Isatuximab plus atezolizumab in patients with advanced solid tumors: results from a phase I/II, open-label, multicenter study.

BACKGROUND: The anti-CD38 antibody isatuximab is approved for the treatment of relapsed/refractory multiple myeloma, but there are no data on its efficacy in solid tumors. This phase I/II study (NCT03637764) assessed the safety and activity of isatuximab plus atezolizumab (Isa + Atezo), an anti-programmed death-ligand 1 (PD-L1) antibody, in patients with immunotherapy-naive solid tumors: epithelial ovarian cancer (EOC), glioblastoma (GBM), hepatocellular carcinoma (HCC), and squamous cell carcinoma of the head and neck (SCCHN). PATIENTS AND METHODS: Phase I assessed safety, tolerability, pharmacokinetics, pharmacodynamics, and the recommended phase II dose (RP2D) of isatuximab 10 mg/kg intravenously (i.v.) every week for 3 weeks followed by once every 3 weeks + atezolizumab 1200 mg i.v. every 3 weeks. Phase II used a Simon's two-stage design to assess the overall response rate or progression-free survival rate at 6 months (GBM cohort). Interim analysis was carried out at 6 months following first dose of the last enrolled patient in each cohort. Pharmacodynamic biomarkers were tested for CD38, PD-L1, tumor-infiltrating immune cells, and FOXP3+ regulatory T cells (Tregs) in the tumor microenvironment (TME). RESULTS: Overall, 107 patients were treated (EOC, n = 18; GBM, n = 33; HCC, n = 27; SCCHN, n = 29). In phase I, Isa + Atezo showed an acceptable safety profile, no dose-limiting toxicities were observed, and RP2D was confirmed. Most patients experienced ≥1 treatment-emergent adverse event (TEAE), with ≤48.5% being grade ≥3. The most frequent TEAE was infusion reactions. The study did not continue to stage 2 based on prespecified targets. Tumor-infiltrating CD38+ immune cells were reduced and almost cleared after treatment. Isa + Atezo did not significantly modulate Tregs or PD-L1 expression in the TME. CONCLUSIONS: Isa + Atezo had acceptable safety and tolerability. Clinical pharmacodynamic evaluation revealed efficient target engagement of isatuximab via treatment-mediated reduction of CD38+ immune cells in the TME. Based on clinical data, CD38 inhibition does not improve responsiveness to PD-L1 blockade in these patients.

Prenatal exposure to nickel and atopic dermatitis at age 3 years: a birth cohort study with cytokine profiles.

BACKGROUND: Nickel, the fifth most common element on Earth, is the leading inducer of contact allergies in humans, with potent immunological effects. Nickel-induced contact allergies predominantly affect females. Maternal exposure to nickel has been associated with several developmental abnormalities. However, how a maternal nickel exposure affects the development of atopic diathesis and immune abnormalities in children has never been addressed. OBJECTIVES: We aimed to determine whether maternal nickel exposure affects the development of atopic dermatitis and immune abnormalities in their children. METHODS: Using a birth cohort study, we analysed 140 mother-child pairs recruited in 2012-2015 from central Taiwan. Maternal exposure to nickel was estimated using urinary nickel levels measured by inductively coupled plasma mass spectrometry (ICP-MS). The serum levels of 65 analytes and IgE in 3-year-old children were profiled with a multiplex ELISA. The correlation between the maternal urinary nickel concentration and serum analyte levels was assessed using Spearmen's correlation. Multivariant regression analysis was performed to evaluate the association between maternal urinary nickel levels and serum analyte concentrations in their children. RESULTS: The geometric means of the maternal urinary nickel and the children's serum IgE levels were 2.27 µg/L and 69.71 IU/mL, respectively. The maternal nickel exposure was associated with increased serum levels of IL-1ß, IL-2, TNF-α, and leukaemia inhibitory factor (LIF) but with decreased serum levels of matrix metalloproteinase-1 (MMP-1), IL-2R, and eotaxin-1 in the children. In addition, the development of childhood atopic dermatitis at 3 years old was significantly associated with the child's serum levels of IgE and IL-2R, but it was negatively associated with the maternal nickel exposure. CONCLUSIONS: This is the first study showing the potential immunological effects of maternal nickel exposure in their children at an early developmental stage.

Identification of a novel HLA-DQB1 allele, HLA-DQB1*03:168, by sequence-based typing in a Taiwanese individual.

HLA-DQB1*03:168 differs from HLA-DQB1*03:03:02:01 by the single nucleotide substitution resulting in one amino acid change.

