Detailed dynamical features of the slow hydration water in the vicinity of poly(ethylene oxide) chains.

Poly(ethylene oxide) (PEO) is a well-known biocompatible polymer and has widely been used for medical applications. Recently, we have investigated the dynamic behavior of hydration water in the vicinity of PEO chains at physiological temperature and shown the presence of slow water with diffusion coefficient one order of magnitude less than that of bulk water. This could be evidence for the intermediate water that is critical for biocompatibility; however, its detailed dynamical features were not established. In this article, we analyze the quasi-elastic neutron scattering from hydration water through mode distribution analysis and present a microscopic picture of hydration water as well as its relation to cold crystallization.

Strong plastic responses in aerenchyma formation in F1 hybrids of Imperata cylindrica under different soil moisture conditions.

Hybrids can express traits plastically, enabling them to occupy environments that differ from parental environments. However, there is insufficient evidence demonstrating how phenotypic plasticity in specific traits mediates hybrid performance. Two parental ecotypes of Imperata cylindrica produce F1 hybrids. The E-type in wet habitats has larger internal aerenchyma than the C-type in dry habitats. This study evaluated relationships between habitat utilisation, aerenchyma plasticity, and growth of I. cylindrica accessions. We hypothesize that plasticity in expressing parental traits explains hybrid establishment in habitats with various soil moisture conditions. Aerenchyma formation was examined in the leaf midribs, rhizomes and roots of two parental ecotypes and their F1 hybrids in their natural habitats. In common garden experiments, we examined plastic aerenchyma formation in leaf midribs, rhizomes and roots of natural and artificial F1 hybrids and parental ecotypes and quantified vegetative growth performance. In the natural habitats where soil moisture content varied widely, the F1 hybrids showed larger variation in aerenchyma formation in rhizomes than their parental ecotypes. In the common garden experiments, F1 hybrids showed high plasticity of aerenchyma formation in rhizomes, and their growth was similar to that of C-type and E-type under drained and flooded conditions, respectively. The results demonstrate that F1 hybrids of I. cylindrica exhibit plasticity in aerenchyma development in response to varying local soil moisture content. This characteristic allows the hybrids to thrive in diverse soil moisture conditions.

Treatment outcomes of proton beam therapy combined with retrograde intra-arterial infusion chemotherapy for locally advanced oral cancer in the elderly.

The aim of this study was to evaluate the therapeutic efficacy and safety of proton beam therapy combined with retrograde intra-arterial infusion chemotherapy in elderly patients with locally advanced oral cancer. Between February 2009 and October 2019, 42 oral cancer patients aged ≥75 years were treated with this therapy. Median age was 80 years (range 75-90 years) and the median follow-up duration was 39 months (range 2-106 months). Of the 42 patients, 34 (81%) were diagnosed with stage IV cancer. The 3-year overall survival, local control, progression-free survival, and disease-specific survival rates were 56%, 69%, 32%, and 67%, respectively. Regarding acute toxicities, grade 3 neutropenia was observed in six patients (14%), anaemia in five (12%), acute kidney injury in one (2%), and oral mucositis in 18 (42%). Late toxicities of grade 3 were observed in seven patients: dysphagia in six (14%) and osteonecrosis of the jaw in one (2%). This study showed that proton beam therapy combined with retrograde intra-arterial infusion chemotherapy was effective for elderly patients with oral cancer, and toxicities were tolerable and manageable. The study findings suggest that this therapy is a potential treatment option for elderly oral cancer patients with difficulty in surgery and systemic chemotherapy.

Charge-neutral fermions and magnetic field-driven instability in insulating YbIr3Si7.

Kondo lattice materials, where localized magnetic moments couple to itinerant electrons, provide a very rich backdrop for strong electron correlations. They are known to realize many exotic phenomena, with a dramatic example being recent observations of quantum oscillations and metallic thermal conduction in insulators, implying the emergence of enigmatic charge-neutral fermions. Here, we show that thermal conductivity and specific heat measurements in insulating YbIr3Si7 reveal emergent neutral excitations, whose properties are sensitively changed by a field-driven transition between two antiferromagnetic phases. In the low-field phase, a significant violation of the Wiedemann-Franz law demonstrates that YbIr3Si7 is a charge insulator but a thermal metal. In the high-field phase, thermal conductivity exhibits a sharp drop below 300 mK, indicating a transition from a thermal metal into an insulator/semimetal driven by the magnetic transition. These results suggest that spin degrees of freedom directly couple to the neutral fermions, whose emergent Fermi surface undergoes a field-driven instability at low temperatures.

