Erratum: Using Diffuse Scattering to Observe X-Ray-Driven Nonthermal Melting [Phys. Rev. Lett. 126, 015703 (2021)].

This corrects the article DOI: 10.1103/PhysRevLett.126.015703.

Using Diffuse Scattering to Observe X-Ray-Driven Nonthermal Melting.

We present results from the SPring-8 Angstrom Compact free electron LAser facility, where we used a high intensity (∼10^{20} W/cm^{2}) x-ray pump x-ray probe scheme to observe changes in the ionic structure of silicon induced by x-ray heating of the electrons. By avoiding Laue spots in the scattering signal from a single crystalline sample, we observe a rapid rise in diffuse scattering and a transition to a disordered, liquidlike state with a structure significantly different from liquid silicon. The disordering occurs within 100 fs of irradiation, a timescale that agrees well with first principles simulations, and is faster than that predicted by purely inertial behavior, suggesting that both the phase change and disordered state reached are dominated by Coulomb forces. This method is capable of observing liquid scattering without masking signal from the ambient solid, allowing the liquid structure to be measured throughout and beyond the phase change.

The analgesic effect of rescue administration of intravenous acetaminophen in cancer patients may be associated with sex and opioid dose, and the effect would appear to patients administered under 45 mg/day opioid (oral morphine equivalents).

There have been no investigations examining the analgesic effect of rescue administration of intravenous acetaminophen (IV APAP) for pain in cancer patients. Fifty cancer patients who received IV APAP for pain at Ashiya Municipal Hospital (Hyogo, Japan) between January 2014 and July 2016 were retrospectively evaluated. The degree of pain was evaluated using a 4-point verbal rating scale. Pain intensity differences ≥ 1 defined the IV APAP effective group, and the patient' characteristics were compared by a medical chart review. Variables were extracted from medical records for logistic regression analyses of factors associated with analgesic effect. The cut-off value of opioid dose (oral morphine equivalent) was determined using receiver operator characteristic (ROC) curve analysis. Thirty eight (76%) patients experienced an analgesic effect of rescue administration of IV APAP. Sex (odds ratio [OR] 5.4014; p = 0.0397) and opioid dose used for pain control (OR 0.9901; p = 0.0147) were found to be associated with the efficacy of rescue administration of IV APAP. The cut-off value of opioid dose (oral morphine equivalent), which may be difficult to match the analgesic effect of IV APAP, was calculated to be more than 45 mg/day. This study demonstrated the efficacy of a rescue administration of IV APAP for pain in cancer patients, and revealed that sex and opioid dose may be associated with the analgesic effect. Furthermore, this study also proposes a criterion for the analgesic effect.

Three-dimensional evaluation of subclinical extension of extramammary Paget disease: visualization of the histological border and its comparison to the clinical border.

BACKGROUND: In extramammary Paget disease (EMPD), Paget cells are sometimes detected outside the clinical border (subclinical extension). However, the spreading pattern of Paget cells in subclinical extension remains unclear. In addition, the macroscopic appearances of lesions accompanied by subclinical extension are totally unknown. OBJECTIVES: To characterize the spreading pattern of Paget cells as well as the macroscopic appearance of lesions of EMPD with subclinical extension. METHODS: Nineteen patients with primary anogenital EMPD underwent mapping biopsies and excisional surgeries; biopsy samples were then taken at the periphery of well-demarcated lesions. Samples were transparentized and subjected to whole-mount immunostaining with anticytokeratin 7 antibody to label Paget cells. The histological border was evaluated in three dimensions by two-photon microscopy. The shape and location of the histological border were compared with those of the clinical border. RESULTS: In 21 samples taken at the lesion where subclinical extension was not shown by mapping biopsy, the shape and location of the histological border were almost identical to those of the clinical border. However, two samples exhibited small foci of Paget cells outside the clinical border, showing subclinically extended satellite lesions. In the two samples taken at the lesions where subclinical extension was shown by mapping biopsy, a continuous arrangement of Paget cells extending beyond the clinical border was identified. Subclinically extended Paget cells were detected solely outside hypopigmented patches with erythema. CONCLUSIONS: In EMPD, at least two patterns of subclinical extension exist: continuous and satellite lesions. Subclinical extension might exist preferentially outside hypopigmented patches with erythema.

