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In the First-HD pivotal trial, the maximum deutetrabenazine dose evaluated to treat chorea associated with Huntington’s disease (HD chorea) was 48 mg/d, which is the approved maximum dose for this population. In ARC-HD, an open-label extension study evaluating the long-term efficacy and safety of deutetrabenazine to treat HD chorea, dosage ranged from 6 mg/d to 72 mg/d, with doses ≥12 mg/d administered twice daily. Doses in ARC-HD were increased by 6 mg/d per week in a response-driven manner based on efficacy and tolerability until 48 mg/d (Week 8). At the investigator’s discretion, further increases were permitted by 12 mg/d per week to a maximum of 72 mg/d. This post-hoc analysis evaluates the safety and tolerability of deutetrabenazine >48 mg/d compared to ≤48 mg/d to treat HD chorea in ARC-HD.
Patient counts and safety assessments were attributed to patients when they received a dose of either ≤48 mg/d or >48 mg/d. For 9 selected adverse events (AEs), we compared AE rates adjusted for duration of drug exposure (as number of AEs/year) at ≤48 mg/d or >48 mg/d. The AE rates were determined after titration when participants were on stable doses of deutetrabenazine.
All 113 patients were exposed to doses ≤48 mg/d (177.1 patient-years) and 49 patients were ever exposed to doses >48 mg/d (74.1 patient-years). In patients taking deutetrabenazine >48 mg/d compared to ≤48 mg/d after the titration period, there were no apparent differences in exposure-adjusted AE rates.
Based on clinical experience, some patients with HD may benefit from doses higher than 48 mg/d to adequately control chorea. These doses were tolerated without apparent increase in the exposure-adjusted rates of selected AEs after titration. This analysis does not address the occurrence of other AEs or whether adequate efficacy was achieved at lower doses, factors that may have influenced dose increases.
Teva Pharmaceutical Industries Ltd., Petach Tikva, Israel
Chorea is a prominent motor dysfunction in Huntington’s disease (HD). Deutetrabenazine, a vesicular monoamine transporter 2 (VMAT2) inhibitor, is FDA-approved for the treatment of chorea in HD. In the pivotal, 12-week First-HD trial, deutetrabenazine treatment reduced the Unified Huntington’s Disease Rating Scale (UHDRS) total maximal chorea (TMC) score versus placebo. ARC-HD, an open-label extension study, evaluated long-term safety and efficacy of deutetrabenazine dosed in a response-driven manner for treatment of HD chorea.
Patients who completed First-HD (Rollover) and patients who converted overnight from a stable dose of tetrabenazine (Switch) were included. Safety was assessed over the entire treatment period; exposure-adjusted incidence rates (EAIRs; adverse events [AEs] per person-year) were calculated. A stable, post-titration time point of 8 weeks was chosen for efficacy analyses.
Of 119 patients enrolled (Rollover, n=82; Switch, n=37), 100 (84%) completed ≥1 year of treatment (mean [SD] follow-up, 119  weeks). End of study EAIRs for patients in the Rollover and Switch cohorts, respectively, were: any AE, 2.6 and 4.3; serious AEs, 0.13 and 0.14; AEs leading to dose suspension, 0.05 and 0.04. Overall, 68% and 73% of patients in Rollover and Switch, respectively, experienced a study drug–related AE. Most common AEs possibly related to study drug were somnolence (17% Rollover; 27% Switch), depression (23%; 19%), anxiety (9%; 11%), insomnia (10%; 8%), and akathisia (9%; 14%). Rates of AEs of interest include suicidality (9%; 3%) and parkinsonism (6%; 11%). In both cohorts, mean UHDRS TMC score and total motor score (TMS) decreased from baseline to Week 8; mean (SD) change in TMC score (units) was –4.4 (3.1) and –2.1 (3.3) and change in TMS was –7.1 (7.3) and –2.4 (8.7) in Rollover and Switch, respectively. While receiving stable dosing from Week 8 to 132 (or end of treatment), patients showed minimal change in TMC score (0.9 [5.0]), but TMS increased compared to Week 8 (9.0 [11.3]). Upon drug withdrawal, there were no remarkable AEs and TMC scores increased 4.4 (3.7) units compared to end of treatment.
The type and severity of AEs observed in long-term deutetrabenazine exposure are consistent with the previous study. Efficacy in reducing chorea persisted over time. There was no unexpected worsening of HD or chorea associated with HD upon deutetrabenazine withdrawal.
Teva Pharmaceutical Industries Ltd., Petach Tikva, Israel
Adults who were born preterm are at increased risk of hypertension and cardiovascular disease in later life. Infants born late preterm are the majority of preterm births; however, the effect of late preterm on risk of cardiovascular disease is unclear. The objective of this study was to assess whether vascular health and cardiac autonomic control differ in a group of late preterm newborn infants compared to a group of term-born infants.
