Validation of a novel scoring system for changes in skeletal manifestations of hypophosphatasia in newborns, infants, and children: The Radiographic Global Impression of Change scale

Hypophosphatasia (HPP) is the heritable metabolic disease characterized by impaired skeletal mineralization due to low activity of the tissue-nonspecific isoenzyme of alkaline phosphatase. Although HPP during growth often manifests with distinctive radiographic skeletal features, no validated method was available to quantify them, including changes over time. We created the Radiographic Global Impression of Change (RGI-C) scale to assess changes in the skeletal burden of pediatric HPP. Site-specific pairs of radiographs of newborns, infants, and children with HPP from three clinical studies of asfotase alfa, an enzyme replacement therapy for HPP, were obtained at baseline and during treatment. Each pair was scored by three pediatric radiologists ( raters ), with nine raters across the three studies. Intrarater and interrater agreement was determined by weighted Kappa coefficients. Interrater reliability was assessed using intraclass correlation coefficients (ICCs) and by two-way random effects analysis of variance (ANOVA) and a mixed-model repeated measures ANOVA. Pearson correlation coefficients evaluated relationships of the RGI-C to the Rickets Severity Scale (RSS), Pediatric Outcomes Data Collection Instrument Global Function Parent Normative Score, Childhood Health Assessment Questionnaire Disability Index, 6-Minute Walk Test percent predicted, and Z-score for height in patients aged 6 to 12 years at baseline. Eighty-nine percent (8/9) of raters showed substantial or almost perfect intrarater agreement of sequential RGI-C scores (weighted Kappa coefficients, 0.72 to 0.93) and moderate or substantial interrater agreement (weighted Kappa coefficients, 0.53 to 0.71) in patients aged 0 to 12 years at baseline. Moderate-to-good interrater reliability was observed (ICC, 0.57 to 0.65). RGI-C scores were significantly (p ≤ 0.0065) correlated with the RSS and with measures of global function, disability, endurance, and growth in the patients aged 6 to 12 years at baseline. Thus, the RGI-C is valid and reliable for detecting clinically important changes in skeletal manifestations of severe HPP in newborns, infants, and children, including during asfotase alfa treatment. © 2018 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals Inc

The MicroRNA, miR‐18a, Regulates NeuroD and Photoreceptor Differentiation in the Retina of Zebrafish

During embryonic retinal development, six types of retinal neurons are generated from multipotent progenitors in a strict spatiotemporal pattern. This pattern requires cell cycle exit (i.e. neurogenesis) and differentiation to be precisely regulated in a lineage‐specific manner. In zebrafish, the bHLH transcription factor NeuroD governs photoreceptor genesis through Notch signaling but also governs photoreceptor differentiation though distinct mechanisms that are currently unknown. Also unknown are the mechanisms that regulate NeuroD and the spatiotemporal pattern of photoreceptor development. Members of the miR‐17‐92 microRNA cluster regulate CNS neurogenesis, and a member of this cluster, miR‐18a, is predicted to target neuroD mRNA. The purpose of this study was to determine if, in the developing zebrafish retina, miR‐18a regulates NeuroD and if it plays a role in photoreceptor development. Quantitative RT‐PCR showed that, of the three miR‐18 family members (miR‐18a, b, and c), miR‐18a expression most closely parallels neuroD expression. Morpholino oligonucleotides and CRISPR/Cas9 gene editing were used for miR‐18a loss‐of‐function (LOF) and both resulted in larvae with more mature photoreceptors at 70 hpf without affecting cell proliferation. Western blot showed that miR‐18a LOF increases NeuroD protein levels and in vitro dual luciferase assay showed that miR‐18a directly interacts with the 3′ UTR of neuroD. Finally, tgif1 mutants have increased miR‐18a expression, less NeuroD protein and fewer mature photoreceptors, and the photoreceptor deficiency is rescued by miR‐18a knockdown. Together, these results show that, independent of neurogenesis, miR‐18a regulates the timing of photoreceptor differentiation and indicate that this occurs through post‐transcriptional regulation of NeuroD.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/147840/1/dneu22666.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/147840/2/dneu22666_am.pd

MOG CNS Autoimmunity and MOGAD.