Feasibility of laparoscopic-assisted transanal pelvic exenteration in locally advanced rectal cancer with anterior invasion.

BACKGROUND: Transanal (Ta) pelvic exenteration is a promising, minimally invasive method for treating locally advanced colorectal cancer. However, since it is technically difficult to perform, Ta pelvic exenteration is rarely reported in locally advanced T4 rectal cancer cases. The aim of this study was to evaluate the feasibility of transabdominal laparoscopy-assisted Ta pelvic exenteration. METHODS: Six patients (4 males and 2 females) had laparoscopy-assisted Ta total or posterior pelvic exenteration for locally advanced or recurrent colorectal cancer cases at the Nagasaki University Hospital between September 2018 and August 2019. Clinical and pathological outcomes were measured and analyzed. RESULTS: The median operation time and intraoperative blood loss were 481 (range 456-709) minutes and 352.5 (range 257-1660) ml, respectively. R0 resection was achieved in all cases, and no patient required open surgery. Two patients had grade 3 complications (Clavien-Dindo) or higher. There was no mortality, and no reoperation was required. CONCLUSIONS: The results suggest that laparoscopic-assisted Ta pelvic exenteration is an acceptable procedure, may help overcome the current technical difficulties, and may improve outcomes in patients with locally advanced rectal cancer.

Evidence for an Fulde-Ferrell-Larkin-Ovchinnikov State with Segmented Vortices in the BCS-BEC-Crossover Superconductor FeSe.

We present resistivity and thermal-conductivity measurements of superconducting FeSe in intense magnetic fields up to 35 T applied parallel to the ab plane. At low temperatures, the upper critical field µ_{0}H_{c2}^{ab} shows an anomalous upturn, while thermal conductivity exhibits a discontinuous jump at µ_{0}H^{*}≈24 T well below µ_{0}H_{c2}^{ab}, indicating a first-order phase transition in the superconducting state. This demonstrates the emergence of a distinct field-induced superconducting phase. Moreover, the broad resistive transition at high temperatures abruptly becomes sharp upon entering the high-field phase, indicating a dramatic change of the magnetic-flux properties. We attribute the high-field phase to the Fulde-Ferrel-Larkin-Ovchinnikov (FFLO) state, where the formation of planar nodes gives rise to a segmentation of the flux-line lattice. We point out that strongly orbital-dependent pairing as well as spin-orbit interactions, the multiband nature, and the extremely small Fermi energy are important for the formation of the FFLO state in FeSe.

Complications of Endovascular Treatments for Brain Arteriovenous Malformations: A Nationwide Surveillance.

BACKGROUND AND PURPOSE: Embolization is widely performed to treat brain arteriovenous malformations, but little has been reported on factors contributing to complications. We retrospectively reviewed a nationwide surveillance to identify risk factors contributing to complications and short-term clinical outcomes in the endovascular treatment of brain arteriovenous malformations. MATERIALS AND METHODS: Data for endovascular treatment of brain arteriovenous malformations were extracted from the Japanese nationwide surveillance. Patient characteristics, brain arteriovenous malformation features, procedures, angiographic results, complications, and clinical outcomes at 30 days postprocedure were analyzed. RESULTS: A total of 1042 endovascular procedures (788 patients; mean, 1.43 ± 0.85 procedures per patient) performed in 111 institutions from 2010 to 2014 were reviewed. Liquid materials were used in 976 procedures (93.7%): to perform presurgical embolization in 638 procedures (61.2%), preradiosurgical embolization in 160 (15.4%), and as sole endovascular treatment in 231 (22.2%). Complete or near-complete obliteration of brain arteriovenous malformations was obtained in 386 procedures (37.0%). Procedure-related complications occurred in 136 procedures (13.1%), including hemorrhagic complications in 59 (5.7%) and ischemic complications in 57 (5.5%). Univariate analysis identified deep venous drainage, associated aneurysms, infratentorial location, and preradiosurgical embolization as statistically significant risk factors for complications. Multivariate analysis showed that embolization of brain arteriovenous malformations in the infratentorial location was significantly associated with complications. Patients with complications due to endovascular procedures had worse clinical outcomes 30 days after the procedures than those without complications. CONCLUSIONS: Complications arising after endovascular treatment of brain arteriovenous malformations are not negligible even though they may play a role in adjunctive therapy, especially in the management of infratentorial brain arteriovenous malformations.

