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Faricimab is a bispecific antibody that acts through dual inhibition of both angiopoietin-2 and vascular endothelial growth factor A. We report primary results of two phase 3 trials evaluating intravitreal faricimab with extension up to every 16 weeks for neovascular age-related macular degeneration (nAMD).TENAYA and LUCERNE were randomised, double-masked, non-inferiority trials across 271 sites worldwide. Treatment-naive patients with nAMD aged 50 years or older were randomly assigned (1:1) to intravitreal faricimab 6·0 mg up to every 16 weeks, based on protocol-defined disease activity assessments at weeks 20 and 24, or aflibercept 2·0 mg every 8 weeks. Randomisation was performed through an interactive voice or web-based response system using a stratified permuted block randomisation method. Patients, investigators, those assessing outcomes, and the funder were masked to group assignments. The primary endpoint was mean change in best-corrected visual acuity (BCVA) from baseline averaged over weeks 40, 44, and 48 (prespecified non-inferiority margin of four letters), in the intention-to-treat population. Safety analyses included patients who received at least one dose of study treatment. These trials are registered with ClinicalTrials.gov (TENAYA NCT03823287 and LUCERNE NCT03823300).Across the two trials, 1329 patients were randomly assigned between Feb 19 and Nov 19, 2019 (TENAYA n=334 faricimab and n=337 aflibercept), and between March 11 and Nov 1, 2019 (LUCERNE n=331 faricimab and n=327 aflibercept). BCVA change from baseline with faricimab was non-inferior to aflibercept in both TENAYA (adjusted mean change 5·8 letters [95% CI 4·6 to 7·1] and 5·1 letters [3·9 to 6·4]; treatment difference 0·7 letters [-1·1 to 2·5]) and LUCERNE (6·6 letters [5·3 to 7·8] and 6·6 letters [5·3 to 7·8]; treatment difference 0·0 letters [-1·7 to 1·8]). Rates of ocular adverse events were comparable between faricimab and aflibercept (TENAYA n=121 [36·3%] vs n=128 [38·1%], and LUCERNE n=133 [40·2%] vs n=118 [36·2%]).Visual benefits with faricimab given at up to 16-week intervals demonstrates its potential to meaningfully extend the time between treatments with sustained efficacy, thereby reducing treatment burden in patients with nAMD.F Hoffmann-La Roche.

Unstable pelvic fractures, especially vertical shear fractures, require surgery for correct reduction, rigid fixation, and improved postoperative outcomes. Herein, we assess the effectiveness of our minimally invasive procedure for the management of unstable pelvic fractures.We hypothesized that this procedure would be useful for the management of unstable pelvic fractures.This study included 28 patients with unstable pelvic fractures (vertical shear injuries; AO types C1-3) treated using minimally invasive surgery for spinopelvic fixation (MIS-SP) between 2014 and 2020 (mean follow-up time, 15 months). The MIS-SP requires four percutaneous pedicle screws and four iliac screw insertions. Subsequently, reduction and fixation are performed.The mean preoperative displacement of the posterior pelvic elements in craniocaudal correction was 17.6 (range, 9.0-32.2) mm. The mean length of the craniocaudal reduction was 16.5 (8.1-30.1) mm, with a mean reduction rate of 93.5% (78%-100%). The mean length of the mediolateral reduction was 11.3 (3.9-19.6) mm, with a mean reduction rate of 87.3% (76%-100%).Our novel reduction and fixation procedure is a powerful, minimally invasive option for the treatment of unstable pelvic ring fractures.III.

This study aimed to investigate the effects of aspirin on peri-operative hidden blood loss during hip fracture surgery by adjusting for possible factors affecting blood loss using a propensity score matching method. We retrospectively collected data from a cohort of isolated hip fracture patients (aged ≥ 65 years)who underwent surgery from January 2010 to December 2019. The study’s primary outcome was blood loss from admission to the day after surgery in the aspirin and control groups. We estimated the hidden blood loss, calculated based on patient’s blood volume, haemoglobin measurements, and blood transfusions. The secondary outcome focused on the requirement for blood transfusion. We adjusted for possible factors affecting blood loss using a propensity score matching method and statistically examined the effects of aspirin on hip fracture surgery. We enrolled 806 patients of whom 271 (34%) were taking anticoagulant and antiplatelet drugs, while 114 (14%) were taking only aspirin (aspirin group). A total of 535 patients were not taking antiplatelets and anticoagulants (control group). In propensity score matching, 103 patients were matched. Aspirin was not associated with a significantly higher risk of hidden blood loss (aspirin group; median 598 mL [410–783 mL] vs control group; median 556 ml [321–741 mL], p = 0.14) and higher risk of blood transfusion requirement (aspirin group; 49 patients [48%] vs control group; 39 patients [38%], p = 0.21). Aspirin did not affect peri-operative blood loss in hip fracture surgery. We concluded that patients taking aspirin can safely undergo hip fracture surgery without delay.

