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\"Three generations of crime-fighters join together for the greater good: Sentinel, Wildcat, the Flash, Black Canary, Starman, Sand, Hourman, Atom Smasher, the Star-Spangled Kid and Hawkgirl. The heroes of the present and legends of the past come together to form the Justice Society of America! They have been called upon to save one of their own from one of the darkest powers ever to walk this earth... Celebrated comics writer Geoff Johns began his career here, as he mixed in younger, edgier characters with the elder statesmen of superheroes to create one of the standout DC Comics series in the 2000s.\"-- Provided by publisher.

Currently there are no immunosuppression regimens FDA-approved to prevent rejection in pediatric heart transplantation (HT). In recent years, everolimus (EVL) has emerged as a potential alternative to standard tacrolimus (TAC) as the primary immunosuppressant to prevent rejection that may also reduce the risk of cardiac allograft vasculopathy (CAV), chronic kidney disease (CKD) and cytomegalovirus (CMV) infection. However, the 2 regimens have never been compared head-to-head in a randomized trial. The study design and rationale are reviewed in light of the challenges inherent in rare disease research. The TEAMMATE trial (IND 127980) is the first multicenter randomized clinical trial (RCT) in pediatric HT. The primary purpose is to evaluate the safety and efficacy of EVL and low-dose TAC (LD-TAC) compared to standard-dose TAC and mycophenolate mofetil (MMF). Children aged <21 years at HT were randomized (1:1 ratio) at 6 months post-HT to either regimen, and followed for 30 months. Children with recurrent rejection, multi-organ transplant recipients, and those with an estimated glomerular filtration rate (eGFR) <30 mL/min/1.73m2 were excluded. The primary efficacy hypothesis is that, compared to TAC/MMF, EVL/LD-TAC is more effective in preventing 3 MATEs: acute cellular rejection (ACR), CKD and CAV. The primary safety hypothesis is that EVL/LD-TAC does not have a higher cumulative burden of 6 MATEs (antibody mediated rejection [AMR], infection, and post-transplant lymphoproliferative disorder [PTLD] in addition to the 3 above). The primary endpoint is the MATE score, a composite, ordinal surrogate endpoint reflecting the frequency and severity of MATEs that is validated against graft loss. The study had a target sample size of 210 patients across 25 sites and is powered to demonstrate superior efficacy of EVL/LD-TAC. Trial enrollment is complete and participant follow-up will be completed in 2023. The TEAMMATE trial is the first multicenter RCT in pediatric HT. It is anticipated that the study will provide important information about the safety and efficacy of everolimus vs tacrolimus-based regimens and will provide valuable lessons into the design and conduct of future trials in pediatric HT

Currently, there are no Food and Drug Administration–approved devices available that can provide long-term mechanical circulatory support to smaller children with severe heart failure as a bridge to heart transplant (HT). In recent years, the Berlin Heart EXCOR Pediatric ventricular assist device (VAD) has emerged as a potential treatment option. Systematic data on the safety and efficacy of the EXCOR are limited. The Investigational Device Exemption (IDE) clinical study is designed to evaluate the safety and probable benefit of the EXCOR to support regulatory review of the device under the Humanitarian Device Exemption regulation. The study design and rationale are reviewed in light of the well-described challenges inherent in small population studies. The Berlin Heart EXCOR IDE clinical study is a prospective, multicenter, single-arm, clinical cohort study. Children aged 0 to 16 years with severe heart failure (Interagency Registry for Mechanically Assisted Circulatory Support profile 1 or 2) due to 2-ventricle heart disease and actively listed for HT comprise the primary study cohort. The control population is a propensity-matched retrospective cohort of children supported with extracorporeal membrane oxygenation, the only bridge device available to smaller children before the EXCOR. The primary efficacy end point is survival to heart transplantation or recovery. The primary safety end point is the incidence of serious adverse events as defined by pediatric Interagency Registry for Mechanically Assisted Circulatory Support criteria. The study will enroll a total of 48 subjects in 2 cohorts based on body surface area (cohort 1 <0.7 m 2, cohort 2 0.7-1.5 m 2) and is powered to show safety superiority to a prespecified performance goal of 0.25 serious adverse events per day of support. Children ineligible for the primary cohort will still have access to the device in a third compassionate-use cohort where adverse event data will be collected for additional safety characterization of the device. The Berlin Heart IDE clinical study will be the first bridge-to-HT VAD study designed exclusively for children. It is anticipated that the study will provide important information on the safety and efficacy of the Berlin Heart EXCOR Pediatric in children while providing valuable lessons into the design and conduct of future VAD studies in children.

