Progranulin Deficiency Promotes Circuit-Specific Synaptic Pruning by Microglia via Complement Activation.

Microglia maintain homeostasis in the brain, but whether aberrant microglial activation can cause neurodegeneration remains controversial. Here, we use transcriptome profiling to demonstrate that deficiency in frontotemporal dementia (FTD) gene progranulin (Grn) leads to an age-dependent, progressive upregulation of lysosomal and innate immunity genes, increased complement production, and enhanced synaptic pruning in microglia. During aging, Grn(-/-) mice show profound microglia infiltration and preferential elimination of inhibitory synapses in the ventral thalamus, which lead to hyperexcitability in the thalamocortical circuits and obsessive-compulsive disorder (OCD)-like grooming behaviors. Remarkably, deleting C1qa gene significantly reduces synaptic pruning by Grn(-/-) microglia and mitigates neurodegeneration, behavioral phenotypes, and premature mortality in Grn(-/-) mice. Together, our results uncover a previously unrecognized role of progranulin in suppressing aberrant microglia activation during aging. These results represent an important conceptual advance that complement activation and microglia-mediated synaptic pruning are major drivers, rather than consequences, of neurodegeneration caused by progranulin deficiency.

Conformational surveillance of Orai1 by a rhomboid intramembrane protease prevents inappropriate CRAC channel activation.

Calcium influx through plasma membrane calcium release-activated calcium (CRAC) channels, which are formed of hexamers of Orai1, is a potent trigger for many important biological processes, most notably in T cell-mediated immunity. Through a bioinformatics-led cell biological screen, we have identified Orai1 as a substrate for the rhomboid intramembrane protease RHBDL2. We show that RHBDL2 prevents stochastic calcium signaling in unstimulated cells through conformational surveillance and cleavage of inappropriately activated Orai1. A conserved disease-linked proline residue is responsible for RHBDL2's recognizing the active conformation of Orai1, which is required to sharpen switch-like signaling triggered by store-operated calcium entry. Loss of RHBDL2 control of CRAC channel activity causes severe dysregulation of downstream CRAC channel effectors, including transcription factor activation, inflammatory cytokine expression, and T cell activation. We propose that this surveillance function may represent an ancient activity of rhomboid proteases in degrading unwanted signaling proteins.

RTL1/PEG11 imprinted in human and mouse brain mediates anxiety-like and social behaviors and regulates neuronal excitability in the locus coeruleus.

RTL1/PEG11, which has been associated with anxiety disorders, is a retrotransposon-derived imprinted gene in the placenta. However, imprinting patterns and functions of RTL1 in the brain have not been well-investigated. We found Rtl1 was paternally, but not maternally, expressed in brain stem, thalamus, and hypothalamus of mice, and imprinting status of RTL1 was maintained in human brain. Paternal Rtl1 knockout (Rtl1m+/p-) mice had higher neonatal death rates due to impaired suckling, and low body weights beginning on embryonic day 16.5. High paternal expression of Rtl1 was detected in the locus coeruleus (LC) and Rtl1m+/p- mice showed an increased delay in time of onset for action potentials and inward currents with decreased neuronal excitability of LC neurons. Importantly, Rtl1m+/p- mice exhibited behaviors associated with anxiety, depression, fear-related learning and memory, social dominance, and low locomotor activity. Taken together, our findings demonstrate RTL1 is imprinted in brain, mediates emotional and social behaviors, and regulates excitability in LC neurons.

Comparing transfusion reactions between pre-storage and post-storage leukoreduced apheresis platelets: an analysis using propensity score matching.

Transfusion reactions induced by platelet transfusions may be reduced and alleviated by leukocyte reduction of platelets. Although leukoreduction of apheresis platelets can be performed either pre-storage or post-storage, seldom studies directly compare the incidence of transfusion reaction in these two different blood products. We conducted a retrospective study to compare the transfusion reactions between pre-storage and post-storage leukoreduced apheresis platelets. We reviewed the general characteristics and the transfusion reactions, symptoms, and categories for inpatients who received pre-storage or post-storage leukoreduced apheresis platelets. Propensity-score matching was performed to adjust for baseline differences between groups. A total of 40,837 leukoreduction apheresis platelet orders were reviewed. 116 (0.53%) transfusion reactions were reported in 21,884 transfusions with pre-storage leukoreduction, and 174 (0.91%) reactions were reported in 18,953 transfusions with post-storage leukoreduction. Before propensity-score matching, the odds ratio for transfusion reactions in the pre-storage group relative to the post-storage group was 0.57 (95% confidence interval [CI] 0.45-0.72, P < 0.01); the odds ratio after matching was 0.63 (95% CI 0.49-0.80, P < 0.01). A two-proportion z-test revealed pre-storage leukoreduction significantly decreases the symptoms of chills, fever, itching, urticaria, dyspnea, and hypertension as compared with those in post-storage leukoreduction. Pre-storage leukoreduced apheresis platelet significantly decreased febrile non-hemolytic transfusion reaction as compared with post-storage groups. This study suggests pre-storage leukoreduction apheresis platelet significantly decreases the transfusion reaction as compared with those in post-storage leukoreduction.