Proximal femoral fractures can occur in patients with osteoporosis. However, the relationship between bone mineral density (BMD) of the proximal femur and fracture type and instability remains unclear. This study aimed to determine whether there is a relationship between the site-specific BMD of the proximal femur and the instability of proximal femoral fracture.The instability of proximal femoral fractures is related to the site-specific BMD of the proximal femur.Using dual-energy X-ray absorptiometry (DEXA), the BMD on the non-fractured side was retrospectively examined in 252 women who underwent surgery for proximal femoral fracture at our hospital. The BMD was measured at three sites: the femoral neck (neck), trochanter (trochanter), and intertrochanteric region (inter). The BMD at several sites was compared between the femoral neck and trochanteric fractures. Femoral neck fractures were classified into the displaced and non-displaced types, and trochanteric fractures were classified into stable and unstable types. A comparative analysis was conducted for each proximal femur site and fracture type.Both total and site-specific BMDs were lower in trochanteric fractures than in femoral neck fractures. No difference was observed between BMD and displaced or non-displaced femoral neck fractures. However, the BMD of the intertrochanteric region was lower in unstable trochanteric fractures (0.57±0.12 g/cmSeveral factors, including the patient's age and the bone component of each region, may influence the lower BMD in trochanteric fractures. In trochanteric fractures, the site-specific BMD of the proximal femur may predict the type of fracture and the degree of instability, especially in those with low BMD at the intertrochanteric site. The study findings suggest that a decrease in the BMD of the intertrochanteric region of femoral trochanteric fractures, which is thought to be involved in instability, is associated with fracture-type instability.III, retrospective study.

Background: To compare the clinical, surgical and radiographic outcomes of O-arm navigated C-arm free, simultaneous single-position oblique lumbar interbody fusion (OLIF) and percutaneous pedicle screw (PPS) fixation with minimally invasive posterior/ transforaminal lumbar interbody fusion (MI-PLIF/TLIF).Methods: This is retrospective comparative study. The study included 98 patients, 63 in single position OLIF (group SO) and 35 in MI-PLIF/TLIF (group P/T). Surgical time, blood loss, mobilization time after surgery and complications were analyzed for all patients. Clinical evaluation included visual analog scale (VAS) for back pain, oswestry disability index (ODI). Radiological parameters included cage height (CH), cage to disc ratio (CDR), DH change, pre and postoperative disc height (DH), foraminal height (FH), foraminal area (FA), segmental lordosis (SL). Results: In group SO (vs group P/T), surgical time, blood loss and mobilization time were 117.7± 34.1 minutes (171.8 ± 40.6 minutes, pppConclusions: Simultaneous single position O-arm navigated C-arm free OLIF reduces the surgical time, blood loss, mobilization time after operation without the risk of an adverse event of intraoperative radiation to operating staff. Good indirect decompression can be achieved with this method. Clinical results were similar in both groups.

Minimally invasive posterior or transforaminal lumbar interbody fusion (MI-PLIF/TLIF) are widely accepted procedures for lumbar instability due to degenerative or traumatic diseases. Oblique lateral interbody fusion (OLIF) is currently receiving considerable attention because of the reductions in damage to the back muscles and neural tissue. The aim of this study was to compare clinical and radiographic outcomes of simultaneous single-position OLIF and percutaneous pedicle screw (PPS) fixation with MI-PLIF/TLIF. This retrospective comparative study included 98 patients, comprising 63 patients with single-position OLIF (Group SO) and 35 patients with MI-PLIF/TLIF (Group P/T). Cases with more than 1 year of follow-up were included in this study. Mean follow-up was 32.9 ± 7.0 months for Group SO and 33.7 ± 7.5 months for Group P/T. Clinical and radiological evaluations were performed. Comparing Group SO to Group P/T, surgical time and blood loss were 118 versus 172 min (p &lt, 0.01) and 139 versus 374 mL (p &lt, 0.01), respectively. Cage height, change in disk height, and postoperative foraminal height were significantly higher in Group SO than in Group P/T. The fusion rate was 96.8% in Group SO, similar to the 94.2% in Group P/T (p = 0.985). The complication rate was 6.3% in Group SO and 14.1% in Group P/T (p = 0.191). Simultaneous single position O-arm-navigated OLIF reduces the surgical time, blood loss, and time to ambulation after surgery. Good indirect decompression can be achieved with this method.

