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We developed a subtractive manufacturing with swelling induced stochastic folding of sacrificial materials for fabricating complex perfusable tissues in high-throughput multi-well plate formats.

Spinal muscular atrophy (SMA) is associated with developmental disruption of motor axons in ventral roots of the spinal cord alongside motor axon degeneration. The pathogenesis of peripheral axonal change during development is pertinent to understand treatment response. Nerve excitability techniques, stimulating the median motor nerve at the wrist, were utilised to investigate axonal change during neurodevelopment in 24 children with SMA, compared with 71 age-matched controls. Longitudinal axonal response to nusinersen treatment in 18 children was also investigated. Significant differences in axonal development were noted in the youngest children with SMA, signified by reduced compound muscle action potential (CMAP) (P = 0.030), higher axonal threshold (P = 0.016), rheobase (minimal current amplitude of infinite duration, required to generate an action potential) (P = 0.012) and greater changes in depolarising and hyperpolarising threshold electrotonus. Subexcitability increased in all children with SMA, compared to controls. With treatment, nerve excitability changes were observed prominently in young children, with increases in CMAP, reduction in axonal threshold, fanning-in of threshold electrotonus, increase in resting current-threshold slope and reduction in subexcitability. Whilst motor axons continue to mature in SMA, developmental delays in passive and active membrane properties occur especially in early childhood. Concurrently, motor axons actively undergo degeneration. Nusinersen restores the developmental trajectory of motor axons reducing degeneration, especially in children with early treatment initiation. Our findings move the field forward in understanding the developmental aspect of childhood-onset motor neurone diseases and changes in axonal function associated with disease modification. KEY POINTS: Pathomechanisms in spinal muscular atrophy involve concurrent neurodevelopmental and neurodegenerative processes. The greatest delays in maturation of the passive and active properties of the peripheral motor axon are seen in early childhood. Nusinersen facilitates developmental recovery of the motor axon whilst also reducing neurodegeneration. Axonal dysfunction is reversed with SMN repletion particularly when intervention occurs early in development.

Background/purpose To investigate nerve excitability changes in patients with fibromyalgia and the correlation with clinical severity. Methods We enrolled 20 subjects with fibromyalgia and 22 sex and age-matched healthy subjects to receive nerve excitability test and nerve conduction study to evaluate the peripheral axonal function. Results In the fibromyalgia cohort, the sensory axonal excitability test revealed increased superexcitability (%) (P = 0.029) compared to healthy control. Correlational study showed a negative correlation between increased subexcitability (%) (r = −0.534, P = 0.022) with fibromyalgia impact questionnaire (FIQ) score. Computer modeling confirmed that the sensory axon excitability pattern we observed in fibromyalgia cohort was best explained by increased Barrett–Barrett conductance, which was thought to be attributed to paranodal fast K+ channel dysfunction. Conclusion The present study revealed that paranodal sensory K+ conductance was altered in patients with fibromyalgia. The altered conductance indicated dysfunction of paranodal fast K+ channels, which is known to be associated with the generation of pain.

Objectives The existing studies based on the rational voter theory analyze voter turnout as the aggregate of individuals' binary choice of to vote or not to vote. However, when people need to travel to vote, the cost associated with different transportation modes directly affects their voting decisions. We thus generalize the rational voter theory by taking an individual's specific choice of transportation mode into account. Methods We show that our proposed discrete choice model can be estimated via the approach of Berry, Levinsohn, and Pakes (1995) (henceforth, BLP). We then use transportation and census data to analyze voters' behavior in Taiwan where absentee voting is not allowed. Results As compared to the observed 30.14 percent turnout rates of travel‐to‐vote electorates in Taiwan's 2014 local elections, the counterfactual simulations herein suggest that the turnout rates would be 61.77 percent if absentee voting were to be allowed. Conclusion The BLP method allows us to estimate a generalized rational voter model accounting for the transportation mode choice.

With the help of metrology, we can identify research hotspots and development trends in dynamic electrocardiography, and thereby provide corresponding reference material to aid further theoretical research.All research data derived from the core collection of Web of Science, and all searches were completed on the same day (February 6, 2022). The obtained data were stored in plain text format and imported into CiteSpace for subsequent analysis. Citation analysis and visualization technology were used to draw a visual map of the research elements, using factors such as annual literature volume, country, journal, author, abstract, keywords, and citation.After screening, 2,937 papers were obtained. Research on ambulatory electrocardiography is increasing worldwide every year. Using research hotspots, keyword-clustering time-zone maps, and high-frequency emerging words, the research in this field was roughly divided into two stages, with 2017 as the divider. The first stage primarily focuses on areas such as atrial fibrillation, stroke, autonomic nerve function, catheter ablation, and T-wave alternation. The second stage saw the focus shift to wearable devices, sudden cardiac death, obstructive sleep apnea, feature extraction, cryptogenic stroke, and similar topics.With the development of various wearable technologies, the daily monitoring of healthy people engaged in sporting activities and the development of innovative analysis algorithms providing more accurate data may represent the hotspots and direction of future research.

