Efficacy and Safety of Vamorolone Over 48 Weeks in Boys With Duchenne Muscular Dystrophy: A Randomized Controlled Trial

Background 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

An Inconvenient Corpse: Settler Adaptation to Winter Death and Burial through Structural and Oral History

While the archaeology of death and burial is a popular avenue of research, considerations for burial practices during winter months in northerly climates when temperatures regularly drop below 0°C / 32°F aren’t regularly considered. Excavations in search of the early 17th-century burials associated with Sir George Calvert’s English colony in Ferryland, Newfoundland considered different options for winter body disposal. While burial on land presented the most plausible option in the colonial period, deaths during the winter would have posed a problem for settlers. With limited options for digging in frozen ground, the storage of dead bodies during the winter became commonplace throughout North America. The practice dominated the northeast coast in particular, but was not the only option. This paper explores the logistics of early winter burial practices such as winter storage and grave digging through structural evidence and oral testimony, and considers how these practices were adapted throughout the 18th to 21st centuries

Managing Editor\u27s Note

A message from the 2023-2024 Managing Editor of the Binghamton University Undergraduate Journal, Sydney Werner

Transatlantic Traditions: The History of Welsh Quarrying and its Connections to Newfoundland Slate

Previous archaeological investigations have conclusively shown that the presence of Welshmen has co-occurred with the practice of local slate quarrying in Newfoundland since the early colonial ventures of the 17th century. The island experienced a resurgence in Welsh culture in the 19th century when a number of small slate quarries were established overlooking both the Bay of Islands on the west coast and Smith Sound in Trinity Bay. The following article outlines the history of these 19th-century Newfoundland quarries, as well as the social, political and economic factors which encouraged the migration of Welsh quarrymen across the Atlantic to remote and isolated areas of the island. The brief but intensive quarrying activity of the 19th and 20th centuries left indelible marks on the Trinity Bay landscape, and this article concludes by outlining preliminary explorations of archaeological remains near the town of Hickman’s Harbour on Random Island

Declining but Pronounced State-Level Disparities in Prescription Opioid Distribution in the United States

The 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

Establishing Methods for the Detection of Thiamine in Resource-Deficient Settings

Thiamine (vitamin B1) is vital for various metabolic functions within the human body, such as the TCA cycle and pentose-phosphate pathway. In vertebrates, it cannot be produced by the body itself, and therefore must be taken in through diet. Thiamine deficiency can lead to symptoms such as weakness, fatigue, and loss of appetite, and certain neurological disorders. HPLC is a traditional method utilized for thiamine analysis, but the maintenance and expertise required to properly operate an HPLC instrument makes it unsuitable for resource-deficient settings. Therefore, two assay formats are considered for the detection of thiamine: an enzymatic plate digestion assay format and a lateral flow assay format. The enzymatic plate digestion assay format relies on the relationship between thiamine and the enzyme that inhibits its activity: thiaminase. By subjecting biological sample solutions in parallel to incubation in the presence and absence of thiaminase I (an enzyme that degrades thiamine) we can compare the signal from the background matrix relative to that including thiamine. Thiamine (non-fluorescent) is then oxidized to thiochrome (fluorescent), and the fluorescence of solutions can be determined relative to an external standard curve. The thiaminase enzyme is utilized to create control matrices depleted of thiamine. Developing a diluent for thiamine standards that is similar to the matrix of the biological samples in the assay is key for achieving accurate results. The lateral flow assay format is directly suited for an at-home user to detect thiamine at the point-of-care. A thiamine derivative is immobilized on the membrane strip, and dye-encapsulating liposomes that are functionalized with a periplasmic thiamine-binding protein are pre-mixed with samples to provide a visible signal indicative of thiamine content when added to the strip. The utilization of this format is intended for future applications in human biological samples

The Avalon Historic Petroglyphs Project: Investigating Historic Graffiti and Petroglyphs on Newfoundland’s Eastern Avalon Peninsula

Newfoundland’s Avalon Peninsula contains many examples of petroglyphs, historic graffiti and inscriptions/engravings dating from the 17th to 20th centuries. This paper highlights the sites of Kingman’s Cove (CfAf-25) and Brigus South (CgAf-21), the computational photography and conservation techniques used in their recording, and current interpretations on who made them, why, when, and what they represent. The results show the broad potential of historic inscriptions for understanding the movements of people who are often poorly represented in the documentary record, the importance of peripheral landscapes and features as foci for self-expression, place-making and remembrance, and the need for innovative methodologies to record these ephemeral and endangered features. Furthermore, these sites are often of continued relevance to local communities (whose intimate landscape knowledge is typically required for their study) while also bearing a contemporary legacy as seen in nearby similar spatially-focused areas of modern graffiti

