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No approved treatment for peanut allergy exists for children younger than 4 years of age, and the efficacy and safety of epicutaneous immunotherapy with a peanut patch in toddlers with peanut allergy are unknown. We conducted this phase 3, multicenter, double-blind, randomized, placebo-controlled trial involving children 1 to 3 years of age with peanut allergy confirmed by a double-blind, placebo-controlled food challenge. Patients who had an eliciting dose (the dose necessary to elicit an allergic reaction) of 300 mg or less of peanut protein were assigned in a 2:1 ratio to receive epicutaneous immunotherapy delivered by means of a peanut patch (intervention group) or to receive placebo administered daily for 12 months. The primary end point was a treatment response as measured by the eliciting dose of peanut protein at 12 months. Safety was assessed according to the occurrence of adverse events during the use of the peanut patch or placebo. Of the 362 patients who underwent randomization, 84.8% completed the trial. The primary efficacy end point result was observed in 67.0% of children in the intervention group as compared with 33.5% of those in the placebo group (risk difference, 33.4 percentage points; 95% confidence interval, 22.4 to 44.5; P<0.001). Adverse events that occurred during the use of the intervention or placebo, irrespective of relatedness, were observed in 100% of the patients in the intervention group and 99.2% in the placebo group. Serious adverse events occurred in 8.6% of the patients in the intervention group and 2.5% of those in the placebo group; anaphylaxis occurred in 7.8% and 3.4%, respectively. Serious treatment-related adverse events occurred in 0.4% of patients in the intervention group and none in the placebo group. Treatment-related anaphylaxis occurred in 1.6% in the intervention group and none in the placebo group. In this trial involving children 1 to 3 years of age with peanut allergy, epicutaneous immunotherapy for 12 months was superior to placebo in desensitizing children to peanuts and increasing the peanut dose that triggered allergic symptoms. (Funded by DBV Technologies; EPITOPE ClinicalTrials.gov number, NCT03211247.).

Neonatal enterovirus myocarditis is a rare but serious infection that is often an underrecognized cause of cardiovascular collapse. Enterovirus myocarditis in patients with such collapse should be suspected when signs of congestive heart failure and tachyarrhythmia are present. The majority of reported electrical disturbances associated with enterovirus myocarditis are ventricular in origin, but the infection can present as atrial tachyarrhythmia. Atrial tachyarrhythmias associated with enterovirus myocarditis are difficult to manage because of their resistance to conventional antiarrhythmic therapy. We present 2 cases of neonates with atrial tachycardia associated with enterovirus myocarditis who responded to a combination of amiodarone and flecainide.

Acute neurotoxic effects of high dose methylmercury (MeHg) in humans have been well documented in the scientific literature. However, low dose effects are less well described. This study was designed to evaluate the effects of low dose MeHg (<100 nM) on human brain cells in a tissue culture model. Neuroblastoma cells (SH-Sy5y) were used in the cell culture model to study low dose effects of MeHg on cell growth, cell survival, oxidative stress and the phosphorylation of tau protein, as a measure of potential markers of cellular events associated with tauopathies. When cells were incubated in culture with MeHg (50 nM and 100 nM), there were significant decreases in cell viability as well as a significant increase in reactive oxygen species. In addition, the level of phosphorylated tau was significantly increased following treatment at both 50 nM and 100 nM MeHg, as compared to controls. Pretreatment of neuroblastoma cells with the antioxidant, N-acetylcysteine, as well as a calpain inhibitor, MDL- 28170, significantly attenuated the effects of MeHg (50 nM and 100 nM) on cell viability as well as on tau phosphorylation. Furthermore, MeHg has also been reported to alter glutamate homeostasis in the neuronal environment, resulting in excitotoxicity. Exposure of cells to a combination of MeHg (50 nM) and glutamate (1 mM) resulted in a greater decrease in cell viability as well as a greater induction in tau phosphorylation, as compared to exposures with MeHg and glutamate alone. MK-801 (4 μM), an NMDA receptor antagonist, and the intracellular calcium chelator, BAPTA-AM, both significantly inhibited tau hyperphosphorylation and protected cells from the effects of combination exposures to glutamate and MeHg. This study suggests that MeHg may increase the cellular response to glutamate thereby enhancing its excitoxicity. The overall conclusion of this work is that, low dose MeHg toxicity in neuroblastoma cells may be related to its induction of tau phosphorylation through an induction of oxidative stress, alteration in intracellular calcium levels as well as activation of μ-calpain and that blockade of this pathway may produce protective effects against MeHg induced neurological effects.

