Co-administration of FVIII with IVIG reduces immune response to FVIII in hemophilia A mice.

Hemophilia A is an X-linked recessive congenital bleeding disorder. Exogenous infusion of FVIII is the treatment of choice, and the development of immunoglobulins against FVIII (inhibitors) remains the major challenge in clinical management of the disease. Here, we investigated the effect of co-administration of FVIII with intravenous immunoglobulin (IVIG) on the development of inhibitors in previously untreated hemophilia A mice. A group of hemophilia A mice (C57BL/6FVIII-/-) received weekly injections of recombinant human FVIII (rFVIII) for twelve consecutive weeks while a second group received co-injections of rFVIII + IVIG. An in-house enzyme-linked immunosorbent assay (ELISA) was designed to detect antibodies to rFVIII. Every mouse in the first group developed antibodies to rFVIII. In contrast, mice treated with rFVIII + IVIG showed significantly lower antibody titers. Interestingly, when co-administration of IVIG was discontinued after 12 weeks in some mice (rFVIII continued), these mice experienced an increase in antibody titer. In contrast, mice that continued to receive rFVIII + IVIG retained significantly lower titers. In conclusion, prophylactic rFVIII co-administration with IVIG modulated the immune response to FVIII and resulted in decreased anti-FVIII antibody titer. These findings suggest that co-injection therapy with IVIG could potentially be effective in the management of hemophilia A patients at risk of inhibitor development.

Evidence Map and Systematic Review of Disinfection Efficacy on Environmental Surfaces in Healthcare Facilities.

Healthcare-associated infections (HAIs) contribute to patient morbidity and mortality with an estimated 1.7 million infections and 99,000 deaths costing USD $28-34 billion annually in the United States alone. There is little understanding as to if current environmental surface disinfection practices reduce pathogen load, and subsequently HAIs, in critical care settings. This evidence map includes a systematic review on the efficacy of disinfecting environmental surfaces in healthcare facilities. We screened 17,064 abstracts, 635 full texts, and included 181 articles for data extraction and study quality assessment. We reviewed ten disinfectant types and compared disinfectants with respect to study design, outcome organism, and fourteen indictors of study quality. We found important areas for improvement and gaps in the research related to study design, implementation, and analysis. Implementation of disinfection, a determinant of disinfection outcomes, was not measured in most studies and few studies assessed fungi or viruses. Assessing and comparing disinfection efficacy was impeded by study heterogeneity; however, we catalogued the outcomes and results for each disinfection type. We concluded that guidelines for disinfectant use are primarily based on laboratory data rather than a systematic review of in situ disinfection efficacy. It is critically important for practitioners and researchers to consider system-level efficacy and not just the efficacy of the disinfectant.

Effect of unfractionated heparin and low molecular weight heparin on the clotting of platelet-reduced whole blood: an in-vitro study utilizing thromboelastography.

Treatment of venous thromboembolism with concomitant thrombocytopenia is challenging. The platelet threshold for safe administration of anticoagulants is under debate, with minimum platelet count of 50 × 109/l being recommended as the safe cutoff. However, some evidence suggests administration of anticoagulants may still be safe at platelet levels of 30 × 109/l. Therefore, we developed an in-vitro thromboelastography (TEG) study to examine the effect of therapeutic or prophylactic levels of unfractionated heparin (UFH) and low molecular weight heparin (LMWH) on the clotting profile of platelet-reduced whole blood. Using magnetic bead-based antibody chromatography, platelets were removed to achieve platelet-depleted blood (<10 × 109/l of platelets). Platelet-depleted blood was then mixed with whole blood to produce blood samples with platelet counts of 30 × 109, 50 × 109 and 150 × 109/l. These blood samples were incubated with therapeutic or prophylactic levels of UFH or LMWH in disposable TEG cups. Clotting was initiated with 10 mmol/l calcium and optimized tissue factor levels for each anticoagulant used (2.25 pmol/l for UFH and 2.05 pmol/l for LMWH). Clotting was monitored by TEG at 37 °C for 180 min. The following TEG parameters were evaluated: R (time to clot), maximum amplitude (strength of clot) and area under the curve in 15 min (overall speed and strength of the clot at 15 min of clotting). No statistically significant differences were observed between platelet counts of 30 × 109 and 50 × 109/l for R, maximum amplitude or area under the curve in 15 min for most of the therapeutic and prophylactic doses of UFH and LMWH tested in this study. Use of anticoagulants compromised all of the TEG parameters relative to a normal platelet count of 150 × 109/l, in a dose dependent manner. The current study demonstrates that in-vitro clotting is impaired with use and increasing doses of anticoagulants. Despite this observation, we did not observe a significant difference in clotting between platelet levels of 30 × 109 and 50 × 109/l. Overall, this work provides further insight in the debated use of anticoagulants in patients with venous thromboembolism and concomitant thrombocytopenia, and provides support for possible use of anticoagulants at lower platelet thresholds.

