Principles of Bracing in the Early Management of Developmental Dysplasia of the Hip

Bracing is considered a gold standard in treating Developmental Dysplasia of the Hip (DDH) in infants under 6 months of age with reducible hips. A variety of braces are available that work on similar principles of limiting hip adduction and extension. This paper summarises the current evidence regarding bracing in DDH. Most of the literature pertains to the Pavlik harness (PH) and there are few studies for other brace types. Bracing eliminates dislocating forces from the hamstrings, the block to reduction of the psoas and improves the muscle line of pull to stabilise the hip joint. Recent studies have shown no benefit in bracing for stable dysplasia. The rates of PH treatment failure in Ortolani-positive hips have been reported to be high. Barlow positive hips have lower Graf grades and are more amenable to PH treatment. There is consensus that the earlier the diagnosis of DDH and initiation of PH treatment, the better the outcome. Failure rates due to unsuccessful reduction and AVN are higher with treatment initiated after age 4–6 months. Studies have shown no benefits of staged weaning of braces. While there is no maximum time in brace, current consensus suggests a minimum of 6 weeks. The key to successful bracing lies in education and communication with the family.     

Diagnosis of hypertension: Ambulatory pediatric American Heart Association/European Society of Hypertension versus blood pressure load thresholds

The agreement between the traditionally‐used ambulatory blood pressure (ABP)‐load thresholds in children and recently‐recommended pediatric American Heart Association (AHA)/European Society of Hypertension (ESH) ABP thresholds for diagnosing ambulatory hypertension (AH), white coat hypertension (WCH), and masked hypertension (MH) has not been evaluated. In this cross‐sectional study on 450 outpatient participants, the authors evaluated the agreement between previously used ABP‐load 25%, 30%, 40%, 50% thresholds and the AHA/ESH thresholds for diagnosing AH, WCH, and MH. The American Academy of Pediatrics thresholds were used to diagnose office hypertension. The AHA threshold diagnosed ambulatory normotension/hypertension closest to ABP load 50% in 88% (95% CI 0.79, 0.96) participants (k 0.67, 95% CI 0.59, 0.75) and the ESH threshold diagnosed ambulatory normotension/hypertension closest to ABP load 40% in 86% (95% CI 0.77, 0.94) participants (k 0.66, 95% CI 0.59, 0.74). In contrast, the AHA/ESH thresholds had a relatively weaker agreement with ABP load 25%/30%. Therefore, the diagnosis of AH was closest between the AHA threshold and ABP load 50% (difference 3%, 95% CI ‐2.6%, 8.6%, p = .29) and between the ESH threshold and ABP load 40% (difference 4%, 95% CI ‐2.1%, 10.1%, p = .19) than between the AHA/ESH and ABP load 25%/30% thresholds. A similar agreement pattern persisted between the AHA/ESH and various ABP load thresholds for diagnosing WCH and MH. The AHA and ESH thresholds diagnosed AH, WCH, and MH closest to ABP load 40%/50% than ABP load 25%/30%. Future outcome‐based studies are needed to guide the optimal use of these ABP thresholds in clinical practice.     

ProKinO: A Unified Resource for Mining the Cancer Kinome

Protein kinases represent a large and diverse family of evolutionarily related proteins that are abnormally regulated in human cancers. Although genome sequencing studies have revealed thousands of variants in protein kinases, translating “big” genomic data into biological knowledge remains a challenge. Here, we describe an ontological framework for integrating and conceptualizing diverse forms of information related to kinase activation and regulatory mechanisms in a machine readable, human understandable form. We demonstrate the utility of this framework in analyzing the cancer kinome, and in generating testable hypotheses for experimental studies. Through the iterative process of aggregate ontology querying, hypothesis generation and experimental validation, we identify a novel mutational hotspot in the αC‐β4 loop of the kinase domain and demonstrate the functional impact of the identified variants in epidermal growth factor receptor (EGFR) constitutive activity and inhibitor sensitivity. We provide a unified resource for the kinase and cancer community, ProKinO, housed at http://vulcan.cs.uga.edu/prokino .     

Antimicrobial dosing in critically ill patients with sepsis-induced acute kidney injury

Severe sepsis often leads to multiple organ dysfunction syndromes (MODS) with acute kidney injury (AKI). AKI affects approximately, 35% of Intensive Care Unit patients, and most of these are due to sepsis. Mortality rate of sepsis-induced AKI is high. Inappropriate use of antimicrobials may be responsible for higher therapeutic failure, mortality rates, costs and toxicity as well as the emergence of resistance. Antimicrobial treatment is particularly difficult due to altered pharmacokinetic profile, dynamic changes in patient''s clinical status and, in many cases, need for renal replacement therapy. This article aims to describe the appropriate antimicrobial dosing and reviews the factors contributing to the difficulties in establishing precise guidelines for antimicrobial dosing in sepsis-induced AKI patients. Search strategy: Text material was collected by systematic search in PubMed, Google (1978–2013) for original articles.     

