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Chronic arthropathy is a potentially debilitating complication for people with haemophilia - a genetic, X-linked, recessive bleeding disorder, characterised by the absence or deficiency of a clotting factor protein. Staging classifications, such as the Arnold-Hilgartner classification for haemophilic arthropathy of the knee, radiologically reflect the extent of knee joint destruction with underlying chronic synovitis. Management of this highly morbid disease process involves intensive prophylactic measures, and chemical or radioisotope synovectomy in its early stages. However, failure of non-surgical therapy in people with progression of chronic arthropathy often prompts surgical management, including synovectomy, joint debridement, arthrodesis, and arthroplasty, depending on the type of joint and extent of the damage. To date, management of people with mild to moderate chronic arthropathy from haemophilia remains controversial; there is no agreed standard treatment. Thus, the benefits and disadvantages of non-surgical and surgical management of mild to moderate chronic arthropathy in people with haemophilia needs to be systematically reviewed. OBJECTIVES: To assess the efficacy and safety of surgery for mild to moderate chronic arthropathy in people with haemophilia A or B.We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Coagulopathies Trials Register, CENTRAL, MEDLINE, Embase, CINAHL, and two trial registers to August 2022. We also handsearched relevant journals and conference abstract books.Randomized controlled trials (RCTs) and quasi-RCTs comparing surgery and non-surgical interventions, for any joint with chronic arthropathy, in people with haemophilia, who were at least 12 years old.The review authors did not identify any trials to include in this review.The review authors did not identify any trials to include in this review.The review authors did not identify any trials to include in this review. Due to a lack of research in this particular area, we plan to update the literature search every two years, and will update review if any new evidence is reported. There is a need for a well-designed RCT that assesses the safety and efficacy of surgical versus non-surgical interventions for chronic arthropathy in people with haemophilia.

This is a protocol for a Cochrane Review (intervention). The objectives are as follows: To assess the efficacy and safety of surgery for chronic arthropathy in people with haemophilia A or B.

Pediatric organ donation represents only a low proportion of overall organ donation in many parts of world, unable to match the needs for pediatric organ transplantation. Pediatric organ donation after circulatory determination of death (DCD) is increasingly explored in pediatric transplantation, as it increases the availability of organ grafts. A 6-year-old Caucasian boy with a history of arteriovenous malformation presented with a catastrophic intracranial bleed, resulting in severe brainstem dysfunction despite maximal medical and surgical measures. He did not fulfill the criteria for brain death, which must be met for pediatric organ donation in Singapore. Due to parental request, his organs were donated after withdrawal of life support and determination of death by circulatory criteria. Pediatric organ DCD poses many challenges in the pediatric population, especially in the absence of a local practice guideline. We present the first case of a pediatric organ DCD that has occurred in Singapore. Further work is needed, particularly in establishing a national policy for pediatric organ DCD and increasing overall awareness and acceptance toward pediatric organ donations.

ObjectivesDeath is a significant event that affects healthcare providers emotionally. We aimed to determine internal medicine (IM) and paediatric (PD) residents’ responses and the impact on the residents following patient deaths, and to compare any differences between IM and PD residents. We also aimed to determine whether sufficient resources and measures were in place to support residents through their grief process.MethodsThis is a single-centre, cross-sectional study involving residents from IM and PD programmes from an academic tertiary hospital in Singapore. The residents completed a questionnaire regarding their responses and emotions after experiencing patient deaths.ResultsA total of 122 residents (85 IM and 37 PD, equally distributed between year 1 to year 4 of residency training) participated, with 100% response rate. Only half (57%) felt they would be comfortable treating a dying patient and 66.4% reported feeling sad following their patient’s death. Most (79.5%) were not aware of support resources that were available and 82% agreed that formal bereavement training should be included in the residency curriculum. PD residents had more negative symptoms than IM residents, with poor concentration (PD 35.1% vs IM 16.5%, p=0.02) and lethargy (PD 35.1% vs IM 9.4%, pConclusionIn our Asian context, residents are negatively affected by patient deaths, especially the PD residents. There is a need to incorporate relevant bereavement training for all residents.