A new automated method for high-throughput carbon and hydrogen isotope analysis of gaseous and dissolved methane at atmospheric concentrations.

RATIONALE: The dual isotope ratio analysis, carbon (δ13 C value) and hydrogen (δ2 H value), of methane (CH4 ) is a valuable tracer tool within a range of areas of scientific investigation, not least wetland ecology, microbiology, CH4 source identification and the tracing of geological leakages of thermogenic CH4 in groundwater. Traditional methods of collecting, purification, separating and analysing CH4 for δ13 C and δ2 H determination are, however, very time consuming, involving offline manual extractions. METHODS: Here we describe a new gas chromatography, pyrolysis/combustion, isotope ratio mass spectrometry (IRMS) system for the automated analysis of either dissolved or gaseous CH4 down to ambient atmospheric concentrations (2.0 ppm). Sample introduction is via a traditional XYZ autosampler, allowing either helium (He) purging of gas or sparging of water from a range of suitable, airtight bottles. RESULTS: The system routinely achieves precision of <0.3‰ for δ13 C values and <3.0‰ for δ2 H values, based on long-term replicate analysis of an in-house CH4 /He mix standard (BGS-1), corrected to two externally calibrated reference gases at near atmospheric concentrations of methane. Depending upon CH4 concentration and therefore bottle size, the system runs between 21 (140-mL bottle) and 200 samples (12-mL exetainer) in an unattended run overnight. CONCLUSIONS: This represents the first commercially available IRMS system for dual δ13 C and δ2 H analysis of methane at atmospheric concentrations and a step forward for the routine (and high-volume) analysis of CH4 in environmental studies.

Optimising a targeted test reduction intervention for patients admitted to the intensive care unit: The Targeted Intensive Care Test Ordering Cluster Trial intervention.

BACKGROUND: Approaches to routine diagnostic testing in the intensive care unit include time-scheduled testing and targeted testing. Blood tests and chest radiographs requested on a routine, time-scheduled basis may reduce the risk of missing important findings. Targeted testing, considering individual patient needs, may reduce unnecessary testing, wasted clinician time, and costs. However, existing evidence of targeted testing interventions is generally of low quality, and the optimal testing approach is uncertain. OBJECTIVES: The aim of the study was to describe the development of an intervention to reduce unnecessary diagnostic test ordering by clinicians working in intensive care, with the aim of informing the design of a pivotal clinical trial. METHODS: The Capability, Opportunity, Motivation-Behaviour model was used as a theoretical framework for change. The intervention components were informed by systematically identifying, assessing, and classifying targeted testing interventions in behavioural terms. Feedback from intensive care clinicians and patients was sought using surveys and a consumer reference group. RESULTS: The mean percentage of routine tests considered unnecessary by 201 intensive care clinicians was 33 (standard deviation = 16). When presented with a statement of the pros and cons for targeted versus liberal testing (n = 154), 93 (60%) consumer survey respondents preferred a more liberal approach, 33 (21%) preferred a more restrictive approach, and 28 (18%) were unsure. There were 24 behavioural interventions identified and incorporated into the final intervention. This had five major components: (i) a management committee to acquire, disseminate, and coordinate intervention-related information, (ii) a targeted testing guideline for sites, (iii) educational material for sites, (iv) site medical and nursing champions, and (v) site audit and feedback. CONCLUSIONS: Although surveyed intensive care clinicians report substantial unnecessary routine diagnostic testing, on the basis of currently available evidence, consumers prefer a more liberal approach. This feedback, and a framework to identify behavioural interventions, has been used to inform the design of a proposed targeted testing clinical trial.

