Applying the Wake-Up-like Effect to Enhance the Capabilities of Two-Dimensional Ferroelectric Field-Effect Transistors.

For traditional ferroelectric field-effect transistors (FeFETs), enhancing the polarization domain of bulk ferroelectric materials is essential to improve device performance. However, there has been limited investigation into the enhancement of polarization field in two-dimensional (2D) ferroelectric material such as CuInP2S6 (CIPS). In this study, similar to bulk ferroelectric materials, CIPS exhibited enhanced polarization field upon application of external cyclic voltage. Moreover, unlike traditional ferroelectric materials, the polarization enhancement of CIPS is not due to redistribution of the defect but rather originates from a mechanism: the long-distance migration of Cu ions. We termed this mechanism the "wake-up-like effect". After incorporating the wake-up-like effect into the graphene/CIPS/WSe2 FeFET device, we successfully increased the hysteresis window and enhanced the current on/off ratio by 4 orders of magnitude. Moreover, the FeFET yielded remarkable achievements, such as multilevel nonvolatile memory with 21 distinct conductance levels, a high on/off ratio exceeding 106, a long retention time exceeding 103 s, and neuromorphic computing with 93% accuracy at recognizing handwritten digits. Introducing the wake-up-like effect to 2D CIPS may pave the way for innovative approaches to achieve advanced multilevel nonvolatile memory and neuromorphic computing capabilities for next-generation micro-nanoelectronic devices.

Artificial Funnel Nanochannel Device Emulates Synaptic Behavior.

Creating artificial synapses that can interact with biological neural systems is critical for developing advanced intelligent systems. However, there are still many difficulties, including device morphology and fluid selection. Based on Micro-Electro-Mechanical System technologies, we utilized two immiscible electrolytes to form a liquid/liquid interface at the tip of a funnel nanochannel, effectively enabling a wafer-level fabrication, interactions between multiple information carriers, and electron-to-chemical signal transitions. The distinctive ionic transport properties successfully achieved a hysteresis in ionic transport, resulting in adjustable multistage conductance gradient and synaptic functions. Notably, the device is similar to biological systems in terms of structure and signal carriers, especially for the low operating voltage (200 mV), which matches the biological neural potential (∼110 mV). This work lays the foundation for realizing the function of iontronics neuromorphic computing at ultralow operating voltages and in-memory computing, which can break the limits of information barriers for brain-machine interfaces.

Sentinel lymph node biopsy versus observation in high risk cutaneous squamous cell carcinoma of head and neck: a propensity score matching analysis.

Sentinel lymph node biopsy (SLNB) has gained considerable attention in the management of head and neck cutaneous squamous cell carcinoma (HNcSCC). The aim of this study was to compare the oncologic outcomes between observation and SLNB in cN0 high-risk HNcSCC patients. We retrospectively enrolled patients from the SEER database and evaluated the impact of observation versus SLNB on disease-specific survival (DSS) and overall survival (OS) using a Propensity Score Matching (PSM) analysis. A total of 9804 patients were included, with 1169 cases treated by SLNB. Successful retrieval of the sentinel lymph node was achieved in 1130 procedures. After PSM and subsequent multivariate analysis, SLNB was found to be an independent predictor for improved DSS, with a hazard ratio of 0.70 (95% confidence interval: 0.56-0.86). In patients presenting with two or three high-risk factors, SLNB was associated with better DSS (p = 0.021 and p = 0.044), but similar OS (p = 0.506 and p = 0.801) when compared to observation. However, in patients exhibiting four high-risk factors, SLNB demonstrated significantly improved DSS (p = 0.040) and OS (p = 0.028) compared to observation. Our findings suggest that SLNB is a highly feasible technique in HNcSCC and provides significant survival benefits. It is strongly recommended in patients with two or more high-risk factors, as it can help guide treatment decisions and improve patient outcomes.

Ceftriaxone-induced severe hemolytic anemia, renal calculi, and cholecystolithiasis in a 3-year-old child: a case report and literature review.

