Detection of Plasmodium vivax using Automated Hematology Analyzer in the Korean Army.

BACKGROUND: This study aimed to evaluate whether our equation model developed from the Sysmex hematology analyzer can discriminate patients with Plasmodium vivax (P. vivax) infection from those with acute febrile illness (AFI) and healthy controls. Besides, we compared our model with the previously studied models. METHODS: A total of 312 blood samples were collected from the P. vivax, AFI, and healthy control groups. All samples were tested for routine complete blood count conducted by using a Sysmex XE-2100 or XE-5000 analyzer. We compared the reportable and research parameters generated from the Sysmex analyzer among the three groups. The selected parameters that showed a significant difference between the P. vivax and the other group were included in the logistic regression analysis to develop our model (N-OIpv model). Moreover, we analyzed the CBC data according to the previous models, such as the presence of abnormal blue coded events in the WBC/BASO scattergram called the observer-interpretation (OIpv) model, and the previous equation model (N-OD1pv model) developed by Campuzano-Zuluaga et al. Results: The N-OIpv model, which consists of three parameters, such as mean cell volume, plateletcrit, and Lymph-X, showed the best performance for detection of malaria (97.4% accuracy). Also, this model can increase the sensitivity by about 11.9% to 18.1% compared with the OIpv and N-OD1pv models, respectively. CONCLUSIONS: We concluded that the N-OIpv model using the Sysmex hematology analyzer is a useful diagnostic tool in the routine laboratory workup for malaria.

A female with typical fragile-X phenotype caused by maternal isodisomy of the entire X chromosome.

Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability, especially in males. Females with FXS tend to be relatively mildly affected because of compensation by a second X chromosome with a normal FMR1 gene. In most cases, FXS is caused by an expansion of the CGG repeats (>200 triplets, full mutation, FM) in the 5'-untranslated region of the FMR1 gene. Premutation alleles (PM, 55-200 repeats), usually lack the clinical features of FXS, are highly unstable when transmitted to offspring and can give rise to FM, especially in female meiosis. We describe a 3-year-old girl with typical FXS, with only a fully expanded FMR1 allele (288 CGG repeats) due to uniparental isodisomy of X chromosome, inherited from mother carrying a premutation allele. The patient's FMR1 methylation region is completely methylated due to full mutation of CGG repeat. This unusual and rare case indicates the importance of a detailed genomic approach to explain nontraditional Mendelian inheritance pattern.

Behavior Modeling for Charge Storage in Single-Poly Floating Gate Device.

Single-poly floating gate is an efficient device for charge storage due to low power program, and implemented in a standard CMOS process. In floating gate, charges are injected and removed through the thin gate oxide. Among the gate leakage current mechanisms, FN tunneling is significant in the high electric field, while PF emission in the low electric field. We extracted FN and PF components from the measured current and built an accurate model which include fringing field effect induced by the 3-dimensional structure. This model helps engineers reflect exact behaviors of charge storage device in their circuit design.

Comparison of three multiplex PCR assays for detection of respiratory viruses: Anyplex II RV16, AdvanSure RV, and Real-Q RV.

BACKGROUND: Due to its great sensitivity, the nucleic acid amplification test (NAAT) is widely used for detection of respiratory viruses (RV). However, few reports have described a direct comparison between multiplex RT-PCR assays for RV. The objective of this study was to perform a direct comparison of three multiplex RT-PCR assays for the detection of respiratory viruses. METHODS: A total of 201 respiratory samples (161 nasopharyngeal swab samples and 40 sputum samples) were tested with three commercial RV assays: Seegene Anyplex II RV16 (AP), LG AdvanSure RV (AD), and Biosewoom Real-Q RV (RQ). The additional tests for the discrepant results were conducted by repeat RV assay or monoplex PCR coupled direct sequencing. Data analysis using percent agreement, kappa, and prevalence-adjusted and bias-adjusted kappa (PABAK) values was performed for comparisons among the three RV assays. RESULTS: Of the 201 samples, AP, AD, and RQ detected 105 (52.2%), 99 (49.3%), and 95 (47.3%) positive cases respectively. The overall agreement, kappa, and PABAK values for the three assays ranged between 97%-98%, 0.76-0.86, and 0.93-0.96 respectively. The performance of the three assays was very similar, with 94%-100% agreement for all comparisons, each virus types. The additional testing of samples showed discrepant results demonstrating that AD assay had the highest rate of concordance with original results. CONCLUSIONS: We suggest that all multiplex assay would be suitable for the detection of for respiratory viruses in clinical setting.