Age-Dependent Variation in Glycosylation Features of Alpha-2-Macroglobulin.

Alpha-2-macroglobulin (A2M) is a glycosylated broad spectrum inhibitor of numerous proteases, including those involved in blood coagulation. Glycosylation characteristics can affect protein structure and function. This study compares glycosylation characteristics of A2M in newborn umbilical cord (NUCP) and adult pooled plasmas. Peptide N-Glycosidase F treatment was used to evaluate the total N-glycan content of the molecules. Neuraminidase treatment, and affinity for Ricinus Communis Agglutinin I were used to examine terminal sialic acid and galactose content, respectively. Two-dimensional (2D) electrophoresis was used to determine charge-related isoform profiles and fluorophore-assisted carbohydrate electrophoresis (FACE) was used to characterize N-glycan profiles. Results revealed no difference in total N-glycan mass, however, a statistically significant difference was shown in the change in charge associated with sialic acid loss in the NUCP A2M population. 2D electrophoresis indicated a lower pI range for NUCP A2M isoforms. In addition, NUCP A2M displayed a trend toward higher terminal galactose quantities than adult A2M. FACE revealed an increased abundance of more branched, higher molecular weight glycans in NUCP A2M. These differences in glycan branching and charged residues may impact A2M receptor-based clearance and thus could be responsible for the increased A2M concentration seen in NUCP, and newborns.

Revealing internal flow behaviour in arc welding and additive manufacturing of metals.

Internal flow behaviour during melt-pool-based metal manufacturing remains unclear and hinders progression to process optimisation. In this contribution, we present direct time-resolved imaging of melt pool flow dynamics from a high-energy synchrotron radiation experiment. We track internal flow streams during arc welding of steel and measure instantaneous flow velocities ranging from 0.1 m s-1 to 0.5 m s-1. When the temperature-dependent surface tension coefficient is negative, bulk turbulence is the main flow mechanism and the critical velocity for surface turbulence is below the limits identified in previous theoretical studies. When the alloy exhibits a positive temperature-dependent surface tension coefficient, surface turbulence occurs and derisory oxides can be entrapped within the subsequent solid as result of higher flow velocities. The widely used arc welding and the emerging arc additive manufacturing routes can be optimised by controlling internal melt flow through adjusting surface active elements.

Rivaroxaban and dabigatran did not affect clotting profiles in plasma reconstituted with varying levels of autologous platelets to the same degree as heparin when evaluated using thromboelastography.

OBJECTIVE: Current recommendations for treating patients with thromboembolism and concomitant thrombocytopenia are based on anecdotal data and expert opinion, rather than clinical studies. Our aim was to use an in-vitro model employing thromboelastography (TEG) to evaluate clot formation as a surrogate indicator of clinical tendency to hemorrhage, and investigate the interactions of plasma at varying concentrations of platelets in the presence of anticoagulants. METHODS: Platelet-rich and platelet-poor plasma isolated from whole blood were mixed together to obtain platelet concentrations ranging from less than 10-150 × 10 platelets/l. Clotting was initiated with tissue factor and measured by TEG. RESULTS: Different tissue factor concentrations were required to model clinical clotting profiles for plasma that contained heparin (UFH), low molecular weight heparin (LMWH), or fondaparinux. No tissue factor was required for rivaroxaban or dabigatran-clotting reactions. The time to initiate coagulation (R) was significantly delayed at platelet concentrations less than 30 × 10/l for UFH and LMWH, less than 20 × 10/l for fondaparinux, and less than 10 × 10/l for rivaroxaban and dabigatran. The strength of the clot was significantly compromised at all platelet concentrations in the presence of UFH, LMWH or fondaparinux. In contrast, rivaroxaban and dabigatran compromised clot strength at platelet concentrations less than 10 × 10/l. CONCLUSION: All anticoagulants tested compromised coagulation at specific platelet concentration thresholds. Rivaroxaban and dabigatran had reduced impact on clot formation at low-platelet concentrations compared with heparinoids, suggesting that the factor-specific inhibitors may be more favorable than traditional heparin-based treatment of thromboembolism in the presence of thrombocytopenia.