A total of 35 healthy late preterm newborn infants, with normal growth (34–36 completed weeks’ gestation) and 139 term-born infants (37–42 weeks’ gestation) were compared in this study. Aortic wall thickening, assessed as aortic intima–media thickness (IMT) by high-resolution ultrasound, and cardiac autonomic control, assessed by heart rate variability, were measured during the first week of life. Postnatal age of full-term and late preterm infants at the time of the study was 5 days (standard deviation [SD] 5) and 4 days (SD 3), respectively.
Infants born late preterm show reduced aortic IMT (574 μm [SD 51] vs. 612 μm [SD 73]) and reduced heart rate variability [log total power 622.3 (606.5) ms2 vs. 1180. 6 (1114.3) ms2], compared to term infants. These associations remained even after adjustment for sex and birth weight.
Infants born late preterm show selective differences in markers of cardiovascular risk, with potentially beneficial differences in aortic wall thickness in contrast to potentially detrimental differences in autonomic control, when compared with term-born control infants. These findings provide pathophysiologic evidence to support an increased risk of hypertension and sudden cardiac death in individuals born late preterm.
Finely laminated (cm–μm scale) metalliferous precipitates are widespread in the surficial environment, especially around mineral deposits and reflect biogeochemical processes that can pervade near-surface environments on a larger scale. Examples in this paper involve precipitates of the transition metals Fe, Cu and Mn with minor Co, Ni, V and Zn; the metalloids As and Sb; and authigenic Au. Mobility and re-precipitation are driven primarily by geochemical disequilibrium, especially with respect to pH and redox states, that arises from complex interactions between biological processes, geological processes, and variations in the surrounding environment. Different degrees of chemical disequilibrium arise on small spatial scales on time scales of days to millennia. Interactions between biota, waters and rocks in these small near-surface settings affect the biogeochemical environments. Sulfur- and iron-oxidising bacteria are common biogeochemical agents associated with sulfide-bearing lithologies, but localised reductive environments can also develop, leading to gradients in pH and redox state and differential metal mobility. In general, there is commonly a spatial separation of Fe-rich precipitates from those with Cu and Mn, and other transition metals also follow Cu and Mn rather than Fe. Metalloids As and Sb have a strong affinity for Fe under oxidising conditions, but not under more reducing conditions. However, complex biogeochemical parageneses of laminated metalliferous deposits preclude prediction of finer formation details. The textures, mineral species, and metal associations within these deposits are likely to be encountered in all facets of mineral deposit development: initial exploration activity of near-surface locations, mining of shallow portions of orebodies, especially supergene zones, and downstream environmental management with respect to discharging metalliferous waters.
Rapid spread of coronavirus disease 2019 (COVID-19) has affected people with intellectual disability disproportionately. Existing data does not provide enough information to understand factors associated with increased deaths in those with intellectual disability. Establishing who is at high risk is important in developing prevention strategies, given risk factors or comorbidities in people with intellectual disability may be different to those in the general population.
To identify comorbidities, demographic and clinical factors of those individuals with intellectual disability who have died from COVID-19.
An observational descriptive case series looking at deaths because of COVID-19 in people with intellectual disability was conducted. Along with established risk factors observed in the general population, possible specific risk factors and comorbidities in people with intellectual disability for deaths related to COVID-19 were examined. Comparisons between mild and moderate-to-profound intellectual disability subcohorts were undertaken.
Data on 66 deaths in individuals with intellectual disability were analysed. This group was younger (mean age 64 years) compared with the age of death in the general population because of COVID-19. High rates of moderate-to-profound intellectual disability (n = 43), epilepsy (n = 29), mental illness (n = 29), dysphagia (n = 23), Down syndrome (n = 20) and dementia (n = 15) were observed.
This is the first study exploring associations between possible risk factors and comorbidities found in COVID-19 deaths in people with intellectual disability. Our data provides insight into possible factors for deaths in people with intellectual disability. Some of the factors varied between the mild and moderate-to-profound intellectual disability groups. This highlights an urgent need for further systemic inquiry and study of the possible cumulative impact of these factors and comorbidities given the possibility of COVID-19 resurgence.
New York City's first case of SARS-associated coronavirus (SARS-CoV-2) disease 2019 (COVID-19) was identified on 1 March 2020, prompting rapid restructuring of hospital-based services to accommodate the increasing numbers of medical admissions. Non-essential services were eliminated but in-patient treatment of psychiatric illnesses was necessarily maintained.
To detail the response of the NYU Langone Health in-patient psychiatric services to the COVID-19 outbreak from 1 March to 1 May 2020.
