Use of Zoledronic Acid in the Treatment of Paget's Disease

This review examines the use of zoledronic acid in the treatment of Paget’s disease of bone. It begins with a brief discussion of the theories of pathogenesis of Paget’s disease, its clinical manifestations, and the history of bisphosphonate treatment in this disorder. Risk of oversuppression of bone by the more potent bisphosphonates and their association with avascular necrosis of the jaw are noted

Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited. Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19. Design, Setting, and Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020. Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108). Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%). Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. Conclusions and Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707

Medical care costs of Paget\u27s disease of bone in a privately insured population

INTRODUCTION: Medical care costs are difficult to calculate in diseases such as Paget\u27s disease because they have low detection rates and a wide range of clinical manifestations that commonly occur in aging patient populations. MATERIALS AND METHODS: Using 2001-2002 MarketScan Research databases, this study linked medical claims, prescription records, and encounter data on 2.8 million active and retired employees to create a longitudinal panel with 24 months of observation. Patients with Paget\u27s disease were identified by ICD-9 code 731.0. Matched controls (MC) were identified through an exact match procedure using gender, age, and predicted Medicare costs estimated with a risk adjuster. Diagnostic and expenditure records were extracted for the sample and prevalence rates calculated for 20 conditions with well-documented associations to Paget\u27s disease. Comorbidities and health care costs of Paget\u27s disease patients were compared to those of the MCs, and the differences tested using Chi-square and t tests. RESULTS: Our study identified 244 matched pairs. The average age was 72.7 years; 50.8% were female. Significantly higher comorbidities (P \u3c 0.05) were detected in Paget\u27s disease patients relative to MCs for: pathological fractures (4.9% vs. 0.4%), heart murmurs (3.3% vs. 0.4%), low back pain (19.7% vs. 8.6%), spinal stenosis (16.4% vs. 9.8%), and hearing loss (13.5% vs. 5.7%), respectively. Biannual per patient outpatient costs were significantly higher in Paget\u27s disease patients (Paget\u27s disease $9301 vs. MC$6339, P \u3c 0.05), especially for services associated with physician visits and diagnostic tests. Prescription costs for antiresportive agents and analgesics were also higher (Paget\u27s disease $1115 vs. MC$507, P \u3c 0.05). Inpatient costs (Paget\u27s disease $16,144 vs. MC$21,480) were comparable. CONCLUSION: This study is the first to describe the excessive costs of Paget\u27s disease, based on known patterns of disease expression, evaluation, and treatment

Third‐generation bisphosphonates for cochlear otosclerosis stabilizes sensorineural hearing loss in long‐term follow‐up

Objective: To assess long‐term hearing outcomes in patients treated with third‐generation bisphosphonates for otosclerosis‐related progressive sensorineural hearing loss (SNHL). Study Design Retrospective case series review Methods: We performed a retrospective case series review of patients with otosclerosis and progressive SNHL. Patients were treated with either risedronate or zoledronate after a diagnosis of otosclerosis with a significant SNHL component. Bone conduction pure tone threshold averages (BC‐PTAs) and word recognition scores (WRS) before and after bisphosphonate administration in long‐term follow‐up was analyzed. Significant change in BC‐PTA was defined as greater than 10dB or between 4% and 18% in WRS based on binomial variance. Results: Seven patients were identified and 14 ears met inclusion criteria. Three patients were female and the mean age was 48.3 ± 10.3 years. The mean duration between treatment with bisphosphonate administration and long‐term post‐treatment follow‐up audiometry was 87.6 ± 18.3 months, with a range of 61.6 to 109.1 months and median of 89.2 months. Analysis using BC‐PTA and WRS demonstrated that 11 ears remained stable while 2 improved and 1 worsened. No patient experienced any major complication as the result of bisphosphonate therapy. Conclusion: Treatment with third‐generation bisphosphonates is associated with stability in otosclerosis‐related sensorineural hearing over 5‐ to 9‐year period. These results suggest that such medications may prevent the progression of SNHL in patients with otosclerosis. Level of Evidence 4 (Case series)

Bite Size Maths: Building Mathematics Low Socioeconomic Student Capability in Regional/Remote Australia