A Case Report of Syndromic Multinodular Goitre in Adolescence: Exploring the Phenotype Overlap between Cowden and DICER1 Syndromes.

BACKGROUND: Hereditary tumour predisposition syndromes may increase the risk for development of thyroid nodules at a young age. We present the case of an adolescent female with Cowden syndrome who had some atypical phenotypic features which overlapped with the DICER1 syndrome. MATERIAL AND METHODS: A 17-year-old female presented with a 3-month history of progressive right neck swelling. Fine needle cytology of the thyroid revealed a follicular neoplasm with features suggestive of follicular variant of papillary thyroid carcinoma and she underwent a hemithyroidectomy. Enlarging nodules in the remaining thyroid led to a completion thyroidectomy at 19 years of age. The patient's past medical history included an ovarian mixed malignant germ cell tumour, pulmonary nodules and cysts, renal cysts, mucocutaneous lesions, an arachnoid cyst, and a fibrous breast lesion. Macrocephaly was noted on physical examination. RESULTS: Based on the patient's complex phenotype and young age, a hereditary predisposition syndrome was suspected and genetic testing of PTEN and DICER1 was undertaken. A heterozygous truncating germ-line PTEN mutation was identified, which combined with clinical findings, met criteria for the diagnosis of Cowden syndrome. Additional loss of heterozygosity of the wild-type PTEN allele was detected in the right thyroid lesion and ovarian tumour. No DICER1 mutations were identified. CONCLUSIONS: Genetic testing was crucial in elucidating this patient's predisposition to the early development of neoplastic and non-neoplastic conditions. Our report also highlights the phenotypic overlap between the Cowden and DICER1 syndromes and illustrates the importance of recognising the variable phenotypic features of hereditary syndromes in order to enable timely implementation of appropriate care.

The majority of irregular menstrual cycles in adolescence are ovulatory: results of a prospective study.

PURPOSE: While ovulation is most likely to occur in adolescent girls with regular menstrual cycles, there are limited data on the incidence of ovulation in girls with irregular menstrual cycles in early postmenarcheal years. The aim of the study was to evaluate the presence of ovulation in healthy postmenarcheal girls with irregular menstrual cycles. METHODS, DESIGN AND SUBJECTS: Prospective cohort study over 12 weeks including 40 healthy postmenarcheal girls recruited from the population-based cohort of adolescents from Western Australian Pregnancy Cohort (Raine) Study with irregular menstrual cycles defined by either menstrual cycles <21 days or >35 days in duration or cycle length that varied from month to month by >4 days according to menstrual diaries. MAIN OUTCOME MEASURE: Ovulation defined by urinary pregnanediol-3α-glucuronide/creatinine measurements higher than three times above minimum value obtained from 12 samples (1 per week). RESULTS: Forty girls (37 Caucasians) with irregular menstrual cycles aged 15.1 (median (IQR) 14.9-15.4) years who were 2.3 (1.9-3.3) years postmenarche were assessed. Urinary pregnanediol-3α-glucuronide/creatinine values identified that 33 girls (82.5%) ovulated during the 3 months of observation and 7 girls had anovulatory cycles. Menstrual diaries collected for a median (IQR) of 159 (137.5-188.2) days showed median minimal and maximum menstrual cycle duration of 24 (11.5-29) and 38.5 (35-48) days, respectively. CONCLUSIONS: A large proportion of healthy adolescent girls with irregular menstrual cycles are still ovulating despite irregular and infrequent menses.