Broadband, millimeter-wave antireflection coatings for large-format, cryogenic aluminum oxide optics.

We present two prescriptions for broadband ($ {\sim} 77 - 252\;{\rm GHz} $), millimeter-wave antireflection coatings for cryogenic, sintered polycrystalline aluminum oxide optics: one for large-format (700 mm diameter) planar and plano-convex elements, the other for densely packed arrays of quasi-optical elements-in our case, 5 mm diameter half-spheres (called "lenslets"). The coatings comprise three layers of commercially available, polytetrafluoroethylene-based, dielectric sheet material. The lenslet coating is molded to fit the 150 mm diameter arrays directly, while the large-diameter lenses are coated using a tiled approach. We review the fabrication processes for both prescriptions, then discuss laboratory measurements of their transmittance and reflectance. In addition, we present the inferred refractive indices and loss tangents for the coating materials and the aluminum oxide substrate. We find that at 150 GHz and 300 K the large-format coating sample achieves $ (97 \pm 2)\% $ transmittance, and the lenslet coating sample achieves $ (94 \pm 3)\% $ transmittance.

Magnesium oxide and hip fracture in the elderly: a population-based retrospective cohort analysis.

Using national insurance claims of Taiwan, we found that magnesium oxide (MgO) use is associated with an increased risk of hip fracture in the elderly. Further studies are warranted to explore the mechanisms associated with MgO use that lead to hip fracture. PURPOSE: The purpose of this study was to investigate the association between MgO use and hip fracture risk in the elderly (age > 65 years). METHODS: This nationwide population-based retrospective study was conducted from 1996 to 2013. Individuals with (n = 26,069) and without (n = 26,069) MgO use were enrolled after propensity score matching. Primary outcome was a hip fracture. After adjusting for age, sex, comorbidities, and medications, multivariate Cox proportional hazards regression models were used to calculate incidences and risk of hip fracture [hazard ratio (HR)]. RESULTS: During the mean follow-up duration of 4.8 years in the MgO cohort and 5.7 years in the non-MgO cohort, respectively 1547 and 1107 cases developed a hip fracture. MgO use was identified as a risk factor for hip fracture in both univariate [crude HR, 1.68; 95% confidence interval (CI), 1.55-1.81; p < 0.001] and multivariate [adjusted HR (aHR), 1.66; 95% CI, 1.54-1.80; p < 0.001] Cox proportional hazards regression models. The cumulative incidence of hip fracture was significantly higher in the MgO cohort than in the non-MgO cohort (1.23 per 100 person-years vs. 0.74 per 100 person-years, logrank test, p < 0.001). CONCLUSION: MgO use is an independent risk factor for hip fracture in the elderly.

Detection of CMB-Cluster Lensing using Polarization Data from SPTpol.

We report the first detection of gravitational lensing due to galaxy clusters using only the polarization of the cosmic microwave background (CMB). The lensing signal is obtained using a new estimator that extracts the lensing dipole signature from stacked images formed by rotating the cluster-centered Stokes QU map cutouts along the direction of the locally measured background CMB polarization gradient. Using data from the SPTpol 500 deg^{2} survey at the locations of roughly 18 000 clusters with richness λ≥10 from the Dark Energy Survey (DES) Year-3 full galaxy cluster catalog, we detect lensing at 4.8σ. The mean stacked mass of the selected sample is found to be (1.43±0.40)×10^{14}M_{⊙} which is in good agreement with optical weak lensing based estimates using DES data and CMB-lensing based estimates using SPTpol temperature data. This measurement is a key first step for cluster cosmology with future low-noise CMB surveys, like CMB-S4, for which CMB polarization will be the primary channel for cluster lensing measurements.

Incidence and risk factors for hip fracture in elderly patients undergoing lumbar spine surgery: a nationwide database study with 11-year follow-up.

