Tumor-Derived cGAMP Triggers a STING-Mediated Interferon Response in Non-tumor Cells to Activate the NK Cell Response.

Detection of cytosolic DNA by the enzyme cGAS triggers the production of cGAMP, a second messenger that binds and activates the adaptor protein STING, which leads to interferon (IFN) production. Here, we found that in vivo natural killer (NK) cell killing of tumor cells, but not of normal cells, depends on STING expression in non-tumor cells. Experiments using transplantable tumor models in STING- and cGAS-deficient mice revealed that cGAS expression by tumor cells was critical for tumor rejection by NK cells. In contrast, cGAS expression by host cells was dispensable, suggesting that tumor-derived cGAMP is transferred to non-tumor cells, where it activates STING. cGAMP administration triggered STING activation and IFN-ß production in myeloid cells and B cells but not NK cells. Our results reveal that the anti-tumor response of NK cells critically depends on the cytosolic DNA sensing pathway, similar to its role in defense against pathogens, and identify tumor-derived cGAMP as a major determinant of tumor immunogenicity with implications for cancer immunotherapy.

The Anorexia Nervosa Genetics Initiative: Study description and sample characteristics of the Australian and New Zealand arm.

OBJECTIVES: Anorexia nervosa is a severe psychiatric disorder with high mortality rates. While its aetiology is poorly understood, there is evidence of a significant genetic component. The Anorexia Nervosa Genetics Initiative is an international collaboration which aims to understand the genetic basis of the disorder. This paper describes the recruitment and characteristics of the Australasian Anorexia Nervosa Genetics Initiative sample, the largest sample of individuals with anorexia nervosa ever assembled across Australia and New Zealand. METHODS: Participants completed an online questionnaire based on the Structured Clinical Interview Diagnostic and Statistical Manual of Mental Disorders (4th ed.; DSM-IV) eating disorders section. Participants who met specified case criteria for lifetime anorexia nervosa were requested to provide a DNA sample for genetic analysis. RESULTS: Overall, the study recruited 3414 Australians and 543 New Zealanders meeting the lifetime anorexia nervosa case criteria by using a variety of conventional and social media recruitment methods. At the time of questionnaire completion, 28% had a body mass index ⩽ 18.5 kg/m2. Fasting and exercise were the most commonly employed methods of weight control, and were associated with the youngest reported ages of onset. At the time of the study, 32% of participants meeting lifetime anorexia nervosa case criteria were under the care of a medical practitioner; those with current body mass index < 18.5 kg/m2 were more likely to be currently receiving medical care (56%) than those with current body mass index ⩾ 18.5 kg/m2 (23%). Professional treatment for eating disorders was most likely to have been received from general practitioners (45% of study participants), dietitians (42%) and outpatient programmes (42%). CONCLUSIONS: This study was effective in assembling the largest community sample of people with lifetime anorexia nervosa in Australia and New Zealand to date. The proportion of people with anorexia nervosa currently receiving medical care, and the most common sources of treatment accessed, indicates the importance of training for general practitioners and dietitians in treating anorexia nervosa.

Validation of a prediction rule for the identification of children with intra-abdominal injuries after blunt torso trauma.