Process improvement/quality improvement study.
Over this time period, our two in-patient psychiatric units (57 total beds) treated 238 patients, including COVID-19-positive and -negative individuals. Testing for COVID-19 was initially limited to symptomatic patients but expanded over the 62-day time frame. In total, 122 SARS-CoV-2 polymerase chain reaction (PCR) tests were performed in 98 patients. We observed an overall rate of COVID-19 infection of 15.6% in the patients who were tested, with an asymptomatic positive rate of 13.7%. Although phased roll-out of testing impaired the ability to fully track on-unit transmission of COVID-19, 3% of cases were clearly identified as results of on-unit transmission.
Our experience indicates that, with appropriate precautions, patients in need of in-patient psychiatric admission who have COVID-19 can be safely managed. We provide suggested guidelines for COVID-19 management on in-patient psychiatric units which incorporate our own experiences as well as published recommendations.
Poverty and social exclusion are a gendered phenomenon. They are rooted deeply in the stereotypes, biases, prejudices, and discriminations against women, especially those suffering from poor living conditions. Unfortunately, gender inequality is manifested in most, if not all, major life domains. It is therefore important to understand the gender aspect of poverty and social exclusion through a psychological lens. We begin this chapter by introducing the concepts of multi-dimensional poverty and social exclusion with a sketch of the gender disparities displayed in these areas. We turn next to several mainstream psychological theories which have attempted to investigate and interpret the relationship between poverty and gender inequality from the dispositional, motivational, cognitive, and behavioural perspectives. Finally, we evaluate the reliability, objectivity, and generalisability of the reviewed theories and studies and offer suggestions for future research.
Previous genetic association studies have failed to identify loci robustly associated with sepsis, and there have been no published genetic association studies or polygenic risk score analyses of patients with septic shock, despite evidence suggesting genetic factors may be involved. We systematically collected genotype and clinical outcome data in the context of a randomized controlled trial from patients with septic shock to enrich the presence of disease-associated genetic variants. We performed genomewide association studies of susceptibility and mortality in septic shock using 493 patients with septic shock and 2442 population controls, and polygenic risk score analysis to assess genetic overlap between septic shock risk/mortality with clinically relevant traits. One variant, rs9489328, located in AL589740.1 noncoding RNA, was significantly associated with septic shock (p = 1.05 × 10–10); however, it is likely a false-positive. We were unable to replicate variants previously reported to be associated (p < 1.00 × 10–6 in previous scans) with susceptibility to and mortality from sepsis. Polygenic risk scores for hematocrit and granulocyte count were negatively associated with 28-day mortality (p = 3.04 × 10–3; p = 2.29 × 10–3), and scores for C-reactive protein levels were positively associated with susceptibility to septic shock (p = 1.44 × 10–3). Results suggest that common variants of large effect do not influence septic shock susceptibility, mortality and resolution; however, genetic predispositions to clinically relevant traits are significantly associated with increased susceptibility and mortality in septic individuals.
Wild sheep and many primitive domesticated breeds have two coats: coarse hairs covering shorter, finer fibres. Both are shed annually. Exploitation of wool for apparel in the Bronze Age encouraged breeding for denser fleeces and continuously growing white fibres. The Merino is regarded as the culmination of this process. Archaeological discoveries, ancient images and parchment records portray this as an evolutionary progression, spanning millennia. However, examination of the fleeces from feral, two-coated and woolled sheep has revealed a ready facility of the follicle population to change from shedding to continuous growth and to revert from domesticated to primitive states. Modifications to coat structure, colour and composition have occurred in timeframes and to sheep population sizes that exclude the likelihood of variations arising from mutations and natural selection. The features are characteristic of the domestication phenotype: an assemblage of developmental, physiological, skeletal and hormonal modifications common to a wide variety of species under human control. The phenotypic similarities appeared to result from an accumulation of cryptic genetic changes early during vertebrate evolution. Because they did not affect fitness in the wild, the mutations were protected from adverse selection, becoming apparent only after exposure to a domestic environment. The neural crest, a transient embryonic cell population unique to vertebrates, has been implicated in the manifestations of the domesticated phenotype. This hypothesis is discussed with reference to the development of the wool follicle population and the particular roles of Notch pathway genes, culminating in the specific cell interactions that typify follicle initiation.
The C40 city-network claims a position of global leadership in the governance of climate change. This chapter provides a brief overview of the history of the network, its member cities, and their collective aims and objectives. The chapter introduces the empirical puzzle around which the book is organized, namely the ability of the C40 to achieve coordinated action from a diverse collection of cities despite relying on voluntary participation and engagement. The ability to do so sets the C40 apart from other similar city-networks and begs the question as to how it has been able to achieve coordination and collective effort. The chapter asserts that such voluntary coordination is only possible through the formation of a collective identity and draws on ideas from the scholarship on social fields, social constructivism, and social movements to develop a theory of global urban governance fields that explains when, how, and why the C40 has managed to generate convergence around a set of governance norms and a shared governance identity.