Objectives To assess the impacts of social situation changes due to the coronavirus disease 2019 (COVID-19) pandemic on headache-related disability and other symptoms in patients with migraine in Japan. Methods We conducted a multicentre, cross-sectional study including 659 outpatients with migraine diagnosed by headache specialists. The participants were asked about the impacts of the first wave of the COVID-19 pandemic on headache-related disability, headache days, headache intensity, stress, physical activity, hospital access and their work and home lives. For headache-related disability, the total Migraine Disability Assessment (MIDAS) score and part A and B scores were analysed. Multivariate stepwise linear regression analysis was performed to identify the clinical predictors of changes in the total MIDAS score before and during the COVID-19 pandemic. Logistic regression analysis was performed to determine the factors related to new-onset headache during the COVID-19 pandemic. Results Finally, 606 migraine patients (73 M/533 F; age, 45.2 ± 12.0 years) were included in the study, excluding those with incomplete data. Increased stress, substantial concern about COVID-19 and negative impacts of the first wave of the COVID-19 pandemic on daily life were reported in 56.8 %, 55.1 and 45.0 % of the participants, respectively. The total MIDAS and A and B scores did not significantly change after the first wave of the COVID-19 pandemic. New-onset headache, which was observed in 95 patients (15.7 %), was associated with younger age and worsened mood and sleep in the logistic regression analysis. The multivariate stepwise linear regression analysis of changes in the total MIDAS score before and during the first wave of COVID-19 pandemic identified worsened sleep, increased acute medication use, increased stress, medication shortages, comorbidities, the absence of an aura and new-onset headache were determinants of an increased total MIDAS score during the first wave of the COVID-19 pandemic. Conclusions In this multicentre study, clinical factors relevant to headache-related disability, such as new-onset headache, stress and sleep disturbances, were identified, highlighting the importance of symptom management in migraine patients during the first wave of the COVID-19 pandemic.

IntroductionGiven an increasing use of dipeptidyl peptidase-4 (DPP-4) inhibitors to treat patients with type 2 diabetes mellitus in the real-world setting, we conducted a prospective observational study (Japan-based Clinical Research Network for Diabetes Registry: J-BRAND Registry) to elucidate the safety and efficacy profile of long-term usage of alogliptin.Research design and methodsWe registered 5969 patients from April 2012 through September 2014, who started receiving alogliptin (group A) or other classes of oral hypoglycemic agents (OHAs; group B), and were followed for 3 years at 239 sites nationwide. Safety was the primary outcome. Symptomatic hypoglycemia, pancreatitis, skin disorders of non-extrinsic origin, severe infections, and cancer were collected as major adverse events (AEs). Efficacy assessment was the secondary outcome and included changes in hemoglobin A1c (HbA1c), fasting blood glucose, fasting insulin and urinary albumin.ResultsOf the registered, 5150 (group A: 3395 and group B: 1755) and 5096 (3358 and 1738) were included for safety and efficacy analysis, respectively. Group A patients mostly (>90%) continued to use alogliptin. In group B, biguanides were the primary agents, while DPP-4 inhibitors were added in up to ~36% of patients. The overall incidence of AEs was similar between the two groups (42.7% vs 42.2%). Kaplan-Meier analysis revealed the incidence of cancer was significantly higher in group A than in group B (7.4% vs 4.8%, p=0.040), while no significant incidence difference was observed in the individual cancer. Multivariate Cox regression analysis revealed that the imbalanced patient distribution (more elderly patients in group A than in group B), but not alogliptin usage per se, contributed to cancer development. The incidence of other major AE categories was with no between-group difference. Between-group difference was not detected, either, in the incidence of microvascular and macrovascular complications. HbA1c and fasting glucose decreased significantly at the 0.5-year visit and nearly plateaued thereafter in both groups.ConclusionsAlogliptin as a representative of DPP-4 inhibitors was safe and durably efficacious when used alone or with other OHAs for patients with type 2 diabetes in the real world setting.