Physician adherence to anaphylaxis guidelines among different age groups in emergency departments: 20-Year observational study.

BACKGROUND: Anaphylaxis is an acute and serious allergic reaction. Little is known about physician adherence to anaphylaxis guidelines among patients across different age groups. OBJECTIVE: To investigate real-world physician adherence to anaphylaxis guidelines among children, adults, and older adults in emergency departments. METHODS: This study retrospectively analyzed all consecutive patients with anaphylaxis who presented to 2 emergency departments at 2 branches of the largest tertiary hospital in Taiwan, between 2001 and 2020. Patients who met the diagnostic criteria for anaphylaxis were enrolled and grouped by age: children (<18 years), adults (18-64 years), and older adults (≥65 years). RESULTS: We enrolled 771 patients with anaphylaxis (159 children, 498 adults, and 114 older adults). Intramuscular epinephrine was administered in 294 cases (38.1%). There was a significant age-group difference in the rate of intramuscular epinephrine administration (46.5% in children, 37.3% in adults, and 29.8% in older adults; P trend = .004). When stratified by severity, 14.3% of older adults with moderate reactions received intramuscular epinephrine, whereas 35.2% of adults and 55.3% of children received intramuscular epinephrine (P trend < .001), whereas such difference was not found in patients with severe reactions. Upon discharge from emergency departments, 15.3% received allergist referral (52.2% in children, 6.6% in adults, and 1.8% in older adults; P trend < .001); 12.5% received education on avoidance of triggers (18.9%, 11.4%, and 7.9%; P trend = .01), and 16.1% received education on alarm symptoms (21.4%, 15.1%, and 13.2%; P trend = .05). CONCLUSION: The real-world physician adherence to anaphylaxis guidelines remains suboptimal in emergency departments, particularly among older adults. Physician continuing education is needed to improve the gap between anaphylaxis guidelines and clinical practice.

Low-dose prasugrel versus standard-dose ticagrelor in east Asian patients with acute coronary syndrome.

Low-dose prasugrel demonstrated a similar effectiveness profile to clopidogrel in East Asian ACS patients, but its comparison with another new-generation potent P2Y12 inhibitor, ticagrelor, remains unclear. To compare the effectiveness and safety of low-dose prasugrel against those of standard-dose ticagrelor in East Asian patients with ACS. This retrospective cohort study used Taiwan's National Health and Welfare Database. This study included ACS patients who underwent percutaneous coronary intervention and, at discharge between January 1, 2018 and December 31, 2020, were prescribed with low-dose prasugrel plus aspirin or standard-dose ticagrelor plus aspirin. Stabilized inverse probability of treatment weighting was used to balance the covariates across these two groups. The primary effectiveness outcome was a composite of acute myocardial infarction, ischemic stroke, and cardiovascular death; the secondary effectiveness outcome was each of the individual components of the primary outcome, transient ischemic attack, and repeat revascularization. The primary safety outcome was a composite of intracranial hemorrhage and gastrointestinal bleeding, and the two secondary safety outcomes were intracranial hemorrhage and gastrointestinal bleeding. A total of 24,807 patients were included in this study. Among them, 1,493 were low-dose prasugrel users and 23,314 were standard-dose ticagrelor users. No significant differences were found in primary effectiveness [HR: 0.97 (0.74-1.28)] or primary safety outcomes [HR: 1.22 (0.73-2.01)] between the two study groups. For East Asian patients with ACS, low-dose prasugrel provides comparable effectiveness without increasing bleeding risk compared to standard-dose ticagrelor. Low-dose prasugrel may be an appropriate alternative for East Asian populations.

