Metric fixed point theory and partial impredicativity.

We show that the Priess-Crampe & Ribenboim fixed point theorem is provable in [Formula: see text]. Furthermore, we show that Caristi's fixed point theorem for both Baire and Borel functions is equivalent to the transfinite leftmost path principle, which falls strictly between [Formula: see text] and [Formula: see text]. We also exhibit several weakenings of Caristi's theorem that are equivalent to [Formula: see text] and to [Formula: see text]. This article is part of the theme issue 'Modern perspectives in Proof Theory'.

Safety of tapering tacrolimus dose in patients with well-controlled anti-acetylcholine receptor antibody-positive myasthenia gravis.

BACKGROUND AND PURPOSE: Tapering immunosuppressants is desirable in patients with well-controlled myasthenia gravis (MG). However, the association between tapering of calcineurin inhibitor dosage and reduction-associated exacerbation is not known. The aim of this study was to clarify the frequency of reduction-associated exacerbation when tacrolimus is tapered in stable patients with anti-acetylcholine receptor antibody-positive MG, and to determine the factors that predict exacerbations. METHODS: We retrospectively analyzed 115 patients in whom tacrolimus dosage was tapered. The reduction-associated exacerbation was defined as the appearance or worsening of one or more MG symptoms <3 months after the reduction. RESULTS: Tacrolimus dosage was successfully tapered in 110 patients (96%) without any exacerbation. Five patients (4%) experienced an exacerbation, but symptoms were reversed in all patients when the tacrolimus dose was increased to the previous maintenance level. No patient developed an MG crisis. The age at onset was significantly earlier (30 vs. 56 years, P = 0.025) and the reduction in dosage was significantly larger (2.0 vs. 1.0 mg/day, P = 0.002) in patients with reduction-associated exacerbation than in those without exacerbation. The cut-off values determined in a receiver-operating characteristic curve analysis were 52 years (sensitivity, 57%; specificity, 100%) for the age at onset and 1.5 mg (sensitivity, 80%; specificity, 100%) for the dose reduction. CONCLUSION: Tapering of tacrolimus was possible in most patients with well-controlled anti-acetylcholine receptor antibody-positive MG. Early age at onset and a large reduction from maintenance dosage were associated with exacerbation. Reductions ≤1.5 mg/day from the maintenance dosage should be considered for patients with late-onset disease.

Temporal mapping of photochemical reactions and molecular excited states with carbon specificity.

Photochemical reactions are essential to a large number of important industrial and biological processes. A method for monitoring photochemical reaction kinetics and the dynamics of molecular excitations with spatial resolution within the active molecule would allow a rigorous exploration of the pathway and mechanism of photophysical and photochemical processes. Here we demonstrate that laser-excited muon pump-probe spin spectroscopy (photo-µSR) can temporally and spatially map these processes with a spatial resolution at the single-carbon level in a molecule with a pentacene backbone. The observed time-dependent light-induced changes of an avoided level crossing resonance demonstrate that the photochemical reactivity of a specific carbon atom is modified as a result of the presence of the excited state wavefunction. This demonstrates the sensitivity and potential of this technique in probing molecular excitations and photochemistry.

Prognostic value of sequencing-based minimal residual disease detection in patients with multiple myeloma who underwent autologous stem-cell transplantation.