Impaired functional movement may occur after spinal surgery, which increases risk of fall episode and hip fracture. Patients with long-segment thoracolumbar spine fusions had a significantly higher risk of hip fracture than those with only discectomies. Fall prevention is necessary due to the highly increased hip fracture risk. INTRODUCTION: Spinal surgeries are performed to treat spondylolisthesis, fractures, scoliosis, or other deformities. Impaired balance mechanisms and functional movement may occur after spinal surgery. Fall episodes may cause hip fractures, which have negative impacts on quality of life and increase mortality. The incidence of hip fracture after spinal surgery is still unknown. The aim of this study was to examine the association between various types of spinal surgeries and hip fractures in the elderly by using a nationwide database. We hypothesized that the spinal surgeries may increase hip fracture risk in the elderly. METHODS: We used the National Health Insurance Research Database (NHIRD) to identify 3345 patients undergoing spinal surgery and a random dataset to identify 6690 age-, sex- and Charlson comorbidity index (CCI)-matched controls to compare the incidence of hip fractures in an 11-year follow-up period. We also enrolled 82,730 patients with spinal surgeries from the inpatient dataset to investigate the impact of different types of spinal surgeries. RESULTS: Patients who received spinal surgeries had higher risks of hip fractures, especially patients aged 60 to 79 years and female patients. The patients with long-segment thoracolumbar spinal fusions had a significantly higher risk of hip fracture than those with only discectomies. Short segmental lumbar spine fusions also slightly increased the risk of hip fracture compared with discectomies. CONCLUSION: Fall prevention for the elderly undergoing lumbar spinal surgery is necessary due to the highly increased hip fracture risk.

Identification of a novel HLA-DQB1 allele, DQB1*06:111, by sequence-based typing in a Taiwanese individual.

HLA-DQB1*06:111 differs from HLA-DQB1*06:02:01 by the single nucleotide substitution resulting in one amino acid change.

Extensively drug-resistant tuberculosis in Myanmar: burden and mutations causing second-line drug resistance.

SETTING: Two tuberculosis (TB) reference laboratories in Myanmar. OBJECTIVES: To determine the proportion of extensively drug-resistant TB (XDR-TB) cases among multidrug-resistant TB (MDR-TB) cases and the mutations that cause resistance to second-line drugs in Myanmar. DESIGN: This was a cross-sectional, retrospective study. Multidrug-resistant Mycobacterium tuberculosis isolates were collected during 2015-2016. Phenotypic drug susceptibility testing (DST) was performed and drug-resistant mutations identified by sequencing. Genotypes were determined to explain relationships between drug resistance patterns and genotypes. RESULTS: Of 89 MDR-TB isolates, 12 were XDR-TB and 24 were pre-XDR-TB, with 21 resistant to fluoroquinolones (FQs) and 3 to second-line injectable agents (SLIDs). High rates of cross-resistance among second-line drugs were observed. Correlations between phenotypic and molecular DST against FQs and SLIDs were 91% in both cases. The most frequent mutation in FQ-resistant isolates was D94G (8/21) in gyrA and A1401G (11/15) in rrs in those resistant to SLIDs. The dominant genotype was the Beijing type (76/89). CONCLUSION: There were high proportions of XDR-TB and pre-XDR-TB among MDR-TB cases; cross-resistance among second-line drugs was high, with various types of genetic mutations. These data suggest that resistance to second-line anti-tuberculosis drugs should be monitored intensively, and molecular DST should be employed.

HLA-A*33:74N, a novel HLA-A*33 variant, identified by sequence-based typing in a Taiwanese individual.

A one nucleotide replacement in codon 803 of HLA-A*33:03:01 results in a novel allele, HLA-A*33:74N.

HLA-B*40:247, a novel HLA-B*40 variant, identified by sequence-based typing in a Taiwanese individual.

A one nucleotide replacement in codon 261 of HLA-B*40:01:01 results in a novel allele, HLA-B*40:247.

HLA-A*11:134, a novel HLA-A*11 variant, identified by sequence-based typing in a Taiwanese individual.

A one nucleotide replacement in codon 31 of HLA-A*11:01:01 results in a novel allele, HLA-A*11:134.

Transient Grating Spectroscopy in Magnetic Thin Films: Simultaneous Detection of Elastic and Magnetic Dynamics.

Surface magnetoelastic waves are coupled elastic and magnetic excitations that propagate along the surface of a magnetic material. Ultrafast optical techniques allow for a non-contact excitation and detection scheme while providing the ability to measure both elastic and magnetic components individually. Here we describe a simple setup suitable for excitation and time resolved measurements of high frequency magnetoelastic waves, which is based on the transient grating technique. The elastic dynamics are measured by diffracting a probe laser pulse from the long-wavelength spatially periodic structural deformation. Simultaneously, a magnetooptical measurement, either Faraday or Kerr effect, is sensitive to the out-of-plane magnetization component. The correspondence in the response of the two channels probes the resonant interaction between the two degrees of freedom and reveals their intimate coupling. Unraveling the observed dynamics requires a detailed understanding of the spatio-temporal evolution of temperature, magnetization and thermo-elastic strain in the ferromagnet. Numerical solution of thermal diffusion in two dimensions provides the basis on which to understand the sensitivity in the magnetooptic detection.