STUDY OBJECTIVE: We validate the accuracy of a previously derived clinical prediction rule for the identification of children with intra-abdominal injuries after blunt torso trauma. METHODS: We conducted a prospective observational study of children with blunt torso trauma who were evaluated for intra-abdominal injury with abdominal computed tomography (CT), diagnostic laparoscopy, or laparotomy at a Level I trauma center during a 3-year period to validate a previously derived prediction rule. The emergency physician providing care documented history and physical examination findings on a standardized data collection form before knowledge of the results of diagnostic imaging. The clinical prediction rule being evaluated included 6 "high-risk" variables, the presence of any of which indicated that the child was not at low risk for intra-abdominal injury: low age-adjusted systolic blood pressure, abdominal tenderness, femur fracture, increased liver enzyme levels (serum aspartate aminotransferase concentration >200 U/L or serum alanine aminotransferase concentration >125 U/L), microscopic hematuria (urinalysis >5 RBCs/high powered field), or an initial hematocrit level less than 30%. RESULTS: One thousand three hundred twenty-four children with blunt torso trauma were enrolled, and 1,119 (85%) patients had the variables in the decision rule documented by the emergency physician and therefore made up the study sample. The prediction rule had the following test characteristics: sensitivity=149 of 157, 94.9% (95% confidence interval [CI] 90.2% to 97.7%) and specificity=357 of 962, 37.1% (95% CI 34.0 to 40.3%). Three hundred sixty-five patients tested negative for the rule; thus, strict application would have resulted in a 33% reduction in abdominal CT scanning. Of the 8 patients with intra-abdominal injury not identified by the prediction rule, 1 underwent a laparotomy. This patient had a serosal tear and a mesenteric hematoma at laparotomy, neither of which required specific surgical intervention. CONCLUSION: A clinical prediction rule consisting of 6 variables, easily available to clinicians in the ED, identifies most but not all children with intra-abdominal injury. Application of the prediction rule to this sample would have reduced the number of unnecessary abdominal CT scans performed but would have failed to identify 1 child undergoing (a nontherapeutic) laparotomy. Thus, further refinement of this prediction rule in a large, multicenter cohort is necessary before widespread implementation.

Is hospital admission and observation required after a normal abdominal computed tomography scan in children with blunt abdominal trauma?

OBJECTIVES: The objective was to determine if hospital admission of children with blunt abdominal trauma for observation of possible intraabdominal injury (IAI) is necessary after a normal abdominal computed tomography (CT) scan in the emergency department (ED). METHODS: The authors conducted a prospective observational cohort study of children less than 18 years of age with blunt abdominal trauma who underwent an abdominal CT scan in the ED. Abdominal CT scans were obtained with intravenous contrast but no oral contrast. The decision to hospitalize the patient was made by the attending emergency physician (EP) with the trauma or pediatric surgery teams. An abnormal abdominal CT scan was defined by the presence of any visualized IAI or findings suggestive of possible IAI (e.g., intraperitoneal fluid without solid organ injury). Patients were followed to determine if IAI was later diagnosed and the need for acute therapeutic intervention if IAI was present. RESULTS: A total of 1,295 patients underwent abdominal CT, and 1,085 (84%) patients had normal abdominal CT scans in the ED and make up the study population. Seven-hundred thirty-seven (68%) were hospitalized, and 348 were discharged to home. None of the 348 patients discharged home and 2 of the 737 hospitalized patients were identified with an IAI after a normal initial abdominal CT. The IAIs in patients with normal initial CT scans included a 10-year-old with a mesenteric hematoma and serosal tear at laparotomy and a 10-year-old with a perinephric hematoma on repeat CT. Neither underwent specific therapy. The negative predictive value (NPV) of a normal abdominal CT scan for IAI was 99.8% (95% confidence interval [CI] = 99.3% to 100%). CONCLUSIONS: Children with blunt abdominal trauma and a normal abdominal CT scan in the ED are at very low risk of having a subsequently diagnosed IAI and are very unlikely to require a therapeutic intervention. Hospitalization of children for evaluation of possible undiagnosed IAI after a normal abdominal CT scan has a low yield and is generally unnecessary.

A comparison of the sleep-wake patterns of cosleeping and solitary-sleeping infants.

This study examined whether 3-15, month-old cosleeping infants displayed differences in time spent in active versus quiet sleep, and in the number/duration of nighttime awakenings when compared with solitary-sleeping infants; and also whether they spent the majority of the night sleeping face-to-face, as previously reported. Nine cosleeping and nine solitary-sleeping infants were matched on age, gender, ethnicity, maternal age, and family SES. Video recordings of nighttime sleep yielded percentage of time in active sleep, quiet sleep, and awake, number of wakenings, and the percentage of time cosleeping infants and mothers spent face-to-face. Across age, cosleeping infants had more awakenings per night mean 5.8(1.50) versus 3.2(1.95); t = 3.16, p = .006). The percent of the nighttime spent awake did not differ between groups, suggesting that cosleeping infants had shorter awakenings. Cosleeping infants spent 40% of the night face-to-face with their mothers.