Search

Multiple active vaccination approaches have proven ineffective in reducing the substantial morbidity and mortality caused by respiratory syncytial virus (RSV) in infants and older adults (aged ≥65 years). A vaccine conferring a substantial and sustainable boost in neutralising activity is required to protect against severe RSV disease. To that end, we evaluated the safety and immunogenicity of DS-Cav1, a prefusion F subunit vaccine.In this randomised, open-label, phase 1 clinical trial, the stabilised prefusion F vaccine DS-Cav1 was evaluated for dose, safety, tolerability, and immunogenicity in healthy adults aged 18-50 years at a single US site. Participants were assigned to receive escalating doses of either 50 μg, 150 μg, or 500 μg DS-Cav1 at weeks 0 and 12, and were randomly allocated in a 1:1 ratio within each dose group to receive the vaccine with or without aluminium hydroxide (AlOH) adjuvant. After 71 participants had been randomised, the protocol was amended to allow some participants to receive a single vaccination at week 0. The primary objectives evaluated the safety and tolerability at every dose within 28 days following each injection. Neutralising activity and RSV F-binding antibodies were evaluated from week 0 to week 44 as secondary and exploratory objectives. Safety was assessed in all participants who received at least one vaccine dose; secondary and exploratory immunogenicity analysis included all participants with available data at a given visit. The trial is registered with ClinicalTrials.gov, NCT03049488, and is complete and no longer recruiting.Between Feb 21, 2017, and Nov 29, 2018, 244 participants were screened for eligibility and 95 were enrolled to receive DS-Cav1 at the 50 μg (n=30, of which n=15 with AlOH), 150 μg (n=35, of which n=15 with AlOH), or 500 μg (n=30, of which n=15 with AlOH) doses. DS-Cav1 was safe and well tolerated and no serious vaccine-associated adverse events deemed related to the vaccine were identified. DS-Cav1 vaccination elicited robust neutralising activity and binding antibodies by 4 weeks after a single vaccination (p0·0001 for F-binding and neutralising antibodies). In analyses of exploratory endpoints at week 44, pre-F-binding IgG and neutralising activity were significantly increased compared with baseline in all groups. At week 44, RSV A neutralising activity was 3·1 fold above baseline in the 50 μg group, 3·8 fold in the 150 μg group, and 4·5 fold in the 500 μg group (p0·0001). RSV B neutralising activity was 2·8 fold above baseline in the 50 μg group, 3·4 fold in the 150 μg group, and 3·7 fold in the 500 μg group (p0·0001). Pre-F-binding IgG remained significantly 3·2 fold above baseline in the 50 μg group, 3·4 fold in the 150 μg group, and 4·0 fold in the 500 μg group (p0·0001). Pre-F-binding serum IgA remained 4·1 fold above baseline in the 50 μg group, 4·3 fold in the 150 μg group, and 4·8 fold in the 500 μg group (p0·0001). Although a higher vaccine dose or second immunisation elicited a transient advantage compared with lower doses or a single immunisation, neither significantly impacted long-term neutralisation. There was no long-term effect of dose, number of vaccinations, or adjuvant on neutralising activity.In this phase 1 study, DS-Cav1 vaccination was safe and well tolerated. DS-Cav1 vaccination elicited a robust boost in RSV F-specific antibodies and neutralising activity that was sustained above baseline for at least 44 weeks. A single low-dose of pre-F immunisation of antigen-experienced individuals might confer protection that extends throughout an entire RSV season.The National Institutes of Allergy and Infectious Diseases.

Purpose This study investigated the auditory comprehension of Japanese sentences including relative clauses (RCs) by 52 Japanese-speaking children with typical development (TD) and 16 children with specific language impairment (SLI). Method A picture-pointing task measured RC and main clause (MC) comprehension for object and subject relatives in sentences with varying lengths. The accuracy of RC only, MC only, and combined comprehension (RC and MC) was analyzed with linear mixed-effects (logistic) models to examine accuracy and the effects of the deep gap–filler distance (structural complexity), the surface linear distance, and sentence length for the two participant groups. Six language tests and two working memory tests were administered to determine language and working memory status. A factor analysis grouped them into two factors that were examined as predictors of comprehension performance. Results Initial models indicated that children with SLI performed more poorly than their peers with TD. Working memory abilities predicted the comprehension of subject and object relative sentences, but language abilities other than a general measure of sentence comprehension were only limited predictors. In a series of pairwise comparisons, children with SLI did not exhibit comprehension facilitation for RC sentences with lower structural complexity, nor did they exhibit comprehension facilitation when the linear distance between the gap and the filler was shorter, perhaps because of their overall lower performance. Children with TD made more errors on sentences with higher structural complexity but did not exhibit any linear distance effects. Neither group exhibited effects of noun phrase or sentence length. Conclusions Japanese-speaking children with TD exhibited negative comprehension effects of increased deep structure complexity, but not of linear surface distance or sentence noun phrase length. The children with SLI face challenges in comprehending both subject and object relative sentences compared to their typically developing peers. Their poorer working memory abilities are the primary factor that constrains their performance.

Experimental studies have suggested benzophenone-3 (BP-3), a sunscreen ingredient, may have endocrine-disrupting properties. A cohort of girls were recruited at ages 6–7 years and returned semi-annually for pubertal maturation staging, provided blood for serum hormone analyses [estradiol, estrone, testosterone, dehydroepiandrosterone-sulfate (DHEA-S)], and urine to measure BP-3 concentrations. We found a significant negative linear association between amount of reported sunscreen use and testosterone levels at the onset of puberty (N = 157, adjusted β = −0.0163, 97.5% CI:-0.0300,-0.0026). The 2nd quartile of the BP-3 biomarker had earlier thelarche compared to the 1st quartile (N = 282, adjusted HR = 1.584, 97.5% CI:1.038,2.415). Results suggest that higher report of sunscreen use may be associated with lower testosterone levels at thelarche and a non-linear relationship between the BP-3 urinary biomarker and onset of puberty, although the clinical significance of the finding is limited and may be a random effect. Improved methods of BP-3 exposure characterization are needed.

The spontaneous regression of an osteochondroma is extremely rare. We report a case of medial femoral condyle impaction fracture over the site of spontaneous regression of a pedunculated osteochondroma discovered on advanced imaging after an acute injury in a 16-year-old male American football athlete. Although spontaneous regression of an osteochondroma has been described, the case presented reveals questions regarding resultant architectural changes to the bone after resorption, leaving it prone to injury. This is the first case that describes increased injury risk potential at the site of osteochondral regression.