Optical Effects of Focused Fractional Nanosecond 1064-nm Nd:YAG Laser: Techniques of Application on Human Skin.

BACKGROUND AND OBJECTIVES: Considering the pulse widths of picosecond and nanosecond lasers used in cutaneous laser surgery differ by approximately one order of magnitude, can nanosecond lasers produce the optical effect in human skin similar to laser-induced optical breakdown (LIOB) caused by picosecond lasers? METHODS: Cutaneous changes induced by a focused fractional nanosecond 1064-nm Nd:YAG laser were evaluated by VISIA-CR imaging, histological examination, and harmonic generation microscopy (HGM). RESULTS: A focused fractional nanosecond 1064-nm Nd:YAG laser can generate epidermal vacuoles or dermal cavities similar to the phenomenon of LIOB produced by picosecond lasers. The location and extent of photodisruption can be controlled by the laser fluence and focus depth. Moreover, laser-induced shock wave propagation and thermal degeneration of papillary collagen can be observed by HGM imaging. CONCLUSION: Focused fractional nanosecond lasers can produce an optical effect on human skin similar to LIOB caused by picosecond lasers. With techniques of application, the treatment can induce epidermal and dermal repair mechanisms in a tunable fashion to improve skin texture, wrinkles, scars, and dyspigmentation, without disrupting the epidermal surface.

Contemporary Management of Pediatric Brainstem Tumors.

Brain tumors are the second most common malignancy in childhood. Around 15-20% of pediatric brain tumors occur in the brainstem. The most common type of brainstem tumor are diffuse tumors in the ventral pons, whereas focal tumors tend to arise from the midbrain, medulla, and dorsal pons. Glioma is the most common pathological entity. Contemporary management consists of surgery, radiotherapy, chemotherapy, and other adjuvant treatment. Surgical options range from biopsy to radical excision. Biopsy can be performed for diagnostic and prognostic purposes, or in the setting of clinical trials, mainly for diffuse intrinsic pontine gliomas. For focal tumors, surgeons need to carefully balance clinical outcomes against possible neurological sequelae in order to achieve maximal safe resection. Radiotherapy is essential for control of high-grade tumors and may be applied to residual or recurrent low-grade tumors. Proton therapy may provide similar efficacy and less neurotoxicity in comparison to conventional photon therapy. Oncological treatment continues to evolve from conventional chemotherapy to targeted therapy, immunotherapy, and other novel treatment methods and holds great potential as adjuvant therapy for pediatric brainstem tumors.

Differential effects of long- and short-term exposure to PM2.5 on accelerating telomere shortening: from in vitro to epidemiological studies.

Exposure to air pollutants has been associated with DNA damage and increases the risks of respiratory diseases, such as asthma and COPD; however short- and long-term effects of air pollutants on telomere dysfunction remain unclear. We investigated the impact of short- and long-term exposure to fine particulate matter with an aerodynamic diameter below 2.5 µm (PM2.5) on telomere length in human bronchial epithelial BEAS-2B cells, and assessed the potential correlation between PM2.5 exposure and telomere length in the LIGHTS childhood cohort study. We observed that long-term, but not short-term, PM2.5 exposure was significantly associated with telomere shortening, along with the downregulation of human telomerase reverse transcriptase (hTERT) mRNA and protein levels. Moreover, long-term exposure to PM2.5 induced proinflammatory cytokine secretion, notably interleukin 6 (IL-6) and IL-8, triggered subG1 cell cycle arrest, and ultimately caused cell death. Long-term exposure to PM2.5 upregulated the LC3-II/ LC3-I ratio but led to p62 protein accumulation in BEAS-2B cells, suggesting a blockade of autophagic flux. Moreover, consistent with our in vitro findings, our epidemiological study found significant association between annual average exposure to higher PM2.5 and shortening of leukocyte telomere length in children. However, no significant association between 7-day short-term exposure to PM2.5 and leukocyte telomere length was observed in children. By combining in vitro experimental and epidemiological studies, our findings provide supportive evidence linking potential regulatory mechanisms to population level with respect to long-term PM2.5 exposure to telomere shortening in humans.

Slow Well-Being Gardening: Creating a Sensor Network for Radiation Therapy Patients via Horticultural Therapeutic Activity.

