The efficacy of therapeutic interventions on paediatric burn patients' height, weight, body composition, and muscle strength: A systematic review and meta-analysis.

OBJECTIVE: To evaluate the efficacy of therapeutic interventions on pediatric burn patients' height, weight, body composition, and muscle strength. METHODS: A systematic literature search was conducted in PubMed, Embase, and Web of Science up to March 2021. Eligible interventional studies reported metrics on the height, weight, body composition, or muscle strength of pediatric burn patients in a peer-reviewed journal. Meta-analyses were performed if ≥ 2 trials of clinical homogeneity reported on an outcome measure at the same time point post-burn. RESULTS: Twenty-six interventional studies were identified, including twenty-two randomised controlled trials and four non-randomised trials. Most studies were conducted by a single institution. On average, the burn covered 45.3% ( ± 9.9) of the total body surface area. Three categories of interventions could be distinguished: rehabilitative exercise programs, pharmacologic agents, and nutrition support. CONCLUSIONS: Each of the interventions had a positive effect on height, weight, body composition, or muscle strength. The decision to initiate an intervention should be made on a case-by-case basis following careful consideration of the benefits and risks. In future research, it is important to evaluate the heterogeneity of intervention effects and whether participation in an intervention allowed pediatric burn patients to reach the physical and functional status of healthy peers.

Physician-led thoracic ultrasound-guided biopsy; a district general hospital perspective.

BACKGROUND: Physician-led thoracic ultrasound (TUS)-guided biopsies provide a prompt route to tissue diagnosis in pleural and peripheral lung malignancies. This retrospective study reviews the diagnostic performance and safety of this approach in a UK District General Hospital. METHODS: Time to biopsy, diagnostic yield and complication rate were analysed in a cohort of 49 patients undergoing ultrasound-guided tissue sampling between September 2019 and December 2022. RESULTS: Fifty-one TUS-guided biopsies were attempted. Mean time from decision to biopsy was 5 days. The overall diagnostic yield was 82%. Complication rate was low; 3 minor adverse effects were reported which led to no change in routine care. CONCLUSION: This single centre retrospective study shows that physician-led TUS-guided biopsy provides a safe and timely method of obtaining a tissue diagnosis in thoracic malignancy. It offers an alternative to computer tomography (CT)-guided or thoracoscopic biopsies and should be considered in selected patients where local procedural expertise exists.

Children's growth and motor development following a severe burn: a systematic review.

Background: The epidemiological data on post-burn growth, body composition and motor development is ambiguous and scattered. The aim of this systematic review was therefore to summarize the current body of evidence on post-burn growth, body composition and motor development in children. Methods: A literature search was conducted in PubMed, EMBASE and Web of Science up to March 2021. We considered observational studies that reported (1) metrics on weight, height, body composition, bone mineral content, bone mineral density or motor development, in (2) paediatric burn patients and (3) published in a peer-reviewed journal. Results: A total of 16 studies were included. Each of the included studies used quantitative methods, but with differing methodology: prospective cohort studies (n = 8), retrospective chart reviews (n = 3), case-control studies (n = 2), cross sectional studies (n = 2) and a retrospective cohort study (n = 1). When combined, the included studies represented 2022 paediatric burn patients, with a mean age of 7.7 (±3.2) years. The average burn size was 52.8% (±12.7) of the total body surface area. Identified outcome measures included weight (n = 12), height (n = 7), muscular strength (n = 4), bone mineral content (n = 5), bone mineral density (n = 5), body mass index (n = 3), fat mass (n = 5), lean body mass (n = 7) and fine and gross motor development (n = 1). Conclusions: Following an initial decline, patients' growth and motor development started to recover during the first or second year post-burn. Nonetheless, burns may have a profound and prolonged effect on the paediatric burn patients' muscular strength, bone mineral content and lean body mass. It should be noted that the vast majority of studies included only patients with burns covering ≥30% total body surface area. The evidence presented in this review may thus not be representative of the whole paediatric burn population.

The Effect of Burns on Children's Growth Trajectory: A Nationwide Cohort Study.

