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Directed Evolution of Hedgehog Protein Autoprocessing Activity: Combined Experimental & Computational Approach
Get PDFSonic hedgehog protein is vital for embryonic development while also being linked to multiple cancers and holoprosencephaly. The native reaction of hedgehog is a sterolysis reaction whereby cholesterol binds to the HhC catalytic domain and attacks the HhN signaling domain, resulting in a covalent HhN-cholesterol signaling product. The structure of the sterol recognition region (SRR) of Sonic Hedgehog, where cholesterol binds, is currently unknown. In this thesis, I used directed evolution to select a triple mutant of Hedgehog’s catalytic HhC domain, (D46H, Q150H, A196T), which is over 5000 times more catalytically efficient at reacting with epicoprostanol (ECP), a non-native substrate and an inhibitor of wild-type hedgehog protein. A sterol screen of the mutant revealed that it also accepts lithocholic acid (LCA) as a substrate, which is promising for future bioconjugation experiments. Investigations into the role of each mutation reveal the necessity of A196T in accepting LCA’s carboxyl tail, the significance that Q150H has on hydrolysis, as well as the necessary and synergistic effects of D46H. Computational models of HhC give some insight into the structural role of the mutations, but the largely disordered loop region of the SRR leaves more questions unanswered about its structure
COVID-19 and Global Institutional Shift from National to Subnational Governments
Get PDFThe COVID-19 Pandemic saw dramatic global shifts in legislative powers between central and local governments. With changes in the severity and duration of the pandemic, in the federations of Nigeria, Australia, and Canada, policymaking regarding border and school closures and states of emergency saw an increasing involvement of regional governments. We suggest that looking at the national and regional PPI data for our hypotheses could indicate directly the severity of the pandemic in these nations. Federalisms particularly provide a case of institutional change evidencing that COVID-era decision-making saw a change in the rules and expectations of governance in the nations we analyze. Emergency powers that would have generally fallen upon national governments were instead adopted by provincial bodies, the alternative spheres of policy creation that mark federalism as a political system, because of inactivity at the national level
Declining but Pronounced State-Level Disparities in Prescription Opioid Distribution in the United States
Get PDFThe United States (US) opioid epidemic is a persistent and pervasive public health emergency that claims the lives of over 80,000 Americans per year as of 2021. There have been sustained efforts to reverse this crisis over the past decade, including a number of measures designed to decrease the use of prescription opioids for the treatment of pain. This study analyzed the changes in federal production quotas for prescription opioids and the distribution of prescription opioids for pain and identified state-level differences between 2010 and 2019. Data (in grams) on opioid production quotas and distribution (from manufacturer to hospitals, retail pharmacies, practitioners, and teaching institutions) of 10 prescription opioids (codeine, fentanyl, hydrocodone, hydromorphone, meperidine, methadone, morphine, oxycodone, oxymorphone, and tapentadol) for 2010 to 2019 were obtained from the US Drug Enforcement Administration. Amounts of each opioid were converted from grams to morphine milligram equivalent (MME), and the per capita distribution by state was calculated using population estimates. Total opioid production quotas increased substantially from 2010 to 2013 before decreasing by 41.5% from 2013 (87.6 MME metric tons) to 2019 (51.3). The peak year for distribution of all 10 prescription opioids was between 2010 and 2013, except for codeine (2015). The largest quantities of opioid distribution were observed in Tennessee (520.70 MME per person) and Delaware (251.45) in 2011 and 2019. There was a 52.0% overall decrease in opioid distribution per capita from 2010 to 2019, with the largest decrease in Florida (−61.6%) and the smallest in Texas (−18.6%). Southern states had the highest per capita distribution for eight of the ten opioids in 2019. The highest to lowest state ratio of total opioid distribution, corrected for population, decreased from 5.25 in 2011 to 2.78 in 2019. The mean 95th/5th ratio was relatively consistent in 2011 (4.78 ± 0.70) relative to 2019 (5.64 ± 0.98). This study found a sustained decline in the distribution of ten prescription opioids during the last five years. Distribution was non-homogeneous at the state level. Analysis of state-level differences revealed a fivefold difference in the 95th:5th percentile ratio between states, which has remained unchanged over the past decade. Production quotas did not correspond with the distribution, particularly in the 2010–2016 period. Future research, focused on identifying factors contributing to the observed regional variability in opioid distribution, could prove valuable to understanding and potentially remediating the pronounced disparities in prescription opioid-related harms in the US
Diagnostic outcome of pro bono neurogenetic diagnostic service in Sri Lanka: A wealth creation
Get PDFThe inherited disease community in Sri Lanka has been widely neglected. This article aimed to present accumulated knowledge in establishing a pro bono cost-effective national, island-wide, free-of-charge molecular diagnostic service, suggesting a model for other developing countries. The project provided 637 molecular diagnostic tests and reports free of charge to a nation with limited resources. We pioneered the implementation of mobile clinics and home visits, where the research team acted as barefoot doctors with the concept of the doctor and the researcher at the patient’s doorstep. Establishing pro bono, cost-effective molecular diagnostics is feasible in developing countries with limited resources and state funding through the effort of dedicated postgraduate students. This service could provide an accurate molecular diagnosis of Duchenne muscular dystrophy, Huntington’s disease, Spinocerebellar ataxia, and Spinal muscular atrophy, a diagnostic yield of 54% (343/637), of which 43% (147/343) of the patients identified as amenable for available gene therapies. Initiated human resource development by double doctoral degree opportunities with international collaborations. Established a neurobiobank and a national registry in Sri Lanka, a rich and unique repository, wealth creation for translational collaborative research and sharing of information in neurological diseases, as well as a lodestar for aspiring initiatives from other developing countries
Efficacy and Safety of Vamorolone Over 48 Weeks in Boys With Duchenne Muscular Dystrophy: A Randomized Controlled Trial
Get PDFBackground and Objectives
Vamorolone is a dissociative agonist of the glucocorticoid receptor that has shown similar efficacy and reduced safety concerns in comparison with prednisone in Duchenne muscular dystrophy (DMD). This study was conducted to determine the efficacy and safety of vamorolone over 48 weeks and to study crossover participants (prednisone to vamorolone; placebo to vamorolone).
