Comparison of two measures of behavior change in children after day surgery.

BACKGROUND: A contemporary, well-validated instrument for the measurement of behavior change in children after general anesthesia is lacking. The Post Hospitalization Behavior Questionnaire for Ambulatory Surgery (PHBQ-AS) has been developed as an updated version of the original Post Hospitalization Behavior Questionnaire (PHBQ) to better reflect the current patient population and modern anesthetic practices. AIMS: To assess the reliability of the PHBQ-AS and determine concurrent validity with another measure of child behavior, the Strength and Difficulties Questionnaire (SDQ). METHODS: We compared the PHBQ-AS with the SDQ in 248 children presenting for day-case surgery. A baseline SDQ measurement was taken prior to surgery, and then, both scales were administered on days 3, 14, and 28 postsurgery. RESULTS: The PHBQ-AS demonstrated good reliability in terms of internal consistency with a Cronbach's alpha of 0.79 and split-half correlation with Spearman Brown adjustment of 0.85. There was weak correlation with the SDQ on day 3 postoperatively (Pearson's r = 0.201), moderate correlation on day 14 (Pearson's r = 0.421), and weak-to-moderate correlation on day 28 (Pearson's r = 0.340). A cut-off score of 3.2 on the PHBQ-AS for the diagnosis of negative behavior demonstrated equivalence with the SDQ results; however, the SDQ results remained relatively constant throughout the study period and reflected the expected rate of increased risk of problem behavior in children. CONCLUSIONS: The PHBQ-AS showed good reliability but only had weak-to-moderate correlation with another measure of child behavior, the SDQ. Further validation is required before the PHBQ-AS is used for the routine measurement of behavior change in children after anesthesia, or alternatively, a new instrument needs to be developed in order for research to advance in this area.

A trivalent gC2/gD2/gE2 vaccine for herpes simplex virus generates antibody responses that block immune evasion domains on gC2 better than natural infection.

Vaccines for prevention and treatment of genital herpes are high public health priorities. Our approach towards vaccine development is to focus on blocking virus entry mediated by herpes simplex virus type 2 (HSV-2) glycoprotein D (gD2) and to prevent the virus from evading complement and antibody attack by blocking the immune evasion domains on HSV-2 glycoproteins C (gC2) and E (gE2), respectively. HSV-2 gC2 and gE2 are expressed on the virion envelope and infected cell surface where they are potential targets of antibodies that bind and block their immune evasion activities. We demonstrate that antibodies produced during natural infection in humans or intravaginal inoculation in guinea pigs bind to gC2 but generally fail to block the immune evasion domains on this glycoprotein. In contrast, immunization of naïve or previously HSV-2-infected guinea pigs with gC2 subunit antigen administered with CpG and alum as adjuvants produces antibodies that block domains involved in immune evasion. These results indicate that immune evasion domains on gC2 are weak antigens during infection, yet when used as vaccine immunogens with adjuvants the antigens produce antibodies that block immune evasion domains.

Does dexmedetomidine given as a premedication or intraoperatively reduce post-hospitalisation behaviour change in children? A study protocol for a randomised controlled trial in a tertiary paediatric hospital.

INTRODUCTION: It has been reported that post-hospitalisation behaviour change (PHBC) occurs in over 50% of children undergoing a general anaesthetic and manifests as behaviours such as sleep and eating disorders, defiance of authority, nightmares, enuresis and temper tantrums. The effect is usually short-lived (2-4 weeks); however, in 5-10% of children, these behaviours can last up to 12 months. The risk factors for developing PHBC include underlying anxiety in the child or parent, a previous bad hospital experience, emergence delirium and preschool age. A recent meta-analysis of alpha-2 agonists (including dexmedetomidine) found that they effectively reduce the incidence of emergence delirium but none of the studies looked at longer term outcomes, such as PHBC. METHODS AND ANALYSIS: Two-year-old to seven-year-old children requiring general anaesthesia for common day-case procedures will be randomly assigned to one of three groups: a dexmedetomidine pre medication group, an intraoperative dexmedetomidine group and a control group. Baseline anxiety levels of the parent will be recorded and the anxiety of the child during induction of anaesthesia will also be recorded using validated tools. The primary outcome will be negative behaviours after hospitalisation and these will be measured using the Post Hospitalisation Behaviour Questionnaire for Ambulatory Surgery and the Strengths and Difficulties Questionnaire. These questionnaires will be administered by a blinded researcher at days 3, 14 and 28 post surgery. ETHICS AND DISSEMINATION: Ethics approval has been granted by the Children's Health Queensland human research ethics committee (HREC/15/QRCH/248) and the University of Queensland human research ethics office (#2016001715). Any amendments to this protocol will be submitted to the ethics committees for approval. TRIAL REGISTRATION NUMBER: ANZCTR:12616000096459; Pre-results.

