Factors affecting the effect of naldemedine for opioid-induced constipation: a single-institution, retrospective analysis.

Naldemedine is the newest orally available, peripherally selective µ-opioid receptor antagonist blocker approved for opioid-induced constipation (OIC) treatment in adult patients. On the other hand, some patients have insufficient OIC control even with naldemedine. Thus, this retrospective study was conducted to identify factors affecting the effect of naldemedine. The participants were 210 patients who had received naldemedine at our institute between June 2017 and August 2019. Variables associated with alleviation of OIC were extracted from clinical records and used for regression analysis. The effect of naldemedine was determined according to the degree of constipation. The degree of constipation was categorized as grade 0 - 2 with reference to the CTCAE version 5.0. Multivariate ordered logistic regression analysis was conducted to identify factors affecting the effect of naldemedine. Use of naldemedine within 2 days of opioid initiation [odds ratio (OR) =0.346, 95% confidence interval (CI) =0.173-0.693; P = 0.003], concomitant use of anticholinergics (OR = 2.033, 95% CI = 1.150-3.594; P = 0.015), tramadol (OR = 0.488, 95% CI = 0.250-0.953; P =0.036), and chronic non-cancer pain (OR = 0.429, 95% CI = 0.197-0.937; P = 0.034) were identified as significant factors related to the effect of naldemedine.

Predictors of the usefulness of mirogabalin for neuropathic pain: a single-institution retrospective study.

Mirogabalin is a novel, preferentially selective α2δ-1 ligand to treat neuropathic pain. However, this agent is not always effective for patients with neuropathic pain. We therefore attempted to identify factors that could predict the efficacy of mirogabalin. The study comprised 133 patients given mirogabalin for alleviation of neuropathic pain between April and November 2019 at our hospital. Variables were extracted from medical records for regression analysis of factors associated to alleviation of neuropathic pain. We evaluated the effect of mirogabalin at two weeks after administration. Groups were categorized according to degree of improvement: poor, effective, or very effective. Multivariate ordered logistic regression analysis was conducted to identify predictors for the usefulness of mirogabalin. Threshold measures were analysed using receiver operating characteristic (ROC) curves. Maintenance dose [odds ratio (OR) = 0.90; 95% confidence interval (CI) = 0.84-0.98; P = 0.01], concomitant use of opioids (OR = 0.26, 95% CI = 0.08-0.83; P = 0.023) and Neurotropin® (NTP) (OR = 4.78, 95% CI =1.04-21.93; P = 0.044) were factors significantly correlated to the effect of mirogabalin. ROC curve analysis of the effective group indicated a threshold maintenance dose of≤ 20 mg/day (area under the curve [AUC] = 0.53). In conclusion, maintenance dose (≤ 20 mg), concomitant use of opioids and NTP were identified as predictors for the utility of mirogabalin.

Dissipation-Based Quantum Sensing of Magnons with a Superconducting Qubit.

Hybrid quantum devices expand the tools and techniques available for quantum sensing in various fields. Here, we experimentally demonstrate quantum sensing of a steady-state magnon population in a magnetostatic mode of a ferrimagnetic crystal. Dispersively coupling the magnetostatic mode to a superconducting qubit allows for the detection of magnons using Ramsey interferometry with a sensitivity on the order of 10^{-3} magnons/sqrt[Hz]. The protocol is based on dissipation as dephasing via fluctuations in the magnetostatic mode reduces the qubit coherence proportionally to the number of magnons.

Breaking the trade-off between fast control and long lifetime of a superconducting qubit.

The rapid development in designs and fabrication techniques of superconducting qubits has made coherence times of qubits longer. In the future, however, the radiative decay of a qubit into its control line will be a fundamental limitation, imposing a trade-off between fast control and long lifetime of the qubit. Here, we break this trade-off by strongly coupling another superconducting qubit along the control line. This second qubit, which we call "Josephson quantum filter" (JQF), prevents the first qubit from emitting microwave photons and thus suppresses its relaxation, while transmitting large-amplitude control microwave pulses due to the saturation of the quantum filter, enabling fast qubit control. This device functions as an automatic decoupler between a qubit and its control line and could help in the realization of a large-scale superconducting quantum processor by reducing the heating of the qubit environment and the crosstalk between qubits.