INTRODUCTION: Few data exist to understand the recovery phase of pit viper envenomation. A recently published placebo-controlled clinical trial affords this opportunity. The purpose of this study is to examine the time course of recovery from copperhead snake (Agkistrodon contortrix) envenomation patients managed with and without the use of antivenom, stratified by age, sex, anatomic site of envenomation, initial severity of envenomation, and geographic region. METHODS: This is a post-hoc subgroup analysis of data from a multi-center double-blinded clinical trial of Fab antivenom (FabAV) vs. placebo. Outcomes were the Patient-Specific Functional Scale (PSFS) score at 3, 7, 10, and 14 days after envenomation. Least-squares mean PSFS score curves were calculated for each subgroup, and repeated measures ANOVA was used to estimate between-group comparisons. RESULTS: Seventy-two subjects were included, of whom 44 received FabAV. Males demonstrated better overall recovery than females (model predicted PSFS score 6.18 vs 4.99; difference 1.19; 95% CI 0.12 to 2.25; p = 0.029). No sex difference was found in response to FabAV. Overall recovery and effect of FabAV were similar in adult vs adolescent patients, patients with upper vs lower extremity envenomation, and patients with initially mild vs moderate envenomation signs. Analysis by geographic location was not successful due to ANOVA mode instability. CONCLUSIONS: Male victims of copperhead snake envenomation demonstrate slightly better recovery than females, but response to Fab antivenom overall is similar across all subgroups studied. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s13181-019-00733-y) contains supplementary material, which is available to authorized users.

Objective: To use a previously published criterion standard to compare the accuracy of 4 different mass casualty triage systems (Sort, Assess, Lifesaving Interventions, Treatment/Transport [SALT], ...

Ebola viruses (EBOV) express cytotoxic structural glycoprotein GP1,2 to mediate virus entry. To explore a novel viral fitness mechanism, we used mass spectrometry to investigate how EBOV-GP1,2 expression is regulated in the endoplasmic reticulum (ER). We found that ER protein 57 (ERp57), a member of protein disulfide isomerases (PDIs) that promote protein folding, targets EBOV-GP1,2 cysteine residues required for correct cross-linking, thus adverselytriggering misfolding, which in turn activates the unfolded protein response. Misfolded EBOV-GP1,2 is targeted by ER-associated protein degradation machinery and, unexpectedly, is degraded in lysosomes via autophagosomes, but not proteasomes. Five other PDIs also have similar inhibitory activity. In contrast, the expression of Marburg virus and some other enveloped virus glycoproteins is increased by ERp57. Thus, PDIs can negatively regulate EBOV glycoprotein expression, which enables optimum viral infectivity and minimizes cytotoxicity. Importantly, PDIs emerge as potential targets for inhibition of Ebola virus infection.

Background/purpose Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has emerged as a highly contagious and lethal virus, devastating healthcare systems throughout the world. Following a period of stability, the coronavirus disease 2019 (COVID-19) pandemic appears to be re-intensifying globally. As the virus continues to evolve, so does our understanding of its implications on ST-segment elevation myocardial infarction (STEMI). We sought to describe a single center STEMI experience at one of the epicenters during the COVID-19 pandemic. Methods/materials We conducted a retrospective, observational study comparing STEMI patients during the pandemic period (March 1, 2020 to August 31, 2020) to those with STEMI during the pre-pandemic period (March 1, 2019 to August 31, 2019) at NYU Langone Hospital – Long Island, a tertiary care center in Nassau County, New York. Additionally, we describe our subset of COVID-19 patients with STEMI during the pandemic. Results The acute myocardial infarction (AMI) team was activated for a total of 183 patients during both periods. There were a similar number of AMI team activations during the pandemic period (n = 93) compared to the pre-pandemic period (n = 90). Baseline characteristics did not differ during both periods however, infection control measures and additional investigation were required to clarify the diagnosis during the pandemic, resulting in a signal towards longer door-to-balloon times (95.9 min vs. 74.4 min, p = 0.0587). We observed similar inpatient length of stay (LOS) (3.6 days vs. 5.0 days, p = 0.0901) and mortality (13.2% vs. 9.2%, p = 0.5876). There was a total of 6 COVID-19 positive patients who presented with STEMI, of which 4 were emergently taken to the cardiac catheterization laboratory with successful percutaneous coronary intervention (PCI) performed in 3 patients. The 2 patients who were not offered primary PCI expired, as both were treated medically, one with thrombolytics. Conclusions Our single center study, in New York, at one of the epicenters of the pandemic, demonstrated a similar number of AMI team activations, mimicking the seasonal variability seen in 2019, but with a signal towards longer door-to-balloon time. Despite this, inpatient LOS and mortality remained similar., Highlights • The ongoing COVID-19 pandemic continues to evolve, as does our understanding of its implications on STEMI. • Our study demonstrated similar AMI activations but longer door-to-balloon times during the pandemic compared to the pre-pandemic period. • As we continue to manage these pandemic patients, despite longer door-to-balloon times, primary PCI remains the standard of care for STEMI.

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has emerged the highly contagious and lethal virus, devastating healthcare systems throughout the world. The ongoing coronavirus disease 2019 (COVID-19) pandemic continues to rapidly evolve, as does our understanding of its implications on the cardiovascular system. The purpose of our study was to describe a single center STEMI experience at the epicenter of the COVID-19 pandemic. Methods: This was a retrospective, observational study, which included consecutive suspected STEMI patients from March 1 2020 through May 31 2020 compared to with the same time period in 2019, at a tertiary referral center in New York. Cohort 1 (2019 pre-pandemic period) included all patients with suspected STEMI from March 1 2019 to May 31 2019. Cohort 2 (2020 pandemic period) included all patients with suspected STEMI from March 1 2020 to May 31 2020. Statistical analysis was performed using t-test and chi-squared test. Results: Cohort 2 saw a similar number (n=46) of acute myocardial infarction (AMI) team activations when compared to cohort 1 (n=42) (Figure 1). As expected during the pandemic, infection control measures and additional investigation were required to clarify the diagnosis in cohort 2 resulting in significantly longer door to balloon times (96.3 minutes vs. 72.7 minutes, p=0.0307). Despite this, we observed similar inpatient length of stay (4.3 days vs. 4.9 days, p=0.1807) and mortality (11.1% vs. 12.1%, p=0.5141). Conclusions: Our single center study, at the epicenter of the pandemic, demonstrated similar AMI team activations compared to 2019, but longer door-to-balloon time. Despite this, inpatient length of stay and mortality remained unchanged. As we continue to manage these patients amidst this dynamic pandemic, our approach should continue to focus on the safety of healthcare workers with an understanding that primary PCI remains the standard of care for patients with STEMI.

Background: Mitral regurgitation (MR) frequently accompanies aortic stenosis (AS). Several studies have reported that certain patients see improvement in their MR following transcatheter aortic valve replacement (TAVR) alone using earlier generation valves. The purpose of this study was to determine the predictors and short-term outcome impact of MR in patients undergoing TAVR using all generation valves across all risk groups. Methods: In this retrospective, study from 2012-2019, we reviewed data on 1,626 low, intermediate and high-risk patients who underwent TAVR. Included were patients with baseline MR who underwent transfemoral TAVR. We excluded prior valve replacement and aborted TAVR. Our primary outcome was persistence or worsening of baseline MR post-TAVR. Additional endpoints included an inpatient composite (intensive care unit length of stay >24 hours, post-TAVR length of stay >2 days and inpatient death), 30-day composite (30-day death or 30-day readmission) and 1-year composite (1-year death or readmission). Results: Of the 1,626 patients screened, 552 had significant baseline MR (>moderate), which improved in 79.7% of patients. Female patients, those with higher right ventricular systolic pressures and those who underwent TAVR using earlier generation valves were more likely to have persistence or worsening of significant baseline MR. Patients whose significant baseline MR (>moderate) persisted or worsened, had higher rates (92.2 vs. 84.1%, p=0.0343) of our inpatient composite and higher rates (36.6% vs. 25.5%, p=0.0243) of our 1-year composite when compared to patients whose significant baseline MR (>moderate) improved post-TAVR. Conclusions: Our study identifies certain clinical characteristics, which could help identify the subset of patients who may require closer post-procedural follow-up and warrant possible staged mitral valve intervention post-TAVR across all risk groups.

