Conservative Arm Research Articles

The complete mitochondrial genome of the Epinephelus polyphekadion (Teleostei, Serranidae)

In this study, the complete mitochondrial genome of the Epinephelus polyphekadion has been sequenced by the next-generation sequencing (NGS) techniques strategy. The mitochondrial genome is 16,691 bp in length and consists of 13 protein-coding genes, 2 rRNA genes, 22 tRNA genes and a control region. The nucleotide compositions of the light strand are 27.90% A, 29.05% T, 27.48% G and 15.58% C. With the exception of ND6 and eight tRNA genes, all other mitochondrial genes are encoded on the heavy-strand (H-strand). All the tRNAs have clover secondary structure with conservative anticodon arm, TΨC arm and D arm except for tRNA-Ser(GCT) and tRNA-Pro(TGG), which D arm consists of 13 bp and 7 bp single-base, respectively. Phylogenetic tree showed that E. latifasciatus, E. polyphekadion, E. epistictus, E. akaara and E. stictus of the Epinephelus formed a monophyletic group, whereas E. latifasciatus, E. polyphekadion and E. epistictus formed a sister group.

Systemic steroids in COPD-the beauty and the beast

The recommendations regarding the use of systemic steroids in COPD differ substantially depending on the phase of the disease. In moderate and severe acute exacerbations oral steroids are advocated based on the findings of several placebo-controlled trials that have been performed in secondary-care settings: these studies showed that systemic steroids improve lung function, dyspnoea and gas exchange. In addition, steroid use resulted in fewer treatment failures, a lower relapse rate and shorter hospital stays [1-4]. Importantly, giving steroids orally is non-inferior to the i.v. application [5] and an 8-week treatment is not superior to a 2-week therapy [6]. Recently, it could even be shown that 5-day treatment is non-inferior to a 14-day course [7]. In the trial with longer term therapy [6] hyperglycemia requiring treatment was identified as considerable side effect, in the other trials no major adverse events were observed. In contrast, in stable COPD positive effects of systemic steroids are scarce: there is some evidence that higher doses (≥ 30 mg prednisolone/day) may improve lung function over a short period, whereas this was not observed in doses of less than 10–15 mg prednisolone/day [8]. In a 2-year trial with 5 mg prednisolone + 1600 μg budesonide/day efficacy regarding lung function decline was not significantly better than budesonide alone [9]. In addition, there are substantial side effect problems. In particular, it is well established that respiratory and peripheral muscle strength [10] are affected. This is caused by a myopathy that is characterized by atrophy and necrosis [11] and may lead to reduced survival. Besides, there is evidence that chronic therapy with systemic steroids is one of the risk factors for the high rate of osteoporosis that is observed in COPD [12]. What does the paper by Horita et al. published in this issue of the journal [13] add to the literature? To my knowledge this is the first analysis that systematically evaluates the effects of systemic steroids on mortality in a considerable sample of COPD patients with severe and very severe COPD. The authors analyzed patients (N = 444) that had been randomized to the conservative treatment arm in the National Emphysema Treatment trial (NETT). They calculated a hazard ratio for death of 1.54 for the steroid user group. Then, in order to make sure that this result was not induced by unidentified confounders they performed a propensity score matching. Based on this analysis the hazard ratio for death in the steroid group was 1.73. Thus, the observed effect seems to be robust and real. Nevertheless, the authors righteously mention several potential weaknesses of their study: a) it is not prospective, but a prospective trial with this endpoint does not seem feasible, b) the steroid dose was not verified, c) only patients with an FEV1 ≤ 45% predicted had been included in the NETT trial, but logic tells that systemic steroids should only be considered when all other therapies are not sufficiently effective and it is quite unlikely that this occurs in patients with a moderate lung function impairment. It is quite worrisome though that in the NETT trial only a minority of the patients were treated with long acting bronchodilators. In summary, the study results support the recommendations in guidelines and strategy documents to stay away from the chronic use of systemic steroids in COPD [14]. As a consequence, in patients in stable condition that are currently treated with systemic steroids this therapy should be tapered/stopped. This can be quite demanding: patients may develop fatigue, low blood pressure, joint pain, weakness and even psychotic symptoms [15]. Importantly, discontinuation of chronic systemic steroid therapy did not result in an increase of COPD exacerbations [16]. There is only one scenario where steroid cessation may be harmful: some patients with an asthma-COPD overlap may profit from long-term use of systemic steroids [17] and may get worse when steroids are stopped. Based on the cited literature and supported by the findings of Horita et al. [13] there are some simple messages regarding the use of systemic steroids in COPD: a) in moderate or severe acute exacerbations oral steroids should be prescribed in a moderate dose (40 mg prednisolone) for 5 days, b) there is no place for systemic steroids in stable phase COPD, c) in patients treated with systemic steroids outside of an exacerbation steroid treatment should be withdrawn, d) before doing so therapy should be optimized and patients should be re-evaluated to make sure that they do not have an asthma-COPD overlap.