Ceftriaxone is widely used in pediatric outpatient care for its efficacy against respiratory and digestive system infections, yet its increasing association with severe immune hemolytic reactions requires heightened vigilance from pediatricians. This report details a rare and severe case of ceftriaxone-induced severe immune hemolytic anemia (IHA), hemolytic crisis, myocardial injury, liver injury, renal calculi, and cholecystolithiasis in a previously healthy 3-year-old child. The child, treated for bronchitis, experienced sudden pallor, limb stiffness, and altered consciousness following the fifth day of ceftriaxone infusion, with hemoglobin (Hb) levels precipitously dropping to 21 g/L. Immediate cessation of ceftriaxone and the administration of oxygen therapy, blood transfusion, intravenous immunoglobulin (IVIG), and corticosteroids led to a gradual recovery. Despite initial improvements, the patient's condition necessitated extensive hospital care due to complications including myocardial injury, liver injury, renal calculi, and cholecystolithiasis. After a 12-day hospital stay and a 3-month follow-up, the child showed complete normalization of Hb and liver function and resolution of calculi. In children, ceftriaxone infusion may trigger severe, potentially fatal, hemolytic reactions. Pediatricians must promptly recognize symptoms such as pallor, limb stiffness, and unresponsiveness, indicative of ceftriaxone-induced severe IHA, and immediately discontinue the drug. Effective management includes timely blood transfusion, respiratory support, IVIG administration, and corticosteroids when necessary, along with rigorous vital signs monitoring. Continued vigilance is imperative, even after cessation of ceftriaxone, to promptly address any residual adverse effects.

Oncologic and functional results between sentinel lymph node biopsy and elective neck dissection in cT1/2N0 maxillary squamous cell carcinoma.

OBJECTIVE: To evaluate the oncologic safety and quality of life associated with the use of sentinel lymph node biopsy (SLNB) as compared to elective neck dissection (END) in patients with cT1/2N0 maxillary squamous cell carcinoma. METHODS: This study constituted a retrospective analysis of consecutively treated patients who underwent SLNB or END, with data collected prospectively. We analyzed the impact of the different neck procedures on regional control and disease-specific survival via the Cox model. Patients in both groups completed the University of Washington Quality of Life questionnaire. RESULTS: We included a total of 130 patients, with 47 receiving SLNB. In all cases, the sentinel lymph node could be identified, and of these, 5 had a positive result, yielding a sensitivity of 83.3 %, a specificity of 100 %, a false negative rate of 16.7 %, and a negative predictive value of 97.6 %. The sensitivity, specificity, false negative rate, and negative predictive value of END in detecting occult metastasis were 64.3 %, 100 %, 35.7 %, and 93.2 %, respectively. In comparison to END after propensity score matching, SLNB exhibited no significant difference in its effects on regional control (p = 0.519, HR: 1.05, 95 % CI: 0.52-1.93) and disease-specific survival (p = 0.634, HR: 1.22, 95 % CI: 0.53-1.99). Patients in SLNB group showed significantly higher mean scores of shoulder and taste domains at 3 months, 6 months, and 12 months postoperatively compared to those in END group. CONCLUSION: SLNB could act as a viable alternative to END in cT1/2N0 maxillary squamous cell carcinoma with comparable prognosis and better quality of life.

A model for evaluating the performance of compulsory education inputs in ethnic areas in China.

A scientific performance evaluation model is necessary to establish a performance evaluation index system for compulsory education in ethnic areas and to conduct objective and impartial evaluations. After conducting theoretical analysis and reviewing literature, it was determined that existing educational input performance evaluation models are general and fail to reflect the unique characteristics of compulsory education development in ethnic areas of China. Therefore, this study intends to improve their self-adaptability and degree of fit. Based on the features of China's ethnic areas and the current situation of compulsory education development, a trinity evaluation model of compulsory education input performance in ethnic regions was constructed using the classical performance evaluation theoretical framework. This model includes the "implementation topic - target concept - performance dimension." The government is the main organization responsible for organizing and implementing the entire performance evaluation, with publicness and responsiveness as the value idea of evaluation. The "4E″ of enough, equity, efficiency, and effectiveness are the evaluation objectives, and input, allocation, output, and effect are the dimensions of the building of the performance evaluation index system. The "4E″ evaluation objectives are integrated into the performance evaluation dimensions and index system. The reconstructed theoretical model of performance evaluation combines universality and specificity, highlights the dual attributes of "tool-value," realizes the organic combination of internal and external performance evaluation, illustrates the overall performance evaluation process and ensures objective, fair, and accurate performance evaluation results. It provides useful guidelines for further optimizing compulsory education investment policies and promoting high-quality and well-balanced compulsory education in China's ethnic areas.