Counteracting effect of threat on reward enhancements during working memory.

Cognitive performance has been shown to be enhanced when performance-based rewards are at stake. On the other hand, task-irrelevant threat processing has been shown to have detrimental effects during several cognitive tasks. Crucially, the impact of reward and threat on cognition has been studied largely independently of one another. Hence, our understanding of how reward and threat simultaneously contribute to performance is incomplete. To fill in this gap, the present study investigated how reward and threat interact with one another during a cognitive task. We found that threat of shock counteracted the beneficial effect of reward during a working memory task. Furthermore, individual differences in self-reported reward-sensitivity and anxiety were linked to the extent to which reward and threat interacted during behaviour. Together, the current findings contribute to a limited but growing literature unravelling how positive and negative information processing jointly influence cognition.

Network analysis reveals increased integration during emotional and motivational processing.

In recent years, a large number of human studies have investigated large-scale network properties of the brain, typically during the resting state. A critical gap in the knowledge base concerns the understanding of network properties of a focused set of brain regions during task conditions engaging these regions. Although emotion and motivation recruit many brain regions, it is currently unknown how they affect network-level properties of inter-region interactions. In the present study, we sought to characterize network structure during "mini-states" engendered by emotional and motivational cues investigated in separate studies. To do so, we used graph-theoretic network analysis to probe network-, community-, and node-level properties of the trial-by-trial functional connectivity between regions of interest. We used methods that operate on weighted graphs that make use of the continuous information of connectivity strength. In both the emotion and motivation datasets, global efficiency increased and decomposability decreased. Thus, processing became less segregated with the context signaled by the cue (potential shock or potential reward). Our findings also revealed several important features of inter-community communication, including notable contributions of the bed nucleus of the stria terminalis, anterior insula, and thalamus during threat and of the caudate and nucleus accumbens during reward. Together, the results suggest that one way in which emotional and motivational processing affect brain responses is by enhancing signal communication between regions, especially between cortical and subcortical ones.

Conscious expectancy rather than associative strength elicits brain activity during single-cue fear conditioning.

The neurocognitive processes underlying Pavlovian conditioning in humans are still largely debated. The conventional view is that conditioned responses (CRs) emerge automatically as a function of the contingencies between a conditioned stimulus (CS) and an unconditioned stimulus (US). As such, the associative strength model asserts that the frequency or amplitude of CRs reflects the strength of the CS-US associations. Alternatively, the expectation model asserts that the presentation of the CS triggers conscious expectancy of the US, which is responsible for the production of CRs. The present study tested the hypothesis that there are dissociable brain networks related to the expectancy and associative strength theories using a single-cue fear conditioning paradigm with a pseudo-random intermittent reinforcement schedule during functional magnetic resonance imaging. Participants' (n = 21) trial-by-trial expectations of receiving shock displayed a significant linear effect consistent with the expectation model. We also found a positive linear relationship between the expectancy model and activity in frontoparietal brain areas including the dorsolateral prefrontal cortex (PFC) and dorsomedial PFC. While an exploratory analysis found a linear relationship consistent with the associated strength model in the insula and early visual cortex, our primary results are consistent with the view that conscious expectancy contributes to CRs.

Reactive control in suicide ideators and attempters: An examination of the congruency sequence effect in cognitive and emotional Simon tasks.

