Divergent Learning-Related Transcriptional States of Cortical Glutamatergic Neurons.

Experience-dependent gene expression reshapes neural circuits, permitting the learning of knowledge and skills. Most learning involves repetitive experiences during which neurons undergo multiple stages of functional and structural plasticity. Currently, the diversity of transcriptional responses underlying dynamic plasticity during repetition-based learning is poorly understood. To close this gap, we analyzed single-nucleus transcriptomes of L2/3 glutamatergic neurons of the primary motor cortex after 3 d motor skill training or home cage control in water-restricted male mice. "Train" and "control" neurons could be discriminated with high accuracy based on expression patterns of many genes, indicating that recent experience leaves a widespread transcriptional signature across L2/3 neurons. These discriminating genes exhibited divergent modes of coregulation, differentiating neurons into discrete clusters of transcriptional states. Several states showed gene expressions associated with activity-dependent plasticity. Some of these states were also prominent in the previously published reference, suggesting that they represent both spontaneous and task-related plasticity events. Markedly, however, two states were unique to our dataset. The first state, further enriched by motor training, showed gene expression suggestive of late-stage plasticity with repeated activation, which is suitable for expected emergent neuronal ensembles that stably retain motor learning. The second state, equally found in both train and control mice, showed elevated levels of metabolic pathways and norepinephrine sensitivity, suggesting a response to common experiences specific to our experimental conditions, such as water restriction or circadian rhythm. Together, we uncovered divergent transcriptional responses across L2/3 neurons, each potentially linked with distinct features of repetition-based motor learning such as plasticity, memory, and motivation.

The impact of Renin-Angiotensin System Inhibitors on bone fracture risk: a nationwide nested case-control study.

BACKGROUND: The therapeutic efficacy of renin-angiotensin system inhibitors (RASi) in elderly patients with hypertension and at risk of fractures has been in the limelight because of accumulating evidence that localized RAS activation in bone tissue leads to osteoclastic bone resorption, resulting in osteoporosis. This study set out to investigate the association between RASi use and fracture incidence in a large cohort. METHODS: We employed a nested case-control design to investigate the association between RASi use and newly developed fractures. A case was defined as a patient newly diagnosed with a fracture between January 2004 and December 2015. We selected 1,049 cases and controls using 1:1 propensity score matching. Conditional logistic regression analysis was conducted to estimate the association between RASi exposure and fracture incidence. RESULTS: Overall, RASi usage was significantly associated with lower odds for fracture incidence (ever-users vs never-users: OR, 0.73; 95% CI, 0.59-0.91). We found that ARB-only users experienced fewer fractures than RASi-never users (OR, 0.65; 95% CI, 0.49-0.86), whereas ACEi-only users or ARB/ACEi-ever users did not. In subgroup analysis, RASi-ever users without cerebrovascular disease, those with a BMI exceeding 23, and statin exposure had significantly lower ORs. CONCLUSIONS: The present study established a significant association between RASi use and reduced fracture incidence, thus highlighting the potential clinical utility of RASi use as a preventive strategy in elderly patients at risk for osteoporotic fractures.

Shewanella goraebulensis sp. nov., isolated from sea water.

A novel Gram-stain-negative, facultatively anaerobic and rod-shaped bacterial strain, designated as DAU312T, was isolated from the sea water of the eastern coast of the Republic of Korea. Optimal growth was observed at 25 °C, pH 7.0-8.0 and with NaCl concentrations of 2.0 % (w/v). Catalase and oxidase activities were detected. On the basis of 16S rRNA gene sequences, strain DAU312T showed the highest similarity (99.2 %) to the type strain Shewanella electrodiphila MAR441T. The complete genome sequence of strain DAU312T contains 4 893 483 bp and 40.5 mol% G+C. Phylogenetic analyses based on 16S rRNA gene sequences and the up-to-date bacterial core genes showed that strain DAU312T, S. electrodiphila MAR441T and S. olleyana were all part of the same monophyletic clade. Their average nucleotide identity, digital DNA-DNA hybridization and two-way average amino acid identity values with each other and type strains of close Shewanella species were 83.4-77.5 %, 27.3-22.0 % and 89.8-81.2 %, respectively. The major cellular fatty acids (>10 %) were iso-C15 : 0, summed feature 3 (C16 : 1 ω7с and/or C16 : 1 ω6с) and C16 : 0. Phosphatidylethanolamine and phosphatidylglycerol were the main polar lipids. The respiratory quinones were Q-7, Q-8, MK-7 and MMK-7. Based on these polyphasic taxonomic findings, the name Shewanella goraebulensis sp. nov. is suggested for strain DAU312T, which is considered to represent a novel species of the genus Shewanella. The type strain is DAU312T (=KCTC 72427 T=JCM 35744T=KCCM 43478T).