ObjectivesTo elucidate the motor unit response to intrathecal nusinersen in children with symptomatic spinal muscular atrophy (SMA) using a novel motor unit number estimation technique.MethodsMScanFit MUNE studies were sequentially undertaken from the abductor pollicis brevis muscle after stimulation of the median nerve in a prospective cohort of symptomatic children with SMA, undergoing intrathecal treatment with nusinersen at a single neuromuscular centre from June 2017 to August 2019. Electrophysiological measures included compound muscle action potential (CMAP), motor unit number estimation (MUNE), motor unit number contributing to 50%–100% of CMAP (N50) and measures of collateral reinnervation including largest single motor unit potential (LSMUP) and amplitude of the smallest unit contributing to N50 (A50).ResultsTwenty children (median age 99 months, range 4–193) were followed for a median of 13.8 (4–33.5) months. Therapeutic intervention was an independent and significant contributor to an increase in CMAP (p = 0.005), MUNE (p = 0.001) and N50 (p = 0.04). The magnitude of this electrophysiological response was increased in children with shorter disease durations (pInterpretationNusinersen therapy facilitated functional innervation in SMA through recovery of smaller motor units. Delineation of biomechanisms of therapeutic response may be the first step in identifying potential novel targets for disease modification in this and other motor neuropathies. MScanFit MUNE techniques may have a broader role in establishing biomarkers of therapeutic response in similar adult-onset diseases.

Peripheral neuropathy is a commonly reported adverse effect of oxaliplatin treatment, representing a significant limitation which may require discontinuation of effective therapy. The present study investigated the neuroprotective potential of riluzole in patients undergoing oxaliplatin treatment in a randomised-controlled trial comparing riluzole and placebo-control. Fifty-two patients (17 females, 58.1 ± 12.7 years) receiving oxaliplatin treatment were randomised into either a treatment (50 mg riluzole) or lactose placebo group. The primary outcome measure was the total neuropathy score-reduced (TNSr). Secondary outcome measures include nerve excitability measures, 9-hole pegboard and FACT-GOG NTX questionnaire. Patients were assessed at baseline, pre-cycle 10 or 12, 4-week and 12-week post-treatment. Both the treatment and placebo groups developed objective and patient reported evidence of neurotoxicity over the course of oxaliplatin treatment, although there were no significant differences across any parameters between the two groups. However, across follow-up assessments, the treatment group experienced greater neuropathy, represented by a higher TNSr score at 4-week post-chemotherapy of 8.3 ± 2.7 compared with 4.6 ± 3.6 (p = 0.032) which was sustained at 12-week post-treatment (p = 0.089). Similarly, patients in the treatment group reported worse symptoms with a FACT-GOG NTX score of 37.4 ± 10.2 compared with 43.3 ± 7.4 (p = 0.02) in the placebo group at 4-week post-treatment. This study is the first to provide an objective clinical investigation of riluzole in oxaliplatin-induced peripheral neuropathy employing both functional and neurophysiological measures. Although the recruitment target was not reached, the results do not show any benefit of riluzole in minimising neuropathy and may suggest that riluzole worsens neuropathy associated with oxaliplatin treatment.

Metabolic syndrome (MS) was conceptualized to identify people at risk for cardiovascular disease and type 2 diabetes; however, the epidemiology of MS and its combinations of components in older adults remains unclear. Data from the Senior Health Examination Program of the New Taipei City Government in Taiwan in 2014 were obtained for this study. All participants aged 65 years or older and those with a prior history of cardiovascular disease, cerebrovascular disease, or diabetes mellitus were excluded. 29,164 senior citizens were retrieved for this study, and 12,331 (41.28%) of the participants were male. Female participants were more likely to have MS (42.7% vs.31.3%, p

Objective The present study investigates the peripheral neuropathy in Primary Sjögren's syndrome (pSS) using the nerve excitability test to further elucidate how peripheral nerves are affected by the autoantibodies. Methods Each patient received clinical evaluation, examination for anti‐SSA/Ro and anti‐SSB/La antibodies titer, paired motor and sensory nerve excitability test, thermal quantitative sensory test (QST), and nerve conduction study (NCS). Results A total of 40 pSS patients wasenrolled. Motor axonal study of the pSS with positive anti‐SSA/Ro or anti‐SSB/La antibodies (n = 28) was found to have increased stimulus for 50% compound muscle action potential (CMAP) (P

International guidelines have promoted palliative care (PC) for stroke survivors, but definition and implementation have been less than ideal. This practice gap is more prominent in China, where discussion of death remains taboo.The aim of this study was to explore the perspectives of PC among caregivers of hospitalized patients with stroke.A descriptive qualitative study design was used. Seventeen in-depth interviews with bedside caregivers in a first-rank tertiary hospital (general hospital with bed capacity exceeding 500) in China were analyzed thematically."Promoting comfort" stands at the core of PC and was operationalized by "meeting physical care needs," "ensuring communication," "providing psychoemotional care," "providing cognitive stimulation," and "avoiding discussion on death and dying." Caregivers who took care of older adults for a long time have described the use of "cognitive stimulation" to promote patients' positive emotional and cognitive reactions. All interviewees avoided mentioning "death" to protect patients' feelings, because they believed discussion of death was hurtful.The high care demand for patients with stroke is a defining feature of stroke PC and should be recognized in addition to its prognosis estimation to promote this concept. The healthcare system should integrate PC as part of the regular service for patients with severe stroke to shift the focus of care from survival to promotion of comfort. A discussion of the dying process requires sensitivity and should be approached in a discussion of advanced PC planning, which views death as a meaningful transition.