Methods
A randomized, double-blind, placebo-controlled and prednisone-controlled clinical trial of 2 doses of vamorolone was conducted in participants with DMD, in the ages from 4 years to younger than 7 years at baseline. The interventions were 2 mg/kg/d of vamorolone and 6 mg/kg/d of vamorolone for 48 weeks (period 1: 24 weeks + period 2: 24 weeks) and 0.75 mg/kg/d of prednisone and placebo for the first 24 weeks (before crossover). Efficacy was evaluated through gross motor outcomes and safety through adverse events, growth velocity, body mass index (BMI), and bone turnover biomarkers. This analysis focused on period 2.
Results
A total of 121 participants with DMD were randomized. Vamorolone at a dose of 6 mg/kg/d showed maintenance of improvement for all motor outcomes to week 48 (e.g., for primary outcome, time to stand from supine [TTSTAND] velocity, week 24 least squares mean [LSM] [SE] 0.052 [0.0130] rises/s vs week 48 LSM [SE] 0.0446 [0.0138]). After 48 weeks, vamorolone at a dose of 2 mg/kg/d showed similar improvements as 6 mg/kg/d for North Star Ambulatory Assessment (NSAA) (vamorolone 6 mg/kg/d–vamorolone 2 mg/kg/d LSM [SE] 0.49 [1.14]; 95% CI −1.80 to 2.78, p = 0.67), but less improvement for other motor outcomes. The placebo to vamorolone 6 mg/kg/d group showed rapid improvements after 20 weeks of treatment approaching benefit seen with 48-week 6 mg/kg/d of vamorolone treatment for TTSTAND, time to run/walk 10 m, and NSAA. There was significant improvement in linear growth after crossover in the prednisone to vamorolone 6 mg/kg/d group, and rapid reversal of prednisone-induced decline in bone turnover biomarkers in both crossover groups. There was an increase in BMI after 24 weeks of treatment that then stabilized for both vamorolone groups.
Discussion
Improvements of motor outcomes seen with 6 mg/kg/d of vamorolone at 24 weeks of treatment were maintained to 48 weeks of treatment. Vamorolone at a dose of 6 mg/kg/d showed better maintenance of effect compared with vamorolone at a dose of 2 mg/kg/d for most (3/5) motor outcomes. Bone morbidities of prednisone (stunting of growth and declines in serum bone biomarkers) were reversed when treatment transitioned to vamorolone.
Trial Registration Information
ClinicalTrials.gov Identifier: NCT03439670.
Classification of Evidence
This study provides Class I evidence that for boys with DMD, the efficacy of vamorolone at a dose of 6 mg/kg/d was maintained over 48 weeks
A five-year quasi-experimental study to evaluate the impact of empiric antibiotic order sets on antibiotic use metrics among hospitalized adult patients
Get PDFObjective: Evaluation of adult antibiotic order sets (AOSs) on antibiotic stewardship metrics has been limited. The primary outcome was to evaluate the standardized antimicrobial administration ratio (SAAR). Secondary outcomes included antibiotic days of therapy (DOT) per 1,000 patient days (PD); selected antibiotic use; AOS utilization; Clostridioides difficile infection (CDI) cases; and clinicians’ perceptions of the AOS via a survey following the final study phase.
Design: This 5-year, single-center, quasi-experimental study comprised 5 phases from 2017 to 2022 over 10-month periods between August 1 and May 31.
Setting: The study was conducted in a 752-bed tertiary care, academic medical center.