BACKGROUND: Most patients with multiple myeloma (MM) are considered to be incurable, and relapse owing to minimal residual disease (MRD) is the main cause of death among these patients. Therefore, new technologies to assess deeper response are required. PATIENTS AND METHODS: We retrospectively analyzed 125 patients with MM who underwent high-dose melphalan plus autologous stem-cell transplantation (ASCT) to detect MRD in autograft/bone marrow (BM) cells using a next-generation sequencing (NGS)-based method and allele-specific oligonucleotide-polymerase chain reaction (ASO-PCR). RESULTS: NGS-based method was applicable to 90% and this method had at least one to two logs greater sensitivity compared to ASO-PCR. MRD negative by NGS [MRDNGS(-)] (defined as <10-6) in post-ASCT BM cases (n = 26) showed a significantly better progression-free survival (PFS) (96% at 4 years, P < 0.001) and overall survival (OS) (100% at 4 years, P =0.04) than MRDNGS(+) in post-ASCT BM cases (n = 25). When restricting the analysis to the 39 complete response cases, patients who were MRDNGS(-) (n = 24) showed a significantly better PFS than those that were MRDNGS(+) (n = 15) (P =0.02). Moreover, MRDNGS(-) in post-ASCT BM cases (n = 12) showed significantly a better PFS than MRDNGS(+) cases (n = 7) where MRD was not detected by ASO-PCR (P = 0.001). Patients whose autografts were negative by NGS-based MRD assessment (<10-7) (n = 19) had 92% PFS and 100% OS at 4 years post-ASCT. Conversely, the NGS-based MRD positive patients who received post-ASCT treatment using novel agents (n = 49) had a significantly better PFS (P = 0.001) and tended to have a better OS (P= 0.214) than those that were untreated (n = 33). CONCLUSIONS: Low level MRD detected by NGS-based platform but not ASO-PCR has significant prognostic value when assessing either the autograft product or BM cells post-ASCT.

Photoexcited Muon Spin Spectroscopy: A New Method for Measuring Excess Carrier Lifetime in Bulk Silicon.

We have measured excess carrier lifetime in silicon using photoexcited muon spin spectroscopy. Positive muons implanted deep in a wafer can interact with the optically injected excess carriers and directly probe the bulk carrier lifetime while minimizing the effect from surface recombination. The method is based on the relaxation rate of muon spin asymmetry, which depends on the excess carrier density. The underlying microscopic mechanism has been understood by simulating the four-state muonium model in Si under illumination. We apply the technique to different injection levels and temperatures, and demonstrate its ability for injection- and temperature-dependent lifetime spectroscopy.

Reliability and validity of the Japanese version of the coping inventory for adults for stressful situations in healthy people.

The present study examined the validity and reliability of the Japanese version of the Coping Inventory for Stressful Situations-2nd Edition™ (CISS; hereafter the CISS-J). The participants were 1,268 healthy Japanese individuals. The factor analyses yielded three major scales (task-, emotion-, and avoidance-oriented coping) corresponding to the original version. In addition, the avoidance-oriented scale of the CISS-J contained two subscales (Distraction and Social diversion), as in the original version. Cronbach's α coefficient was found to be .75-.89 for the three scales and two subscales. Results show that the CISS-J is useful for assessing the coping strategies among this sample of Japanese individuals.

Acoustic characteristics of voluntary expiratory sounds after swallow for detecting dysphagia.

This research was designed to investigate the acoustic characteristics of voluntary expiratory sounds after swallow for detecting dysphagia. Forty-nine patients with complaints of swallow difficulty received a videofluorographic (VF) examination. They were divided into three groups: nine who did not have any apparent disease (Group N), 22 patients with head and neck cancer (Group H&N) and 18 patients with other diseases including cerebrovascular disease (Group OD). After liquid barium swallows, they exhaled voluntarily without voicing. Videofluorographic findings were classified into four groups: normal (Normal), acceptable swallow (Acceptable), swallow with residue (Resid) and swallows with penetration or aspiration (Pen/Asp). The duration of expiratory sounds was measured on the time waveform. Frequency characteristics of expiratory sounds were obtained using one-third octave band analysis ranging from 62·5 to 2000·0 Hz of central frequency. The averaged level of the 1000·0-Hz band was chosen as the reference band level (RB level). The revised averaged level of each band was obtained by subtracting the RB level from the averaged level of each band. Zero decibel of the revised magnitude of the 125·0-Hz band was set as the critical value to differentiate dysphagia (Resid or Pen/Asp) from no dysphagia (Normal or Acceptable). Comparison of this assessment with VF findings showed a significant percentage agreement (85·4%). These results suggest that frequency characteristics of post-swallow expiratory sounds can differentiate dysphagia from no dysphagia among multiple dysphagic patient groups.

