Management of Spasticity in Moderate and Severe Traumatic Brain Injury: Evaluation of Clinical Practice Guidelines.

INTRODUCTION: Moderate to severe traumatic brain injury (TBI) can result in development of spasticity, which adversely affects function and quality of life. Given the foundation of optimal clinical practice is use of the best available evidence, we aimed to identify, describe, and evaluate methodological quality of evidence-based spasticity clinical practice guidelines (CPGs). METHODS: A comprehensive search for CPGs encompassed electronic databases and online sources. Eligible CPGs were evaluated using the validated Appraisal of Guidelines for Research and Evaluation II (AGREE II) instrument. RESULTS: Five CPGs were eligible for review; 2 were specific to acquired brain injury and 1 to TBI. The 3 brain injury-specific CPGs contained 423 recommendations overall, but only 8 spasticity recommendations. On the basis of AGREE appraisals, all CPGs performed well in the areas of reporting scope and purpose; clearly presenting recommendations; including various stakeholders in the CPG development process; and reporting conflict of interest. However, only one CPG performed adequately on describing facilitators and barriers to implementation, advice, and tools on how to implement recommendations and provision of audit criteria. Intraclass correlation coefficient (ICC) for agreement between raters showed high agreement (ICC > 0.80) for most guidelines. CONCLUSION: Given the unique etiological features and treatment challenges associated with managing spasticity after TBI, more TBI-specific spasticity CPGs are required. These should incorporate information on the facilitators and barriers to implementation, advice on implementing recommendations, and audit criteria.

Use and definitions of perioperative mortality rates in low-income and middle-income countries: a systematic review.

BACKGROUND: Aggregate and risk-stratified perioperative mortality rates (POMR) are well-documented in high-income countries where surgical databases are common. In many low-income and middle-income country (LMIC) settings, such data are unavailable, compromising efforts to understand and improve surgical outcomes. We undertook a systematic review to determine how POMR is used and defined in LMICs and to inform baseline rates. METHODS: We searched PubMed for all articles published between Jan 1, 2009, and Sept 1, 2014, reporting surgical mortality in LMICs. Search criteria, inclusion and exclusion criteria, and study assessment methodology are reported in the appendix. Titles and abstracts were screened independently by two reviewers. Full-text review and data extraction were completed by four trained clinician coders with regular validation for consistency. We extracted the definition of POMR used, clinical risk scores reported, and strategies for risk adjustment in addition to reported mortality rates. FINDINGS: We screened 2657 abstracts and included 373 full-text articles. 493 409 patients in 68 countries and 12 surgical specialties were represented. The most common definition for the numerator of POMR was in-hospital deaths following surgery (55·3%) and for the denominator it was the number of operative patients (96·2%). Few studies reported preoperative comorbidities (41·8%), ASA status (11·3%), and HIV status (7·8%), with a smaller proportion stratifying on or adjusting mortality for these factors. Studies reporting on planned procedures recorded a median mortality of 1·2% (n=121 [IQR 0·0-4·7]). Median mortality was 10·1% (n=182 [IQR 2·5-16·2) for emergent procedures. INTERPRETATION: POMR is frequently reported in LMICs, but a standardised approach for reporting and risk stratification is absent from the literature. There was wide variation in POMR across procedures and specialties. A quality assessment checklist for surgical mortality studies could improve mortality reporting and facilitate benchmarking across sites and countries. FUNDING: None.

Effect of food on selumetinib pharmacokinetics and gastrointestinal tolerability in adolescents with neurofibromatosis type 1-related plexiform neurofibromas.

