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In this paper, dynamic analysis of a multi-battery dual mode charger, powered by a single solar array and suitable for lead-acid and lithium-ion cell-based batteries is presented. Each battery is interfaced to the solar array by means of a current-controlled buck power stage, operating either in constant power or constant voltage mode. Operation in former/latter charging mode implies regulating input/output voltage of the converter, which is a non-trivial situation since while feeding different batteries, all the converters share the same input terminals, connected to the solar array. It is revealed that when at least one of the batteries operates in constant power charging mode, open-loop instability occurs whenever converter input voltage is lower than maximum power point voltage of the solar array. Consequently, input voltage regulating controller must be designed to stabilize closed-loop dynamics for the worst case of instability, which is also derived. Moreover, it is shown that the dynamics of the converters operating under output voltage control are perceived as disturbances by input voltage control loop and must be properly rejected. Simple loop shaping design is proposed based on a PI controller, allowing stabilizing the system in case of worst case instability and rejecting output voltage control induced disturbances at the expense of non-constant, operating-point dependent closed-loop damping.

The transcriptional response of β-actin to extra-cellular stimuli is a paradigm for transcription factor complex assembly and regulation. Serum induction leads to a precisely timed pulse of β-actin transcription in the cell population. Actin protein is proposed to be involved in this response, but it is not known whether cellular actin levels affect nuclear β-actin transcription. We perturbed the levels of key signaling factors and examined the effect on the induced transcriptional pulse by following endogenous β-actin alleles in single living cells. Lowering serum response factor (SRF) protein levels leads to loss of pulse integrity, whereas reducing actin protein levels reveals positive feedback regulation, resulting in elevated gene activation and a prolonged transcriptional response. Thus, transcriptional pulse fidelity requires regulated amounts of signaling proteins, and perturbations in factor levels eliminate the physiological response, resulting in either tuning down or exaggeration of the transcriptional pulse.

Acute myocardial infarction and perforated peptic ulcer disease with associated peritonitis are both medical emergencies requiring urgent intervention. This patient presented with both emergencies simultaneously. Current literature is devoid of guidance as to which should be addressed initially. A multidisciplinary discussion was conducted leading to a unanimous decision for initiating percutaneous coronary intervention (PCI). After successful PCI, the patient was immediately taken to the operating room for laparoscopic repair of the perforated viscous. Subsequent to the operative repair, the patient became hemodynamically unstable and a repeat electrocardiogram demonstrated complete right coronary occlusion. Shock ensued and the patient died in the intensive care unit despite this plan of care. It is our opinion that this case reveals the need for expert panels to devise decision algorithms for concomitant presentations of life-threatening diseases.

Purpose: To describe the clinical course of a patient with a retrobulbar orbital tumor causing myopic shift and macular pucker. Observation: Following complete surgical removal of a retrobulbar orbital cavernous hemangioma, the myopic shift improved but the macular pucker persisted even 3 years after orbital surgery, with no sign of tumor recurrence. Conclusion and importance: Chorioretinal folds secondary to chronic mechanical force from an orbital tumor may persist long after the tumor is removed. This case may assist ophthalmologists in their discussions with, and counseling of, patients regarding visual prognosis following excision of orbital tumors that are causing retinal changes. Keywords: Cavernous hemangioma, Macular pucker, Choroidal folds, Orbit tumor, Orbit mass

The heuristic perturb-and-observe-based maximum-power-point tracking (MPPT) algorithm of photovoltaic (PV) generator is still the most popular technique in use, despite the broad spectrum of developed other MPPT algorithms. The correct direction of the next perturbation step requires that the previous perturbation is settled down properly and the applied perturbation step size is large enough to overcome the PV-power changes induced by the varying irradiation level and/or the power-grid-originated PV-voltage ripple. The requirements for the minimum perturbation step size are well defined in the available literature. The design equations to predict the PV-power settling time are derived by assuming that the PV-interfacing converter operates in continuous conduction mode (CCM). A large perturbation step size may drive the interfacing converter to enter into discontinuous conduction mode (DCM), which will delay the PV-power settling process and destroy the validity of the predicted settling times. In order to avoid confusing the MPPT process, the maximum perturbation step size has to be limited as well. This paper provides theoretical foundations for the proper design of the maximum step size based on the DC-DC interfacing-converter dynamic behavior. The theoretical findings are validated with experiments as well as by simulations by means of a boost-type DC-DC converter and real PV panel.

β-Glucosidases are key enzymes in the process of cellulose utilization. It is the last enzyme in the cellulose hydrolysis chain, which converts cellobiose to glucose. Since cellobiose is known to have a feedback inhibitory effect on a variety of cellulases, β-glucosidase can prevent this inhibition by hydrolyzing cellobiose to non-inhibitory glucose. While the optimal temperature of the Clostridium thermocellum cellulosome is 70 °C, C. thermocellum β-glucosidase A is almost inactive at such high temperatures. Thus, in the current study, a random mutagenesis directed evolutionary approach was conducted to produce a thermostable mutant with Kcat and Km, similar to those of the wild-type enzyme. The resultant mutant contained two mutations, A17S and K268N, but only the former was found to affect thermostability, whereby the inflection temperature (Ti) was increased by 6.4 °C. A17 is located near the central cavity of the native enzyme. Interestingly, multiple alignments revealed that position 17 is relatively conserved, whereby alanine is replaced only by serine. Upon the addition of the thermostable mutant to the C. thermocellum secretome for subsequent hydrolysis of microcrystalline cellulose at 70 °C, a higher soluble glucose yield (243%) was obtained compared to the activity of the secretome supplemented with the wild-type enzyme.