This study considers the flux of radioactivity in flowback fluid from shale gas development in three areas: the Carboniferous, Bowland Shale, UK; the Silurian Shale, Poland; and the Carboniferous Barnett Shale, USA. The radioactive flux from these basins was estimated, given estimates of the number of wells developed or to be developed, the flowback volume per well and the concentration of K (potassium) and Ra (radium) in the flowback water. For comparative purposes, the range of concentration was itself considered within four scenarios for the concentration range of radioactive measured in each shale gas basin, the groundwater of the each shale gas basin, global groundwater and local surface water. The study found that (i) for the Barnett Shale and the Silurian Shale, Poland, the 1 % exceedance flux in flowback water was between seven and eight times that would be expected from local groundwater. However, for the Bowland Shale, UK, the 1 % exceedance flux (the flux that would only be expected to be exceeded 1 % of the time, i.e. a reasonable worst case scenario) in flowback water was 500 times that expected from local groundwater. (ii) In no scenario was the 1 % exceedance exposure greater than 1 mSv—the allowable annual exposure allowed for in the UK. (iii) The radioactive flux of per energy produced was lower for shale gas than for conventional oil and gas production, nuclear power production and electricity generated through burning coal.

Children with congenital heart disease (CHD) are at risk for advanced heart failure (AHF). We sought to define the mortality and resource utilization in CHD-related AHF in children and young adults. All hospitalizations in the Pediatric Health Information System database involving patients ≤21 years old with a CHD diagnosis and heart failure requiring at least 7 days of continuous inotropic support between 2004 and 2015 were included. Hospitalizations including CHD surgery were excluded. Of 465,482 CHD hospitalizations, AHF was present in 2,712 (0.6%) [58% infant, 55% male, 30% single ventricle]. AHF therapies frequently used included extracorporeal membrane oxygenation (ECMO) (15%) and cardiac transplant (16%). Ventricular assist device (VAD) support was rare (3%), although VAD use significantly increased from 2004 to 2015 (P < .0010). Hospital mortality in CHD with AHF was 26%, with higher mortality associated with single ventricle heart disease (OR 1.64, 95% CI 1.23-2.19; P = .0009), infancy (OR 1.71, 95% CI 1.17-2.5; P = .0057), non-white race (OR 1.28, 95% CI 1.04-1.59; p=0.0234), and chronic complex comorbidities (OR 1.76, 95% CI 1.34-2.30; P < .0001). Over the 11-year study period, despite the significant increase in CHD-related AHF hospitalizations (P < .0001), hospital mortality improved (P = .0011). Median hospital costs were $252,000, a 6-fold increase above those without AHF, and was primarily driven by hospital length of stay (P < .0001). AHF in children with CHD in uncommon but increasing and is associated with significant morbidity, mortality and resource utilization. Approximately 1 in 5 children do not survive to hospital discharge. Many risk factors for mortality may not be modifiable, and further study is needed to identify modifiable risk factors and improve care for this complex population.