At one time considered a possible form of neuromyelitis optica (NMO) spectrum disorder (NMOSD), it is now accepted that myelin oligodendrocyte glycoprotein (MOG) antibody (Ab)-associated disorder (MOGAD) is a distinct entity from either NMO or multiple sclerosis (MS) and represents a broad spectrum of clinical phenotypes. Whereas Abs targeting aquaporin-4 (AQP4) in NMO are pathogenic, the extent that anti-MOG Abs contribute to CNS damage in MOGAD is unclear. Both AQP4-specific Abs in NMO and MOG-specific Abs in MOGAD are predominantly IgG1, a T cell-dependent immunoglobulin (Ig) subclass. Key insights in neuroimmunology and MOGAD pathogenesis have been learned from MOG experimental autoimmune encephalomyelitis (EAE), described 2 decades before the term MOGAD was introduced. MOG-specific T cells are required in MOG EAE, and while anti-MOG Abs can exacerbate EAE and CNS demyelination, those Abs are neither necessary nor sufficient to cause EAE. Knowledge regarding the spectrum of MOGAD clinical and radiologic presentations is advancing rapidly, yet our grasp of MOGAD pathogenesis is incomplete. Understanding both the humoral and cellular immunology of MOGAD has implications for diagnosis, treatment, and prognosis

An academic hospitalist model to improve healthcare worker communication and learner education: Results from a quasi‐experimental study at a veterans affairs medical center

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/102160/1/jhm2105.pd

Five-year efficacy and safety of asfotase alfa therapy for adults and adolescents with hypophosphatasia

Hypophosphatasia (HPP) features low tissue-nonspecific alkaline phosphatase (TNSALP) isoenzyme activity resulting in extracellular accumulation of its substrates including pyridoxal 5\u27-phosphate (PLP), the principal circulating form of vitamin B6, and inorganic pyrophosphate (PPi), a potent inhibitor of mineralization. Asfotase alfa is an enzyme replacement therapy developed to treat HPP. This multinational, randomized, open-label study (NCT01163149; EudraCT 2010-019850-42) evaluated the efficacy and safety of asfotase alfa in adults and adolescents 13-66 years of age with HPP. The study comprised a 6-month primary treatment period and a 4.5-year extension phase. In the primary treatment period, 19 patients were randomized to receive asfotase alfa 0.3 mg/kg/d subcutaneously (SC; n = 7), asfotase alfa 0.5 mg/kg/d SC (n = 6), or no treatment (control; n = 6) for 6 months. In the extension phase, patients received asfotase alfa (0.5 mg/kg/d for 6 mo-1 y, then 1 mg/kg/d 6 d/wk). During the primary treatment period, changes from Baseline to Month 6 in plasma PLP and PPi concentrations (coprimary efficacy measure) were greater in the combined asfotase alfa group compared with the control group, reaching statistical significance for PLP (P = 0.0285) but not for PPi (P = 0.0715). However, for the total cohort, the within subject changes in both PLP and PPi after 6 months and over 5 years of treatment with asfotase alfa were significant (P \u3c 0.05). Secondary efficacy measures included transiliac crest histomorphometry, dual-energy X-ray absorptiometry (DXA), and the 6-Minute Walk Test (6MWT). A significant decrease from Baseline in mineralization lag time was observed in the combined asfotase alfa group at Year 1. There were no significant differences between treated and control patients in DXA mean bone mineral density results at 6 months; Z-scores and T-scores were within the expected range for age at Baseline and remained so over 5 years of treatment. On the 6MWT, median (min, max) distance walked increased from 355 (10, 620; n = 19) meters before treatment to 450 (280, 707; n = 13) meters at 5 years (P \u3c 0.05). Results for the exploratory outcome measures suggested improvements in gross motor function, muscle strength, and patient-reported functional disability over 5 years of treatment. There were no deaths during this study. Asfotase alfa was generally well tolerated; the most common adverse events were mild to moderate injection site reactions. This study suggests that in adults and adolescents with pediatric-onset HPP, treatment with asfotase alfa is associated with normalization of circulating TNSALP substrate levels and improved functional abilities

Prospectus, October 6, 1982

PROSPECTUS FOCUS ON VILLA GROVE; News Digest; Villa Grove looks ahead to future; Voter turnout appreciated; What\u27s your opinion on draft revitalization?: Draft dialogue wanted by student; Listeners available for PC students; Christian humorist appears; Guides needed; Addition bids out, construction to begin this fall; C-U Happenings...; Voter turnout doubled since last election; Loan funding may increase; Can you picture this?; Winter is comin, are you ready?; Three-year restoration project for historic \u27Sunnyside\u27; Growth and tradition mark Villa Grove\u27s 150 years; Classified; Places and Faces in Villa Grove; \u27Wouldn\u27t trade my life for the world,\u27 says bear trainer; Newton-John gives \u27love-filled performace\u27; Live sound makes for smokin\u27 rock; \u27Playboy\u27 sued over photo; Students, instructors cast in fall play; Security does more than give tickets; New seminar offers transfer; Community Calendar; Voices join in \u27Messiah\u27; Convocations sponsors films; Cougar has two in top ten; Are the NFL players holding fans for ransom?; Area seniors to visit PC Campus; Reps to appear at PC; Women\u27s team looking good, may reach finals; Fast Freddy Contest; More participation expected; Golf Scores; Cross Countryhttps://spark.parkland.edu/prospectus_1982/1009/thumbnail.jp