We report a rare case of severe congenital dyserythropoietic anemia type 1 with fetal onset. Our patient presented with fetal hydrops from 19 weeks of gestation, requiring multiple intrauterine transfusions. At birth, she had severe hemolytic anemia with severe jaundice, and was subsequently transfusion dependent. She eventually developed severe iron overload and fulminant liver failure before her demise at 5 months of age. Genetic testing revealed a novel mutation in CDAN1.

Introduction Bone marrow aspirate and trephine (BMAT) biopsy is a commonly performed procedure in hematology-oncology practice. Although complications are uncommon, they can cause significant morbidity and mortality. Simulation models are an excellent tool to teach novice doctors basic procedural skills before performing the actual procedure on patients to improve patient safety and well-being. Methods There are no commercial BMAT simulators, and this technical report describes the rationale, technical specifications, and construction of a low-cost, easily constructed, reusable BMAT simulator that reproduced the tactile properties of tissue layers for use as a teaching tool in our resident BMAT simulation course. Preliminary data of learner responses to the simulator were also collected. Results From April 2013 to November 2013, 32 internal medicine residents underwent the BMAT simulation course. Eighteen (56%) completed the online survey, 11 residents with previous experience doing BMAT and 7 without experience. Despite the difference in operative experience, both experienced and novice residents all agreed or strongly agreed that the model aided their understanding of the BMAT procedure. All agreed or strongly agreed that this enhanced their knowledge of anatomy and 16 residents (89%) agreed or strongly agreed that this model was a realistic simulator. Conclusions We present a novel, low-cost, easily constructed, realistic BMAT simulator for training novice doctors to perform BMAT.

Initiating continuous renal replacement therapy (CRRT) in infants exposes them to the dual hemodynamic challenges of high circuit extracorporeal volumes and potential membrane reactions, in the case of acrylonitrile AN69 membranes. The use of the new Prismaflex HF20 membrane in hemodynamically unstable low-body-weight infants on inotropic support has not been reported. We describe the use of the HF20 (Gambro Lundia AB, Lund, Sweden) membrane in four low-body-weight infants (2.3 to 5.4 kg) with multi-organ dysfunction syndrome who were critically ill in the Pediatric Intensive Care Unit (PICU), hemodynamically unstable, and on inotropes. We were able to achieve target volume loss in all infants without compromising their hemodynamic status. Mean arterial pressures were maintained between 39 and 57 mmHg. The relatively low circuit volume of the HF20 set (60 ml) obviated the need for blood prime in the majority; however, when blood prime was required, there was no adverse reaction with the polyarylethersulfone (PAES) membrane. Solute clearance in these small infants was efficient with correction of metabolic acidosis and electrolyte abnormalities. Excellent circuit lifespan (56.3 ± 32.3 h) was observed. CRRT using the HF20 membrane is safe and hemodynamically well tolerated in high-risk, unstable low-body-weight infants with cardiac dysfunction on multiple inotropes.

Current practices and available resources for nutrition therapy in paediatric intensive care units (PICUs) in the Asia Pacific-Middle East region are expected to differ from western countries. Existing guidelines for nutrition management in critically ill children may not be directly applicable in this region. This paper outlines consensus statements developed by the Asia Pacific-Middle East Consensus Working Group on Nutrition Therapy in the Paediatric Critical Care Environment. Challenges and recommendations unique to the region are described.Following a systematic literature search from 2004-2014, consensus statements were developed for key areas of nutrient delivery in the PICU. This review focused on evidence applicable to the Asia Pacific-Middle East region. Quality of evidence and strength of recommendations were rated according to the Grading of Recommendation Assessment, Development and Evaluation approach.Enteral nutrition (EN) is the preferred mode of nutritional support. Feeding algorithms that optimize EN should be encouraged and must include: assessment and monitoring of nutritional status, selection of feeding route, time to initiate and advance EN, management strategies for EN intolerance and indications for using parenteral nutrition (PN). Despite heterogeneity in nutritional status of patients, availability of resources and diversity of cultures, PICUs in the region should consider involvement of dieticians and/or nutritional support teams.Robust evidence for several aspects of optimal nutrition therapy in PICUs is lacking. Nutritional assessment must be implemented to document prevalence and impact of malnutrition. Nutritional support must be given greater priority in PICUs, with particular emphasis in optimizing EN delivery.背景与目的：亚太中东地区儿科重症监护病房（PICU）营养治疗的现状和可用 资源与西方国家不同。现有的对危重症儿童营养管理的指南可能不能直接用于这 一地区。本文概述了亚太中东共识工作组制定的儿科重症监护环境下营养治疗的 共识声明，描述了这一地区独特的挑战和建议。方法与研究设计：系统检索了 2004-2014 年间的文献，形成了PICU 营养应用关键领域的共识声明。本综述重 点关注适用于亚太中东地区的证据。推荐的证据和强度的质量是根据推荐评估、 制定和评价方法的分级评分的。结果：肠内营养（EN）是首选的营养支持模 式、应鼓励最优化EN，其必须包括：评估和检测营养状态、给食途径的选择、 开始和增加EN 的时间、EN 不耐受的管理策略和使用肠外营养的适应症。因为 存在患者营养状态的异质性、资源的可用性和文化的多样性，这个地区的PICU 应该考虑营养师和/或营养团队的参与。结论：PICU 最佳营养治疗几个方面强有 力的证据是不足的。营养评估必须落实到患病率的记录和营养不良的影响。 PICU 必须优先考虑营养支持，尤其强调最优化EN 的应用。.

