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Recently, extracting inherent biological system information (e.g. cellular networks) from genome-wide expression profiles for developing personalized diagnostic and therapeutic strategies has become increasingly important. However, accurately constructing single-sample networks (SINs) to capture individual characteristics and heterogeneity in disease remains challenging. Here, we propose a sample-specific-weighted correlation network (SWEET) method to model SINs by integrating the genome-wide sample-to-sample correlation (i.e. sample weights) with the differential network between perturbed and aggregate networks. For a group of samples, the genome-wide sample weights can be assessed without prior knowledge of intrinsic subpopulations to address the network edge number bias caused by sample size differences. Compared with the state-of-the-art SIN inference methods, the SWEET SINs in 16 cancers more likely fit the scale-free property, display higher overlap with the human interactomes and perform better in identifying three types of cancer-related genes. Moreover, integrating SWEET SINs with a network proximity measure facilitates characterizing individual features and therapy in diseases, such as somatic mutation, mut-driver and essential genes. Biological experiments further validated two candidate repurposable drugs, albendazole for head and neck squamous cell carcinoma (HNSCC) and lung adenocarcinoma (LUAD) and encorafenib for HNSCC. By applying SWEET, we also identified two possible LUAD subtypes that exhibit distinct clinical features and molecular mechanisms. Overall, the SWEET method complements current SIN inference and analysis methods and presents a view of biological systems at the network level to offer numerous clues for further investigation and clinical translation in network medicine and precision medicine.

Background Early childhood is a critical stage for the prevention of dental caries. The prevalence of caries in preschool children is still high in Taiwan, where National Health Insurance covers 99% of the population. The effort to improve the oral health of preschool children should be based on conceptual model that encompasses more than individual-level factors. This study input nationwide survey data in a conceptual model to evaluate the effects of comprehensive factors related to the high prevalence of caries in preschool children. Methods This observation study examined factors related to the oral health of preschool children by employing a comprehensive multilevel model to analyse nationally representative data from the Taiwan Oral Health Survey of Preschool Children (TOHPC) 2017–2018. Individual-level, family-level and community-level contextual effects were evaluated through multilevel analysis in this study. The proportional change in variance (PCV) was used to compare the multilevel model with the null model and individual-level, family-level, and community-level context effects. Results The estimated deft index for preschool children was 1.34 (1.22–1.47) at age 3, 2.20 (2.08–2.32) at age 4, and 3.05 (2.93–3.18) at age 5. The overall prevalence of caries in preschool children in Taiwan was 34.27% (30.76%, 37.78%) at age 3, 51.67% (48.99%, 54.35%) at age 4, and 62.05% (59.66%, 64.44%) at age 5. The model that included the individual-, family-, and community-context levels exhibited the highest reduction of variance (PCV = 53.98%). The PCV was further reduced to 35.61% when only the level of accessibility to dental services for individuals, families, and the community was considered. For the model in which no community-context cofactors were considered and the model considering only the individual level, the PCVs were 20.37% and 5.52%, respectively. Conclusions The most notable finding of this study is that to improve the oral health of preschool children, community-level factors should be targeted. Such community-based programs would effectively improve the oral health knowledge and behaviours of the parents and caregivers of preschool children. We suggest training more professional oral health educators to provide more community-based oral health promotion campaigns.

The all-optical cross-wavelength quadrature amplitude modulation orthogonal frequency-division multiplexing (QAM-OFDM) data switching in the silicon rich silicon carbide (Si-rich SiC) micro-ring (μ-ring) waveguide is demonstrated for the first time by using the two-photon absorption (TPA) induced free carrier absorption (FCA) process. With enlarging the allowable 4-QAM OFDM data bandwidth to 1.16 GHz, the all-optical 4-QAM OFDM pump-to-probe switching with allowable bandwidth of 1.16 GHz can achieve a raw data rate up to 2.32 Gbit/s with forward error correction (FEC) qualified error vector magnitude (EVM), signal-to-noise ratio (SNR), and bit-err-ratio (BER) of 31.9%, 9.92 dB, and 8.7 × 10−4, respectively. With upgrading the bandwidth of electrical pre-amplifier to 1.5 GHz, the wavelength-converted probe data can successfully pass the FEC criterion with qualified SNR of 9.49 dB, BER of 1.4 × 10−3 and EVM of 33.5%, to demonstrate the all-optical switching data rate approaching 3 Gbit/s.