This study evaluates the short- and long-term effect of burns on children's height and weight, by comparing their pre and postburn growth trajectory. We invited children (≤17 years old), who sustained a burn requiring surgical treatment or admission at one of the Dutch burn centers in 2013 (n = 175). As well as children who sustained a severe burn, covering >10% of the total body surface area (TBSA), throughout 2009-2018 (n = 228). Data was collected from a survey on health-related topics, Youth Health Care records, and the Dutch Burn Repository R3. For all participants, height and weight were converted to Z-scores using Dutch reference values. Linear mixed modeling, nested on the individual level, was used to examine the associations between burns and children's height and weight Z-scores. Children's height and weight Z-scores remained within the normal range throughout the study period. During the first-year postburn, children's height and weight Z-scores decreased by -0.21 (95% CI -0.41, -0.01) and -0.23 (95% CI -0.46, -0.04), respectively. Beyond the first-year postburn, estimates were consistent with a positive linear association between burn size and the overall effect of burns on participants' height and weight Z-scores. This included a modest, but statistically significant, effect among participants with a burn covering ≤4.5% and >14.0% of the TBSA. Sensitivity analyses did not alter our findings. In conclusion, children were on track or even surpassed their growth potential. Our findings could therefore be considered reassuring to patients, parents, and clinicians.

Efficacy and safety of switching from intravenous to oral antibiotics (amoxicillin-clavulanic acid) versus a full course of intravenous antibiotics in neonates with probable bacterial infection (RAIN): a multicentre, randomised, open-label, non-inferiority trial.

BACKGROUND: Switching from intravenous antibiotic therapy to oral antibiotic therapy among neonates is not yet practised in high-income settings due to uncertainties about exposure and safety. We aimed to assess the efficacy and safety of early intravenous-to-oral antibiotic switch therapy compared with a full course of intravenous antibiotics among neonates with probable bacterial infection. METHODS: In this multicentre, randomised, open-label, non-inferiority trial, patients were recruited at 17 hospitals in the Netherlands. Neonates (postmenstrual age ≥35 weeks, postnatal age 0-28 days, bodyweight ≥2 kg) in whom prolonged antibiotic treatment was indicated because of a probable bacterial infection, were randomly assigned (1:1) to switch to an oral suspension of amoxicillin 75 mg/kg plus clavulanic acid 18·75 mg/kg (in a 4:1 dosing ratio, given daily in three doses) or continue on intravenous antibiotics (according to the local protocol). Both groups were treated for 7 days. The primary outcome was cumulative bacterial reinfection rate 28 days after treatment completion. A margin of 3% was deemed to indicate non-inferiority, thus if the reinfection rate in the oral amoxicillin-clavulanic acid group was less than 3% higher than that in the intravenous antibiotic group the null hypothesis would be rejected. The primary outcome was assessed in the intention-to-treat population (ie, all patients who were randomly assigned and completed the final follow-up visit on day 35) and the per protocol population. Safety was analysed in all patients who received at least one administration of the allocated treatment and who completed at least one follow-up visit. Secondary outcomes included clinical deterioration and duration of hospitalisation. This trial was registered with ClinicalTrials.gov, NCT03247920, and EudraCT, 2016-004447-36. FINDINGS: Between Feb 8, 2018 and May 12, 2021, 510 neonates were randomly assigned (n=255 oral amoxicillin-clavulanic group; n=255 intravenous antibiotic group). After excluding those who withdrew consent (n=4), did not fulfil inclusion criteria (n=1), and lost to follow-up (n=1), 252 neonates in each group were included in the intention-to-treat population. The cumulative reinfection rate at day 28 was similar between groups (one [<1%] of 252 neonates in the amoxicillin-clavulanic acid group vs one [<1%] of 252 neonates in the intravenous antibiotics group; between-group difference 0 [95% CI -1·9 to 1·9]; pnon-inferiority<0·0001). No statistically significant differences were observed in reported adverse events (127 [50%] vs 113 [45%]; p=0·247). In the intention-to-treat population, median duration of hospitalisation was significantly shorter in the amoxicillin-clavulanic acid group than the intravenous antibiotics group (3·4 days [95% CI 3·0-4·1] vs 6·8 days [6·5-7·0]; p<0·0001). INTERPRETATION: An early intravenous-to-oral antibiotic switch with amoxicillin-clavulanic acid is non-inferior to a full course of intravenous antibiotics in neonates with probable bacterial infection and is not associated with an increased incidence of adverse events. FUNDING: The Netherlands Organization for Health Research and Development, Innovatiefonds Zorgverzekeraars, and the Sophia Foundation for Scientific Research.

Epidemiology and screening of intentional burns in children in a Dutch burn centre.