Effects of glutamate positive modulators on cognitive deficits in schizophrenia: a systematic review and meta-analysis of double-blind randomized controlled trials.

Hypofunction of N-methyl-d-aspartate (NMDA) receptors has been proposed to have an important role in the cognitive impairments observed in schizophrenia. Although glutamate modulators may be effective in reversing such difficult-to-treat conditions, the results of individual studies thus far have been inconsistent. We conducted a systematic review and meta-analysis to examine whether glutamate positive modulators have beneficial effects on cognitive functions in patients with schizophrenia. A literature search was conducted to identify double-blind randomized placebo-controlled trials in schizophrenia or related disorders, using Embase, Medline, and PsycINFO (last search: February 2015). The effects of glutamate positive modulators on cognitive deficits were evaluated for overall cognitive function and eight cognitive domains by calculating standardized mean differences (SMDs) between active drugs and placebo added to antipsychotics. Seventeen studies (N=1391) were included. Glutamate positive modulators were not superior to placebo in terms of overall cognitive function (SMD=0.08, 95% confidence interval=-0.06 to 0.23) (11 studies, n=858) nor each of eight cognitive domains (SMDs=-0.03 to 0.11) (n=367-940) in this population. Subgroup analyses by diagnosis (schizophrenia only studies), concomitant antipsychotics, or pathway of drugs to enhance the glutamatergic neurotransmission (glycine allosteric site of NMDA receptors or α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors) suggested no procognitive effect of glutamate positive modulators. Further, no effect was found in individual compounds on cognition. In conclusion, glutamate positive modulators may not be effective in reversing overall cognitive impairments in patients with schizophrenia as adjunctive therapies.

Differentiation between primary central nervous system lymphoma and glioblastoma: a comparative study of parameters derived from dynamic susceptibility contrast-enhanced perfusion-weighted MRI.

AIM: To evaluate the diagnostic performance of parameters derived from dynamic susceptibility contrast-enhanced perfusion-weighted magnetic resonance imaging, including first-pass slope ratio (FSR), which is potentially easier to derive than the other proposed parameters in this study, for differentiating primary central nervous system lymphoma (PCNSL) from glioblastoma. MATERIALS AND METHODS: Twenty-eight patients (10 PCNSLs and 18 glioblastomas) were analysed. Six perfusion parameters - corrected cerebral blood volume ratio (cCBVR), uncorrected CBV ratio (uCBVR), FSR, leakage coefficient (K2), percentage of signal-intensity recovery measured at the end of the first-pass (PSRend), and PSR measured using mean signal-intensity after the first-pass (PSRmean) - were derived from enhancing areas selected semi-automatically. Comparisons of cCBVR and uCBVR and of PSRend and PSRmean were conducted. The differences between PCNSL and glioblastoma were compared for the six parameters, and their diagnostic performance was evaluated by receiver operating characteristic curve analysis. RESULTS: For both tumours, cCBVR was significantly higher than uCBVR, and PSRend was significantly lower than PSRmean. PCNSL demonstrated lower cCBVR, uCBVR and FSR, and higher K2, PSRend and PSRmean compared with glioblastoma (p=0.0044 or less). On receiver operating characteristic curve analysis, the areas under the curve were 0.822 for cCBVR, 0.944 for uCBVR, 0.917 for FSR, 0.917 for K2, 0.933 for PSRend, and 0.894 for PSRmean. No significant difference was observed among the parameters, except cCBVR, which was significantly inferior to uCBVR. CONCLUSIONS: PCNSL can be differentiated from glioblastoma with high diagnostic value using any of the parameters, except cCBVR. FSR demonstrates high differential performance comparable to the other parameters.

Predicting Plasma Olanzapine Concentration Following a Change in Dosage: A Population Pharmacokinetic Study.