Fitness, body composition and vascular health in adolescent and young adult survivors of paediatric brain cancer and cranial radiotherapy.

Background Survivors of paediatric brain cancer and/or cranial radiotherapy (CRT) are at an increased risk of developing serious comorbidities. Established risk factors for chronic disease include central obesity, endothelial abnormalities and diminished fitness. Objectives Here we characterised anthropometry, body composition, bone mineral density (BMD), heart rate (HR), blood pressure (BP), endothelial function, muscular strength and endurance and aerobic fitness in adolescent and young adult (AYA) survivors. Methods Twenty survivors (10 male, 10 female; 20 ± 2 years) were compared with 19 matched controls. Muscular strength was assessed using three repetition maximum tests, while muscular endurance was determined as number of repetitions performed per minute. Peak oxygen uptake (VO2 peak) was assessed on a treadmill using a modified chronotropic protocol. Anthropometric measurements, HR and BP were taken using standard clinical protocols, while body composition and BMD were determined using dual X-ray absorptiometry (DXA). Endothelial function was measured using the flow mediated dilation technique. Results Survivors demonstrated deficits in muscular strength (latissimus dorsi pull-down, p = 0.020; bicep curl, p = 0.009), muscular endurance (squats, p = 0.012; sit-ups, p = 0.030; push-ups, p = 0.013), minute ventilation at peak exericse (p = 0.002) and VO2peak (L/min, p = 0.002; mL/kg/min, p = 0.008; mL/kg LBM/min, p = 0.010). Additionally, survivors had greater waist-to-hip ratios (p = 0.032), resting HR (p = 0.048) and higher percentage of total body (p = 0.017), central (p = 0.009) and peripheral (p = 0.032) fat. Lean body mass (p = 0.004) and BMD (p = 0.005) were lower in the survivor group. Conclusion AYA survivors of paediatric brain cancer and/or CRT exhibit altered body composition, increased resting HR and reduced BMD, muscular strength, muscular endurance and cardiorespiratory fitness compared to controls.

In-vitro assessment of the effect of dabigatran on thrombosis of adult and neonatal plasma: comparisons using thromboelastography and microscopic visualization of fibrin clot structure.

: Thromboelastography (TEG) is a global assay used for evaluating features of clot formation in vitro. Dabigatran is a reversible direct inhibitor of thrombin that has not been studied in neonates using a sophisticated global assay, such as TEG. Neonatal hemostasis differs from adult hemostasis in both quantitative and qualitative characteristics. Our aim was to compare the TEG clotting profile of neonatal and adult platelet-poor plasma when exposed to different concentrations of dabigatran. We used commercially collected adult pooled plasma and neonatal cord blood collected from placentas of healthy full term newborns. Platelet-poor plasma was isolated, pooled, and frozen. Prior to experiment, plasma was thawed and filtered. A reaction mixture of CaCl2, corn trypsin inhibitor, tissue factor, and dabigatran in imidazole buffer was mixed with plasma in a TEG cup. Time to clot initiation (R-time), speed of clot strengthening (α-angle), and maximum clot strength (maximal amplitude) were measured. Scanning electron microscopy was performed to evaluate fibrin clot structure. Without dabigatran, there was no significant difference in TEG measurements between neonatal and adult samples. However, neonatal plasma clotting with dabigatran had slower onset, slower speed, and weaker clots that were more porous with thicker fibers, compared with adult plasma clotting. Thus, neonatal plasma may be more sensitive to dabigatran as assessed by our in-vitro TEG study.

Inhibition of plasmin generation in plasma by heparin, low molecular weight heparin, and a covalent antithrombin-heparin complex.