Understanding the needs and experiences of underrepresented students at Binghamton University Libraries

This study focuses on how Binghamton University Libraries can assist in enhancing the experience of international students campus. There is a key focus on students from the Indian subcontinent. Due to limited time and resources, there were only three participants selected for this study.https://orb.binghamton.edu/library_research_scholars_2024/1001/thumbnail.jp

A population-based study of children suggests blunted morning cortisol rhythms are associated with alterations of the systemic inflammatory state

Background: In children, digital media, lifestyle, and the COVID pandemic have impacted sunlight exposure, exercise, and diet patterns - cues that entrain the circadian clock. We hypothesized that low morning cortisol reflects a weak circadian clock, impacting the pro-inflammatory state. The primary objective was to test relationships between diurnal cortisol fluctuations and the inflammatory state in children as a means of providing indirect support for this hypothesis. Methods: The Cardiovascular Health Intervention Program (CHIP) was a population-based cross-sectional and longitudinal study of circadian health in public elementary school children in Southern Maine, USA (recruitment period 2012–2017). Participants were 689 students in 4th grade (baseline; age=9.2 ± 0.4 years), and 647 students in 5th grade (age=10.5 ± 0.5 years). Nine salivary cortisol measures per child (2 awakening and 1 prior to bed for 3 sequential days) (n = 1336 child phenotype days; n = 7987 cortisol assays), 10 cytokines measured in morning and evening saliva samples (n = 202 child phenotype days), and lipids were measured. Clinical outcomes were blood pressure, weight and height (body mass index [BMI]; BMI = kg/m2), among others. Findings: Upon-waking cortisol levels were 0.28 ± 0.13 µg/dL, 30-minute post-waking 0.33 ± 0.15 µg/dL, and evening 0.08 ± 0.10 µg/dL. Salivary cytokine levels (n = 202) showed interleukins (IL) IL-1β and IL-8 were highest in early morning (upon awakening; AM), and IL-6 and tumor necrosis factor (TNF) TNF-α highest before bed (PM) (IL-1β AM \u3e PM [−4.02 fold; p \u3c 0.001]; IL-8 AM \u3e PM [−1.36 fold; p \u3c 0.001]; IL-6 AM \u3c PM [+1.49 fold; p \u3c 0.001]; TNF-α AM \u3c PM [+1.73 fold; p = 0.03]. Regression modeling showed high morning cortisol was associated with high morning IL-1β (p = 3.82 ×10−6), but low evening IL-1β (p = 6.27 ×10−4). Regression modeling of BMI z-score as the response variable showed the expected significant relationships to high density lipoprotein (HDL) (negative; p \u3c 0.001), mean arterial pressure (positive; p \u3c 0.001), and morning cortisol (negative; p = 0.01) but only weak relationships to either evening cortisol (p = 0.1) or cytokine (positive; p = 0.02; from the model with smallest Rsquared) levels. Interpretation: We provide preliminary data on diurnal fluctuations of inflammatory cytokines in saliva in a population-based cohort of children. Correlation of morning and evening cortisol levels with inflammatory cytokines in the same saliva samples showed that high morning cortisol was associated with high morning IL-1β and low evening IL-1β. Future studies may test the hypothesis that strong diurnal cycling of IL-1β may serve as a homeostatic mechanism keeping the immune system in check, and that low morning cortisol (possible circadian misalignment) may lead to less stringent control of inflammatory networks

Forgotten Places in Political Spaces

The way in which many people, perhaps particularly those in secure and affluent circumstances, view their ancestry and heritage, and display it to others, is often a matter of pride. In some contexts, however, the identification of ‘ancestors’ and ‘heritage’ can have critically important - and sometimes dire - political, social and spiritual ramifications. Here we examine examples in which archaeological and/or historical evidence points to a distancing or ‘active forgetting’ of ancestors and places associated with them. The motives for creating these ‘forgotten places’ are diverse and might include a fear of ‘ghosts’ or death, the desire to project a newly constructed or evolved political identity to outsiders or distant relations, as well as social-political and economic need to distance themselves from their ancestors. In this paper we will explore four examples from Indigenous settings in northern and eastern Canada where peripheral, or forgotten, spaces were actively constructed