Attenuation of the secondary injury of spinal cord injury (SCI) can suppress the spread of spinal cord tissue damage, possibly resulting in spinal cord sparing that can improve functional prognoses. Granulocyte colony-stimulating factor (G-CSF) is a haematological cytokine commonly used to treat neutropenia. Previous reports have shown that G-CSF promotes functional recovery in rodent models of SCI. Based on preclinical results, we conducted early phase clinical trials, showing safety/feasibility and suggestive efficacy. These lines of evidence demonstrate that G-CSF might have therapeutic benefits for acute SCI in humans. To confirm this efficacy and to obtain strong evidence for pharmaceutical approval of G-CSF therapy for SCI, we conducted a phase 3 clinical trial designed as a prospective, randomized, double-blinded and placebo-controlled comparative trial. The current trial included cervical SCI [severity of American Spinal Injury Association (ASIA) Impairment Scale (AIS) B or C] within 48 h after injury. Patients are randomly assigned to G-CSF and placebo groups. The G-CSF group was administered 400 μg/m2/day × 5 days of G-CSF in normal saline via intravenous infusion for five consecutive days. The placebo group was similarly administered a placebo. Allocation was concealed between blinded evaluators of efficacy/safety and those for laboratory data, as G-CSF markedly increases white blood cell counts that can reveal patient treatment. Efficacy and safety were evaluated by blinded observer. Our primary end point was changes in ASIA motor scores from baseline to 3 months after drug administration. Each group includes 44 patients (88 total patients). Our protocol was approved by the Pharmaceuticals and Medical Device Agency in Japan and this trial is funded by the Center for Clinical Trials, Japan Medical Association. There was no significant difference in the primary end point between the G-CSF and the placebo control groups. In contrast, one of the secondary end points showed that the ASIA motor score 6 months (P = 0.062) and 1 year (P = 0.073) after drug administration tend to be higher in the G-CSF group compared with the placebo control group. Moreover, in patients aged over 65 years old, motor recovery 6 months after drug administration showed a strong trend towards a better recovery in the G-CSF treated group (P = 0.056) compared with the control group. The present trial failed to show a significant effect of G-CSF in primary end point although the subanalyses of the present trial suggested potential G-CSF benefits for specific population., Koda et al. present the results of a randomized phase 3 trial comparing granulocyte colony-stimulating factor versus placebo in patients with acute spinal cord injury. While the primary endpoint was not met, a sub-analysis revealed a trend towards superior efficacy of G-CSF versus placebo in an elderly population.

Pancreatic ductal adenocarcinoma (PDAC) with mismatch repair (MMR) deficiency is a rare subtype, clinicopathological features of which have not been fully understood. A 70-year-old woman was admitted for the investigation of a 20-mm pancreatic tumor in the pancreatic head, detected during the cause scrutiny of exacerbation of diabetes mellitus and panhypopituitarism. The tumor decreased in size after administration of hydrocortisone for panhypopituitarism. Autoimmune pancreatitis, complicated with hypophysitis, was suspected, and prednisolone treatment was administered. The tumor did not show enlargement for 3 years during which a dose of prednisolone was maintained. However, 1.5 years after the cessation of prednisolone administration, the tumor size increased again. On endoscopic ultrasonography, the tumor was found to be a 25.2-mm mass lesion with almost uniformly low echogenicity and blood flow signal, and anisonucleosis on cytodiagnosis was revealed. Pancreatoduodenectomy was performed, and on histological analysis, moderately differentiated tubular adenocarcinoma with massive lymphocytic infiltration was observed. Immunohistochemistry revealed a concomitant loss of MSH2 and MSH6 in the tumor cells, which implicated mutant MSH2 gene. She has remained well with no recurrence for 2.9 years since her surgery. We herein report a case of PDAC with MMR deficiency, resected after long-term observation.