Parietal stimulation reverses age-related decline in exploration, learning, and decision-making.

Aging can compromise decision-making and learning, potentially due to reduced exploratory behaviors crucial for novel problem-solving. We posit that invigorating exploration could mitigate these declines. Supporting this hypothesis, we found that older mice mirrored human aging, displaying less exploration and learning during decision-making, but optogenetic stimulation of their posterior parietal cortex boosted initial exploration, subsequently improving learning. Thus, enhancing exploration-driven learning could be a key to countering cognitive aging.

Stocking-only versus additional eccentric compression after below-the-knee truncal vein sclerotherapy: A SOVAECS prospective randomized within-person trial.

OBJECTIVE: After foam sclerotherapy in the truncal saphenous vein, the clinical effects of additional eccentric compression has not yet been explored. METHODS: Between April 2020 and February 2021, we enrolled 42 patients (84 limbs) who underwent bilateral endovenous combined therapy for great saphenous vein (GSV) reflux. Each patient received the same type of endovenous ablation in both above-the-knee GSVs (laser, radiofrequency, cyanoacrylate glue), and combined foam sclerotherapy was performed on both below-the-knee GSVs. Subsequently, we conducted a prospective randomized, single-blind, within-person study in which each patient's bilateral truncal saphenous vein of the calves underwent two different compression therapies: wearing of a regular class II compression stocking on one side (RC group) and additional eccentric compression on the other side (AC group). The primary end point was the occlusion range (score, 0-10) of the below-the-knee truncal GSV after foam sclerotherapy. The secondary outcomes were the pain score (visual analog scale score range, 0-10) of the paired limb, the required number of additional foam sclerotherapy sessions, compliance with compression therapy, and procedure-related complications. RESULTS: For the above-the-knee GSV, endovenous laser treatment (n = 44), endovenous radiofrequency ablation (n = 14), and endovenous cyanoacrylate glue ablation (n = 26) were performed. The mean subcompression pressure of the medial calf in the supine and standing positions were 16.7 ± 2.34 mm Hg and 24.5 ± 6.6 mm Hg in the RC group and 38.5 ± 5.5 mm Hg and 45.3 ± 8.2 mm Hg in the AC group, respectively (P = .000). The secondary outcomes of pain score, number of additional foam sclerotherapy sessions, and pigmentation were not significantly different statistically between the two groups. The patient-reported satisfaction scores (range, 0-10) on compression at 24 hours postoperatively were 8.03 ± 1.9 for the AC group and 7.98 ± 1.9 for the RC group (P = .317; Wilcoxon signed ranks test). In both groups, the closure rate of the above-the-knee GSV at 1 month postoperatively was 100%. No procedure-related complications were identified within 1 month postoperatively, including no deep vein thrombosis, numbness, or skin necrosis requiring additional medical attention. CONCLUSIONS: The 24 hours of additional eccentric compression on the truncal GSV compared with the use of a conventional knee-level stocking only did not yield any clinical advantages in terms of the occlusion range, postoperative pain, need for additional sclerotherapy, or skin pigmentation after foam sclerotherapy. The decision on which type of compression therapy to perform after foam sclerotherapy in the truncal vein should be comprehensively determined.

Incidence and Clinical Impact of Endovenous Glue-Induced Hypersensitivity Among Patients Who Underwent Endovenous Cyanoacrylate Ablation Procedures: A Registry-Based Cohort Study.

