Phase 1 Study of CK0801 in Treatment of Bone Marrow Failure Syndromes.

BACKGROUND: An inflammatory bone marrow microenvironment contributes to acquired bone marrow failure syndromes. CK0801, an allogeneic T regulatory (Treg) cell therapy product, can potentially interrupt this continuous loop of inflammation and restore hematopoiesis. METHODS: In this phase 1 dose-escalation study of CK0801 Treg cells, we enrolled patients with bone marrow failure syndromes with suboptimal response to their prior therapy to determine the safety and efficacy of this treatment for bone marrow failure syndromes. RESULTS: We enrolled nine patients with a median age of 57 years (range, 19 to 74) with an underlying diagnosis of aplastic anemia (n=4), myelofibrosis (n=4), or hypoplastic myelodysplasia (n=1). Patients had a median of three prior therapies for a bone marrow failure syndrome. Starting dose levels of CK0801 were 1 × 106 (n=3), 3 × 106 (n=3), and 10 × 106 (n=3) cells per kg of ideal body weight. No lymphodepletion was administered. CK0801 was administered in the outpatient setting with no infusion reactions, no grade 3 or 4 severe adverse reactions, and no dose-limiting toxicity. At 12 months, CK0801 induced objective responses in three of four patients with myelofibrosis (two had symptom response, one had anemia response, and one had stable disease) and three of four patients with aplastic anemia (three had partial response). Three of four transfusion-dependent patients at baseline achieved transfusion independence. Although the duration of observation was limited at 0.9 to 12 months, there were no observed increases in infections, no transformations to leukemia, and no deaths. CONCLUSIONS: In previously treated patients, CK0801 demonstrated no dose-limiting toxicity and showed evidence of efficacy, providing proof of concept for targeting inflammation as a therapy for bone marrow failure. (Funded by Cellenkos Inc.; Clinicaltrials.gov number, NCT03773393.).

Enteral nutrition support for infants with pulmonary hypoplasia: A qualitative evaluation of caregiver and provider perspectives.

BACKGROUND: Enteral nutrition is a critical intervention that supports the growth of children with pulmonary hypoplasia (PH). We explored the experiences of caregivers and providers caring for children with PH to better understand gaps in knowledge transfer and identify barriers and facilitators to caregiving to inform interventions that may improve support. METHODS: This qualitative study included 10 interviews with caregivers and 10 clinical team members at a single integrated care program for children with PH. An inductive and iterative coding strategy was employed to produce a codebook. After cluster analysis, themes were generated to capture participant sentiments. RESULTS: Themes were defined along a care continuum (1) initiation, (2) adaptation, and (3) maintenance that represented distinct phases of adjustment to enteral nutrition support (1) in the perinatal period and initial neonatal intensive care unit (NICU) admission, (2) from discharge planning through the family's first days at home and establishment of a stable feeding regime, and (3) through long-term follow-up and weaning. Notable subthemes included uncertainty, partnerships in training, and obstacles to adaptation. CONCLUSIONS: Among children with PH, the caregiver-provider relationship during the perinatal and NICU course is critical to promoting caregiver adaptation to the needs of the child. Ongoing considerations to support resource alignment and transition to a stable feeding regimen may facilitate caregiver adjustment to a "new normal," culminating in successful growth and/or weaning. These findings will inform interventions focused on training curricula, discharge planning, and the provision of follow-up in the context of an integrated care program for PH.

Electrographic Seizures and Brain Injury in Children Requiring Extracorporeal Membrane Oxygenation.

