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Abstract Repeat expansions in FGF14 cause autosomal dominant late-onset cerebellar ataxia (SCA27B) with estimated pathogenic thresholds of 250 (incomplete penetrance) and 300 AAG repeats (full penetrance), but the sequence of pathogenic and non-pathogenic expansions remains unexplored. Here, we demonstrate that STRling and ExpansionHunter accurately detect FGF14 expansions from short-read genome data using outlier approaches. By combining long-range PCR and nanopore sequencing in 169 patients with cerebellar ataxia and 802 controls, we compare FGF14 expansion alleles, including interruptions and flanking regions. Uninterrupted AAG expansions are significantly enriched in patients with ataxia from a lower threshold (180–200 repeats) than previously reported based on expansion size alone. Conversely, AAGGAG hexameric expansions are equally frequent in patients and controls. Distinct 5’ flanking regions, interruptions and pre-repeat sequences correlate with repeat size. Furthermore, pure AAG (pathogenic) and AAGGAG (non-pathogenic) repeats form different secondary structures. Regardless of expansion size, SCA27B is a recognizable clinical entity characterized by frequent episodic ataxia and downbeat nystagmus, similar to the presentation observed in a family with a previously unreported nonsense variant (SCA27A). Overall, this study suggests that SCA27B is a major overlooked cause of adult-onset ataxia, accounting for 23–31% of unsolved patients. We strongly recommend re-evaluating pathogenic thresholds and integrating expansion sequencing into the molecular diagnostic process.

BackgroundCommunity-based mask wearing has been shown to reduce the transmission of SARS-CoV-2. However, few studies have conducted an economic evaluation of mask mandates, specifically in public transportation settings. This study evaluated the cost-effectiveness of implementing mask mandates for subway passengers in the United States by evaluating its potential to reduce COVID-19 transmission during subway travel.Materials and methodsWe assessed the health impacts and costs of subway mask mandates compared to mask recommendations based on the number of infections that would occur during subway travel in the U.S. Using a combined box and Wells-Riley infection model, we estimated monthly infections, hospitalizations, and deaths averted under a mask mandate scenario as compared to a mask recommendation scenario. The analysis included costs of implementing mask mandates and COVID-19 treatment from a limited societal perspective. The cost-effectiveness (net cost per averted death) of mandates was estimated for three different periods based on dominant SARS-CoV-2 variants: Alpha, Beta, and Gamma (November 2020 to February 2021); Delta (July to October 2021); and early Omicron (January to March 2022).ResultsCompared with mask recommendations only, mask mandates were cost-effective across all periods, with costs per averted death less than a threshold of $11.4 million (ranging from cost-saving to $3 million per averted death). Additionally, mask mandates were more cost-effective during the early Omicron period than the other two periods and were cost saving in January 2022. Our findings showed that mandates remained cost-effective when accounting for uncertainties in input parameters (e.g., even if mandates only resulted in small increases in mask usage by subway ridership).ConclusionsThe findings highlight the economic value of mask mandates on subways, particularly during high virus transmissibility periods, during the COVID-19 pandemic. This study may inform stakeholders on mask mandate decisions during future outbreaks of novel viral respiratory diseases.

The potential of genome sequencing (GS), which allows detection of almost all types of genetic variation across nearly the entire genome of an individual, greatly expands the possibility for diagnosing genetic disorders. The opportunities provided with this single test are enticing to researchers and clinicians worldwide for human genetic research as well as clinical application. Multiple studies have highlighted the advantages of GS for genetic variant discovery, emphasizing its added value for routine clinical use. We have implemented GS as first-line genetic testing for patients with rare diseases. Here, we report on our experiences in establishing GS as a reliable diagnostic method for almost all types of genetic disorders, from validating diagnostic accuracy of sequencing pipelines to clinical implementation in routine practice.