BACKGROUND: The characteristics of endovenous glue-induced hypersensitivity (EGIH) remain unclear. OBJECTIVE: To assess the clinical impacts on patients with EGIH after endovenous cyanoacrylate-glue ablation (CA). MATERIALS AND METHODS: A prospectively designed endovenous CA-specific registry was created, and a total of 335 limbs from 173 patients who underwent endovenous CA were enrolled for a cohort study. RESULTS: Symptomatic EGIH was observed in 55 (31.8%) patients. Beyond the target vein area, systemic side effects were noted in 5.8% of the treated patients after CA. The median onset time was 13 postoperative days (range: 1-35 days). The median duration was 7 days, but about 10.9% of the affected patients experienced symptoms lasting longer than 4 weeks. In the EGIH and non-EGIH groups, significant improvements in venous clinical severity score and Chronic Venous Insufficiency Quality of Life Questionnaire-14 scores were observed 3 months postoperatively. The development of EGIH did not affect the postoperative patient-reported satisfaction scores ( p = .524). CONCLUSION: EGIH is observed in a substantial proportion of patients. The side effects do not affect the clinical outcomes and patient-reported outcome measures. Further studies are required on the detailed pathogenesis and definition of EGIH.

Prevention, diagnosis, and treatment of opioid use disorder under the supervision of opioid stewardship programs: it's time to act now.

The third opium war may have already started, not only due to illicit opioid trafficking from the Golden Crescent and Golden Triangle on the international front but also through indiscriminate opioid prescription and opioid diversion at home. Opioid use disorder (OUD), among unintentional injuries, has become one of the top 4 causes of death in the United States (U.S.). An OUD is defined as a problematic pattern of opioid use resulting in clinically significant impairment or distress, consisting of 2 or more of 11 problems within 1 year, as described by the Diagnostic and Statistical Manual for Mental Disorders, Fifth Edition. Observation of aberrant behaviors of OUD is also helpful for overworked clinicians. For the prevention of OUD, the Opioid Risk Tool and the Current Opioid Misuse Measure are appropriate screening tests before and during opioid administration, respectively. Treatment of OUD consists of 3 opioid-based U.S. Food and Drug Administration-approved medications, including methadone, buprenorphine, and naltrexone, and non-opioid-based symptomatic medications for reducing opioid withdrawal syndromes, such as α2 agonists, ß-blockers, antidiarrheals, antiemetics, non-steroidal anti-inflammatory drugs, and benzodiazepines. There are at least 6 recommendable guidelines and essential terms related to OUD. Opioid stewardship programs are now critical to promoting appropriate use of opioid medications, improving patient outcomes, and reducing misuse of opioids, influenced by the successful implementation of antimicrobial stewardship programs. Despite the lack of previous motivation, now is the critical time for trying to reduce the risk of OUD.

FARCI: Fast and Robust Connectome Inference.

The inference of neuronal connectome from large-scale neuronal activity recordings, such as two-photon Calcium imaging, represents an active area of research in computational neuroscience. In this work, we developed FARCI (Fast and Robust Connectome Inference), a MATLAB package for neuronal connectome inference from high-dimensional two-photon Calcium fluorescence data. We employed partial correlations as a measure of the functional association strength between pairs of neurons to reconstruct a neuronal connectome. We demonstrated using in silico datasets from the Neural Connectomics Challenge (NCC) and those generated using the state-of-the-art simulator of Neural Anatomy and Optimal Microscopy (NAOMi) that FARCI provides an accurate connectome and its performance is robust to network sizes, missing neurons, and noise levels. Moreover, FARCI is computationally efficient and highly scalable to large networks. In comparison with the best performing connectome inference algorithm in the NCC, Generalized Transfer Entropy (GTE), and Fluorescence Single Neuron and Network Analysis Package (FluoroSNNAP), FARCI produces more accurate networks over different network sizes, while providing significantly better computational speed and scaling.

A Canonical Scheme of Bottom-Up and Top-Down Information Flows in the Frontoparietal Network.

