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Functional lateralization of the prefrontal cortex has been implicated in stress and emotional disorders, yet underlying gene expression changes remains unknown. Here, we report molecular signatures lateralized by chronic social defeats between the two medial prefrontal cortices (mPFCs). Stressed mice show 526 asymmetrically expressed genes between the mPFCs. This cortical asymmetry selectively occurs in stressed mice with depressed social activity, but not in resilient mice with normal behavior. We have isolated highly asymmetric genes including connective tissue growth factor (CTGF), a molecule that modulates wound healing at the periphery. Knockdown of CTGF gene in the right mPFC by shRNA led to a stress-resistant behavioral phenotype. Overexpression of CTGF in the right mPFC using viral transduction induces social avoidance while the left mPFC thereof prevent stress-induced social avoidance. Our study provides a molecular window into the mechanism of stress-induced socioemotional disorders, which can pave the way for new interventions by targeting cortical asymmetry. Supplementary Information The online version contains supplementary material available at 10.1186/s13041-021-00802-w.

Objectives We aimed to compare tuberculosis (TB) risk during biologics treatment between patients with RA who did (prophylaxis) and did not (non-prophylaxis) undergo chemoprophylaxis following pre-biologic latent TB screening in Korea of an intermediate TB burden. Methods Using the 2002–16 Korea National Health Insurance database, we conducted a cohort study examining TB risk, defined by International Classification of Diseases Tenth Revision codes plus anti-TB drugs, among RA patients initiating a biologic drug with and without chemoprophylaxis after screening triage for latent TB. To control baseline confounding, we used propensity score-based fine stratification (PSS) and weighting. Cox proportional hazards models estimated hazard ratios and 95% CIs comparing TB risk between the prophylaxis vs non-prophylaxis groups. Results The PSS-weighted study cohort (mean age 57.0 years; 81.3% female) included 2249 and 7225 RA patients in the prophylaxis and non-prophylaxis groups, respectively. During 2.42 years of biologics treatment, 118 patients developed TB with the incidence rate per 100 person-years of 0.33 in the prophylaxis and 0.63 in the non-prophylaxis groups. The PSS-weighted hazard ratio (95% CI) for TB associated with the prophylaxis was 0.52 (0.32, 0.86). During the follow-up time, the incidence rate of TB remained consistently low in the prophylaxis group but it was highest in the first year, then time-dependently declined in the non-prophylaxis group. Conclusion This population-based cohort study warns that the current screening-based preventive strategy generates a substantially higher TB risk after biologics initiation among screening-negative patients compared with screening-positive patients receiving chemoprophylaxis, when the background TB burden is not low.

In this population-based cohort study on comparative osteoporotic fracture risks between different biologic disease-modifying drugs among patients with rheumatoid arthritis (RA), we did not find a significant difference in the risk of osteoporotic fractures between RA patients receiving TNF inhibitors versus abatacept or tocilizumab. We aimed to investigate the comparative risk of osteoporotic fractures between rheumatoid arthritis (RA) patients who initiated TNF inhibitors (TNFis) versus abatacept or tocilizumab. Using the Korea National Health Insurance Service datasets from 2002 to 2016, RA patients who initiated TNFis, abatacept, or tocilizumab were identified. The primary outcome was a composite end point of non-vertebral fractures and hospitalized vertebral fractures; secondary outcomes were two components of the primary outcome and fractures occurring at the humerus/forearm. Propensity score (PS) matching with a variable ratio up to 10 TNFi initiators per 1 comparator drug initiator was used to adjust for > 50 baseline confounders. We estimated hazard ratios (HRs) and 95% confidence interval (CI) of fractures comparing TNFi initiators to abatacept and to tocilizumab by Cox proportional hazard models stratified by a matching ratio. After PS-matching, 2307 TNFi initiators PS-matched on 588 abatacept initiators, and 2462 TNFi initiators on 640 tocilizumab initiators were included. A total of 77 fractures occurred during a mean follow-up of 454 days among TNFi and abatacept initiators and 83 fractures during 461 days among TNFi and tocilizumab initiators. The PS-matched HR (95% CI) was 0.91 (0.48–1.71) comparing TNFi versus abatacept initiators, and 1.00 (0.55–1.83) comparing TNFi versus tocilizumab initiators. Analysis on vertebral and non-vertebral fractures showed similar results. In this nationally representative cohort, we did not find a significant difference in the risk of fractures between TNFi initiators versus abatacept or tocilizumab among RA patients.