Well-being can reflect people's psychological conditions and be used alongside physiological parameters to evaluate patients' physical and mental health. The modern medical environment increasingly incorporates digital carriers, human-computer interaction devices, sensible spaces, and the execution of suitable algorithms. Slow design in healthy human-computer interaction is often used to reflect people's dependence on or support from behaviors or objects, promoting the stability of behaviors as well as meaningful and positive changes. Therefore, in this study, we propose a slow sensing model, develop a Slow Well-Being Gardening system, and use it to evaluate behavioral data from radiation therapy patients during treatment sessions and horticultural therapy. This study is based on SENS and slow design, setting the hospital lounge as a sensible space and establishing a sensor system. After a 10-day inspection, the process was evaluated and verified. Ultimately, data from facial detection (smile) and HRV showed that the patients in the experimental group experienced a significant improvement in their well-being, feeling better than those in the control group who maintained the most common state in normal treatment. Therefore, it can be inferred that the Slow Well-Being Gardening model is indeed valid and can be further developed.

Histone deacetylase III interactions with BK polyomavirus large tumor antigen may affect protein stability.

BACKGROUND: Human polyomavirus BK (BKPyV) causes associated nephropathy and contributes to urinary tract cancer development in renal transplant recipients. Large tumor antigen (LT) is an early protein essential in the polyomavirus life cycle. Protein acetylation plays a critical role in regulating protein stability, so this study investigated the acetylation of the BKPyV LT protein. METHODS: The BKPyV LT nucleotide was synthesized, and the protein was expressed by transfection into permissive cells. The BKPyV LT protein was immunoprecipitated and subjected to LC-MS/MS analysis to determine the acetylation residues. The relative lysine was then mutated to arginine in the LT nucleotide and BKPyV genome to analyze the role of LT lysine acetylation in the BKPyV life cycle. RESULTS: BKPyV LT acetylation sites were identified at Lys3 and Lys230 by mass spectrometry. HDAC3 and HDAC8 and their deacetylation activity are required for BKPyV LT expression. In addition, mutations of Lys3 and Lys230 to arginine increased LT expression, and the interaction of HDAC3 and LT was confirmed by coimmunoprecipitation. CONCLUSIONS: HDAC3 is a newly identified protein that interacts with BKPyV LT, and LT acetylation plays a vital role in the BKPyV life cycle.

In vivo miRNA knockout screening identifies miR-190b as a novel tumor suppressor.

MicroRNAs (miRNAs) play important roles in the development of various cancers including lung cancer which is one of the devastating diseases worldwide. How miRNAs function in de novo lung tumorigenesis remains largely unknown. We here developed a CRISPR/Cas9-mediated dual guide RNA (dgRNA) system to knockout miRNAs in genetically engineered mouse model (GEMM). Through bioinformatic analyses of human lung cancer miRNA database, we identified 16 downregulated miRNAs associated with malignant progression and performed individual knockout with dgRNA system in KrasG12D/Trp53L/L (KP) mouse model. Using this in vivo knockout screening, we identified miR-30b and miR-146a, which has been previously reported as tumor suppressors and miR-190b, a new tumor-suppressive miRNA in lung cancer development. Over-expression of miR-190b in KP model as well as human lung cancer cell lines significantly suppressed malignant progression. We further found that miR-190b targeted the Hus1 gene and knockout of Hus1 in KP model dramatically suppressed lung tumorigenesis. Collectively, our study developed an in vivo miRNA knockout platform for functionally screening in GEMM and identified miR-190b as a new tumor suppressor in lung cancer.

Association of exposure to environmental vanadium and manganese with lung function among young children: A population-based study.