Ethnicity as an independent predictive factor for the results of computed tomography pulmonary angiography and ultrasonography of the lower limbs.

BACKGROUND: Asians, Pacific Islanders and Maori have significantly lower rates of venous thromboembolism (VTE) compared to Europeans, but its clinic implication regarding diagnosis and prevention is unclear. AIMS: To investigate if ethnicity affects the yield of computed tomography pulmonary angiography (CTPA) and ultrasonography of the lower limbs. METHODS: Data previously collected for 523 patients from another study were used to analyse the effect of ethnicity on the results of CTPA; 1587 consecutive ultrasonography of lower limbs was retrospectively analysed according to ethnicity. The Wells score was retrospectively calculated to determine the pretest probability of VTE. RESULTS: The positive rates of CTPA were 23.3% for European patients and 9.3% for non-European patients. The rate ratio was 2.50 (confidence interval [CI] 1.27-4.95). European patients were 2.5 times more likely to have a positive scan result than non-Europeans, given same pretest probability. There was a larger difference among patients with low and moderate pretest probability with a rate ratio of 4.27 (CI 1.62-11.3). The positive rates of ultrasound scans (USS) among European patients were 16.6 and 9.0% for non-European patients. Rate ratio was 1.85 (CI 1.27-4.95). The difference was also more significant amongst patients with low and moderate pretest probability. The rate ratio was 2.31 (CI 1.38-3.86) for European patients compared to non-European patients. CONCLUSION: Given the same pretest probability according to the Wells score, European patients had significantly higher positive rates of CTPA and ultrasonography of the lower limbs than non-European patients. Further prospective studies are required to confirm our findings and establish an appropriate pretest assessment tool for non-European patients.

Ultrafast energy- and momentum-resolved dynamics of magnetic correlations in the photo-doped Mott insulator Sr2IrO4.

Measuring how the magnetic correlations evolve in doped Mott insulators has greatly improved our understanding of the pseudogap, non-Fermi liquids and high-temperature superconductivity. Recently, photo-excitation has been used to induce similarly exotic states transiently. However, the lack of available probes of magnetic correlations in the time domain hinders our understanding of these photo-induced states and how they could be controlled. Here, we implement magnetic resonant inelastic X-ray scattering at a free-electron laser to directly determine the magnetic dynamics after photo-doping the Mott insulator Sr2IrO4. We find that the non-equilibrium state, 2 ps after the excitation, exhibits strongly suppressed long-range magnetic order, but hosts photo-carriers that induce strong, non-thermal magnetic correlations. These two-dimensional (2D) in-plane Néel correlations recover within a few picoseconds, whereas the three-dimensional (3D) long-range magnetic order restores on a fluence-dependent timescale of a few hundred picoseconds. The marked difference in these two timescales implies that the dimensionality of magnetic correlations is vital for our understanding of ultrafast magnetic dynamics.

A novel allele, HLA-B*15:259, was identified in a Taiwanese individual by sequence-based typing.

A one nucleotide replacement in codon 24 of HLA-B*15:54 results in a novel allele, HLA-B*15:259.

Efficacy and safety of LY2963016 insulin glargine in patients with type 1 and type 2 diabetes previously treated with insulin glargine.

The safety and efficacy of LY2963016 insulin glargine (LY IGlar) and Lantus insulin glargine (IGlar), products with identical primary amino acid sequences, were assessed in subgroups of patients with type 1 (T1D, n = 452) or type 2 diabetes (T2D, n = 299) reporting prestudy IGlar treatment in 52-week open-label (ELEMENT-1) and 24-week double-blind (ELEMENT-2) studies. At randomization, patients transitioned from their prestudy IGlar to equivalent doses of LY IGlar or IGlar. Primary efficacy (change in glycated haemoglobin from baseline to 24 weeks), other efficacy and select safety outcomes of LY IGlar were compared with those of IGlar. Continuous data were analysed using analysis of covariance, categorical data by Fisher's exact test, and treatment comparisons for hypoglycaemia by Wilcoxon test. No statistically significant treatment differences were identified for efficacy and safety outcomes except for weight change (T1D), overall incidence of detectable insulin antibodies (T2D), and serious adverse events (T2D). These differences were neither consistently observed across both studies nor observed in the total study populations, and their magnitude suggests they were not clinically meaningful. LY IGlar and IGlar show similar efficacy and safety profiles in patients reporting prestudy IGlar treatment.