Prognostic impact of residual lateral lymph node metastasis after neoadjuvant (chemo)radiotherapy in patients with advanced low rectal cancer.

Background: There is a lack of large studies focusing on the prognostic significance of lateral lymph node (LLN) metastasis following LLN dissection (LLND) in rectal cancer. The aim of this study was to evaluate the prognostic impact of LLN metastases on survival of patients with advanced low rectal cancer. Methods: Consecutive patients with locally advanced, but not metastatic, extraperitoneal rectal cancer treated with neoadjuvant (chemo)radiotherapy plus total mesorectal excision between 2004 and 2015 were included in the study. LLND was performed when pretreatment imaging documented enlarged LLNs (7 mm or greater in size). Localization of nodal metastases and long-term outcomes were analysed. Kaplan-Meier analysis was used to compare the survival of patients with ypN0 disease with that of patients with mesorectal ypN+/LLN- status and patients with positive LLNs. The Cox proportional hazards model was used to evaluate predictors of disease-free survival (DFS) and local recurrence. Results: A total of 613 patients were included in the study; LLND was performed in 212 patients (34·6 per cent) and 57 (9·3 per cent) had LLN metastasis. Patients with LLN metastasis had improved DFS and local recurrence cumulative incidence rates compared with patients with mesorectal ypN2+/LLN- disease (DFS: P = 0·014; local recurrence: P = 0·006). Although the DFS rate of patients with LLN metastasis was worse than that of patients with ypN0 disease (P < 0·001), the cumulative incidence of local recurrence was similar (P = 0·491). In multivariable analysis, residual LLN metastasis was not an independent predictor of worse DFS or local recurrence. Conclusion: LLN metastasis is not an independent predictor of local recurrence or survival. Survival of patients presenting with LLN metastasis after (chemo)radiotherapy was intermediate between that of patients with ypN0 status and those with mesorectal ypN2 positivity.

Antecedentes: No existen en la literatura grandes estudios dirigidos a investigar la importancia pronóstica de las metástasis en los ganglios linfáticos laterales (lateral lymph nodes, LLN) después de la disección de los mismos (LLN dissection, LLND) en pacientes con cáncer de recto. El objetivo de este estudio fue evaluar el impacto pronóstico de las metástasis en los LLN sobre la supervivencia de los pacientes con cáncer de recto. Métodos: Se analizaron 613 pacientes consecutivos con cáncer de recto localmente avanzado extraperitoneal y no metastásico tratados con (quimio)radioterapia neoadyuvante seguida de resección total del mesorrecto (total mesorectal excision, TME) entre 2004 y 2015. Se realizó una LLND cuando el estudio mediante pruebas de imagen previo el tratamiento mostró LLN aumentados de tamaño ≥ 7 mm. Se analizó la localización de las metástasis ganglionares y los resultados a largo plazo. El análisis de supervivencia se realizó mediante el método de Kaplan­Meier para comparar las supervivencias de los pacientes ypN0 frente a los pacientes ypN con positividad mesorrectal/LLN negativos y frente a los pacientes LLN positivos. Se utilizó el modelo de riesgo proporcional de Cox para evaluar los factores predictivos de supervivencia libre de enfermedad y de recidiva local. Resultados: Se realizó una LLND en 212 (34,6%) pacientes, y 57 (9,3%) pacientes presentaban metástasis en los LLN. Los pacientes con metástasis en los LLN presentaron mejores curvas de incidencia acumulada de recidiva local y de supervivencia libre de enfermedad en comparación con los pacientes con ganglios mesorrectales ypN2 positivos/LLN negativos (respectivamente, P = 0,0135 y P = 0,0060). Aunque la curva de la supervivencia libre de enfermedad de los pacientes con metástasis en los LLN fue peor que la de los pacientes ypN0 (P < 0,0001), la incidencia acumulada de recidiva local fue similar (P = 0,4905). En el análisis multivariable, la metástasis residual en los LLN no fue un factor predictivo independiente de peor supervivencia libre de enfermedad ni de recidiva local. Conclusión: Las metástasis en los LLN no es un factor predictivo independiente de recidiva local o supervivencia. Los pacientes que presentaron metástasis en los LLN después de (quimio)radioterapia mostraron características de supervivencia intermedias entre ypN0 y pacientes con ganglios mesorrectales ypN2 positivos.