The project, Bite size maths: Building mathematics low socioeconomic student capability in regional/remote Australia, establishes the foundations for a change in the way that online education is offered to low socioeconomic students in regional/remote Australia. The Bite size maths project is a $140,000 project funded in 2016 through the Department of Education and Training (DET) as part of the Higher Education Participation and Partnerships Programme (HEPPP) 2015 National Priorities Pool. The Bite size maths project has delivered an innovative set of interactive modules (as an online learning system) that can be used singly or linked together in a Massive Open Online Course (MOOC—http://www.bitesizemaths.net). The 20 interactive modules developed within the project provide a foundation for improvements in mathematics education across the higher education sector as well as throughout the school system in regional/remote Australia. The use of self-paced learning in the form of guided instruction and opportunities for practice have the potential to profoundly impact on the learning experiences of undergraduate students who have little or no experience in mathematics. Mathematics forms the core of multiple course structures at universities, and previous research emphasises the importance of engaging undergraduate students in building a strong mathematics foundation. This is particularly the case in regional/remote Australia where universities, like those in the Regional Universities Network (RUN), focus particularly on professional careers, such as education and health care, that require mathematical competencies. Contemporary students need to be both proficient in and comfortable with mathematics, so as to bridge the gap between curriculum and understanding the mathematics that is required in such careers. The Bite size maths project showed, for the first time, that a MOOC can be designed on the basis of studies of human cognitive architecture, in this case the principles and effects of cognitive load theory. Development and trials of five modules demonstrated that the combination of worked examples and practice questions (the worked example effect in cognitive load theory) makes a significant difference to test results of students who have little experience in mathematics. After the initial trials, a MOOC (comprised of 20 interactive modules) was built incorporating a number of improvements and innovations. These included other cognitive load effects, as well as point-of-contact feedback. This is the first time that point-of-contact feedback developed at SCU has been used as part of a MOOC. This feedback serves to let students know about their learning approaches, provides guidance on appropriate learning styles, and allows feedback from the students on how well the MOOC facilitated their learning. The end result is a set of integrated resources that can be embedded in undergraduate mathematics units as interactive modules or as a MOOC. The interactive modules in the MOOC offer course-based resources that are designed to allow students to tackle ‘bite-size chunks’ of the coursework mathematics in which they must develop expertise. The MOOC offers a self-paced introduction to key features of undergraduate mathematics, and is adaptive in that it also offers continual graded assessment and point-of-contact feedback. The content of the modules is based on the literature, as well as on a dedicat students. Many of these students have had less experience in mathematics than their urban counterparts. Furthermore, there is a broad range of mathematical capabilities within this group. As one of the 21 projects funded under the HEPPP 2015 National Priorities Pool, Bite size maths addresses the HEPPP Priority Funding Area, “More effective programme implementation”. The Bite size maths project facilitates more equitable and effective program delivery via a mathematics intervention resource that caters for the wide range of student abilities and economic circumstances evident in the education sector in regional/remote areas. In so doing, the Bite size maths project targets low socioeconomic students who are at particular disadvantage, and provides modules that build student expertise and confidence. Commonwealth and State governments, via the National STEM School Education Strategy (Education Council, 2015) have mandated increased emphasis on science and mathematics in pre-service teaching and increased rigour of pre-service courses. This project will assist not only education students, but also those in other courses that require mathematics skills. It provides higher education teachers, senior managers and policy advisors with a tested approach to support significant long-term improvements in the quality of mathematics learning in universities. Importantly, the Bite size maths project offers: 
 • A new vision of the way that mathematics can be learned in online settings and how this can be integrated in the preparation of graduates with mathematics capabilities suited to their professions, and 
 • A mechanism for university teachers to grow the mathematics capability of their students. 
 Successful take-up of the interactive modules or the MOOC requires: 
 • Leadership, clarity of purpose and influence whereby the Bite size maths partners champion the mathematics MOOC at regional and national levels 
 • Strong collaborative relationships between RUN partners to be nurtured and strengthened 
 • Planning for 2017 trials and subsequent roll-out of the interactive modules or the MOOC 
 • Communication about the resource to mathematics students at risk of failure, university mathematics teachers, staff in other disciplines, senior management teams at tertiary institutions, educational policy makers and other senior government strategists 
 • Review of institutional protocols around enrolment, pre-requisites, course accreditation and assessment in order to successfully embed the interactive modules and the MOOC 
 • Resourcing for trials, development and embedding of the interactive modules in mathematics units 
 • Mentoring mechanisms such as workshops for university educators and a website for feedback/support, and 
 • Promotion of the modules and the MOOC by the Department of Education and Training as a means of improving the mathematical capabilities of low socioeconomic or otherwise disadvantaged students at regional/rural universities. 
 This report presents the four main components of the project: 
 • Reviewing undergraduate mathematics in regional/rural Australia (identification of at- risk students, overview of intervention processes and identification of major issues) 
 • Developing and trialling of five online learning system modules 
 • Developing 20 interactive modules that comprise the MOOC, using feedback from the trial 
 • Reporting on the potential of the MOOC as a resource for use in the university sector