Background Short bowel syndrome is a multisystemic disorder that results from the loss of a significant amount of small bowel. The goal of treatment in these patients is to achieve complete enteral autonomy while minimizing complications. Our unit has 30 years of experience in the management of short gut patients. During the past decade, our results have improved significantly, especially in children with severe short bowel syndrome. This brief communication looks at the algorithm presently used in our unit. Methods In this communication, the principles in management of short bowel syndrome in our unit are discussed. In addition, our algorithm is published for the first time. A brief summary of our results is provided. Results Twenty-seven children were enrolled from 2000 to 2009. In this cohort, two patients died because of significant liver disease: one after having two liver and bowel transplants. Overall, survival stands at 92%. All had autologous gastrointestinal reconstruction, and 19 patients underwent bowel lengthening (longitudinal intestinal lengthening and tailoring). The median residual length of bowel of this subgroup at first operation was 25 cm in those who had their gut measured. Two patients were lost to follow-up. Two patients remain on supplemental total parenteral nutrition (TPN), with an overall 91% of surviving patients off TPN at a median of 6 months after reconstruction. Conclusions We believe this improvement is related to the development—over many years—of a structured pathway for managing these patients.

In a single-group trial, 48 children with severe heart failure received a ventricular assist device designed for children. Survival rates were significantly higher in this group than among propensity-score–matched children receiving support with extracorporeal membrane oxygenation. Systolic heart failure causes 280,000 deaths in adults annually in the United States. 1 Heart failure is much less common among children than among adults, but it is highly lethal, with 46% of children with heart failure dying or undergoing transplantation within 5 years after diagnosis, according to one estimate. 2 The survival rate among children after heart transplantation is estimated at 83% at 3 years, 3 , 4 but the limited availability of donor hearts for children prolongs the waiting period, 5 resulting in a high rate of death among children on waiting lists. 6 – 8 Options for mechanical circulatory support as a bridge to . . .

BackgroundFluid overload (FO) is common after neonatal congenital heart surgery and may contribute to mortality and morbidity. It is unclear if the effects of FO are independent of acute kidney injury (AKI).MethodsThis was a retrospective cohort study which examined neonates (age < 30 days) who underwent cardiopulmonary bypass in a university-affiliated children’s hospital between 20 October 2010 and 31 December 2012. Demographic information, risk adjustment for congenital heart surgery score, surgery type, cardiopulmonary bypass time, cross-clamp time, and vasoactive inotrope score were recorded. FO [(fluid in–out)/pre-operative weight] and AKI defined by Kidney Disease Improving Global Outcomes serum creatinine criteria were calculated. Outcomes were all-cause, in-hospital mortality and median postoperative hospital and intensive care unit lengths of stay.ResultsOverall, 167 neonates underwent cardiac surgery using cardiopulmonary bypass in the study period, of whom 117 met the inclusion criteria. Of the 117 neonates included in the study, 76 (65%) patients developed significant FO (>10%), and 25 (21%) developed AKI ≥ Stage 2. When analyzed as FO cohorts (< 10%,10–20%, > 20% FO), patients with greater FO were more likely to have AKI (9.8 vs. 18.2 vs. 52.4%, respectively, with AKI ≥ stage 2; p = 0.013) and a higher vasoactive-inotrope score, and be premature. In the multivariable regression analyses of patients without AKI, FO was independently associated with hospital and intensive care unit lengths of stay [0.322 extra days (p = 0.029) and 0.468 extra days (p < 0.001), respectively, per 1% FO increase). In all patients, FO was also associated with mortality [odds ratio 1.058 (5.8% greater odds of mortality per 1% FO increase); 95% confidence interval 1.008,1.125;p = 0.032].ConclusionsFluid overload is an important independent contributor to outcomes in neonates following congenital heart surgery. Careful fluid management after cardiac surgery in neonates with and without AKI is warranted.