Mechanism of increased microbial autofluorescence by heat treatment.

The total direct count (TDC) microbial enumeration method is rapid and suitable for analysing environmental samples containing numerous un-culturable micro-organisms. Conventional TDC methods require the addition of a fluorescent stain and are thus unsuitable for automatic monitoring. We unexpectedly found that heated micro-organisms emit strong autofluorescence. This study was conducted to determine how heating enhances the autofluorescence of bacteria and fungi and to evaluate whether the phenomenon could be exploited to develop a new TDC method. Bacterial autofluorescence was augmented by heating cells at 200°C. ELISA results indicated that levels of advanced glycation end products (AGEs) increased in heated microbes. Catechin, an inhibitor of the Maillard reaction, disrupted the intensification of autofluorescence. These results suggest that the enhanced autofluorescence is associated with the formation of AGEs and that the reaction could be utilized as alternative probe in TDC methods. SIGNIFICANCE AND IMPACT OF THE STUDY: Autofluorescence of bacteria and fungi was prominently intensified by heat treatment at 200°C. This phenomenon was associated with advanced glycation end products formed in micro-organisms via the Maillard reaction. The fluorescence signal was strong enough to be utilized as an alternative probe for fluorescent dye in the total direct count method. This phenomenon could be incorporated in an automatic apparatus for microbial enumeration, as it does not require staining.

The Japanese Postmarketing Adverse Event Relief System: A Confluence of Regulatory Science, the Legal System, and Clinical Pharmacology.

The Japanese Postmarketing Relief System provides for compensation to patients with adverse reactions, based on the acknowledgment that unpredicted adverse events occur inevitably once a drug is marketed. The system also provides new knowledge about the benefit-risk profile of a drug that may be incorporated into product labeling. The system relies on causality assessments that are based on sound clinical pharmacology principles. The system may serve as a model for other countries' healthcare systems.

A laser-induced pulsed water jet for layer-selective submucosal dissection of the esophagus.

Background and aims: Conventional water jet devices have been used for injecting fluid to lift up lesions during endoscopic submucosal dissection or endoscopic mucosal resection procedures. However, these devices cannot dissect the submucosal layer effectively. Here we aim to elucidate the dissection capability of a laser-induced pulsed water jet and to clarify the mechanism of dissection with layer selectivity. Materials (Subjects) and methods: Pulsed water jets were ejected from a stainless nozzle by accelerating saline using the energy of a pulsed holmium: yttrium-aluminum-garnet laser. The impact force (strength) of the jet was evaluated using a force meter. Injection of the pulsed jet into the submucosal layer was documented by high-speed imaging. The physical properties of the swine esophagus were evaluated by measuring the breaking strength. Submucosal dissection of the swine esophagus was performed and the resection bed was evaluated histologically. Results: Submucosal dissection of the esophagus was accomplished at an impact force of 1.11-1.47 N/pulse (laser energy: 1.1-1.5 J/pulse; standoff distance: 60 mm). Histological specimens showed clear dissection at the submucosal layer without thermal injury. The mean static breaking strength of the submucosa (0.11 ± 0.04 MPa) was significantly lower than that of the mucosa (1.32 ± 0.18 MPa), and propria muscle (1.45 ± 0.16 MPa). Conclusions: The pulsed water jet device showed potential for achieving selective submucosal dissection. It could achieve mucosal, submucosal, and muscle layer selectivity owing to the varied breaking strengths.

High-Convexity Tightness Predicts the Shunt Response in Idiopathic Normal Pressure Hydrocephalus.