Objective The purpose of this study was to clarify the clinical features of ischemic patients for whom cigarette smoking was the sole risk factor for ischemic stroke. Methods Among the 1,329 patients (male, n=833; female, n=496) with acute ischemic stroke who were admitted to our hospital between April 2005 and September 2016, 346 (26%) were smokers [male, n=308 (36.9%); female, 38 (7.6%)]. In 42 (3.1%; male, n=41; female, n=1) cases, cigarette smoking was considered to be the sole risk factor for ischemic stroke. Data regarding gender, age, the clinical type of ischemic stroke, the National Institutes of Health Stroke Scale (NIHSS) score at the admission, the modified Rankin scale (mRS) scores before the onset and at discharge, the progression of symptoms, and the recurrence of infarction were investigated. Results The mean age of the 42 patients was 63.2±12.4 years (range, 26-86 years). The clinical types of ischemic stroke included atherothrombosis (n=19), lacunar (n=17), other type (n=2) and undetermined type (n=4). The median NIHSS score at the time of admission for ischemic stroke was 2 (interquartile range: IQR 1-4.25). The median mRS scores before the onset and at the discharge were 0 (IQR 0-0) and 1 (IQR 0-2), respectively. One patient had symptoms of progression; no patients had recurrence of infarction. Conclusion Our findings suggest that cigarette smoking alone may induce ischemic stroke; moreover, patients for whom smoking was the sole risk factor for ischemic stroke showed milder symptoms in comparison to patients with other risk factors; however, ischemic stroke was induced from youth. Since cigarette smoking has detrimental effects on the central nervous system, we suggest that people be encouraged to quit smoking in order to maintain good health.

The purpose of this study was to investigate the effects of memantine on brain ischemia. Because we can measure nitric oxide (NO) production and hydroxyl radical metabolism continuously, we investigated the effect of memantine on NO production and hydroxyl radical metabolism in cerebral ischemia and reperfusion.Memantine (25 µmol/kg) was administered intraperitoneally to 6 C57BL/6 mice 30 minutes before ischemia. Seven additional mice received no injection (controls). NO production and hydroxyl radical metabolism were continuously monitored using bilateral striatal microdialysis in vivo. Hydroxyl radical formation was monitored using the salicylate trapping method. Forebrain ischemia was produced in all mice by occluding the common carotid artery bilaterally for 10 minutes. Levels of the NO metabolites nitrite (NOThe regional cerebral blood flow was significantly higher in the memantine group than in the control group after reperfusion. Furthermore, the level of 2,3-dihydroxybenzoic acid was significantly lower in the memantine group than in the control group during ischemia and reperfusion. Levels of NOThese data suggest that memantine exerts partially neuroprotective effects against cerebral ischemic injury.

Objective Naratriptan has been reported to reduce the frequency of cluster headache. The purpose of this study was to determine whether naratriptan is effective as a prophylactic treatment for cluster headache in Japan. Methods We retrospectively reviewed all 43 patients with cluster headache who received preventive treatment with naratriptan from April 2009 to April 2015. The International Classification of Headache Disorders, 3rd Edition (beta version) (ICHD-3 beta) was used to diagnose cluster headache. This study was conducted at 3 centers (Department of Neurology, Saitama Medical University; Saitama Neuropsychiatric Institute; Saitama Medical University International Medical Center). Patients were recruited from these specialized headache outpatient centers. Naratriptan was taken before the patient went to bed. Results The study population included 30 men (69.8%) and 13 women (30.2%). Twenty-two cases received other preventive treatments (51.2%), while 21 cases only received naratriptan (48.8%). Among the 43 cases, 37 patients (86.0%) achieved an improvement of cluster headache on naratriptan. Conclusion Naratriptan has been suggested as a preventive medicine for cluster headache because of the longer the biological half-life in comparison to other triptans. The internal use of naratriptan 2 hours before attacks appears to achieve a good response in patients with cluster headache.

Background The purpose of this study was to investigate the effects of memantine on brain ischemia. Because we can measure nitric oxide (NO) production and hydroxyl radical metabolism continuously, we investigated the effect of memantine on NO production and hydroxyl radical metabolism in cerebral ischemia and reperfusion. Methods Memantine (25 µmol/kg) was administered intraperitoneally to 6 C57BL/6 mice 30 minutes before ischemia. Seven additional mice received no injection (controls). NO production and hydroxyl radical metabolism were continuously monitored using bilateral striatal microdialysis in vivo. Hydroxyl radical formation was monitored using the salicylate trapping method. Forebrain ischemia was produced in all mice by occluding the common carotid artery bilaterally for 10 minutes. Levels of the NO metabolites nitrite (NO2−) and nitrate (NO3−) were determined using the Griess reaction. Survival rates of hippocampal CA1 neurons were calculated and 8-hydroxydeoxyguanosine (8-OHdG)-immunopositive cells were counted to evaluate the oxidative stress in hippocampal CA1 neurons 72 hours after the start of reperfusion. Results The regional cerebral blood flow was significantly higher in the memantine group than in the control group after reperfusion. Furthermore, the level of 2,3-dihydroxybenzoic acid was significantly lower in the memantine group than in the control group during ischemia and reperfusion. Levels of NO2− and NO3− did not differ significantly between the 2 groups. Although survival rates in the CA1 did not differ significantly, there were fewer 8-OHdG-immunopositive cells in animals that had received memantine than in control animals. Conclusions These data suggest that memantine exerts partially neuroprotective effects against cerebral ischemic injury.