INTRODUCTION: Due to high inter-individual variability in peripheral pharmacokinetic parameters, dosing of antipsychotics currently relies on clinical trial-and-error, and predicting antipsychotic plasma concentrations before changing a dose has been a challenge. METHODS: Patients with schizophrenia receiving a stable dose of olanzapine were included. 2 plasma samples were collected at 2 given time points for the measurement of plasma olanzapine concentrations. At least 7 days after a dosage change of olanzapine, a third sample was collected. The plasma concentration of the third sample was predicted in a blinded fashion using a mixed-effects model with NONMEM(®), using the following information: the 2 baseline plasma concentrations, the interval between the last dose and blood draw, and clinical and demographic information. RESULTS: 31 subjects (mean±SD age=56.0±11.6; 19 men) were enrolled. The mean prediction (95% confidence interval) errors were 1.6 (-2.8 to 6.0) ng/mL. A highly significant correlation was observed between the observed and predicted concentrations of the third sample (r=0.91, p<0.001). DISCUSSION: Plasma olanzapine concentrations following an actual dosage change can be predicted in advance with a high degree of certainty.

Optimisation of pharmacotherapy in psychiatry through therapeutic drug monitoring, molecular brain imaging and pharmacogenetic tests: focus on antipsychotics.

BACKGROUND: For psychotic disorders (i.e. schizophrenia), pharmacotherapy plays a key role in controlling acute and long-term symptoms. To find the optimal individual dose and dosage strategy, specialized tools are used. Three tools have been proven useful to personalize drug treatments: therapeutic drug monitoring (TDM) of drug levels, pharmacogenetic testing (PG), and molecular neuroimaging. METHODS: In these Guidelines, we provide an in-depth review of pharmacokinetics, pharmacodynamics, and pharmacogenetics for 50 antipsychotics. Over 30 international experts in psychiatry selected studies that have measured drug concentrations in the blood (TDM), gene polymorphisms of enzymes involved in drug metabolism, or receptor/transporter occupancies in the brain (positron emission tomography (PET)). RESULTS: Study results strongly support the use of TDM and the cytochrome P450 (CYP) genotyping and/or phenotyping to guide drug therapies. Evidence-based target ranges are available for titrating drug doses that are often supported by PET findings. CONCLUSION: All three tools discussed in these Guidelines are essential for drug treatment. TDM goes well beyond typical indications such as unclear compliance and polypharmacy. Despite its enormous potential to optimize treatment effects, minimize side effects and ultimately reduce the global burden of diseases, personalized drug treatment has not yet become the standard of care in psychiatry.

Experience improves performance of hysterosalpingo-contrast sonography (HyCoSy): a comprehensive and well-tolerated screening modality for the subfertile patient.

PURPOSE: To investigate the clinical observations, provider experience, safety, and tolerance of the hysterosalpingo-contrast sonography (HyCoSy) procedure. MATERIALS AND METHODS: A retrospective study design in which data was collected from ninety-six subfertile women who underwent the HyCoSy procedure at the University of Louisville over a 16-month interval. RESULTS: Ninety-six HyCoSy procedures were performed by a single investigator and contained complete records for review. The authors observed significant decreases in the quantities of saline and air utilized per procedure over time (p < 0.0001 and p = 0.0001). Results from the HyCoSy studies were more often non-diagnostic or non-patent in women with a body mass index (BMI) > 30. Reported pain scores did not statistically differ over the course of the study interval. There were no procedure-related complications noted. CONCLUSION: The HyCoSy procedure is a timely and minimally invasive study that can be implemented in an office setting with minimal prior operator experience that improves over time.

Cordycepin as a sensitizer to tumour necrosis factor (TNF)-α-induced apoptosis through eukaryotic translation initiation factor 2α (eIF2α)- and mammalian target of rapamycin complex 1 (mTORC1)-mediated inhibition of nuclear factor (NF)-κB.

