess the heat treatment-related effects on microbial viability, classical agar-based tests were applied to obtain the counts of 4 various microbiological groups including total bacterial, thermophilic bacterial, mesophilic aerobic bacterial endospore, and thermophilic aerobic bacterial endospore counts, and additional novel insights into cell permeability and spore germination profiles post-heat treatment were obtained using real-time flow cytometry (FC) methods. No significant differences in the plate counts of the indigenous microorganisms tested, the plate counts of the inoculated B. licheniformis, or the relative percentage of germinating endospores were observed between MVH- and THE-treated samples, at equal temperatures in the range specified above, indicating that both methods inactivated inoculated endospores to a similar degree (up to 70% as measured by FC and 5 log reduction as measured by plate counting for some treatments of inoculated endospores). Furthermore, increased cell permeability of indigenous microflora was observed by FC after MVH compared with THE treatment of uninoculated skim milk, which was reflected in lower total bacterial count at a treatment temperature of 105°C. This work demonstrates the utility of FC as a rapid method for assessing cell viability and spore inactivation for postthermal processing in dairy products and overall provides evidence that MVH is at least as effective at eliminating native microflora and inoculated B. licheniformis endospores as THE.

Developments allergy in 2019 through the eyes of Clinical and Experimental Allergy, Part II clinical allergy.

In the second of two linked articles, we describe the development in clinical as described by Clinical & Experimental Allergy and other journals in 2019. Epidemiology, clinical allergy, asthma and rhinitis are all covered. In this article, we described the development in the field of allergy as described by Clinical and Experimental Allergy in 2019. Epidemiology, clinical allergy, asthma and rhinitis are all covered.

Developments allergy in 2019 through the eyes of clinical and experimental allergy, part I mechanisms.

In the first of two linked articles, we describe the development in the mechanisms underlying allergy as described by Clinical & Experimental Allergy and other journals in 2019. Experimental models of allergic disease, basic mechanisms, clinical mechanisms and allergens are all covered.

Coupling Rydberg Atoms to Microwave Fields in a Superconducting Coplanar Waveguide Resonator.

Rydberg helium atoms traveling in pulsed supersonic beams have been coupled to microwave fields in a superconducting coplanar waveguide (CPW) resonator. The atoms were initially prepared in the 1s55s ^{3}S_{1} Rydberg level by two-color two-photon laser excitation from the metastable 1s2s ^{3}S_{1} level. Two-photon microwave transitions between the 1s55s ^{3}S_{1} and 1s56s ^{3}S_{1} levels were then driven by the 19.556 GHz third-harmonic microwave field in a quarter-wave CPW resonator. This superconducting microwave resonator was fabricated from niobium nitride on a silicon substrate and operated at temperatures between 3.65 and 4.30 K. The populations of the Rydberg levels in the experiments were determined by state-selective pulsed electric field ionization. The coherence of the atom-resonator coupling was studied by time-domain measurements of Rabi oscillations.

Precision Microwave Spectroscopy of the Positronium n=2 Fine Structure.

We report a new measurement of the positronium (Ps) 2^{3}S_{1}→2^{3}P_{0} interval. Slow Ps atoms, optically excited to the radiatively metastable 2^{3}S_{1} level, flew through a microwave radiation field tuned to drive the transition to the short-lived 2^{3}P_{0} level, which was detected via the time spectrum of subsequent ground state Ps annihilation radiation. After accounting for Zeeman shifts we obtain a transition frequency ν_{0}=18501.02±0.61 MHz, which is not in agreement with the theoretical value of ν_{0}=18498.25±0.08 MHz.

Slow Decay Processes of Electrostatically Trapped Rydberg NO Molecules.

Nitric oxide (NO) molecules initially traveling at 795 m/s in pulsed supersonic beams have been photoexcited to long-lived hydrogenic Rydberg-Stark states, decelerated and electrostatically trapped in a cryogenically cooled, chip-based transmission-line Rydberg-Stark decelerator. The decelerated and trapped molecules were detected in situ by pulsed electric field ionization. The operation of the decelerator was validated by comparison of the experimental data with the results of numerical calculations of particle trajectories. Studies of the decay of the trapped molecules on timescales up to 1 ms provide new insights into the lifetimes of, and effects of blackbody radiation on, Rydberg states of NO.

Excitation and characterization of long-lived hydrogenic Rydberg states of nitric oxide.

High Rydberg states of nitric oxide (NO) with principal quantum numbers between 40 and 100 and lifetimes in excess of 10 µs have been prepared by resonance enhanced two-color two-photon laser excitation from the X 2Π1/2 ground state through the A 2Σ+ intermediate state. Molecules in these long-lived Rydberg states were detected and characterized 126 µs after laser photoexcitation by state-selective pulsed electric field ionization. The laser excitation and electric field ionization data were combined to construct two-dimensional spectral maps. These maps were used to identify the rotational states of the NO+ ion core to which the observed series of long-lived hydrogenic Rydberg states converge. The results presented pave the way for Rydberg-Stark deceleration and electrostatic trapping experiments with NO, which are expected to shed further light on the decay dynamics of these long-lived excited states, and are of interest for studies of ion-molecule reactions at low temperatures.