Goal-directed behavior often involves temporal separation and flexible context-dependent association between sensory input and motor output. The control of goal-directed behavior is proposed to lie in the frontoparietal network, but the computational architecture of this network remains elusive. Based on recent rodent studies that measured and manipulated projection neurons in the frontoparietal network together with findings from earlier primate studies, we propose a canonical scheme of information flows in this network. The parietofrontal pathway transmits the spatial information of a sensory stimulus or internal motor bias to drive motor programs in the frontal areas. This pathway might consist of multiple parallel connections, each controlling distinct motor effectors. The frontoparietal pathway sends the spatial information of cognitively processed motor plans through multiple parallel connections. Each of these connections could support distinct spatial functions that use the motor target information, including attention allocation, multi-body part coordination, and forward estimation of movement state (i.e., forward models). The parallel pathways in the frontoparietal network enable dynamic interactions between regions that are tuned for specific goal-directed behaviors. This scheme offers a promising framework within which the computational architecture of the frontoparietal network and the underlying circuit mechanisms can be delineated in a systematic way, providing a holistic understanding of information processing in this network. Clarifying this network may also improve the diagnosis and treatment of behavioral deficits associated with dysfunctional frontoparietal connectivity in various neurological disorders including Alzheimer's disease.

Disengagement of Motor Cortex during Long-Term Learning Tracks the Performance Level of Learned Movements.

Not all movements require the motor cortex for execution. Intriguingly, dependence on motor cortex of a given movement is not fixed, but instead can dynamically change over the course of long-term learning. For instance, rodent forelimb movements that initially require motor cortex can become independent of the motor cortex after an extended period of training. However, it remains unclear whether long-term neural changes rendering the motor cortex dispensable are a simple function of the training length. To address this issue, we trained mice (both male and female) to perform two distinct forelimb movements, forward versus downward reaches with a joystick, concomitantly over several weeks, and then compared the involvement of the motor cortex between the two movements. Most mice achieved different levels of motor performance between the two movements after long-term training. Of the two movements, the one that achieved higher trial-to-trial consistency (i.e., consistent-direction movement) was significantly less affected by inactivation of motor cortex than the other (i.e., variable-direction movement). Two-photon calcium imaging of motor cortical neurons revealed that the consistent-direction movement activates fewer neurons, producing weaker and less consistent population activity than the variable-direction movement. Together, the motor cortex was less engaged and less necessary for learned movements that achieved higher levels of consistency. Thus, the long-term reorganization of neural circuits that frees the motor cortex from the learned movement is not a mere function of training length. Rather, this reorganization tracks the level of motor performance that the animal achieves during training.SIGNIFICANCE STATEMENT Long-term training of a movement reshapes motor circuits, disengaging motor cortex potentially for automatized execution of the learned movement. Acquiring new motor skills often involves learning of multiple movements (e.g., forehand and backhand strokes when learning tennis), but different movements do not always improve at the same time nor reach the same level of proficiency. Here we showed that the involvement of motor cortex after long-term training differs between similar yet distinct movements that reached different levels of expertise. Motor cortex was less engaged and less necessary for the more proficient movement. Thus, disengagement of motor cortex is not a simple function of training time, but instead tracks the level of expertise of a learned movement.

Disengagement of motor cortex from movement control during long-term learning.

Motor learning involves reorganization of the primary motor cortex (M1). However, it remains unclear how the involvement of M1 in movement control changes during long-term learning. To address this, we trained mice in a forelimb-based motor task over months and performed optogenetic inactivation and two-photon calcium imaging in M1 during the long-term training. We found that M1 inactivation impaired the forelimb movements in the early and middle stages, but not in the late stage, indicating that the movements that initially required M1 became independent of M1. As previously shown, M1 population activity became more consistent across trials from the early to middle stage while task performance rapidly improved. However, from the middle to late stage, M1 population activity became again variable despite consistent expert behaviors. This later decline in activity consistency suggests dissociation between M1 and movements. These findings suggest that long-term motor learning can disengage M1 from movement control.

Corticostriatal Flow of Action Selection Bias.

The posterior parietal cortex (PPC) performs many functions, including decision making and movement control. It remains unknown which input and output pathways of PPC support different functions. We addressed this issue in mice, focusing on PPC neurons projecting to the dorsal striatum (PPC-STR) and the posterior secondary motor cortex (PPC-pM2). Projection-specific, retrograde labeling showed that PPC-STR and PPC-pM2 represent largely distinct subpopulations, with PPC-STR receiving stronger inputs from association areas and PPC-pM2 receiving stronger sensorimotor inputs. Two-photon calcium imaging during decision making revealed that the PPC-STR population encodes history-dependent choice bias more strongly than PPC-pM2 or general PPC populations. Furthermore, optogenetic inactivation of PPC-STR neurons or their terminals in STR decreased history-dependent bias, while inactivation of PPC-pM2 neurons altered movement kinematics. Therefore, PPC biases action selection through its STR projection while controlling movements through PPC-pM2 neurons. PPC may support multiple functions through parallel subpopulations, each with distinct input-output connectivity.