Abstract Background Genomics enables individualized diagnosis and treatment, but large challenges remain to functionally interpret rare variants. To date, only one causative variant has been described for KCNK9 imprinting syndrome (KIS). The genotypic and phenotypic spectrum of KIS has yet to be described and the precise mechanism of disease fully understood. Methods This study discovers mechanisms underlying KCNK9 imprinting syndrome (KIS) by describing 15 novel KCNK9 alterations from 47 KIS-affected individuals. We use clinical genetics and computer-assisted facial phenotyping to describe the phenotypic spectrum of KIS. We then interrogate the functional effects of the variants in the encoded TASK3 channel using sequence-based analysis, 3D molecular mechanic and dynamic protein modeling, and in vitro electrophysiological and functional methodologies. Results We describe the broader genetic and phenotypic variability for KIS in a cohort of individuals identifying an additional mutational hotspot at p.Arg131 and demonstrating the common features of this neurodevelopmental disorder to include motor and speech delay, intellectual disability, early feeding difficulties, muscular hypotonia, behavioral abnormalities, and dysmorphic features. The computational protein modeling and in vitro electrophysiological studies discover variability of the impact of KCNK9 variants on TASK3 channel function identifying variants causing gain and others causing loss of conductance. The most consistent functional impact of KCNK9 genetic variants, however, was altered channel regulation. Conclusions This study extends our understanding of KIS mechanisms demonstrating its complex etiology including gain and loss of channel function and consistent loss of channel regulation. These data are rapidly applicable to diagnostic strategies, as KIS is not identifiable from clinical features alone and thus should be molecularly diagnosed. Furthermore, our data suggests unique therapeutic strategies may be needed to address the specific functional consequences of KCNK9 variation on channel function and regulation.

IntroductionSchools close in reaction to seasonal influenza outbreaks and, on occasion, pandemic influenza. The unintended costs of reactive school closures associated with influenza or influenza-like illness (ILI) has not been studied previously. We estimated the costs of ILI-related reactive school closures in the United States over eight academic years.MethodsWe used prospectively collected data on ILI-related reactive school closures from August 1, 2011 to June 30, 2019 to estimate the costs of the closures, which included productivity costs for parents, teachers, and non-teaching school staff. Productivity cost estimates were evaluated by multiplying the number of days for each closure by the state- and year-specific average hourly or daily wage rates for parents, teachers, and school staff. We subdivided total cost and cost per student estimates by school year, state, and urbanicity of school location.ResultsThe estimated productivity cost of the closures was $476 million in total during the eight years, with most (90%) of the costs occurring between 2016-2017 and 2018-2019, and in Tennessee (55%) and Kentucky (21%). Among all U.S. public schools, the annual cost per student was much higher in Tennessee ($33) and Kentucky ($19) than any other state ($2.4 in the third highest state) or the national average ($1.2). The cost per student was higher in rural areas ($2.9) or towns ($2.5) than cities ($0.6) or suburbs ($0.5). Locations with higher costs tended to have both more closures and closures with longer durations.ConclusionsIn recent years, we found significant heterogeneity in year-to-year costs of ILI-associated reactive school closures. These costs have been greatest in Tennessee and Kentucky and been elevated in rural or town areas relative to cities or suburbs. Our findings might provide evidence to support efforts to reduce the burden of seasonal influenza in these disproportionately impacted states or communities.

Abstract Background Targeted sequencing approaches such as gene panel or exome sequencing have become standard of care for the diagnosis of rare and common genetic disease. The detection and interpretation of point mutations, small insertions and deletions, and even exon‐level copy number variants are well established in clinical genetic testing. Other types of genetic variation such as mobile elements insertions (MEIs) are technically difficult to detect. In addition, their downstream clinical interpretation is more complex compared to point mutations due to a larger genomic footprint that can not only predict a clear loss of protein function but might disturb gene regulation and splicing even when located within the non‐coding regions. As a consequence, the contribution of MEIs to disease and tumor development remains largely unexplored in routine diagnostics. Methods In this study, we investigated the occurrence of MEIs in 7,693 exome datasets from individuals with rare diseases and healthy relatives as well as 788 cancer patients analyzed by panel sequencing. Results We present several exemplary cases highlighting the diagnostic value of MEIs and propose a strategy for the detection, prioritization, and clinical interpretation of MEIs in routine clinical diagnostics. Conclusion In this paper, we state that detection and interpretation of MEIs in clinical practice in targeted NGS data can be performed relatively easy despite the fact that MEIs very rarely occur in coding parts of the human genome. Large scale reanalysis of MEIs in existing cohorts may solve otherwise unsolvable cases.

Abstract A recurrent de novo missense variant in KCNC1, encoding a voltage‐gated potassium channel expressed in inhibitory neurons, causes progressive myoclonus epilepsy and ataxia, and a nonsense variant is associated with intellectual disability. We identified three new de novo missense variants in KCNC1 in five unrelated individuals causing different phenotypes featuring either isolated nonprogressive myoclonus (p.Cys208Tyr), intellectual disability (p.Thr399Met), or epilepsy with myoclonic, absence and generalized tonic‐clonic seizures, ataxia, and developmental delay (p.Ala421Val, three patients). Functional analyses demonstrated no measurable currents for all identified variants and dominant‐negative effects for p.Thr399Met and p.Ala421Val predicting neuronal disinhibition as the underlying disease mechanism.