BACKGROUND: Single-center studies suggest that up to 30% of children undergoing extracorporeal membrane oxygenation have electrographic seizures. The aim of this study was to characterize seizure prevalence, seizure risk factors, and brain injury prevalence in the pediatric extracorporeal membrane oxygenation population at a tertiary care children's hospital. METHODS: We performed a retrospective systematic review of medical records for 86 consecutive children (neonates to age 21 years) who received Neurology consults and continuous video electroencephalography while undergoing extracorporeal membrane oxygenation from November 2015 to September 2018. RESULTS: Continuous video electroencephalography was initiated in 86 of 170 children who required extracorporeal membrane oxygenation (51%); median duration of continuous vodeo electroencephalography was four days. Nineteen of 86 had electroencephalography-confirmed seizures (22%). Sixteen of 19 had seizures within the first 48 hours on continuous video electroencephalography. Interictal epileptiform discharges were a significant risk factor for seizures; 89% of those with seizures versus 46% of those without had interictal epileptiform discharges (P < 0.001, Fisher's exact test). Children with seizures also had higher pericannulation lactate (median 6.7, interquartile range of 4.3 to 19.0 for those with, and median 4.0, interquartile range of 2.0 to 7.3 for those without; P = 0.02, Mann-Whitney U test). Seizures were associated with hemorrhage on neuroimaging (68% of children with seizures had intracranial hemorrhage versus 34% of those without, P = 0.01, chi-square test). CONCLUSION: Approximately half the children undergoing extracorporeal membrane oxygenation received continuous video electroencephalography during the study period, and 22% had seizures. Interictal epileptiform discharges and elevated pre-extracorporeal membrane oxygenation lactate levels were risk factors for seizures; seizures were associated with intracranial hemorrhage.

Rapid System Review Score-A Tool to Measure Predictive Interventions in Patients Admitted to the Postanesthesia Care Unit.

PURPOSE: The Rapid System Review (RSR) score was developed to predict the number of postanesthesia care unit (PACU) interventions. We hypothesized that if RSR score was <0, no PACU interventions were expected; however as the RSR score increased, the number of PACU interventions would also increase. DESIGN: Observational clinical study. METHODS: The RSR score was tabulated as 0 to 3, 4 to 6, 7 to 9, 10 to 12, and 13 to 15. The corresponding number of PACU interventions was expected to be 1 to 3, 4 to 6, 7 to 9, 10 to 12, and 13 to 15. FINDINGS: The Pearson correlation coefficient comparing RSR score and PACU interventions was 0.9 (P < 0.0001). The result was statistically significant. CONCLUSIONS: These results suggest that as RSR score changes, the number of interventions would also alter proportionally.

African bush elephants respond to a honeybee alarm pheromone blend.

We here report the responses of African bush elephants (Loxodonta africana) to a crude approximation of the honeybee alarm pheromone blend. We show that the elephants had an avoidance response to the semiochemical blend. The use of honeybee alarm pheromones to manage elephant movements in a non-invasive manner, using natural cues to which elephants may have an evolved response, holds potential for development of new options for an integrated system for elephant movement management and protection.

Pediatric Somatic Symptom and Related Disorders: Primary Care Provider Perspectives.

Somatization, or physical symptoms that are inconsistent with a physiological cause that may or may not involve an identified stressor, is common in outpatient pediatrics. When these symptoms persist, they can impair function and progress to a somatic symptom and related disorder (SSRD), resulting in increased health care use and increased demands on primary care providers (PCPs). We performed a needs assessment among PCPs to better understand how best to support providers caring for children with SSRDs. Pediatric PCPs (n = 77) were surveyed to better understand their training, experience, perceptions, and practices of SSRD care. Findings indicate that PCPs have limited training in SSRD care but express interest in learning more. Many barriers to effective care were reported. We hope to use these findings to develop training materials and support services for pediatric PCPs managing SSRDs.

Hind-casting the quantity and composition of discards by mixed demersal fisheries in the North Sea.

