Dimers Aren't Forever: CD80 Breaks up with PD-L1

Targeting the CTLA-4 and PD-1 “checkpoints” is an effective treatment for a number of cancers. In this issue of Immunity, Hui et al. reveal that interaction between a CTLA-4 ligand, CD80, and its counterpart in the PD-1 pathway, PD-L1, affects both PD-1 and CTLA-4 function, raising new questions about the biological effects of using checkpoint inhibitors alone and in combination

Electrometry of a single resonator mode at a Rydberg-atom–superconducting-circuit interface

The electric-field distribution in a single mode of a λ/4 superconducting coplanar waveguide (CPW) microwave resonator has been probed using beams of helium Rydberg atoms. In the experiments the atoms were prepared in the 1s55s3S1 Rydberg level by laser photoexcitation. They then traveled over the CPW resonator that was fabricated on a NbN superconducting chip operated at 3.8 K. The resonator was driven at its third-harmonic frequency, near resonant with the two-photon 1s55s3S1→1s56s3S1 transition at ω55s,56s/2=2π×19.556499 GHz. The coherence times of the atom–resonator-field interaction were determined at selected locations above the resonator by time-domain measurements of Rabi oscillations and found to be up to 0.8μs for Rabi frequencies of ∼2π×3 MHz. The coherence times of the atomic superposition states, generated following the interaction of the atoms with the microwave field in the resonator, were inferred from high-resolution cavity-enhanced Ramsey spectra to be ∼2.5μs. These Ramsey spectra also allowed the measurement of residual uncanceled dc electric fields of 26.6±0.6 mV/cm at the position of the atoms ∼300μm above the surface of the superconducting chip. These results represent an essential step toward applications of hybrid systems, comprising Rydberg atoms coherently coupled to superconducting microwave circuits, in quantum optics and quantum information processing

Cavity-enhanced Ramsey spectroscopy at a Rydberg-atom–superconducting-circuit interface

The coherent interaction of Rydberg helium atoms with microwave fields in a λ/4 superconducting coplanar waveguide resonator has been exploited to probe the spectral characteristics of an individual resonator mode. This was achieved by preparing the atoms in the 1s55s 3S1 Rydberg level by resonance enhanced two-color two-photon excitation from the metastable 1s2s 3S1 level. The atoms then traveled over the resonator in which the third harmonic microwave field, at a frequency of ωres=2π×19.556 GHz, drove the two-photon 1s55s 3S1 → 1s56s 3S1 transition. By injecting a sequence of Ramsey pulses into the resonator and monitoring the coherent evolution of the Rydberg state population by state-selective pulsed electric field ionization as the frequency of the microwave field was tuned, spectra were recorded that allowed the resonator resonance frequency and quality factor to be determined with the atoms acting as microscopic quantum sensors

Comparison of human uterine cervical electrical impedance measurements derived using two tetrapolar probes of different sizes

BACKGROUND We sought to compare uterine cervical electrical impedance spectroscopy measurements employing two probes of different sizes, and to employ a finite element model to predict and compare the fraction of electrical current derived from subepithelial stromal tissue. METHODS Cervical impedance was measured in 12 subjects during early pregnancy using 2 different sizes of the probes on each subject. RESULTS Mean cervical resistivity was significantly higher (5.4 vs. 2.8 Ωm; p < 0.001) with the smaller probe in the frequency rage of 4–819 kHz. There was no difference in the short-term intra-observer variability between the two probes. The cervical impedance measurements derived in vivo followed the pattern predicted by the finite element model. CONCLUSION Inter-electrode distance on the probes for measuring cervical impedance influences the tissue resistivity values obtained. Determining the appropriate probe size is necessary when conducting clinical studies of resistivity of the cervix and other human tissues

Opportunities for improving the efficiency of paediatric HIV treatment programmes

Objectives: To conduct two economic analyses addressing whether to: routinely monitor HIV-infected children on antiretroviral therapy (ART) clinically or with laboratory tests; continue or stop cotrimoxazole prophylaxis when children become stabilized on ART. Design and methods: The ARROW randomized trial investigated alternative strategies to deliver paediatric ART and cotrimoxazole prophylaxis in 1206 Ugandan/Zimbabwean children. Incremental cost-effectiveness and value of implementation analyses were undertaken. Scenario analyses investigated whether laboratory monitoring (CD4 tests for efficacy monitoring; haematology/biochemistry for toxicity) could be tailored and targeted to be delivered cost-effectively. Cotrimoxazole use was examined in malaria-endemic and non-endemic settings. Results: Using all trial data, clinical monitoring delivered similar health outcomes to routine laboratory monitoring, but at a reduced cost, so was cost-effective. Continuing cotrimoxazole improved health outcomes at reduced costs. Restricting routine CD4+ monitoring to after 52 weeks following ART initiation and removing toxicity testing was associated with an incremental cost-effectiveness ratio of $6084 per quality-adjusted life-year (QALY) across all age groups, but was much lower for older children (12+ years at initiation; incremental cost-effectiveness ratio =$769/QALY). Committing resources to improve cotrimoxazole implementation appears cost-effective. A healthcare system that could pay $600/QALY should be willing to spend up to$12.0 per patient-year to ensure continued provision of cotrimoxazole. Conclusion: Clinically driven monitoring of ART is cost-effective in most circumstances. Routine laboratory monitoring is generally not cost-effective at current prices, except possibly CD4 testing amongst adolescents initiating ART. Committing resources to ensure continued provision of cotrimoxazole in health facilities is more likely to represent an efficient use of resources