Aims Long-term tunnelled central venous catheters deliver potentially toxic medications such as chemotherapy and parenteral nutrition. Recurrent central line associated bloodstream infections (CLASBI) are a potentially serious complication. Introduction of central line care bundles can dramatically reduce paediatric CLABSI rates (Wheeler et al., Paediatrics 2011), however despite these interventions some patients develop recurrent CLABSIs. This study reports the recurrent CLABSI rate and organisms found in two regional paediatric hospitals. Methods Paediatric patients diagnosed with a CLABSI between January 2012 and December 2012 were identified retrospectively in two regional paediatric institutions. All subsequent infection and line events were recorded for these patients. CLABSIs were classified according to the Centres for Disease Control and Prevention definition. Line event data was verified by comparing theatre records, clinic and discharge letters and radiology images. Results Eighty seven patients were included in the study (44 patients from centre 1, 43 patients from centre 2). 165 CLABSIs were diagnosed during the study period (87 first CLABSI and 78 subsequent CLABSIs). Forty three patients (50%) developed a second CLABSI. And 22 (25%) developed a third CLABSI. The median number of line days from 1st CLABSI per patient was 389 days in centre 1 and 188 days in centre 2. 112 CLABSIs were due to a Gram negative pathogen (68%). 44 CLABSIs were due to a Gram positive (27%) pathogen. 9 CLABSIs were due to fungi (5%). The overall recurrent CLABSI rate after one CLABSI was 4.2 per 1000 catheter days (3.3 per 1000 catheter days in centre 1, 5.1 per 1000 catheter days in centre 2). Repeat infections with identical pathogens occurred on 16 occasions. The most commonly identified organisms were Enterococcus faecalis (29), Escherischia coli (27), Klebsiella pneumoniae (23), Staphylococcus epidermidis (21), Staphylococcus aureus (12). Conclusion Patients who develop one CLABSI are at high risk of recurrent catheter associated sepsis. Gram negative organisms are the most frequently identified group of pathogens.

In the primary analysis of SPRING-2 at week 48, dolutegravir showed non-inferior efficacy to and similar tolerability to raltegravir in adults infected with HIV-1 and naive for antiretroviral treatment. We present the 96 week results. SPRING-2 is an ongoing phase 3, randomised, double-blind, active-controlled, non-inferiority study in treatment-naive adults infected with HIV-1 that started in Oct 19, 2010. We present results for the safety cutoff date of Jan 30, 2013. Patients had to be aged 18 years or older and have HIV-1 RNA concentrations of 1000 copies per mL or more. Patients were randomly assigned (1:1) to receive either dolutegravir (50 mg once daily) or raltegravir (400 mg twice daily), plus investigator-selected tenofovir–emtricitabine or abacavir–lamivudine. Prespecified 96 week secondary endpoints included proportion of patients with HIV-1 RNA less than 50 copies per mL, CD4 cell count changes from baseline, safety, tolerability, and genotypic or phenotypic resistance. We used an intention-to-treat exposed population (received at least one dose of study drug) for the analyses. Sponsor staff were masked to treatment assignment until primary analysis at week 48; investigators, site staff, and patients were masked until week 96. This study is registered with ClinicalTrials.gov, NCT01227824. Of 1035 patients screened, 827 were randomly assigned to study group, and 822 received at least one dose of the study drug (411 patients in each group). At week 96, 332 (81%) of 411 patients in the dolutegravir group and 314 (76%) of 411 patients in the raltegravir group had HIV-1 RNA less than 50 copies per mL (adjusted difference 4·5%, 95% CI −1·1% to 10·0%) confirming non-inferiority. Secondary analyses of efficacy such as per protocol (HIV RNA <50 copies per mL: 83% for dolutegravir and 80% for raltegravir) and treatment-related discontinuation equals failure (93% without failure for dolutegravir; 91% for raltegravir) supported non-inferiority. Virological non-response occurred less frequently in the dolutegravir group (22 [5%] patients for dolutegravir vs 43 [10%] patients for raltegravir). Median increases in CD4 cell count from baseline were similar between groups (276 cells per μL for dolutegravir and 264 cells per μL for raltegravir). Ten patients (2%) in each group discontinued because of adverse events, with few such events between weeks 48 and 96 (zero in the dolutegravir group and one in the raltegravir group). No study-related serious adverse events occurred between week 48 and week 96. At virological failure, no additional resistance to integrase inhibitors or nucleotide reverse transcriptase inhibitors was detected since week 48 or in any patient receiving dolutegravir. At week 96, once-daily dolutegravir was non-inferior to twice-daily raltegravir in treatment-naive, patients with HIV-1. Once-daily dosing without requirement for a pharmacokinetic booster makes dolutegravir-based therapy an attractive treatment option for HIV-1-infected treatment-naive patients. ViiV Healthcare.