993

Introduction: In critical illness, hyperglycemia is associated with organ dysfunction and failure, morbidity and mortality. Although not thoroughly evaluated in children, evidence from existing randomized controlled trials contradictory. Most trials in adults suggest that strict glycemic control results in improved outcomes compared to conservative control. Methods: This was a 2-center prospective randomized controlled trial which enrolled children 1month-18 years old who were admitted to the medical/surgical ICU (PICU) or cardiac ICU (CICU) and was receiving on mechanical ventilation, vasopressors or both. After admission to the ICU blood glucose was screened regularly. Once patients became hyperglycemic (BG > 140mg/dL), patients were randomly assigned to undergo either strict glucose control using an insulin infusion with a target blood glucose of 80-140mg/dL or conservative control with a target <220mg/dL with ICU unit (PICU vs CICU) as the stratification. Our primary endpoint was the change in PELOD from day of enrollment (day 0) to day 6 or ICU discharge (whichever came first). Results: We randomized 153 patients where 75 were assigned to the conservative arm and 78 to the strict arm. Average decrease in PELOD did not differ by strict and conservative arms (4.5 vs 6.5, respectively) . However, for CICU patients (n=121), the average decrease in PELOD of 9.3 in the strict arm was significantly greater than the average decrease of 4.6 in the conservative arm (p=.0384). The change in PELOD for PICU patients (n=32) did not significantly differ. No difference was observed in secondary outcomes such as mortality or length of stay (LOS). A total of 6 deaths were observed with 2 (2.7%) on the conservative arm and 4 (5.1%) on the strict arm (p=.6816). For CICU patients, ICU LOS average was 4.4d vs 3.6d in the conservative arm respectively (p=.8104). In the PICU, those averages were 15.4d vs 12.5d (p=.2708) for the conservative and strict arms, respectively. Conclusions: Although this study did not meet its primary endpoint, there was no difference in the change in PELOD form day 0 to day 6/discharge overall. This study did meet a pre-specified secondary outcome where we did observe greater improvement in PELOD in the CICU patients whose blood glucose was in a target range of 80-140mg/dL without increased risk of mortality or other adverse events. This data suggests that strict glycemic control may hasten organ recovery following cardiac surgery in children. Because of low enrollment in the PICU arm, it is challenging to make definitive conclusions on this population.

The Percutaneous shunting in Lower Urinary Tract Obstruction (PLUTO) study and randomised controlled trial: evaluation of the effectiveness, cost-effectiveness and acceptability of percutaneous vesicoamniotic shunting for lower urinary tract obstruction