International audience; High-βθe (a ratio of the electron thermal pressure to the poloidal magnetic pressure) steady-state long-pulse plasmas with steep central electron temperature gradient are achieved in the Experimental Advanced Superconducting Tokamak. An intrinsic current is observed to be modulated by turbulence driven by the electron temperature gradient. This turbulent current is generated in the countercurrent direction and can reach a maximum ratio of 25% of the bootstrap current. Gyrokinetic simulations and experimental observations indicate that the turbulence is the electron temperature gradient mode (ETG). The dominant mechanism for the turbulent current generation is due to the divergence of ETG-driven residual flux of current. Good agreement has been found between experiments and theory for the critical value of the electron temperature gradient triggering ETG and for the level of the turbulent current. The maximum values of turbulent current and electron temperature gradient lead to the destabilization of an m/n =1/1 kink mode, which by counteraction reduces the turbulence level (m and n are the poloidal and toroidal mode number, respectively). These observations suggest that the self-regulation system including turbulence, turbulent current, and kink mode is a contributing mechanism for sustaining the steady-state long-pulse high-βθe regime

Background The use of masks is an effective measure to prevent severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) infection; however, mask reuse is not recommended. Studies examining the factors associated with mask reuse during the coronavirus disease (COVID-19) pandemic are limited. This nationwide survey aimed to determine the prevalence and factors associated with mask reuse among Taiwanese citizens during the pandemic. Methods From May 18 through May 31, 2020, a computer-assisted telephone interview system was used to randomly select Taiwanese citizens who were interviewed for COVID-19 preventive behaviors and knowledge on the usage of masks. Multivariate logistic regression was used to identify factors associated with mask reuse during the COVID-19 pandemic. Moreover, generalized estimating equations (GEE) were used to analyze the rate of mask reuse among participants before and during the pandemic. Results For a total of 1,075 participants, the overall mean age was 57.4 years, and 82.2% of participants reported mask reuse during the COVID-19 pandemic. After controlling for other covariates, participants who had a greater knowledge on mask usage or had a high supply of masks were less likely to reuse masks during the pandemic. GEE analysis showed that compared with the participants' mask wearing behaviors before the COVID-19 pandemic, they were more likely to reuse masks during the pandemic. Conclusions The rate of mask reuse among the general population during the pandemic was significantly higher than that before the pandemic. Individuals were less likely to reuse masks if they had adequate knowledge on mask usage or had a high supply of masks. Since mask reuse is associated with a higher risk of COVID-19 due to the possibility of wearing SAS-CoV-2-contaminated masks, it is imperative to educate people on the correct usage of masks. Further, the government should provide sufficient masks to the general population to decrease the reuse of masks. Key messages Mask reuse increased during the COVID-19 pandemic due to the shortage in supply. It is imperative to educate people about the correct usage of masks.

Introduction: A spectrum of non-motor manifestations in amyotrophic lateral sclerosis (ALS) patients has been increasingly recognized, with cognitive and behavioral impairments the most prominent. Evidence suggests that ALS overlaps on a pathological, genetic, and clinical level with frontotemporal dementia (FTD), thereby suggesting a frontotemporal spectrum disorder (ALS-FTSD). Cognitive impairment has been reported in up to 75% of ALS patients, whilst the rate of behavioral dysfunction ranges up to 50%.Areas covered: The present review explores the current understanding of cognitive and behavioral changes in ALS with a particular emphasis on its implications on prognosis and survival.Expert commentary: Further longitudinal studies are needed to clarify the evolution of cognitive impairment in ALS and how this may ultimately influence survival. Improving understanding of cognitive changes has important implications toward the capacity of patients in making critical medical decisions. There is a need to develop a universally accepted and validated cognitive assessment tool to be administered in a multidisciplinary clinic that is efficient and sensitive, as well as being integrated into the design and analysis of future ALS drug trials. In addition, revision of the ALS diagnostic criteria is critically needed that should accommodate cognitive and behavioral symptoms in addition to motor manifestations.

Temperature resulting from the joule heating power and the turn-on and turn-off dissipation of high-power, high-frequency applications is the root cause of their thermal instability, electrical performance degradation, and even thermal-fatigue failure. Thus, the study presents thermal and electrical characterizations of the power MOSFET module packaged in SOT-227 under natural convection and forced convection through three-dimensional (3D) thermal-electric (TE) coupled field analysis. In addition, the influences of some key parameters like electric loads, ambient conditions, thermal management considerations (heat sink, heat spreader) and operation conditions (duty cycle and switching frequency) on the power loss and thermal performance of the power module are addressed. The study starts from a suitable estimation of the power losses, where the conduction losses are calculated using the temperature- and gate-voltage-dependent on-state resistance and drain current through the device, and the switching losses are predicted based on the ideal switching waveforms of the power MOSFETs applied. The effectiveness of the theoretical predictions in terms of device’s power losses and temperatures is demonstrated through comparison with the results of circuit simulation and thermal experiment.

The osseointegration of metallic implants is reliant on a cascade of molecular interactions and the delivery of macromolecules to the implant environment that occurs before substantial bone formation. Early blood vessel formation is a requisite first step in the healing timeline for osteoid formation, where vascular development can be accelerated as a result of controlled hypoxic conditioning. In this study, alginate-derived xerogel films containing varied concentrations of disodium succinate salt which has been shown to induce pseudohypoxia (short-term hypoxic effects while maintaining an oxygenated environment) were developed. Xerogels were characterized for their morphology, succinate release over time and cellular response with osteoblast-mimicking Saos-2 and human umbilical vein endothelial cells (HUVEC). Scanning electron microscopy revealed a multiscale topography that may favour osseointegration and alamarBlue assays indicated no cytotoxic effects during in vitro proliferation of Saos-2 cells. pH measurements of eluted succinate reach 95 % of peak value after 7 h of immersion for all gels containing 10 mM of succinate or less, and 60 % within the first 40 min. In vitro exposure of HUVECs to succinate-conditioned media increased the net concentration of total proteins measured by bicinchoninic acid (BCA) assay and maintains stable vascular endothelial growth factor (VEGF) and extracellular platelet-derived growth factor (PDGF) for vessel formation through comparison of enzyme-linked immunosorbent assays (ELISAs) of the culture media and cell lysate. Tube formation assays also showed a sustained increase in tube diameter across the first 48 h of HUVEC culture when succinate concentrations of 1 and 10 μM in the xerogel. Overall, the succinate-alginate films serve as a prospective organic coating for bone-interfacing implant materials which may induce temporary pseudohypoxic conditions favourable for early angiogenesis and bone regeneration in vivo at succinate concentrations of 1 or 10 μM.