Objective Lennox-Gastaut syndrome (LGS) is an epileptic encephalopathy frequently associated with multiple types of seizures. The classical Na+ channel inhibitors are in general ineffective against the seizures in LGS. Rufinamide is a new Na+ channel inhibitor, but approved for the treatment of LGS. This is not consistent with a choice of antiseizure drugs (ASDs) according to simplistic categorical grouping. Methods The effect of rufinamide on the Na+ channel, cellular discharges, and seizure behaviors was quantitatively characterized in native neurons and mammalian models of epilepsy, and compared with the other Na+ channel inhibitors. Results With a much faster binding rate to the inactivated Na+ channel than phenytoin, rufinamide is distinctively effective if the seizure discharges chiefly involve short bursts interspersed with hyperpolarized interburst intervals, exemplified by spike and wave discharges (SWDs) on electroencephalograms. Consistently, rufinamide, but not phenytoin, suppresses SWD-associated seizures in pentylenetetrazol or AY-9944 models, which recapitulate the major electrophysiological and behavioral manifestations in typical and atypical absence seizures, including LGS. Interpretation Na+ channel inhibitors shall have sufficiently fast binding to exert an action during the short bursts and then suppress SWDs, in which cases rufinamide is superior. For the epileptiform discharges where the interburst intervals are not so hyperpolarized, phenytoin could be better because of the higher affinity. Na+ channel inhibitors with different binding kinetics and affinity to the inactivated channels may have different antiseizure scope. A rational choice of ASDs according to in-depth molecular pharmacology and the attributes of ictal discharges is advisable. ANN NEUROL 2021;89:1099-1113.

Background and purpose Perampanel is a newly approved anticonvulsant uniquely targeting AMPA receptors, which mediate the most abundant form of excitatory synaptic transmission in the brain. However, the network mechanism underlying the anti-epileptic effect of the AMPAergic inhibition remains to be explored. Experimental approach The mechanism of perampanel action was studied with the basolateral amygdala network containing pyramidal-inhibitory neuronal resonators in seizure models of 4-aminopyridine (4-AP) and electrical kindling. Key results Application of either 4-AP or electrical kindling to the basolateral amygdala readily induces AMPAergic transmission-dependent reverberating activities between pyramidal-inhibitory neuronal resonators, which are chiefly characterized by burst discharges in inhibitory neurons and corresponding recurrent inhibitory postsynaptic potentials in pyramidal neurons. Perampanel reduces post-kindling "paroxysmal depolarizing shift" especially in pyramidal neurons and, counterintuitively, eliminates burst activities in inhibitory neurons and inhibitory synaptic inputs onto excitatory pyramidal neurons to result in prevention of epileptiform discharges and seizure behaviours. Intriguingly, similar effects can be obtained with not only the AMPA receptor antagonist CNQX but also the GABAA receptor antagonist bicuculline, which is usually considered as a proconvulsant. Conclusion and implications Ictogenesis depends on the AMPA receptor-dependent recruitment of pyramidal-inhibitory neuronal network oscillations tuned by dynamic glutamatergic and GABAergic transmission. The anticonvulsant effect of perampanel then stems from disruption of the coordinated network activities rather than simply decreased neuronal excitability or excitatory transmission. Positive or negative modulation of epileptic network reverberations may be pro-ictogenic or anti-ictogenic, respectively, constituting a more applicable rationale for the therapy against seizures.

Anticonvulsants targeting KMechanisms underlying epileptogenesis with A-channel inhibition and antiepileptic actions of A-channel activation were investigated with electrophysiological, pharmacological, optogenetic, and behavioral approaches.Pre-synaptic KTrans-synaptic voltage-dependent A-channels serve as a biophysical-biochemical transducer responsible for a novel form of synaptic plasticity. Such a network-level switch into and out of the oscillatory mode may underlie a wide scope of telencephalic information processing or, at its extreme, epileptic seizures. A-channels thus constitute a potential target of antiepileptic therapy.

Lennox-Gastaut syndrome (LGS) is an epileptic encephalopathy frequently associated with multiple types of seizures. The classical NaThe effect of rufinamide on the NaWith a much faster binding rate to the inactivated NaNa

Motivated by an earthquake impact study, this paper develops new tests with several invariant properties for functional data. For multi-sample functional ANOVA (mfANOVA), based on local polynomial regression, exact local and global ANOVA decompositions into within- and between-group of variations are obtained. A local mfANOVA test is developed to examine differences in a local neighborhood, and combining local quantities, a global mfANOVA test statistic is formed. We show that both the local and global mfANOVA test statistics are location, scale, and translation invariant, allow interchanging the order of smoothing and ANOVA projection, and have asymptotic F -distributions under the null hypotheses with the Gaussian assumption. This paper contributes to the literature by being the first, to our knowledge, to study mfANOVA tests with several invariant properties. Simulation studies are presented to compare the proposed global mfANOVA test with some existing procedures. Application to an earthquake impact study in Taiwan reveals that when an earthquake in 2016 resulted in closed highways, the patterns of traffic flows were significantly different between three time periods, before the earthquake, during, and after the repair period. The information could be useful in planning for disaster preparedness.