Safety and efficacy of PD-1/PD-L1 blockade in patients with preexisting antinuclear antibodies.

PURPOSE: Immune checkpoint inhibitors (ICIs) show promising clinical activity in advanced cancers. However, the safety and efficacy of PD-1/PD-L1 blockade in patients with preexisting antinuclear antibodies (ANA) are unclear. METHODS: 191 patients treated with nivolumab, pembrolizumab, atezolizumab, or durvalumab for unresectable advanced cancers between September 2014 and December 2018 were identified retrospectively. Patients were divided into positive (ANA titers ≥ 1:160) and negative ANA groups (ANA titers < 1:160). Development of immune-related adverse events (irAEs), the overall response rate (ORR), and disease control rate (DCR) were monitored. RESULTS: Positive ANA titers were seen in 9 out of 191 patients. Four patients in the positive ANA group and 69 patients in the negative group developed irAEs of any grade without a significant difference between the groups. The development of endocrine, pulmonary, and cutaneous irAEs was not significant, whereas positive ANA was significantly higher in patients who developed colitis (2/9) than in patients who did not (3/182, P = 0.0002). DCR in the positive and negative ANA group was 37.5% and 67.5%, respectively, and was not statistically significant, but had better efficacy in patients without ANA (P = 0.08). ANA-related autoimmune diseases such as SLE, Sjögren's syndrome, MCTD, scleroderma, dermatomyositis, and polymyositis was not induced in either group. However, one patient with preexisting dermatomyositis had a flare up after initiation of atezolizumab. CONCLUSION: Further studies to identify predictive factors for the development of irAEs are required to provide relevant patient care and maximize the therapeutic benefits of ICIs.

Modified clot waveform analysis to measure plasma coagulation potential in the presence of the anti-factor IXa/factor X bispecific antibody emicizumab.

Essentials The activated partial prothrombin time (aPTT) cannot predict the activity of emicizumab (Emi). Adjusted clot waveform analyses using a prothrombin time (PT)/aPTT initiator were developed. Activity of Emi in the co-presence of factor VIII or bypassing agents was quantified. This assay is useful for assessing coagulation potential in Emi-treated hemophilia A. SUMMARY: Background Emicizumab is an anti-activated factor IX/FX bispecific antibody that mimics activated FVIII cofactor function. Emicizumab does not require activation by thrombin, and its effect on shortening the activated partial thromboplastin time (APTT) is much greater than that of FVIII. Therefore, the APTT has limited utility in hemophilia A (HA) patients treated with emicizumab. Aim To evaluate the global coagulation potential of emicizumab. Methods Clot waveform analysis (CWA) with prothrombin time (PT)/APTT mixed reagents was used to define hemostatic monitoring protocols in HA patients. A modified parameter, adjusted-|min1| (Ad|min1|), was developed. Maximum and minimum percentage transmittance were defined as 100% and 0% in the precoagulation and postcoagulation phases, respectively. Ad|min1| was calculated as an index of the maximum velocity of the coagulation process. Results Ad|min1| obtained with mixed-trigger reagent (PT/APTT/buffer, 1 : 15 : 135) in the presence of emicizumab optimally corresponded to the conversion rate estimated in animals; 0.2-0.4 IU dL-1 equivalent FVIII per 1 µg mL-1 emicizumab). Ex vivo addition of emicizumab to HA plasma with or without inhibitors resulted in concentration-dependent increases in Ad|min1|, with some individual variations. The addition of various concentrations of FVIII to HA plasma mixed with emicizumab resulted in dose-dependent increases in Ad|min1|. Similarly, mixtures of activated prothrombin complex concentrate and emicizumab added to HA plasma resulted in dose-dependent increases in Ad|min1|. In contrast, enhanced coagulation potential appeared to be better defined by the clot time than by Ad|min1| in experiments using recombinant activated FVII. Conclusion The PT/APTT reagent-triggered adjusted CWA could provide a useful means of assessing global coagulation potential in emicizumab-treated HA patients, with enhanced activity neither masking nor being masked by FVIII or bypassing agents.