OBJECTIVES/SPECIFIC AIMS: Oncostreams represent a novel growth pattern of GBM. In this study we uncovered the cellular and molecular mechanism that regulates the oncostreams function in GBM growth and invasion. METHODS/STUDY POPULATION: We studied oncostreams organization and function using genetically engineered mouse gliomas models (GEMM), mouse primary patient derived GBM model and human glioma biopsies. We evaluated the molecular landscape of oncostreams by laser capture microdissection (LCM) followed by RNA-Sequencing and bioinformatics analysis. RESULTS/ANTICIPATED RESULTS: Oncostreams are multicellular structures of 10-20 cells wide and 2-400 μm long. They are distributed throughout the tumors in mouse and human GBM. Oncostreams are heterogeneous structures positive for GFAP, Nestin, Olig2 and Iba1 cells and negative for Neurofilament. Using GEMM we found a negative correlation between oncostream density and animal survival. Moreover, examination of patient’s glioma biopsies evidenced that oncostreams are present in high grade but no in low grade gliomas. This suggests that oncostreams may play a role in tumor malignancy. Our data also indicated that oncostreams aid local invasion of normal brain. Transcriptome analysis of oncostreams revealed 43 differentially expressed (DE) genes. Functional enrichment analysis of DE genes showed that “collagen catabolic processes”, “positive regulation of cell migration”, and “extracellular matrix organization” were the most over-represented GO biological process. Network analysis indicated that Col1a1, ACTA2, MMP9 and MMP10 are primary target genes. These genes were also overexpressed in more malignant tumors (WT-IDH) compared to the less malignant (IDH1- R132H) tumors. Confocal time lapse imagining of 3D tumor slices demonstrated that oncostreams display a collective motion pattern within gliomas that has not been seen before. DISCUSSION/SIGNIFICANCE OF IMPACT: In summary, oncostreams are anatomically and molecularly distinctive, regulate glioma growth and invasion, display collective motion and are regulated by the extracellular matrix. We propose oncostreams as novel pathological markers valuable for diagnosis, prognosis and designing therapeutics for GBM patients.

Owing to the good trade-off between implementation and performance, fixed-step direct maximum power point tracking techniques (e.g., perturb and observe and incremental conductance algorithms) have gained popularity over the years. In order to optimize their performance, perturbation frequency and perturbation step size are usually determined a priori. While the first mentioned design parameter is typically dictated by the worst-case settling time of the combined energy conversion system, the latter must be high enough to both differentiate the system response from that caused by irradiation variation and match the finite resolution of the analog-to-digital converter in case of digital implementation. Well-established design guidelines, however, aim to optimize steady-state algorithm performance while leaving transients nearly untreated. To improve transient behavior while keeping the steady-state operation unaltered, variable step direct maximum power point tracking algorithms based on adaptive perturbation step size were proposed. This paper proposes a concept of utilizing adaptive perturbation frequency rather than variable step size, based on recently revised guidelines for designing fixed-step direct maximum power point tracking techniques. Preliminary results demonstrate the superiority of the proposed method over adaptive perturbation step size operation during transients, without compromising the steady state performance.

Given a Gaussian stationary increment processes, we show that a Skorokhod-Hitsuda stochastic integral with respect to this process, which obeys the Wick-Itô calculus rules, can be naturally defined using ideas taken from Hida's white noise space theory. We use the Bochner-Minlos theorem to associate a probability space to the process, and define the counterpart of the S-transform in this space. We then use this transform to define the stochastic integral and prove an associated Itô formula.

An analytical method of evaluating vehicle fuel consumption under standard operating conditions is presented. In the proposed model, vehicle fuel consumption is separated into two different operating modes: cruising at constant speed and acceleration. In each of these modes fuel consumption is calculated based on the instantaneous engine efficiency, approximated using an analytical function rather than typically considered consumption map. The approximation is based on speed-power decoupling, employing two single dimension polynomials instead of a two-dimensional lookup table. The adequacy and accuracy of the model is verified using experimental calculations. Moreover, it is shown that the effect of various design parameters on vehicle fuel consumption can be studied utilizing the proposed model.

Parkinsonism is associated with major changes in neuronal activity throughout the cortico-basal ganglia loop. Current measures quantify changes in baseline neuronal and network activity but do not capture alterations in information propagation throughout the system. Here, we applied a novel non-invasive magnetic stimulation approach using a custom-made mini-coil that enabled us to study transmission of neuronal activity throughout the cortico-basal ganglia loop in both normal and parkinsonian primates. By magnetically perturbing cortical activity while simultaneously recording neuronal responses along the cortico-basal ganglia loop, we were able to directly investigate modifications in descending cortical activity transmission. We found that in both the normal and parkinsonian states, cortical neurons displayed similar multi-phase firing rate modulations in response to magnetic stimulation. However, in the basal ganglia, large synaptically driven stereotypic neuronal modulation was present in the parkinsonian state that was mostly absent in the normal state. The stimulation-induced neuronal activity pattern highlights the change in information propagation along the cortico-basal ganglia loop. Our findings thus point to the role of abnormal dynamic activity transmission rather than changes in baseline activity as a major component in parkinsonian pathophysiology. Moreover, our results hint that the application of transcranial magnetic stimulation (TMS) in human patients of different disorders may result in different neuronal effects than the one induced in normal subjects.

The Bene Israel Jewish community from West India is a unique population whose history before the 18th century remains largely unknown. Bene Israel members consider themselves as descendants of Jews, yet the identity of Jewish ancestors and their arrival time to India are unknown, with speculations on arrival time varying between the 8th century BCE and the 6th century CE. Here, we characterize the genetic history of Bene Israel by collecting and genotyping 18 Bene Israel individuals. Combining with 486 individuals from 41 other Jewish, Indian and Pakistani populations, and additional individuals from worldwide populations, we conducted comprehensive genome-wide analyses based on FST, principal component analysis, ADMIXTURE, identity-by-descent sharing, admixture linkage disequilibrium decay, haplotype sharing and allele sharing autocorrelation decay, as well as contrasted patterns between the X chromosome and the autosomes. The genetics of Bene Israel individuals resemble local Indian populations, while at the same time constituting a clearly separated and unique population in India. They are unique among Indian and Pakistani populations we analyzed in sharing considerable genetic ancestry with other Jewish populations. Putting together the results from all analyses point to Bene Israel being an admixed population with both Jewish and Indian ancestry, with the genetic contribution of each of these ancestral populations being substantial. The admixture took place in the last millennium, about 19-33 generations ago. It involved Middle-Eastern Jews and was sex-biased, with more male Jewish and local female contribution. It was followed by a population bottleneck and high endogamy, which can lead to increased prevalence of recessive diseases in this population. This study provides an example of how genetic analysis advances our knowledge of human history in cases where other disciplines lack the relevant data to do so.