Vertical sacral fracture is one of the most difficult fractures to treat. Posterior fixation using spinal dual rods is a novel method for treating this fracture, but its biomechanical strength has not yet been reported. The aim of this study was to evaluate the biomechanical strength produced by posterior fixation using spinal instrumentation. Sacral fractures were created in eight pelvic bone models and classifi ed into a posterior plate fixation group [P group, n＝4] and a spinal instrumentation group [R group, n＝4]. The biomechanical strength was tested by pushing down on the S1 vertebra from the top. The mean maximum loads were 1,057.4 N and 1,489.4 N in the P and R groups, respectively (p＝ 0.014). The loads applied to the construct at displacements of 5mm and 7.5mm from the start of the universal testing machine loading were also significantly higher in the R group. The mean stiffness levels in the P and R groups were 88.3N/mm and 119.6N/mm, respectively (p＝0.014). Posterior fixation using spinal instrumentation is biomechanically stronger than conventional posterior plate fixation. This procedure may be the optimal method for treating unstable sacral fracture fixation.

Cervical orthosis is used to immobilize the neck in various disorders such as trauma and post-operation. However, it is still uncertain how cervical orthosis restricts the degree of movement of the cervical spine during swallowing and how they affect swallowing physiology. The purpose of this study was to evaluate these issues using the Philadelphia(®) Collar. We conducted videofluorography of swallowing in 39 healthy subjects (23 men, 16 women; mean age of 34.3 years) with and without cervical orthosis. To compare the two conditions regarding the cervical spine motion, we determined the angular and positional changes of the occipital bone (C0) and each cervical vertebra (C1-C7) from the oral phase to the pharyngeal phase. Similarly, to compare swallowing physiology, we assessed the start and end times and the durations of soft palate elevation, rapid hyoid anterosuperior movement, epiglottis inversion, closure of the laryngeal vestibule, and pharyngoesophageal segment (PES) opening. Finally, we compared the transit times of contrast agent in the two conditions. The respective extensions of C1, C2, and C3 were 0.31°, 0.07°, and 0.05° (mean) with cervical orthosis, and the respective flexions of C1, C2, and C3 were 0.98°, 1.42°, and 0.85° (mean) without. These results suggested that cervical orthosis restricted the flexion of C1-C3. Analysis of swallowing physiology revealed that the average durations of hyoid anterosuperior elevation, epiglottic inversion, and PES opening were prolonged by 0.09, 0.19, and 0.05 s, respectively. In conclusion, the cervical orthosis restricted the movement of the cervical spine during swallowing and changed swallowing physiology.

Background The purpose of this study was to investigate the effects of edaravone on nitric oxide (NO) production, hydroxyl radical (OH−) metabolism, and neuronal nitric oxide synthase (nNOS) expression during cerebral ischemia and reperfusion. Methods Edaravone (3 mg/kg) was administered intravenously to 14 C57BL/6 mice just before reperfusion. Eleven additional mice received saline (controls). NO production and OH− metabolism were continuously monitored using bilateral striatal in vivo microdialysis. OH− formation was monitored using the salicylate trapping method. Forebrain ischemia was produced in all mice by bilateral occlusion of the common carotid artery for 10 minutes. Levels of NO metabolites, nitrite (NO2−) and nitrate (NO3−), were determined using the Griess reaction. Brain sections were immunostained with an anti-nNOS antibody and the fractional area density of nNOS-immunoreactive pixels to total pixels determined. Results Blood pressure and regional cerebral blood flow were not significantly different between the edaravone and control groups. The levels of NO2− did not differ significantly between the 2 groups. The level of NO3− was significantly higher in the edaravone group compared with the control group after reperfusion. 2,3-dihydroxybenzoic acid levels were lower in the edaravone group compared with those in the control group after reperfusion. Immunohistochemistry showed nNOS expression in the edaravone group to be significantly lower than that in the control group 96 hours after reperfusion. Conclusions These in vivo data indicate that edaravone may have a neuroprotective effect by reducing levels of OH− metabolites, increasing NO production and decreasing nNOS expression in brain cells.