International estimates of the incidence of non-accidental burns (NAB) in children admitted to burn centres vary from 1% to 25%. Hardly any data about Dutch figures exist. The aim of this study was to evaluate the incidence, treatment and outcome of burns due to suspected child abuse in paediatric burns. We described the process of care and outcome, including the accuracy of the SPUTOVAMO screening tool and examined child, burn and treatment characteristics related to suspicions of child abuse or neglect. A retrospective study was conducted in children aged 0-17 years with a primary admission after burn injuries to the burn centre Rotterdam in the period 2009-2013. Data on patient, injury and treatment characteristics were collected, using the Dutch Burn Repository R3. In addition, medical records were reviewed. In 498 paediatric admissions, suspected child abuse or neglect was present in 43 children (9%). 442 screening questionnaires (89%) were completed. In 52 out of 442 questionnaires (12%) the completed SPUTOVAMO had one or more positive signs. Significant independent predictors for suspected child abuse were burns in the genital area or buttocks (OR=3.29; CI: 143-7.55) and a low socio-economic status (OR=2.52; 95%CI: 1.30-4.90). The incidence of suspected child abuse indicating generation of additional support in our population is comparable to studies with a similar design in other countries.

Pain insensitivity syndrome misinterpreted as inflicted burns.

We present a case study of a 10-year-old child with severe burns that were misinterpreted as inflicted burns. Because of multiple injuries since early life, the family was under suspicion of child abuse and therefore under supervision of the Child Care Board for 2 years before the boy was burned. Because the boy incurred the burns without feeling pain, we conducted a thorough medical examination and laboratory testing, evaluated detection and pain thresholds, and used MRI to study brain morphology and brain activation patterns during pain between this patient and 3 healthy age- and gender-matched controls. We found elevated detection and pain thresholds and lower brain activation during pain in the patient compared with the healthy controls and reference values. The patient received the diagnosis of hereditary sensory and autonomic neuropathy type IV on the basis of clinical findings and the laboratory testing, complemented with the altered pain and detection thresholds and MRI findings. Hereditary sensory and autonomic neuropathy IV is a very rare congenital pain insensitivity syndrome characterized by the absence of pain and temperature sensation combined with oral mutilation due to unawareness, fractures, and anhidrosis caused by abnormalities in the peripheral nerves. Health care workers should be aware of the potential presence of this disease to prevent false accusations of child abuse.

Cyst(e)ine requirements in enterally fed very low birth weight preterm infants.

OBJECTIVE: Optimal nutrition is of utmost importance for the preterm infant's later health and developmental outcome. Amino acid requirements for preterm infants differ from those for term and older infants, because growth rates differ. Some nonessential amino acids, however, cannot be sufficiently synthesized endogenously. Cyst(e)ine is supposed to be such a conditionally essential amino acid in preterm infants. The objective of this study was to determine, at 32 and 35 weeks' postmenstrual age, cyst(e)ine requirements in fully enterally fed very low birth weight preterm infants with gestational ages of <29 weeks. METHODS: Infants were randomly assigned to 1 of the 5 graded cystine test diets that contained generous amounts of methionine. Cyst(e)ine requirement was determined with the indicator amino acid oxidation technique ([1-(13)C]phenylalanine) after 24-hour adaptation. RESULTS: Fractional [1-(13)C]phenylalanine oxidation was established in 47 very low birth weight preterm infants (mean gestational age: 28 weeks +/- 1 week SD; birth weight: 1.07 kg +/- 0.21 kg SD). Increase in dietary cyst(e)ine intake did not result in a decrease in fractional [1-(13)C]phenylalanine oxidation. CONCLUSIONS: These data do not support the hypothesis that endogenous cyst(e)ine synthesis is limited in very low birth weight preterm infants with gestational ages of <29 weeks, both at 32 and 35 weeks postmenstrual age. It is safe to conclude that cyst(e)ine requirement is <18 mg/kg per day in enterally fed very low birth weight preterm infants who are older than 32 weeks' postmenstrual age and whose methionine intake is adequate. Therefore, cyst(e)ine is probably not a conditionally essential amino acid in these infants.

Human Experience Modeler: context-driven cognitive retraining to facilitate transfer of learning.

We describe a cognitive rehabilitation mixed-reality system that allows therapists to explore natural cuing, contextualization, and theoretical aspects of cognitive retraining, including transfer of training. The Human Experience Modeler (HEM) mixed-reality environment allows for a contextualized learning experience with the advantages of controlled stimuli, experience capture and feedback that would not be feasible in a traditional rehabilitation setting. A pilot study for testing the integrated components of the HEM is discussed where the participant presents with working memory impairments due to an aneurysm.