Human monocyte-derived dendritic cells (mdDCs) are versatile cells that are used widely for research and experimental therapies. Although different culture conditions can affect their characteristics, there are no known subpopulations. Since monocytes differentiate into dendritic cells (DCs) in a variety of tissues and contexts, we asked whether they can give rise to different subpopulations. In this work we set out to characterize two human mdDC subpopulations that we identified and termed small (DC-S) and large (DC-L). Morphologically, DC-L are larger, more granular and have a more complex cell membrane. Phenotypically, DC-L show higher expression of a wide panel of surface molecules and stronger responses to maturation stimuli. Transcriptomic analysis confirmed their separate identities and findings were consistent with the phenotypes observed. Although they show similar apoptotic cell uptake, DC-L have different capabilities for phagocytosis, demonstrate better antigen processing, and have significantly better necrotic cell uptake. These subpopulations also have different patterns of cell death, with DC-L presenting an inflammatory, "dangerous" phenotype while DC-S mostly downregulate their surface markers upon cell death. Apoptotic cells induce an immune-suppressed phenotype, which becomes more pronounced among DC-L, especially after the addition of lipopolysaccharide. We propose that these two subpopulations correspond to inflammatory (DC-L) and steady-state (DC-S) DC classes that have been previously described in mice and humans.

Balance impairment is common in people with multiple sclerosis (PwMS) and frequently impacts quality of life by decreasing mobility and increasing the risk of falling. However, there are only scarce data examining the contribution of specific neurological functional systems on balance measures in MS. Therefore, the primary aim of our study was to examine the differences in posturography parameters and fall incidence according to the pyramidal, cerebellar and sensory systems functional systems in PwMS. The study included 342 PwMS, 211 women and mean disease duration of 8.2 (S.D = 8.3) years. The study sample was divided into six groups according to the pyramidal, cerebellar and sensory functional system scores, derived from the Expanded Disability Status Scale (EDSS) data. Static postural control parameters were obtained from the Zebris FDM-T Treadmill (zebris® Medical GmbH, Germany). Participants were defined as "fallers" and "non-fallers" based on their fall history. Our findings revealed a trend that PwMS affected solely in the pyramidal system, have reduced stability compared to patients with cerebellar and sensory dysfunctions. Moreover, the addition of sensory impairments to pyramidal dysfunction does not exacerbate postural control. The patients in the pure sensory group demonstrated increased stability compared to each of the three combined groups; pyramidal-cerebellar, pyramidal-sensory and pyramidal-cerebellar-sensory groups. As for fall status, the percentage of fallers in the pure pyramidal, cerebellar and sensory groups were 44.3%, 33.3% and 19.5%, respectively. As for the combined functional system groups, the percentage of fallers in the pyramidal-cerebellar, pyramidal-sensory and pyramidal-cerebellar-sensory groups were 59.7%, 40.7% and 65%, respectively. This study confirms that disorders in neurological functional systems generate different effects on postural control and incidence of falls in the MS population. From a clinical standpoint, the present information can benefit all those engaged in physical rehabilitation of PwMS.

The mixed dyslipidemia phenotype is characterized by elevated triglycerides (TG), low HDL cholesterol (HDL-C), increased ApoB levels, and premature coronary atherosclerosis. Fibrate-statin combination therapy reduces ApoB levels and coronary events in the mixed dyslipidemia population. We sought to identify gene-gene interactions that affect ApoB response to statin-fenofibric acid therapy in the mixed dyslipidemia population. Using a predefined subset of single-nucleotide polymorphisms (SNPs) that were previously associated with TG, VLDL, or HDL-C, we applied gene-gene interaction testing in a randomized, double-blind, clinical trial examining the response to fenofibric acid (FNA) and its combination with statin in 1,865 individuals with mixed dyslipidemia. Of 11,783 possible SNP pairs examined, we detected a single significant interaction between rs12130333, located within the ANGPTL3 gene region, and rs4240705, within the RXRA gene, on ApoB reduction after statin-FNA therapy (P = 4.0 × 10−6). ApoB response to therapy gradually reduced with the increasing number of T alleles in the rs12130333 but only in the presence of the GG genotype of rs4240705. Individuals doubly homozygous for the minor alleles at rs12130333 and rs4240705 showed a paradoxical increase of 1.8% in ApoB levels after FNA-statin combination therapy. No gene-gene interaction was identified other than an interaction between SNPs in the ANGPTL3 and RXRA regions, which results in the inhibition of ApoB reduction in response to statin-FNA therapy. Further study is required to examine the clinical applicability of this genetic interaction and its effect on coronary events.

Efforts to develop metallic zinc for biodegradable implants have significantly advanced following an earlier focus on magnesium (Mg) and iron (Fe). Mg and Fe base alloys experience an accelerated corrosion rate and harmful corrosion products, respectively. The corrosion rate of pure Zn, however, may need to be modified from its reported ~20 µm/year penetration rate, depending upon the intended application. The present study aimed at evaluating the possibility of using Fe as a relatively cathodic biocompatible alloying element in zinc that can tune the implant degradation rate via microgalvanic effects. The selected Zn–1.3wt %Fe alloy composition produced by gravity casting was examined in vitro and in vivo. The in vitro examination included immersion tests, potentiodynamic polarization and impedance spectroscopy, all in a simulated physiological environment (phosphate-buffered saline, PBS) at 37 °C. For the in vivo study, two cylindrical disks (seven millimeters diameter and two millimeters height) were implanted into the back midline of male Wister rats. The rats were examined post implantation in terms of weight gain and hematological characteristics, including red blood cell (RBC), hemoglobin (HGB) and white blood cell (WBC) levels. Following retrieval, specimens were examined for corrosion rate measurements and histological analysis of subcutaneous tissue in the implant vicinity. In vivo analysis demonstrated that the Zn–1.3%Fe implant avoided harmful systemic effects. The in vivo and in vitro results indicate that the Zn–1.3%Fe alloy corrosion rate is significantly increased compared to pure zinc. The relatively increased degradation of Zn–1.3%Fe was mainly related to microgalvanic effects produced by a secondary Zn11Fe phase.

Whole genome analysis in large samples from a single population is needed to provide adequate power to assess relative strengths of natural selection across different functional components of the genome. In this study, we analyzed next-generation sequencing data from 962 European Americans, and found that as expected approximately 60% of the top 1% of positive selection signals lie in intergenic regions, 33% in intronic regions, and slightly over 1% in coding regions. Several detailed functional annotation categories in intergenic regions showed statistically significant enrichment in positively selected loci when compared to the null distribution of the genomic span of ENCODE categories. There was a significant enrichment of purifying selection signals detected in enhancers, transcription factor binding sites, microRNAs and target sites, but not on lincRNA or piRNAs, suggesting different evolutionary constraints for these domains. Loci in "repressed or low activity regions" and loci near or overlapping the transcription start site were the most significantly over-represented annotations among the top 1% of signals for positive selection.