Changes in the timing of bird migration in spring and autumn in a coastal forest near the city of Niigata, central Honshu, Japan, were analyzed based on 27 years of bird-banding records. Half of the bird species studied, including all migratory types except residents, arrived or departed significantly earlier in spring due to an increase in spring temperatures. The rate of change we observed in spring migration timing due to changes in temperature was identical to or slightly greater than those reported in studies from other countries. The spring arrival of the Narcissus Flycatcher Ficedula narcissina and the Japanese Thrush Turdus cardis, both long-distance summer migrants to the nearby mountains, became earlier (advanced), however, for reasons that remained unclear. Median capture date in autumn was significantly associated with year for five species. Of these, the median capture date of the Japanese White-eye Zosterops japonicus, a resident and wandering bird, and the Black-faced Bunting Emberiza spodocephala, a wandering bird, advanced annually, while for the Japanese Robin Luscinia akahige and two other species (all long-distance migrants), it was delayed. We hypothesize that forest succession from a simple pine forest to a mixed forest with well-developed sub-canopy and shrub layers may have strongly influenced the Japanese White-eye and the Black-faced Bunting due to changes in population structure in the study area, resulting in an earlier median autumn capture date. Forest succession may also have influenced the Japanese Robin's food resources, enabling it to stay longer in the study area and resulting in a delay in autumn departure date. Thus, changes in bird migration timing differ according to different environmental factors in spring and autumn.

Alexander disease (AxD) is a rare neurodegenerative disorder with a prevalence rate of 1 in 2,700,000.1 Its pathologic characteristics include the formation of cytoplasmic inclusions in astrocytes, called Rosenthal fibers, and white matter degeneration.2 The genetic mutation of glial fibrillary acidic protein ( GFAP )3 is observed in approximately 97% of cases.

Background The aim of this study was to determine the effectiveness of tongue-tie division (frenuloplasty/ frenulotomy) for speech articulation disorder in children with ankyloglossia (tongue-tie). Methods Articulation test was done in five children (3–8 years old) with speech problems who underwent tongue-tie division. The test consisted of 50 pictures of common Japanese words with 2–3 syllables. The patients were interviewed by a speech therapist and asked to pronounce what the picture card showed. Misarticulations of substitution, omission, and distortion were assessed. The preoperative results were compared with postoperative examinations at 1 month, 3–4 months, and 1–2 years. Results Nineteen substitutions that were observed in four patients preoperatively decreased to 10 in three patients at 1 month, 7 in three patients at 3–4 months, and 1 in one patient at 1–2 years postoperatively. Five omissions that were observed in four patients preoperatively decreased to 3 in three patients at 1 month, 2 in two patients at 3–4 months, and 1 in one patient at 1–2 years postoperatively. Thirteen distortions that were observed in five patients preoperatively decreased to 8 in four patients at 3–4 months but increased to 11 in three patients at 1–2 years postoperatively. Conclusions Substitution and omission improved relatively early after tongue-tie division and progressed to distortion, which is a less-impaired form of articulation disorder. Thus, distortion required more time for improvement and remained a defective speaking habit in some patients.

In our previous study, we focused on the motion of cervical spines in video-fluorography (VF), and we revealed that the physiological lordosises were reduced during normal swallowing. In the study, cervical spines were required to be manually extracted in all the frames of VF. Therefore the study had a difficulty in performing the statistical analysis based on a large amount of patient data. The present study proposes an automatic tracking method of cervical spines in VF by use of the two-dimensional template matching technique. In the method, cervical spines can be extracted automatically, though templates should be set manually only in the first frame of VF. The automatic tracking method was applied to cervical spines, from C1 to C6, in actual VF of ten cases who were planned to undergo posterior cervical spinal fusion. The cervical spines were able to be tracked at the accuracy of more than 77% in the Jaccard index. The experimental results demonstrated that the proposed method was able to analyze the motion of cervical spines in VF during swallowing.

Plasmon-induced hot-electron generation has recently received considerable interest and has been studied to develop novel applications in optoelectronics, photovoltaics and green chemistry. Such hot electrons are typically generated from either localized plasmons in metal nanoparticles or propagating plasmons in patterned metal nanostructures. Here we simultaneously generate these heterogeneous plasmon-induced hot electrons and exploit their cooperative interplay in a single metal-semiconductor device to demonstrate, as an example, wavelength-controlled polarity-switchable photoconductivity. Specifically, the dual-plasmon device produces a net photocurrent whose polarity is determined by the balance in population and directionality between the hot electrons from localized and propagating plasmons. The current responsivity and polarity-switching wavelength of the device can be varied over the entire visible spectrum by tailoring the hot-electron interplay in various ways. This phenomenon may provide flexibility to manipulate the electrical output from light-matter interaction and offer opportunities for biosensors, long-distance communications, and photoconversion applications., Plasmon-induced hot electrons have potential applications spanning photodetection and photocatalysis. Here, Hoang et al. study the interplay between hot electrons generated by localized and propagating plasmons, and demonstrate wavelength-controlled polarity-switchable photoconductivity