Congenital lower urinary tract obstruction (LUTO) is a disease associated with high perinatal mortality and childhood morbidity. Fetal vesicoamniotic shunting (VAS) bypasses the obstruction with the potential to improve outcome. To determine the effectiveness, cost-effectiveness and patient acceptability of VAS for fetal LUTO. A multicentre, randomised controlled trial incorporating a prospective registry, decision-analytic health economic model and preplanned Bayesian analysis using elicited opinions. Patient acceptability was evaluated by interview in a qualitative study. Fetal medicine departments in the UK, Ireland and the Netherlands. Pregnant women with a male singleton fetus with LUTO. In utero percutaneous VAS compared with conservative care. The primary outcome was survival to 28 days. Secondary outcome measures were survival and renal function at 1 year of age, cost of care and cost per additional life-year and per disability-free survival at the end of 1 year. The trial stopped early with 31 women randomised because of difficulties in recruitment. Of those randomised to VAS and conservative management, 3/16 (19%) and 2/15 (13%), respectively, did not receive their allocated intervention. Based on intention-to-treat analysis, survival at 28 days was higher if allocated VAS (50%) than conservative management (27%) [relative risk (RR) 1.88, 95% confidence interval (CI) 0.71 to 4.96, p = 0.27]. At 12 months survival was 44% in the VAS arm and 20% in the conservative arm (RR 2.19, 95% CI 0.69 to 6.94, p = 0.25). Neither difference was statistically significant. Of survivors at 1 year, two in the VAS arm had no evidence of renal impairment and four in the VAS arm and two in the conservative arm required medical management. One baby in the conservative arm had end-stage renal failure at 1 year. VAS was more expensive because of additional surgery and intensive care. VAS cost £15,500 per survivor at 1 year and £43,900 per disability-free year. Elicited expert opinions showed uncertainty in the effect of VAS at 28 days. In a Bayesian analysis combining elicited opinion with the results, uncertainty of the benefit of VAS remained (RR 1.31, 95% credible interval 0.84 to 2.18). The acceptability study identified visualisation of the fetus during ultrasound scanning, perceiving a personal benefit, and altruism as positive influences on recruitment. Fear of the VAS procedure and the perceived severity of LUTO influenced non-participation. The need for more detailed information about the condition and its implications during pregnancy and following delivery was a further important finding of this research. Recruitment was hampered by logistical and regulatory difficulties, a lower incidence of LUTO and lower antenatal diagnosis rate [estimated to be 3.34 (95% CI 2.95 to 3.72) per 10,000 total births and 47%, respectively, in an associated epidemiological study] and high termination of pregnancy rates. In the registry women also demonstrated a clear preference for conservative management. Survival to 28 days and 1 year appears to be higher with VAS than with conservative management, but it is not possible to prove benefit beyond reasonable doubt. Notably, prognosis in both arms for survival and renal function is poor. VAS was substantially more costly and unlikely to be regarded as cost-effective based on the 1-year data. Parents should be counselled about the risks of pregnancy loss with or without VAS insertion. The National Institute for Health and Care Excellence interventional procedures guidance (IPG 202) should be updated to reflect this new evidence. Babies in the PLUTO trial should be followed up long term for the different outcomes. ISRCTN53328556. This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment ; Vol. 17, No. 59. See the NIHR Journals Library website for further project information.

Conservative Management Vs. Allogeneic Hematopoietic Cell Transplantation For Polycythemia Vera: A Systematic Review and Decision-Analysis

BackgroundConservative treatment which typically includes phlebotomy or hydroxyurea or other cytoreductive therapy (plus aspirin) (ConsRxAsa) is effective treatment with acceptable complications for management of polycythemia Vera (PV) but is not considered curative [thus resulting in a shorter life expectancy (LE) in comparison to LE in the general population]. On the other hand, an allogeneic hematopoietic cell transplantation (allo-HCT) from a HLA compatible donor is considered a curative treatment option, but is potentially associated with high-risk of life-threatening complications. We sought to answer the question of which of these two treatment options results in better survival. MethodsBecause there are no direct randomized controlled trials (RCT) addressing the question if ConsRxAsa is superior to allo-HCT, we resorted to a decision-analysis to answer this question. We constructed a Markov model to represent and analyze the decision of ConsRxAsa vs. Allo-HCT. The results of the model were expressed in terms of life expectancy (LE) and survival probabilities. We performed a systematic review (and when possible a meta-analysis) to inform parameters in the model. ConsRxAsa arm was modeled by simulating the natural history of PV. For Allo-HCT arm, we adopted our previously published model (Biol Blood Marrow Transplant 2009;15:1415-21) but modified it to evaluate the effect of both conventional and reduced-intensity allo-HCT performed in chronic phase of PV. ResultsWe identified 165 relevant articles of which only 7 described testing various treatments for PV in RCTs. However, most data used to populate the decision model came from one RCT and one cohort study. Using base case of age of 45 years, we estimated a probability of survival at 10 and 20 years of 86% and 67% for ConsRxAsa versus 55% and 32% for allo-HCT (Fig). This translates into an average LE of 17.1 years for ConsRxAsa vs. 11.6 years for allo-HCT, respectively. Sensitivity analysis according to age, early transplant-related mortality, risk of bleeding or thrombosis did not affect the results. Adopting median age of 65 years and comparing reduced-intensity allo-HCT vs. ConsRxAsa, we found that the average LE was 8.6 years for allo-HCT vs. 12.5 in the conservative treatment arm. Again, conservative treatment remained superior under a wide range of assumptions. Conclusionsintegration of current best existing evidence into the decision model shows that conservative management of PV appears to provide a better survival compared to offering an allo-HCT in chronic phase of P. Vera. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Guidelines on the management of anaemia and red cell transfusion in adult critically ill patients.