Many commercial fisheries seek to maximise the economic value of the catch that they bring ashore and market for human consumption by discarding undersize or low value fish. Information on the quantity, size and species composition of discarded fish is vital for stock assessments and for devising legislation to minimise the practice. However, except for a few major species, data are usually extremely sparse and reliant on observers aboard a small sample of fishing vessels. Expanding these data to estimate total regional discards is highly problematic. Here, we develop a method for utilising additional information from scientific trawl surveys to model the quantities of fish discarded by the commercial fisheries. As a case-study, we apply the model to the North Sea over the period 1978-2011, and show a long-term decline in the overall quantity of fish discarded, but an increase in the proportion of catch which is thrown away. The composition of discarded catch has shifted from predominantly (∼80%) roundfish, to >50% flatfish. Undersized plaice constitute the largest single fraction of discards, unchanged from the beginning of the 20th century. Overall, around 60% of discarded fish are rejected on the basis of size rather than for reasons of species value or quota restrictions. The analysis shows that much more information can be gained on discarding by utilising additional sources of data rather than relying solely on information gathered by observers. In addition, it is clear that reducing fishing intensity and rebuilding stocks is likely to be more effective at reducing discards in the long term, than any technical legislation to outlaw the practice in the short term.

Cascading ecological effects of eliminating fishery discards.

Discarding by fisheries is perceived as contrary to responsible harvesting. Legislation seeking to end the practice is being introduced in many jurisdictions. However, discarded fish are food for a range of scavenging species; so, ending discarding may have ecological consequences. Here we investigate the sensitivity of ecological effects to discarding policies using an ecosystem model of the North Sea--a region where 30-40% of trawled fish catch is currently discarded. We show that landing the entire catch while fishing as usual has conservation penalties for seabirds, marine mammals and seabed fauna, and no benefit to fish stocks. However, combining landing obligations with changes in fishing practices to limit the capture of unwanted fish results in trophic cascades that can benefit birds, mammals and most fish stocks. Our results highlight the importance of considering the broader ecosystem consequences of fishery management policy, since species interactions may dissipate or negate intended benefits.

Alleviation of retching and feeding intolerance after fundoplication.

BACKGROUND: Although surgical intervention for gastroesophageal reflux disease (GERD) in children offers the strongest control of GERD, these results are tempered by postoperative problems such as retching, bloat, dysphagia, dumping syndrome, and postprandial hypoglycemia. We created a specialty clinic and an algorithmic approach to ameliorating these problems. Here, we present our experience with the first 60 patients. METHODS: Patients referred to the clinic for feeding problems after fundoplication were tracked as part of quality improvement monitoring. Patients were treated according to a heuristic algorithm intended to reduce iatrogenic causes of feeding intolerance and to identify medical and mechanical contributors to retching. These etiological factors were tracked, along with patient responses. RESULTS: Of the 60 initial patients, 92% completed ≥4 visits. A heuristic algorithm produced near-complete or complete resolution in 97.5% of those patients. In most patients, multiple causes contributed to retching and were commonly iatrogenic (eg, very large boluses, overfeeding, polypharmacy). Surgical failure was a relatively uncommon contributor to intolerance. CONCLUSIONS: Successful results after antireflux surgery depend both on surgical technique and on strategic postoperative feeding. The finding that there are multiple contributors to feeding problems supports a threshold hypothesis for retching and lends credibility to the maxim "retching is rarely reflux." Heuristics that respect surgical constraints on gastric performance, physiological scaling, and the whole patient yield improved growth and tolerance even in complex patients.

Reversal of fish stock decline in the Northeast Atlantic.

Analyses of global fish stocks paint a mixed picture of success, with some holding fishery management responsible for the poor status of many stocks [1-3] or predicting widespread collapse [1, 4]. Some suggest a stable [5] or improving situation [6] in certain jurisdictions. The debate is particularly polarized in the European Union, where the Common Fisheries Policy (CFP) has been criticized for failing to protect stocks [2, 7-10], while others argue that a rebuilding process is underway [11, 12]. We show that substantial change in stock trends occurred in the area around the turn of the century: since then, the fishing pressure (as measured by the exploitation rate) has reduced continuously and there have been increases in biomass, demonstrating the potential for stock recovery. In 2011, for the first time, the majority of assessed stocks, where reference points are defined, were fished sustainably. The reductions in fishing pressure were associated with declines in fishing effort. The last reform of the CFP, in 2002, introduced effort control as part of more enforceable management measures, which were also based on longer-term plans. Further reforms to the CFP are currently being developed, so it is important, when correcting its weaknesses, to also acknowledge and build on the success of a major reduction in the fishing pressure on European fish stocks.