In order to enhance the maximum power point tracking (MPPT) speed of solar generators, offline calculated maximum power line (MPL) is often used as a feed-forward signal added to the output of MPPT controller. MPL is nonlinear static electrical characteristic of renewable energy generators connecting all the maximum power points for given temperature. In this letter, electrical side MPL is derived for a typical wind turbine generator (WTG). It is shown that MPLs of solar and wind generators possess similar structure, supporting the similarity between the two energy conversion processes.

Voltage-type sources have dominated as an input source for power electronics converters for a long type. The existence of duality implies that there are also current-type sources. The growing application of renewable energy sources such as wind and solar energy has evidently shown that the current-type input sources exist in reality such as photovoltaic (PV) generator or the feedback technique used in controlling the power electronics converters in the renewable energy systems changes the power electronic converters to behaving as such. The recent research on renewable energy systems has indicated that the current-type input sources are very challenging input sources affecting the dynamics of the interfacing converters profoundly. This paper provides a comprehensive survey of the effects of the PV generator on the dynamic behavior of the corresponding interfacing power electronic converters.

The application of constant power control and inclusion of energy storage in grid-connected photovoltaic (PV) energy systems may increase the use of two-stage system structures composed of DC–DC-converter-interfaced PV generator and grid-connected inverter connected in cascade. A typical PV-generator-interfacing DC–DC converter is a boost-power-stage converter. The renewable energy system may operate in three different operation modes—grid-forming, grid-feeding, and grid-supporting modes. In the last two operation modes, the outmost feedback loops are taken from the input terminal of the associated power electronic converters, which usually does not pose stability problems in terms of their input sources. In the grid-forming operation mode, the outmost feedback loops have to be connected to the output terminal of the associated power electronic converters, and hence the input terminal will behave as a negative incremental resistor at low frequencies. This property will limit the operation of the PV interfacing converter in either the constant voltage or constant current region of the PV generator for ensuring stable operation. The boost-power-stage converter can be applied as a voltage or current-fed converter limiting the stable operation region accordingly. The investigations of this paper show explicitly that only the voltage-fed mode would provide feasible dynamic and stability properties as a viable interfacing converter.

Genome-wide association studies (GWASs) have recently revealed many genetic associations that are shared between different diseases. We propose a method, disPCA, for genome-wide characterization of shared and distinct risk factors between and within disease classes. It flips the conventional GWAS paradigm by analyzing the diseases themselves, across GWAS datasets, to explore their "shared pathogenetics". The method applies principal component analysis (PCA) to gene-level significance scores across all genes and across GWASs, thereby revealing shared pathogenetics between diseases in an unsupervised fashion. Importantly, it adjusts for potential sources of heterogeneity present between GWAS which can confound investigation of shared disease etiology. We applied disPCA to 31 GWASs, including autoimmune diseases, cancers, psychiatric disorders, and neurological disorders. The leading principal components separate these disease classes, as well as inflammatory bowel diseases from other autoimmune diseases. Generally, distinct diseases from the same class tend to be less separated, which is in line with their increased shared etiology. Enrichment analysis of genes contributing to leading principal components revealed pathways that are implicated in the immune system, while also pointing to pathways that have yet to be explored before in this context. Our results point to the potential of disPCA in going beyond epidemiological findings of the co-occurrence of distinct diseases, to highlighting novel genes and pathways that unsupervised learning suggest to be key players in the variability across diseases.

Epistasis has been suggested to underlie part of the missing heritability in genome-wide association studies. In this study, we first report an analysis of gene-gene interactions affecting HDL cholesterol (HDL-C) levels in a candidate gene study of 2,091 individuals with mixed dyslipidemia from a clinical trial. Two additional studies, the Atherosclerosis Risk in Communities study (ARIC; n = 9,713) and the Multi-Ethnic Study of Atherosclerosis (MESA; n = 2,685), were considered for replication. We identified a gene-gene interaction between rs1532085 and rs12980554 (P = 7.1 × 10(-7)) in their effect on HDL-C levels, which is significant after Bonferroni correction (P(c) = 0.017) for the number of SNP pairs tested. The interaction successfully replicated in the ARIC study (P = 7.0 × 10(-4); P(c) = 0.02). Rs1532085, an expression QTL (eQTL) of LIPC, is one of the two SNPs involved in another, well-replicated gene-gene interaction underlying HDL-C levels. To further investigate the role of this eQTL SNP in gene-gene interactions affecting HDL-C, we tested in the ARIC study for interaction between this SNP and any other SNP genome-wide. We found the eQTL to be involved in a few suggestive interactions, one of which significantly replicated in MESA. Importantly, these gene-gene interactions, involving only rs1532085, explain an additional 1.4% variation of HDL-C, on top of the 0.65% explained by rs1532085 alone. LIPC plays a key role in the lipid metabolism pathway and it, and rs1532085 in particular, has been associated with HDL-C and other lipid levels. Collectively, we discovered several novel gene-gene interactions, all involving an eQTL of LIPC, thus suggesting a hub role of LIPC in the gene-gene interaction network that regulates HDL-C levels, which in turn raises the hypothesis that LIPC's contribution is largely via interactions with other lipid metabolism related genes.

In eukaryotes, targeting the small ribosomal subunit to the mRNA transcript requires a Kozak sequence at the translation initiation site. Despite the critical importance of the Kozak sequence to regulation of gene expression, there have been no correlation studies between its natural variance and efficiency of translation. Combining bioinformatics analysis with molecular biology techniques, and using zebrafish as a test case, we identify Kozak sequences based on their natural variance and characterize their function in vivo. Our data reveal that while the canonical Kozak sequence is efficient, in zebrafish it is neither the most common nor the most efficient translation initiation sequence. Rather, the most frequent natural variation of the Kozak sequence is almost twice as efficient. We conclude that the canonical Kozak sequence is a poor predictor of translation efficiency in different model organisms. Furthermore, our results provide an experimental approach to testing and optimizing an important tool for molecular biology.

OBJECTIVE: To investigate the mRNA expression of genes related to steroidogenesis and OHSS in granulosa cells (GCs) of patients triggered with GnRH agonist compared to patients triggered with hCG. DESIGN: Mural GCs were obtained at the time of oocyte retrieval and gene expression was analyzed using quantitative real time RT-PCR. SETTINGS: Single center, case control study. PATIENT(S): 24 women who were treated with GnRH agonist or hCG for triggering of ovulation. INTERVENTIONS: GC collection. MAIN OUTCOME MEASURE(S): The expression of genes related to steroidogenesis and OHSS in mural GCs. RESULTS: The fertilization rate was similar in the two groups. The mRNA expression of CYP19A1 (0.50 vs 1, arbitrary unit), CYP11A1 (0.6 vs. 1) and 3 beta hydroxysteroid-dehydrogenase (0.39 vs 1) was significantly lower in the GnRH group. The expression of VEGF (0.74 vs. 1) and inhibin β B (0.38 vs 1) was lower in the GnRH analog triggered group. CONCLUSION: Expression of genes related to steroidogenesis is lower at the time of oocyte retrieval in patients triggered with GnRH agonist. The decreased expression of VEGF and inhibin β B in the GnRH agonist group can explain the mechanism of early OHSS prevention.