Forward This document aims to summarize the current literature guiding the use of red cell transfusion in critically ill patients and provides recommendations to support clinicians in their day-to-day practice. Critically ill patients differ in their age, diagnosis, co-morbidities, and severity of illness. These factors influence their tolerance of anaemia and alter the risk to benefit ratio of transfusion. The optimal management for an individual may not fall clearly within our recommendations and each decision requires a synthesis of the available evidence and the clinical judgment of the treating physician. This guideline relates to the use of red cells to manage anaemia during critical illness when major haemorrhage is not present. A previous British Committee for Standards in Haematology (BCSH) guideline has been published on massive haemorrhage (Stainsby et al, 2006), but this is a rapidly changing field. We recommend readers consult recent guidelines specifically addressing the management of major haemorrhage for evidence-based guidance. A subsequent BCSH guideline will specifically cover the use of plasma components in critically ill patients.

Operative vs conservative treatment of traumatic patellar dislocation: results of a prospective randomized controlled clinical trial

Patellar dislocation is a common knee injury with mainly lateral dislocations, leading to ruptures of the medial patellofemoral ligament in most of the cases. Even though several prognostic factors for patellofemoral instability have been identified so far, the appropriate therapy for patients with patellar dislocation remains a controversial issue. The purpose of this study was to compare the outcome after conservative or operative treatment in patients after first-time patellar dislocation. This randomized controlled clinical trial was designed multicentric including patients from six German orthopaedic and trauma departments. Twenty patients with a mean age of 24.6 years with first-time traumatic patella dislocation were included and randomized into either a conservative arm or an operative arm. Plain X-ray images of the knee joint (a.p. and lateral view and tangential view of both patellae) were performed in all cases prior to therapy to exclude osteochondral fragments requiring refixation. An MRI was recommended, but not compulsory. Patients were consulted after 6, 12, and 24 months with a questionnaire including the criteria of the Kujala score, recurrent dislocation, and satisfaction. The mean Kujala score of the conservative vs operative treatment group was 78.6 vs 80.3 after 6 months (p = 0.842), 79.9 vs 88.9 after 12 months (p = 0.165), and 81.3 vs 87.5 after 24 months (p = 0.339). Redislocation rate after 24 months was 37.5 % in the conservative group and 16.7 % in the operative group (p = 0.347). Due to the small number of patients that could be included, no significant difference between the groups could be detected. We see a tendency towards better results after operative treatment. Our multicentric prospective randomized controlled trial revealed no significant difference between conservative and operative treatment for patients after first-time traumatic patellar dislocation. However, a tendency towards a better Kujala score and lower redislocation rates for patients with operative treatment was observed. The small number of patients is a limiting factor of the study, leading to results without statistical significance. A meta-analysis including other study's level I data is desirable for the future.

Fluid balance in critically ill children with acute lung injury*

In the Fluid and Catheter Treatment Trial (NCT00281268), adults with acute lung injury randomized to a conservative vs. liberal fluid management protocol had increased days alive and free of mechanical ventilator support (ventilator-free days). Recruiting sufficient children with acute lung injury into a pediatric trial is challenging. A Bayesian statistical approach relies on the adult trial for the a priori effect estimate, requiring fewer patients. Preparing for a Bayesian pediatric trial mirroring the Fluid and Catheter Treatment Trial, we aimed to: 1) identify an inverse association between fluid balance and ventilator-free days; and 2) determine if fluid balance over time is more similar to adults in the Fluid and Catheter Treatment Trial liberal or conservative arms. Multicentered retrospective cohort study. Five pediatric intensive care units. Mechanically ventilated children (age≥1 month to <18 yrs) with acute lung injury admitted in 2007-2010. None. Fluid intake, output, and net fluid balance were collected on days 1-7 in 168 children with acute lung injury (median age 3 yrs, median PaO2/FIO2 138) and weight-adjusted (mL/kg). Using multivariable linear regression to adjust for age, gender, race, admission day illness severity, PaO2/FIO2, and vasopressor use, increasing cumulative fluid balance (mL/kg) on day 3 was associated with fewer ventilator-free days (p=.02). Adjusted for weight, daily fluid balance on days 1-3 and cumulative fluid balance on days 1-7 were higher in these children compared to adults in the Fluid and Catheter Treatment Trial conservative arm (p<.001, each day) and was similar to adults in the liberal arm. Increasing fluid balance on day 3 in children with acute lung injury at these centers is independently associated with fewer ventilator-free days. Our findings and the similarity of fluid balance patterns in our cohort to adults in the Fluid and Catheter Treatment Trial liberal arm demonstrate the need to determine whether a conservative fluid management strategy improves clinical outcomes in children with acute lung injury and support a Bayesian trial mirroring the Fluid and Catheter Treatment Trial.