Muon spin relaxation and emergence of disorder-induced unconventional dynamic magnetic fluctuations in Dy2Zr2O7.

The disordered pyrochlore oxide Dy2Zr2O7shows the signatures of field-induced spin freezing with remnant zero-point spin-ice entropy at 5 kOe magnetic field. We have performed zero-field and longitudinal field Muon spin relaxation (µSR) studies on Dy2Zr2O7. Our zero field studies reveal the absence of both long-range ordering and spin freezing down to 62 mK. TheµSR relaxation rate exhibits a temperature-independent plateau below 4 K, indicating a dynamic ground state of fluctuating spins similar to the well-known spin ice system Dy2Ti2O7. The low-temperature spin fluctuations persist in the longitudinal field of 20 kOe as well and show unusual field dependence of the relaxation rate, which is uncommon for a spin-liquid system. Our results, combined with the previous studies do not show any evidence of spin ice or spin glass ground state, rather point to a disorder-induced dynamic magnetic ground state in the Dy2Zr2O7material.

Sevoflurane suppresses tumour necrosis factor-α-induced inflammatory responses in small airway epithelial cells after anoxia/reoxygenation.

BACKGROUND: Lung ischaemia-reperfusion (I/R) injury is correlated with poor clinical outcome. The inflammatory cytokines interleukin (IL)-6, IL-8, and monocyte chemotactic protein-1 (MCP-1) are produced by pulmonary epithelial cells during lung transplantation and are considered to be involved in I/R injury. The volatile anaesthetic sevoflurane has been shown to exert a protective effect on I/R injury in various organs. We investigated the effect of sevoflurane on the inflammatory functions of pulmonary epithelial cells in vitro. METHODS: Human normal small airway epithelial cells (SAEC) were incubated under anoxic conditions for 24 h with or without sevoflurane and then stimulated with tumour necrosis factor (TNF)-α under hyperoxic conditions for 5 h with or without sevoflurane. After incubation, IL-6, IL-8, and MCP-1 mRNA expression was analysed by quantitative real-time RT-PCR. The production of IL-6, IL-8, and MCP-1 was assayed by enzyme-linked immunosorbent assay, the effects of sevoflurane on inflammatory gene expression were examined by DNA microarray analysis, and the effects of sevoflurane on NF-κB-mediated inflammatory cytokine production were examined by immunoblotting. RESULTS: Sevoflurane suppressed TNF-α-induced IL-6, IL-8, and MCP-1 gene expression and the production of IL-6 and IL-8 in SAEC under anoxia/reoxygenation conditions. DNA microarray analysis indicated that sevoflurane modulated NF-κB-related gene expression. Sevoflurane significantly inhibited TNF-α-induced translocation of p65 NF-κB into the nucleus. Sevoflurane enhanced TNF-α-induced gene expression of inhibitor κB (IκB) but not of NF-κB. CONCLUSIONS: Sevoflurane suppressed the NF-κB-mediated production of pulmonary epithelial cell-derived inflammatory cytokines, including IL-6 and IL-8, which are capable of causing I/R injury.

Analysis of the nucleotide sequence of chromosome VI from Saccharomyces cerevisiae.

The complete nucleotide sequence of Saccharomyces cerevisiae chromosome VI (270 kb) has revealed that it contains 129 predicted or known genes (300 bp or longer). Thirty-seven (28%) of which have been identified previously. Among the 92 novel genes, 39 are highly homologous to previously identified genes. Local sequence motifs were compared to active ARS regions and inactive loci with perfect ARS core sequences to examine the relationship between these motifs and ARS activity. Additional ARS sequences were predominantly observed in 3' flanking sequences of active ARS loci.