Intervention: Our institution implemented AOSs in the electronic medical record (EMR) for common infections among hospitalized adults.
Results: For the primary outcome, a statistically significant decreases in SAAR were detected from phase 1 to phase 5 (1.0 vs 0.90; P \u3c .001). A statistically significant decreases were detected in DOT per 1,000 PD (4,884 vs 3,939; P = .001), fluoroquinolone orders (407 vs 175;P \u3c .001), carbapenem orders (147 vs 106; P = .024), and clindamycin orders (113 vs 73; P = .01). No statistically significant change in mean vancomycin orders was detected (991 vs 902; P = .221). A statistically significant decrease in CDI cases was also detected (7.8, vs 2.4; P = .002) but may have been attributable to changes in CDI case diagnosis. Clinicians indicated that the AOSs were easy to use overall and that they helped them select the appropriate antibiotics.
Conclusions: Implementing AOS into the EMR was associated with a statistically significant reduction in SAAR, antibiotic DOT per 1,000 PD, selected antibiotic orders, and CDI cases
The IAAM LTBP4 Haplotype is Protective Against Dystrophin-Deficient Cardiomyopathy
Get PDFBackground: Dilated cardiomyopathy (DCM) is a major complication of, and leading cause of mortality in Duchenne muscular dystrophy (DMD). Its severity, age at onset, and rate of progression display wide variability, whose molecular bases have been scarcely elucidated. Potential DCM-modifying factors include glucocorticoid (GC) and cardiological treatments, DMD mutation type and location, and variants in other genes.
Methods and Results: We retrospectively collected 3138 echocardiographic measurements of left ventricular ejection fraction (EF), shortening fraction (SF), and end-diastolic volume (EDV) from 819 DMD participants, 541 from an Italian multicentric cohort and 278 from the Cooperative International Neuromuscular Group Duchenne Natural History Study (CINRG-DNHS). Using generalized estimating equation (GEE) models, we estimated the yearly rate of decrease of EF (–0.80%) and SF (–0.41%), while EDV increase was not significantly associated with age. Utilizing a multivariate generalized estimating equation (GEE) model we observed that mutations preserving the expression of the C-terminal Dp71 isoform of dystrophin were correlated with decreased EDV (–11.01 mL/m2 , p = 0.03) while for dp116 were correlated with decreased EF (–4.14%, p =
Conclusions: We quantitatively describe the progression of systolic dysfunction progression in DMD, confirm the effect of distal dystrophin isoform expression on the dystrophin-deficient heart, and identify a strong effect of LTBP4 genotype of DCM in DMD
Sustainability Hub Newsletter - April 2024
Get PDFIn this issue of the Newsletter, read about how beeswax wraps can reduce your plastic use, a pollinator citizen science kit, and bus charters to the Farmers Market! Then learn what you can plant this month and a recipe you can grow ingredients for! Then, read sustainable tips for spring cleaning, see an environmental art feature, and find out about events happening this Earth Month
A compendium of cross-culturally valid intimate partner violence assessment items for North American Spanish speakers
Get PDFIntimate partner violence (IPV) is physical, psychological, or sexual abuse by a current or former romantic partner. The long- and short-term consequences can lead to severe repercussions. To prevent these consequences of IPV, we need to screen for it and assess it. Across cultures, IPV is present and should be assessed regardless of linguistic boundaries. Spanish is the most widely used language in the U.S. other than English; therefore, assessment instruments that can reliably capture IPV in Spanish are necessary. Although Spanish-language IPV instruments are available, they may be challenging to understand for Spanish speakers because of linguistic differences. In this study, I aim to create a collection of items that assess IPV that can be understood cross-culturally by Spanish speakers in North America. A systematic search was carried out in the Fall of 2022 for records containing Spanish measures of IPV. To identify items, Spanish IPV items were extracted, initially screened, and organized into categories corresponding to the actions they depicted. Then, the items were further screened to ensure there were no duplicates or items with like or similar wording. The finalized list of items was assessed for comprehensibility by a third-party expert translator who helped revise items based on reading level and regional dialect. The catalogue of items has been published on the BU libraries’ open repository and digital preservation service. This study has provided a comprehensive list of Spanish IPV items for enhancing assessment. Next steps include an item response theory analysis to create an IPV measure
Women’s Fashion in England 1800-1834 and its Effects on the Socio-Economic Status of the Working Class
Get PDFThe first quarter of the nineteenth century saw the evolution of how women in England thought of fashion and the effect it had on their social and economic status. Poor and working-class women were passed over for higher-paying opportunities due to their clothes\u27 misalignment with the major fashion trends of the day. The study of the development of social conditions and the change in clothing and designs contributes to an understanding of why those in the lower class were denied mobility in their status.https://orb.binghamton.edu/research_days_posters_2024/1008/thumbnail.jp