Effect of vertebroplasty on pain relief, quality of life, and the incidence of new vertebral fractures: A 12-month randomized follow-up, controlled trial

Uncertainty regarding the benefits of vertebroplasty (VP) for the treatment of acute osteoporotic vertebral fractures has recently arisen. A prospective, controlled, randomized single-center trial (ClinicalTrials.gov registration number NCT00994032) was designed to compare the effects of VP versus conservative treatment on the quality of life and pain in patients with painful osteoporotic vertebral fractures, new fractures and secondary adverse effects were also analyzed during a 12-month follow-up period. A total of 125 patients were randomly assigned to receive conservative treatment or VP. The primary end point was to compare the evolution of the quality of life (Quality of Life Questionnaire of the European Foundation for Osteoporosis [Qualeffo-41] and pain (Visual Analogue Scale [VAS]) during a 12 month follow-up. Secondary outcomes included comparison of analgesic consumption, clinical complications, and radiological vertebral fractures at the same time points. Both arms showed significant improvement in VAS scores at all time points, with greater improvement (p = 0.035) in the VP group at the 2-month follow-up. Significant improvement in Qualeffo total score was seen in the VP group throughout the study, whereas this was not seen in the conservative treatment arm until the 6-month follow-up. VP treatment was associated with a significantly increased incidence of vertebral fractures (odds ratio [OR], 2 · 78; 95% confidence interval [CI], 1.02-7.62, p = 0.0462). VP and conservative treatment are both associated with significant improvement in pain and quality of life in patients with painful osteoporotic vertebral fractures over a 1-year follow-up period. VP achieved faster pain relief with significant improvement in the pain score at the 2-month follow-up but was associated with a higher incidence in vertebral fractures.

Conservative Versus Liberal Red Cell Transfusion in Acute Myocardial Infarction (the CRIT Randomized Pilot Study)

Red blood cell transfusion is common in patients with acute myocardial infarction (AMI). However, observational data suggest that this practice may be associated with worse clinical outcomes and data from clinical trials are lacking in this population. We conducted a prospective multicenter randomized pilot trial in which 45 patients with AMI and a hematocrit level ≤30% were randomized to a liberal (transfuse when hematocrit <30% to maintain 30% to 33%) or a conservative (transfuse when hematocrit <24% to maintain 24% to 27%) transfusion strategy. Baseline hematocrit was similar in those in the liberal and conservative arms (26.9% vs 27.5%, p = 0.4). Average daily hematocrits were 30.6% in the liberal arm and 27.9% in the conservative arm, a difference of 2.7% (p <0.001). More patients in the liberal arm than in the conservative arm were transfused (100% vs 54%, p <0.001) and the average number of units transfused per patient tended to be higher in the liberal arm than in the conservative arm (2.5 vs 1.6, p = 0.07). The primary clinical safety measurement of in-hospital death, recurrent MI, or new or worsening congestive heart failure occurred in 8 patients in the liberal arm and 3 in the conservative arm (38% vs 13%, p = 0.046). In conclusion, compared to a conservative transfusion strategy, treating anemic patients with AMI according to a liberal transfusion strategy results in more patients receiving transfusions and higher hematocrit levels. However, this may be associated with worse clinical outcomes. A large-scale definitive trial addressing this issue is urgently required.