Severe viral respiratory infections in children with IFIH1 loss-of-function mutations.

Viral respiratory infections are usually mild and self-limiting; still they exceptionally result in life-threatening infections in previously healthy children. To investigate a potential genetic cause, we recruited 120 previously healthy children requiring support in intensive care because of a severe illness caused by a respiratory virus. Using exome and transcriptome sequencing, we identified and characterized three rare loss-of-function variants in IFIH1, which encodes an RIG-I-like receptor involved in the sensing of viral RNA. Functional testing of the variants IFIH1 alleles demonstrated that the resulting proteins are unable to induce IFN-ß, are intrinsically less stable than wild-type IFIH1, and lack ATPase activity. In vitro assays showed that IFIH1 effectively restricts replication of human respiratory syncytial virus and rhinoviruses. We conclude that IFIH1 deficiency causes a primary immunodeficiency manifested in extreme susceptibility to common respiratory RNA viruses.

An adjuvanted herpes simplex virus 2 subunit vaccine elicits a T cell response in mice and is an effective therapeutic vaccine in Guinea pigs.

Immunotherapeutic herpes simplex virus 2 (HSV-2) vaccine efficacy depends upon the promotion of antigen-specific immune responses that inhibit reactivation or reactivated virus, thus controlling both recurrent lesions and viral shedding. In the present study, a candidate subunit vaccine, GEN-003/MM-2, was evaluated for its ability to induce a broad-spectrum immune response in mice and therapeutic efficacy in HSV-2-infected guinea pigs. GEN-003 is comprised of HSV-2 glycoprotein D2 (gD2ΔTMR340-363) and a truncated form of infected cell polypeptide 4 (ICP4383-766), formulated with Matrix M-2 (MM-2) adjuvant (GEN-003/MM-2). In addition to eliciting humoral immune responses, CD4(+) and CD8(+) T cells characterized by the secretion of multiple cytokines and cytolytic antigen-specific T cell responses that were able to be recalled at least 44 days after the last immunization were induced in immunized mice. Furthermore, vaccination with either GEN-003 or GEN-003/MM-2 led to significant reductions in both the prevalence and severity of lesions in HSV-2-infected guinea pigs compared to those of phosphate-buffered saline (PBS) control-vaccinated animals. While vaccination with MM-2 adjuvant alone decreased recurrent disease symptoms compared to the PBS control group, the difference was not statistically significant. Importantly, the frequency of recurrent viral shedding was considerably reduced in GEN-003/MM-2-vaccinated animals but not in GEN-003- or MM-2-vaccinated animals. These findings suggest a possible role for immunotherapeutic GEN-003/MM-2 vaccination as a viable alternative to chronic antiviral drugs in the treatment and control of genital herpes disease.

The utility of the Children's Revised Impact of Event Scale in screening for concurrent PTSD following admission to intensive care.

Although there is some information available regarding the utility of the Children's Revised Impact of Event Scale (CRIES) in screening for posttraumatic stress disorder (PTSD), data are scarce and limited to studies sampling children predominantly injured in road traffic accidents. This study investigated the utility of 2 versions, the CRIES-8 and CRIES-13, in identifying those children meeting criteria for PTSD following admission to a pediatric intensive care unit (PICU). The Children's PTSD Inventory (CPTSDI), a diagnostic interview, and the CRIES-13 were administered to 55 children, aged 6-16 years, 6 months following admission to the PICU. Of the 55, 14 (25%) met criteria on the CPTSDI. Cutoff scores of 14.5 on the CRIES-8 and 22.5 on the CRIES-13 maximized sensitivity and specificity and correctly classified 78%-86% of children. Both cutoff scores were lower than those reported in other samples. The CRIES-13 appeared to offer greater utility than the CRIES-8, also in contrast to previous findings. Methodological or sampling differences may account for the discrepancy with prior studies. The proposed cutoffs are recommended specifically for use with PICU patients and replication and further validation of the CRIES with other samples is warranted.