Information-to-work conversion by Maxwell's demon in a superconducting circuit quantum electrodynamical system.

Information thermodynamics bridges information theory and statistical physics by connecting information content and entropy production through measurement and feedback control. Maxwell's demon is a hypothetical character that uses information about a system to reduce its entropy. Here we realize a Maxwell's demon acting on a superconducting quantum circuit. We implement quantum non-demolition projective measurement and feedback operation of a qubit and verify the generalized integral fluctuation theorem. We also evaluate the conversion efficiency from information gain to work in the feedback protocol. Our experiment constitutes a step toward experimental studies of quantum information thermodynamics in artificially made quantum machines.

Nonclassical Photon Number Distribution in a Superconducting Cavity under a Squeezed Drive.

A superconducting qubit in the strong dispersive regime of circuit quantum electrodynamics is a powerful probe for microwave photons in a cavity mode. In this regime, a qubit excitation spectrum is split into multiple peaks, with each peak corresponding to an individual photon number in the cavity (discrete ac Stark shift). Here, we measure the qubit spectrum in a cavity that is driven continuously with a squeezed vacuum generated by a Josephson parametric amplifier. By fitting the obtained spectrum with a model which takes into account the finite qubit excitation power, we determine the photon number distribution, which reveals an even-odd photon number oscillation and quantitatively fulfills Klyshko's criterion for nonclassicality.

Clot waveform analysis using CS-2000i™ distinguishes between very low and absent levels of factor VIII activity in patients with severe haemophilia A.

INTRODUCTION: A recently developed method to assess comprehensive coagulation function, clot waveform analysis (CWA), accurately detect low levels (<1 IU/dL) of factor VIII activity (FVIII:C) in haemophilia A patients (HA-pts). Improvements are needed, however, to differentiate patients with very low from absent levels of FVIII:C. AIM: We attempted to optimize CWA using the coagulation analyser CS-2000i™ to distinguish between very low levels and absent FVIII:C in severe HA-pts. METHODS AND RESULTS: Activated partial thrombin time (aPTT)-based clot waveforms were determined in FVIII-deficient plasmas mixed with various amounts of recombinant FVIII. Clot times (CT) were shortened, and maximum coagulation velocity (|min1|) and acceleration (|min2|) were increased in FVIII dose-dependently at levels ranging from 0.25 to 100 IU/dL. The lowest level of FVIII:C detected was 0.25 IU/dL. Plasma samples from modestly severe (MS-HA; 0.5-<1.0 IU/dL), very severe (VS-HA; 0.25-<0.5 IU/dL), extremely severe (ES-HA; <0.25 IU/dL) and inhibitor-positive HA-pts (HA-inh) were examined. The CT was markedly prolonged in all instances but showed significant differences between the different groups insufficiently. The |min1| and |min2| in HA-inh were lower compared to the other groups (P<.05). A new parameter (slope-|min1|) reflecting average coagulation acceleration was derived. This index (median) was lower in HA-inh (0.0042) compared to ES-HA (0.0068) and VS-HA (0.011) with greater significant differences (P<.01), and an index of <.005 reflected the total absence of FVIII in the presence of inhibitor. CONCLUSION: The slope-|min1| parameter could provide a useful index for evaluating very low and absent levels of FVIII and/or the development of FVIII inhibitor in HA-pts.

Comparison of biological effects of modulated electro-hyperthermia and conventional heat treatment in human lymphoma U937 cells.

