Comparison of four clinical risk scores in comatose patients after out-of-hospital cardiac arrest.

BACKGROUND AND AIMS: Several different scoring systems for early risk stratification after out-of-hospital cardiac arrest have been developed, but few have been validated in large datasets. The aim of the present study was to compare the well-validated Out-of-hospital Cardiac Arrest (OHCA) and Cardiac Arrest Hospital Prognosis (CAHP)-scores to the less complex MIRACLE2- and Target Temperature Management (TTM)-scores. METHODS: This was a post-hoc analysis of the Targeted Hypothermia versus Targeted Normothermia after Out-of-Hospital Cardiac Arrest (TTM2) trial. Missing data were handled by multiple imputation. The primary outcome was discriminatory performance assessed as the area under the receiver operating characteristics-curve (AUROC), with the outcome of interest being poor functional outcome or death (modified Rankin Scale 4-6) at 6 months after OHCA. RESULTS: Data on functional outcome at 6 months were available for 1829 cases, which constituted the study population. The pooled AUROC for the MIRACLE2-score was 0.810 (95% CI 0.790-0.828), 0.835 (95% CI 0.816-0.852) for the TTM-score, 0.820 (95% CI 0.800-0.839) for the CAHP-score and 0.770 (95% CI 0.748-0.791) for the OHCA-score. At the cut-offs needed to achieve specificities >95%, sensitivities were <40% for all four scoring systems. CONCLUSIONS: The TTM-, MIRACLE2- and CAHP-scores are all capable of providing objective risk estimates accurate enough to be used as part of a holistic patient assessment after OHCA of a suspected cardiac origin. Due to its simplicity, the MIRACLE2-score could be a practical solution for both clinical application and risk stratification within trials.

IL-36 receptor agonist and antagonist imbalance drives neutrophilic inflammation in COPD.

Current treatments fail to modify the underlying pathophysiology and disease progression of chronic obstructive pulmonary disease (COPD), necessitating alternative therapies. Here, we show that COPD subjects have increased IL-36γ and decreased IL-36 receptor antagonist (IL-36Ra) in bronchoalveolar and nasal fluid compared with control subjects. IL-36γ is derived from small airway epithelial cells (SAEC) and is further induced by a viral mimetic, whereas IL-36Ra is derived from macrophages. IL-36γ stimulates release of the neutrophil chemoattractants CXCL1 and CXCL8, as well as elastolytic matrix metalloproteinases (MMPs) from small airway fibroblasts (SAF). Proteases released from COPD neutrophils cleave and activate IL-36γ, thereby perpetuating IL-36 inflammation. Transfer of culture media from SAEC to SAF stimulated release of CXCL1, which was inhibited by exogenous IL-36Ra. The use of a therapeutic antibody that inhibits binding to the IL-36R attenuated IL-36γ-driven inflammation and cellular crosstalk. We have demonstrated a mechanism for the amplification and propagation of neutrophilic inflammation in COPD and have shown that blocking this cytokine family via a IL-36R neutralizing antibody could be a promising therapeutic strategy in the treatment of COPD.

Thalamus mediates neocortical Down state transition via GABAB-receptor-targeting interneurons.

Slow-wave sleep is characterized by near-synchronous alternation of active Up states and quiescent Down states in the neocortex. Although the cortex itself can maintain these oscillations, the full expression of Up-Down states requires intact thalamocortical circuits. Sensory thalamic input can drive the cortex into an Up state. Here we show that midline thalamic neurons terminate Up states synchronously across cortical areas. Combining local field potential, single-unit, and patch-clamp recordings in conjunction with optogenetic stimulation and silencing in mice in vivo, we report that thalamic input mediates Down transition via activation of layer 1 neurogliaform inhibitory neurons acting on GABAB receptors. These results strengthen the evidence that thalamocortical interactions are essential for the full expression of slow-wave sleep, show that Down transition is an active process mediated by cortical GABAB receptors, and demonstrate that thalamus synchronizes Down transitions across cortical areas during natural slow-wave sleep.

To extract or not to extract? Management of infraoccluded second primary molars without successors.

Infraocclusion is a term used to describe a tooth which has stopped its relative occlusal growth into the arch after the period of active eruption; as a result, the tooth becomes depressed below the occlusal plane. Although many aetiological mechanisms have been proposed, ankylosis is considered the primary cause of infraocclusion. Complex cases benefit from multidisciplinary management. This paper concentrates on the diagnosis and management of infraoccluded second primary molars, without permanent successors and without significant malocclusion, and provides clinicians with a treatment decision tree to aid in treatment planning.