Neck management in cutaneous squamous cell carcinoma with parotid metastasis.

OBJECTIVE: Our objective is to assess the oncologic outcomes of observation, elective neck dissection (END), and elective neck irradiation (ENI) in the neck management of head and neck cutaneous squamous cell carcinoma (HNcSCC) with parotid metastasis (P+) and to evaluate the quality of life (QoL) of patients who received END or ENI. METHODS: Patients with P+ HNcSCC were retrospectively enrolled. The impact of observation, END, and ENI on regional control (RC) and overall survival (OS) was analyzed using Cox proportional hazards model with presentation via hazard ratio (HR) with a 95% confidence interval (CI). QoL was evaluated using the University of Washington Quality of Life questionnaire. RESULTS: A total of 134 patients were included in our analysis. In the Cox model for RC, both END and ENI had decreased HRs of 0.27 (95% CI: 0.15-0.69) and 0.34 (95% CI: 0.18-0.86), respectively, in comparison with observation. In the Cox model for OS, both END (p = 0.001, HR: 0.22, 95% CI: 0.10-0.72) and ENI (p = 0.006, HR: 0.30, 95% CI: 0.17-0.83) were superior to observation. In patients with three or more positive parotid lymph nodes, END resulted in significantly better RC (p < 0.001) and OS (p = 0.001) compared with ENI. The two groups were found to be comparable in all 12 domains of the University of Washington Quality of Life questionnaire. CONCLUSION: In the neck management of P+ HNcSCC, observation is not recommended. END is the preferred option, but ENI is an alternative method without compromise to survival or QoL, except in cases with three or more metastatic parotid lymph nodes.

A novel homozygous HPDL variant in Japanese siblings with autosomal recessive hereditary spastic paraplegia: case report and literature review.

Biallelic variants of 4-hydroxyphenylpyruvate dioxygenase-like (HPDL) gene have been linked to neurodegenerative disorders ranging from severe neonatal encephalopathy to early-onset spastic paraplegia. We identified a novel homozygous variant, c.340G > T (p.Gly114Cys), in the HPDL gene in two siblings with autosomal recessive hereditary spastic paraplegia (HSP). Despite sharing the same likely pathogenic variant, the older sister had pure HSP, whereas her brother had severe and complicated HSP, accompanied by early-onset mental retardation and abnormalities in magnetic resonance imaging. Given the clinical heterogeneity and potential for treatable conditions in HPDL-related diseases, we emphasize the importance of genetic testing for the HPDL gene.

Dystonia and Parkinsonism in COA7-related disorders: expanding the phenotypic spectrum.

BACKGROUND AND OBJECTIVE: Biallelic mutations in the COA7 gene have been associated with spinocerebellar ataxia with axonal neuropathy type 3 (SCAN3), and a notable clinical diversity has been observed. We aim to identify the genetic and phenotypic spectrum of COA7-related disorders. METHODS: We conducted comprehensive genetic analyses on the COA7 gene within a large group of Japanese patients clinically diagnosed with inherited peripheral neuropathy or cerebellar ataxia. RESULTS: In addition to our original report, which involved four patients until 2018, we identified biallelic variants of the COA7 gene in another three unrelated patients, and the variants were c.17A > G (p.D6G), c.115C > T (p.R39W), and c.449G > A (p.C150Y; novel). Patient 1 presented with an infantile-onset generalized dystonia without cerebellar ataxia. Despite experiencing an initial transient positive response to levodopa and deep brain stimulation, he became bedridden by the age of 19. Patient 2 presented with cerebellar ataxia, neuropathy, as well as parkinsonism, and showed a slight improvement upon levodopa administration. Dopamine transporter SPECT showed decreased uptake in the bilateral putamen in both patients. Patient 3 exhibited severe muscle weakness, respiratory failure, and feeding difficulties. A haplotype analysis of the mutation hotspot in Japan, c.17A > G (p.D6G), uncovered a common haplotype block. CONCLUSION: COA7-related disorders typically encompass a spectrum of conditions characterized by a variety of major (cerebellar ataxia and axonal polyneuropathy) and minor (leukoencephalopathy, dystonia, and parkinsonism) symptoms, but may also display a dystonia-predominant phenotype. We propose that COA7 should be considered as a new causative gene for infancy-onset generalized dystonia, and COA7 gene screening is recommended for patients with unexplained dysfunctions of the central and peripheral nervous systems.