Many complex human diseases are highly sexually dimorphic, suggesting a potential contribution of the X chromosome to disease risk. However, the X chromosome has been neglected or incorrectly analyzed in most genome-wide association studies (GWAS). We present tailored analytical methods and software that facilitate X-wide association studies (XWAS), which we further applied to reanalyze data from 16 GWAS of different autoimmune and related diseases (AID). We associated several X-linked genes with disease risk, among which (1) ARHGEF6 is associated with Crohn's disease and replicated in a study of ulcerative colitis, another inflammatory bowel disease (IBD). Indeed, ARHGEF6 interacts with a gastric bacterium that has been implicated in IBD. (2) CENPI is associated with three different AID, which is compelling in light of known associations with AID of autosomal genes encoding centromere proteins, as well as established autosomal evidence of pleiotropy between autoimmune diseases. (3) We replicated a previous association of FOXP3, a transcription factor that regulates T-cell development and function, with vitiligo; and (4) we discovered that C1GALT1C1 exhibits sex-specific effect on disease risk in both IBDs. These and other X-linked genes that we associated with AID tend to be highly expressed in tissues related to immune response, participate in major immune pathways, and display differential gene expression between males and females. Combined, the results demonstrate the importance of the X chromosome in autoimmunity, reveal the potential of extensive XWAS, even based on existing data, and provide the tools and incentive to properly include the X chromosome in future studies.

BACKGROUND: The ideal test for ovarian reserve should permit the identification of women who have no real chance of pregnancy with IVF treatments consequent upon an extremely reduced ovarian reserve. The aim of the current study was to evaluate pregnancy rates in patients with low AMH levels (0.2-1 ng/ml) and extremely low AMH levels (

Processing bodies (PBs) are non-membranous cytoplasmic structures found in all eukaryotes. Many of their components such as the Dcp1 and Dcp2 proteins are highly conserved. Using live-cell imaging we found that PB structures disassembled as cells prepared for cell division, and then began to reassemble during the late stages of cytokinesis. During the cell cycle and as cells passed through S phase, PB numbers increased. However, there was no memory of PB numbers between mother and daughter cells. Examination of hDcp1a and hDcp1b proteins by electrophoresis in mitotic cell extracts showed a pronounced slower migrating band, which was caused by hyper-phosphorylation of the protein. We found that hDcp1a is a phospho-protein during interphase that becomes hyper-phosphorylated in mitotic cells. Using truncations of hDcp1a we localized the region important for hyper-phosphorylation to the center of the protein. Mutational analysis demonstrated the importance of serine 315 in the hyper-phosphorylation process, while other serine residues tested had a minor affect. Live-cell imaging demonstrated that serine mutations in other regions of the protein affected the dynamics of hDcp1a association with the PB structure. Our work demonstrates the control of PB dynamics during the cell cycle via phosphorylation.

OBJECTIVE: To describe the daily work practice under the threat of defensive medicine among obstetricians and gynecologists. STUDY DESIGN: A prospective cross-sectional survey of obstetricians and gynecologists working at tertiary medical centers in Israel. RESULTS: Among the 117 obstetricians and gynecologists who participated in the survey, representing 10% of the obstetricians and gynecologists registered by the Israel Medical Association, 113 (97%) felt that their daily work practice is influenced by concern about being sued for medical negligence and not only by genuine medical considerations. As a result, 102 (87%) physicians are more likely to offer the cesarean section option, even in the absence of a clear medical indication, 70 (60%) follow court rulings concerning medical practices, and 85 (73%) physicians mentioned that discussions about medical negligence court rulings are included in their departments' meetings. CONCLUSIONS: Defensive medicine is a well-embedded phenomenon affecting the medical decision process of obstetricians and gynecologists.

Various methods have been developed for identifying gene-gene interactions in genome-wide association studies (GWAS). However, most methods focus on individual markers as the testing unit, and the large number of such tests drastically erodes statistical power. In this study, we propose novel interaction tests of quantitative traits that are gene-based and that confer advantage in both statistical power and biological interpretation. The framework of gene-based gene-gene interaction (GGG) tests combine marker-based interaction tests between all pairs of markers in two genes to produce a gene-level test for interaction between the two. The tests are based on an analytical formula we derive for the correlation between marker-based interaction tests due to linkage disequilibrium. We propose four GGG tests that extend the following P value combining methods: minimum P value, extended Simes procedure, truncated tail strength, and truncated P value product. Extensive simulations point to correct type I error rates of all tests and show that the two truncated tests are more powerful than the other tests in cases of markers involved in the underlying interaction not being directly genotyped and in cases of multiple underlying interactions. We applied our tests to pairs of genes that exhibit a protein-protein interaction to test for gene-level interactions underlying lipid levels using genotype data from the Atherosclerosis Risk in Communities study. We identified five novel interactions that are not evident from marker-based interaction testing and successfully replicated one of these interactions, between SMAD3 and NEDD9, in an independent sample from the Multi-Ethnic Study of Atherosclerosis. We conclude that our GGG tests show improved power to identify gene-level interactions in existing, as well as emerging, association studies.

Total cholesterol, low-density lipoprotein cholesterol, triglyceride, and high-density lipoprotein cholesterol (HDL-C) levels are among the most important risk factors for coronary artery disease. We tested for gene-gene interactions affecting the level of these four lipids based on prior knowledge of established genome-wide association study (GWAS) hits, protein-protein interactions, and pathway information. Using genotype data from 9,713 European Americans from the Atherosclerosis Risk in Communities (ARIC) study, we identified an interaction between HMGCR and a locus near LIPC in their effect on HDL-C levels (Bonferroni corrected P(c) = 0.002). Using an adaptive locus-based validation procedure, we successfully validated this gene-gene interaction in the European American cohorts from the Framingham Heart Study (P(c) = 0.002) and the Multi-Ethnic Study of Atherosclerosis (MESA; P(c) = 0.006). The interaction between these two loci is also significant in the African American sample from ARIC (P(c) = 0.004) and in the Hispanic American sample from MESA (P(c) = 0.04). Both HMGCR and LIPC are involved in the metabolism of lipids, and genome-wide association studies have previously identified LIPC as associated with levels of HDL-C. However, the effect on HDL-C of the novel gene-gene interaction reported here is twice as pronounced as that predicted by the sum of the marginal effects of the two loci. In conclusion, based on a knowledge-driven analysis of epistasis, together with a new locus-based validation method, we successfully identified and validated an interaction affecting a complex trait in multi-ethnic populations.