Surgery for elderly patients with ovarian cancer.

The stage and tumor remnants after radical surgery are the most important prognostic factors in patients with ovarian cancer. Because the incidence of ovarian cancer is highest in elderly women, and mostly advanced stages occur, radical surgery is necessary in this population as well as in younger patients. Age and the surgeon's expertise are the factors that influence the quality of surgical treatment of ovarian cancer. Surgical treatment of ovarian cancer should therefore be confined to centers with the required infrastructure and expertise.

Surgery for elderly patients with ovarian cancer.

The stage and tumor remnants after radical surgery are the most important prognostic factors in patients with ovarian cancer. Because the incidence of ovarian cancer is highest in elderly women, and mostly advanced stages occur, radical surgery is necessary in this population as well as in younger patients. Age and the surgeon's expertise are the factors that influence the quality of surgical treatment of ovarian cancer. Surgical treatment of ovarian cancer should therefore be confined to centers with the required infrastructure and expertise.

High-yield, in vitro protein expression using a continuous-exchange, coupled transcription/ translation system.

The Rapid Translation System (RTS 500) (Roche Molecular Biochemicals) is a high-yield protein expression system that utilizes an enhanced E. coli lysate for an in vitro transcription/translation reaction. In contrast to conventional transcription/translation, this system allows protein expression to continue for more than 24 h. We demonstrated the utility of the RTS 500 by expressing different soluble and active proteins that generally pose problems in cell-based expression systems. We first expressed GFP-lunasin, a fusion protein that, because of its toxicity, has been impossible to produce in whole cells. The second protein we expressed, human interleukin-2 (IL-2), is generally difficult to produce, either as the native molecule or as a GSTfusion protein, in a soluble form in bacteria. Finally, we demonstrated the capacity of the RTS 500 to co-express proteins, by the simultaneous production of GFP and CAT in a single reaction. This new technology appears to be particularly usefulfor the convenient production of preparative amounts (100-900 microg) of proteins that are toxic or insoluble in cell-based systems.

The neurosteroid pregnanolone prevents the anxiogenic-like effect of inescapable shock in the rat.

RATIONALE AND OBJECTIVES: The ability of progesterone (P4) and its neurosteroid metabolite, 3alpha-OH-5beta-pregnan-20-one (pregnanolone) in protecting against the anxiogenic-like effect of inescapable shock (IS) in male rats was examined, as these steroids exert anxiolytic, anticonvulsant, and ataxic effects similar to the benzodiazepines (BZ), drugs shown to prevent IS-induced anxiogenesis. METHODS: Adult male rats were injected with pregnanolone (8 mg/kg, SC), P4 (4 mg/rat) or its appropriate vehicle before exposure to IS. Twenty-four hours later, animals were injected with the steroid or its vehicle and then tested in the elevated plus-maze. In a control experiment, animals were injected with chlordiazepoxide (CDP, 15 mg/kg, IP) or vehicle before IS, and tested in the plus-maze 24 h later. RESULTS: Whereas CDP or pregnanolone before IS resulted in the loss of the anxiogenic-like response seen 24 h after IS, P4 before IS did not protect against the anxiogenic-like effect of IS. The acute anxiolytic-like effect of pregnanolone and P4 was lost in animals that were injected with vehicle before the IS, but was observed in animals that were injected with the steroids before IS. Moreover, P4 injection in non-shocked animals was associated with an anxiogenic-like response observed 24 h after steroid administration. CONCLUSION: The protection against the effect of IS afforded by a GABAergic neurosteroid is comparable to that observed with BZs, and thus provides further evidence of an allosteric relationship between the neurosteroid and BZ binding site on the GABA(A) receptor complex.

Histamine as an autocrine growth factor: an unusual role for a widespread mediator.

The involvement of histamine in cancer growth represents an old controversy and direct experimental evidence proving this hypothesis is not still available. In this paper we review the most relevant mechanisms referring to the role of histamine receptors, histidine decarboxylase and histamine release in the onset of an autocrine loop, that enables histamine to act as an autocrine growth factor. We postulate that this autocrine loop, that has been studied in an experimental mammary carcinoma model induced in rats, may be present in different human neoplasias. Therefore, the better understanding of this novel regulatory pathway that is controlled by histamine may contribute to identifying new therapeutic targets.

Identifying personality disorders: towards the development of a clinical screening instrument.