BACKGROUND AND PURPOSE: Although neuroimaging plays an important role in the diagnosis of idiopathic normal pressure hydrocephalus, its predictive value for response to shunt surgery has not been established. The purpose of the current study was to identify neuroimaging markers that predict the shunt response of idiopathic normal pressure hydrocephalus. MATERIALS AND METHODS: Sixty patients with idiopathic normal pressure hydrocephalus underwent presurgical brain MR imaging and clinical evaluation before and 1 year after shunt surgery. The assessed MR imaging features included the Evans index, high-convexity tightness, Sylvian fissure dilation, callosal angle, focal enlargement of the cortical sulci, bumps in the lateral ventricular roof, and deep white matter and periventricular hyperintensities. The idiopathic normal pressure hydrocephalus grading scale total score was used as a primary clinical outcome measure. We used measures for individual symptoms (ie, the idiopathic normal pressure hydrocephalus grading scale subdomain scores, such as gait, cognitive, and urinary scores), the Timed Up and Go test, and the Mini-Mental State Examination as secondary clinical outcome measures. The relationships between presurgical neuroimaging features and postoperative clinical changes were investigated by using simple linear regression analysis. To identify the set of presurgical MR imaging features that best predict surgical outcomes, we performed multiple linear regression analysis by using a bidirectional stepwise method. RESULTS: Simple linear regression analyses demonstrated that presurgical high-convexity tightness, callosal angle, and Sylvian fissure dilation were significantly associated with the 1-year changes in the clinical symptoms. A multiple linear regression analysis demonstrated that presurgical high-convexity tightness alone predicted the improvement of the clinical symptoms 1 year after surgery. CONCLUSIONS: High-convexity tightness is a neuroimaging feature predictive of shunt response in idiopathic normal pressure hydrocephalus.

Quantitative Assessment of Circumferential Enhancement along the Wall of Cerebral Aneurysms Using MR Imaging.

BACKGROUND AND PURPOSE: The incidence of wall enhancement of cerebral aneurysms on vessel wall MR imaging has been described as higher in ruptured intracranial aneurysms than in unruptured intracranial aneurysms, but the difference in the degree of enhancement between ruptured and unruptured aneurysms is unknown. We compared the degree of enhancement between ruptured and unruptured intracranial aneurysms by using quantitative MR imaging measures. MATERIALS AND METHODS: We performed quantitative analyses of circumferential enhancement along the wall of cerebral aneurysms in 28 ruptured and 76 unruptured consecutive cases by using vessel wall MR imaging. A 3D-T1-weighted fast spin-echo sequence was obtained before and after contrast media injection, and the wall enhancement index was calculated. We then compared characteristics between ruptured and unruptured aneurysms. RESULTS: The wall enhancement index was significantly higher in ruptured than in unruptured aneurysms (1.70 ± 1.06 versus 0.89 ± 0.88, respectively; P = .0001). The receiver operating characteristic curve analysis found that the most reliable cutoff value of the wall enhancement index to differentiate ruptured from unruptured aneurysms was 0.53 (sensitivity, 0.96; specificity, 0.47). The wall enhancement index remained significant in the multivariate logistic regression analysis (P < .0001). CONCLUSIONS: Greater circumferential enhancement along the wall of cerebral aneurysms correlates with the ruptured state. A quantitative evaluation of circumferential enhancement by using vessel wall MR imaging could be useful in differentiating ruptured from unruptured intracranial aneurysms.

From adaptive licensing to adaptive pathways: delivering a flexible life-span approach to bring new drugs to patients.

The concept of adaptive licensing (AL) has met with considerable interest. Yet some remain skeptical about its feasibility. Others argue that the focus and name of AL should be broadened. Against this background of ongoing debate, we examine the environmental changes that will likely make adaptive pathways the preferred approach in the future. The key drivers include: growing patient demand for timely access to promising therapies, emerging science leading to fragmentation of treatment populations, rising payer influence on product accessibility, and pressure on pharma/investors to ensure sustainability of drug development. We also discuss a number of environmental changes that will enable an adaptive paradigm. A life-span approach to bringing innovation to patients is expected to help address the perceived access vs. evidence trade-off, help de-risk drug development, and lead to better outcomes for patients.

Correlation of [RuCl3(dppb)(VPy)] cytotoxicity with its effects on the cell membranes: an investigation using Langmuir monolayers as membrane models.