Reactive control is the cognitive ability to adjust thoughts and behaviors when encountering conflict. We investigated how this ability to manage conflict and stress distinguishes suicidal from nonsuicidal individuals. The hypothesis was that suicidal individuals would show poorer reactive control when faced with conflict generated by emotional than neutral stimuli. Hence, individuals with a lifetime history of suicide ideation or attempt and nonsuicidal controls were tested in cognitive and emotional Simon tasks. We examined the congruency sequence effect (CSE) in the Simon tasks as an indication of the efficiency of reactive control in resolving conflict. Whereas controls demonstrated significant CSEs in both tasks, suicide attempters showed a significant CSE in the cognitive task but not in the emotional task. Suicide ideators, on the other hand, displayed marginally significant CSEs in both tasks. Comparing groups with pairwise comparison demonstrated that the difference in CSE was significant only in the emotional task between attempters and controls. Our findings of attempters' inefficiency in adjusting reactive control during the emotional task reflect cognitive inflexibility in coping with conflicting situations during which suicidal individuals become vulnerable to suicide attempts in states of negative emotion.

Impact of state anxiety on the interaction between threat monitoring and cognition.

How does threat processing impact cognitive performance? To investigate this question, in the present functional magnetic resonance imaging study, participants performed a response-conflict task (neutral, congruent, and incongruent trials) that followed a variable-length shock anticipation period or a corresponding delay during which they would not be shocked. The delay period was cued by a geometric-shaped stimulus indicating whether the subject was in the safe (no shock) or threat (potential shock) condition. Behaviorally, participants showed increased reaction time interference (incongruent-neutral) during threat trials, an effect that increased as a function of state anxiety level across participants. Brain imaging data were analyzed for the cue and the subsequent target phase of the task. At the target phase, the left anterior insula exhibited interaction-type responses (i.e., increased interference during threat trials) that were positively associated with state anxiety level - a relationship that paralleled the behavioral pattern. At the cue phase, greater responses to threat vs. safe were observed in a circuit of regions, including the medial PFC, anterior insula, thalamus, and bed nucleus of the stria terminalis/caudate, which we interpreted as engaged by shock monitoring/anticipation processes. In contrast, intriguingly, greater responses to safe vs. threat at the cue phase were observed in a broader set of regions that overlapped with the "resting-state" network. Finally, a standard statistical mediation analysis revealed that the relationship between state anxiety scores and interference-related responses in the left anterior insula during the target phase was partially mediated via cue responses in the medial PFC, consistent with the idea that more anxious individuals had difficulty in engaging the medial PFC during the threat condition. Taken together, our findings suggest that threat monitoring impairs the upcoming resolution of interference. Furthermore, a confluence of effects of cognitive task condition, threat, and individual differences in state anxiety was observed in the anterior insula, a structure that is suggested to be particularly important for the interaction between emotion and cognition.

Functional activation of insula and dorsal anterior cingulate for conflict control against larger monetary loss in young adults with subthreshold depression: a preliminary study.

Subthreshold depression (StD) is associated with higher risk of later developing major depressive disorder (MDD). Deficits of goal-directed behaviors regarding the motional, motivational, and conflict control are found in MDD. The current study examined neural underpinning of conflict control against monetary punishment in StD compared to MDD and healthy controls (HC). Seventy-one participants (HC, n = 27; StD, n = 21; MDD, n = 23) in their mid-20's completed self-reports. Preprocessing of functional magnetic resonance imaging acquired for the Simon task against larger or smaller monetary punishment was conducted using ENIGMA HALFpipe version 1.2.1. Neural correlates of conflict control against monetary punishment that could vary with either diagnosis or PHQ-9 total score were examined using a general linear model of FSL. Simon effect was effective for reaction time and accuracy in every subgroup of diagnosis and regardless of the size of monetary punishment. Conflict control against larger monetary loss was associated with higher functional activation of left insula in StD than HC and MDD. StD showed lower functional activation of left dorsal anterior cingulate (dACC) than MDD for conflict control against larger monetary loss. For conflict control against smaller monetary loss, StD demonstrated higher functional activation of left paracentral lobule and right putamen compared to HC. Directed acyclic graphs showed directional associations from suicidal ideation, sadness, and concentration difficulty to functional activation of paracentral lobule, ventromedial prefrontal cortex (vmPFC), and thalamus for conflict control against monetary loss. Differential functional activation of insula and dACC for conflict control against larger monetary loss could be a brain phenotype of StD. Item-level depressive symptoms of suicidal ideation, sadness, and concentration difficulty could be reflected in the conflict control-related functional activation of paracentral lobule (against smaller monetary loss), vmPFC and thalamus (against larger monetary loss), respectively.