Cordycepin (3'-deoxyadenosine) is one of the major bioactive substances produced by Cordyceps militaris, a traditional medicinal mushroom. Cordycepin possesses several biological activities, including both pro-apoptotic and anti-apoptotic properties. In the present report, we investigated an effect of cordycepin on the survival of cells exposed to tumour necrosis factor (TNF)-α. We found that subtoxic doses of cordycepin increased susceptibility of cells to TNF-α-induced apoptosis. It was associated with suppression of nuclear factor-κB (NF-κB), a major prosurvival component involved in TNF-α signalling. The adenosine transporter and A3 adenosine receptor, but not A1 and A2 adenosine receptors, mediated both anti-NF-κB and pro-apoptotic effects. We found that cordycepin had the potential to phosphorylate eukaryotic translation initiation factor 2α (eIF2α) and that activation of eIF2α mimicked the suppressive effect of cordycepin on the NF-κB pathway. Furthermore, activation of eIF2α sensitized cells to TNF-α-induced apoptosis. To identify molecular events downstream of eIF2α, the role of mammalian target of rapamycin complex 1 (mTORC1) was examined. Selective activation of 3eIF2α, as well as treatment with cordycepin, caused phosphorylation of mTORC1. Rapamycin, an inhibitor of mTORC1, significantly reversed the suppressive effects of eIF2α on NF-κB. These results suggest that cordycepin sensitizes cells to TNF-α-induced apoptosis, at least in part, via induction of the eIF2α-mTORC1 pathway and consequent suppression of NF-κB.

Single-blind randomized clinical trial of transinguinal preperitoneal repair using self-expanding mesh patch vs. Lichtenstein repair for adult male patients with primary unilateral inguinal hernia.

PURPOSE: The aim of the study was to compare proportions of chronic postoperative inguinal pain (CPIP) and other surgical outcomes between transinguinal preperitoneal repair with modified Kugel patch (MK) and Lichtenstein repair (LR). METHODS: Two-hundred adult male patients with primary unilateral inguinal hernia were randomized into MK or LR groups. The primary endpoint was CPIP, pain at 6 months after surgery. Secondary outcomes included recurrence rate, incidence of postoperative complications, time until return to activities, inguinal pain and sensory disturbances assessed at 1 week, 1 month, 3, 6, and 12 months after the operation using an 11-point numerical rating scale (NRS). The study was an intention-to-treat analysis. RESULTS: In comparison of MK (n = 100) and LR (n = 100) with similar backgrounds, proportions of CPIP were similar (7.2 vs. 11.1%, p = 0.3452). Favorable outcomes for MK were duration of operation (32 vs. 40 min, p < 0.0001), NRS of foreign body sensation at 1 year (0 [0-1] vs. 0 [0-2], p = 0.0067), and NRS of numbness at 1 month (0 [0-1] vs. 0 [0-3], p = 0.0078) after the operation. CONCLUSIONS: In regard to CPIP, the short-term results of MK and LR were similar.

Chemoradiation induces upregulation of immunogenic cell death-related molecules together with increased expression of PD-L1 and galectin-9 in gastric cancer.

Surgery alone or combined with chemo- and/or radiation therapy remains the primary treatment for gastric cancer (GC) to date and immunotherapeutic tools such as monoclonal antibodies are only slowly being implemented. This is partly due to the fact that the immune microenvironment in GC during chemoradiation and other treatment modalities is still poorly understood. 7 gastric cancer (GC) cell lines were tested for their response to chemoradiation using 5-FU in combination with X-ray irradiation. We conducted flow cytometric analysis to determine the cells' ability to undergo immunogenic cell death (ICD) and their expression of the two immunosuppressive proteins programmed death-ligand 1 (PD-L1) and galectin-9 (Gal-9). We evaluated the overall immunogenicity of two cell lines (MKN7, MKN74) in co-culture experiments with human monocyte-derived dendritic cells (Mo-DCs). Chemoradiation induces distinct responses in different GC cell lines. We observe ICD in vitro in all tested GC cell lines in the form of calreticulin (CRT) translocation to the plasma membrane. As a resistance mechanism, these cells also upregulated Gal-9 and PD-L1. Mo-DC maturation experiments showed that GCs provoked the maturation of Mo-DCs after chemoradiation in vitro. The addition of α-PD-L1 blocking antibody further enhanced the immunogenicity of these cells while improving DC viability. Blocking Tim-3, as the main receptor for Gal-9, had no such effect. Our findings suggest that the benefits of chemoradiation can substantially depend on tumor subtype and these benefits can be offset by induced immune evasion in GC. Combination treatment using checkpoint inhibitors could potentially lead to enhanced immune responses and yield better patient outcomes.

The substantia nigra is a major target for neurovirulent influenza A virus.