Organ-on-a-chip systems that recapitulate tissue-level functions have been proposed to improve in vitro–in vivo correlation in drug development. Significant progress has been made to control the cellular microenvironment with mechanical stimulation and fluid flow. However, it has been challenging to introduce complex 3D tissue structures due to the physical constraints of microfluidic channels or membranes in organ-on-a-chip systems. Although this problem could be addressed with the integration of 3D bioprinting, it is not an easy task because the two technologies have fundamentally different fabrication processes. Inspired by 4D bioprinting, we develop a 4D subtractive manufacturing technique where a flexible sacrificial material can be patterned on a 2D surface, change shape when exposed to aqueous hydrogel, and subsequently degrade to produce perfusable networks in a natural hydrogel matrix that can be populated with cells. The technique is applied to fabricate organ-specific vascular networks, vascularized kidney proximal tubules, and terminal lung alveoli in a customized 384-well plate and then further scaled to a 24-well plate format to make a large vascular network, vascularized liver tissues, and for integration with ultrasound imaging. This biofabrication method eliminates the physical constraints in organ-on-a-chip systems to incorporate complex ready-to-perfuse tissue structures in an open-well design.

Objective Gene silencing treatments for hereditary transthyretin amyloidosis (ATTRv) have recently been developed with dramatic improvements observed in patient outcomes. However, the optimal time to initiate treatment is not yet known. The aim of this study is to explore the pathophysiological progression of neuropathic features of ATTRv using nerve excitability and motor unit number estimation. Methods We prospectively recruited 14 symptomatic patients and 7 asymptomatic carriers and with varied TTR mutations and compared these to 21 healthy controls. Nerve excitability properties of ulnar motor and sensory axons, and ulnar-ADM motor unit number estimation was collected. Results ‘Fanning in’ of threshold electrotonus was observed in the motor axons of symptomatic ATTRv patients, suggestive of membrane depolarisation. Motor unit number estimation demonstrated a significant reduction in mean unit number between symptomatic and asymptomatic ATTRv patients (p =0.04), with declines seen according to FAP stage and PND score. Significantly increased hyperpolarising current/threshold gradients were seen in sensory axons between symptomatic ATTRv patients and healthy controls (p=0.002), suggesting that upregulation of inwardly rectifying conductance may underlie sensory symptoms and neuropathic pain in ATTRv amyloidosis. Conclusions These findings suggest that ulnar nerve excitability and motor unit number estimation could be used as a tool to identify early nerve disease in ATTRv and monitor progression.

Vasculature is a key component of many biological tissues and helps to regulate a wide range of biological processes. Modeling vascular networks or the vascular interface in organ-on-a-chip systems is an essential aspect of this technology. In many organ-on-a-chip devices, however, the engineered vasculatures are usually designed to be encapsulated inside closed microfluidic channels, making it difficult to physically access or extract the tissues for downstream applications and analysis. One unexploited benefit of tissue extraction is the potential of vascularizing, perfusing, and maturing the tissue in well-controlled, organ-on-a-chip microenvironments and then subsequently extracting that product for in vivo therapeutic implantation. Moreover, for both modeling and therapeutic applications, the scalability of the tissue production process is important. Here we demonstrate the scalable production of perfusable and extractable vascularized tissues in an "open-top" 384-well plate (referred to as IFlowPlate), showing that this system could be used to examine nanoparticle delivery to targeted tissues through the microvascular network and to model vascular angiogenesis. Furthermore, tissue spheroids, such as hepatic spheroids, can be vascularized in a scalable manner and then subsequently extracted for in vivo implantation. This simple multiple-well plate platform could not only improve the experimental throughputs of organ-on-a-chip systems but could potentially help expand the application of model systems to regenerative therapy.

Background Despite the importance of tumor-infiltrating T lymphocytes (TILs) in cancer biology, the relationship between TIL phenotypes and their prognostic relevance for localized non-small-cell lung cancer (NSCLC) has not been well established. Patients and methods Fresh tumor and normal adjacent tissue was prospectively collected from 150 patients with localized NSCLC. Tissue was comprehensively characterized by high-dimensional flow cytometry of TILs integrated with immunogenomic data from multiplex immunofluorescence, T-cell receptor sequencing, exome sequencing, RNA sequencing, targeted proteomics, and clinicopathologic features. Results While neither the magnitude of TIL infiltration nor specific TIL subsets were significantly prognostic alone, the integration of high-dimensional flow cytometry data identified two major immunotypes (IM1 and IM2) that were predictive of recurrence-free survival independent of clinical characteristics. IM2 was associated with poor prognosis and characterized by the presence of proliferating TILs expressing cluster of differentiation 103, programmed cell death protein 1, T-cell immunoglobulin and mucin-domain containing protein 3, and inducible T-cell costimulator. Conversely, IM1 was associated with good prognosis and differentiated by an abundance of CD8+ T cells expressing cytolytic enzymes, CD4+ T cells lacking the expression of inhibitory receptors, and increased levels of B-cell infiltrates and tertiary lymphoid structures. While increased B-cell infiltration was associated with good prognosis, the best prognosis was observed in patients with tumors exhibiting high levels of both B cells and T cells. These findings were validated in patient tumors from The Cancer Genome Atlas. Conclusions Our study suggests that although the number of infiltrating T cells is not associated with patient survival, the nature of the infiltrating T cells, resolved in distinct TIL immunotypes, is prognostically relevant in NSCLC and may inform therapeutic approaches to clinical care.