We investigated whether diagnostic categories and presence of infections were associated with increased mortality or length of stay (LOS) in patients admitted to a pediatric intensive care unit (PICU).A retrospective study of all PICU admissions between October 2002 and April 2016 was performed. Oncologic vs nononcologic, trauma/injuries vs nontraumatic, infectious (gram-positive, gram-negative, fungal bloodstream infections, common respiratory viruses) vs noninfectious diagnoses were evaluated for survival and LOS.Pediatric intensive care unit admissions (n = 2211) were associated with a mortality of 5.3%. Backward binary logistic regression showed that nonsurvival was associated with leukemia (odds ratio [OR], 4.81; 95% confidence interval [CI], 2.2-10.10; P.0005), lymphoma (OR, 21.34; 95% CI, 3.89-117.16; P.0005), carditis/myocarditis (OR, 7.91; 95% CI, 1.98-31.54; P = .003), encephalitis (OR, 6.93; 95% CI, 3.27-14.67; P.0005), bloodstream infections with gram-positive organisms (OR, 5.32; 95% CI, 2.67-10.60; P.0005), gram-negative organisms (OR, 8.23; 95% CI, 4.10-16.53; P.0005), fungi (OR, 3.93; 95% CI, 1.07-14.42; P = .039), and pneumococcal disease (OR, 3.26; 95% CI, 1.21-8.75; P = .019). Stepwise linear regression revealed that LOS of survivors was associated with bloodstream gram-positive infection (B = 98.2; 95% CI, 75.7-120.7; P.0005).Patients with diagnoses of leukemia, lymphoma, cardiomyopathy/myocarditits, encephalitis, and comorbidity of bloodstream infections and pneumococcal disease were significantly at risk of PICU mortality. Length of stay of survivors was associated with bloodstream gram-positive infection. The highest odds for death were among patients with leukemia/lymphoma and bloodstream coinfection. As early diagnosis of these childhood malignancies is desirable but not always possible, adequate and early antimicrobial coverage for gram-positive and gram-negative bacteria might be the only feasible option to reduce PICU mortality in these patients. In Hong Kong, a subtropical Asian city, none of the common respiratory viruses were associated with increased mortality or LOS in PICU.

BACKGROUND: Uncontrolled bleeding continues to be a major cause of mortality in trauma, cardiac surgery, postpartum hemorrhage and liver failure. The aim of this paper is to assess the evidence supporting the efficacy of activated recombinant factor VII (rFVIIa) administration in these settings. METHODS: Electronic literature search. RESULTS: Numerous retrospective trials have mostly shown a decrease in blood transfusion requirements with no increase in thromboembolic events (TEE), but major limitations in trial design make generalization difficult. In most retrospective reports rFVIIa has been administered as a last-ditch attempt to control bleeding, when acidosis, hypothermia and coagulation factor depletion may not allow optimal rFVIIa effect. Prospective randomized controlled trials have not shown any effect of rFVIIa on mortality or TEE, although some have shown a reduction in RBC requirement. CONCLUSION: Stipulated transfusion protocols in prospective trials have reduced anticipated mortality among controls and make future trials for mortality effect unlikely in view of large sample size requirements. Establishment of these protocols and rapid hemostasis are likely to have greater benefits than administration of a single agent.