Clinical and immunohistochemical studies were done for 3-39 d on mice after intracerebral inoculation with the neurovirulent A/WSN/33 (H1N1; WSN) strain of influenza A virus, the nonneurovirulent A/Aichi/2/68 (H3N2; Aichi) strain, and two reassortant viruses between them. The virus strains with the WSN gene segment coding for neuraminidase induced meningoencephalitis in mice. The mice inoculated with the R96 strain, which has only the neuraminidase gene from the WSN strain, had mild symptoms and weak positive immunostaining to the anti-WSN antibody in meningeal regions. Both the WSN and R404BP strains, which contain the WSN gene segments coding for neuraminidase and matrix protein, were clearly neurovirulent both clinically and pathologically. On day 3 after inoculation with either of these two strains, WSN antigen was detected in meningeal and ependymal areas, neurons of circumventricular regions, the cerebral and cerebellar cortices, the substantia nigra zona compacta, and the ventral tegmental area. On day 7, meningeal reactions and neuronal staining were still seen, and advanced accumulation of the viral antigen was evident in the substantia nigra zona compacta and hippocampus. Double immunostaining demonstrated that the WSN antigen was only seen in neurons and not in microglia or reactive astrocytes. Immunostaining for the lectin maackia amurensis agglutinin, which recognizes the Neu5Ac alpha 2,3 Gal sequence, which serves as a binding site for influenza A virus on target cell membranes, showed that positive staining was localized in the ventral substantia nigra and hippocampus. These results suggest that neurovirulent influenza A viruses could be one of the causative agents for postencephalitic parkinsonism.

Patterns for RANTES secretion and intercellular adhesion molecule 1 expression mediate transepithelial T cell traffic based on analyses in vitro and in vivo.

Immune cell migration into and through mucosal barrier sites in general and airway sites in particular is a critical feature of immune and inflammatory responses, but the determinants of transepithelial (unlike transendothelial) immune cell traffic are poorly defined. Accordingly, we used primary culture airway epithelial cells and peripheral blood mononuclear cells to develop a cell monolayer system that allows for apical-to-basal and basal-to-apical T cell transmigration that can be monitored with quantitative immunofluorescence flow cytometry. In this system, T cell adhesion and subsequent transmigration were blocked in both directions by monoclonal antibodies (mAbs) against lymphocyte function-associated antigen 1 (LFA-1) or intercellular adhesion molecule 1 (ICAM-1) (induced by interferon gamma [IFN-gamma] treatment of epithelial cells). The total number of adherent plus transmigrated T cells was also similar in both directions, and this pattern fit with uniform presentation of ICAM-1 along the apical and basolateral cell surfaces. However, the relative number of transmigrated to adherent T cells (i.e., the efficiency of transmigration) was increased in the basal-to-apical relative to the apical-to-basal direction, so an additional mechanism was needed to mediate directional movement towards the apical surface. Screening for epithelial-derived beta-chemokines indicated that IFN-gamma treatment caused selective expression of RANTES (regulated upon activation, normal T cell expressed and secreted), and the functional significance of this finding was demonstrated by inhibition of epithelial-T cell adhesion and transepithelial migration by anti-RANTES mAbs. In addition, we found that epithelial (but not endothelial) cells preferentially secreted RANTES through the apical cell surface thereby establishing a chemical gradient for chemotaxis across the epithelium to a site where they may be retained by high levels of RANTES and apical ICAM-1. These patterns for epithelial presentation of ICAM-1 and secretion of RANTES appear preserved in airway epithelial tissue studied either ex vivo with expression induced by IFN-gamma treatment or in vivo with endogenous expression induced by inflammatory disease (i.e., asthma). Taken together, the results define how the patterns for uniform presentation of ICAM-1 along the cell surface and specific apical sorting of RANTES may serve to mediate the level and directionality of T cell traffic through epithelium (distinct from endothelium) and provide a basis for how this process is precisely coordinated to route immune cells to the mucosal surface and maintain them there under normal and stimulated conditions.

Observation of a large reaction cross section in the drip-line nucleus 22C.