Mapping Korean EDI Medical Procedure Code to SNOMED CT.

The Electronic Data Interchange (EDI) medical procedure code is the code used for health insurance claims in Korea. We mapped Korean EDI codes to SNOMED CT to explore the global interoperability of health insurance claims data. We developed rules for mapping based on the mapping guideline provided by SNOMED CT International. The first and second authors mapped 726 EDI codes used to claim reimbursement in five specialty areas to SNOMED CT. Eight subject matter experts reviewed the mapping results. Out of 726 procedure codes, 82.5% were exactly or partially mapped to SNOMED CT. An EDI code was mapped to an average of 2.04 SNOMED CT concepts. Twenty-one attributes were identified in the EDI codes mapped to SNOMED CT concepts. We identified strategies to improve the EDI code in this study. They include introducing hierarchical structures, adding inclusion and exclusion criteria for procedure codes, and improving EDI code labels.

History-based action selection bias in posterior parietal cortex.

Making decisions based on choice-outcome history is a crucial, adaptive ability in life. However, the neural circuit mechanisms underlying history-dependent decision-making are poorly understood. In particular, history-related signals have been found in many brain areas during various decision-making tasks, but the causal involvement of these signals in guiding behavior is unclear. Here we addressed this issue utilizing behavioral modeling, two-photon calcium imaging, and optogenetic inactivation in mice. We report that a subset of neurons in the posterior parietal cortex (PPC) closely reflect the choice-outcome history and history-dependent decision biases, and PPC inactivation diminishes the history dependency of choice. Specifically, many PPC neurons show history- and bias-tuning during the inter-trial intervals (ITI), and history dependency of choice is affected by PPC inactivation during ITI and not during trial. These results indicate that PPC is a critical region mediating the subjective use of history in biasing action selection.

Circuit Mechanisms of Sensorimotor Learning.

The relationship between the brain and the environment is flexible, forming the foundation for our ability to learn. Here we review the current state of our understanding of the modifications in the sensorimotor pathway related to sensorimotor learning. We divide the process into three hierarchical levels with distinct goals: (1) sensory perceptual learning, (2) sensorimotor associative learning, and (3) motor skill learning. Perceptual learning optimizes the representations of important sensory stimuli. Associative learning and the initial phase of motor skill learning are ensured by feedback-based mechanisms that permit trial-and-error learning. The later phase of motor skill learning may primarily involve feedback-independent mechanisms operating under the classic Hebbian rule. With these changes under distinct constraints and mechanisms, sensorimotor learning establishes dedicated circuitry for the reproduction of stereotyped neural activity patterns and behavior.

The diagnostic value of ultrasonography with 5-15-MHz probes in benign subcutaneous lesions.

BACKGROUND: Ultrasonography (US) has recently proved to be useful in diagnostic dermatology. It is convenient to use, completely safe, and provides valuable information. OBJECTIVE: This study was performed to compare the diagnostic accuracy of US with that of clinical diagnosis in patients with benign subcutaneous lesions. METHODS: We retrospectively examined data for 100 patients with benign subcutaneous lesions who were diagnosed with US and either biopsy or surgery at Seoul National University Boramae Hospital between January 2010 and May 2013. RESULTS: Ultrasonography significantly increased the diagnostic yield of benign subcuta-neous lesions (after physical examination [PE], 52.0%; after US, 82.0%; P < 0.005). Rates of sensitivity and specificity for the diagnosis of lipoma were 61.5 and 92.0%, respectively, after PE, and 100 and 100%, respectively, after US. Rates of sensitivity and specificity for the diagnosis of epidermal cysts were 69.4 and 78.4%, respectively, after PE, and 91.8 and 92.2%, respectively, after US. Additionally, rates of sensitivity and specificity for pilomatrixoma were 12.5 and 98.9%, respectively, after PE, and 75.0 and 100%, respectively, after US. Although the accuracy of diagnosis of vascular anomalies and nerve sheath tumors was increased after US, the difference was not significant (vascular anomalies: 40.0% after PE and 80.0% after US; nerve sheath tumors: 28.6% after PE and 42.9% after US). CONCLUSIONS: This study suggests that US is a simple and reliable tool that can aid the diagnosis of benign subcutaneous lesions.