BACKGROUND The trends in computed tomography (CT) scan uses in Taiwan were examined in different age and sex groups and compared between catastrophic illness and noncatastrophic illness groups. METHODS This retrospective cohort study used data from the National Health Insurance Research Database (NHIRD) in Taiwan to analyze CT scan uses from the beginning of 2000 to the end of 2013. The number, annual growth rate, and cumulative fold change ratio were estimated in different groups classified by sex, age, or disease category (catastrophic illness, noncatastrophic illness). RESULTS The number of CT scan uses per million people per year in Taiwan increased 2.5 times from 24 257 in 2000 to 60 351 in 2013, at the average annual growth rate of 7.4% ± 5.9%. The annual number of CT scan uses in different age groups and disease category groups was significantly higher in males than in females. However, the average annual growth rate and the cumulative fold change ratio were slightly higher in females than in males. The majority of CT scan uses were in middle age and young adult groups. The annual number of CT scan uses in the young adult, child/adolescent, and middle age groups increased 3.7-, 3.5-, and 2.7-fold from 2000 to 2013, but decreased 0.8-fold in the old-age group. The annual number of CT scan uses was highest in the noncatastrophic illness group, followed by the catastrophic illness cancer group and catastrophic illness others group. CONCLUSION CT scan uses in Taiwan increased continuously from 2000 to 2013, even in the groups with higher radiation-related cancer risk. Therefore, clinicians, radiologists, and medical policy makers should weigh diagnostic benefit against sex-specific and age-specific risks in the future.

Tourette syndrome (TS) is an inherited neurophysiologic disorder with onset in childhood, characterized by multiple physical (motor) tics and at least one vocal (phonic) tic. Patients with TS constantly feel immense anxiety in public due to the issues of vocal tics or coprolalia. Therefore, this study aims to design a specialized mask for TS patients to reduce the intensity of vocal tic or coprolalia such that the quality of life can be greatly improved. The paper presents a novel concept of sound absorption using 3d-printed acoustic metamaterials (AMs) with microscale gaps as the impedance-matched surface and experimental study on sound transmission loss. A simple construction based on the acoustically impedance matched surface embedded with asymmetric metallic platelets, hybrid resonances with high energy dissipation can be confined and absorb low-frequency airborne sound in frequencies ranging from 10 to 1300 Hz. The octave band analysis on the samples sound suppression capability is discussed. The field test results revealed an effective sound suppression capability can be fulfilled in the range of 89–94% for the frequency range 10–1300 Hz. The sound absorption performances of customized mask are shown to be effective and the prototypes had been clinically tested on the patients of TS. An alternative low-cost, impedance-matched AMs structure for the patients of TS is successfully developed.

Tourette syndrome is an inherited neurophysiologic disorder with onset in childhood, characterized by multiple physical (motor) tics and at least one vocal (phonic) tic. Between 0.4% and 3.8% of children ages 5–18 may have Tourette's; the prevalence of other tic disorders in school-age children is higher, with the more common tics of eye blinking, coughing, throat clearing, sniffing, and facial movements. This paper is mainly focused on a novel multilayer vibrating plate design in conjunction with the 3D scanned data/3D printed fabrication process for the customized face features. The field test results revealed an effective sound suppression capability in terms of the amplitude of sound pressure can be fulfilled in the range of 69–99% for the frequency range 100–1800 Hz. The sound suppression performance of customized mask is shown to be superior to that of any commercially available mask in the market. Therefore, the design goal is successfully accomplished to design and develop an alternative low-cost, damped vibrating plate structure for the patients of Tourette's syndrome.