A 25-year-old Chinese man presented with a 2-year history of recurrent coma. His plasma ammonia level was extremely elevated, with raised citrulline level and absence of argininosuccinic acid. Adult-onset citrullinaemia, a condition rarely reported outside the Japanese population, was diagnosed. Serial magnetic resonance (MR) imaging, including diffusion-weighted (DW) studies, showed initial involvement of the insula cortex and cingulate gyrus, changing to a pattern of multiple small lesions in the depths of the cortical sulci. This changing pattern of lesions over time on DW MR imaging has not previously been described in adult-onset citrullinaemia.

Introduction Up to 30% of patients with hemophilia A and 5% of patients with hemophilia B develop neutralizing antibodies (inhibitors) against replacement factor VIII or factor IX, respectively. Acute bleeding episodes in these patients with inhibitors are treated with bypassing agents, which include activated recombinant factor VII (rFVIIa). BAY 86-6150 is a modified rFVIIa which in preclinical studies was shown to have prolonged half-life and improved potency compared with currently available rFVIIa. In a phase 1, randomized, double-blind trial, BAY 86-6150 was not associated with any clinically significant adverse events (AEs). We report the immunologic response to BAY 86-6150 in a phase 2/3 clinical trial in patients with hemophilia with inhibitors. Methods TRUST (Treatment with Unique Recombinant FVII Study) was a multicenter, open-label, 2-part study (part A and part B) which included males aged 12−62 years with moderate or severe hemophilia A or B, with a history of high-titer inhibitors (≥5 Bethesda units), and ≥4 bleeding episodes in the 6 months prior to enrollment. Part A was a sequential dose-escalation study of 4 BAY 86-6150 dose levels (6.5, 20, 50, and 90 μg/kg body weight; n≥10/cohort). Dose escalation was dependent on both efficacy and an Independent Data Monitoring Committee (IDMC) approval of safety in 10 patients per cohort who had ≥1 bleeding episode treated with BAY 86-6150. Part B was designed as a single-arm investigation of the efficacy and safety of the recommended dose of BAY 86-6150 determined in all patients from Part A. Safety endpoints were AEs and immunogenicity. Anti-drug antibody testing was performed at screening (prior to exposure), after the second exposure, then every fifth exposure, and at the end of study visit in both part A and part B. Anti-BAY 86-6150 binding antibodies were measured using a validated enzyme-linked immunosorbent assay (ELISA). Samples that revealed a specific immunoreactivity in this assay were further characterized for neutralizing activity using a validated platelet-activated clotting assay. Additional functional assays were performed to determine the cross-reactive neutralizing effect on rFVIIa (NovoSeven®) of any detected anti-BAY 86-6150 antibodies. The presence of neutralizing antibodies was considered a serious adverse event (SAE) requiring prompt IDMC review. Results In cohort 1, 10 patients (mean age, 27.4 years) were treated with 6.5 mg/kg BAY 86-6150. These patients had a total of 73 bleeding events and received a total of 84 study drug injections. No anti-drug antibodies or anti-FVIIa was detected in the patients at screening prior to exposure to the study drug. BAY 86-6150 was well tolerated in all patients with no clinical or laboratory symptoms or signs of venous thromboembolism. Binding antibodies to BAY 86-6150 were detected on a scheduled screening visit in 1 patient after 3 exposures to BAY 86-6150; these anti-BAY 86-6150 antibodies displayed neutralizing activity against BAY 86-6150 and were also cross-reactive and neutralizing for rFVIIa. The affected patient had received rFVIIa before entry into the study. At the time of diagnosis of binding and neutralizing antibodies, the affected patient was not bleeding and did not require emergency treatment. Exposure to BAY 86-6150 was stopped and the trial was terminated at the first cohort. Subsequent bleeding episodes in this patient were successfully managed with FEIBATM (Factor Eight Inhibitor Bypass Activity). No other treatment-related AEs or SAEs were reported in this study. Additionally, the IDMC has recommended safety follow-up assessments for all the patients who actively participated in the trial. Conclusions The TRUST trial has been discontinued as a precautionary measure because of potential safety concerns related to the detection of the antidrug antibodies in 1 patient. Development of neutralizing antibodies against BAY 86-6150 that had a cross-reactive neutralizing effect on rFVIIa was considered a serious risk because of the limited treatment options in patients with inhibitors. These results underline the fact that it is currently not possible to predict immunologic response based on preclinical and phase 1 studies. Disclosures: Hardtke: Bayer Pharma AG: Employment. Schroeder:Bayer Pharma AG: Employment.