The circulatory neutrophil and brain tissue-resident microglia are two important immune cells involved in neuroinflammation. Since neutrophils that infiltrate through the brain vascular vessel may affect the immune function of microglia in the brain, close investigation of the interaction between these cells is important in understanding neuroinflammatory phenomena and immunological aftermaths that follow. This study aimed to observe how morphology and function of both neutrophils and microglia are converted in the inflamed brain. To directly investigate cellular responses of neutrophils and microglia, LysMGFP/+ and CX3CR1GFP/+ mice were used for the observation of neutrophils and microglia, respectively. In addition, low-dose lipopolysaccharide (LPS) was utilized to induce acute inflammation in the central nervous system (CNS) of mice. Real-time observation on mice brain undergoing neuroinflammation via two-photon intravital microscopy revealed various changes in neutrophils and microglia; namely, neutrophil infiltration and movement within the brain tissue increased, while microglia displayed morphological changes suggesting an activated state. Furthermore, neutrophils seemed to not only actively interact with microglial processes but also exhibit reverse transendothelial migration (rTEM) back to the bloodstream. Thus, it may be postulated that, through crosstalk with neutrophils, macrophages are primed to initiate a neuroinflammatory immune response; also, during pathogenic events in the brain, neutrophils that engage in rTEM may deliver proinflammatory signals to peripheral organs outside the brain. Taken together, these results both show that neuroinflammation results in significant alterations in neutrophils and microglia and lay the pavement for further studies on the molecular mechanisms behind such changes.

The immune response following neuroinflammation is a vital element of ischemic stroke pathophysiology. After the onset of ischemic stroke, a specialized vasculature system that effectively protects central nervous system tissues from the invasion of blood cells and other macromolecules is broken down within minutes, thereby triggering the inflammation cascade, including the infiltration of peripheral blood leukocytes. In this series of processes, blood-derived monocytes have a significant effect on the outcome of ischemic stroke through neuroinflammatory responses. As neuroinflammation is a necessary and pivotal component of the reparative process after ischemic stroke, understanding the role of infiltrating monocytes in the modulation of inflammatory responses may offer a great opportunity to explore new therapies for ischemic stroke. In this review, we discuss and highlight the function and involvement of monocytes in the brain after ischemic injury, as well as their impact on tissue damage and repair.

Intraoperative hypothermia occurs frequently, but hyperthermia is relatively rare during general anesthesia. We experienced a case of hyperthermia during living donor liver transplantation that appeared to be significantly associated with biliary obstruction. A 65-year-old male patient was diagnosed with intrahepatic cholangiocarcinoma, and living donor liver transplantation was planned after confirmation of no metastasis via intraoperative frozen biopsy. Following resection of a segment of common bile duct for frozen biopsy, the surgeon clamped the common bile duct, and the patient’s body temperature increased gradually to 39.5°C. As the congested bile was drained, the body temperature decreased to the normal range. This case report suggests that when a patient develops unexplained hyperthermia during hepatobiliary surgery or in a chance of biliary obstruction, clinicians should consider bile congestion as a possible reason for hyperthermia.

Using nationwide data, this study estimated and compared annual health care expenditures per person between noncancer and cancer patients, and among patients with the 4 most common cancers. Two-part models were used to estimate mean expenditures for each group by source of payment and by service type. We found that cancer patients had nearly 4 times higher mean expenditures per person ($16 346) than those without cancer ($4484). These differences were larger among individuals aged 18 to 64 years than those ≥65 years. Medicare was the largest source of payment for cancer patients, especially among those ≥65 years. Among the 4 most common cancers, the most costly cancer was lung cancer. Ambulatory care visits accounted for the majority of health care expenditures for those with breast cancer, while for those with other cancers, inpatient services also contributed to a significant portion of expenditures especially among younger patients. This study demonstrates that cancer patients experience a substantially higher health care expenditure burden than noncancer patients, with lung cancer patients having the highest expenditures. Expenditure estimates varied by age group, source of payment, and service type, highlighting the need for comprehensive policies and programs to reduce the costs of cancer care.