Programmed cell death (PCD) is a fundamental mechanism in tissue and cell homeostasis. It was long suggested that apoptosis regulates the cell number in diverse cell populations; however no clear mechanism was shown. Neutrophils are the short-lived, first-line defense of innate immunity, with an estimated t = 1/2 of 8 hours and a high turnover rate. Here we first show that spontaneous neutrophil constitutive PCD is regulated by cell concentrations. Using a proteomic approach, we identified the S100 A8/9 complex, which constitutes roughly 40% of cytosolic protein in neutrophils, as mediating this effect. We further demonstrate that it regulates cell survival via a signaling mechanism involving MEK-ERK via TLR4 and CD11B/CD18. This mechanism is suggested to have a fine-tuning role in regulating the neutrophil number in bone marrow, peripheral blood, and inflammatory sites.

Genome-wide association studies (GWAS) have in recent years discovered thousands of associated markers for hundreds of phenotypes. However, associated loci often only explain a relatively small fraction of heritability and the link between association and causality has yet to be uncovered for most loci. Rare causal variants have been suggested as one scenario that may partially explain these shortcomings. Specifically, Dickson et al. recently reported simulations of rare causal variants that lead to association signals of common, tag single nucleotide polymorphisms, dubbed "synthetic associations". However, an open question is what practical implications synthetic associations have for GWAS. Here, we explore the signatures exhibited by such "synthetic associations" and their implications based on patterns of genetic variation observed in human populations, thus accounting for human evolutionary history -a force disregarded in previous simulation studies. This is made possible by human population genetic data from HapMap 3 consisting of both resequencing and array-based genotyping data for the same set of individuals from multiple populations. We report that synthetic associations tend to be further away from the underlying risk alleles compared to "natural associations" (i.e. associations due to underlying common causal variants), but to a much lesser extent than previously predicted, with both the age and the effect size of the risk allele playing a part in this phenomenon. We find that while a synthetic association has a lower probability of capturing causal variants within its linkage disequilibrium block, sequencing around the associated variant need not extend substantially to have a high probability of capturing at least one causal variant. We also show that the minor allele frequency of synthetic associations is lower than of natural associations for most, but not all, loci that we explored. Finally, we find the variance in associated allele frequency to be a potential indicator of synthetic associations.

Previous genetic studies have suggested a history of sub-Saharan African gene flow into some West Eurasian populations after the initial dispersal out of Africa that occurred at least 45,000 years ago. However, there has been no accurate characterization of the proportion of mixture, or of its date. We analyze genome-wide polymorphism data from about 40 West Eurasian groups to show that almost all Southern Europeans have inherited 1%-3% African ancestry with an average mixture date of around 55 generations ago, consistent with North African gene flow at the end of the Roman Empire and subsequent Arab migrations. Levantine groups harbor 4%-15% African ancestry with an average mixture date of about 32 generations ago, consistent with close political, economic, and cultural links with Egypt in the late middle ages. We also detect 3%-5% sub-Saharan African ancestry in all eight of the diverse Jewish populations that we analyzed. For the Jewish admixture, we obtain an average estimated date of about 72 generations. This may reflect descent of these groups from a common ancestral population that already had some African ancestry prior to the Jewish Diasporas.

Transcranial magnetic stimulation (TMS) is a stimulation method in which a magnetic coil generates a magnetic field in an area of interest in the brain. This magnetic field induces an electric field that modulates neuronal activity. The spatial distribution of the induced electric field is determined by the geometry and location of the coil relative to the brain. Although TMS has been used for several decades, the biophysical basis underlying the stimulation of neurons in the central nervous system (CNS) is still unknown. To address this problem we developed a numerical scheme enabling us to combine realistic magnetic stimulation (MS) with compartmental modeling of neurons with arbitrary morphology. The induced electric field for each location in space was combined with standard compartmental modeling software to calculate the membrane current generated by the electromagnetic field for each segment of the neuron. In agreement with previous studies, the simulations suggested that peripheral axons were excited by the spatial gradients of the induced electric field. In both peripheral and central neurons, MS amplitude required for action potential generation was inversely proportional to the square of the diameter of the stimulated compartment. Due to the importance of the fiber's diameter, magnetic stimulation of CNS neurons depolarized the soma followed by initiation of an action potential in the initial segment of the axon. Passive dendrites affect this process primarily as current sinks, not sources. The simulations predict that neurons with low current threshold are more susceptible to magnetic stimulation. Moreover, they suggest that MS does not directly trigger dendritic regenerative mechanisms. These insights into the mechanism of MS may be relevant for the design of multi-intensity TMS protocols, may facilitate the construction of magnetic stimulators, and may aid the interpretation of results of TMS of the CNS.

1-Phenyl 2-thiourea (PTU) is a tyrosinase inhibitor commonly used to block pigmentation and aid visualization of zebrafish development. At the standard concentration of 0.003% (200 µM), PTU inhibits melanogenesis and reportedly has minimal other effects on zebrafish embryogenesis. We found that 0.003% PTU altered retinoic acid and insulin-like growth factor (IGF) regulation of neural crest and mesodermal components of craniofacial development. Reduction of retinoic acid synthesis by the pan-aldehyde dehydrogenase inhibitor diethylbenzaldehyde, only when combined with 0.003% PTU, resulted in extraocular muscle disorganization. PTU also decreased retinoic acid-induced teratogenic effects on pharyngeal arch and jaw cartilage despite morphologically normal appearing PTU-treated controls. Furthermore, 0.003% PTU in combination with inhibition of IGF signaling through either morpholino knockdown or pharmacologic inhibition of tyrosine kinase receptor phosphorylation, disrupted jaw development and extraocular muscle organization. PTU in and of itself inhibited neural crest development at higher concentrations (0.03%) and had the greatest inhibitory effect when added prior to 22 hours post fertilization (hpf). Addition of 0.003% PTU between 4 and 20 hpf decreased thyroxine (T4) in thyroid follicles in the nasopharynx of 96 hpf embryos. Treatment with exogenous triiodothyronine (T3) and T4 improved, but did not completely rescue, PTU-induced neural crest defects. Thus, PTU should be used with caution when studying zebrafish embryogenesis as it alters the threshold of different signaling pathways important during craniofacial development. The effects of PTU on neural crest development are partially caused by thyroid hormone signaling.