A late-onset male Fabry disease patient with somatic mosaicism of a classical GLA mutation: a case report.

Fabry disease (FD) is an X-linked lysosomal storage disorder caused by mutations in the α-galactosidase A gene (GLA). Male patients of FD develop early sign and symptoms in childhood or adolescence. However, "de novo somatic mosaicism" is rare and might be developed a relatively mild phenotype despite carrying a classic type. A 34-year-old male patient visited with foamy urine. Renal biopsy findings were consistent with FD. Leukocyte α-galactosidase activity was markedly reduced at 5.3 nmol/hr/mg (normal range, 25-126). Sequence analysis of the patient's GLA gene identified mosaicism for the mutation GLA[NM_000169.2] c.820=/G>C. This mutation results in a substitution of the amino acid in position 274 from glycine to arginine. However, no family members showed FD-related symptoms, and the daughter of the patient was also tested for paternity and was identified as a real biological daughter, but DNA sequence analysis for FD showed no mutations. Based on these results, we diagnosed the patients as de novo mutation with somatic mosaicism. Next generation sequencing turned out that 58% of the readings had the mutated allele in buccal cells, 84% in blood, and 85% in urine, when 100% should be expected in a hemizygous affected male confirming the presence of somatic mosaicisms. The patient has been on treatment for enzyme replacement therapy (agalsidase-ß, 1.0 mg/kg biweekly) for past 9 years and has maintained normal renal function (serum creatinine 1.0 mg/dL) with mild albuminuria (123 mg/g Cr). Therefore, this case suggests somatic mosaicism is one of important phenotype modifiers.

A boy with Coffin-Siris syndrome with a novel frameshift mutation in ARID1B.

Coffin-Siris syndrome (OMIM #135900) is an autosomal dominant inherited disorder, characterized by dysmorphic features, congenital anomalies, and developmental delay. We report the clinical and molecular findings in a patient with Coffin-Siris syndrome. A 3-year-and-6-month-old boy presented with developmental delay, distinctive facial features, hypertrichosis, partial agenesis of the corpus callosum, fifth digit nail hypoplasia, congenital anomalies, and growth retardation. Targeted gene panel sequencing identified a novel heterozygous frameshift mutation c.2147_2148insAC in ARID1B which was predicted as a premature stop codon p. (Gln717Argfs*29). This is the second report of Coffin-Siris syndrome in Korea. Targeted gene panel sequencing can be used as an effective tool for the diagnosis of rare complex syndromes such as Coffin-Siris syndrome.

Genetic Analysis Using a Next Generation Sequencing-Based Gene Panel in Patients With Skeletal Dysplasia: A Single-Center Experience.