Stroke is a life-threatening condition that leads to the death of many people around the world. Reperfusion injury after ischemic stroke is a recurrent problem associated with various surgical procedures that involve the removal of blockages in the brain arteries. Lipid emulsion was recently shown to attenuate ischemic reperfusion injury in the heart and to protect the brain from excitotoxicity. However, investigations on the protective mechanisms of lipid emulsion against ischemia in the brain are still lacking. This study aimed to determine the neuroprotective effects of lipid emulsion in an in vivo rat model of ischemic reperfusion injury through middle cerebral artery occlusion (MCAO). Under sodium pentobarbital anesthesia, rats were subjected to MCAO surgery and were administered with lipid emulsion through intra-arterial injection during reperfusion. The experimental animals were assessed for neurological deficit wherein the brains were extracted at 24 h after reperfusion for triphenyltetrazolium chloride staining, immunoblotting and qPCR. Neuroprotection was found to be dosage-dependent and the rats treated with 20% lipid emulsion had significantly decreased infarction volumes and lower Bederson scores. Phosphorylation of Akt and glycogen synthase kinase 3-β (GSK3-β) were increased in the 20% lipid-emulsion treated group. The Wnt-associated signals showed a marked increase with a concomitant decrease in signals of inflammatory markers in the group treated with 20% lipid emulsion. The protective effects of lipid emulsion and survival-related expression of genes such as Akt, GSK-3β, Wnt1 and β-catenin were reversed by the intra-peritoneal administration of XAV939 through the inhibition of the Wnt/β-catenin signaling pathway. These results suggest that lipid emulsion has neuroprotective effects against ischemic reperfusion injury in the brain through the modulation of the Wnt signaling pathway and may provide potential insights for the development of therapeutic targets.

PurposeTo determine the efficacy and safety of oral propranolol as a first-line treatment for superficially located infantile hemangioma (IH) and propose an assessment tool to measure treatment response.MethodsPatients with superficial IH under 1 year of age were prospectively recruited between May 2012 and December 2013 at the Department of Pediatrics of Chungbuk National University Hospital. Propranolol was administered to 12 infants (median age, 3.8 months) while monitoring cardiovascular and adverse metabolic effects. If a patient showed no adverse events, the dosage was gradually increased up to 3 mg/kg/day and maintained for 1 year. We used our own scoring system to assess treatment response using parameters like change in color, and longest diameter, and thickness of the IH.ResultsEleven out of 12 patients completed the protocol with consistent improvement of hemangiomas during therapy. Patients on propranolol showed a more than 50% involution in the first 3 months, with additional steady involution until 1 year. Patients with the highest scores at 1 month maintained their score and showed better responses until treatment termination. The patient with the lowest score at 1 month did not show any further regression and stopped propranolol treatment 4 months after initiation. In two children with recurrences after successful therapeutic regression, propranolol was effective after being reintroduced. Propranolol treatment was not interrupted in any patient due to adverse events.ConclusionOral propranolol at 3 mg/kg/day showed a consistent, rapid, and therapeutic effect on superficial IHs without significant adverse events.

The 70 kDa heat shock protein (HSP70) is a stress-inducible protein that has been shown to protect the brain from various nervous system injuries. It allows cells to withstand potentially lethal insults through its chaperone functions. Its chaperone properties can assist in protein folding and prevent protein aggregation following several of these insults. Although its neuroprotective properties have been largely attributed to its chaperone functions, HSP70 may interact directly with proteins involved in cell death and inflammatory pathways following injury. Through the use of mutant animal models, gene transfer, or heat stress, a number of studies have now reported positive outcomes of HSP70 induction. However, these approaches are not practical for clinical translation. Thus, pharmaceutical compounds that can induce HSP70, mostly by inhibiting HSP90, have been investigated as potential therapies to mitigate neurological disease and lead to neuroprotection. This review summarizes the neuroprotective mechanisms of HSP70 and discusses potential ways in which this endogenous therapeutic molecule could be practically induced by pharmacological means to ultimately improve neurological outcomes in acute neurological disease.

In the present study, the mechanism of improving HAZ toughness of steel plate with Mg deoxidation after the simulated welding with the heat input of 400 kJ/cm was investigated through in situ observation, characterization with SEM-EDS and TEM-EDS, and thermodynamic calculation. It was found that intragranular acicular ferrite (IAF) and polygonal ferrite (PF) contributed to the improvements of HAZ toughness in steels with Mg deoxidation. With the increase of Mg content in steel, the oxide in micron size inclusion was firstly changed to MgO-Ti2O3, then to MgO with the further increase of Mg content in steel. The formation of nanoscale TiN particles was promoted more obviously with the higher Mg content in the steel. The growth rates of austenite grains at the high-temperature stage (1400~1250 °C) during the HAZ thermal cycle of steels with conventional Al deoxidation and Mg deoxidation containing 0.0027 and 0.0099 wt% Mg were 10.55, 0.89, 0.01 μm/s, respectively. It was indicated that nanoscale TiN particles formed in steel with Mg deoxidation were effective to inhibit the growth of austenite grain. The excellent HAZ toughness of steel plates after welding with a heat input of 400 kJ/cm could be obtained by control of the Mg content in steel to selectively promote the formation of IAF or retard the growth of austenite grain.