Binocular vision requires intricate control of eye movement to align overlapping visual fields for fusion in the visual cortex, and each eye is controlled by 6 extraocular muscles (EOMs). Disorders of EOMs are an important cause of symptomatic vision loss. Importantly, EOMs represent specialized skeletal muscles with distinct gene expression profile and susceptibility to neuromuscular disorders. We aim to investigate and describe the anatomy of adult zebrafish extraocular muscles (EOMs) to enable comparison with human EOM anatomy and facilitate the use of zebrafish as a model for EOM research. Using differential interference contrast (DIC), epifluorescence microscopy, and precise sectioning techniques, we evaluate the anatomy of zebrafish EOM origin, muscle course, and insertion on the eye. Immunofluorescence is used to identify components of tendons, basement membrane and neuromuscular junctions (NMJs), and to analyze myofiber characteristics. We find that adult zebrafish EOM insertions on the globe parallel the organization of human EOMs, including the close proximity of specific EOM insertions to one another. However, analysis of EOM origins reveals important differences between human and zebrafish, such as the common rostral origin of both oblique muscles and the caudal origin of the lateral rectus muscles. Thrombospondin 4 marks the EOM tendons in regions that are highly innervated, and laminin marks the basement membrane, enabling evaluation of myofiber size and distribution. The NMJs appear to include both en plaque and en grappe synapses, while NMJ density is much higher in EOMs than in somatic muscles. In conclusion, zebrafish and human EOM anatomy are generally homologous, supporting the use of zebrafish for studying EOM biology. However, anatomic differences exist, revealing divergent evolutionary pressures.

Extracellular recordings in primates have identified two types of neurons in the external segment of the globus pallidus (GPE): high frequency pausers (HFP) and low frequency bursters (LFB). The aim of the current study was to test whether the properties of HFP and LFB neurons recorded extracellularly in the primate GPe are linked to cellular mechanisms underlying the generation of action potential (AP) firing. Thus, we recorded from primate and rat globus pallidus neurons. Extracellular recordings in primates revealed that in addition to differences in firing patterns the APs of neurons in these two groups have different widths (APex). To quantitatively investigate this difference and to explore the heterogeneity of pallidal neurons we carried out cell-attached and whole-cell recordings from acute slices of the rat globus pallidus (GP, the rodent homolog of the primate GPe), examining both spontaneous and evoked activity. Several parameters related to the extracellular activity were extracted in order to subdivide the population of recorded GP neurons into groups. Statistical analysis showed that the GP neurons in the rodents may be differentiated along six cellular parameters into three subgroups. Combining two of these groups allowed a better separation of the population along nine parameters. Four of these parameters (Fmax, APamp, APhw, and AHPs amplitude) form a subset, suggesting that one group of neurons may generate APs at significantly higher frequencies than the other group. This may suggest that the differences between the HFP and LFB neurons in the primate are related to fundamental underlying differences in their cellular properties.

Allele frequency differences across populations can provide valuable information both for studying population structure and for identifying loci that have been targets of natural selection. Here, we examine the relationship between recombination rate and population differentiation in humans by analyzing two uniformly-ascertained, whole-genome data sets. We find that population differentiation as assessed by inter-continental F(ST) shows negative correlation with recombination rate, with F(ST) reduced by 10% in the tenth of the genome with the highest recombination rate compared with the tenth of the genome with the lowest recombination rate (P<

KCNQ2/KCNQ3 channels are the molecular correlates of the neuronal M-channels, which play a major role in the control of neuronal excitability. Notably, they differ from homomeric KCNQ2 channels in their distribution pattern within neurons, with unique expression of KCNQ2 in axons and nerve terminals. Here, combined reciprocal coimmunoprecipitation and two-electrode voltage clamp analyses in Xenopus oocytes revealed a strong association of syntaxin 1A, a major component of the exocytotic SNARE complex, with KCNQ2 homomeric channels resulting in a approximately 2-fold reduction in macroscopic conductance and approximately 2-fold slower activation kinetics. Remarkably, the interaction of KCNQ2/Q3 heteromeric channels with syntaxin 1A was significantly weaker and KCNQ3 homomeric channels were practically resistant to syntaxin 1A. Analysis of different KCNQ2 and KCNQ3 chimeras and deletion mutants combined with in-vitro binding analysis pinpointed a crucial C-terminal syntaxin 1A-association domain in KCNQ2. Pull-down and coimmunoprecipitation analyses in hippocampal and cortical synaptosomes demonstrated a physical interaction of brain KCNQ2 with syntaxin 1A, and confocal immunofluorescence microscopy showed high colocalization of KCNQ2 and syntaxin 1A at presynaptic varicosities. The selective interaction of syntaxin 1A with KCNQ2, combined with a numerical simulation of syntaxin 1A's impact in a firing-neuron model, suggest that syntaxin 1A's interaction is targeted at regulating KCNQ2 channels to fine-tune presynaptic transmitter release, without interfering with the function of KCNQ2/3 channels in neuronal firing frequency adaptation.

Neuronal voltage-gated Ca(2+) channels are involved in electrical signalling and in converting these signals into cytoplasmic calcium changes. One important function of voltage-gated Ca(2+) channels is generating regenerative dendritic Ca(2+) spikes. However, the Ca(2+) dependent mechanisms used to create these spikes are only partially understood. To start investigating this mechanism, we set out to kinetically and pharmacologically identify the sub-types of somatic voltage-gated Ca(2+) channels in pyramidal neurons from layer 5 of rat somatosensory cortex, using the nucleated configuration of the patch-clamp technique. The activation kinetics of the total Ba(2+) current revealed conductance activation only at medium and high voltages suggesting that T-type calcium channels were not present in the patches. Steady-state inactivation protocols in combination with pharmacology revealed the expression of R-type channels. Furthermore, pharmacological experiments identified 5 voltage-gated Ca(2+) channel sub-types - L-, N-, R- and P/Q-type. Finally, the activation of the Ca(2+) conductances was examined using physiologically derived voltage-clamp protocols including a calcium spike protocol and a mock back-propagating action potential (mBPAP) protocol. These experiments enable us to suggest the possible contribution of the five Ca(2+) channel sub-types to Ca(2+) current flow during activation under physiological conditions.