Natural history and progression of atherosclerotic renal vascular stenosis

Date written: December 2008Final submission: October 2009

Use of bisphosphonates for the treatment of osteonecrosis as a complication of therapy for childhood acute lymphoblastic leukaemia (ALL)

Osteonecrosis is a well-recognised complication of current childhood acute lymphoblastic leukaemia (ALL) therapy. There are few studies on the medical management of osteonecrosis in this setting. We studied the therapeutic and radiological effects of oral and intravenous bisphosphonate use compared with standard care as treatment for osteonecrosis in this population. Patients who developed osteonecrosis as a complication of ALL therapy between 1994 and 2007 were treated at a single paediatric institution. Of 17 patients, 9 were commenced on bisphosphonates and 8 treated conservatively. Both groups were observed with time. Pain, analgesic requirement and musculoskeletal function were assessed monthly. Affected joints were radiologically imaged at set intervals. Each scan was graded using an ellipsoid method to give the total volume of osteonecrosis, by blinded radiologic examination. Three of six patients treated with oral alendronate showed clinical improvement. The three patients that had no improvement were subsequently treated with intravenous pamidronate. All six patients treated with intravenous pamidronate showed clinical improvement. Seven of eight conservatively treated patients deteriorated clinically. All patients demonstrated reduction in the radiological burden of osteonecrosis with time. There was no difference in the rate of reduction between conservative and bisphosphonate arms. Bisphosphonate use, in particular pamidronate, improved pain scores, analgesic requirement and musculoskeletal function in patients with osteonecrosis occurring as a complication of childhood ALL therapy. Objective radiologic benefit of bisphosphonate treatment could not be demonstrated. Risks, benefits and long-term outcome of bisphosphonate use in this population should be addressed in a larger prospective, randomised trial.

Effective Conservative Treatment for Chronic Low Back Pain

Evidence suggests that effective conservative treatment is available for chronic low back pain. The effectiveness of conservative treatment has recently received attention following publication of several randomized controlled trials (RCTs) that reported similar improvements in outcomes from cognitive intervention with exercise as from spinal fusion surgery. This paper will explore the conservative treatment arms of these RCTs with the goal of educating the reader about the principles of cognitive intervention with exercise. These principles can be incorporated into the care of chronic low back pain patients both as primary treatment and as a means of augmenting surgical outcomes.

Persistent reservations against contradicted percutaneous coronary intervention indications: Citation content analysis

Two large trials, Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) and Occluded Artery Trial (OAT), found no benefits of percutaneous coronary intervention (PCI) versus optimal medical therapy in chronic stable coronary artery disease and chronic total occlusion. We examined the stance of articles citing COURAGE and OAT to determine whether some authors continue to defend PCI despite this evidence, what persisting counterarguments are raised to express reservations, and whether specific characteristics of the citations are associated with reservations. We evaluated all citing articles entered in the Web of Science until February 1, 2008. Specific characteristics were recorded for each eligible citation, and a citation content analysis was performed. Counterarguments were categorized on participants, interventions, comparisons, and outcomes. Of 54 articles citing COURAGE and 33 articles citing OAT, 10 (19%) and 5 (15%), respectively, had an overall reserved stance. Alluded reservations included lack of power, eroded effects from crossover, selective inclusion and exclusion of specific types of patients, suboptimal clinical setting, use of bare-metal stents, suspiciously good results in the conservative treatment arm, and suboptimal outcome choices or definitions. Reserved articles were more likely than unreserved ones to have an interventional cardiologist as corresponding author (odds ratio 5.2, 95% confidence interval 1.6-17.1; P = .007) and to be commentaries focusing on one of these trials (odds ratio 3.3, 95% confidence interval 1.0-11.0; P = .05). Despite strong randomized evidence, a fraction of the literature, mostly corresponded by interventional cardiologists, continues to raise reservations about recently contradicted indications of PCI.