Background: Selumetinib is approved for the treatment of pediatric patients with neurofibromatosis type 1 (NF1) who have symptomatic, inoperable plexiform neurofibromas (PN) in multiple countries, including the USA (≥ 2 years). Until recently, individuals had to take selumetinib twice daily (BID) in a fasted state. This study evaluated the effect of a low-fat meal on selumetinib PK parameters and gastrointestinal (GI) tolerability in adolescent participants with NF1-PN. Methods: Eligible participants aged ≥ 12 to < 18 years took 25 mg/m2 selumetinib BID with a low-fat meal (T1) for 28 days, followed by a 7-day washout, and then administration in a fasted state (T2) for another 28 days. Primary objectives were to evaluate the effect of a low-fat meal on AUC0-12,ss and GI tolerability after multiple selumetinib doses in T1 versus T2. Key secondary objectives were additional PK parameters and adverse events (AEs). Results: At primary data cut-off, all 24 participants completed T1, and 23 participants completed T2. There were no significant differences in AUC0-12,ss between T1 and T2. In T1 and T2, 29.2% and 33.3% participants, respectively, reported ≥ 1 GI AE. No GI AEs Grade ≥ 3, or serious AEs, or GI AEs resulting in treatment interruptions, discontinuation, or dose reductions were reported in T1 and T2. Conclusions: Dosing selumetinib with a low-fat meal had no clinically relevant impact on selumetinib AUC0-12,ss nor GI tolerability in adolescents with NF1-PN. Trial registration ClinicalTrialsgov ID: NCT05101148.

Identification of an amino-terminus determinant critical for ryanodine receptor/Ca2+ release channel function.

AIMS: The cardiac ryanodine receptor (RyR2), which mediates intracellular Ca2+ release to trigger cardiomyocyte contraction, participates in development of acquired and inherited arrhythmogenic cardiac disease. This study was undertaken to characterize the network of inter- and intra-subunit interactions regulating the activity of the RyR2 homotetramer. METHODS AND RESULTS: We use mutational investigations combined with biochemical assays to identify the peptide sequence bridging the ß8 with ß9 strand as the primary determinant mediating RyR2 N-terminus self-association. The negatively charged side chains of two aspartate residues (D179 and D180) within the ß8-ß9 loop are crucial for the N-terminal inter-subunit interaction. We also show that the RyR2 N-terminus domain interacts with the C-terminal channel pore region in a Ca2+-independent manner. The ß8-ß9 loop is required for efficient RyR2 subunit oligomerization but it is dispensable for N-terminus interaction with C-terminus. Deletion of the ß8-ß9 sequence produces unstable tetrameric channels with subdued intracellular Ca2+ mobilization implicating a role for this domain in channel opening. The arrhythmia-linked R176Q mutation within the ß8-ß9 loop decreases N-terminus tetramerization but does not affect RyR2 subunit tetramerization or the N-terminus interaction with C-terminus. RyR2R176Q is a characteristic hypersensitive channel displaying enhanced intracellular Ca2+ mobilization suggesting an additional role for the ß8-ß9 domain in channel closing. CONCLUSION: These results suggest that efficient N-terminus inter-subunit communication mediated by the ß8-ß9 loop may constitute a primary regulatory mechanism for both RyR2 channel activation and suppression.

Long-term treatment with botulinum toxin type A in cervical dystonia has low immunogenicity by mouse protection assay.

To evaluate the immunogenicity of botulinum toxin type A (BoNTA; BOTOX) in cervical dystonia (CD). Subjects diagnosed with CD for > or =1 year and previously naïve to BoNTs were treated with BoNTA in a prospective, open-label, multicenter study. Serum samples were analyzed for BoNTA neutralizing antibodies using the Mouse Protection Assay (MPA). Clinical resistance was assessed with a test injection of 20 U BoNTA placed unilaterally into the frontalis (Frontalis Antibody Test; FTAT) or corrugator muscle (Unilateral Brow Injection; UBI). Efficacy was assessed and adverse events were recorded. Of 326 subjects enrolled, 251 (77%) completed the study. Subjects received a median of 9 BoNTA treatments (mean dose per session ranged from 148.4 to 213.0 U over a mean of 2.5 years [range: 3.2 months-4.2 years]). Only 4 of 326 subjects (1.2%) tested positive for antibodies in the MPA; three of these subjects stopped responding clinically to BoNTA (of whom one also showed clinical resistance in the FTAT) and one continued to respond. Consistent improvements in the signs/symptoms of CD were noted. The most frequent treatment-related adverse events were mild to moderate weakness, dysphagia, neck pain, and injection-site pain. The current formulation of BoNTA rarely causes neutralizing antibody formation in CD subjects treated < or =4 years.

Perioperative mortality rates in low-income and middle-income countries: a systematic review and meta-analysis.