Objective Orthohantaviruses are geographically widely distributed and present various clinical manifestations from mild symptoms to the severe form of haemorrhagic fever with renal syndrome (HFRS) in Eurasia. Official registration of HFRS in Kazakhstan started in the year 2000. However, the true prevalence of human infections by orthohantaviruses within Kazakhstan is unknown. The aim of this study was to investigate of the seroprevalence of orthohantavirus infections in patients with fever of unknown origin (FUO) in two regions, Almaty and Kyzylorda region. Methods Paired serum samples from 802 patients with FUO were screened for the presence of orthohantavirus IgG and IgM antibodies by ELISA. Positive samples were further tested by immunoblotting and indirect immunofluorescence tests (IIFT) to determine the respective orthohantavirus serotypes. Suspected acute serum samples were additionally checked by a RT-PCR to identify viral RNA. Results In total 178/802 (22.2%) serum samples reacted with orthohantavirus IgG antibodies and 4/802 (0.5%) with IgM antibodies. All positive samples were tested by immunoblotting which resulted in 2.9% positive samples with IgG antibodies against Puumala (PUUV), Hantaan (HTNV) and Dobrava (DOBV) virus serotypes in Almaty region and 5.4% to PUUV and DOBV serotypes in Kyzylorda region, respectively. In the IFFT, 1.9% positive samples from Almaty and 3.1% from Kyzylorda were confirmed for PUUV and DOBV serotypes. Out of four IgM ELISA positive samples only three were positive against PUUV in the immunoblot and showed weak positive reactivity for the Saaremaa (SAAV), PUUV and HTNV serotypes in the IFFT. Conclusions This study demonstrates the presence of orthohantavirus infections among patients with FUO in Kazakh regions that were so far considered as non-endemic. The healthcare system needs to be prepared accordingly in order to be capable of detecting cases and providing adequate management of patients.

Objective To compare cardiovascular (CV) risk among gout patients initiating allopurinol vs febuxostat. Methods Using 2002–2015 Korean National Health Insurance Service data for the entire Korean population, we conducted a cohort study on gout patients initiating allopurinol or febuxostat. The primary outcome was a composite CV end point of myocardial infarction, stroke/transient ischaemic attack, or coronary revascularization. Secondary outcomes were individual components of the primary outcome, and all-cause mortality. We used propensity score-matching with a 4:1 ratio for allopurinol and febuxostat initiators to control for confounding. Competing risk analyses were done for non-fatal outcomes accounting for deaths. Results We included 39 640 allopurinol initiators propensity score-matched on 9910 febuxostat initiators. The mean age was 59.1 years and 78.4% were male. The incidence rate per 100 person-years for the primary outcome was 1.89 for allopurinol and 1.84 for febuxostat initiators. The corresponding hazard ratio comparing allopurinol vs febuxostat initiators was 1.09 (95% CI: 0.90, 1.32). No significant difference was found for the secondary outcomes, including all-cause mortality (hazard ratio 0.96; 95% CI: 0.79, 1.16). Subgroup analyses limited to those at high CV risk and to equipotent-dose initiators (i.e. allopurinol ⩾300 mg/day vs febuxostat ⩾40 mg/day) showed similar results. Conclusion Overall, this large Korean population-based study suggests no difference in the risk of non-fatal CV events and all-cause mortality between allopurinol and febuxostat initiators. These findings are consistent with the recent US Medicare population study, although the current study population consisted of younger Asians.