Asfotase alfa therapy for children with hypophosphatasia

Background. Hypophosphatasia (HPP) is caused by loss-of-function mutation(s) of the gene that encodes the tissue-nonspecific isoenzyme of alkaline phosphatase (TNSALP). Consequently, cell-surface deficiency of TNSALP phosphohydrolase activity leads to extracellular accumulation of inorganic pyrophosphate, a natural substrate of TNSALP and inhibitor of mineralization. Children with HPP can manifest rickets, skeletal pain, deformity, fracture, muscle weakness, and premature deciduous tooth loss. Asfotase alfa is a recombinant, bone-targeted, human TNSALP injected s.c. to treat HPP. In 2012, we detailed the 1-year efficacy of asfotase alfa therapy for the life-threatening perinatal and infantile forms of HPP. Methods. Here, we evaluated the efficacy and safety of asfotase alfa treatment administered to children 6–12 years of age at baseline who were substantially impaired by HPP. Two radiographic scales quantitated HPP skeletal disease, including comparisons to serial radiographs from similarly affected historical control patients. Results. Twelve children receiving treatment were studied for 5 years. The 6-month primary endpoint was met, showing significant radiographic improvement. Additional significant improvements included patient growth, strength, motor function, agility, and quality of life, which for most patients meant achieving normal values for age- and sex-matched peers that were sustained at 5 years of treatment. For most, pain and disability resolved. Mild to moderate injection-site reactions were common and were sometimes associated with lipohypertrophy. Low anti–asfotase alfa antibody titers were noted in all patients. No evidence emerged for clinically important ectopic calcification or treatment resistance. Conclusions. Asfotase alfa enzyme replacement therapy has substantial and sustained efficacy with a good safety profile for children suffering from HPP. Trial Registration. ClinicalTrials.gov NCT00952484 (https://clinicaltrials.gov/ct2/show/NCT00952484) and NCT01203826 (https://clinicaltrials.gov/ct2/show/NCT01203826). Funding. Alexion Pharmaceuticals Inc. and Shriners Hospitals for Children

Beyond belief: structured techniques prove more effective than a placebo intervention in a problem construction task

Problem construction is one of the first steps in creative problem solving and research has shown clear links between problem construction ability and creative output. Here, we compared two active techniques with that of a placebo intervention and show a benefit in problem construction performance for the active techniques. The active techniques required participants to either utilise six questions (six men), or adopt six perspectives, incorporating a range of specific questions (six hats). The placebo intervention (brain-breathing) was specifically constructed to seem both plausible and effective. We had 118 participants randomly allocated to one of the three groups (six men, six hats, brain-breathing) and, after reading a brief synopsis of their allocated tool, they then attempted to restate a given problem in as many different ways as they could within an allotted time. Performance was measured in terms of the fluency, quality, flexibility and originality of responses. Results showed that using the six men tool produced greater fluency, flexibility and originality relative to brain-breathing and the six hats. Use of the six hats tool also led to the production of more original responses relative to the brain-breathing control group. Importantly, there was no difference in reported motivation between the groups, but those using the six men and the brain-breathing tools found these easier to use compared to the six hats. Furthermore, those using the six men tool found this to be more useful and indicated that they were more likely to use this again in the future. Hence, both six men and six hats tools benefited performance, though in distinct ways. These results support the notion that explicitly scaffolding thinking can benefit creative problem solving

The Elusive Rentier Rich: Piketty's Data Battles and the Power of Absent Evidence

The popularity of Thomas Piketty?s research on wealth inequality has drawn attention to a curious question: why was widening wealth inequality largely neglected by mainstream economists in recent decades? To explore and explain that neglect, I draw on the writing of the early neoclassical economist John Bates Clark, who introduced the notion of the marginal productivity of income distribution at the end of the nineteenth century. I then turn to Piketty?s Capital in order to analyze the salience of marginal productivity theories of income today. I suggest that most of the criticism and praise for Piketty?s research is focused on data that are accessible and measurable, obscuring attention to questions over whether current methods for measuring economic capital are defensible or not. My overarching aim is to explore how ?absent? data in economics as a whole help to reinforce blind spots within mainstream economic theory