Among phase change materials, Ge-rich GeSbTe alloys (GGST) are key alloys for the next generation of embedded phase change memories because of their good thermal stability, allowing their use for the automotive applications. Several studies have investigated GGST crystallization, which takes place in several stages, including phase separation in the amorphous material, the crystallization of the cubic Ge and GST phases before a complete crystallization for higher thermal budget. So far, however, no information is available on the possible changes in density and thickness of such alloys. This paper investigates such variations in density and thickness for a N-doped GGST layer (GGSTN) during isothermal annealing, following the four main stages of its multistep crystallization process. X-ray reflectivity (XRR) and X-ray diffraction were employed for analysis. The study reveals that density and thickness exhibit distinct changes during crystallization, with density increasing by approximately 9% during transition from amorphous to crystalline states. These changes are attributed to alterations in layer morphology, particularly at the Ge crystallization temperature and at the onset of GST crystal formation. Additionally, at high thermal budgets, discrepancies between XRR analysis methods suggest the formation of a thin, lower density layer near the top interface of the GGSTN layer. These results provide insights into the structural evolution of the GGSTN layer, which is crucial for phase change random access memory applications.

Transcription termination is an essential and dynamic process that can tune gene expression in response to diverse molecular signals. Yet, the genomic positions, molecular mechanisms, and regulatory consequences of termination have only been studied thoroughly in model bacteria. Here, we use several RNA-seq approaches to map RNA ends for the transcriptome of the spirochete Borrelia burgdorferi – the etiological agent of Lyme disease. We identify complex gene arrangements and operons, untranslated regions and small RNAs. We predict intrinsic terminators and experimentally test examples of Rho-dependent transcription termination. Remarkably, 63% of RNA 3′ ends map upstream of or internal to open reading frames (ORFs), including genes involved in the unique infectious cycle of B. burgdorferi . We suggest these RNAs result from premature termination, processing and regulatory events such as cis -acting regulation. Furthermore, the polyamine spermidine globally influences the generation of truncated mRNAs. Collectively, our findings provide insights into transcription termination and uncover an abundance of potential RNA regulators in B. burgdorferi . Transcription termination can tune bacterial gene expression in response to diverse signals. Here, the authors use several RNA-seq approaches to map RNA ends for the transcriptome of the spirochete Borrelia burgdorferi , providing insights into various modes of transcription termination and identifying potential RNA regulators in this pathogen.

A major governance problem in closely held corporations is the majority shareholders’ expropriation of minority shareholders. As a solution, legal and finance research recommends that the main shareholder surrender some control to minority shareholders via ownership rights. We test this proposition on a large data set of closely held corporations. We find that shared-ownership firms report a substantially larger return on assets and lower expense-to-sales ratios. These findings are robust to institutionally motivated corrections for endogeneity of ownership structure. We provide evidence on the presence of governance problems and the effectiveness of shared ownership as a solution in settings characterized by illiquidity of ownership.

BackgroundA vaccine containing 6 melanoma-associated peptides to stimulate helper T cells (6MHP) is safe, immunogenic, and clinically active. A phase I/II trial was designed to evaluate safety and immunogenicity of 6MHP vaccines plus programmed death 1 (PD-1) blockade.Participants and methodsParticipants with advanced melanoma received 6MHP vaccines in an incomplete Freund’s adjuvant (6 vaccines over 12 weeks). Pembrolizumab was administered intravenously every 3 weeks. Tumor biopsies at baseline and day 22 were analyzed by multiplex immunohistochemistry. Primary end points were safety (Common Terminology Criteria for Adverse Events V.4.03) and immunogenicity (ex vivo interferon-γ ELISpot assay). Additional end points included changes in the tumor microenvironment (TME) and clinical outcomes.ResultsTwenty-two eligible participants were treated: 6 naïve to PD-1 antibody (Ab) and 16 PD-1 Ab-experienced. Median follow-up was 24.4 months. Most common treatment-related adverse events (any grade) included injection site reactions, fatigue, anemia, lymphopenia, fever, elevated aspartate aminotransferase, pruritus, and rash. Treatment-related dose-limiting toxicities were observed in 3 (14%) participants, which did not cross the study safety bound. A high durable T cell response (Rsp) to 6MHP was detected in only one participant, but twofold T cell Rsps to 6MHP were detected in 7/22 (32%; 90% CI (16% to 52%)) by week 13. Objective clinical responses were observed in 23% (1 complete response, 4 partial responses), including 4/6 PD-1 Ab-naïve (67%) and 1/16 PD-1 Ab-experienced (6%). Overall survival (OS) was longer for PD-1 Ab-naïve than Ab-experienced participants (HR 6.3 (90% CI (2.1 to 28.7)). In landmark analyses at 13 weeks, OS was also longer for those with T cell Rsps (HR 6.5 (90% CI (2.1 to 29.2)) and for those with objective clinical responses. TME evaluation revealed increased densities of CD8+ T cells, CD20+ B cells, and Tbet+ cells by day 22.ConclusionsTreatment with the 6MHP vaccine plus pembrolizumab was safe, increased intratumoral lymphocytes, and induced T cell Rsps associated with prolonged OS. The low T cell Rsp rate in PD-1 Ab-experienced participants corroborates prior murine studies that caution against delaying cancer vaccines until after PD-1 blockade. The promising objective response rate and OS in PD-1 Ab-naïve participants support consideration of a larger study in that setting.