Non-conservative surface decoration of hemoglobin: Influence of neutralization of positive charges at PEGylation sites on molecular and functional properties of PEGylated hemoglobin

High hydrodynamic volume, high viscosity and high colloidal osmotic pressure (COP) of PEGylated hemoglobin (Hb) have been suggested to neutralize the vasoactivity of acellular Hb. Consequences of non-conservative PEGylation (positive charge of the amino groups at the PEGylation sites is neutralized) using succinimidyl-ester of propionic acid PEG5K on the properties of PEGylated Hb have now been investigated. Non-conservative PEGylation of Hb leads to a much higher increase in the COP and viscosity of Hb than conservative extension arm facilitated (EAF) PEGylation of Hb. Introduction of αα-fumaryl crosslinking decreased the COP of non-conservative PEGylated Hb by stabilization of interdimeric interactions. Compared to the EAF-PEGylated αα-fumaryl Hb, non-conservative PEGylated product shows a comparable COP and higher viscosity. Conservative PEGylation of αα-fumaryl Hb by reductive alkylation chemistry does not increase the COP to this level, but enhanced the molecular volume and viscosity comparable to EAF-PEGylated product. Thus, the molecular properties of PEGylated Hb can be fine tuned using different PEGylation platforms and provide a unique opportunity for the design of second generation PEGylated Hbs.

Improving prediction of “inevitable” surgery during non-surgical treatment of sciatica

A randomized trial showed that surgery speeds up recovery of patients suffering sciatica for 6 weeks but prolonged conservative care yields similar results at one year. However 39% of this conservative care group ultimately underwent surgery after a mean period of 18.7 weeks. We evaluated variables to improve prediction of surgery in the conservatively treated cohort. Baseline data on 142 patients enroled in the conservative treatment arm of a randomized trial were analyzed to select those that could contribute to the prediction of surgery. The actual occurrence of surgery was used as dependent outcome of interest. Variables measured at baseline included neurological examination results, the visual analogue scale for pain (VAS) and the Roland disability questionnaire (RDQ). Higher pain intensity and functional limitations at baseline were associated with an increased likelihood of surgery during follow-up. Mutually adjusted Odds Ratios of 1.7 (95% CI; 1.1–2.7) per 20 mm incremental intensification of pain on the VAS score and 1.8 (95% CI; 1.2–2.9) per 3 points of deterioration of the RDQ score quantify the increasing chance of undergoing delayed surgery. Despite maximal efforts to the contrary, surgery could not be prevented for a considerable proportion of patients in a conservatively treated cohort. Compared to those with lower scores initially, patients with more intense leg pain or higher disability scores were at higher risk to undergo delayed surgery. The individual surgical decision process is facilitated by the use of pain and disability scales complemented by patient preferences.

Early aggressive vs. initially conservative treatment in elderly patients with non-ST-elevation acute coronary syndrome: The Italian Elderly ACS study

Elderly patients represent one-third of all admissions for non-ST-elevation acute coronary syndrome (NSTEACS) in the coronary care units. Despite their high-risk characteristics and worse outcomes, compared with younger patients, the elderly receive less aggressive treatments, also due to less clear evidence regarding the most effective treatment strategy. The Italian Elderly ACS study includes patients older than 74 years of age with NSTEACS in a multicenter randomized clinical trial, comparing an early aggressive and an initially conservative approach. Patients not enrolled due to specific exclusion criteria or any other reason will be enrolled in a Registry. Centers with on-site interventional cathlab and centers without on-site cathlab refering patients to a cathlab within a consolidated percutaneous coronary intervention network. Patients admitted within 48 h of the most recent ischemic symptoms are eligible if they show transient ischemic ECG changes and/or CKMB/Tn elevation. Patients with secondary ischemia, ongoing ischemia, or heart failure, despite optimal therapy or recent coronary intervention, serum creatinine more than 2.5 mg/dl, high bleeding risk, and severe concomitant disease, are excluded from the study. Central randomization to a systematic early aggressive approach (coronary angiography within 48 h of admission and, when indicated, coronary revascularization) or an initially conservative approach (optimal medical therapy with coronary angiography in selected cases with refractory ischemia). Follow-up will include patient visits and ECG at 30 days, 6 months, and 1 year, post randomization. PRIMARY END POINT: The composite of all-cause mortality, myocardial (re)infarction, disabling stroke, and rehospitalization for cardiovascular diseases or severe bleeding within 6 months. Expected primary end point rates of 30% in the conservative arm vs. 20% in the invasive arm. According to these estimates, with two-tailed alpha of 0.05, power will be 80, 85, or 90% with 252, 289, and 338 patients per group, respectively. The goal is to enroll 700 patients from 50 centers.