Successful treatment of monomorphic primary central nervous system post-transplantation lymphoproliferative disorder 5 years after kidney transplantation.

A 31-year-old man underwent living-related kidney transplantation in 2004 as a consequence of primary focal segmental glomerulosclerosis (FSGS). Four years after the transplantation, we confirmed nephrotic syndrome caused by recurrent FSGS. We performed plasmapheresis and low-density lipoprotein adsorption. We also combined steroid therapy with a reduction in the dose of tacrolimus and an increased dose of mycophenolate mofetil. The nephrotic syndrome improved dramatically with this combined therapeutic approach. However, 10 months after these treatments, he revisited our hospital because of altered consciousness. We detected multiple tumor masses in his brain that were ring enhanced on contrast magnetic resonance imaging. Consequently, we suspected primary central nervous system post-transplantation lymphoproliferative disorder (CNS-PTLD). We performed a craniotomy to biopsy the brain tumors. The biopsy specimen showed Epstein-Barr virus-associated diffuse large B-cell lymphoma. There is no definitive treatment for CNS-PTLD. Therefore, we treated the primary CNS-PTLD successfully with whole-brain radiation and discontinuation of immunosuppression therapy.

Structural snapshots of V/A-ATPase reveal the rotary catalytic mechanism of rotary ATPases.

V/A-ATPase is a motor protein that shares a common rotary catalytic mechanism with FoF1 ATP synthase. When powered by ATP hydrolysis, the V1 domain rotates the central rotor against the A3B3 hexamer, composed of three catalytic AB dimers adopting different conformations (ABopen, ABsemi, and ABclosed). Here, we report the atomic models of 18 catalytic intermediates of the V1 domain of V/A-ATPase under different reaction conditions, determined by single particle cryo-EM. The models reveal that the rotor does not rotate immediately after binding of ATP to the V1. Instead, three events proceed simultaneously with the 120˚ rotation of the shaft: hydrolysis of ATP in ABsemi, zipper movement in ABopen by the binding ATP, and unzipper movement in ABclosed with release of both ADP and Pi. This indicates the unidirectional rotation of V/A-ATPase by a ratchet-like mechanism owing to ATP hydrolysis in ABsemi, rather than the power stroke model proposed previously for F1-ATPase.

Long-term outcomes of hemostatic therapy for variceal bleeding and the challenge pending in the post-direct-acting antivirals era.

Background and study aims: This study evaluated the longterm outcomes of mainly endoscopic hemostatic therapy for gastrointestinal variceal bleeding and of the transition of hemostatic therapy. Patients and methods: Among 1,163 patients treated for gastrointestinal varices between April 2006 and June 2020, a total of 125 patients who underwent emergency hemostatic therapy were enrolled. Survival rates and secondary evaluation points were analyzed. Additionally, patients were classified into two groups: the previous and latter term. Patients' background, therapeutic method, and treatment results were compared between the groups. Results: 94.4% had cirrhosis. The average Child-Pugh score was 8.90. Successful primary hemostasis rate was 98.4%, and 5.6% died within 2 weeks, all with a Child-Pugh score ≥9. The respective 1- and 5-year survival rates for Child-Pugh grade A/B were 81.3% and 55.4%, while those for Child-Pugh grade C were 58.1% and 17.8%. Child-Pugh grade C or hepatocellular carcinoma was significantly associated with poor prognosis. In total, 21.6% experienced variceal re-bleeding; 62.9% of these cases were triggered by continued alcohol consumption. There was no significant difference in survival between patients with and without variceal re-bleeding and in post-treatment survival between the previous and latter terms. In the latter term, the number of cases caused by continued alcohol consumption significantly increased. Conclusions: Multidisciplinary treatment and continuation of proper management after hemostatic therapy for variceal bleeding are crucial. Continued alcohol consumption leads to variceal bleeding and re-bleeding; its proper management, including alcohol abstinence, is one of the major challenges left in the post-directacting antivirals era.