Objectives: The aim of this study was to detect the seroprevalence of Crimean–Congo haemorrhagic fever virus (CCHFV) in patients with fever of unknown origin (FUO) in endemic (Kyzylorda) and non-endemic (Almaty) oblasts of Kazakhstan. Methods: Paired serum samples from 802 patients with FUO were collected. Serum samples were investigated by ELISA to detect IgG and IgM antibodies against CCHFV. Sera with suspected acute infection were further investigated by RT-PCR to detect the viral RNA. Results: IgG antibodies were detected in 12.7% of the sera from both oblasts. Acute infection was shown by IgM ELISA in four patients from Kyzylorda, with only one developing severe CCHF. Viral RNA was found by RT-PCR in the other three patients’ sera. Phylogenetic analysis of partial L and S segments revealed CCHFV genotype Asia 2 and a possible reassortment between the genotypes Asia 1/Asia 2. Animal husbandry, such as working with cattle and horses, was significantly associated with CCHFV seropositivity. Conclusions: The antibodies and viral RNA detected in sera indicate that mild or even asymptomatic CCHFV infections are presented in Kazakhstan. This study describes the circulation of CCHFV in the so far non-endemic Almaty oblast for the first time. In conclusion, physicians treating patients with FUO in Kazakhstan should be aware of mild CCHF. Keywords: Crimean–Congo haemorrhagic fever virus, Fever of unknown origin, Reassortment, Kazakhstan

Electronic Health (eHealth) is the use of information and communication technologies for health and plays a significant role in improving public health. The rapid expansion and development of eHealth initiatives allow researchers and healthcare providers to connect more effectively with patients. The aim of the CIHLMU Symposium 2020 was to discuss the current challenges facing the field, opportunities in eHealth implementation, to share the experiences from different healthcare systems, and to discuss future trends addressing the use of digital platforms in health. The symposium on eHealth explored how the health and technology sector must increase efforts to reduce the obstacles facing public and private investment, the efficacy in preventing diseases and improving patient quality of life, and the ethical and legal frameworks that influence the proper development of the different platforms and initiatives related to the field. This symposium furthered the sharing of knowledge, networking, and patient/user and practitioner experiences in low- and middle-income countries (LMIC) in both public and private sectors.

Background Limited data are available on whether patients with rheumatoid arthritis (RA) are treated with conventional disease-modifying anti-rheumatic drugs (cDMARDs) according to the current recommendations before they initiate biologic DMARDs (bDMARDs) or JAK inhibitors (JAKis). Objectives We examined the treatment patterns among Korean RA patients who received bDMARDs or JAKis in a real world setting, using the 2002-2016 Korean National Health Insurance Service database that covers the entire Korean population. Methods We identified RA patients who initiated bDMARDs (TNF inhibitor, abatacept, rituximab and tocilizumab) or JAKis (tofacitinib). Their treatment patterns during 1 year after RA diagnosis (defined as free of any RA diagnosis or any DMARD use for one year before the diagnosis) and prior to the initiation of index drugs (bDMARDs or JAKis) were examined regarding: initial cDMARD used, dose and parenteral use of methotrexate (MTX), use and time to combination therapy of cDMARDs, and steroid use. Results 10,145 RA patients were identified who used index drugs from the database (mean age 57 years, 82% female). Among them, 6,986 patients had identifiable dates for RA diagnosis (mean age 57 years, 79% female). The mean (SD) duration from RA diagnosis to index drug initiation was 1,425 (1,162) days with 1,509 (22%) patients having a duration ≤1 year. At diagnosis, the most common 1st cDMARD used was hydroxychloroquine (63%), followed by MTX (55%) and sulfasalazine (29%) with steroids used in 75%. During the 1 year from the diagnosis, 85% of patients eventually used MTX, 42% ever used MTX ≥ 15mg/week, only 3% used parenteral MTX, and 85% patients used combined cDMARDs with a mean 188 days from the RA diagnosis to combination therapy. Patients whose maximal MTX dose reached 20mg/week were rare (9%) and 62% were still on steroid after 1 year. During the 1 year prior to the index drug use (n = 10,145), the most common cDMARD was MTX used in 89% patients with 46% who ever used ≥ 15mg/week and 4% of parenteral users, followed by hydroxychloroquine (55%), leflunomide (52%), sulfasalazine (38%), and tacrolimus (20%). All patients used combination therapy and 98% steroids. Conclusion These data indicate that a substantial proportion of RA patient did not try maximal dose or parenteral use of MTX during the 1 year post-diagnosis as recommended by the current treatment guideline. Instead, they often used cDMARDs combination therapy. During the 1 year before initiating bDMARDs or JAKis, they were treated with intensive cDMARD combination therapy rather than escalating their MTX dose. Reference [1] Smolen, Josef S., et al. “EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2016 update.” Annals of the rheumatic diseases 76.6 (2017): 960-977. Disclosure of Interests None declared