A retrospective cohort study of super-refractory status epilepticus in a tertiary neuro-ICU setting

PURPOSE: Over the last decade, the range of treatments available for the management of super-refractory status epilepticus (SRSE) has expanded. However, it is unclear whether this has had an impact on its high mortality and morbidity. The aim of this study was to investigate whether there has been a change in the outcome of SRSE over time in a neurological intensive care unit (ICU) within a tertiary centre. METHODS: Analysis of a retrospective cohort of 53 admissions from 45 patients to the neurological ICU at the National Hospital for Neurology and Neurosurgery, Queen Square, London, between January 2004 and September 2018. RESULTS: Significant reductions were observed in both duration of SRSE over time and in the time spent in ICU, suggesting that treatment quality has improved over time. A median of four antiseizure drugs (ASDs) were given prior to seizure resolution. In 23 % resolution of SRSE occurred following optimisation of current treatment rather than introduction of a new ASD. The mortality rate was very low at 11 % by 6 months; however, there was no indication of improvement in outcome as all surviving patients had a modified Rankin scale score of 3-5 upon discharge from ICU, classified as moderate-to-severe disability. CONCLUSION: Neither the survival rate nor the outcome score changed significantly over time, suggesting that changes in the treatment of SRSE have had no impact on patient outcome

Anthracyclines and Biomarkers of Myocardial Injury: The Effect of Remote Ischemic Conditioning

Background: Remote ischemic conditioning (RIC) has been beneficial in laboratory studies of anthracycline cardiotoxicity, but its effects in patients is not established. Objectives: The authors studied the effect of RIC on cardiac biomarkers and function during and after anthracycline chemotherapy. Methods: The ERIC-Onc study (Effect of Remote Ischaemic Conditioning in Oncology Patients; NCT02471885) was a randomized, single-blind, sham-controlled study of RIC at each chemotherapy cycle. The primary endpoint was troponin T (TnT) during chemotherapy and up to 1 year. Secondary outcomes included cardiac function, major adverse cardiovascular events (MACE), and MACE or cancer death. Cardiac myosin-binding-protein C (cMyC) was investigated in parallel with TnT. Results: The study was prematurely halted after the evaluation of 55 patients (RIC n = 28, sham n = 27). Biomarkers increased from baseline to cycle 6 of chemotherapy for all patients (median TnT 6 [IQR: 4-9] ng/L to 33 [IQR: 16-36)] ng/L; P ≤ 0.001; cMyC 3 (IQR: 2-5) ng/L to 47 (IQR: 18-49) ng/L; P ≤ 0.001). Mixed-effects regression analysis for repeated measures showed no difference in TnT between the 2 groups (RIC vs sham, mean difference 3.15 ng/L; 95% CI: −0.04 to 6.33; P = 0.053), or cMyC (RIC vs sham, mean difference 4.17 ng/L; 95% CI: −0.12 to 8.45; P = 0.056). There were more MACE and cancer deaths in the RIC group (11 vs 3; HR: 0.25; 95% CI: 0.07-0.90; P = 0.034), with more cancer deaths (8 vs 1; HR: 0.21; 95% CI: 0.04-0.95; P = 0.043) at 1 year. Conclusions: TnT and cMyC significantly increased during anthracycline chemotherapy with 81% having a TnT ≥14 ng/L at cycle 6. RIC did not affect the rise in biomarkers, but there was a small increase in early cancer deaths, possibly related to the greater proportion of patients with metastatic disease randomized to the RIC group (54%vs 37%). (Effect of Remote Ischaemic Conditioning in Oncology Patients [ERIC-ONC]; NCT02471885

Tracking Pediatric Asthma:The Massachusetts Experience Using School Health Records

The Massachusetts Department of Public Health, in collaboration with the U.S. Centers for Disease Control and Prevention Environmental Public Health Tracking Program, initiated a 3-year statewide project for the routine surveillance of asthma in children using school health records as the primary data source. School district nurse leaders received electronic data reporting forms requesting the number of children with asthma by grade and gender for schools serving grades kindergarten (K) through 8. Verification efforts from an earlier community-level study comparing a select number of school health records with primary care provider records demonstrated a high level of agreement (i.e., > 95%). First-year surveillance targeted approximately one-half (n = 958 schools) of all Massachusetts’s K–8 schools. About 78% of targeted school districts participated, and 70% of the targeted schools submitted complete asthma data. School nurse–reported asthma prevalence was as high as 30.8% for schools, with a mean of 9.2%. School-based asthma surveillance has been demonstrated to be a reliable and cost-effective method of tracking disease through use of an existing and enhanced reporting structure