Benzophenone-3 is a putative endocrine disrupting chemical and common ingredient in sunscreens. The potential of endocrine disrupting chemicals to act as agonists or antagonists in critical hormonally regulated processes, such as mammary gland development and mammary tumorigenesis, demands evaluation of its potential in promoting breast cancer. This study identifies the effects of BP-3 on mammary tumorigenesis with high-fat diet during puberty versus adulthood in Trp53-null transplant BALB/c mice. Benzophenone-3 exposure yielded levels in urine similar to humans subjected to heavy topical sunscreen exposure. Benzophenone-3 was protective for epithelial tumorigenesis in mice fed lifelong low-fat diet, while promotional for epithelial tumorigenesis in mice fed adult high-fat diet. Benzophenone-3 increased tumor cell proliferation, decreased tumor cell apoptosis, and increased tumor vascularity dependent on specific dietary regimen and tumor histopathology. Even in instances of an ostensibly protective effect, other parameters suggest greater risk. Although benzophenone-3 seemed protective on low-fat diet, spindle cell tumors arising in these mice showed increased proliferation and decreased apoptosis. This points to a need for further studies of benzophenone-3 in both animal models and humans as a potential breast cancer risk factor, as well as a more general need to evaluate endocrine disrupting chemicals in varying dietary contexts.

Background Benzophenone-3 is a putative endocrine disrupting chemical and common active ingredient in sunscreens and personal care products. The potential of endocrine disrupting chemicals to act as agonists or antagonists in critical hormonally regulated processes, such as mammary gland development and mammary tumorigenesis, demands evaluation of their potential in promoting breast cancer. We previously demonstrated promotion of mammary tumorigenesis by a diet high in saturated animal fat. This study examines the activity of benzophenone-3 in a dietary context to provide insight into its potential role in promoting breast cancer, and how diet might influence this. Methods Mammary tumorigenesis was studied in a BALB/c mouse Trp53-null transplantation model. Three-week-old mice were fed low-fat or high-fat diets, and at ten weeks of age were switched to high-fat or low-fat diets, respectively, while other mice were maintained continuously on low-fat diet. Mice additionally were treated continuously with or without benzophenone-3. The level of benzophenone-3 exposure yielded levels in urine similar to that observed in humans subjected to heavy topical exposure of benzophenone-3-containing commercial sunscreen. Results Benzophenone-3 had complex effects that were dependent upon diet and tumor histopathology. Benzophenone-3 was protective in regard to epithelial tumorigenesis in mice fed low-fat diet and was promotional for epithelial tumorigenesis in mice fed high-fat diet restricted to adulthood. It increased tumor cell proliferation, decreased tumor cell apoptosis, and increased tumor vascularity in a manner dependent on specific dietary regimen and tumor histopathology. Protective effects were not always concordant with a decrease in properties associated with tumor progression. Notably, although benzophenone-3 seemed protective for tumorigenesis in mice fed low-fat diet, spindle cell tumors that arose in these mice showed increased proliferation and decreased apoptosis. Conclusions Benzophenone-3 elicits promotional and protective effects on mammary tumorigenesis dependent upon diet and tumor histopathology. However, even in instances of an ostensibly protective effect, other parameters suggest potential for greater risk. This points to a need for further studies of benzophenone-3 in both animal models and humans as a potential breast cancer risk factor, as well as a more general need to evaluate endocrine disrupting chemicals in the context of varying diets.

A mass casualty incident (MCI) is an event that causes casualties in sufficient number or acuity to overwhelm the locally available medical and public health services and resources. Explosives are uniquely suited to cause MCIs due to their ability to affect large areas and numbers of people, cause severe and complicated injuries, produce massive structural damage, and create environmental hazards (e.g., fire, radiation, chemical, dust, and carbon monoxide). Due to the severity and complexity of explosive MCI, clear and effective command and control is essential in optimizing patient care. The Incident Command System (ICS) is a widely applicable management system designed to enable effective and efficient incident management by integrating a combination of facilities, equipment, personnel, procedures, and communications operating within a common organizational structure. It is the current standard command structure for use in civilian MCIs of any cause. In addition to an appropriate incident command structure, fast and effective on-scene triage is crucial to an effective blast MCI response. The Centers for Disease Control and Prevention (CDC) established standardized triage criteria for MCIs called the Model Uniform Core Criteria for Mass Casualty Triage (MUCC). SALT triage is a MUCC-compliant triage system that uses a two-step process of global sorting, followed by lifesaving interventions (LSI) and individual victim assessment. The unique characteristics of blast MCIs require specific considerations for security, resource allocation, and evacuation priorities.

Background: No previous research has studied whether early snake antivenom administration leads to better clinical outcomes than late antivenom administration in North American pit viper envenomati...

Premenopausal breast cancer is associated with increased animal fat consumption among normal-weight but not overweight women. Our previous findings in obesity-resistant BALB/c mice showed that a diet high in saturated animal fat (HFD) promotes mammary tumorigenesis in both DMBA carcinogenesis and Trp53-null transplant models. Having made these observations in BALB/c mice, which have very modest HFD weight gain, we determined the effects of HFD in FVB mice, which gain significant weight on HFD. Three-week-old FVB mice fed a low-fat diet or HFD were subjected to 7,12-dimethylbenz[a]anthracene-induced carcinogenesis. Like BALB/c mice, HFD promoted mammary tumorigenesis. Development of tumors largely occurred prior to mice becoming obese, indicating the role of animal-derived HFD rather than resulting obesity in tumor promotion. Also similar to BALB/c mice, early-occurring adenosquamous mammary tumors were abundant among HFD-fed FVB mice. Tumors from HFD mice also had increased intra-tumor M2 macrophages. Prior to tumor development, HFD accelerated normal mammary gland development and increased mammary M2 macrophages, similarly to BALB/c mice. The promotional effects of puberty-initiated HFD on carcinogen-induced mammary cancer are thus largely weight gain-independent. Like BALB/c mice, HFD promoted adenosquamous tumors, suggesting a role for early age HFD in promoting this subtype of triple negative mammary cancer. M2 macrophage recruitment was common to both mouse strains. We speculate that a similar effect of HFD on immune function may contribute to epidemiological findings of increased breast cancer risk in young, premenopausal, normal-weight women who consume a diet high in saturated animal fat.