One of the major challenges in drug design is to identify compounds with potential toxicity toward target cells, preferably with molecular-level understanding of their mode of action. In this study, the antitumor property of a ruthenium complex, mer-[RuCl3(dppb)(VPy)] (dppb = 1,4-bis(diphenylphosphine)butane and VPy = 4-vinylpyridine) (RuVPy), was analyzed. Results showed that this compound led to a mortality rate of 50% of HEp-2 cell with 120 ± 10 µmol L(-1), indicating its high toxicity. Then, to prove if its mode of action is associated with its interaction with cell membranes, Langmuir monolayers were used as a membrane model. RuVPy had a strong effect on the surface pressure isotherms, especially on the elastic properties of both the zwitterionic dipalmitoylphosphatidylcholine (DPPC) and the negatively charged dipalmitoylphosphatidylglycerol (DPPG) phospholipids. These data were confirmed by polarization-modulated infrared reflection-absorption spectroscopy (PM-IRRAS). In addition, interactions between the positive group from RuVPy and the phosphate group from the phospholipids were corroborated by density functional theory (DFT) calculations, allowing the determination of the Ru complex orientation at the air-water interface. Although possible contributions from receptors or other cell components cannot be discarded, the results reported here represent evidence for significant effects on the cell membranes which are probably associated with the high toxicity of RuVPy.

Prediction of neurological recovery in spontaneous spinal epidural hematoma using apparent diffusion coefficient values.

OBJECTIVE: Magnetic resonance imaging (MRI) is useful in diagnosing spontaneous spinal epidural hematoma (SSEH). The purpose of the present study is to determine whether apparent diffusion coefficient (ADC) values could determine severity of spinal cord damage and predict functional recovery in SSEH. METHODS: The study involved four consecutive patients with SSEH (two men and two women: aged 21-76 years). Using axial slices, ADC values were determined in four separate regions of the spinal cord. These areas were classified into the following three groups based on findings in T2-weighted images: normal T2 intensity; persistent T2 abnormality; and temporary T2 abnormality. ADC values among different groups were compared. The relationship between preoperative ADC values and neurological grades were also evaluated. RESULTS: ADC values in normal T2 areas were 0.89 ± 0.10 × 10(-3) mm(2) s(-1), whereas those for the persistent T2 abnormality group were significantly lower (0.63 ± 0.14 × 10(-3)). In a patient who was Frankel A on admission and in the follow-up, the ADC value was as low as 0.41 × 10(-3). Functional recovery was also limited in the spinal cord segments with lower ADC values. In the temporary T2 abnormality group, ADC values were significantly higher (1.05 ± 0.10 × 10(-3)). CONCLUSIONS: In SSEH, if MRI demonstrated T2-hyperintensity with lower ADC values, patients may suffer from irreversible spinal cord damages. ADC values of the spinal cord can be added as a new factor that reliably indicated the severity of spinal cord damage and predicted functional recovery.

Measurement and analysis of internal stress distributions created in gelatin simulated-brain tissue by a pulsed laser-induced liquid jet.

Transsphenoidal surgery is currently employed to treat complex lesions beyond the sella turcica; however, the procedure can be limited by difficulties encountered in dealing with small blood vessels, deep and narrow working spaces, and awkward working angles. To overcome these problems, we have developed a pulsed laser-induced liquid jet system that can dissect tumor tissue while preserving fine blood vessels within deep and narrow working spaces. We have previously evaluated the utility and safety of this procedure. However, the effects of the pulsejet after being injected into the brain are not yet well understood. Especially, the behavior of the stress distribution created by the jet is important because it has recently been reported that high acoustic pressures can affect the brain. In this study, we measured internal stress distributions in a gelatin simulated-brain using photoelasticity experiments. We used a high-speed camera with an image sensor on which an array of micropolarizers was attached to measure the stresses and the shear wave created when the pulsejet enters the simulated brain.

Analysis of liquid reservoir effect induced by pulsed laser liquid jet.

A pulsed-laser-induced liquid jet (LILJ) is a new device used in neurosurgery to simultaneously crush, incise, and aspirate tissues and tumors, preserving blood vessels and nerves. In addition, a feature of a pulsed LILJ is its ability to excavate tissue at constant depth while a liquid jet is being repeatedly focused at the same point. To clarify the mechanisms of constant depth of excavation, we employed a gelatin phantom and extracted brain tissue using a high-speed camera, and we then confirmed that the liquid-reservoir-induced LILJ played an important role in enabling the safe usage of an LILJ.