Loco-regional hyperthermia treatment has long history in oncology. Modulated electro-hyperthermia (mEHT, trade name: oncothermia) is an emerging curative treatment method in this field due to its highly selective actions. The impedance-matched, capacitive-coupled modulated radiofrequency (RF) current is selectively focused in the malignant cell membrane of the cancer cells. Our objective is studying the cell-death process and comparing the cellular effects of conventional water-bath hyperthermia treatment to mEHT. The U937 human histiocytic lymphoma cell line was used for the experiments. In the case of conventional hyperthermia treatment, cells were immersed in a thermoregulated water bath, whereas in the case of mEHT, the cells were treated using a special RF generator (LabEHY, Oncotherm) and an applicator. The heating dynamics, the maximum temperature reached (42 °C) and the treatment duration (30 min) were exactly the same in both cases. Cell samples were analysed using different flow cytometric methods as well as microarray gene expression assay and western blot analysis was also used to reveal the molecular basis of the induced effects. Definite difference was observed in the biological response to different heat treatments. At 42 °C, only mEHT induced significant apoptotic cell death. The GeneChip analysis revealed a whole cluster of genes, which are highly up-regulated in case of only RF heating, but not in conventional heating. The Fas, c-Jun N-terminal kinases (JNK) and ERK signalling pathway was the dominant factor to induce apoptotic cell death in mEHT, whereas the cell-protective mechanisms dominated in case of conventional heating. This study has clearly shown that conventional hyperthermia and RF mEHT can result in different biological responses at the same temperature. The reason for the difference is the distinct, non-homogenous energy distribution on the cell membrane, which activates cell death-related signalling pathways in mEHT treatment but not in conventional heat treatment.

Cavity Optomagnonics with Spin-Orbit Coupled Photons.

We experimentally implement a system of cavity optomagnonics, where a sphere of ferromagnetic material supports whispering gallery modes (WGMs) for photons and the magnetostatic mode for magnons. We observe pronounced nonreciprocity and asymmetry in the sideband signals generated by the magnon-induced Brillouin scattering of light. The spin-orbit coupled nature of the WGM photons, their geometrical birefringence, and the time-reversal symmetry breaking in the magnon dynamics impose the angular-momentum selection rules in the scattering process and account for the observed phenomena. The unique features of the system may find interesting applications at the crossroad between quantum optics and spintronics.

Total compensation of pulse transients inside a resonator.

The profile of rf pulses that nuclear spins experience inside a resonator deviates from that of rf voltage signals generated by a NMR spectrometer according to users' pulse programming, when change of the profile in time is comparable to or shorter than the time constant of the resonator. In our previous work [Takeda et al., J. Magn. Reson. 197 (2009) 242-244], we proposed active compensation of rf pulse transients, in which the amplitude transient of the rf pulse can be suppressed without sacrificing the Q factor of the probe. Here we extend the idea of active compensation toward total compensation of the amplitude as well as phase transients. By measuring the transient response of the probe to a given excitation using a pickup coil, the response function determining the transient behavior of the probe is numerically obtained. Then, by numerically solving the convolution equation with the help of Laplace transformation, one can obtain the amplitude and phase profiles of the pulse that should be programmed in the spectrometer in order to apply the rf pulses to the nuclear spins as intended. Accurate rf pulsing based on this idea is experimentally demonstrated, and prospect and requirements for coping with the receiver dead-time problem are discussed.

Clinical usefulness of CEA-mRNA determination in minor effusion.

Malignant pleural effusion of lung cancer is an important prognostic factor, even in minor effusions. Previous studies reported that cytological examination could not detect malignant cells in pleural dissemination cases. Therefore, we used real-time PCR as a more sensitive test to detect malignant cells. The subjects were selected from 132 primary lung cancer patients and 8 benign tumor patients as negative control. These subjects had no apparent pleural effusion or distant metastasis. All subjects were negative on cytological examination and without exfoliation evidence. The follow-up duration was 18.1 +/- 7.1 months (mean +/- SD). In the real-time PCR, the CEA-mRNA and GAPDH-mRNA parameters were measured simultaneously, and the CEA-mRNA ratio was obtained as normalized values of CEA-mRNA divided by GAPDH-mRNA. The CEA-mRNA ratio in our study was correlated with lymph node metastasis (N-factor: p = 0.0948) and lymphatic invasion (Ly-factor: p = 0.0520). Using a proportional hazard model, with recurrence or death as terminal point, the CEA-mRNA ratio affected the recurrence risk by 1.920 (95% CI: 1.104-3.340) in Stage 1a. Using log rank testing, we found significant differences in the recurrence rate between the CEA-mRNA-positive and -negative cases (p = 0.0039) at cut-off point 0.1.