Case description: We present an unusual case of a patient that developed anaplastic thyroid cancer 40 years after treatment for papillary thyroid cancer. The patient presented with locoregional recurrence and distant metastasis. Tumor genotyping identified a BRAF V600E mutation. The patient was treated with drugs targeting BRAF V600E and MEK (vemurafenib and cobimetinib, respectively). The patient had a remarkable response with the right neck tumor shrinking 81% in size and disappearance of the distant metastases over an 8-month period. The patient underwent surgical resection of the residual tumor with genetic testing of the specimen showing persistent BRAF V600E mutation population of cells. Conclusion: Targeted drug therapy has been used with discretion on a case-by-case basis for anaplastic thyroid cancer and may result in good tumor response.

The regulation of mitochondrial function is critical in cellular homeostasis following hemorrhagic shock. Hemorrhagic shock results in fluid loss and reduced availability of oxygen and nutrients to tissues. The spleen is a secondary lymphoid organ playing a key role in 'filtering the blood' and in the innate and adaptive immune responses. To understand the molecular basis of hemorrhagic shock, we investigated the changes in splenocyte mitochondrial respiration, and concomitant immune and metabolic alterations. The hemorrhagic injury (HI) in our rat model was induced by bleeding 60% of the total blood volume followed by resuscitation with Ringers lactate. Another group of animals was subjected to hemorrhage, but did not receive fluid resuscitation. Oxygen consumption rate of splenocytes were determined using a Seahorse analyzer. We found a significantly reduced oxygen consumption rate in splenocytes following HI compared to sham operated rats. The mitochondrial stress test revealed a decreased basal oxygen consumption rate, ATP production, maximal respiration and spare respiratory capacity. The mitochondrial membrane potential, and citrate synthase activity, were also reduced in the splenocytes following HI. Hypoxic response in the splenocyte was confirmed by increased gene expression of Hif1α. Elevated level of mitochondrial stress protein, hsp60 and induction of high mobility group box1 protein (HMGB1) were observed in splenocytes following HI. An increased inflammatory response was demonstrated by significantly increased expression of IL-6, IFN-β, Mip-1α, IL-10 and NFκbp65. In summary, we conclude that splenocyte oxidative phosphorylation and metabolism were severely compromised following HI.

In this paper, we describe development of a high-throughput, highly sensitive method based on Lab Chip CGE-SDS platform for purity determination and characterization of virus-like particle (VLP) vaccines. A capillary gel electrophoresis approach requiring about 41 s per sample for analysis and demonstrating sensitivity to protein initial concentrations as low as 20 μg/mL, this method has been used previously to evaluate monoclonal antibodies, but this application for lot release assay of VLPs using this platform is unique. The method was qualified and shown to be accurate for the quantitation of VLP purity. Assay repeatability was confirmed to be less than 2% relative standard deviation of the mean (% RSD) with interday precision less than 2% RSD. The assay can evaluate purified VLPs in a concentration range of 20-249 μg/mL for VEE and 20-250 μg/mL for EEE and WEE VLPs.

Background There is an ongoing shortage of child mental health professionals. Nurse practitioners (NPs) who completed behavioral and mental health training have proven that they can diagnose and manage many pediatric problems. Purpose To ask the training directors of both child/adolescent psychiatry (CAP) and developmental/behavioral pediatric (DBP) programs about their receptivity and willingness to give additional training for NPs who provide care to children with behavioral and mental health issues and examine the main obstacles to the development of such programs. Methods A survey was sent to 151 CAP and DBP training directors in the United States. Results The return rate was 67% (N = 101). Only 12% expressed objection to the concept of additional NP training in CAP or DBP, but only 53% of training directors currently reported having sufficient faculty to do so. Some training directors reported already having advanced behavioral and mental health training programs for NPs (31%) and most (82%) would consider expanding, if funded. Conclusions There is support for advanced training for NPs, but funding is needed to make this a reality. Implications for practice Expansion of such programs might rapidly improve accessibility and reduce waiting time of mental health providers for children and adolescents.

BackgroundThe unprecedented 2014 epidemic of Ebola virus disease (EVD) prompted an international response to accelerate the availability of a preventive vaccine. A replication-defective recombinant chimpanzee adenovirus type 3–vectored ebolavirus vaccine (cAd3-EBO), encoding the glycoprotein from Zaire and Sudan species, that offers protection in the nonhuman primate model, was rapidly advanced into phase 1 clinical evaluation. MethodsWe conducted a phase 1, dose-escalation, open-label trial of cAd3-EBO. Twenty healthy adults, in sequentially enrolled groups of 10 each, received vaccination intramuscularly in doses of 2×1010 particle units or 2×1011 particle units. Primary and secondary end points related to safety and immunogenicity were assessed throughout the first 8 weeks after vaccination; in addition, longer-term vaccine durability was assessed at 48 weeks after vaccination. ResultsIn this small study, no safety concerns were identified; however, transient fever developed within 1 day after vaccinat...

Hemorrhagic shock leads to whole body hypoxia and nutrient deprivation resulting in organ dysfunction and mortality. Previous studies demonstrated that resveratrol, dichloroacetate, and niacin improve organ function and survival in rats following hemorrhagic shock injury (HI). We hypothesized that a combinatorial formula that collectively promotes survival will decrease the dose of individual compounds toward effective therapy for HI. Sprague-Dawley rats were subjected to HI by withdrawing 60% blood volume. NiDaR (Niacin-Dichloroacetate-Resveratrol; 2 mg/kg dose of each) or vehicle was administered following the shock in the absence of fluid resuscitation, and survival monitored. In order to study alterations in molecular mediators, separate groups of rats were administered NiDaR or vehicle along with resuscitation fluid, following HI. We observed significant improvement (p < 0.05) in survival following HI in animals that received NiDaR, in the absence of fluid resuscitation. In NiDaR treated animals that received resuscitation fluid, MAP was significantly increased compared to Veh-treated rats. HI-induced increase in systemic IL-6 levels and tissue expression of IL-6, IL-10, IL-1β, and IL-18 genes in the heart were attenuated with NiDaR treatment. NiDaR promoted autophagy following HI as demonstrated by reduced p-mTOR, increased p-ULK1 and p-Beclin. The combinatorial formula, NiDaR, reduced inflammation, promoted autophagy, and reduced doses of individual compounds used, and may be more effective in genetically heterogeneous population. In conclusion our experiments demonstrated that the combinatorial drug treatment has salutary effect in rats following HI.

Objective Valid, reliable, and clinically relevant outcome measures are necessary in clinical studies of snake envenomation. The aim of this study was to evaluate the psychometric (validity and reliability) and clinimetric (minimal clinically important difference [MCID]) properties of the Patient-Specific Functional Scale (PSFS) in snakebite envenomation. Methods We performed a secondary analysis of two existing snakebite trials that measured clinical outcomes using the PSFS as well as other quality of life and functional assessments. Data were collected at 3, 7, 10, and 17 days. Reliability was determined using Cronbach’s alpha for internal consistency and the intraclass correlation coefficient (ICC) for temporal stability at 10 and 17 days. Validity was assessed using concurrent validity correlating with the other assessments. The MCID was evaluated using the following criteria: (1) the distribution of stable patients according to both standard error of measurement (SEM) and responsiveness techniques, and (2) anchor-based methods to compare between individuals and to detect discriminant ability of a positive change with a receiver operator characteristic (ROC) curve and optimal cutoff point. Results A total of 86 patients were evaluated in this study. The average PSFS scores were 5.37 (SD 3.23), 7.95 (SD 2.22), and 9.12 (SD 1.37) at 3, 7, and 10 days, respectively. Negligible floor effect was observed (maximum of 8% at 3 days); however, a ceiling effect was observed at 17 days (25%). The PSFS showed good reliability with an internal consistency of 0.91 (Cronbach’s alpha) (95% CI 0.88, 0.95) and a temporal stability of 0.83 (ICC) (95% CI 0.72, 0.89). The PSFS showed a strong positive correlation with quality of life and functional assessments. The MCID was approximately 1.0 for all methods. Conclusions With an MCID of approximately 1 point, the PSFS is a valid and reliable tool to assess quality of life and functionality in patients with snake envenomation.