INTRODUCTION: The Lancet Commission on Global Surgery proposed the perioperative mortality rate (POMR) as one of the six key indicators of the strength of a country's surgical system. Despite its widespread use in high-income settings, few studies have described procedure-specific POMR across low-income and middle-income countries (LMICs). We aimed to estimate POMR across a wide range of surgical procedures in LMICs. We also describe how POMR is defined and reported in the LMIC literature to provide recommendations for future monitoring in resource-constrained settings. METHODS: We did a systematic review of studies from LMICs published from 2009 to 2014 reporting POMR for any surgical procedure. We extracted select variables in duplicate from each included study and pooled estimates of POMR by type of procedure using random-effects meta-analysis of proportions and the Freeman-Tukey double arcsine transformation to stabilise variances. RESULTS: We included 985 studies conducted across 83 LMICs, covering 191 types of surgical procedures performed on 1 020 869 patients. Pooled POMR ranged from less than 0.1% for appendectomy, cholecystectomy and caesarean delivery to 20%-27% for typhoid intestinal perforation, intracranial haemorrhage and operative head injury. We found no consistent associations between procedure-specific POMR and Human Development Index (HDI) or income-group apart from emergency peripartum hysterectomy POMR, which appeared higher in low-income countries. Inpatient mortality was the most commonly used definition, though only 46.2% of studies explicitly defined the time frame during which deaths accrued. CONCLUSIONS: Efforts to improve access to surgical care in LMICs should be accompanied by investment in improving the quality and safety of care. To improve the usefulness of POMR as a safety benchmark, standard reporting items should be included with any POMR estimate. Choosing a basket of procedures for which POMR is tracked may offer institutions and countries the standardisation required to meaningfully compare surgical outcomes across contexts and improve population health outcomes.

Interprofessional student teams augmenting service provision in residential aged care.

The aim of this study was to determine the usefulness of student-led interprofessional consultations within residential aged care in augmenting patient care and enhancing student education. Volunteer fourth and final year health-care students conducted interprofessional consultations. In a mixed methods design, residents' health-care changes and perspectives were collected prospectively, and student and educator perceptions were measured by survey and interview. Sixteen aged care residents were consulted by interprofessional teams. Students identified two new health issues and proposed 17 recommendations for referrals and five changes to medication management. At six-weeks follow-up, two recommendations had been acted upon clinically, and two medication changes had been implemented. Reasons for the low uptake of recommendations were determined. Residents, students and educators reported high levels of satisfaction. Residential care facilities offer a useful interprofessional learning environment. Student consultations are positively regarded by patients, students and educators and may augment existing health services.

Examining potential barriers to early intervention access in Australian hearing impaired children.

OBJECTIVES: Early intervention for children with hearing loss involves assistance in oral speech development, optimal use of hearing devices and fostering a holistic partnership between allied health and the children's families. Adequate access to early intervention has been shown to be vital in the positive development of long term language and social outcomes. However, there has been limited research to identify the factors which may influence access. This study aimed to explore whether access to early intervention by children with hearing loss is affected by: geographical location, socio-economic status and ethnic-minority family status. METHODS: A cross-sectional research design was used in this study incorporating a survey of early intervention coordinators and an audit of an organization database. All (N=11) early intervention coordinators at an "Oral Language Centre for Deaf Children" in the state of Victoria, Australia were surveyed on whether child clients (N=133) were accessing an appropriate level of early intervention corresponding to their level of hearing loss. The length of time for each child to enroll for early intervention following diagnosis was obtained from the database of the organization. Potential differences in access between geographical groups, between socio-economic status groups and between ethnic-minority and non-minority groups were analyzed using inferential statistics. RESULTS: Closer geographical proximity to early intervention services was associated with more appropriate (P=.000) and more prompt (P=.005) access. No difference in access to early intervention was detected for different socio-economic status groups. Although, ethnic-minority family status was not shown to influence the level of access, it took a significantly longer time for ethnic-minority families to enroll for early intervention compared to non-minority families (P=.04). CONCLUSIONS: Findings suggest that geographical proximity and ethnic-minority family status, instead of socio-economic status, are more likely to be potential barriers to early intervention access in children with hearing loss. From the health promotion perspective, attention should be directed towards these potential barriers.