Clinical variability associated with intronic FGF14 GAA repeat expansion in Japan.

BACKGROUND AND OBJECTIVES: The GAA repeat expansion within the fibroblast growth factor 14 (FGF14) gene has been found to be associated with late-onset cerebellar ataxia. This study aimed to investigate the genetic causes of cerebellar ataxia in patients in Japan. METHODS: We collected a case series of 940 index patients who presented with chronic cerebellar ataxia and remained genetically undiagnosed after our preliminary genetic screening. To investigate the FGF14 repeat locus, we employed an integrated diagnostic strategy that involved fluorescence amplicon length analysis polymerase chain reaction (PCR), repeat-primed PCR, and long-read sequencing. RESULTS: Pathogenic FGF14 GAA repeat expansions were detected in 12 patients from 11 unrelated families. The median size of the pathogenic GAA repeat was 309 repeats (range: 270-316 repeats). In these patients, the mean age of onset was 66.9 ± 9.6 years, with episodic symptoms observed in 56% of patients and parkinsonism in 30% of patients. We also detected FGF14 repeat expansions in a patient with a phenotype of multiple system atrophy, including cerebellar ataxia, parkinsonism, autonomic ataxia, and bilateral vocal cord paralysis. Brain magnetic resonance imaging (MRI) showed normal to mild cerebellar atrophy, and a follow-up study conducted after a mean period of 6 years did not reveal any significant progression. DISCUSSION: This study highlights the importance of FGF14 GAA repeat analysis in patients with late-onset cerebellar ataxia, particularly when they exhibit episodic symptoms, or their brain MRI shows no apparent cerebellar atrophy. Our findings contribute to a better understanding of the clinical variability of GAA-FGF14-related diseases.

Number and ratio of metastatic lymph nodes impacts the prognosis of submandibular gland cancer.

This study aimed to assess the impact of the number and ratio of metastatic lymph nodes (LNs) on prognosis in submandibular gland cancer. To this end, patients were selected from the Surveillance, Epidemiology, and End Results database retrospectively. The effect of the number and ratio of metastatic LNs and the American Joint Committee on Cancer (AJCC) N stage on disease-specific survival (DSS) and overall survival (OS) was analyzed. In addition, prognostic models based on LN evaluation methods were developed to predict the OS and DSS. A total of 914 patients were included. Binary recursive partitioning analysis determined the optimal cut-off number of metastatic LNs (0 vs. 1-2. vs. 3+). The presence of 3+ metastatic LNs carried the greatest impact on prognosis, followed by 1-2 positive LNs occurrences. The ratio of metastatic LNs was an independent factor for DSS and OS. The model had a higher likelihood ratio and C-index than those in the Cox model based on the AJCC N stage. Quantitative LN burden and ratio of metastatic LNs provides better survival stratification than the AJCC N stage.

Ferrostatin-1 attenuates hypoxic-ischemic brain damage in neonatal rats by inhibiting ferroptosis.

Background: Hypoxic-ischemic brain damage (HIBD) is a type of brain damage that is caused by perinatal asphyxia and serious damages the central nervous system. At present, there is no effective drug for the treatment of this disease. Besides, the pathogenesis of HIBD remains elusive. While studies have shown that ferroptosis plays an important role in HIBD, its role and mechanism in HIBD are yet to be fully understood. Methods: The HIBD model of neonatal rats was established using the Rice-Vannucci method. A complete medium of PC12 cells was adjusted to a low-sugar medium, and the oxygen-glucose deprivation model was established after continuous hypoxia for 12 h. Laser Doppler blood flow imaging was used to detect the blood flow intensity after modeling. 2,3,5-triphenyl tetrazolium chloride staining was employed to detect ischemic cerebral infarction in rat brain tissue, and hematoxylin and eosin staining and transmission electron microscopy were used to observe brain injury and mitochondrial damage. Immunofluorescence was applied to monitor the expression of GFAP. Real-time quantitative polymerase chain reaction, western blot, and immunofluorescence were utilized to detect the expression of messenger RNA and protein. The level of reactive oxygen species (ROS) in cells was detected using the ROS detection kit. Results: The results showed that ferrostatin-1 (Fer-1) significantly alleviated the brain injury caused by hypoxia and ischemia. Fer-1 significantly increased the expression of SLC3A2, SLC7A11, ACSL3, GSS, and GPX4 (P<0.05) and dramatically decreased the expressions of GFAP, ACSL4, TFRC, FHC, FLC, 4-HNE, HIF-1α, and ROS (P<0.05). Conclusions: Fer-1 inhibits ferroptosis and alleviates HIBD by potentially targeting the GPX4/ACSL3/ACSL4 axis; however, its specific mechanism warrants further exploration.