Early response to therapy is the most important prognostic factor for childhood ALL. CCG investigators have shown that Day-7 and Day-14 BM blast counts were prognostically important although there is great inter-observer variability. BFM group have shown that day 8 prednisolone (PRED) response is highly predictive of the treatment outcome. While gene expression profiling (GEP) of diagnostic marrow can discern a pattern of PRED sensitivity as determined by in vitro MTT assay, the accuracy was low at only 70%. We hypothesized that changes in global GEP after therapy have a higher likelihood to predict response as the signatures of sensitivity and resistance may be unmasked during the therapy. We prospectively studied the changes in GEP using Affymetrix HG-U133A or Plus 2 chips on paired BM samples before and after 7-day course of PRED and one dose IT MTX in 58 patients with newly diagnosed or relapsed ALL. Unsupervised hierarchical clustering revealed that pre- and post- PRED samples in the patients still tended to cluster together, indicating that expression profiles of molecular subgroups were still most important. To remove intrinsic influence of molecular subtypes and identify potential signatures independent of genetic abnormalities, we subtracted Day-0 GEP from its paired Day-8 profile and retained probe sets with significant changes (≥ 10-fold). To avoid the ambiguity of variation in BM blast counting at Day-8, we divided the samples into a stringently reproducible group where “Good” PRED response was defined as that Day-8 blast count in PBL < 109/L and BM lymphoblasts ≤ 30% (n=16). “Poor” response was when Day 8 PBL ≥ 109/L (n=11). This stringently reproducible group (n=27) formed the training group to help define a distinct signature while the rest (n=31 pairs) were used as a blinded test set. 54 and 19 discriminating genes were identified by 2 independent statistical methods respectively, and an integrated predictor model was constructed based on shortlisted entries. This model predicted the PRED response with 100% accuracy for the training set using the leave-one-out cross validation but was less accurate in predicting the BM blast count in blinded test set. But intriguingly, in the blinded test set, this model predicted correctly 19 out of 21 reliable “Good” PRED responses are in CCR (91%), while among 8 predicted as “Poor” responses, only 2 are in CCR (25%). This suggests that as gene expression profiling as early as day 8 of PRED could discern the beginning of leukaemia cell death even before morphological changes are discernable and is highly correlated to eventual outcome. In conclusion, we have shown that analyses on the relative changes of gene expression profile can identify real genetic signatures indicating the sensitivity to PRED administration which is highly correlated with outcome.

Introduction: This study aimed to investigate the risk factors associated with mortality in haematopoietic stem cell transplant (HSCT) patients admitted to our paediatric intensive care unit (PICU) over an 8-year period. Materials and Methods: A retrospective chart review was conducted of all HSCT patients requiring PICU admission at our centre (a tertiary care university hospital in Singapore) from January 2002 to December 2010. Chief outcome measures were survival at the time of PICU discharge and survival at 6 months after initial PICU admission. Results: Ninety-eight patients underwent HSCT during this period; 18 patients (18%) required 24 PICU admissions post-HSCT. The overall survival to PICU discharge was 62.5%. Of those who survived discharge from the PICU, 33% died within 6 months of discharge. Non-survivors to PICU discharge had a higher incidence of sepsis (89% vs 33%, P = 0.013) and organ failure as compared to survivors (cardiovascular failure 100% vs 20%, P = 0.0003; respiratory failure 89% vs 20%, P = 0.002; and renal failure 44% vs 7%, P = 0.047). Mortality rates were higher in patients requiring mechanical ventilation (70% vs 14%, P = 0.010) and inotropic support (70% vs 14%, P = 0.010). Mortality in all patients with renal failure requiring haemodialysis (n = 4) was 100%. Presence of 3 or more organ failures was associated with 80% mortality (P = 0.003). Conclusion: Sepsis, multiple organ failure and the need for mechanical ventilation, inotropes and especially haemodialysis were associated with increased risk of mortality in our cohort of HSCT patients. Key words: Bone marrow transplantation, Outcome, Prognostic factors