Analysis of gene expression in apoptosis of human lymphoma U937 cells induced by heat shock and the effects of alpha-phenyl N-tert-butylnitrone (PBN) and its derivatives.

Hyperthermia, a modality of cancer therapy, has been known as a stress to induce apoptosis. However, the molecular mechanism of heat shock-induced apoptosis, especially on roles of intracellular oxidative stress, is not fully understood. First, when human lymphoma U937 cells were treated with heat shock (44 degrees C, 30 min), the fraction of apoptosis, revealed by phosphatidylserine externalization, increased gradually and peaked at 6 hr after the treatment. In contrast, intracellular superoxide formation increased early during the heat shock treatment and peaked at 30 min after the treatment. When the cells were treated with heat shock in the presence of alpha -phenyl-N-tert-butylnitrone (PBN) and its derivatives, which are potent antioxidants, the DNA fragmentation was inhibited in an order according to the agents' hydrophobicity. PBN showing the highest inhibitory effects suppressed not only intracellular superoxide formation but also various apoptosis indicators. cDNA microarray was employed to analyze gene expression associated with heat shock-induced apoptosis, and the time-course microarray analysis revealed 5 groups showing changes in their pattern of gene expression. Among these genes, c-jun mRNA expression showed more than 40 fold increase 2 hr after heat treatment. The expression level of c-jun mRNA verified by quantitative real-time PCR was about 20 fold increase, and c-jun expression was similarly suppressed by PBN and its derivatives. These results suggest that the change of c-jun expression is an excellent molecular marker for apoptosis mediated by intracellular oxidative stress induced by heat shock.

DNA microarray analysis of genes involved in the process of differentiation in mouse Leydig cell line TTE1.

A Leydig cell line, TTE1, was established from the temperature-sensitive simian virus 40 large T-antigen transgenic mice. The cells showed temperature-sensitive growth characteristics and a differentiated phenotype at a nonpermissive temperature. To identify differentially expressed genes in the process of Leydig cell differentiation, the authors carried out microarray analysis of TTE1 cells cultured at permissive and nonpermissive temperatures. The resulting fluorescence-labeled cDNAs synthesized from mRNAs were hybridized with Clontech's Atlas glass mouse 1.0 microarrays. Of the 1081 genes analyzed, the levels of 31 genes were changed, with 24 genes showing increased levels of expression and the remaining 7 genes showing decreased levels. Tie2 was the most changed transcript, with a 13.5-fold upregulation under the differentiated condition. The authors believe this to be the first report of broadscale gene expression in Leydig cell differentiation using the microarray technology. The ability to analyze broadscale gene expression in this manner provides a powerful tool for investigating the molecular mechanisms of Leydig cell functions.

Establishment of Leydig cell line, TTE1, from transgenic mice harboring temperature-sensitive simian virus 40 large T-antigen gene.

A Leydig cell line, TTE1, has been established from transgenic mice harboring a temperature-sensitive simian virus 40 (tsSV40) large T-antigen gene. The cells grew at a permissive temperature (33 degrees C), but growth was markedly prevented at a nonpermissive temperature (39 degrees C). T-antigen was expressed in the nuclei at 33 degrees C but disappeared at 39 degrees C, indicating that the cells show a temperature-sensitive growth phenotype reflected by the tsSV40 large T-antigen. TTE1 cells did not show any colony-forming activity in soft agar and form tumors in subcutaneous tissue in nude mice, indicating that the cells were not transformed. Alkaline phosphatase and 3beta-hydroxysteroid dehydrogenase (HSD) activities or expression of cytokeratin and vimentin were observed. Reverse transcription-polymerase chain reaction (RT-PCR) analysis indicated that TTE1 cells expressed mRNAs encoding 17beta-HSD types 1 and 3, and inhibin-alpha. The cells with unique characteristics, therefore, should serve useful model study the function of Leydig cell.