Discovery of Highly Isoform Selective Orally Bioavailable Phosphoinositide 3-Kinase (PI3K)-γ Inhibitors.

In this paper, we describe the discovery and optimization of a new chemotype of isoform selective PI3Kγ inhibitors. Starting from an HTS hit, potency and physicochemical properties could be improved to give compounds such as 15, which is a potent and remarkably selective PI3Kγ inhibitor with ADME properties suitable for oral administration. Compound 15 was advanced into in vivo studies showing dose-dependent inhibition of LPS-induced airway neutrophilia in rats when administered orally.

Population structured by witchcraft beliefs.

Anthropologists have long argued that fear of victimization through witchcraft accusations promotes cooperation in small-scale societies 1 . Others have argued that witchcraft beliefs undermine trust and therefore reduce social cohesion 2 . However, there are very few, if any, quantified empirical examples demonstrating how witchcraft labels can structure cooperation in real human communities. Here we show a case from a farming community in China where people labelled zhu were thought capable of supernatural activity, particularly poisoning food. The label was usually applied to adult women heads of household and often inherited down the female line. We found that those in zhu households were less likely to give or receive gifts or farm help to or from non-zhu households; nor did they have sexual partnerships or children with those in non-zhu households. However, those in zhu households did preferentially help and reproduce with each other. Although the tag is common knowledge to other villagers and used in cooperative and reproductive partner choice, we found no evidence that this assortment was based on cooperativeness or quality. We favour the explanation that stigmatization originally arose as a mechanism to harm female competitors. Once established, fear that the trait is transmissible may help explain the persistence of this deep-rooted cultural belief.

Ambient temperature and dietary supplementation interact to shape mosquito vector competence for malaria.

The extent to which environmental factors influence the ability of Anopheles mosquitoes to transmit malaria parasites remains poorly explored. Environmental variation, such as change in ambient temperature, will not necessarily influence the rates of host and parasite processes equivalently, potentially resulting in complex effects on infection outcomes. As proof of principle, we used Anopheles stephensi and the rodent malaria parasite, Plasmodium yoelii, to examine the effects of a range of constant temperatures on one aspect of host defense (detected as alterations in expression of nitric oxide synthase gene - NOS) to parasite infection. We experimentally boosted mosquito midgut immunity to infection through dietary supplementation with the essential amino acid l-Arginine (l-Arg), which increases midgut nitric oxide (NO) levels by infection-induced NOS catalysis in A. stephensi. At intermediate temperatures, supplementation reduced oocyst prevalence, oocyst intensity, and sporozoite prevalence suggesting that the outcome of parasite infection was potentially dependent upon the rate of NOS-mediated midgut immunity. At low and high temperature extremes, however, infection was severely constrained irrespective of supplementation. The effects of l-Arg appeared to be mediated by NO-dependent negative feedback on NOS expression, as evidenced by depressed NOS expression in l-Arg treated groups at temperatures where supplementation decreased parasite infection. These results suggest the need to consider the direct (e.g. effects of mosquito body temperature on parasite physiology) and indirect effects (e.g. mediated through changes in mosquito physiology/immunity) of environmental factors on mosquito-malaria interactions in order to understand natural variation in vector competence.

Discovery and characterization of NVP-QAV680, a potent and selective CRTh2 receptor antagonist suitable for clinical testing in allergic diseases.

Optimization of a 7-azaindole-3-acetic acid CRTh2 receptor antagonist chemotype derived from high throughput screening furnished a highly selective compound NVP-QAV680 with low nM functional potency for inhibition of CRTh2 driven human eosinophil and Th2 lymphocyte activation in vitro. The molecule exhibited good oral bioavailability in the rat, combined with efficacy in rodent CRTh2-dependent mechanistic and allergic disease models and was suitable for clinical development.

Vitamin D in children with cystic fibrosis.

PURPOSE: The Cystic Fibrosis Trust in 2007 published a recommended target of 75-150 nmol/L for 25-hydroxyvitamin D (25-OHD). In 2008 we found that only 10% of pancreatic insufficient (PI) children met this target. An increase in supplementation was implemented and a repeat audit performed in 2010. METHODS: PI children ≥1 year under sole-care in our regional centre were included. Vitamin D3 supplementation increased by >450% to either 3800 IU/day liquid or 800 IU daily plus 20,000 IU weekly tablets. In 2010 pancreatic sufficient (PS) children were also audited separately. RESULTS: The median 25-OHD level increased from 51.5 nmol/L in 2008 (n=78, 10% >75 nmol/L) to 72 nmol/L in 2010 (n=72, 51% >75 nmol/L), p<0.0001. In PS children (n=15 in 2010) 87% had 25-OHD levels <75 nmol/L. CONCLUSIONS: A substantial increase in supplementation led to a significant increase in 25-OHD levels but around half still failed to reach the recommended target.