Animals use visual information to recognize the value of objects and respond with different behaviours, such as evasion or approach. While rodents show defensive behaviour toward an artificial looming stimulus that mimics an approaching avian predator, the visual feature that attracts them to targets with positive value, such as prey, remains unclear. Here, we reveal that rats show curiosity-related behaviours towards a virtual object on screen when it moves interactively with their movements, whereas they show less response to a static object, a regularly moving object, or interactive dislocation of the background. To mimic evading prey, we programmed the object to shrink when touched. Rats preferentially responded to interactive shrinking over interactive enlargement. These results suggest that rats exhibit a selective response to interactive objects. This would seem to be an efficient strategy for finding optimal prey using the evolutionarily conserved prey-predator relationship.

Objectives We examined the association between socioeconomic status (SES) and comorbidity distribution among patients with RA. Methods Information on comprehensive health status of 1088 RA patients (weighted n = 612 303) was obtained from the 2007–2015 Korea National Health and Nutrition Examination Survey database. SES components were household equivalence income, education and area of residence. To minimize confounding by age, patients were stratified by median age (63 years). Age-adjusted odds ratio (OR) with 95% confidence interval (95% CI) was estimated, comparing weighted prevalence of individual comorbidities between low and high SES groups in each age stratum. Results Among RA patients aged Conclusion Among Korean RA patients aged

Background Gout is associated with an increased risk of cardiovascular (CV) disease. Objectives We aimed to investigate comparative CV risk among gout patients who initiated allopurinol versus febuxostat. Methods Using the 2002–2015 Korean National Health Insurance Service (KNHIS) data for the whole Korean population, we conducted a cohort study on patients aged ≥40 years who had ICD-10 diagnosis code for gout and initiated allopurinol or febuxostat without prior history of urate lowering therapy, excluding those with chronic kidney disease, cancer, or dialysis treatment. The primary outcome was a composite CV endpoint of hospitalisation for myocardial infarction, stroke/transient ischaemic attack, or coronary revascularisation. Secondary outcomes were individual components of the primary outcome, and hospitalisation for heart failure (HF). Follow-up time started from the day after the first date the study drug was initiated and continued through to the earliest date among the following censoring events: discontinuation of the study drugs, outcome occurrence, disenrollment, end of study dataset, or death. After propensity score (PS)-matching with a 4:1 ratio for allopurinol and febuxostat initiators to adjust for baseline confounding, we estimated hazard ratio (HR) and 95% confidence interval (CI) of CV risks in allopurinol initiators versus febuxostat. Results We included 39 636 allopurinol initiators PS-matched on 9909 febuxostat initiators with a mean age of 59 years and 78% male. Before PS matching, baseline CV risk factors including hypertension, dyslipidemia, diabetes, and previous ischaemic heart disease were more prevalent in febuxostat initiators. The incidence rate per 100 person-years for primary composite endpoint was 2.33 in allopurinol and 2.12 in febuxostat initiators in the primary as-treated analysis. The HR (95% CI) for the primary outcome associated with allopurinol was 1.18 (0.98–1.42) versus febuxostat. Secondary outcome analyses showed similar results (table 1). Propensity-score matching was used to adjust more than 50 covariates including demographic characteristics, medical comorbidities such as CV risk factors, use of gout specific and non-specific medications, and health care utilisation pattern. CI=confidence interval; CV=cardiovascular; HR=hazard ratio; MI=myocardial infarction; TIA=transient ischaemic attack Conclusions In this large Korean population-based cohort study, CV risks appear to be numerically, but not statistically significantly, elevated among allopurinol initiators compared to febuxostat initiators. Disclosure of Interest None declared

Corticotropin-releasing factor (CRF) that is released from the paraventricular nucleus (PVN) of the hypothalamus is essential for mediating stress response by activating the hypothalamic-pituitary-adrenal axis. CRF-releasing PVN neurons receive inputs from multiple brain regions that convey stressful events, but their neuronal dynamics on the timescale of behavior remain unknown. Here, our recordings of PVN CRF neuronal activity in freely behaving mice revealed that CRF neurons are activated immediately by a range of aversive stimuli. By contrast, CRF neuronal activity starts to drop within a second of exposure to appetitive stimuli. Optogenetic activation or inhibition of PVN CRF neurons was sufficient to induce a conditioned place aversion or preference, respectively. Furthermore, conditioned place aversion or preference induced by natural stimuli was significantly decreased by manipulating PVN CRF neuronal activity. Together, these findings suggest that the rapid, biphasic responses of PVN CRF neurons encode the positive and negative valences of stimuli.

