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Abstract Rationale The around-the-clock presence of an in-house attending critical care physician (24/7 coverage) is purported to be associated with improved outcomes among high-risk children with critical illness. Objectives To evaluate the association of 24/7 in-house coverage with outcomes in children with critical illness. Methods Patients younger than 18 years of age in the Virtual Pediatric Systems Database (2009–2014) were included. The main analysis was performed using generalized linear mixed effects multivariable regression models. In addition, multiple sensitivity analyses were performed to test the robustness of our findings. Measurements and Main Results A total of 455,607 patients from 125 hospitals were included (24/7 group: 266,319 patients; no 24/7 group: 189,288 patients). After adjusting for patient and center characteristics, the 24/7 group was associated with lower mortality in the intensive care unit (ICU) (24/7 vs. no 24/7; odds ratio [OR], 0.52; 95% confidence interval [CI], 0.33–0.80; P = 0.002), a lower incidence of cardiac arrest (OR, 0.73; 95% CI, 0.54–0.99; P = 0.04), lower mortality after cardiac arrest (OR, 0.56; 95% CI, 0.340–0.93; P = 0.02), a shorter ICU stay (mean difference, −0.51 d; 95% CI, −0.93 to −0.09), and shorter duration of mechanical ventilation (mean difference, −0.68 d; 95% CI, −1.23 to −0.14). Conclusions In this large observational study, we demonstrated that pediatric critical care provided in the ICUs staffed with a 24/7 intensivist presence is associated with improved overall patient survival and survival after cardiac arrest compared with patients treated in ICUs staffed with discretionary attending coverage. However, results from a few sensitivity analyses leave some ambiguity in these results.

To the Editor: In their report of a prospective trial of corticosteroids as adjunctive therapy for bacterial meningitis, Lebel et al. (Oct. 13 issue) 1 concluded that dexamethasone \"had a significantly beneficial effect on the inflammatory profile of the cerebrospinal fluid in the first 24 hours of treatment and also on hearing.\" On the basis of the reported data, such a conclusion is not entirely accurate. When the results of their two studies are analyzed separately, one finds a statistically significant reduction in the number of children who had seizures, subdural effusions, neurologic abnormalities at the time of discharge, or moderate . . . No extract is available for articles shorter than 400 words.

IN the city of Stockton, California, is waged a most peculiar and unusual warfare. It is not attended with the clashing of swords, a pyrotechnic display or any of the other incidents characteristic of regular warfare, but by the bitter feelings aroused by a reform movement relative to the clearing out of one of Stockton's most interesting and characteristic landmarks, or...

Existing treatments for postherpetic neuralgia, and for neuropathic pain in general, are limited by modest efficacy and unfavourable side-effects. The angiotensin II type 2 receptor (AT2R) is a new target for neuropathic pain. EMA401, a highly selective AT2R antagonist, is under development as a novel neuropathic pain therapeutic agent. We assessed the therapeutic potential of EMA401 in patients with postherpetic neuralgia. In this multicentre, placebo-controlled, double-blind, randomised, phase 2 clinical trial, we enrolled patients (aged 22–89 years) with postherpetic neuralgia of at least 6 months' duration from 29 centres across six countries. We randomly allocated 183 participants to receive either oral EMA401 (100 mg twice daily) or placebo for 28 days. Randomisation was done according to a centralised randomisation schedule, blocked by study site, which was generated by an independent, unmasked statistician. Patients and staff at each site were masked to treatment assignment. We assessed the efficacy, safety, and pharmacokinetics of EMA401. The primary efficacy endpoint was change in mean pain intensity between baseline and the last week of dosing (days 22–28), measured on an 11-point numerical rating scale. The primary efficacy analysis was intention to treat. This trial is registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12611000822987. 92 patients were assigned to EMA401 and 91 were assigned to placebo. The patients given EMA401 reported significantly less pain compared with baseline values in the final week of treatment than did those given placebo (mean reductions in pain scores −2·29 [SD 1·75] vs −1·60 [1·66]; difference of adjusted least square means −0·69 [SE 0·25]; 95% CI −1·19 to −0·20; p=0·0066). No serious adverse events related to EMA401 occurred. Overall, 32 patients reported 56 treatment-emergent adverse events in the EMA401 group compared with 45 such events reported by 29 patients given placebo. EMA401 (100 mg twice daily) provides superior relief of postherpetic neuralgia compared with placebo at the end of 28 days of treatment. EMA401 was well tolerated by patients. Spinifex Pharmaceuticals.