Spinocerebellar ataxia (SCA) is a progressive neurodegenerative disease that affects the cerebellum and spinal cord. Among the 40 types of SCA, SCA type 3 (SCA3), also referred to as Machado–Joseph disease, is the most common. In the present study, we investigated the therapeutic effects of intracranial transplantation of human olfactory ensheathing cells (hOECs) in the ATXN3-84Q mouse model of SCA3. Motor function begins to decline in ATXN3-84Q transgenic mice at approximately 13 weeks of age. ATXN3-84Q mice that received intracranial hOEC transplantation into the dorsal raphe nucleus of the brain exhibited significant improvements in motor function, as measured by the rotarod performance test and footprint pattern analysis. In addition, intracranial hOEC transplantation alleviated cerebellar inflammation, prohibited Purkinje cells from dying, and enhanced the neuroplasticity of cerebellar Purkinje cells. The protein levels of tryptophan hydroxylase 2, the rate-limiting enzyme for serotonin synthesis in the cerebellum, and ryanodine receptor (RYR) increased in mice that received intracranial hOEC transplantation. Because both serotonin and RYR can enhance Purkinje cell maturation, these effects may account for the therapeutic benefits mediated by intracranial hOEC transplantation in SCA3 mice. These results indicate that intracranial hOEC transplantation has potential value as a novel strategy for treating SCA3.

A birefringent-refraction (BR) sensor for measuring refractive indices of liquid solutions based on phase interrogation in a heterodyne interferometer is proposed. We theoretically investigate a comprehensive performance comparison between a surface plasmon resonance (SPR) sensor and the proposed BR sensor in terms of sensitivity and the dynamic range in refractive index measurements. In comparison with a typical SPR sensor, the simulations and experiments show that BR sensors can achieve the same order of sensitivity but with a flexible incident angle and a wide RI range.

To evaluate the effectiveness of a modified four-session Comprehensive Behavioral Intervention for Tics programme for decreasing tics in children and adolescents with Tourette's syndrome.Comprehensive Behavioral Intervention for Tics programme has been shown to decrease tic severity. However, the lack of behaviour therapists in countries, such as in Taiwan, may preclude application of the standard eight-session, 10-week programme.Randomized controlled study.Participants aged 6-18 years diagnosed with Tourette's syndrome or chronic tic disorder were recruited from February 2015 through September 2016. Participants in the control and intervention groups (N = 23 each) received the routine care (daily pyridoxine [50 mg] and psychoeducation). The intervention group received additional four behavioural intervention sessions over a 3-month period that included psychoeducation, habit reversal training, relaxation training, and education on tic relapse prevention. The outcome measures, Yale Global Tic Severity Scale scores, were assessed at before and after the completion of programme for both groups and again at 3 months follow-up for the intervention group. The effect of the intervention on severity scores was assessed using a generalized estimated equation.Comparison of scores before and after intervention showed that the intervention significantly decreased the severity of total motor tics (B = -3.28, p .01) and total tics (B = -5.86, p .01) as compared with control treatment. YGTSS scores for the intervention group were lower at 3-month follow-up as compared with before treatment or immediately after treatment completion (total tics, p .001).The modified four-session Comprehensive Behavioral Intervention for Tics programme was more effective than routine care for decreasing tic severity in our cohort of 6- to 18-year olds. This improvement was maintained 3 months after intervention.Healthcare providers, including nurses, in countries currently not adopting Comprehensive Behavioral Intervention for Tics programme should be made aware of the positive effects of this modified intervention for Tourette's syndrome.目的: 评价经改良的四期综合性行为干预措施(用于抽动治疗方案)对减轻患有图雷特综合征的儿童和青少年的抽动行为的有效性。 背景: 有研究表明,综合性行为干预(用于抽动治疗方案)可降低抽动行为的严重程度。然而,在台湾等地区,行为治疗师人手短缺可能会妨碍八期十周方案的实施效果。 设计: 随机对照研究。 方法: 2015年2月至2016年9月招募6-18岁经诊断患有图雷特综合征或慢性抽动障碍的参与者。对照组和干预组(每组N=23人)的参与者均接受了常规护理(每日服用吡哆醇【50毫克】,进行心理教育)。干预组在3个月内还接受了另外4次行为干预治疗,包括心理教育、习惯逆转训练、放松训练和预防抽动搐复发教育。在治疗方案完成前后分别对两组的结果指标--耶鲁综合抽动严重程度量表评分进行评价,并在3个月随访时再次对干预组的结果指标进行评价。同时采用广义估计方程来评估干预措施对严重程度量表评分的影响。 结果: 干预前后评分的比较结果表明,与对照治疗相比,干预措施显著降低了整体运动抽动(B = −3.28,p.01)和整体抽动(B = −5.86,p.01)的严重程度。与治疗前或治疗完成后相比,干预组在3个月随访时的耶鲁综合抽动严重程度量表评分较低(整体抽动,p0.001)。 结论: 经改良的四期综合性行为干预措施(用于抽动治疗方案)对降低6-18岁群体的抽动严重程度比常规治疗更有效。这一改善情况可在干预后保持3个月。 影响: 针对目前尚未采用综合性行为干预措施(用于抽动治疗方案)的国家,包括护士在内的医疗服务提供者应了解此种改良的干预方案对图雷特综合征的积极治疗效果。.