Drowsiness is an awake state with increased sleep drive, yet the neural correlates and underlying mechanisms remains unclear. Here, we established a mouse model of drowsiness, where mice are fasted for 1 day and then allowed to overeat high-fat food (to promote sleep) while positioned in an open-field box (to promote vigilance). They fall into a long-lasting drowsy state, as reflected by repeated and open-eyed nodding of the head while in a standing position. Simultaneous recording of electroencephalogram (EEG) and neck electromyogram (EMG) readouts revealed that this drowsy state including nodding state had multiple stages in terms of the relationship between the level of vigilance and head movement: delta oscillations decreased in power prior to the head-nodding period and increased during the non-nodding period. Cav3.1-knockout mice, which have reduced delta oscillations, showed frequent head nodding with reduced duration of nodding episodes compared to wild-type mice. This suggests that the balance of drive is tilted in favor of wakefulness, likely due to their previously proposed decrease in sleep-promoting functions. Our findings indicate that delta oscillations play a dominant role in controlling vigilance dynamics during sleep/wake competition and that our novel mouse model may be useful for studying drowsiness and related neurological disorders.

SUMMARYCorticotropin-releasing factor (CRF), which is released from the paraventricular nucleus (PVN) of the hypothalamus, is essential for mediating stress response by activating the hypothalamic-pituitary-adrenal (HPA) axis. CRF-releasing PVN neurons receive inputs from multiple brain regions that convey stressful events, but their rapid neuronal dynamics on the timescale of behavior remain unknown. Here, our optical recordings of PVN CRF neuronal activity in freely behaving mice revealed that PVN CRF neurons are activated immediately by a range of stress-inducing aversive stimuli, including predator odor. By contrast, CRF neuronal activity starts to drop within a second of exposure to appetitive stimuli, such as food. These findings suggest that PVN CRF neurons receive real-time information about aversive and appetitive stimuli. Their role in mediating the sensory detection and regulating the neuroendocrine axis resembles those of AgRP/NPY neurons and SFO neurons that regulate neurophysiology responses and mediate sensory detection of food and water.

As animals forage, they must obtain useful targets by orchestrating appropriate actions that range from searching to chasing, biting and carrying. Here, we reveal that neurons positive for the α subunit of Ca2+/calmodulin-dependent kinase II (CaMKIIα) in the medial preoptic area (MPA) that send projections to the ventral periaqueductal gray (vPAG) mediate these target-directed actions in mice. During photostimulation of the MPA-vPAG circuit, mice vigorously engaged with 3D objects and chased moving objects. When exposed to a cricket, they hunted down the prey and bit it to kill. By applying a head-mounted object control with timely photostimulation of the MPA-vPAG circuit, we found that MPA-vPAG circuit-induced actions occurred only when the target was detected within the binocular visual field. Using this device, we successfully guided mice to navigate specified routes. Our study explains how the brain yields a strong motivation to acquire a target object along the continuum of hunting behavior.