Reaction cross sections (sigma(R)) for 19C, 20C and the drip-line nucleus 22C on a liquid hydrogen target have been measured at around 40A MeV by a transmission method. A large enhancement of sigma(R) for 22C compared to those for neighboring C isotopes was observed. Using a finite-range Glauber calculation under an optical-limit approximation the rms matter radius of 22C was deduced to be 5.4+/-0.9 fm. It does not follow the systematic behavior of radii in carbon isotopes with N < or = 14, suggesting a neutron halo. It was found by an analysis based on a few-body Glauber calculation that the two-valence neutrons in 22C preferentially occupy the 1s(1/2) orbital.

A study of vertebrobasilar artery dissection with subarachnoid hemorrhage.

We retrospectively studied clinical characteristics of 368 patients with cerebral artery dissections who were diagnosed in 172 Japanese hospitals. Of these patients, 130 (35%) presented with subarachnoid hemorrhage, 217 (59%) with cerebral infarctions, and 21 (6%) with transient ischemic attacks. We analyzed 109 (84%) subarachnoid hemorrhage cases caused by vertebrobasilar artery dissection to evaluate conservative and surgical treatment from the viewpoint of postoperative rerupture and infarction.Subsequent ruptures were observed in 14% of the 21 cases with nonsurgical treatment. For the preventive purpose of rerupture, 88 patients received surgical interventions: 68 trappings, 13 proximal occlusions, 6 aneurysmal sac occlusions and 1 stenting. Rerupture was experienced in 33% of the aneurysmal sac occlusion patients while not occurring in the other three surgical interventions. In the group without vascular anastomosis, postoperative cerebral infarction was observed in 25% of the trapping, none of the proximal occlusion and 33% of the aneurysmal sac occlusion cases.In this study, aneurysmal sac occlusion treatments were more frequently complicated by rerupture or cerebral infarction postoperatively than the other treatment methods. It was difficult to determine which surgical treatment can achieve better surgical outcome among the proximal occlusion and trapping with or without vascular anastomosis.

Freeze-fracture and electrophysiological studies of newly developed acetylcholine receptors in Xenopus embryonic muscle cells.

The development of acetylcholine receptors on Xenopus embryonic muscle cells both in culture and in situ was studied using electrophysiology and freeze-fracture electron microscopy. Acetylcholine sensitivity first appeared at developmental stage 20 and gradually increased up to about stage 31. Freeze-fracture of muscle cells that were nonsensitive to acetylcholine revealed diffusely distributed small P-face intramembraneous particles. When cells acquired sensitivity to acetylcholine, a different group of diffusely distributed large P-face particles began to appear. This group of particles was analyzed by subtracting the size distribution found on nonsensitive cells from that found on sensitive cells. We call this group of particles difference particles. The sizes of difference particles were large (peak diameter 11 nm). The density of difference particles gradually increased with development. The density of small particles (less than 9 nm) did not change with development. At later stages (32-36) aggregates of large particles appeared, which probably represent acetylcholine receptor clusters. The size distribution of difference particles was close to that of the aggregated particles, suggesting that at least part of difference particles represent diffusely distributed acetylcholine receptors. Difference particles exist mostly in solitary form (occasionally double), indicating that an acetylcholine receptor can be functional in solitary form. This result also shows that diffuse acetylcholine receptors that have previously been observed with 125I-alpha-bungarotoxin autoradiography do indeed exist in solitary forms not as microaggregates.

Differential development of two classes of acetylcholine receptors in Xenopus muscle in culture.

Physiological properties of acetylcholine receptors on muscle cells at very early stages of ontogeny were compared with those of cells at later stages. Two changes were observed that contributed to an overall shortening of the mean open time of single-channels. First, there was a shift in the relative proportions of two receptor types with different conductances and mean open times, such that the contribution of receptors with large conductance and short open time increased as development proceeded. Second, there was a sharp reduction in the mean open time of channels having small conductance, with no similar change in channels having large conductance.

Fibrous apatite grown on modified collagen.

Fibrous apatite has been grown by the enzymatic hydrolysis of calcium beta-glycerophosphate on reconstituted calfskin collagen tapes which had been modified by the addition of a phosphoprotein, phosvitin, in the presence of a cross-linking agent, dimethylsuberimidate. The deposits were identified as a carbonate-bearing hydroxyapatite by x-ray diffraction, and scanning electron micrographs confirmed their fibrous character.