Developments in the field of clinical allergy in 2018 through the eyes of Clinical and Experimental Allergy, Part II.

In this article, we describe developments in the field of clinical allergy as described by Clinical and Experimental Allergy in 2018; epidemiology, asthma and rhinitis, clinical allergy and allergens are all covered.

Confinement of High- and Low-Field-Seeking Rydberg Atoms Using Time-Varying Inhomogeneous Electric Fields.

Helium atoms in high- and low-field-seeking Rydberg states with linear and quadratic Stark shifts have been confined in two dimensions and guided over a distance of 150 mm using time-varying inhomogeneous electric fields. This was achieved with an electrode structure composed of four parallel cylindrical rods to which voltages were applied to form oscillating and rotating saddle-point fields. These two modes of operation result in time-averaged pseudopotentials that confine samples in high- and low-field-seeking states about the axis of the device. The experimental data have been compared to the results of numerical particle trajectory calculations that include effects of blackbody radiation and electric field ionization. The results highlight important contributions from single-photon blackbody-induced transitions that cause large changes in the principal quantum number of the Rydberg atoms.

Electric Rydberg-Atom Interferometry.

An electric analogue of the longitudinal Stern-Gerlach matter-wave interferometer has been realized for atoms in Rydberg states with high principal quantum number n. The experiments were performed with He atoms prepared in coherent superpositions of the n=55 and n=56 circular Rydberg states in a zero electric field by a π/2 pulse of resonant microwave radiation. These atoms were subjected to a pulsed inhomogeneous electric field to generate a superposition of momentum states before a π pulse was applied to invert the internal states. The same pulsed inhomogeneous electric field was then reapplied for a second time to transform the motional states to have equal momenta before a further π/2 pulse was employed to interrogate the final Rydberg state populations. This Hahn-echo microwave pulse sequence, interspersed with a pair of equivalent inhomogeneous electric field pulses, yielded two spatially separated matter waves. Interferences between these matter waves were observed as oscillations in the final Rydberg state populations as the amplitude of the pulsed electric field gradients was adjusted.

Novel Treatment of Staphylococcus aureus Device-Related Infections Using Fibrinolytic Agents.

Staphylococcal infections involving biofilms represent a significant challenge in the treatment of patients with device-related infections. Staphylococcus aureus biofilms have been shown to be SaeRS regulated and dependent on the coagulase-catalyzed conversion of fibrinogen into fibrin on surfaces coated with human plasma. Here we investigated the treatment of staphylococcal biofilm device-related infections by digesting the fibrin biofilm matrix with and without existing antimicrobials. The fibrinolytic agents plasmin, streptokinase, and nattokinase, and TrypLE, a recombinant trypsin-like protease, were used to digest and treat S. aureus biofilms grown in vitro using in vivo-like static biofilm assays with and without antimicrobials. Cytotoxicity, the potential to induce a cytokine response in whole human blood, and the risk of induction of tolerance to fibrinolytic agents were investigated. A rat model of intravascular catheter infection was established to investigate the efficacy of selected fibrinolytic agents in vivo Under biomimetic conditions, the fibrinolytic agents effectively dispersed established S. aureus biofilms and, in combination with common antistaphylococcal antimicrobials, effectively killed bacterial cells being released from the biofilm. These fibrinolytic agents were not cytotoxic and did not affect the host immune response. The rat model of infection successfully demonstrated the activity of the selected fibrinolytic agents alone and in combination with antimicrobials on established biofilms in vivo TrypLE and nattokinase most successfully removed adherent cells from plasma-coated surfaces and significantly improved the efficacy of existing antimicrobials against S. aureus biofilms in vitro and in vivo These biofilm dispersal agents represent a viable future treatment option for S. aureus device-related infections.

Developments in the field of allergy in 2017 through the eyes of Clinical and Experimental Allergy.

In this article, we described the development in the field of allergy as described by Clinical and Experimental Allergy in 2017. Experimental models of allergic disease, basic mechanisms, clinical mechanisms, allergens, asthma and rhinitis and clinical allergy are all covered.

Genetics and Crime: Integrating New Genomic Discoveries Into Psychological Research About Antisocial Behavior.

Drawing on psychological and sociological theories of crime causation, we tested the hypothesis that genetic risk for low educational attainment (assessed via a genome-wide polygenic score) is associated with criminal offending. We further tested hypotheses of how polygenic risk relates to the development of antisocial behavior from childhood through adulthood. Across the Dunedin and Environmental Risk (E-Risk) birth cohorts of individuals growing up 20 years and 20,000 kilometers apart, education polygenic scores predicted risk of a criminal record with modest effects. Polygenic risk manifested during primary schooling in lower cognitive abilities, lower self-control, academic difficulties, and truancy, and it was associated with a life-course-persistent pattern of antisocial behavior that onsets in childhood and persists into adulthood. Crime is central in the nature-nurture debate, and findings reported here demonstrate how molecular-genetic discoveries can be incorporated into established theories of antisocial behavior. They also suggest that improving school experiences might prevent genetic influences on crime from unfolding.