Three-dimensional (3D) tissue models such as epithelial spheroids or organoids have become popular for pre-clinical drug studies. However, different from 2D monolayer culture, the characterization of 3D tissue models from non-invasive brightfield images is a significant challenge. To address this issue, here we report a Deep-Learning Uncovered Measurement of Epithelial Networks (Deep-LUMEN) assay. Deep-LUMEN is an object detection algorithm that has been fine-tuned to automatically uncover subtle differences in epithelial spheroid morphology from brightfield images. This algorithm can track changes in the luminal structure of tissue spheroids and distinguish between polarized and non-polarized lung epithelial spheroids. The Deep-LUMEN assay was validated by screening for changes in spheroid epithelial architecture in response to different extracellular matrices and drug treatments. Specifically, we found the dose-dependent toxicity of Cyclosporin can be underestimated if the effect of the drug on tissue morphology is not considered. Hence, Deep-LUMEN could be used to assess drug effects and capture morphological changes in 3D spheroid models in a non-invasive manner.Significance of the workDeep learning has been applied for the first time to autonomously detect subtle morphological changes in 3D multi-cellular spheroids, such as spheroid polarity, from brightfield images in a label-free manner. The technique has been validated by detecting changes in spheroid morphology in response to changes in extracellular matrices and drug treatments.

Evaluate management of challenging malocclusions conservatively (no extractions or orthognathic surgery). Most malocclusions have a predominately environmental etiology. Optimal esthetics and function are restored by aligning the dentition over the apical base of bone at the appropriate vertical dimension of occlusion (VDO). Extra-alveolar (E-A) anchorage is achieved at three intraoral sites: mandibular buccal shelf (MBS), infrazygomatic crest (IZC), and anterior ramus. MBS and IZC bone screws effectively anchor the conservative correction of severe dental and skeletal malocclusions. All bone screw sites are effective for anchoring lever arms to recover impacted teeth. Rather than extracting teeth, E-A anchorage corrects crowding by retracting the posterior segments to increase arch length. Skeletal malocclusion is corrected by aligning teeth over the apical base of bone and restoring the VDO by retracting and posteriorly rotating the dental arches as segments. Challenging dental and skeletal malocclusions can be treated routinely via determinate mechanics anchored with E-A bone screws.

Background For patients who have acute promyelocytic leukemia (APL) in second complete remission (CR2), optimal postremission strategies remain undefined. Methods The role of an oral arsenic trioxide (As2 O3 )-based regimen in the management of patients who had APL in CR2 was examined. Results Seventy-three patients with APL in first relapse (R1) were studied. Oral As2 O3 -based reinduction resulted uniformly in CR2, irrespective of previous As2 O3 exposure. All patients received oral As2 O3 -based maintenance in CR2. At a median follow-up of 94 months (range, 9-205 months), 43 patients (58.9%) were still in CR2, and 49 (67.1%) had finished the planned 2-year CR2 maintenance with all-trans retinoic acid, oral As2 O3 , and ascorbic acid. Reinduction and maintenance treatments were well tolerated. Grade 1 and 2 headache occurred in 20 patients (27.4%). Hepatotoxicity, all in the form of transaminitis, occurred in 35 patients (47.9%; grade 1 and 2, n = 26; grade 3 and 4, n = 9). Three patients had self-limiting QTc prolongation. The 10-year leukemia-free survival rate was 56.8%. Thirty patients developed R2. Oral As2 O3 -based reinduction led to CR3 in 27 patients (90%). Post-CR3 strategies included autologous hematopoietic stem cell transplantation and oral As2 O3 maintenance. At a post-CR3 follow-up of 30 months (range, 3-166 months), 11 patients were still in CR3. The 5-year and 10-year overall survival rates in the R1 cohort were 79.5% and 67.3%, respectively. Prior receipt of oral As2 O3 maintenance in CR1 was the only risk factor for inferior leukemia-free survival. Central nervous system involvement occurred in 15 patients, including 5 who remained alive. Relapse during oral As2 O3 therapy was the only significant risk factor for central nervous system involvement. Conclusions For patients with relapsed APL, As2 O3 remained effective despite repeated As2 O3 exposures. Oral As2 O3 maintenance was an effective postremission strategy for CR2. Cancer 2018;124:2316-26. © 2018 American Cancer Society.

Summary: A thorough understanding of cellular development is incumbent on assessing the complexities of fate and kinetics of individual clones within a population. Here, we develop a system for robust periodical assessment of lineage outputs of thousands of transient clones and establishment of bona fide cellular trajectories. We appraise the development of dendritic cells (DCs) in fms-like tyrosine kinase 3 ligand culture from barcode-labeled hematopoietic stem and progenitor cells (HSPCs) by serially measuring barcode signatures and visualize these multidimensional data using developmental interpolated t-distributed stochastic neighborhood embedding (DiSNE) time-lapse movies. We identify multiple cellular trajectories of DC development that are characterized by distinct fate bias and expansion kinetics and determine that these are intrinsically programmed. We demonstrate that conventional DC and plasmacytoid DC trajectories are largely separated already at the HSPC stage. This framework allows systematic evaluation of clonal dynamics and can be applied to other steady-state or perturbed developmental systems. : Lin et al. develop a framework to longitudinally track and visualize clonal cellular trajectories during dendritic cell development. The authors demonstrate that properties including fate bias and the timing and size of clonal bursts are heterogeneous within populations yet largely imprinted in single progenitors at early developmental stages. Keywords: dendritic cells, hematopoiesis, single cell, cellular barcoding, t-SNE, DiSNE, lineage, fate, kinetics, cellular trajectory

Correction for ‘Deep-LUMEN assay – human lung epithelial spheroid classification from brightfield images using deep learning’ by Lyan Abdul et al., Lab Chip, 2020, DOI: 10.1039/d0lc01010c.