Endoscopic botulinum toxin injection for the treatment of diabetic gastropathy in pancreas and islet-cell transplant patients.

OBJECTIVES: Gastroparesis is a well-recognized, long-term complication of diabetes. Prokinetic drugs are often not effective, prompting the development of alternative therapies. We report our experience of using one such alternative, endoscopic botulinum toxin injection, to ameliorate diabetic gastropathy in association with pancreas and islet-cell transplant patients. MATERIALS AND METHODS: Three male diabetic patients aged 42 to 55 years had been treated with botulinum toxin in our center. Two patients were both after-simultaneous pancreas-kidney transplant and 1 was awaiting islet-cell transplant after pancreatectomy. Mechanical gastric outlet obstruction was first excluded by radiological and endoscopic studies. Between 100 and 200 IU of toxin were then injected in the prepyloric region using an endoscopic technique. A subjective scoring scale was used to assess symptoms before and after botulinum therapy. RESULTS: Improvement in subjective symptom severity scoring was seen in all patients, with a posttreatment improvement from 55% to 91%. Such improvement was temporary in 2 patients and long-lasting in 1 patient. CONCLUSIONS: The time for improvement of gastric autonomic function after pancreas or islet-cell transplantation remains unclear. Some patients may continue to be symptomatic, leading to increasing morbidity. However, endoscopic botulinum injections may provide short-term relief while waiting for improvement and spare patients the morbidity associated with more-invasive therapies.

Stimulus-driven attentional capture by a static discontinuity between perceptual groups.

After C. L. Folk, R. W. Remington, and J. C. Johnston (1992) proposed their contingent-orienting hypothesis, there has been an ongoing debate over whether purely stimulus-driven attentional capture can occur for visual events that are salient by virtue of a distinctive static property (as opposed to a dynamic property such as abrupt onset). The present study identified 3 methodological criteria for establishing that attentional capture is stimulus driven and not contingent on top-down attentional control settings. In 5 experiments, attentional capture occurred for a static discontinuity at the boundary between one group of homogeneous items (red Xs) abutted next to a group of homogeneous items that were featurally different (green Xs) within a single row. Experiment 1 intentionally violated one of the criteria for demonstrating stimulus-driven capture so as to establish that contingent attentional capture can occur for this novel type of static cue. In the remaining 4 experiments, even with all 3 criteria for stimulus-driven capture partially or completely satisfied, the static discontinuity captured attention. These attentional capture effects are the first to be obtained when all 3 criteria for establishing that they are purely stimulus driven have been satisfied.

Pars plana vitrectomy in eyes containing a treated posterior uveal melanoma.

PURPOSE: To determine the safety of pars plana vitrectomy in eyes containing a treated posterior uveal melanoma. DESIGN: Interventional case series. METHODS: Retrospective case series of patients with posterior uveal melanoma who underwent pars plana vitrectomy. Complications, vitreous cytology, local tumor control, and metastasis were assessed. RESULTS: Nine patients met study criteria. Tumors were treated with (125)I plaque radiotherapy (seven patients) or transpupillary thermotherapy (two patients). Vitrectomy was performed for vitreous hemorrhage (five patients), macular pucker (two patients), macular hole (one patient), and rhegmatogenous retinal detachment (one patient). Vitrectomy was performed at a mean of 24.7 months (range, 7-47 months) after melanoma treatment. Dispersion of tumor cells at vitrectomy was not observed in any patients. Melanoma cells were detected in the vitreous aspirate in one of seven cases examined cytologically. This patient had intratumoral and vitreous hemorrhage before plaque radiotherapy, underwent combined vitrectomy/cataract extraction, and developed intraocular tumor dissemination 56 months after vitrectomy. No other patients developed intraocular tumor dissemination. At mean follow-up of 24 months (range, 3-63 months) after vitrectomy, none of the nine patients developed systemic metastasis. CONCLUSIONS: Pars plana vitrectomy rarely may lead to intraocular tumor dissemination, although the risk of this complication is probably low if the tumor has been treated and has responded to therapy before vitrectomy. Vitrectomy should be approached with caution if a vitreous hemorrhage is present, especially if the hemorrhage occurred before tumor treatment, as this may seed tumor cells into the vitreous cavity.