Exposure to environmental metals has been associated with health outcomes including respiratory health. Little is known about the impact of exposure to environmental metals on lung function among young children in general population. This study aimed to investigate the associations of exposure to metals with lung function among young children in a population-based cohort. A total of 1488 children aged 5-8 years attended a follow-up visit as part of the Longitudinal Investigation of Global Health in Taiwanese Schoolchildren (LIGHTS) cohort. We measured urinary samples of vanadium (median: 1.21 ng/mL; interquartile range (IQR): 0.73-1.98), manganese (median: 0.23 ng/mL; IQR: 0.13-0.47), arsenic (median: 40.51 ng/mL; IQR: 21.66-70.49), nickel (median: 1.09 ng/mL; IQR: 0.31-3.60), and cadmium (median: 0.26 ng/mL; IQR: 0.11-0.43) and performed lung function tests. Urinary vanadium concentrations were inversely associated with FVC (ß coefficient for the highest quartile versus the other quartiles: -33.40, p = 0.001), FEV1 (ß: -41.31, p < 0.001), FEV1/FVC ratio (ß: -1.00, p = 0.009), PEF (ß: -92.12, p = 0.004), and FEF25-75 (ß: -82.85, p < 0.001), after adjusting for relevant confounders. Urinary manganese concentrations were inversely associated with FVC (ß: -26.60, p = 0.007), FEV1 (ß: -31.62, p = 0.001), PEF (ß: -84.86, p = 0.009), and FEF25-75 (ß: -69.21, p = 0.002). Stratification analyses found inverse associations of urinary vanadium and manganese concentrations with lung function parameters predominantly among children exposed to environmental tobacco smoke. We did not find significant associations of urinary arsenic, nickel, and cadmium concentrations with lung function parameters. In conclusion, this study adds new evidence showing inverse associations of vanadium and manganese exposure with lung function among young children in the general population. Children with environmental tobacco smoke exposure are particularly vulnerable to adverse impact of vanadium and manganese exposure on lung function.

SENS+: A Co-Existing Fabrication System for a Smart DFA Environment Based on Energy Fusion Information.

In factories, energy conservation is a crucial issue. The co-fabrication space is a modern-day equivalent of a new factory type, and it makes use of Internet of Things (IoT) devices, such as sensors, software, and online connectivity, to keep track of various building features, analyze data, and produce reports on usage patterns and trends that can be used to improve building operations and the environment. The co-fabrication user requires dynamic and flexible space, which is different from the conventional user's usage. Because the user composition in a co-fabrication space is dynamic and unstable, we cannot use the conventional approach to assess their usage and rentals. Prototyping necessitates a specifically designed energy-saving strategy. The research uses a "seeing-moving-seeing" design thinking framework, which enables designers to more easily convey their ideas to others through direct observation of the outcomes of their intuitive designs and the representation of their works through design media. The three components of human behavior, physical manufacture, and digital interaction are primarily the focus of this work. The computing system that connects the physical machine is created through communication between the designer and the digital interface, giving the designer control over the physical machine. It is an interactive fabrication process formed by behavior. The Sensible Energy System+ is an interactive fabrication process of virtual and real coexistence created by combining the already-existing technology, the prototype fabrication machine, and SENS. This process analyzes each step of the fabrication process and energy, fits it into the computing system mode to control the prototype fabrication machine, and reduces the problem between virtual and physical fabrication and energy consumption.

Enhanced IRE1α Phosphorylation/Oligomerization-Triggered XBP1 Splicing Contributes to Parkin-Mediated Prevention of SH-SY5Y Cell Death under Nitrosative Stress.

Mutations in parkin, a neuroprotective protein, are the predominant cause of autosomal recessive juvenile Parkinson's disease. Neuroinflammation-derived nitrosative stress has been implicated in the etiology of the chronic neurodegeneration. However, the interactions between genetic predisposition and nitrosative stress contributing to the degeneration of dopaminergic (DA) neurons remain incompletely understood. Here, we used the SH-SY5Y neuroblastoma cells to investigate the function of parkin and its pathogenic mutants in relation to cell survival under nitric oxide (NO) exposure. The results showed that overexpression of wild-type parkin protected SH-SY5Y cells from NO-induced apoptosis in a reactive oxygen species-dependent manner. Under nitrosative stress conditions, parkin selectively upregulated the inositol-requiring enzyme 1α/X-box binding protein 1 (IRE1α/XBP1) signaling axis, an unfolded protein response signal through the sensor IRE1α, which controls the splicing of XBP1 mRNA. Inhibition of XBP1 mRNA splicing either by pharmacologically inhibiting IRE1α endoribonuclease activity or by genetically knocking down XBP1 interfered with the protective activity of parkin. Furthermore, pathogenic parkin mutants with a defective protective capacity showed a lower ability to activate the IRE1α/XBP1 signaling. Finally, we demonstrated that IRE1α activity augmented by parkin was possibly mediated through interacting with IRE1α to regulate its phosphorylation/oligomerization processes, whereas mutant parkin diminished its binding to and activation of IRE1α. Thus, these results support a direct link between the protective activity of parkin and the IRE1α/XBP1 pathway in response to nitrosative stress, and mutant parkin disrupts this function.

Roles of IL-1 and IL-10 family cytokines in the progression of systemic lupus erythematosus: Friends or foes?