: The clinical limitations of unfractionated heparin (UFH) and low molecular weight heparin (LMWH) led to the development of an antithrombin-heparin covalent complex (ATH), which displays superior anticoagulant abilities compared with UFH. A recent study investigating its interaction with fibrinolysis showed that ATH inhibited free and fibrin bound plasmin and decreased plasmin generation on fibrin clots. These studies were conducted using purified components and did not elucidate the interaction of ATH with plasmin in the presence of its natural inhibitors α2-antiplasmin (α2-AP) and α2-macroglobulin (α2-M). The aim of this study was to determine the effects of ATH, UFH, and LMWH on plasmin generation in plasma, under more physiological conditions. Plasmin generation in plasma in the absence and presence of anticoagulants was initiated by tissue plasminogen activator and soluble fibrin fragments, and plasmin and plasmin-α2-M complexes generated over time were quantified chromogenically. Generation of plasmin-α2-AP complexes and consumption of plasminogen were quantified by ELISA. Plasmin generation was decreased in the presence of UFH and ATH, whereas LMWH had no effect. Neither plasminogen consumption nor generation of plasmin-α2-AP complexes were affected by UFH or ATH. However, plasmin-α2-M complexes were slightly reduced by ATH suggesting that ATH may be able to compete with α2-M for plasmin. Plasmin generation may be mildly inhibited by heparin-based anticoagulants; however, heparin-catalyzed antithrombin activity is not a major inhibitor of plasmin, as compared to its natural inhibitors α2-AP and α2-M. This adds to our understanding of ATH mechanisms of action and aids in its development for clinical use.

Early cessation and non-response are important and possibly related problems in growth hormone therapy: An OZGROW analysis.

OBJECTIVE: To investigate growth hormone (GH) treatment and treatment cessation with respect to efficacy and efficiency. To identify factors that best classify or predict cessation type: completed treatment (CT), early cessation (EC), or non-response (NR). DESIGN: Observational study (1990-2013) of the Australian GH Program comparing CT, EC, and NR groups with respect to demographic, clinical, and response criteria. All patients treated for GH deficiency (GHD; 909), short stature and slow growth (SSSG; 2144), and Turner Syndrome (TS; 626) were included. Information was retrieved from the OZGROW database. RESULTS: 51.9% of patients were EC, 40.7% CT and 7.4% NR.Median treatment durations for NR patients were often longer than patients who completed treatment. EC and NR groups were both associated with poor growth response with males overrepresented.Socioeconomic status differentiated NR (higher) and EC (lower) groups. CONCLUSIONS: EC was observed at very high rates and appears, generally, to be a little-recognised but frequent problem in GH therapy.EC and delayed recognition of NR may be interrelated being differentiated by the decision to cease or continue treatment following poor response.Poor treatment compliance is likely a major causal factor in EC.Strategies to address poor response and compliance have been developed, however, given the scale of these problems, it may be that long acting GH formulations or individualized treatment need consideration.

Access to cochlear implants: Time to reflect.

Cochlear implant (CI) intervention is expensive and accessed mainly by developed countries. The introduction of Universal Newborn Hearing Screening and funding via a public health service give children better access to CIs. However for adults large disparities exist between utilization and estimated prevalence. In the UK CI selection criteria are restrictive compared with many other countries. Improved audiological awareness and screening programmes for adults would improve access to hearing technologies that would improve health and quality of life. Hearing loss itself has significant medical and financial burdens on society and by investing in early intervention and using best technology this would mitigate some of the rising associated medical costs.

Characterization and novel analyses of acute stress response patterns in a population-based cohort of young adults: influence of gender, smoking, and BMI.