Summary Background Human monoclonal antibodies that potently and broadly neutralise HIV-1 are under development to prevent and treat HIV-1 infection. In this phase 1 clinical trial we aimed to determine the safety, tolerability, and pharmacokinetic profile of the broadly neutralising monoclonal antibody VRC07-523LS, an engineered variant of VRC01 that targets the CD4 binding site of the HIV-1 envelope protein. Methods This phase 1, open-label, dose-escalation clinical trial was done at the National Institutes of Health Clinical Center in Bethesda, MD, USA. Individuals were recruited from the greater Washington, DC, area by IRB-approved written and electronic media. We enrolled healthy, HIV-1-negative adults aged 18–50 years. Inclusion criteria were good general health, measured through clinical laboratory tests, medical history, and physical examination. Participants self-selected into one of seven open groups during enrolment without randomisation. Four groups received a single intravenous dose of 1, 5, 20, or 40 mg/kg of VRC07-523LS, and one group received a single 5 mg/kg subcutaneous dose. Two groups received three doses of either 20 mg/kg intravenous VRC07-523LS, or 5 mg/kg subcutaneous VRC07-523LS at 12-week intervals. The primary outcome was the safety and tolerability of VRC07-523LS, assessed by dose, route, and number of administrations. This study is registered with ClinicalTrials.gov, NCT03015181. Findings Between Feb 21, 2017, and September 13, 2017, we enrolled 26 participants, including 11 (42%) men and 15 (58%) women. Two (8%) participants withdrew from the study early: one participant in group 1 enrolled in the study but never received VRC07-523LS, and one participant in group 6 chose to withdraw after a single administration. One (4%) participant in group 7 received only one of the three scheduled administrations. 17 participants received intravenous administrations and 8 participants received subcutaneous administrations. VRC07-523LS was safe and well tolerated, we observed no serious adverse events or dose-limiting toxic effects. All reported local and systemic reactogenicity was mild to moderate in severity. The most commonly reported symptoms following intravenous administration were malaise or myalgia in three (18%) participants and headache or chills in two (12%) participants. The most commonly reported symptoms following subcutaneous administration were pain and tenderness in four participants (50%) and malaise or headache in three (38%) participants. Interpretation Safe and well tolerated, VRC07-523LS is a strong and practical candidate for inclusion in HIV-1 prevention and therapeutic strategies. The results from this trial also indicate that an HIV-1 broadly neutralising monoclonal antibody engineered for improved pharmacokinetic and neutralisation properties can be safe for clinical use. Funding National Institutes of Health.

Purpose This sentence processing experiment examined the abilities of children with specific language impairment (SLI) and children with typical language development (TD) to establish relations between pronouns or reflexives and their antecedents in real time. Method Twenty-two children with SLI and 24 age-matched children with TD (7;3–10;11 [years;months]) participated in a cross-modal picture priming experiment to determine whether they selectively activated the correct referent at the pronoun or reflexive in sentences. Triplets of auditory sentences, identical except for the presence of a pronoun, a reflexive, or a noun phrase along with a picture probe were used. Results The children with TD were slightly more accurate in their animacy judgments of pictures, but the groups exhibited the same reaction time (RT) pattern. Both groups were slower for sentences with pronouns than with reflexives or noun phrases. The children with SLI had longer RTs than their peers with TD. Conclusions Children with SLI activated only the appropriate antecedent at the pronoun or reflexive, reflecting intact core knowledge of binding as was true for their TD peers. The overall slower RT for children with SLI suggests that any deficit may be the result of processing deficits, perhaps attributable to interference effects.

// Yirong Zhu 1 , Mark D. Aupperlee 2 , Yong Zhao 2 , Ying Siow Tan 2 , Erin L. Kirk 4 , Xuezheng Sun 4 , Melissa A. Troester 4, 5, 6 , Richard C. Schwartz 3 , Sandra Z. Haslam 2 1 Cell and Molecular Biology Program and Breast Cancer and the Environment Research Program, Michigan State University, East Lansing, MI, USA 2 Department of Physiology and Breast Cancer and the Environment Research Program, Michigan State University, East Lansing, MI, USA 3 Department of Microbiology and Molecular Genetics and Breast Cancer and the Environment Research Program, Michigan State University, East Lansing, MI, USA 4 Department of Epidemiology, University of North Carolina at Chapel Hill, NC, USA 5 Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, NC, USA 6 Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, NC, USA Correspondence to: Sandra Z. Haslam, email: shaslam@msu.edu Richard C. Schwartz, email: schwart9@msu.edu Keywords: dietary animal fat, breast cancer, puberty, adulthood, Trp53-null Received: July 22, 2016 Accepted: October 19, 2016 Published: November 04, 2016 ABSTRACT Premenopausal breast cancer is associated with increased animal fat consumption among normal weight, but not overweight women (Farvid et al., 2014). Our previous findings in obesity-resistant BALB/c mice similarly showed promotion of carcinogen-induced mammary tumorigenesis by a diet high in saturated animal fat (HFD). This effect was specific to pubertal versus adult HFD. This study identifies the effects of HFD during puberty versus adulthood in Trp53-null transplant BALB/c mice and investigates its mechanism of enhancing tumorigenesis. Either pubertal or adult HFD is sufficient to increase incidence of Trp53-null mammary tumors. Puberty-restricted HFD exposure promoted tumor cell proliferation, increased angiogenesis, and increased recruitment of total and M2 macrophages in epithelial tumors. Adult-restricted exposure to HFD similarly increased proliferation, angiogenesis, recruitment of total and M2 macrophages, and additionally reduced apoptosis. Adult HFD also increased incidence of spindle cell carcinomas resembling claudin-low breast cancer, and thus adult HFD in the Trp53-null transplantation system may be a useful model for human claudin low breast cancer. Importantly, these results on Trp53-null and our prior studies on DMBA-induced mammary tumorigenesis demonstrate a pubertal window of susceptibility to the promotional effects of HFD, indicating the potential of early life dietary intervention to reduce breast cancer risk.