The alternative sigma factor RpoS regulates transcription of over 1,000 genes in Escherichia coli in response to many different stresses. RpoS levels rise continuously after exposure to stress, and the consequences of changing levels of RpoS for the temporal patterns of expression of RpoS-regulated genes have not been described. We measured RpoS levels at various times during the entry to stationary phase, or in response to high osmolarity or low temperature, and found that the time required to reach maximum levels varied by several hours. We quantified the transcriptome across these stresses using RNA-seq. The number of differentially expressed genes differed among stresses, with 1,379 DE genes identified in stationary phase, 633 in high osmolarity, and 302 in cold shock. To quantify the timing of gene expression, we fit sigmoid or double sigmoid models to differentially expressed genes in each stress. During the entry into stationary phase, genes whose expression rose earlier tended to be those that had been found to respond most strongly to low levels of RpoS. The timing of individual gene’s expression was not correlated across stresses. Taken together, our results demonstrate E. coli activates RpoS with different timing in response to different stresses, which in turn generates a unique pattern of timing of the transcription response to each stress. Bacteria adapt to changing environments by altering the transcription of their genes. Specific proteins can regulate these changes. This study explored how a single protein called RpoS controls how many genes change expression during adaptation to three stresses. We found that: (i) RpoS is responsible for activating different genes in different stresses; (ii) that during a stress, the timing of gene activation depends on the what stress it is; and (iii) that how much RpoS a gene needs in order to be activated can predict when that gene will be activated during the stress of stationary phase.

The obvious place to start is the look of the games. Both look impressive, with the smooth motion of players on the pitch and the realism of the pitch surface and stadium surrounds all authentic, but where FIFA has it over Pro Evo in this department is the leagues and real teams available to play. Being the officially endorsed game for FIFA and several European leagues, there is a level of familiarity in playing as a club you love. Although FIFA may look prettier and feel more familiar, Pro Evo has the feel of the real gameplay down pat. When you run into an opponent, your player will stagger after the contact. There are four difficulty levels on FIFA and five on Pro Evo. To test the differences, I played two identical fixtures with identical line-ups between Australia and England on the easiest level. First up was FIFA where the Socceroos suffered a demoralising 3-2 loss in golden goal extra time.

Despite being landed in commercial cephalopod fisheries, species of Alloteuthis are not yet well defined, with A. subulata and A. media often confused. DNA barcoding combined with morphometric analyses has begun to clarify the distinction between these two morphologically similar species but has been limited in its geographic coverage to date. Herein, we provide DNA barcodes for 228 specimens collected from Guinea Bissau in the south, up the Atlantic coast, to the Irish shelf and North Sea. Employing species delimitation analyses, and with comparison to the literature, we identified 24 individuals of A. africana, 66 individuals of A. subulata and 138 individuals of A. media. We confirm that A. media has the northernmost distribution and is the only species identified by DNA sequencing from the Irish shelf and North Sea. We analysed morphometric measures and indices from 388 individuals from the North Sea, a subset of which (n = 58) were barcoded. The most useful traits for identification were tail length as a percentage of dorsal mantle length, and largest club sucker width as a percentage of head width. By comparison to other published data, we determined that A. media phenotypes vary substantially across the geographic range of this species. This partly explains the difficulties in morphological identification and suggests regional identification guides may be required in support of fisheries management. Interregional analyses suggest character displacement may occur where species co-exist.