Electronic, mechanical and gas sensing properties of two-dimensional γ-SnSe.

Two-dimensional (2D) materials are excellent candidates for advanced flexible electronics and gas sensors. Herein, we systematically investigate the layer-dependent electronic structures, mechanical properties and gas sensing characteristics of the newly synthesized γ-SnSe based on first-principles calculations. Bulk γ-SnSe is a typical van der Waals layered material with an indirect narrow band gap, while monolayer and multilayer γ-SnSe can be obtained through mechanical exfoliation due to its low cleavage energy. The band gap of γ-SnSe gradually increases with decreasing layers, reaching a value of 2.25 eV for the monolayer due to weakened interlayer coupling. Mechanical analysis reveals strong anisotropy in multilayer γ-SnSe, whereas the monolayer exhibits a negative Poisson's ratio (-0.023/-0.025). Additionally, based on the analysis of electronic structures, adsorption energies and charge transfer of the host materials after adsorption of various gases, it is found that the γ-SnSe monolayer demonstrates enhanced sensitivity and selectivity towards NO, NO2, and SO2 compared to CO, CO2, H2S and NH3. These findings highlight the potential of γ-SnSe as an excellent gas-sensitive material for the detection of nitrogen oxides and sulfur dioxide.

Microbleed clustering in thalamus sign in CADASIL patients with NOTCH3 R75P mutation.

Background and objective: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited cerebral microvascular disease characterized by the development of vascular dementia and lacunar infarctions. This study aimed to identify the genetic and clinical features of CADASIL in Japan. Methods: We conducted genetic analysis on a case series of patients clinically diagnosed with CADASIL. Clinical and imaging analyses were performed on 32 patients with pathogenic mutations in the NOTCH3 gene. To assess the presence of cerebral microbleeds (CMBs), we utilized several established rating scales including the Fazekas scale, Scheltens rating scale, and Microbleed Anatomical Rating Scale, based on brain MRI images. Results: Among the 32 CADASIL patients, 24 cases were found carrying the R75P mutation in NOTCH3, whereas the remaining eight cases had other NOTCH3 mutations (R75Q, R110C, C134F, C144F, R169C, and R607C). The haplotype analysis of the R75P mutation uncovered the presence of a founder effect. A brain MRI analysis revealed that cases with the R75P mutation had a significantly higher total number of CMBs, particularly in the thalamus when compared to patients with other NOTCH3 mutations. Among 15 out of 24 cases with the R75P mutation, we observed a notable clustering of CMBs in the thalamus, termed microbleed clustering in thalamus sign (MCT sign). Conclusion: We propose that the MCT sign observed in NOTCH3 R75P-related CADASIL patients may serve as a potentially characteristic imaging feature. This finding offers further insights into the interactions between genotypes and phenotypes between NOTCH3 and CADASIL.

Genetic, electrophysiological, and pathological studies on patients with SCN9A-related pain disorders.