In our previous study, we have found that thrombospondin-1 (TSP-1) is synthesized de novo upon monocyte and neutrophil apoptosis, leading to a phagocytic and tolerizing phenotype of dendritic cells (DC), even prior to DC-apoptotic cell interaction. Interestingly, we were able to show that heparin binding domain (HBD), the N-terminal portion of TSP-1, was cleaved and secreted simultaneously in a caspase- and serine protease- dependent manner. In the current study we were interested to examine the role of HBD in the clearance of apoptotic cells, and whether the phagocytic and tolerizing state of DCs is mediated by the HBD itself, or whether the entire TSP-1 is needed. Therefore, we have cloned the human HBD, and compared its interactions with DC to those with TSP-1. Here we show that rHBD by itself is not directly responsible for immune paralysis and tolerizing phenotype of DCs, at least in the monomeric form, but has a significant role in rendering DCs phagocytic. Binding of TSP-1-C-terminal domain on the other hand induces a tolerizing phenotype in dendritic cells.

There is a considerable gap between investigating the dynamics of single neurons and the computational aspects of neural networks. A growing number of studies have attempted to overcome this gap using the excitation in brain slices elicited by various chemical manipulations of the bath solution. However, there has been no quantitative study on the effects of these manipulations on the cellular and network factors controlling excitability. Using the whole-cell configuration of the patch-clamp technique we recorded the membrane potential from the soma of layer 5 pyramidal neurons in acute brain slices from the somatosensory cortex of young rats at 22 degrees C and 35 degrees C. Using blockers of synaptic transmission, we show distinct changes in cellular properties following modification of the ionic composition of the artificial cerebrospinal fluid (ACSF). Thus both cellular and network changes may contribute to the observed effects of slice excitation solutions on the physiology of single neurons. Furthermore, our data suggest that the difference in the ionic composition of current standard ACSF from that of CSF measured in vivo cause ACSF to depress network activity in acute brain slices. This may affect outcomes of experiments investigating biophysical and physiological properties of neurons in such preparations. Our results strongly advocate the necessity of redesigning experiments routinely carried out in the quiescent acute brain slice preparation.

The activity of trans-membrane proteins such as ion channels is the essence of neuronal transmission. The currently most accurate method for determining ion channel kinetic mechanisms is single-channel recording and analysis. Yet, the limitations and complexities in interpreting single-channel recordings discourage many physiologists from using them. Here we show that a genetic search algorithm in combination with a gradient descent algorithm can be used to fit whole-cell voltage-clamp data to kinetic models with a high degree of accuracy. Previously, ion channel stimulation traces were analyzed one at a time, the results of these analyses being combined to produce a picture of channel kinetics. Here the entire set of traces from all stimulation protocols are analysed simultaneously. The algorithm was initially tested on simulated current traces produced by several Hodgkin-Huxley-like and Markov chain models of voltage-gated potassium and sodium channels. Currents were also produced by simulating levels of noise expected from actual patch recordings. Finally, the algorithm was used for finding the kinetic parameters of several voltage-gated sodium and potassium channels models by matching its results to data recorded from layer 5 pyramidal neurons of the rat cortex in the nucleated outside-out patch configuration. The minimization scheme gives electrophysiologists a tool for reproducing and simulating voltage-gated ion channel kinetics at the cellular level.

The claim that genetic properties of neurons significantly influence their synaptic network structure is a common notion in neuroscience. The nematode Caenorhabditis elegans provides an exciting opportunity to approach this question in a large-scale quantitative manner. Its synaptic connectivity network has been identified, and, combined with cellular studies, we currently have characteristic connectivity and gene expression signatures for most of its neurons. By using two complementary analysis assays we show that the expression signature of a neuron carries significant information about its synaptic connectivity signature, and identify a list of putative genes predicting neural connectivity. The current study rigorously quantifies the relation between gene expression and synaptic connectivity signatures in the C. elegans nervous system and identifies subsets of neurons where this relation is highly marked. The results presented and the genes identified provide a promising starting point for further, more detailed computational and experimental investigations.

Perturbation studies, in which functional performance is measured after deletion, mutation, or lesion of elements of a biological system, have been traditionally employed in many fields in biology. The vast majority of these studies have been qualitative and have employed single perturbations, often resulting in little phenotypic effect. Recently, newly emerging experimental techniques have allowed researchers to carry out concomitant multi-perturbations and to uncover the causal functional contributions of system elements. This study presents a rigorous and quantitative multi-perturbation analysis of gene knockout and neuronal ablation experiments. In both cases, a quantification of the elements' contributions, and new insights and predictions, are provided. Multi-perturbation analysis has a potentially wide range of applications and is gradually becoming an essential tool in biology.

Background: Nonattendance at scheduled outpatient visits among children with asthma has been associated with an increased risk of acute asthma events and increased health care expenses. Specific risk factors for nonattendance have been suggested, but a comprehensive overview is lacking., Objective: To investigate risk factors for nonattendance among children with asthma and assess whether nonattendance associates with acute events through a systematic review and meta-analysis., Methods: The study (PROSPERO: CRD42023471893) was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines using the PubMed, Ovid MEDLINE, Embase, ClinicalTrials.gov, and Cochrane Library databases and search terms "asthma/wheeze," "child," and "nonattendance." Original peer-reviewed studies in English were included and evaluated for risk of bias using the Newcastle Ottawa scale. A meta-analysis was performed for all risk factors. Finally, we analyzed whether nonattendance was associated with the risk of acute events., Results: A total of 17 studies encompassing 27,023 children with asthma were included. The meta-analysis was performed on 11 eligible studies, with 25,948 children, and identified the following risk factors for nonattendance; teenage versus preteen (odds ratio [OR] 1.26; 95% confidence interval [95% CI] 1.06-1.49; P < .01), non-White versus White ethnicity (OR 1.51; 95% CI 1.04-2.18; P = .03) and lower disease severity (OR 1.41; 95% CI 1.13-1.77; P < .01). There were no significant findings in the meta-analysis for insurance status, atopy, sex, or rural residence. Nonattendance associated with an increased risk of acute asthma events (OR 1.11; 95% CI 1.07-1.16; P < .01)., Conclusions: This systematic review and meta-analysis identified specific risk factors to facilitate the development of a strategy against nonattendance for pediatric patients with asthma. This is particularly important given nonattendance being associated with an increased risk of acute asthma., (Copyright © 2024 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)