Zoonotic coronaviruses (CoVs) are substantial threats to global health, as exemplified by the emergence of two severe acute respiratory syndrome CoVs (SARS-CoV and SARS-CoV-2) and Middle East respiratory syndrome CoV (MERS-CoV) within two decades 1 – 3 . Host immune responses to CoVs are complex and regulated in part through antiviral interferons. However, interferon-stimulated gene products that inhibit CoVs are not well characterized 4 . Here, we show that lymphocyte antigen 6 complex, locus E (LY6E) potently restricts infection by multiple CoVs, including SARS-CoV, SARS-CoV-2 and MERS-CoV. Mechanistic studies revealed that LY6E inhibits CoV entry into cells by interfering with spike protein-mediated membrane fusion. Importantly, mice lacking Ly6e in immune cells were highly susceptible to a murine CoV—mouse hepatitis virus. Exacerbated viral pathogenesis in Ly6e knockout mice was accompanied by loss of hepatic immune cells, higher splenic viral burden and reduction in global antiviral gene pathways. Accordingly, we found that constitutive Ly6e directly protects primary B cells from murine CoV infection. Our results show that LY6E is a critical antiviral immune effector that controls CoV infection and pathogenesis. These findings advance our understanding of immune-mediated control of CoV in vitro and in vivo—knowledge that could help inform strategies to combat infection by emerging CoVs. Here, the authors identify lymphocyte antigen 6E (LY6E) as a coronavirus (CoV) restriction factor that prevents infection of B cells and dendritic cells. LY6E inhibits both human and mouse CoV entry into cells by interfering with viral spike protein-mediated membrane fusion. It facilitates an antiviral immune response that prevents liver disease and reduces death in the mouse model of MHV-A59 CoV infection.

To increase our understanding of the genetic basis of adiposity and its links to cardiometabolic disease risk, we conducted a genome-wide association meta-analysis of body fat percentage (BF%) in up to 100,716 individuals. Twelve loci reached genome-wide significance ( P <5 × 10 −8 ), of which eight were previously associated with increased overall adiposity (BMI, BF%) and four (in or near COBLL1/GRB14 , IGF2BP1 , PLA2G6 , CRTC1 ) were novel associations with BF%. Seven loci showed a larger effect on BF% than on BMI, suggestive of a primary association with adiposity, while five loci showed larger effects on BMI than on BF%, suggesting association with both fat and lean mass. In particular, the loci more strongly associated with BF% showed distinct cross-phenotype association signatures with a range of cardiometabolic traits revealing new insights in the link between adiposity and disease risk. A genome-wide association meta-analysis study here shows novel genetic loci to be associated to body fat percentage, and describes cross-phenotype association that further demonstrate a close relationship between adiposity and cardiovascular disease risk.

Pierre Guermonprez and colleagues have worked out how a subset of dendritic cells expands in individuals with severe malaria. Plasmodium infection causes an accumulation of xanthine in infected red blood cells. The researchers found that type I interferon triggers an increase in the enzyme that metabolizes xanthine to uric acid. Uric acid then acts on mast cells to release Flt3 ligand, an important regulator of dendritic cells, which in turn stimulate T cells to respond to the infection. Innate sensing mechanisms trigger a variety of humoral and cellular events that are essential to adaptive immune responses. Here we describe an innate sensing pathway triggered by Plasmodium infection that regulates dendritic cell homeostasis and adaptive immunity through Flt3 ligand (Flt3l) release. Plasmodium- induced Flt3l release in mice requires Toll-like receptor (TLR) activation and type I interferon (IFN) production. We found that type I IFN supports the upregulation of xanthine dehydrogenase, which metabolizes the xanthine accumulating in infected erythrocytes to uric acid. Uric acid crystals trigger mast cells to release soluble Flt3l from a pre-synthesized membrane-associated precursor. During infection, Flt3l preferentially stimulates expansion of the CD8-α + dendritic cell subset or its BDCA3 + human dendritic cell equivalent and has a substantial impact on the magnitude of T cell activation, mostly in the CD8 + compartment. Our findings highlight a new mechanism that regulates dendritic cell homeostasis and T cell responses to infection.

Formation of the mammalian brain requires choreographed migration of neurons to generate highly ordered laminar structures such as those in the cortices of the forebrain and the cerebellum. These processes are severely disrupted by mutations in reelin 1 which cause widespread misplacement of neurons and associated ataxia in reeler mice 2 , 3 . Reelin is a large extracellular protein secreted by pioneer neurons that coordinates cell positioning during neurodevelopment 1 , 4 , 5 , 6 , 7 , 8 . Two new autosomal recessive mouse mutations, scrambler 9 and yotari 10 have been described that exhibit a phenotype identical to reeler 9 , 10 , 11 . Here we report that scrambler and yotari arise from mutations in mdab1 ( ref. 12 ), a mouse gene related to the Drosophila gene disabled ( dab ) 13 . Both scrambler and yotari mice express mutated forms of mdab1 messenger RNA and little or no mDab1 protein. mDab1 is a phosphoprotein that appears to function as an intracellular adaptor in protein kinase pathways. Expression analysis indicates that mdab1 is expressed in neuronal populations exposed to Reelin. The similar phenotypes of reeler , scrambler , yotari and mdab1 null mice 14 indicate that Reelin and mDab1 function as signalling molecules that regulate cell positioning in the developing brain.

Traditional techniques for monitoring and managing visitor flows are expensive and time consuming. This research note presents a novel, cost-effective, and quick method for managers to assess the level of use within their management area. Using free crowdsourced heatmaps provided by Strava, GPS recorded use was georeferenced with existing trail data. By overlaying the designated trail network with actual use, this note presents a method through which managers can quickly see where undesignated use is occurring and how extreme that use may be. Similarly, this method can be used as a first step in the process of deciding where traditional monitoring efforts should be employed. The advantages and limitations of this approach are subsequently discussed. Keywords Crowdsourced data, heatmaps, Strava, undesignated trails, visitor use, visitor use monitoring