BACKGROUND AND AIMS: Voltage-gated sodium channel Nav1.7, encoded by the SCN9A gene, has been linked to diverse painful peripheral neuropathies, represented by the inherited erythromelalgia (EM) and paroxysmal extreme pain disorder (PEPD). The aim of this study was to determine the genetic etiology of patients experiencing neuropathic pain, and shed light on the underlying pathogenesis. METHODS: We enrolled eight patients presenting with early-onset painful peripheral neuropathies, consisting of six cases exhibiting EM/EM-like disorders and two cases clinically diagnosed with PEPD. We conducted a gene-panel sequencing targeting 18 genes associated with hereditary sensory and/or autonomic neuropathy. We introduced novel SCN9A mutation (F1624S) into a GFP-2A-Nav1.7rNS plasmid, and the constructs were then transiently transfected into HEK293 cells. We characterized both wild-type and F1624S Nav1.7 channels using an automated high-throughput patch-clamp system. RESULTS: From two patients displaying EM-like/EM phenotypes, we identified two SCN9A mutations, I136V and P1308L. Among two patients diagnosed with PEPD, we found two additional mutations in SCN9A, F1624S (novel) and A1632E. Patch-clamp analysis of Nav1.7-F1624S revealed depolarizing shifts in both steady-state fast inactivation (17.4 mV, p < .001) and slow inactivation (5.5 mV, p < .001), but no effect on channel activation was observed. INTERPRETATION: Clinical features observed in our patients broaden the phenotypic spectrum of SCN9A-related pain disorders, and the electrophysiological analysis enriches the understanding of genotype-phenotype association caused by Nav1.7 gain-of-function mutations.

Two-Dimensional Planar Penta-NiPN with Ultrahigh Carrier Mobility and Its Potential Application in NO and NO2 Gas Sensing.

Two-dimensional (2D) materials with novel structures and electronic properties are promising candidates for the next generation of micro- and nano-electronic devices. Herein, inspired by the recent experimental synthesis of penta-NiN2 (ACS Nano, 2021, 15, 13539-13546), we propose for the first time a novel ternary penta-NiPN monolayer with high stability by partial element substitution. Our predicted penta-NiPN monolayer is a quasi-direct bandgap (1.237 eV) semiconductor with ultrahigh carrier mobilities (103-105 cm2V-1s-1). Furthermore, we systematically studied the adsorption properties of common gas molecules (CO, CO2, CH4, H2, H2O, H2S, N2, NO, NO2, NH3, and SO2) on the penta-NiPN monolayer and its effects on electronic properties. According to the energetic, geometric, and electronic analyses, the penta-NiPN monolayer is predicted to be a promising candidate for NO and NO2 molecules. The excellent electronic properties of and the unique selectivity of the penta-NiPN monolayer for NO and NO2 adsorption suggest that it has high potential in advanced electronics and gas sensing applications.

Self-wavelength shifting in two-dimensional perovskite for sensitive and fast gamma-ray detection.

Lead halide perovskites have recently emerged as promising X/γ-ray scintillators. However, the small Stokes shift of exciton luminescence in perovskite scintillators creates problems for the light extraction efficiency and severely impedes their applications in hard X/γ-ray detection. Dopants have been used to shift the emission wavelength, but the radioluminescence lifetime has also been unwantedly extended. Herein, we demonstrate the intrinsic strain in 2D perovskite crystals as a general phenomenon, which could be utilized as self-wavelength shifting to reduce the self-absorption effect without sacrificing the radiation response speed. Furthermore, we successfully demonstrated the first imaging reconstruction by perovskites for application of positron emission tomography. The coincidence time resolution for the optimized perovskite single crystals (4 × 4 × 0.8 mm3) reached 119 ± 3 ps. This work provides a new paradigm for suppressing the self-absorption effect in scintillators and may facilitate the application of perovskite scintillators in practical hard X/γ-ray detections.

Association between factor of parotid lymph node and prognosis in parotid cancer.

INTRODUCTION: Survival significance of parotid lymph node (LN) factors in parotid cancer remains unclear, our goal was to assess the impact of number, size, and extranodal extension (ENE) of metastatic parotid LNs on prognosis in parotid cancer. MATERIALS AND METHODS: Patients with surgically treated parotid cancer were retrospectively enrolled. Primary outcome variable was recurrence-free survival (RFS) and overall survival (OS). The hazard ratios (HRs) of main predictive variables including the number, size, and ENE of positive parotid LNs on RFS and OS were analyzed using Cox model. The secondary outcome variable was ENE of metastatic parotid LN, its association with clinicopathologic variables were evaluated using Chi-square test. RESULTS: In total, 453 patients (186 male and 267 female) were included. The 10-year RFS and OS rates were 73% (95%CI: 69%-77%) and 61% (95%CI: 55%-67%), respectively. In Cox model, compared none parotid LN metastasis, one metastatic parotid LN did not offer additional compromise of RFS (p = 0.224) or OS (p = 0.135), but two or more positive LNs decreased the control of RFS (HR: 2.017; 95%CI: 1.378-4.632) and OS (HR: 2.173; 95%CI: 1.367-4.275). When accounting for the number of metastatic LNs, LN size or ENE was no longer related to RFS or OS. ENE of parotid LN tended to develop if there was presence of T3/4 stage, lymphovascular invasion, high histologic grade, N2/3 stage, and three or more positive parotid LNs. CONCLUSION: Quantitative parotid LN burden but not ENE or LN size is an important determinant of survival in patients with parotid cancer.