INTRODUCTION Given recent findings of subclinical sensory deficits in colorectal cancer patients before oxaliplatin treatment, in the current study we aimed to identify evidence of subclinical peripheral neuropathy on multimodal testing before chemotherapy commencement. METHODS Clinical, functional, and neurophysiological assessments were undertaken in 93 colorectal cancer patients before chemotherapy. RESULTS There was no neurophysiological evidence of neuropathy, with 92 of 93 sural sensory values within normative reference values for age and no significant abnormalities detected in nerve conduction or nerve excitability studies. Clinical neurological assessment revealed 75.9% of patients with no signs or symptoms, 10.3% with reduction in distal vibration or pinprick sensitivity, and 6.9% with reduction in ankle reflexes only. There was no difference in manual dexterity (using the 9-hole peg-board test) compared with normative data. DISCUSSION The present study has established a low likelihood of significant distal symmetrical polyneuropathy in colorectal cancer patients before initiation of chemotherapy. Muscle Nerve 57: 615-621, 2018.

In the present study, the curing of brominated polyisobutylene-co-p-methylstyrene (BIMS) using OO-tert-Butyl O-2-(ethylhexyl) monoperoxycarbonate (TBEC) was prepared for low gas permeability applications, and were evaluated in the presence of various coagents. The amount of the coagent used in curing the butyl rubber directly affected rheometric and mechanical properties of the final product. BIMS was found curable by TBEC in the presence of N,N’-m-phenylenedimaleimide (MP) and the crosslinking density (v) were positively correlated to MP content. The mechanical strength and gas barrier properties were also improved upon the increased crosslinking density in BIMS. The peroxide based cured BIMS materials were demonstrated as improved gas barrier properties than the sulfur cured one. Hence, the development of peroxide based vulcanisation may offer an alternative method for the processing of low gas permeability of BIMS.

Peripheral immunity plays a key role in maintaining homeostasis and conferring crucial neuroprotective effects on the injured nervous system, while at the same time may contribute to increased vulnerability to neuropathic pain. Little is known about the reciprocal relationship between entrapment neuropathy and peripheral immunity. This study investigated immune profile in patients with carpal tunnel syndrome (CTS), the most prevalent entrapment neuropathy. All patients exhibited neurophysiological abnormalities in the median nerve, with the majority reporting neuropathic pain symptoms. We found a significant increase in serum CCL5, CXCL8, CXCL10 and VEGF, and in CD4+ central and effector memory T cells in CTS patients, as compared to healthy controls. CCL5 and VEGF were identified as having the highest power to discriminate between patients and controls. Interestingly, and contrary to the prevailing view of CCL5 as a pro-nociceptive factor, the level of circulating CCL5 was inversely correlated with neuropathic pain intensity and median nerve motor latency. In contrast, the level of central memory T cells was positively associated with abnormal neurophysiological findings. These results suggest that entrapment neuropathy is associated with adaptive changes in the homeostasis of memory T cells and an increase in systemic inflammatory modulating cytokines/chemokines, which potentially regulate neuropathic symptoms.

Peripheral neuropathy is a commonly reported adverse effect of oxaliplatin treatment, representing a significant limitation which may require discontinuation of effective therapy. The present study investigated the neuroprotective potential of riluzole in patients undergoing oxaliplatin treatment in a randomised-controlled trial comparing riluzole and placebo-control.Fifty-two patients (17 females, 58.1 ± 12.7 years) receiving oxaliplatin treatment were randomised into either a treatment (50 mg riluzole) or lactose placebo group. The primary outcome measure was the total neuropathy score-reduced (TNSr). Secondary outcome measures include nerve excitability measures, 9-hole pegboard and FACT-GOG NTX questionnaire. Patients were assessed at baseline, pre-cycle 10 or 12, 4-week and 12-week post-treatment.Both the treatment and placebo groups developed objective and patient reported evidence of neurotoxicity over the course of oxaliplatin treatment, although there were no significant differences across any parameters between the two groups. However, across follow-up assessments, the treatment group experienced greater neuropathy, represented by a higher TNSr score at 4-week post-chemotherapy of 8.3 ± 2.7 compared with 4.6 ± 3.6 (p = 0.032) which was sustained at 12-week post-treatment (p = 0.089). Similarly, patients in the treatment group reported worse symptoms with a FACT-GOG NTX score of 37.4 ± 10.2 compared with 43.3 ± 7.4 (p = 0.02) in the placebo group at 4-week post-treatment.This study is the first to provide an objective clinical investigation of riluzole in oxaliplatin-induced peripheral neuropathy employing both functional and neurophysiological measures. Although the recruitment target was not reached, the results do not show any benefit of riluzole in minimising neuropathy and may suggest that riluzole worsens neuropathy associated with oxaliplatin treatment.