Over the last few decades, molecular neurobiology has uncovered many genes whose deficiency in mice results in behavioral traits associated with human neuropsychiatric disorders such as autism, obsessive-compulsive disorder (OCD), and schizophrenia. However, the etiology of these common diseases remains enigmatic with the potential involvement of a battery of genes. Here, we report abnormal behavioral phenotypes of mice deficient in a cell adhesion molecule Ninjurin 1 (Ninj1), which are relevant to repetitive and anxiety behaviors of neuropsychiatric disorders. Ninj1 knockout (KO) mice exhibit compulsive grooming-induced hair loss and self-made lesions as well as increased anxiety-like behaviors. Histological analysis reveals that Ninj1 is predominantly expressed in cortico-thalamic circuits, and neuron-specific Ninj1 conditional KO mice manifest aberrant phenotypes similar to the global Ninj1 KO mice. Notably, the brains of Ninj1 KO mice display altered synaptic transmission in thalamic neurons as well as a reduced number of functional synapses. Moreover, the disruption of Ninj1 leads to glutamatergic abnormalities, including increased ionotropic glutamate receptors but reduced glutamate levels. Furthermore, chronic treatment with fluoxetine, a drug reportedly ameliorates compulsive behaviors in mice, prevents progression of hair loss and alleviates the compulsive grooming and anxiety-like behavior of Ninj1 KO mice. Collectively, our results suggest that Ninj1 could be involved in neuropsychiatric disorders associated with impairments of repetitive and anxiety behaviors.

In the version of this article initially published, a sentence in the fifth paragraph of the Results read, "Immunohistochemistry revealed that VGLUT2+ MPA neurons rarely expressed CaMKIIα, which is a putative marker for subcortical glutamatergic neurons." It should have read, "Immunohistochemistry revealed that CaMKIIα+ MPA neurons rarely expressed VGLUT2, which is a putative marker for subcortical glutamatergic neurons." The error has been corrected in the HTML and PDF versions of the article. In the supplementary information originally posted online, the wrong version of Supplementary Fig. 1 was posted and some of the supplementary videos were interchanged. In the corrected Supplementary Fig. 1, the top right subpanel was added and the original Supplementary Fig. 1a was divided into 1a and 1b, with subsequent panels incremented accordingly. The legend was changed from "a. Schematic illustrating electrical lesioning of the rat anterior hypothalamus. Electrical lesion areas (gray) in five representative brain sections are depicted. Scale bar, 1 mm" to "a. Repetitive electrical stimulations of the anterior hypothalamus using bipolar electrodes (Left) caused a lesion at the hypothalamic area (middle, marked by asterisk) successfully in 7 rats (Right, overlapped images of brain sections located from the bregma -0.24 mm). Scale bar, 1 mm. b. Electrical lesion areas (gray) in five representative brain sections from anterior to posterior are depicted." The errors have been corrected online.

Basal ganglia (BG) circuits orchestrate complex motor behaviors predominantly via inhibitory synaptic outputs. Although these inhibitory BG outputs are known to reduce the excitability of postsynaptic target neurons, precisely how this change impairs motor performance remains poorly understood. Here, we show that optogenetic photostimulation of inhibitory BG inputs from the globus pallidus induces a surge of action potentials in the ventrolateral thalamic (VL) neurons and muscle contractions during the post-inhibitory period. Reduction of the neuronal population with this post-inhibitory rebound firing by knockout of T-type Ca2+ channels or photoinhibition abolishes multiple motor responses induced by the inhibitory BG input. In a low dopamine state, the number of VL neurons showing post-inhibitory firing increases, while reducing the number of active VL neurons via photoinhibition of BG input, effectively prevents Parkinson disease (PD)-like motor symptoms. Thus, BG inhibitory input generates excitatory motor signals in the thalamus and, in excess, promotes PD-like motor abnormalities. VIDEO ABSTRACT.

Background and Objectives Joint National Committee guidelines attempt to vary treatment recommendations for patients based on considerations of their comorbidities. The aim of the present study is to estimate the age-standardized prevalence of common comorbidities among Korean hypertension patients. Subjects and Methods We analyzed the Korea National Health and Nutrition Examination Survey from 2007 to 2013. Among the 58423 participants, 30092 adults, aged ≥30 yrs who completed a health examination and interview survey, were selected. The survey procedures were used to estimate weighted prevalence and odds ratios for 8 comorbidities, including obesity, diabetes mellitus, dyslipidemia, cardiovascular disease, chronic kidney disease, and thyroid disease. Results Most chronic conditions were more prevalent in adults with hypertension than in those without hypertension. Common comorbidities were obesity (60.1%), dyslipidemia (57.6%), and impaired fasting glucose (45.1%). Hypertensive patients with two or more comorbid diseases were 42.2% and those with three or more diseases were 17.7%. The age- and sex-specific prevalence of three or more comorbid diseases among male hypertension patients was significantly higher than those patients in the 30-59 (p