The HONEYPOT Randomized Controlled Trial Statistical Analysis Plan

♦ Background: The HONEYPOT study is a multicenter, open-label, blinded-outcome, randomized controlled trial designed to determine whether, compared with standard topical application of mupirocin for nasal staphylococcal carriage, exit-site application of antibacterial honey reduces the rate of catheter-associated infections in peritoneal dialysis patients.♦ Objective: To make public the pre-specified statistical analysis principles to be adhered to and the procedures to be performed by statisticians who will analyze the data for the HONEYPOT trial.♦ Methods: Statisticians and clinical investigators who were blinded to treatment allocation and treatment-related study results and who will remain blinded until the central database is locked for final data extraction and analysis determined the statistical methods and procedures to be used for analysis and wrote the statistical analysis plan. The plan describes basic analysis principles, methods for dealing with a range of commonly encountered data analysis issues, and the specific statistical procedures for analyzing the primary, secondary, and safety outcomes.♦ Results: A statistical analysis plan containing the pre-specified principles, methods, and procedures to be adhered to in the analysis of the data from the HONEYPOT trial was developed in accordance with international guidelines. The structure and content of the plan provide sufficient detail to meet the guidelines on statistical principles for clinical trials produced by the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use.♦ Conclusions: Making public the pre-specified statistical analysis plan for the HONEYPOT trial minimizes the potential for bias in the analysis of trial data and the interpretation and reporting of trial results.Key words: Randomized controlled trial, statistical analysis plan, outcome reporting bias, pre-specified statistical analyses, International Conference on Harmonization, intention-to-treat, catheter-associated infectionsThe HONEYPOT study is a multicenter randomized controlled trial of exit-site application of antibacterial honey for the prevention of catheter-associated infections in peritoneal dialysis (PD) patients (1). The trial is registered with the Australian New Zealand Clinical Trials Registry (No. 12607000537459). The primary hypothesis is that, in PD patients, daily exit-site application of standardized antibacterial honey in addition to daily cleansing per standard practice will lengthen the time to a catheter-associated infection (exit site, tunnel, peritonitis) relative to daily cleansing and topical mupirocin prophylaxis in nasal staphylococcal carriers. The trial began recruiting patients in August 2008 and reached its recruitment target in June 2011. The final follow-up visit was conducted in June 2012. The central database is expected to be ready for analysis by December 2012.The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) recommends that data from clinical trials be analyzed according to a pre-specified statistical analysis plan (SAP) (2). The ICH recommendation aims to promote appropriate analysis and reporting of trial data and avoidance of the bias that can arise from data-driven specification of analyses and selective reporting of statistical results. Some authors have taken the ICH guidelines a step further by suggesting that a pre-specified SAP should be a requirement rather than merely a recommendation and that the SAP should be placed in the public domain before the people responsible for performing the analyses have access to unblinded data (3).The SAP for the HONEYPOT trial has been developed and finalized without knowledge of treatment allocation and treatment-related study results. The plan describes the pre-specified statistical analysis principles to be adhered to and the procedures to be performed by statisticians responsible for analyzing the trial data. The present report describes important features of the trial design and the statistical methods and procedures included in the analysis plan.     

Experimental spinal cord ischemia: model characterization and improved outcome with arterial hypertension

OBJECTIVE: Paraplegia from spinal cord ischemia is a devastating complication of thoracoabdominal aortic aneurysm repair. Perioperative hypoperfusion of the spinal cord is a critical determinant of residual neurologic deficits. We determined if functional and histologic outcome is dependent on systemic blood pressure in a rat model of spinal cord ischemia. DESIGN: Randomized, controlled, prospective study. SETTING: Research laboratory at a university teaching hospital. SUBJECTS: Adult male Wistar rats. INTERVENTIONS: Endotracheally intubated adult male Wistar rats (300-450 g) anesthetized with halothane underwent a thoracotomy and placement of a clip across the descending aorta for 27 mins. Mean proximal arterial blood pressure (MPABP) was monitored with a cannula placed in the left common carotid artery. Halothane was adjusted (1.25-1.5%) to maintain MPABP between 70 and 90 mm Hg (n = 20) or 140 and 150 mm Hg (n = 20). Shamoperated rats (n = 10) had a thoracotomy without aortic clamping at an MPABP of 70-90 mm Hg. Following 1, 24, 48, and 72 hrs of recovery from anesthesia, motor function of the hind paws was scored as follows: 0, no evidence of deficit; 1, toes flat under body when walking but with ataxia; 2, knuckle walks; 3, movements in hind limbs but unable to knuckle walk; 4, no movement, drags hind limbs. Body temperature was maintained between 37 and 38 degrees C throughout the experiment. MEASUREMENTS AND MAIN RESULTS: All sham operated rats with MPABP 70-90 mm Hg recovered without neurologic deficits, whereas those that underwent aortic occlusion with MPABP between 70 and 90 mm Hg emerged from anesthesia with grade 3 and 4 deficits and remained in this condition without improvement at 72 hrs. Histopathology at 72 hrs demonstrated moderate to severe neuronal loss with involvement of dorsal, intermediate, and ventral horns. Only eight of 20 rats that underwent aortic occlusion with MPABP between 140 and 150 mm Hg had grade 1 and 2 deficits on emergence but had no neurologic deficit after 1 hr. Most of the surviving neurons in these animals appeared normal histologically, particularly motor neurons around the periphery of the ventral horn. CONCLUSIONS: Systemic blood pressure is a critical determinant of outcome following spinal cord ischemia, and controlled peri-operative blood pressure augmentation may ameliorate neurologic deficits in patients who undergo thoracoabdominal vascular procedures and are at risk for spinal cord hypoperfusion.