Objective Air pollution had been reported to be associated with the reproductive health of women. However, the association of particulate matter (PM) and acid gases air pollution with premenstrual syndrome (PMS) warrants investigation. This study investigated the effects of air pollution on PMS risk. Population We combined data from the Taiwan Air Quality-Monitoring Database and the Longitudinal Health Insurance Database. In total, an observational cohort of 85 078 Taiwanese women not diagnosed as having PMS. Methods Air pollutant concentrations were grouped into four levels based on the concentration quartiles of several types of air pollutants. Main outcome measures We then applied univariable and multivariable Cox proportional hazard regression models to assess PMS risk in association with each pollutant type. Results Women exposed to Q4-level SO2 exhibited a 7.77 times higher PMS risk compared with those to Q1-level SO2 (95% confidence interval [CI] = 6.22–9.71). Women exposed to Q4-level NOx exhibited a 2.86 times higher PMS risk compared with those exposed to Q1-level NOx (95% CI = 2.39–3.43). Women exposed to Q4-level NO exhibited a 3.17 times higher PMS risk compared with women exposed to Q1-level NO (95% CI = 2.68–3.75). Finally, women exposed to Q4-level PM with a ≤2.5-µm diameter (PM2.5) exhibited a 3.41 times higher PMS risk compared with those exposed to Q1-level PM2.5 (95% CI = 2.88–4.04). Conclusions High incidences of PMS were noted in women who lived in areas with higher concentrations of SO2, NOx, NO, NO2 and PM2.5.

Understanding of maturational properties of sensory and motor axons is of central importance for determining the impact of nerve changes in health and in disease in children and young adults.This study investigated maturation of sensory axons using axonal excitability parameters of the median nerve in 47 children, adolescents and young adults (25 males, 22 females; age range 1-25 years) and compared them to concurrent motor studies.The overall pattern of sensory maturation was similar to motor maturation demonstrating prolongation of the strength duration time constant (P 0.001), reduction of hyperpolarising threshold electrotonus (P = 0.002), prolongation of accommodation half-time (P = 0.005), reduction in hyperpolarising current-threshold slope (P = 0.03), and a shift to the right of the refractory cycle curve (P 0.001), reflecting changes in passive membrane properties and fast potassium channel conductances. Sensory axons, however, had a greater increase in strength duration time constant and more attenuated changes in depolarising threshold electrotonus and current-threshold parameters, attributable to a more depolarised resting membrane potential evident from early childhood and maintained in adults. Peak amplitude was established early in sensory axons whereas motor amplitude increased with age (P 0.001), reflecting non-axonal motor unit changes.Maturational trajectories of sensory and motor axons were broadly parallel in children and young adults, but sensory-motor differences were initiated early in maturation.Identifying the evolution of biophysical changes within and between sensory and motor axons through childhood and adolescence is fundamental to understanding developmental physiology and interpreting disease-related changes in immature nerves.

Recent unprecedented advances in treatment for spinal muscular atrophy (SMA) enabled patients to access the first approved disease modifying therapy for the condition. There are however many uncertainties, regarding timing of treatment initiation, response to intervention, treatment effects and long-term outcomes, which are complicated by the evolving phenotypes seen in the post-treatment era for patients with SMA. Biomarkers of disease, with diagnostic, prognostic, predictive, and pharmacodynamic value are thus urgently required, to facilitate a wider understanding in this dynamic landscape. A spectrum of these candidate biomarkers, will be evaluated in this review, including genetic, epigenetic, proteomic, electrophysiological, and imaging measures. Of these, SMN2 appears to be the most significant modifier of phenotype to date, and its use in prognostication shows considerable clinical utility. Longitudinal studies in patients with SMA highlight an emerging role of circulatory markers such as neurofilament, in tracking disease progression and response to treatment. Furthermore, neurophysiological biomarkers such as CMAP and MUNE values show considerable promise in the real word setting, in following the dynamic response and output of the motor unit to therapeutic intervention. The specific value for these possible biomarkers across diagnosis, prognosis, prediction of treatment response, efficacy, and safety will be central to guide future patient-targeted treatments, the design of clinical trials, and understanding of the pathophysiological mechanisms of disease and intervention.

Breast cancer, especially triple-negative breast cancer, is one of the deadliest cancers in women. To date, there is a lack of a good therapeutic regimen for it. PPARγ has been reported to be a tumor suppressor and could be activated by many agonists involved in cancer inhibition. Therefore, the expression of PPARγ in breast cancer was analyzed by online software UALCAN whose data were from the TCGA database. The results revealed that the PPARγ expression was reduced in breast cancer tissues. Furthermore, the methylation in the PPARγ promoter was also assayed and the results indicated that the methylation level in the PPARγ promoter in breast cancer tissue was higher than that in normal tissue. In order to verify the methylation in promoter involved in the regulation of gene PPARγ expression, the 5'-Aza and fluorescence assays were performed and the results proved that methylation in promoter participated in gene PPARγ expression regulation. Pioglitazone, a PPARγ agonist, still was not investigated in breast cancer. Therefore, the effects of pioglitazone on breast cancer cells were tested by cell viability, scratch and transwell assays, and results indicated that the pioglitazone has the inhibition effect on the proliferation and migration of breast cancer cells by PPARγ which was correlated with the JAK2/STAT3 pathway. In order to further confirm the inhibition effect of pioglitazone on breast cancer in vivo, the nude mice model was administrated by gavage with pioglitazone. And the results indicated that pioglitazone could inhibit the growth of breast cancer in the PPARγ overexpression group in vivo. In summary, the expression of gene PPARγ was decreased in breast cancer tissues, which was correlated with its methylation in the promoter region. Moreover, pioglitazone could exert its inhibition on breast cancer proliferation and migration by the JAK2/STAT3 pathway.