Dysregulation of the biological stress response system has been implicated in the development of psychological, metabolic, and cardiovascular disease. Whilst changes in stress response are often quantified as an increase or decrease in cortisol levels, three different patterns of stress response have been reported in the literature for the Trier Social Stress Test (TSST) (reactive-responders (RR), anticipatory-responders (AR) and non-responders (NR)). However, these have never been systematically analyzed in a large population-based cohort. The aims of this study were to examine factors that contribute to TSST variation (gender, oral contraceptive use, menstrual cycle phase, smoking, and BMI) using traditional methods and novel analyses of stress response patterns. We analyzed the acute stress response of 798, 18-year-old participants from a community-based cohort using the TSST. Plasma adrenocorticotrophic hormone, plasma cortisol, and salivary cortisol levels were quantified. RR, AR, and NR patterns comprised 56.6%, 26.2%, and 17.2% of the cohort, respectively. Smokers were more likely to be NR than (RR or AR; adjusted, p < 0.05). Overweight and obese subjects were less likely to be NR than the other patterns (adjusted, p < 0.05). Males were more likely to be RR than NR (adjusted, p = 0.05). In addition, we present a novel AUC measure (AUCR), for use when the TSST baseline concentration is higher than later time points. These results show that in a young adult cohort, stress-response patterns, in addition to other parameters vary with gender, smoking, and BMI. The distribution of these patterns has the potential to vary with adult health and disease and may represent a biomarker for future investigation.

Increased Body Mass Index during Therapy for Childhood Acute Lymphoblastic Leukemia: A Significant and Underestimated Complication.

Objective & Design. We undertook a retrospective review of children diagnosed with acute lymphoblastic leukemia (ALL) and treated with modern COG protocols (n = 80) to determine longitudinal changes in body mass index (BMI) and the prevalence of obesity compared with a healthy reference population. Results. At diagnosis, the majority of patients (77.5%) were in the healthy weight category. During treatment, increases in BMI z-scores were greater for females than males; the prevalence of obesity increased from 10.3% to 44.8% (P < 0.004) for females but remained relatively unchanged for males (9.8% to 13.7%, P = 0.7). Longitudinal analysis using linear mixed-effects identified associations between BMI z-scores and time-dependent interactions with sex (P = 0.0005), disease risk (P < 0.0001), age (P = 0.0001), and BMI z-score (P < 0.0001) at diagnosis and total dose of steroid during maintenance (P = 0.01). Predicted mean BMI z-scores at the end of therapy were greater for females with standard risk ALL irrespective of age at diagnosis and for males younger than 4 years of age at diagnosis with standard risk ALL. Conclusion. Females treated on standard risk protocols and younger males may be at greatest risk of becoming obese during treatment for ALL. These subgroups may benefit from intervention strategies to manage BMI during treatment for ALL.

Otitis media with effusion.

Otitis media with effusion (OME) is a common problem facing general practitioners, pediatricians and otolaryngologists. This article reviews the etiopathogenesis, epidemiology, presentation, natural history and management of OME. The literature was reviewed by using the PubMed search engine and entering a combination of terms including 'otitis media with effusion', 'epidemiology' and 'management'. Relevant articles were identified and examined for content. What is the take home message? While OME is a very common entity in the pediatric population, the majority of cases will resolve spontaneously. Surgery in the form of grommet insertion, with or without adenoidectomy is the most effective treatment in persistent symptomatic cases.

Acute otitis media.

Acute otitis media (AOM) is a common problem facing general practitioners, paediatricians and otolaryngologists. This article reviews the aetiopathogenesis, epidemiology, presentation, natural history, complications and management of AOM. The literature was reviewed by using the PubMed search engine and entering a combination of terms including 'AOM', 'epidemiology' and 'management'. Relevant articles were identified and examined for content. What is the take-home message? AOM is a very common problem affecting the majority of children at least once and places a large burden on health care systems throughout the world. Although symptomatic relief is often enough for most children, more severe and protracted cases require treatment with antibiotics, especially in younger children.

Chronic otitis media.

Chronic otitis media (COM) is a common problem facing general practitioners, pediatricians and otolaryngologists. This article reviews the aetiopathogenesis, epidemiology, presentation, natural history, complications and management of COM. The literature was reviewed by using the PubMed search engine and entering a combination of terms including "COM", "diagnosis", "incidence", "complications" and "management". Relevant articles were identified and examined for content. What is the "take-home" message for the clinician? COM is a common problem with various sub-categories according to the disease state. It most commonly presents with painless otorrhoea and hearing loss. Treatment options vary according to the activity and type of disease encountered. COM carries significant patient morbidity.