The study objective was to identify a set of personality disorder (PD) criteria from the DSM PD diagnostic sets that can be used to detect subjects with an increased likelihood of having a PD diagnosis. In a series of outpatients evaluated systematically in two waves for every criteria item for 12 DSM-III-R PDs, stepwise logistic regression identified 45 criteria as discriminative for their specific PDs, which are selected for further analysis to assess their ability to discriminate for any PD. Receiver operating characteristic (ROC) analysis is used to evaluate their discriminative power in an independent conjoined sample (N = 1,342) from six centers that assessed every PD criteria item by structured instrument (Structured Clinical Interview for DSM-III-R PDs [SCID-II, Personality Disorder Examination [PDE], and Structured Interview for DSM-III-R PDs [SIDP-R]). The cutoff that maximizes information gain is used to determine the diagnostic threshold (DT). Initially, 15 of 45 criteria are identified. At the 0.43 PD prevalence, a DT of 2 or more of the 15 PD criteria across samples is optimal. The maximum information gain (MIG) is .42 bits, and the AUR is 0.94+/-.007. Other performance indices at this cutoff are .90 sensitivity, .84 specificity, .81 positive predictive power (PPP), .91 negative predictive power (NPP), and .86 hit rate (HR). Taken collectively, the 15 PD criteria selected by the data reduction techniques suggest a narrowed set to be assessed in screening for the presence or absence of any PD with comparable or better psychometric properties than other tests routinely used for diagnosing medical and psychiatric disorders. If specific PD categorization is needed, a second-step comprehensive assessment should follow.

C3 toxin activates the stress signaling pathways, JNK and p38, but antagonizes the activation of AP-1 in rat-1 cells.

Lysophosphatidic acid (LPA) stimulates the c-Fos serum response element (SRE) by activating two distinct signal pathways regulated by the small GTPases, Ras and RhoA. Ras activates the ERK cascade leading to phosphorylation of the transcription factors Elk-1 and Sap1a at the Ets/TCF site. RhoA regulates an undefined pathway required for the activation of the SRF/CArG site. Here we have examined the role of the Ras and RhoA pathways in activation of the SRE and c-Fos expression in Rat-1 cells. Pertussis toxin and PD98059 strongly inhibited LPA-stimulated c-Fos expression and activation of a SRE:Luc reporter. C3 toxin completely inhibited RhoA function, partially inhibited SRE:Luc activity, but had no effect on LPA-stimulated c-Fos expression. Thus, in a physiological context the Ras-Raf-MEK-ERK pathway, but not RhoA, is required for LPA-stimulated c-Fos expression in Rat-1 cells. C3 toxin stimulated the stress-activated protein kinases JNK and p38 and potentiated c-Jun expression and phosphorylation; these properties were shared by another cellular stress agonist the protein kinase C inhibitor Ro-31-8220. However, C3 toxin alone or in combination with growth factors did not stimulate AP-1:Luc activity and actually antagonized the synergistic activation of AP-1:Luc observed in response to co-stimulation with growth factors and Ro-31-8220. These data indicate that C3 toxin is a cellular stress which antagonizes activation of AP-1 at a point downstream of stress-activated kinase activation or immediate-early gene induction.

Proteolytic cleavage of ras GTPase-activating protein during apoptosis.

p120-ras GTPase-activating protein (rasGAP) associates with Ras and negatively regulates Ras signaling by stimulating the intrinsic rate of Ras GTPase activity. rasGAP also associates with other cellular signaling proteins which suggest that rasGAP may play a role in coordinating other signal transduction pathways. Disruption of rasGAP in vivo results in extensive apoptosis. Fas-mediated apoptosis results in the activation of caspases that cleave cellular substrates which are important for maintaining cytoplasmic and nuclear integrity. We show here that rasGAP is proteolytically cleaved by caspases early in Fas-induced apoptosis of Jurkat cells. rasGAP was also cleaved by DNA-damaging chemotherapeutic agents and TNF-related apoptosis inducing ligand (TRAIL), also known as Apo2L. Based on the size of the products generated by cleavage of deletion mutants of rasGAP we predict that cleavage of rasGAP occurs in the hydrophobic region and between the SH2(2) and ras-p21 interacting domain which would leave an intact ras-p21 interacting domain. Interestingly, cleavage of rasGAP in vitro enhanced rasGAP hydrolysis activity. Our results demonstrate that diverse apoptotic stimuli cause caspase-mediated cleavage of rasGAP early in apoptosis.