Cibenzoline, an ATP-sensitive K(+) channel blocker, binds to the K(+)-binding site from the cytoplasmic side of gastric H(+),K(+)-ATPase.

1. Cibenzoline, (+/-)-2-(2,2-diphenylcyclopropyl-2-imidazoline succinate, has been clinically used as one of the Class I type antiarrhythmic agents and also reported to block ATP-sensitive K(+) channels in excised membranes from heart and pancreatic beta cells. In the present study, we investigated if this drug inhibited gastric H(+),K(+)-ATPase activity in vitro. 2. Cibenzoline inhibited H(+),K(+)-ATPase activity of permeabilized leaky hog gastric vesicles in a concentration-dependent manner (IC(50): 201 microM), whereas no effect was shown on Na(+),K(+)-ATPase activity of dog kidney (IC(50): >1000 microM). Similarly, cibenzoline inhibited H(+),K(+)-ATPase activity of HEK-293 cells (human embryonic kidney cell line) co-transfected with rabbit gastric H(+),K(+)-ATPase alpha- and beta-subunit cDNAs (IC(50): 183 microM). 3. In leaky gastric vesicles, inhibition of H(+),K(+)-ATPase activity by cibenzoline was attenuated by the addition of K(+) (0.5 - 5 mM) in a concentration-dependent manner. The Lineweaver-Burk plot of the H(+),K(+)-ATPase activity shows that cibenzoline increases K(m) value for K(+) without affecting V(max), indicating that this drug inhibits H(+),K(+)-ATPase activity competitively with respect to K(+). 4. The inhibitory effect of H(+),K(+)-ATPase activity by cibenzoline with normal tight gastric vesicles did not significantly differ from that with permeabilized leaky gastric vesicles, indicating that this drug reacted to the ATPase from the cytoplasmic side of the membrane. 5. These findings suggest that cibenzoline is an inhibitor of gastric H(+),K(+)-ATPase with a novel inhibition mechanism, which inhibits gastric H(+),K(+)-ATPase by binding its K(+)-recognition site from the cytoplasmic side.

[The influence of age on hemodynamics and the dose requirements of propofol and buprenorphine in total intravenous anesthesia combined with continuous epidural anesthesia].

A retrospective study was performed to determine the influence of age on hemodynamics and awakening time in total intravenous anesthesia (TIVA) using propofol and buprenorphine combined with continuous epidural anesthesia for abdominal surgery. Thirty-five patients (36-87 yr) were allocated to the following five groups by age: 36-49 yr, 50-59 yr, 60-69 yr, 70-79 yr and 80-87 yr. All patients were premedicated with midazolam i.m. Anesthesia was maintained with propofol infusion with 40% oxygen in air, intravenous buprenorphine plus vecuronium and continuous epidural anesthesia using 2% mepivacaine. After extubation, the epidural bolus dose (buprenorphine 0.1-0.2 mg with droperidol 1.25-2.5 mg) and epidural infusion (buprenorphine 17 micrograms.h-1 with droperidol 0.1 mg.h-1) were administered. Intraoperative heart rate (HR) and mean arterial pressure (MAP) decreased but remained within 30% of preanesthetic level. HR did not differ in five groups, although MAP decreased significantly in patients above 50 yr of age. The doses of midazolam (1-5 mg), propofol (2.7-7.4 mg.kg-1.h-1) and buprenorphine (40-200 micrograms) decreased with age (P < 0.01), while the maintenance doses of mepivacaine (40-140 mg.h-1) and vecuronium (0.03-0.09 mg.kg-1.h-1) showed no significant decrease. Awakening time was not significantly prolonged with age (r = 0.27, P = 0.12). Two patients in each group required analgesics within 20 hours. Neither nausea, respiratory depression nor awareness was found. We suggest that the combination of TIVA and continuous epidural anesthesia would be useful to maintain stable hemodynamic state and to obtain early recovery time, especially in the elderly.