Difference in coronary artery intima and media calcification in autopsied patients with chronic kidney disease.

BACKGROUND: In patients with chronic kidney disease (CKD), coronary artery calcification occurs at two distinct sites in the vessel wall: the intima and the media. Arterial media calcification (AMC), a nonocclusive condition, affects hemodynamics differently compared to arterial intima calcification (AIC), which occurs in atherosclerotic plaques. Arterial calcification is considered a cell-regulated process resembling intramembranous bone formation. The purpose of this retrospective observational study was to clarify the morphological differences between AIC and AMC and to evaluate the role of vascular smooth muscle cells (VSMCs) and macrophages in AIC and AMC formation. METHODS: We histologically analyzed 14 tissue specimens from 14 autopsies of patients with CKD Stage 5D who underwent hemodialysis and 5 specimens from 5 patients with CKD Stage 2 - 3 (90 ml/min/1.73 m2 > estimated GFR >= 30 ml/min/1.73 m2). We performed immunohistochemical staining of osteopontin (OPN) as a marker for bone matrix protein, alpha-smooth muscle actin (alphaSMA) for VSMCs, Cbfa1/Runx2 as a marker for osteoblastic differentiation of VSMCs, and CD68 for macrophages. RESULTS: In the CKD 2/3 group, we also found AIC and AMC. OPN and CD68 expression in the CKD 2/3 group was similar to that in the CKD 5D group. Although we did not find Cbfa1/Runx2 positive cell expression in the CKD 2/3 group, we did find it in the CKD 5D group. We found CD68-positive cells predominantly in AIC and absent in AMC in both groups. CONCLUSIONS: These findings suggest that the influence of Cbfa1/Runx2 pathway in coronary artery calcification depends on the CKD Stage. Expression of CD68-positive cells depends on the location of the coronary artery calcification.

3D Quantitative Synthetic MRI in the Evaluation of Multiple Sclerosis Lesions.

BACKGROUND AND PURPOSE: Synthetic MR imaging creates multiple contrast-weighted images based on a single time-efficient quantitative scan, which has been mostly performed for 2D acquisition. We assessed the utility of 3D synthetic MR imaging in patients with MS by comparing its diagnostic image quality and lesion volumetry with conventional MR imaging. MATERIALS AND METHODS: Twenty-four patients with MS prospectively underwent 3D quantitative synthetic MR imaging and conventional T1-weighted, T2-weighted, FLAIR, and double inversion recovery imaging, with acquisition times of 9 minutes 3 seconds and 18 minutes 27 seconds for the synthetic MR imaging and conventional MR imaging sequences, respectively. Synthetic phase-sensitive inversion recovery images and those corresponding to conventional MR imaging contrasts were created for synthetic MR imaging. Two neuroradiologists independently assessed the image quality on a 5-point Likert scale. The numbers of cortical lesions and lesion volumes were quantified using both synthetic and conventional image sets. RESULTS: The overall diagnostic image quality of synthetic T1WI and double inversion recovery images was noninferior to that of conventional images (P = .23 and .20, respectively), whereas that of synthetic T2WI and FLAIR was inferior to that of conventional images (both Ps < .001). There were no significant differences in the number of cortical lesions (P = .17 and .53 for each rater) or segmented lesion volumes (P = .61) between the synthetic and conventional image sets. CONCLUSIONS: Three-dimensional synthetic MR imaging could serve as an alternative to conventional MR imaging in evaluating MS with a reduced scan time.

Direct evidence of electronic ferroelectricity in YbFe2O4 using neutron diffraction and nonlinear spectroscopy.