The aim of this systematic review was to critically examine the existing literature regarding the effectiveness of tongue-tie division in infants with ankyloglossia, using the new grades of recommendations, assessment, development, and evaluation (GRADE) rating system. A clinical question was structured according to patient, intervention, comparison, and outcome, as follows: in infants with poor breast-feeding and ankyloglossia (patient), does frenotomy (intervention), compared to lactation support alone (comparison), improve feeding (outcome)? An electronic literature search was systematically conducted from databases including PubMed, Japana Centra Revuo Medicina (Igaku Chuo Zasshi), CINAHL, and Cochrane Library using the key words "ankyloglossia," "tongue-tie," "frenotomy," and/or "breast-feeding" in English and equivalent terms in Japanese. The literature search yielded four randomized clinical trials, and 12 observational studies for analysis. The quality of the literature was rated in regard to the two most important outcomes (sucking/latching, and nipple pain) and five less important outcomes (milk supply/milk production, continuation of breast-feeding, weight gain, adverse events, and dyad distress) in accordance with the GRADE system. Evidence levels of the most important outcomes were rated either A (strong evidence) or B (moderate evidence), and less important outcomes were rated C (weak evidence); every outcome consistently showed a favorable effect of frenotomy on breast-feeding. The literature review supported an overall moderate quality of evidence for the effectiveness of frenotomy for the treatment of breast-feeding difficulties in infants with ankyloglossia. No major complications from frenotomy were reported.

We performed a phase I/IIa clinical trial and confirmed the safety and feasibility of granulocyte colony-stimulating factor (G-CSF) as neuroprotective therapy in patients with acute spinal cord injury (SCI). In this study, we retrospectively analyzed the clinical outcome in SCI patients treated with G-CSF and compared these results to a historical cohort of SCI patients treated with high-dose methylprednisolone sodium succinate (MPSS). In the G-CSF group (n = 28), patients were treated from August 2009 to July 2012 within 48 h of the injury, and G-CSF (10 μg/kg/day) was administered intravenously for five consecutive days. In the MPSS group (n = 34), patients underwent high-dose MPSS therapy from August 2003 to July 2005 following the NASCIS II protocol. We evaluated the ASIA motor score and the AIS grade elevation between the time of treatment and 3-month follow-up and adverse events. The ΔASIA motor score was significantly higher in the G-CSF group than in the MPSS group (p

Study design An open-labeled multicenter prospective nonrandomized controlled clinical trial. Objective To confirm the feasibility of using granulocyte colony-stimulating factor (G-CSF) for treatment of acute spinal cord injury (SCI). Summary of background data We previously reported that G-CSF promotes functional recovery after compression-induced SCI in mice. On the basis of these findings, we conducted a multicenter prospective controlled clinical trial to assess the feasibility of G-CSF therapy for patients with acute SCI. Methods The trial ran from August 2009 to March 2011, and included 41 patients with SCI treated within 48 hours of onset. Informed consent was obtained from all patients. After providing consent, patients were divided into 2 groups. In the G-CSF group (17 patients), G-CSF (10 μg/kg/d) was intravenously administered for 5 consecutive days, and in the control group (24 patients), patients were similarly treated except for the G-CSF administration. We evaluated motor and sensory functions using the American Spinal Cord Injury Association score and American Spinal Cord Injury Association impairment scale at 1 week, 3 months, 6 months, and 1 year after onset. Results Only 2 patients did not experience American Spinal Cord Injury Association impairment scale improvement in the G-CSF group. In contrast, 15 patients in the control group did not experience American Spinal Cord Injury Association impairment scale improvement. In the analysis of increased American Spinal Cord Injury Association motor score, a significant increase in G-CSF group was detected from 1 week after the administration compared with the control group. After that, some spontaneous increase of motor score was detected in control group, but the significant increase in G-CSF group was maintained until 1 year of follow-up. Conclusion Despite the limitation that patient selection was not randomized, the present results suggest the possibility that G-CSF administration has beneficial effects on neurological recovery in patients with acute SCI. Level of evidence 3.