Clinical phenotypic diversity of NOTCH2NLC-related disease in the largest case series of inherited peripheral neuropathy in Japan.

BACKGROUND: NOTCH2NLC GGC repeat expansions have been associated with various neurogenerative disorders, including neuronal intranuclear inclusion disease and inherited peripheral neuropathies (IPNs). However, only a few NOTCH2NLC-related disease studies in IPN have been reported, and the clinical and genetic spectra remain unclear. Thus, this study aimed to describe the clinical and genetic manifestations of NOTCH2NLC-related IPNs. METHOD: Among 2692 Japanese patients clinically diagnosed with IPN/Charcot-Marie-Tooth disease (CMT), we analysed NOTCH2NLC repeat expansion in 1783 unrelated patients without a genetic diagnosis. Screening and repeat size determination of NOTCH2NLC repeat expansion were performed using repeat-primed PCR and fluorescence amplicon length analysis-PCR. RESULTS: NOTCH2NLC repeat expansions were identified in 26 cases of IPN/CMT from 22 unrelated families. The mean median motor nerve conduction velocity was 41 m/s (range, 30.8-59.4), and 18 cases (69%) were classified as intermediate CMT. The mean age of onset was 32.7 (range, 7-61) years. In addition to motor sensory neuropathy symptoms, dysautonomia and involuntary movements were common (44% and 29%). Furthermore, the correlation between the age of onset or clinical symptoms and the repeat size remains unclear. CONCLUSIONS: These findings of this study help us understand the clinical heterogeneity of NOTCH2NLC-related disease, such as non-length-dependent motor dominant phenotype and prominent autonomic involvement. This study also emphasise the importance of genetic screening, regardless of the age of onset and type of CMT, particularly in patients of Asian origin, presenting with intermediate conduction velocities and dysautonomia.

Nav1.7 P610T mutation in two siblings with persistent ocular pain after corneal axon transection: impaired slow inactivation and hyperexcitable trigeminal neurons.

Despite extensive study, the mechanisms underlying pain after axonal injury remain incompletely understood. Pain after corneal refractive surgery provides a model, in humans, of the effect of injury to trigeminal afferent nerves. Axons of trigeminal ganglion neurons that innervate the cornea are transected by laser-assisted in situ keratomileusis (LASIK). Although most patients do not experience postoperative pain, a small subgroup develop persistent ocular pain. We previously carried out genomic analysis and determined that some patients with persistent pain after axotomy of corneal axons during refractive surgery carry mutations in genes that encode the electrogenisome of trigeminal ganglion neurons, the ensemble of ion channels and receptors that regulate excitability within these cells, including SCN9A, which encodes sodium channel Nav1.7, a threshold channel abundantly expressed in sensory neurons that has been implicated in a number of pain-related disorders. Here, we describe the biophysical and electrophysiological profiling of the P610T Nav1.7 mutation found in two male siblings with persistent ocular pain after refractive surgery. Our results indicate that this mutation impairs the slow inactivation of Nav1.7. As expected from this proexcitatory change in channel function, we also demonstrate that this mutation produces increased spontaneous activity in trigeminal ganglion neurons. These findings suggest that this gain-of-function mutation in Nav1.7 may contribute to pain after injury to the axons of trigeminal ganglion neurons.NEW & NOTEWORTHY Mechanisms underlying pain after axonal injury remain elusive. A small subgroup of patients experience pain after corneal refractive surgery, providing a human pain model after well-defined injury to axons. Here we analyze a mutation (P610T) in Nav1.7, a threshold sodium channel expressed in nociceptors, found in two siblings with persistent ocular pain after refractive surgery. We show that it impairs channel slow inactivation, thereby triggering inappropriate repetitive activity in trigeminal ganglion axons that signal eye pain.