We report the first observation of room temperature spontaneous electric polarization in an electronic ferroelectric material, a YbFe2O4 single crystal. The observation was based on second harmonic generation (SHG), a nonlinear optical process. Tensor analysis of the SHG signal revealed that this material has a polar charge superstructure with Cm symmetry. This result settles the long-term discussion on the uncertainty about electronic ferroelectric properties, including the charge order structure. We present a complete picture of the polar charge ordering of this material via consistent results from two different characterization methods. The SHG signal shows the same temperature dependence as the superlattice signal observed in neutron diffraction experiments. These results prove ferroelectric coupling to electron ordering in YbFe2O4, which results in electronic ferroelectricity which is enabled by the real space ordering of iron cations with different valences. The existence of electronic ferroelectricity holds promise for future electronics technologies where devices run a thousand times faster than frequency of the present CPU (a few gigahertz) embedded in smartphones, etc.

Electron-phonon superconductivity in C-doped topological nodal-line semimetal Zr5Pt3: a muon spin rotation and relaxation (µSR) study.

In the present work, we demonstrate that C-doped Zr5Pt3is an electron-phonon superconductor (with critical temperatureTC= 3.8 K) with a nonsymmorphic topological Dirac nodal-line semimetal state, which we report here for the first time. The superconducting properties of Zr5Pt3C0.5have been investigated by means of magnetization, resistivity, specific heat, and muon spin rotation and relaxation (µSR) measurements. We find that at low temperatures, the depolarization rate is almost constant and it can be well described by a single-bands-wave model with a superconducting gap of 2Δ(0)/kBTC= 3.84, somewhat higher than the value of BCS theory. From the transverse field µSR analysis, we estimate the London penetration depthλL= 469 nm, superconducting carrier densityns= 1.83 × 1026 m-3, and effective massm* = 1.428me. The zero field µSR confirms the absence of any spontaneous magnetic field in the superconducting ground state. In order to gain additional insights into the electronic ground state of C-doped Zr5Pt3, we also performed first-principles calculations within the framework of density functional theory (DFT). The observed homogenous electronic character of the Fermi surface as well as the mutual decrease ofTCand density of states at the Fermi level are consistent with the experimental findings of this study. However, the band structure reveals the presence of robust, gapless fourfold-degenerate nodal lines protected by 63screw rotations and glide mirror planes. Therefore, Zr5Pt3represents a novel, unprecedented condensed matter system to investigate the intricate interplay between superconductivity and topology.

Clinical impact of a combined therapy of peritoneal dialysis and hemodialysis.

AIMS: Although peritoneal dialysis (PD) is recommended as the first-line treatment for end-stage renal disease, limitations exist to achieving good clinical status when the residual renal function (RRF) has declined. Combined therapy with PD and hemodialysis (HD) is the treatment of choice for patients who cannot control body fluid status and/or cannot obtain adequate solute removal by PD alone. The aim of this study was to evaluate the clinical efficacy of this combined therapy. METHODS: In this retrospective study, 53 patients on PD and diagnosed with underdialysis and/or overhydration with declining RRF were recruited. Parameters of volume control, uremic solute removal, anemia, and predictors for encapsulating peritoneal sclerosis (EPS) were compared before and 1 year after combined therapy. RESULTS: The patients' hydration status improved significantly with reductions in atrial natriuretic peptide and blood pressure. Serum creatinine and beta2 microglobulin also decreased significantly. The hemoglobin level increased remarkably from 8.2 ± 1.6 to 10.7 ± 1.2 g/dl (p < 0.01) and the reticulocyte count also increased significantly, even though at the same time the dose of recombinant human erythropoietin decreased significantly. The dialysate to plasma creatinine ratio obtained from the fast peritoneal equilibration test (PET) decreased significantly from 0.65 ± 0.11 to 0.59 ± 0.13, and the level of interleukin 6 in PET drainage also significantly decreased. Furthermore, serum C-reactive protein and fibrinogen decreased significantly. CONCLUSIONS: Combined therapy with PD and HD is an effective way to control fluid status and to correct inadequate solute removal, leading to improvement in inflammation, peritoneal function and anemia.