The C40 has made assertive claims with respect to its ability to engender increased engagement, ambition, and scope of climate governance over both time and space. This chapter provides an independent corroboration of these claims, which have to-date been based on internal network data and analysis, by drawing on a novel dataset of over 10,000 climate governance actions adopted by C40 cities between 2001 and 2018. The chapter confirms that the C40 has increased the level of member city engagement, action, and ambition across geographic and economic divides. This renders the C40 distinct from other voluntary city-networks such as ICLEI and is deeply puzzling given the inability of these networks to deploy coercion or hard compliance mechanisms to close the gap between nominal commitments and concrete actions. The chapter concludes by considering three alternative explanations: as a function of economic development; as a function of inter-city learning, and as a function of the efforts of the network bureaucracy. Each is shown to be incomplete, thus demonstrating the need for a novel means of theorizing coordination in city-networks like the C40.
Whereas the C40 was fragmented in its early years, the network underwent a process of transformative change that began with the selection of Michael Bloomberg, as mayor of New York City, as C40 Chair in late 2009. As described in Chapters 1 and 3, both coordination and convergence around a common set of governance norms and a collective identity were increasingly apparent during the four-year period (2010-2014) in which New York occupied the C40 Chair. The theory of global urban governance fields is applied to explain why Bloomberg and New York were able to achieve what both the Clinton Climate Initiative and previous C40 Chairs could not. Bloomberg and New York brought with them considerable claims to material, reputational, and institutional capital, but it was the ability to link these to securing recognition for the cities of the C40 from external audiences – international financial institutions like the World Bank, multinational corporations, private capital markets – that authorized them to set the terms upon which such recognition would be granted within the governance field. In so doing the C40 began to converge toward a common set of governance norms – autonomy and global accountability – that underpin the production of coordinated action.
While voluntary city-networks lack formal mechanisms of coercion, they remain subject to complex political and power relations that shape their capacity to produce collective efforts. This chapter develops a general theory of global urban governance fields that brings to light the ways in which power is present in city-networks like the C40. The chapter starts from the premise that coordination in these networks requires convergence around a shared sense of what it means to “be” a global urban climate governor. While multiple actors – not only cities but also private corporations, philanthropic foundations, civil society organizations, and international organizations - seek to shape the content of field norms, practices, and collective identity, in newly created governance fields the authority to do so is contested. Actors make particular claims to authority, based on material resources, expertise, reputation, and institutional position, but only through the mechanism of recognition are these acknowledged as authoritative. The ability to secure recognition for the members of the governance field enables those actors to secure deference to particular terms of recognition (the governance norms, practices), shaping how governance is understood and practiced by those within the field.
Convergence and coordination in the C40 emerged as a function of the authority of Michael Bloomberg and New York City to establish and project onto the governance field a particular set of governance norms and a sense of collective identity. This chapter demonstrates the extent to which convergence around those norms and identity not only continued, but also rather accelerated, following the shift in C40 leadership that took place in early 2014. The analytic focus thus shifts from an emphasis on agency – who claims authority, how actors attempt to shape the substance of the governance field – to the structuring effects that governance fields exert once those ideational and identity contours are entrenched. The chapter documents the extent to which the C40 governance field, from 2014-2018, consolidated around governance norms of autonomous agency and global accountability. The theory of global urban governance fields is deployed to illuminate the manner in which these norms constitute both the parameters within which member cities have come to understand and enact their role as global climate governors, and the mechanism of recognition through which these norms are replicated and reinforced across the C40.
The C40 is in many ways a success story. It has generated increased engagement and coordination, with the vast majority of member cities now committed to the collective goal of carbon neutrality by midcentury. This level of coordination was virtually unthinkable a mere decade ago, and the theory of global urban governance fields helps to identify and explain its origins and underpinnings. The ability of the C40 to generate convergence and consolidation around a common understanding of how to “be” a global urban climate governor has enabled the C40 to generate collective effort in the face of voluntary participation. This chapter sets out the ways in which this insight contributes to pushing forward the scholarship on cities, global climate governance, and the role of cities in international relations more broadly. It also highlights important questions that emerge as a result, including the relationship between the content of C40 norm/identity convergence and the potential contribution it can make to achieving collective goals of decarbonization and transformative sustainability, how to measure and assess progress and performance, and for whom/to whom cities are rendering themselves accountable as global climate governors.