Skeletal dysplasia (SD), a heterogeneous disease group with rare incidence and various clinical manifestations, is associated with multiple causative genes. For clinicians, accurate diagnosis of SD is clinically and genetically difficult. The development of next-generation sequencing (NGS) has substantially aided in the genetic diagnosis of SD. In this study, we conducted a targeted NGS of 437 genes - included in the nosology of SD published in 2019 - in 31 patients with a suspected SD. The clinical and genetic diagnoses were confirmed in 16 out of the 31 patients, and the diagnostic yield was 51.9%. In these patients, 18 pathogenic variants were found in 13 genes (COL2A1, MYH3, COMP, MATN3, CTSK, EBP, CLCN7, COL1A2, EXT1, TGFBR1, SMAD3, FIG4, and ARID1B), of which, four were novel variants. The diagnosis rate was very high in patients with a suspected familial SD and with radiological evidence indicating clinical SD (11 out of 15, 73.3%). In patients with skeletal involvement and other clinical manifestations including dysmorphism or multiple congenital anomalies, and various degrees of developmental delay/intellectual disability, the diagnosis rate was low (5 out of 16, 31.2%) but rare syndromic SD could be diagnosed. In conclusion, NGS-based gene panel sequencing can be helpful in diagnosing SD which has clinical and genetic heterogeneity. To increase the diagnostic yield of suspected SD patients, it is important to categorize patients based on the clinical features, family history, and radiographic evidence.

Beneficial effect of task-irrelevant threat on response inhibition.

It is widely accepted that task-irrelevant threats utilize processing resources, resulting in impaired cognitive processes. However, if some subcomponents of the cognitive processes are activated by a threat, these cognitive processes may be facilitated. In the present study, we investigated whether task-irrelevant threats enhance cognitive control if the threat and task-relevant processes commonly recruit a cognitive process, inhibitory process. To examine the impact of task-irrelevant threats on inhibitory control, we had participants perform a stop-signal task with mild electric shocks. They were at risk for receiving the shocks randomly in threat blocks while no such shock was administered in safe blocks. The results showed that the stop-signal reaction time decreased under threat compared to safe conditions, indicating that inhibitory control was enhanced under threat. This beneficial effect of threat on response inhibition was more evident in participants with high state anxiety. An additional measurement of motor execution indicated that the interaction between threat and response inhibition was not derived from general arousal under threat. Results suggest that emotion and cognition do not interact simply by sharing processing resources but are related more closely to each other than we have previously thought by engaging a common processing.

A novel de novo heterozygous DYRK1A mutation causes complete loss of DYRK1A function and developmental delay.

Dual-specificity tyrosine phosphorylation-regulated kinase 1 A (DYRK1A) is essential for human development, and DYRK1A haploinsufficiency is associated with a recognizable developmental syndrome and variable clinical features. Here, we present a patient with DYRK1A haploinsufficiency syndrome, including facial dysmorphism, delayed motor development, cardiovascular system defects, and brain atrophy. Exome sequencing identified a novel de novo heterozygous mutation of the human DYRK1A gene (c.1185dup), which generated a translational termination codon and resulted in a C-terminally truncated protein (DYRK1A-E396ter). To study the molecular effect of this truncation, we generated mammalian cell and Drosophila models that recapitulated the DYRK1A protein truncation. Analysis of the structure and deformation energy of the mutant protein predicted a reduction in protein stability. Experimentally, the mutant protein was efficiently degraded by the ubiquitin-dependent proteasome pathway and was barely detectable in mammalian cells. More importantly, the mutant kinase was intrinsically inactive and had little negative impact on the wild-type protein. Similarly, the mutant protein had a minimal effect on Drosophila phenotypes, confirming its loss-of-function in vivo. Together, our results suggest that the novel heterozygous mutation of DYRK1A resulted in loss-of-function of the kinase activity of DYRK1A and may contribute to the developmental delay observed in the patient.

The First Korean Case of Baraitser-Winter Cerebro-Fronto-Facial Syndrome with a Novel Mutation in ACTB Diagnosed Via Targeted Gene Panel Sequencing and Literature Review.