PurposeHouse dust mite (HDM) has been suggested to be the most important aeroallergen responsible for atopic asthma in Korea. We aimed to investigate that specific IgE antibodies to HDM and other common indoor aeroallergens contribute differently to total serum IgE and show different relationships with longitudinal fractional exhaled nitric oxide (FeNO) measurements in Korean atopic asthmatic patients.MethodsA total of 193 children aged 8 to 16 years with intermittent or mild persistent atopic asthma were recruited. Sera were assayed for total IgE and specific IgE antibodies to HDM and other common indoor allergens. FeNO was serially measured 10 times or more over 2 years when subjects were not receiving controller medications.ResultsIn 152 children who completed the study, IgE antibodies to specific HDM were more prevalent than those to other common indoor aeroallergens. In addition, IgE antibody titers to HDM were the strongest contributor to total IgE increases. Furthermore, only HDM-specific IgE antibody titer significantly correlated with maximum FeNO (r=0.21, P=0.029) and the rate of FeNO higher than 21 parts per billion (ppb) (r=0.30, P=0.002). Eight patients (5%) were found to have maximum FeNO of 21 ppb or less, suggesting the presence of a low FeNO phenotype among atopic asthmatic patients.ConclusionThe quantity of HDM-specific IgE antibody provides a possible explanation for increases of total IgE and significantly correlates with the amount and frequency of FeNO increases in Korean atopic asthmatic patients.

We report the effect of zirconium oxide (ZrO2) layers on the electrical characteristics of multilayered tin disulfide (SnS2) formed by atomic layer deposition (ALD) at low temperatures. SnS2 is a two-dimensional (2D) layered material which exhibits a promising electrical characteristics as a channel material for field-effect transistors (FETs) because of its high mobility, good on/off ratio and low temperature processability. In order to apply these 2D materials to large-scale and flexible electronics, it is essential to develop processes that are compatible with current electronic device manufacturing technology which should be conducted at low temperatures. Here, we deposited a crystalline SnS2 at 150 °C using ALD, and we then annealed at 300 °C. X-ray diffraction (XRD) and Raman spectroscopy measurements before and after the annealing showed that SnS2 had a hexagonal (001) peak at 14.9° and A1g mode at 313 cm−1. The annealed SnS2 exhibited clearly a layered structure confirmed by the high resolution transmission electron microscope (HRTEM) images. Back-gate FETs with SnS2 channel sandwiched by top and bottom ZrO2 on p++Si/SiO2 substrate were suggested to improve electrical characteristics. We used a bottom ZrO2 layer to increase adhesion between the channel and the substrate and a top ZrO2 layer to improve contact property, passivate surface, and protect from process-induced damages to the channel. ZTZ (ZrO2/SnS2/ZrO2) FETs showed improved electrical characteristics with an on/off ratio of from 0.39×103 to 6.39×103 and a mobility of from 0.0076 cm2/Vs to 0.06 cm2/Vs.

Growing evidence supports a role for soluble amyloid-β oligomer intermediates in the synaptic dysfunction associated with Alzheimer's disease (AD), but the molecular mechanisms underlying this effect remain unclear. We found that acute treatment of cultured rat hippocampal neurons with nanomolar concentrations of Aβ oligomers reduced the recycling pool and increased the resting pool of synaptic vesicles. Endocytosis of synaptic vesicles and the regeneration of fusion-competent vesicles were also severely impaired. Furthermore, the release probability of the readily-releasable pool (RRP) was increased, and recovery of the RRP was delayed. All these effects were prevented by antibody against Aβ. Moreover reduction of the pool size was prevented by inhibiting calpain or CDK5, while the defects in endocytosis were averted by overexpressing phosphatidylinositol-4-phosphate-5-kinase type I-γ, indicating that these two downstream pathways are involved in Aβ oligomers-induced presynaptic dysfunction.

This research deals with mobile robot SLAM algorithm based on extended kalman filter. To enhance a accuracy of robot pose, one more extended kalman filter is used in a rough surface environment. The robot has uncertain kinematic model due to a caterpillar. When the robot drives on irregular surface, it's heading can be corrupted. We propose a method to correct uncertain robot pose using one more extended kalman filter through simulation results.