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease of unknown etiology that can affect nearly every organ system in the body. Besides genetic and environmental factors, unbalanced pro-inflammatory and anti-inflammatory cytokines contribute to immune dysregulation, trigger an inflammatory response, and induce tissue and organ damage. Inflammatory responses in SLE can be promoted and/or maintained by the availability of cytokines that are overproduced systemically and/or in local tissues. Several key cytokines have been considered potential targets for the reduction of chronic inflammation in SLE. Recent studies indicated that dysregulated production of several cytokines, including those of the IL-1 family and IL-10 family, orchestrate immune activation and self-tolerance, play critical roles in the pathogenesis of SLE. Among IL-1 family cytokines, IL-1, IL-18, IL-33, IL-36, IL-37, and IL-38 had been the most thoroughly investigated in SLE. Additionally, IL-10 family cytokines, IL-10, IL-20, IL-22, IL-26, IL-28, and IL-29 are dysregulated in SLE. Therefore, a better understanding of the initiation and progression of SLE may provide suitable novel targets for therapeutic intervention. In this review, we discuss the involvement of inflammation in the pathogenesis of SLE, with a focus on IL-1 family and IL-10 family cytokines, and highlight pathophysiological approaches and therapeutic potential for treating SLE.

Association of advanced paternal age with lung function at school age.

BACKGROUND: Epidemiological studies suggest that advanced paternal age impact offspring health, but its impact on respiratory health is unclear. This study aimed to investigate the association of paternal age with lung function and fraction of exhaled nitric oxide (FeNO) in children. METHODS: We analyzed data from 1330 single-born children (576 girls, 43.3%; mean age, 6.4 years), who participated in the Longitudinal Investigation of Global Health in Taiwanese Schoolchildren (LIGHTS) cohort and received measurements of lung function and FeNO at 6-year follow-up visits. Covariate-adjusted regression analyses were applied. RESULTS: Every 5-year increase in paternal age at birth was associated with 0.51% decrease in FEV1/FVC ratio (95% CI - 0.86 to - 0.15; p = 0.005) and 19.86 mL/s decrease in FEF75 (95% CI: - 34.07 to - 5.65; p = 0.006). Stratified analyses revealed that increasing paternal age at birth was associated with decreasing FEV1/FVC ratio and FEF75 only among children with prenatal exposure to environmental tobacco smoke (ETS) or not being breastfed. Sensitivity analyses using paternal age as a categorical variable found decreasing FEV1/FVC ratio and FEF75 in the groups of paternal age 35-39 and ≥ 40 years. There was no association of paternal age at birth with FeNO. CONCLUSION: Our findings provide novel evidence linking advanced paternal age at birth with decreasing lung function in children at school age. Children with prenatal exposure to ETS or not being breastfed are more vulnerable to the adverse effect of advanced paternal age on childhood lung function. Further studies are warranted to confirm this novel adverse effect of advanced paternal age.

Cord blood IgE predicts allergic sensitization, elevation of exhaled nitric oxide, and asthma in schoolchildren.

BACKGROUND: Few data are available in Asian children regarding the validity of cord blood immunoglobulin E (IgE) in predicting allergic sensitization and pulmonary function. The relationship between cord blood IgE and fraction of exhaled nitric oxide (FeNO) remains unknown. This study investigated the associations of cord blood IgE with allergic sensitization, FeNO, pulmonary function, and allergic diseases in Asian children. METHODS: Five hundred and sixty-six Asian children with valid cord blood IgE measurements at birth participated a 6-year follow-up visit including a questionnaire, serum total and allergen-specific IgE, FeNO measurement, and spirometry. Regression-based analyses with covariates adjustment were applied. RESULTS: Cord blood IgE levels were significantly associated with FeNO levels (ß = 0.131, p < .001) and serum total IgE levels (ß = 0.325, p < .001). Cord blood IgE levels were positively associated with allergic sensitization (adjusted odds ratio [AOR] = 2.22, p < .001), and sensitization to mites (p = .002), animals (p = .023), and foods (p = .048). Subjects with cord blood IgE ≥0.24 kU/L (the optimal cutoff) were significantly associated with an increased risk of allergic sensitization (AOR = 2.63, p < .001) and asthma (AOR = 2.35, p = .024) than those with cord blood IgE <0.24 kU/L. Subjects with cord blood IgE ≥0.24 kU/L had significantly higher FeNO levels than those with cord blood IgE <0.24 kU/L (p = .028). There were no significant associations between cord blood IgE levels and pulmonary function parameters. CONCLUSION: Cord blood IgE ≥0.24 kU/L predicts allergic sensitization, FeNO elevation, and asthma among Asian schoolchildren, suggesting cord blood IgE would be useful for identifying newborns at risk of subsequent allergic sensitization and allergic airway inflammation.