Aims/Introduction To elucidate whether axonal changes arise in the prediabetic state and to find a biomarker for early detection of neurophysiological changes. Materials and Methods We enrolled asymptomatic diabetes patients, as well as prediabetic and normoglycemic individuals to test sensory nerve excitability, and we analyzed those findings and their correlation with clinical profiles. Results In nerve excitability tests, superexcitability in the recovery cycle showed increasing changes in the normoglycemic, prediabetes and diabetes cohorts (−19.09 ± 4.56% in normoglycemia, −22.39 ± 3.16% in prediabetes and −23.71 ± 5.15% in diabetes, P = 0.002). Relatively prolonged distal sensory latency was observed in the median nerve (3.12 ± 0.29 ms in normoglycemia, 3.23 ± 0.38 ms in prediabetes and 3.45 ± 0.43 ms in diabetes, P = 0.019). Superexcitability was positively correlated with fasting plasma glucose (r = 0.291, P = 0.009) and glycated hemoglobin (r = 0.331, P = 0.003) in all participants. Conclusions Sensory superexcitability and latencies are the most sensitive parameters for detecting preclinical physiological dysfunction in prediabetes. In addition, changes in favor of superexcitability were positively correlated with glycated hemoglobin for all participants. These results suggest that early axonal changes start in the prediabetic stage, and that the monitoring strategy for polyneuropathy should start as early as prediabetes., We explored early changes of axonal function in prediabetes using axonal excitability test. The changes progressed from normoglycemia, prediabetes and early diabetes. Superexcitability is the most sensitive parameter for sensory axonal dysfunction. Fasting sugar and glycated hemoglobin were correlated with superexcitability in all participants.

This study aimed to investigate the mechanism underlying the inhibitory effect of tumor suppressor gene miR-186 and zinc finger protein 545 (ZNF545) on the proliferation of multiple myeloma (MM) cells. CD138 magnetic beads were used to isolate different types of myeloma cell lines (KM3, U266, RPMI-8226, and H929), which were then infected by lentivirus carrying the miR-186 gene. Using uninfected myeloma cells as the control, MTT [3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide, Thiazolyl Blue Tetrazolium Bromide] assay was performed to calculate the rate of cell proliferation at different time points. In addition, the correlation between the expression of Jagged 1 and miR-186 was analyzed by real-time Polymerase Chain Reaction (PCR). Furthermore, the effect of 5-Aza-2-deoxycytidine and acetylase inhibitor Trichomycin A (TSA) on the expression of ZNF545 and proliferation/apoptosis of MM cells was investigated using Reverse Transcription-Polymerase Chain Reaction (RT-PCR), Western blotting (WB), MTS [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium] cell proliferation assay, and Annexin V-FITC/PI staining. Compared with the control group, the proliferation of miR-186-overexpressing U266 and RPMI-8226 cells was significantly decreased. In cell cloning experiments, miR-186 decreased the number of U266 and RPMI-8226 clones while reducing the protein expression of Jagged 1. The expression level of ZNF545 in myeloma patients was also reduced to some extent. ZNF545 protein also promoted the apoptosis of myeloma cells. By inhibiting the proliferation of myeloma cells, miR-186 gene and ZNF protein may be used as tumor suppressors in the treatment of myeloma.

Stent grafts are medical devices used to treat abdominal aortic aneurysms (AAAs) in endovascular aneurysm repair (EVAR). Computational and experimental models have been developed to study stent graft delivery and deployment during EVAR; however, frictional properties have not been taken into account in most previous studies. The objective of this study was to determine the coefficients of friction of three commercially available stent grafts (Cook Zenith, Medtronic Endurant, and Vascutek Anaconda), their delivery sheaths, a porcine aorta, and two mock arterial materials. Stent grafts were obtained and separated into stents, graft fabric, and sheaths. Using a custom-made friction measurement apparatus, the coefficients of friction were measured between five material pairs: (i) the stents and inner surface of the sheath, (ii) the graft fabric and inner surface of the sheath, (iii) the outer surface of the sheath and a porcine aorta, (iv) the outer surface of the sheath and three different polyvinyl alcohol (PVA) cryogels, and (v) the outer surface of the sheath and a polydimethylsiloxane (PDMS) sheet. The results show that the coefficients of friction between the graft fabric and the sheath were higher than those between the stents and the sheath. The PVA cryogels showed more comparable frictional properties to the porcine aorta than did the PDMS sheet, suggesting that PVA cryogels provide a more accurate approximation for the in vivo frictional properties. These results can be used to improve the accuracy of computational models for stent graft delivery and deployment and to select appropriate materials for vascular phantoms.

Diabetes may impair the capacity for neuroplasticity such that patients experience a slower and poorer recovery after stroke. The current study investigated changes in cortical function in stroke patients with diabetes to determine how this comorbidity may affect poststroke cortical plasticity and thereby functional recovery. From a cohort of 57 participants, threshold-tracking transcranial magnetic stimulation was used to assess cortical function over the ipsilateral and contralesional hemispheres in 7 patients with diabetes after an acute stroke compared with 12 stroke patients without diabetes. Cortical function was also assessed in 8 patients with diabetes without stroke and 30 normal control subjects. After acute stroke, short-interval intracortical inhibition (SICI) was reduced over both motor cortices in stroke patients without diabetes compared with normal control patients, while in stroke patients with diabetes, SICI was only reduced over the contralesional but not the ipsilesional cortex compared with control patients with diabetes. In addition, SICI was significantly reduced in the control patients with diabetes compared with normal control patients. These results have demonstrated the absence of ipsilesional cortical excitability change after diabetic strokes, suggesting impaired capacity for neuroplasticity over this hemisphere as a consequence of a “double-hit” phenomenon because of preexisting alterations in cortical function in nonstroke patients with diabetes. The reliance on reorganization over the contralesional cortex after stroke will likely exert influence on poststroke recovery in patients with diabetes.