Background: Frequency discrimination is often impaired in children developing language atypically. However, findings in the detection of small frequency changes in these children are conflicting. Previous studies on children’s auditory perceptual abilities usually involved establishing differential sensitivity thresholds in sample populations who were not tested for auditory deficits. To date, there are no data comparing suprathreshold frequency discrimination ability in children tested for both auditory processing and language skills. Purpose: : This study examined the perception of small frequency differences (Δf) in children with auditory processing disorder (APD) and/or specific language impairment (SLI). The aim was to determine whether children with APD and children with SLI showed differences in their behavioral responses to frequency changes. Results were expected to identify different degrees of impairment and shed some light on the auditory perceptual overlap between pediatric APD and SLI. Research Design: An experimental group design using a two-alternative forced-choice procedure was used to determine frequency discrimination ability for three magnitudes of Δf from the 1000-Hz base frequency. Study Sample: Thirty children between 10 years of age and 12 years, 11 months of age: 17 children with APD and/or SLI, and 13 typically developing (TD) peers participated. The clinical groups included four children with APD only, four children with SLI only, and nine children with both APD and SLI. Data Collection and Analysis: Behavioral data collected using headphone delivery were analyzed using the sensitivity index d′, calculated for three Δf was 2%, 5%, and 15% of the base frequency or 20, 50, and 150 Hz. Correlations between the dependent variable d′ and the independent variables measuring auditory processing and language skills were also obtained. A stepwise regression analysis was then performed. Results: TD children and children with APD and/or SLI differed in the detection of small-tone Δf. In addition, APD or SLI status affected behavioral results differently. Comparisons between auditory processing test scores or language test scores and the sensitivity index d′ showed different strengths of correlation based on the magnitudes of the Δf. Auditory processing scores showed stronger correlation to the sensitivity index d′ for the small Δf, while language scores showed stronger correlation to the sensitivity index d′ for the large Δf. Conclusion: Although children with APD and/or SLI have difficulty with behavioral frequency discrimination, this difficulty may stem from two different levels: a basic auditory level for children with APD and a higher language processing level for children with SLI; the frequency discrimination performance seemed to be affected by the labeling demands of the same versus different frequency discrimination task for the children with SLI.

Anti- N-methyl-d-aspartate (anti-NMDA) receptor encephalitis is a treatable cause of autoimmune encephalitis. It remains unclear if the natural history of this disease is altered by choice of acute therapy or the employment of chronic immunotherapy. Chart review was undertaken for pediatric patients diagnosed with anti-NMDA receptor encephalitis. Data obtained included patient demographics, disease manifestations, treatment course, and clinical outcomes. Ten patients with anti-NMDA receptor encephalitis were identified. All patients were treated with immunotherapy in the acute period, and all patients experienced good recovery. Neurologic relapse did not occur in any patient. All patients received varied forms of chronic immunosuppression to prevent relapses. Complications of chronic immunotherapy occurred in 50% of patients. The benefits of chronic immunotherapy and the duration of use should be carefully weighed against the risks. Complications from immunotherapy are not uncommon and can be serious. Clinical trials assessing the benefit of long-term immunotherapy in this population are needed.

Traumatic abrasions on human extremities as a result of direct contact with sea, lake, river, or aquarium animals or from traumatic injuries sustained in seawater may develop into solitary or linear granulomatous lesions. One of the more common microbial etiologies for such infections is Mycobacterium marinum. An astute pediatrician, family physician, or nurse practitioner should have a high index of suspicion and obtain specific cultures to support the growth of Mycobacterium species. Mycobacterium marinum infections will not respond to antibiotics typically chosen to treat simple skin and soft tissue infections. Rather, M. marinum infections are best treated by prolonged antimicrobial treatment regimens for 3 to 6 months and, in some cases, may require polypharmacologic therapy. We present the case of a 6-year-old girl who suffered a traumatic abrasion on her right ankle in seawater. For 10 days, the skin infection morphed from cellulitis, papules, pustules, and eventually into sporotrichoid linear granuloma. After several failed antibiotic trials, M. marinum was eventually identified from the depth of her lesions. The patient improved after a 3-month course of clarithromycin. This case report is the first to include pictures demonstrating the clinical progression and resolution of M. marinum infection.

Glioblastoma (GBM) is the most common and aggressive primary brain cancer. Current standard-of-care for glioblastoma (GBM) includes surgery followed by concurrent therapy with radiation and temozolomide (TMZ) followed by adjuvant TMZ (days 1-5 every 28 days). Almost all GBM patients experience recurrent/progressive disease, with a median survival of 3-9 months after recurrence. Second-line treatment for recurrent GBM with bevacizumab (BEV) has not improved survival, and effective therapies for GBM are lacking. Unmethylated promoter status for O6-methylguanine DNA methyltransferase (MGMT) is a validated biomarker for TMZ-resistance and is correlated with poor prognosis. VAL-083 is a bi-functional DNA-targeting agent rapidly inducing interstrand cross-links at N7-guanine, leading to DNA double-strand breaks and cell death. VAL-083's cytotoxicity is independent of MGMT status, and VAL-083 overcomes TMZ-resistance in GBM cell lines, GBM cancer stem cells, and in vivo GBM models. The trial described here is an open-label two-arm biomarker-driven phase 2 clinical trial in MGMT-unmethylated GBM patients with either recurrent disease (Group 1) or newly diagnosed GBM patients requiring adjuvant therapy after chemoirradiation with temozolomide (Group 2). Patients receive VAL-083 IV at 30 or 40 mg/m2/day on days 1, 2, and 3 of a 21-day cycle. The primary objective of this study is to determine the effect of VAL-083 on median overall survival (mOS) in MGMT-unmethylated recurrent GBM patients (Group 1) compared to historical control, and progression-free survival (PFS) in newly diagnosed GBM patients requiring adjuvant therapy after chemoirradiation with temozolomide (Group 2), compared to historical control. Secondary efficacy endpoints include progression-free survival (PFS) (Group 1), overall response rate (ORR), duration of response (DOR), and quality-of-life (QoL). Tumor response will be assessed by MRI approximately every 42 days, as per RANO criteria. The initial starting dose in this study was 40 mg/m2/day, which was subsequently reduced to 30 mg/m2/day to improve tolerance due to myelosuppression. As of 21st January 2020, thirty-five (35) subjects had enrolled at a starting dose of 40 mg/m2/day, and 31 subjects had enrolled at a starting dose of 30 mg/m2/day in Group 1, and 9 subjects enrolled at a starting dose of 30 mg/m2/day in Group 2. As anticipated from prior studies with VAL-083, myelosuppression (thrombocytopenia and neutropenia) has been the most common adverse event observed. Enrollment and safety data update will be provided at the meeting. Clinicaltrials.gov identifier: NCT02717962 Citation Format: Barbara J. O'Brien, Carlos Kamiya-Matsuoka, Shiao-Pei Weathers, Alfred Yung, Monica Loghin, Rebecca Harrison, Nazanin Majd, Jeffrey A. Bacha, Dennis M. Brown, Anne Steino, Gregory Johnson, Sarath Kanekal, John Langlands, Lorena M. Lopez, Richard M. Schwartz, Marta Penas-Prado, John F. de Groot. Phase 2 study of dianhydrogalactitol (VAL-083) in patients with MGMT-unmethylated, bevacizumab-naïve glioblastoma in the recurrent or adjuvant setting [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT272.