Integration of immunohistochemistry, RNA sequencing, and multiplex ligation-dependent probe amplification for molecular classification of pediatric medulloblastoma.

BACKGROUND: Medulloblastoma (MB) is commonly classified into four molecular groups, that is, WNT, SHH, group 3, and group 4, for prognostic and therapeutic purposes. METHODS: Here we applied immunohistochemistry (IHC) and RNA sequencing (RNA-seq) for the molecular classification of MB, and utilized multiplex ligation-dependent probe amplification (MLPA) to determine chromosomal alterations and specific gene amplifications. RESULTS: We retrospectively enrolled 37 pediatric MB patients. Twenty-three had genomic material available for gene/RNA analysis. For IHC, ß-catenin, GAB1, and YAP were the biomarkers to segregate MB into three subgroups, WNT (1/23), SHH (5/23), and non-WNT/non-SHH (17/23). However, four cases (17.3%) were found to be misclassified after analysis by RNA-seq. The result of MLPA revealed two group 3 tumors carrying MYC amplification, and three SHH tumors harboring MYCN amplification. While IHC provided rapid subgroup stratification, it might result in incorrect subgrouping. Thus, validation of the IHC result with genomic data analysis by RNA-seq or other tools would be preferred. In addition, MLPA can detect important genetic alterations and is helpful for the identifications of high-risk patients. CONCLUSIONS: Our study revealed that integration of these diagnostic tools can provide a precise and timely classification of MB, optimizing an individualized, risk-directed postoperative adjuvant therapy for these patients. This workflow can be applied in a countrywide fashion to guide future clinical trials for patients with MB.

Efficacy and Safety of "I-Stop-Mini Adjustable" Sling System versus Transobturator Midurethral "Obtryx" Sling System in Stress Urinary Incontinence: A Retrospective Cohort Study.

STUDY OBJECTIVE: To compare the safety, efficacy, and adverse events of the new mini-adjustable sling system "I-stop-mini" with transobturator midurethral slings "Obtryx" (Boston Scientific, Marlborough, MA) in women with stress urinary incontinence. DESIGN: A single-center, retrospective cohort study. SETTING: Department of Obstetrics and Gynecology, Taipei Veterans General Hospital, Taiwan. PATIENTS: A total of 347 patients who underwent I-stop-mini or Obtryx for stress urinary incontinence treatment. INTERVENTIONS: Midurethral sling with either I-stop-mini or Obtryx. MEASUREMENTS AND MAIN RESULTS: The primary outcomes were objective success and subjective cure rates between the 2 groups. Objective success was evaluated using a 1-hour pad test, and subjective cure was evaluated using a questionnaire score (Incontinence Impact Questionnaire, Urinary Distress Inventory, and International Consultation on Incontinence Questionnaire Short Form). Secondary outcomes were the evaluation of surgical outcomes, operative data, and adverse events between the 2 groups. In total, 171 of 200 I-stop-mini subjects and 127 of 147 Obtryx subjects completed 12 months of follow-up. Regarding the objective success between the I-stop-mini group and the Obtryx group, 1-month postoperative (3.6 ± 5.2 vs 3.9 ± 12.6; p = .765), 6-month postoperative (3.9 ± 5.1 vs 4.2 ± 12.6; p = .848), and 12-month postoperative (4.6 ± 5.6 vs 4.5 ± 13.6; p = .980) 1-hour pad tests showed no significant difference. The 12-month subjective cure rates decreased from 94.7% (1-month postoperative) to 91.2% (12-month postoperative) in the I-stop-mini group and 95.2% (1-month postoperative) to 85.0% (12-month postoperative) in the Obtryx group. Similar and durable efficacy was observed between the 2 groups. The I-stop-mini group had shorter operative times and hospital stays than the Obtryx group; however, both groups showed similar adverse event rates. CONCLUSION: The objective success and subjective cure rates of I-stop-mini did not differ to those of Obtryx. However, long-term data and further prospective studies on I-stop-mini are necessary to arrive at a definite conclusion.