Tourette syndrome (TS) is often comorbid with attention deficit hyperactivity disorder, obsessive-compulsive disorder, and depression. Medications are the main treatment for TS. Relationships between TS medication therapy and psychiatric comorbidities remain unclear. This study explored the impacts of TS medication on the risk of psychiatric comorbidities using a nationally representative sample of TS in Taiwan.Data from National Health Insurance Research Database in Taiwan was used to identify 997,213 children and adolescents aged 6-18 years who had received a diagnosis of TS based on ICD-9-CM codes in 2000-2010. Cox's proportional hazard regression analysis was conducted to estimate the risk of comorbidities among subjects with and without tic medication therapy.We found that in TS patients, a lower risk of psychiatric comorbidities occurred in the tic medication therapy group (p = 0.012) and the crude hazard ratio (HR) was 0.6 (95% confidence interval (CI) = 0.4-0.8, p 0.001). After adjusting for potential confounders of gender, age, income, level of care, department visited, brain injury, and the number of suicide attempts, the risk of comorbidities was still significantly lower in the tic medication therapy group (adjusted HR = 0.5, 95% CI = 0.3-0.6, p 0.001).One limitation was that we did not include all mediations used to treat psychiatric comorbidities among TS patients. This study found the effectiveness of TS medications on improving psychiatric comorbidities.Compared to those without medication, medication therapy appears to have a benefit of decreasing the risk of psychiatric comorbidities. Strategies to improve medication regimens should be considered in clinical settings.

Amyotrophic lateral sclerosis (ALS) is a lethal degenerating disease, characterized by progressive muscular atrophy without any effective treatment. Here, we demonstrated the efficacy of abrograting autophagy in motor neurons (MN) by treatment with n-butylidenephthalide (n-BP) in ALS transgenic mice (SOD1(G93A)). Pre-symptomatic oral administration of 250 mg/kg/bid n-BP significantly prolonged the survival period (203.9 ± 18.3 days), improved motor function, and attenuated MN loss compared to vehicle control (126.4 ± 7.2 days). This prolonged survival of ALS mice is much more robust than that reported with riluzole (140 days), which is an approved clinical therapy for ALS. The therapeutic mechanism targeted by n-BP involved the autophagic pathway as evidenced by decreased LC3-II expression (a biomarker of autophagy), enhanced mTOR levels, and attenuated autophagic activity, altogether increasing MN survival in a dose-dependent manner. This result was also confirmed by double transgenic mice (SOD1(G93A):LC3-GFP) which showed that oral administration of n-BP reduced GFP density and decreased caspase-3 expression. In addition, electron microscopy revealed that n-BP administration not only decreased autophagosome number but also reduced morphological dysfunction of mitochondria. In summary, these results indicate that down-regulation of autophagy activation via n-BP may pose as a therapeutic regimen for ALS and relevant neurodegenerative diseases.

Summary Epileptic seizures constitute a common neurological disease primarily diagnosed by characteristic rhythms or waves in the local field potentials (LFPs) of cerebral cortices or electroencephalograms. With a basolateral amygdala (BLA) kindling model, we found that the dominant frequency of BLA oscillations is in the delta range (1–5 Hz) in both normal and seizure conditions. Multi-unit discharges are increased with higher seizure staging but remain phase-locked to the delta waves in LFPs. Also, the change in synchrony precedes and outlasts the changes in discharging units as well as behavioral seizures. One short train of stimuli readily drives the pyramidal-inhibitory neuronal networks in BLA slices into prolonged reverberating activities, where the burst and interburst intervals may concurrently set a “natural wavelength” for delta frequencies. Seizures thus could be viewed as erroneous temporospatial continuums to normal oscillations in a system with a built-in synchronizing and resonating nature for information relay., Graphical Abstract, Highlights • Delta oscillations constitute the natural frequencies in basolateral amygdala • Neuronal burst and interburst intervals set the wavelength for delta oscillations • Delta oscillations may be readily transmitted distantly and translated behaviorally • Synchrony precedes and outlasts increase in discharges and seizures in ictogenesis, Behavioral Neuroscience; Systems Neuroscience; Techniques in Neuroscience