Importance Chikungunya virus (CHIKV) is a mosquito-borneAlphavirusprevalent worldwide. There are currently no licensed vaccines or therapies. Objective To evaluate the safety and tolerability of an investigational CHIKV virus–like particle (VLP) vaccine in endemic regions. Design, Setting, and Participants This was a randomized, placebo-controlled, double-blind, phase 2 clinical trial to assess the vaccine VRC-CHKVLP059-00-VP (CHIKV VLP). The trial was conducted at 6 outpatient clinical research sites located in Haiti, Dominican Republic, Martinique, Guadeloupe, and Puerto Rico. A total of 400 healthy adults aged 18 through 60 years were enrolled after meeting eligibility criteria. The first study enrollment occurred on November 18, 2015; the final study visit, March 6, 2018. Interventions Participants were randomized 1:1 to receive 2 intramuscular injections 28 days apart (20 µg, n = 201) or placebo (n = 199) and were followed up for 72 weeks. Main Outcomes and Measures The primary outcome was the safety (laboratory parameters, adverse events, and CHIKV infection) and tolerability (local and systemic reactogenicity) of the vaccine, and the secondary outcome was immune response by neutralization assay 4 weeks after second vaccination. Results Of the 400 randomized participants (mean age, 35 years; 199 [50%] women), 393 (98%) completed the primary safety analysis. All injections were well tolerated. Of the 16 serious adverse events unrelated to the study drugs, 4 (25%) occurred among 4 patients in the vaccine group and 12 (75%) occurred among 11 patients in the placebo group. Of the 16 mild to moderate unsolicited adverse events that were potentially related to the drug, 12 (75%) occurred among 8 patients in the vaccine group and 4 (25%) occurred among 3 patients in the placebo group. All potentially related adverse events resolved without clinical sequelae. At baseline, there was no significant difference between the effective concentration (EC50)—which is the dilution of sera that inhibits 50% infection in viral neutralization assay—geometric mean titers (GMTs) of neutralizing antibodies of the vaccine group (46; 95% CI, 34-63) and the placebo group (43; 95% CI, 32-57). Eight weeks following the first administration, the EC50 GMT in the vaccine group was 2005 (95% CI, 1680-2392) vs 43 (95% CI, 32-58;P Conclusions and Relevance Among healthy adults in a chikungunya endemic population, a virus-like particle vaccine compared with placebo demonstrated safety and tolerability. Phase 3 trials are needed to assess clinical efficacy. Trial Registration ClinicalTrials.gov Identifier:NCT02562482

Background During respiratory syncytial virus season, many children present to pediatric offices and urgent care medical facilities with cough, tachypnea, intercostal retraction, wheezing, as well as disturbed appetite and sleep. Identification of the responsible viral pathogen is quite difficult because several pathogens can produce similar signs and symptoms. Methods Nasopharyngeal specimens were collected from symptomatic sick children younger than 6 years, in 8 geographically representative primary care pediatric practices during a 4-month RSV season. Institutional review board approval and signed parental consent were obtained. The primary objective of the study was the estimation of the sensitivity and specificity of the Becton Dickinson (BD) Veritor RSV point-of-care (POC) assay as compared with reverse transcriptase-polymerase chain reaction (RT-PCR). Results Of 523 specimens, 58.3% (n = 305) were from patients younger than 2 years. The BD Veritor RSV POC assay sensitivity and specificity are 81.6% (146/179) and 99.1% (341/344), respectively. When compared with RT-PCR, the BD Veritor RSV POC assay false positive was 0.9% (3/344, with a 95% confidence interval of 0.3%-2.5%) and the false negative was 18.4% (33/179, with a 95% confidence interval of 13.4%-24.5%). The BD Veritor RSV POC assay identified more true positive specimens (n = 146) than viral cell culture (n = 134 positive specimens). Conclusions In 8 participating primary care pediatric offices with 523 evaluable subjects, POC BD Veritor RSV tests performed better than viral cell culture results when RT-PCR was the reference standard.

Bright light therapy and the broader realm of chronotherapy remain underappreciated and underutilized, despite their empirical support. Efficacy extends beyond seasonal affective disorder and includes nonseasonal depression and sleep disorders, with emerging evidence for a role in treating attention-deficit/hyperactivity disorder, delirium, and dementia. A practical overview is offered, including key aspects of underlying biology, indications for treatment, parameters of treatment, adverse effects, and transformation of our relationship to light and darkness in contemporary life.

Increased proliferation and breast cancer risk has been observed in postmenopausal women receiving estrogen (E) + progestin hormone replacement therapy (HRT). Progestin action is mediated through two progesterone receptor (PR) isoforms, PRA and PRB, with unique transcriptional activity and function. The current study examines hormonal regulation of PR isoforms in the normal postmenopausal human breast and the mechanism by which progestins increase proliferation and breast cancer risk. Archival benign breast biopsies from postmenopausal and premenopausal women, and luminal breast tumor biopsies from postmenopausal women, were analyzed for regulation of PRA and PRB expression by E and E+medroxyprogesterone acetate (MPA). In the postmenopausal breast without HRT, PRA and PRB expression was decreased compared to the premenopausal breast. Both E (n = 12) and E+MPA (n = 13) HRT in the postmenopausal breast were associated with increased PRA and PRB expression, increased nuclear cyclin E expression, and decreased nuclear p27 expression compared to no HRT (n = 16). With E+MPA HRT, there was a further decrease in nuclear p27 and increased Receptor Activator of NF-kappa B Ligand (RANKL) expression compared to E-alone HRT. In luminal breast cancers, E+MPA HRT (n = 6) was also associated with decreased nuclear expression of the cell cycle inhibitor p27 compared to E HRT (n = 6), but was not associated with increased proliferation. These results suggest that p27 mediates progestin-induced proliferation in the normal human breast and that regulation of this proliferative response by E+MPA is lost in breast tumors.

Summary Background The Zika virus epidemic and associated congenital infections have prompted rapid vaccine development. We assessed two new DNA vaccines expressing premembrane and envelope Zika virus structural proteins. Methods We did two phase 1, randomised, open-label trials involving healthy adult volunteers. The VRC 319 trial, done in three centres, assessed plasmid VRC5288 (Zika virus and Japanese encephalitis virus chimera), and the VRC 320, done in one centre, assessed plasmid VRC5283 (wild-type Zika virus). Eligible participants were aged 18–35 years in VRC19 and 18–50 years in VRC 320. Participants were randomly assigned 1:1 by a computer-generated randomisation schedule prepared by the study statistician. All participants received intramuscular injection of 4 mg vaccine. In VRC 319 participants were assigned to receive vaccinations via needle and syringe at 0 and 8 weeks, 0 and 12 weeks, 0, 4, and 8 weeks, or 0, 4, and 20 weeks. In VRC 320 participants were assigned to receive vaccinations at 0, 4, and 8 weeks via single-dose needle and syringe injection in one deltoid or split-dose needle and syringe or needle-free injection with the Stratis device (Pharmajet, Golden, CO, USA) in each deltoid. Both trials followed up volunteers for 24 months for the primary endpoint of safety, assessed as local and systemic reactogenicity in the 7 days after each vaccination and all adverse events in the 28 days after each vaccination. The secondary endpoint in both trials was immunogenicity 4 weeks after last vaccination. These trials are registered with ClinicalTrials.gov, numbers NCT02840487 and NCT02996461. Findings VRC 319 enrolled 80 participants (20 in each group), and VRC 320 enrolled 45 participants (15 in each group). One participant in VRC 319 and two in VRC 320 withdrew after one dose of vaccine, but were included in the safety analyses. Both vaccines were safe and well tolerated. All local and systemic symptoms were mild to moderate. In both studies, pain and tenderness at the injection site was the most frequent local symptoms (37 [46%] of 80 participants in VRC 319 and 36 [80%] of 45 in VRC 320) and malaise and headache were the most frequent systemic symptoms (22 [27%] and 18 [22%], respectively, in VRC 319 and 17 [38%] and 15 [33%], respectively, in VRC 320). For VRC5283, 14 of 14 (100%) participants who received split-dose vaccinations by needle-free injection had detectable positive antibody responses, and the geometric mean titre of 304 was the highest across all groups in both trials. Interpretation VRC5283 was well tolerated and has advanced to phase 2 efficacy testing. Funding Intramural Research Program of the Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health.