Allometric Prediction of Energy Expenditure in Infants and Children.

Predicting energy needs in children is complicated by the wide range of patient sizes, confusing traditional estimation equations, nonobjective stress-activity factors, and so on. These complications promote errors in bedside estimates of nutritional needs by rendering the estimation methods functionally unavailable to bedside clinicians. Here, the authors develop a simple heuristic energy prediction equation that requires only body mass (not height, age, or sex) as input. Expert estimation of energy expenditure suggested a power-law relationship between mass and energy. A similar mass-energy expenditure relationship was derived from published pediatric echocardiographic data using a Monte Carlo model of energy expenditure based on oxygen delivery and consumption. A simplified form of the equation was compared with energy required for normal growth in a cohort of historical patients weighing 2 to 70 kg. All 3 methods demonstrate that variation in energy expenditure in children is dominated by mass and can be estimated by the following equation: Power(kcal/kg/d) = 200 × [Mass(kg)((-0.4))]. This relationship explains 85% of the variability in energy required to maintain expected growth over a broad range of surgical clinical contexts. A simplified power-law equation predicts real-world energy needs for growth in patients over a wide range of body sizes and clinical contexts, providing a more useful bedside tool than traditional estimators.

Nutritional support of the pediatric trauma patient.

Of all the interventions available to aid recovery of the injured child, few have the power of proper nutritional support. Healing after trauma depends not only on restoration of oxygen delivery, but on "substrate delivery," or provision of calories to support metabolic power and specific nutrients to allow rebuilding of injured tissue. Failure to deliver adequate substrate to the cells is revealed as another form of shock. Nutritional interventions after trauma are most effective when informed by the specific ways that children diverge physiologically (metabolic rate, biomechanics, physiological response to trauma) from adults. This review describes these responses and outlines a general strategy for safely delivering energy and specific substrates to protect and heal injured children, regardless of body size and type of injury.

Sustainable exploitation of temperate fish stocks.

The theory of maximum sustainable yield (MSY) underpins many fishery management regimes and is applied principally as a single species concept. Using a simple dynamic biomass production model we show that MSY can be identified from a long time series of multi-stock data at a regional scale in the presence of species interactions and environmental change. It suggests that MSY is robust and calculable in a multispecies environment, offering a realistic reference point for fishery management. Furthermore, the demonstration of the existence of MSY shows that it is more than a purely theoretical concept. There has been an improvement in the status of stocks in the Northeast Atlantic, but our analysis suggests further reductions in fishing effort would improve long-term yields.

Systematic discovery of new genes in the Saccharomyces cerevisiae genome.

We used genome-wide comparative analysis of predicted protein sequences to identify many novel small genes, named smORFs for small open reading frames, within the budding yeast genome. Further analysis of 117 of these new genes showed that 84 are transcribed. We extended our analysis of one smORF conserved from yeast to human. This investigation provides an updated and comprehensive annotation of the yeast genome, validates additional concepts in the study of genomes in silico, and increases the expected numbers of coding sequences in a genome with the corresponding impact on future functional genomics and proteomics studies.

The use of direct cDNA selection to rapidly and effectively identify genes in the fungus Aspergillus fumigatus.

Aspergillus fumigatus is one of the causes of invasive lung disease in immunocompromised individuals. To rapidly identify genes in this fungus, including potential targets for chemotherapy, diagnostics, and vaccine development, we constructed cDNA libraries. We began with non-normalized libraries, then to improve this approach we constructed a normalized cDNA library using direct cDNA selection. Normalization resulted in a reduction of the frequency of clones with highly expressed genes and an enrichment of underrepresented cDNAs. Expressed sequence tags generated from both the original and the normalized libraries were compared with the genomes of Saccharomyces cerevisiae, Schizosaccharomyces pombe, and Candida albicans, indicating that a large proportion of A. fumigatus genes do not have orthologs in these fungal species. This method allowed the expeditious identification of genes in a fungal pathogen. The same approach can be applied to other human or plant pathogens to rapidly identify genes without the need for genomic sequence information.