Alphavirus replicon particles encoding the fusion or attachment glycoproteins of respiratory syncytial virus elicit protective immune responses in BALB/c mice and functional serum antibodies in rhesus macaques.

Respiratory syncytial virus (RSV) is a major cause of acute respiratory tract disease in humans. Towards development of a prophylactic vaccine, we genetically engineered Venezuelan equine encephalitis virus (VEEV) replicons encoding the fusion (Fa) or attachment (Ga or Gb) proteins of the A or B subgroups of RSV. Intramuscular immunization with a formulation composed of equal amounts of each replicon particle (3vRSV replicon vaccine) generated serum neutralizing antibodies against A and B strains of RSV in BALB/c mice and rhesus macaques. When contrasted with purified natural protein or formalin-inactivated RSV formulated with alum, the 3vRSV replicon vaccine induced balanced Th1/Th2 T cell responses in mice. This was evident in the increased number of RSV-specific IFN-gamma(+) splenocytes following F or G peptide stimulation, diminished quantity of eosinophils and type 2 T cell cytokines in the lungs after challenge, and increased in vivo lysis of RSV peptide-loaded target cells. The immune responses in mice were also protective against intranasal challenge with RSV. Thus, the replicon-based platform represents a promising new strategy for vaccines against RSV.

Evaluation of neurovirulence and biodistribution of Venezuelan equine encephalitis replicon particles expressing herpes simplex virus type 2 glycoprotein D.

The safety of a propagation-defective Venezuelan equine encephalitis virus (VEEV) replicon particle vaccine was examined in mice. After intracranial inoculation we observed approximately 5% body weight loss, modest inflammatory changes in the brain, genome replication, and foreign gene expression. These changes were transient and significantly less severe than those caused by TC-83, a live-attenuated vaccinal strain of VEEV that has been safely used to immunize military personnel and laboratory workers. Replicon particles injected intramuscularly or intravenously were detected at limited sites 3 days post-administration, and were undetectable by day 22. There was no evidence of dissemination to spinal cord or brain after systemic administration. These results demonstrate that propagation-defective VEEV replicon particles are minimally neurovirulent and lack neuroinvasive potential.

Clinical indicators of radiographic findings in patients with suspected community-acquired pneumonia: who needs a chest x-ray?

PURPOSE: To develop a prediction rule for the use of chest radiographs in evaluating for community-acquired pneumonia (CAP) based on presenting signs and symptoms. PATIENTS AND METHODS: Adult patients with acute respiratory symptoms and positive chest radiographic results from October 2004 through April 2005 were enrolled as positive cases (n = 350). An equal number of age-matched controls with acute respiratory symptoms but negative radiographic results were included. Data analyses were performed on the 6 most common individual clinical indicators (cough, sputum production, fever, tachycardia, tachypnea, and abnormal physical examination results). Additional analyses were performed for any vital sign abnormality and for the presence of vital sign or physical examination abnormalities. RESULTS: The data show that vital sign and physical examination findings are useful screening parameters for CAP, demonstrating a sensitivity of 95%, a specificity of 56%, and an odds ratio of 24.9 [corrected] in the presence of vital sign or physical examination abnormalities. In light of these results, the authors developed a prediction rule for low-risk patients with reliable follow-up, which states that chest radiographs are unnecessary in the presence of normal vital signs and physical examination findings. CONCLUSION: The data suggest that chest radiographs are unnecessary in patients with acute respiratory symptoms who present with normal vital signs and physical examination findings. Because approximately 5% of cases would be missed, however, these criteria are useful only for patients with reliable follow-up and a low likelihood of morbidity if CAP is not detected initially.