A novel avian influenza subtype, A/H7N9, emerged in 2013 and represents a public health threat with pandemic potential. We have previously shown that DNA vaccine priming increases the magnitude and quality of antibody responses to H5N1 monovalent inactivated boost. We now report the safety and immunogenicity of a H7 DNA-H7N9 monovalent inactivated vaccine prime-boost regimen. In this Phase 1, open label, randomized clinical trial, we evaluated three H7N9 vaccination regimens in healthy adults, with a prime-boost interval of 16 weeks. Group 1 received H7 DNA vaccine prime and H7N9 monovalent inactivated vaccine boost. Group 2 received H7 DNA and H7N9 monovalent inactivated vaccine as a prime and H7N9 monovalent inactivated vaccine as a boost. Group 3 received H7N9 monovalent inactivated vaccine in a homologous prime-boost regimen. Overall, 30 individuals between 20 to 60 years old enrolled and 28 completed both vaccinations. All injections were well tolerated with no serious adverse events. 2 weeks post-boost, 50% of Group 1 and 33% of Group 2 achieved a HAI titer ≥1:40 compared with 11% of Group 3. Also, at least a fourfold increase in neutralizing antibody responses was seen in 90% of Group 1, 100% of Group 2, and 78% of Group 3 subjects. Peak neutralizing antibody geometric mean titers were significantly greater for Group 1 (GMT = 440.61, p, Avian influenza: A vaccine for a deadly emergent strain A vaccine candidate to treat a deadly subtype of avian influenza was shown to induce protective antibodies in initial clinical trials. As of March 2017, avian influenza strain A/H7N9 has killed 497 people since 2013, with 1349 confirmed cases. Julie Ledgerwood and her team from the United States’ National Institutes of Health in collaboration with colleagues at the Centers for Disease Control and Prevention tested their two-stage vaccine protocol in humans, showing it to be effective and safe. The vaccine consists of an initial injection of viral DNA, which ‘primes’ the immune system to the pathogen, followed by a follow-up injection of an inactivated purified viral protein, which further boosts the host’s production of protective antibodies. The study shows the viability of this vaccine regimen and suggests further investigation into its appropriateness for treating avian influenza in humans.

Study Objective Amphiregulin is a member of the epidermal growth factor family. In breast tissue, amphiregulin is a mediator of estrogen and progesterone signaling. The objectives were to examine the relationship of amphiregulin levels during peripuberty with estrogen levels. Design, Setting, Participants, Interventions, and Main Outcome Measures The participants in this analysis were a subset from a longitudinal study of pubertal maturation, the Breast Cancer and the Environment Research Program. They were recruited between ages 3 and 7 years. Blood specimens were selected for hormone analysis between 24 months before and 6 months after breast development. Serum amphiregulin levels were analyzed using enzyme-linked immunosorbent assay. Results Amphiregulin levels were measured in 188 girls; 8.5% had a maternal history of breast cancer, and 30.9% of samples were below the limit of detection. Amphiregulin levels were greatest at 18 months before the onset of breast development (P

Roger Brown considered how children come to attach a word to things and categories of things in the world. Attaching words or names to things and categories is basic to human language—the label Specific Language Impairment(SLI) is one example. Children with SLI have deficits in working memory that may underlie their language deficits. Children with phonological disorders are routinely excluded from studies of SLI in order to avoid including children whose speech production limitations might be the result of apparent nonlinguistic limitations in language production. Pragmatics is a heterogeneous category of language abilities including presuppositions about the knowledge and social status of the listener, the communicative intent or function of utterances, the structure of narratives and discourse and conversation, as well as the more global use of language and nonlinguistic means of communication. Children with SLI also have deficits in conversation that may reflect either social deficits or structural language deficits.

PurposeThis study investigated prosodic boundary effects on the comprehension of attachment ambiguities in children with cochlear implants (CIs) and normal hearing (NH) and tested the absolute boundary hypothesis and the relative boundary hypothesis. Processing speed was also investigated.MethodFifteen children with NH and 13 children with CIs (ages 8–12 years) who are monolingual speakers of Brazilian Portuguese participated in a computerized comprehension task with sentences containing prepositional phrase attachment ambiguity and manipulations of prosodic boundaries.ResultsChildren with NH and children with CIs differed in how they used prosodic forms to disambiguate sentences. Children in both groups provided responses consistent with half of the predictions of the relative boundary hypothesis. The absolute boundary hypothesis did not characterize the syntactic disambiguation of children with CIs. Processing speed was similar in both groups.ConclusionsChildren with CIs do not use prosodic information to disambiguate sentences or to facilitate comprehension of unambiguous sentences similarly to children with NH. The results suggest that cross-linguistic differences may interact with syntactic disambiguation. Prosodic contrasts that affect sentence comprehension need to be addressed directly in intervention with children with CIs.

It is well documented that macrophages and eosinophils play important roles in normal murine pubertal mammary gland development. Although it is accepted that estrogen (E) and progesterone (P) are key players in mammary gland development, the roles these hormones might play in regulating the actions of leukocytes in that process is an understudied area. We show here that P and E, respectively, induce unique, but overlapping, sets of proinflammatory and angiogenic cytokines and chemokines, in the pubertal female BALB/c mammary gland, as well as induce infiltration of macrophages and eosinophils to the mammary periepithelium. This extends earlier studies showing P induction of proinflammatory products in pubertal and adult mammary epithelial organoids and P-induced in vivo infiltration of leukocytes to the adult mammary periepithelium. Importantly, epidermal growth factor receptor-signaling, which is likely mediated by amphiregulin (Areg), a downstream mediator of E and P, is both necessary and sufficient for both E- and P-induced recruitment of macrophages and eosinophils to the pubertal mammary periepithelium. We further show that receptor activator of nuclear factor κB ligand (RANKL), although not sufficient of itself to cause macrophage and eosinophil recruitment, contributes to an optimal response to P. The potency of Areg is highlighted by the fact that it is sufficient to induce macrophage and eosinophil recruitment at levels equivalent to that induced by either E or P. Our finding of a dominant role for Areg in hormonally induced leukocyte recruitment to the pubertal mammary gland parallels its dominance in regulating ductal outgrowth and its role in P-induced proliferation in the pubertal gland.