Long pulsed 1064 nm Nd:YAG laser treatment for wrinkle reduction and skin laxity: evaluation of new parameters.

INTRODUCTION: Among non-ablative devices for wrinkle reduction and skin laxity, long pulsed 1064 nm Nd:YAG laser (LPND) has considerable effectiveness. It can penetrate to deep dermis due to its longer wavelength. This study assesses the efficacy and safety of LPND applying new parameters for skin rejuvenation in Korean subjects. METHODS: A prospective randomized split-faced study was done (n = 20). Half of the face was treated with three passes of LPND at a spot size of 12 mm, 20-24 J/cm(2) fluence, 12 ms width, and frequency of 2 Hz, for three sessions, every four weeks. Outcomes were measured by wrinkle evaluation of blinded investigators, subjects' self-assessment, objective measurements of elasticity, and skin biopsy. RESULTS: Four weeks after the final treatment sessions, the average wrinkle grades of the treated side were reduced by 45.1%. Skin elasticity was significantly increased. The increment of collagen and elastic fiber in papillary dermis was confirmed histologically. No adverse reaction was reported. Pain on the treated side was mild without needing anesthesia. DISCUSSION: The authors studied new parameters for LPND for improvement of wrinkles and skin laxity with fewer treatment sessions without serious complications. Histologic findings corresponded to clinical improvement. CONCLUSION: New parameters of LPND can achieve wrinkle improvement with few side effects.

Spatial and temporal eye-hand coordination relies on the parietal reach region.

Coordinated eye movements are crucial for precision control of our hands. A commonly believed neural mechanism underlying eye-hand coordination is interaction between the neural networks controlling each effector, exchanging, and matching information, such as movement target location and onset time. Alternatively, eye-hand coordination may result simply from common inputs to independent eye and hand control pathways. Thus far, it remains unknown whether and where either of these two possible mechanisms exists. A candidate location for the former mechanism, interpathway communication, includes the posterior parietal cortex (PPC) where distinct effector-specific areas reside. If the PPC were within the network for eye-hand coordination, perturbing it would affect both eye and hand movements that are concurrently planned. In contrast, if eye-hand coordination arises solely from common inputs, perturbing one effector pathway, e.g., the parietal reach region (PRR), would not affect the other effector. To test these hypotheses, we inactivated part of PRR in the macaque, located in the medial bank of the intraparietal sulcus encompassing the medial intraparietal area and area 5V. When each effector moved alone, PRR inactivation shortened reach but not saccade amplitudes, compatible with the known reach-selective activity of PRR. However, when both effectors moved concurrently, PRR inactivation shortened both reach and saccade amplitudes, and decoupled their reaction times. Therefore, consistent with the interpathway communication hypothesis, we propose that the planning of concurrent eye and hand movements causes the spatial information in PRR to influence the otherwise independent eye control pathways, and that their temporal coupling requires an intact PRR.

Optic ataxia: from Balint's syndrome to the parietal reach region.

Optic ataxia is a high-order deficit in reaching to visual goals that occurs with posterior parietal cortex (PPC) lesions. It is a component of Balint's syndrome that also includes attentional and gaze disorders. Aspects of optic ataxia are misreaching in the contralesional visual field, difficulty preshaping the hand for grasping, and an inability to correct reaches online. Recent research in nonhuman primates (NHPs) suggests that many aspects of Balint's syndrome and optic ataxia are a result of damage to specific functional modules for reaching, saccades, grasp, attention, and state estimation. The deficits from large lesions in humans are probably composite effects from damage to combinations of these functional modules. Interactions between these modules, either within posterior parietal cortex or downstream within frontal cortex, may account for more complex behaviors such as hand-eye coordination and reach-to-grasp.