Role of Extension Arm in PEG-Hb Conjugates on the Stability of the Tetramer: Non-conservative EAF Maleimide Thio-PEG Mediated PEGylation

PEGylation induced increase in colloidal osmotic pressure (COP) of Hb, one of the unique molecular properties of PEG-Hb conjugates, facilitates the neutralization of the vasoconstrictive activity of acellular Hb is a function of chemistry of conjugation of PEG-chains. The dependence of COP with the chemistry is a consequence of PEGylation induced weakening of interdimeric interactions. The conservative Extension Arm Facilitated (EAF) PEGylation exerts least influence on lowering the tetramer stability as compared to direct PEGylation. We have now designed a new, non-conservative EAF PEGylation that uses acylation chemistry to introduce the extension arm onto proteins to delineate the role of the extension arm and of the charge at the site of attachment in PEG-Hb conjugate on tetramer stability. The non-conservative EAF PEGylation does not lower the tetramer stability just as the non-conservative direct PEGylation of Hb. The impact of the extension arm in PEGylated Hb in terms of their structure and potential significance of higher tetramer stability of PEG-Hb conjugates generated by EAF-PEGylation in the in vivo toxicity and in the design of oxygen carrying plasma expander has been discussed.

A randomized trial of aggressive versus conservative phototherapy for hyperbilirubinemia in infants weighing less than 1500 g: Short- and long-term outcomes

Treatment regimens for hyperbilirubinemia vary for very low birth weight infants. The present study seeks to determine whether the initiation of conservative phototherapy is as effective as aggressive phototherapy in reducing peak bilirubin levels without increasing adverse effects. The present randomized, controlled study included infants with birth weights between 500 g and 1500 g, stratified into two birth weight groups. In one group, aggressive phototherapy was commenced by 12 h of age, while in the other group, conservative phototherapy was commenced if serum bilirubin levels exceeded 150 mumol/L. The primary outcome variables were peak serum bilirubin levels and hours of phototherapy. Secondary outcomes were age at peak bilirubin levels, number of infants with rebound hyperbilirubinemia, and number of adverse short- and long-term outcomes. Of 174 eligible infants, 95 consented to participate -49 in the conservative arm and 46 in the aggressive arm. Ninety-two infants completed the study. There was no significant difference in peak bilirubin levels except in infants who weighed less than 1000 g -171.2+/-26 mumol/L (conservative) versus 139.2+/-46 mumol/L (aggressive); P<0.02. There was no difference in duration of phototherapy or rebound hyperbilirubinemia. There were no differences in short-term adverse outcomes. Of the 87 infants who survived until hospital discharge, 82 (94%) had some follow-up and 75 (86%) attended follow-up until 18 months corrected age. The incidence of cerebral palsy, abnormal mental developmental index at 18 months corrected age, or combined outcome of cerebral palsy and death did not significantly differ between the two groups. In infants weighing less than 1000 g, peak bilirubin levels were significantly higher using conservative phototherapy regimens and there was a tendency for poor neurodevelopmental outcome.

Abstract 2804: Early Invasive Management of Acute Coronary Syndromes without ST-elevation: Relation between Rate of Invasive Therapies and Very Long-term Mortality in the Randomized Trials

Background Randomized trials evaluating an early invasive against a conservative strategy show a benefit over a conservative approach in the composite of death, MI and revascularisation/recurrent ischemia. However, the rate of invasive therapies differed significantly in the trials. Moreover, there were also large differences in the rate of invasive therapies in the invasive versus the conservative arms ( cross-over rate) in the different studies. Therefore we studied the differences in rate of invasive therapy in the study arms of the above trials, and correlated them with the benefit of the invasive therapy with regard to the very long-term mortality as recently published. Methods and Results We analyzed very long-term mortality (30,932 patient-years) in the 9 trials carried out between 1996 and 2004, which randomized 10,558 patients with non-ST-elevation acute coronary syndromes to an early invasive or an ischemia-guided conservative strategy. Differences in the revascularization rate between the invasive and conservative strategies in the trials ranged between 10% and 39%. There was no relation of the differences in revascularization between invasive and conservative strategies and the benefit on mortality whatsoever (see figure ). Conclusion Although most trials on non ST-elevation ACS reported a reduction in the composite of death, MI and revascularisation/ recurrent ischemia, an early invasive strategy does not lead to improved survival on the very long-term. There seems no relation between the difference in revascularisation rate and benefit on the very long term, which may explain the lack of efficacy of early intervention on very long-term mortality.