Baraitser-Winter Cerebro-fronto-facial syndrome (BWCFF, OMIM #243310, #614583) is caused by a heterozygous gain-of-function mutation of ACTB and ACTG1 that encodes actin. The syndrome is characterized by striking facial features, structural brain abnormalities, ocular coloboma, hearing loss, cardiac defects, intellectual disabilities, short stature, and developmental delay. We report a two-year-old girl who had distinctive facial features, including hypertelorism, arched eyebrows, bilateral ptosis, short broad nose with a flat nasal tip, long philtrum, retrognathia, low-set ears, and a thin upper lip. In addition, she also exhibited short stature, pectus excavatum, developmental delay, brain malformation, and hearing loss. Targeted gene panel sequencing identified a de novo heterozygous missense variant c.826G>A (p.Glu276Lys) in ACTB This is the first Korean case of BWCFF with a novel mutation in ACTB.

Nonclassic congenital lipoid adrenal hyperplasia diagnosed at 17 months in a Korean boy with normal male genitalia: emphasis on pigmentation as a diagnostic clue.

Congenital lipoid adrenal hyperplasia (CLAH) is one of the most fatal conditions caused by an abnormality of adrenal and gonadal steroidogenesis. CLAH results from loss-of-function mutations of the steroidogenic acute regulatory (STAR) gene; the disease manifests with electrolyte imbalances and hyperpigmentation in neonates or young infants due to adrenocortical hormone deficiencies, and 46, XY genetic male CLAH patients can be phenotypically female. Meanwhile, some patients with STAR mutations develop hyperpigmentation and mild signs of adrenal insufficiency, such as hypoglycemia, after infancy. These patients are classified as having nonclassic CLAH (NCCLAH) caused by STAR mutations that retain partial activity of STAR. We present the case of a Korean boy with normal genitalia who was diagnosed with NCCLAH. He presented with whole-body hyperpigmentation and electrolyte abnormalities, which were noted at the age of 17 months after an episode of sepsis with peritonitis. The compound heterozygous mutations p.Gly221Ser and c.653C>T in STAR were identified by targeted gene-panel sequencing. Skin hyperpigmentation should be considered an important clue for diagnosing NCCLAH.

Clinical characteristics and disease progression of retinitis pigmentosa associated with PDE6B mutations in Korean patients.

Due to the genotype-phenotype heterogeneity in retinitis pigmentosa (RP), molecular diagnoses and prediction of disease progression is difficult. This study aimed to report ocular and genetic data from Korean patients with PDE6B-associated RP (PDE6B-RP), and establish genotype-phenotype correlations to predict the clinical course. We retrospectively reviewed targeted next-generation sequencing or whole exome sequencing data for 305 patients with RP, and identified PDE6B-RP in 15 patients (median age, 40.0 years). Amongst these patients, ten previously reported PDE6B variants (c.1280G > A, c.1488del, c.1547T > C, c.1604T > A, c.1669C > T, c.1712C > T, c.2395C > T, c.2492C > T, c.592G > A, and c.815G > A) and one novel variant (c.712del) were identified. Thirteen patients (86.7%) experienced night blindness as the first symptom at a median age of 10.0 years. Median age at diagnosis was 21.0 years and median visual acuity (VA) was 0.20 LogMAR at the time of genetic analysis. Nonlinear mixed models were developed and analysis revealed that VA exponentially decreased over time, while optical coherence tomography parameters linearly decreased, and this was related with visual field constriction. A high proportion of patients with the c.1669C > T variant (7/9, 77.8%) had cystoid macular edema; despite this, patients with this variant did not show a higher rate of functional or structural progression. This study will help clinicians predict functional and structural progression in patients with PDE6B-RP.

Biomimetic variable-focus lens system controlled by winding-type SMA actuator.

Inspired by the biomechanics of the human eye, which includes a crystalline lens, ciliary muscles, and zonular fibers, the proposed variablefocus lens system consists of a PDMS lens, winding-type SMA actuator, and load arms. The PDMS lens is encircled and stretched by the load arms joined to an outer ring that is rotated by the winding-type SMA actuator, thereby changing the focal length of the lens. In contrast to other single tunable-focus lenses, the proposed system uses a gel-type PDMS lens, which is insensitive to gravity and external vibration, and can be made into a biconvex or aspheric shape. The design of the proposed system is described in detail, and experimental results demonstrate the validity of the proposed system.