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Background: SMA1 is a neurodegenerative disease caused by bi-allelic survival motor neuron 1 gene (SMN1) deletion/mutation. In the phase 1 study, SMN GRT onasemnogene abeparvovec (AVXS-101) improved outcomes of symptomatic SMA1 patients. We report preliminary data of STR1VE, a pivotal study (NCT03306277) evaluating efficacy and safety of a one-time intravenous AVXS-101 infusion. Methods: STR1VE is a phase 3, multicenter, open-label, single-arm study in SMA1 patients aged <6 months (bi-allelic SMN1 loss, 2xSMN2). Primary outcomes: independent sitting for ≥30 seconds (18 months) and survival (14 months). Secondary outcomes: ability to thrive and ventilatory support (18 months). Exploratory outcomes: CHOP-INTEND and Bayley Scales of Infant and Toddler Development scores. Results: Enrollment is complete with 22 patients dosed. Mean age at symptom onset, genetic diagnosis, and enrollment was 1.9 (0–4.0), 2.1 (0.5–4.0), and 3.7 (0.5–5.9) months. At baseline, no patient required ventilatory/nutritional support, and all exclusively fed by mouth. Mean baseline CHOP-INTEND score was 32.6 (17.0–52.0), which increased 6.9 (-4.0–16.0, n=20), 10.4 (2.0–18.0, n=12), and 11.6 (-3.0–23.0, n=9) points at 1, 2, and 3 months; updates provided at congress. Conclusions: Preliminary data from STR1VE show rapid motor function improvements in SMA1 patients, paralleling phase 1 findings.
Childhood maltreatment (CM) plays an important role in the development of major depressive disorder (MDD). The aim of this study was to examine whether CM severity and type are associated with MDD-related brain alterations, and how they interact with sex and age.
Within the ENIGMA-MDD network, severity and subtypes of CM using the Childhood Trauma Questionnaire were assessed and structural magnetic resonance imaging data from patients with MDD and healthy controls were analyzed in a mega-analysis comprising a total of 3872 participants aged between 13 and 89 years. Cortical thickness and surface area were extracted at each site using FreeSurfer.
CM severity was associated with reduced cortical thickness in the banks of the superior temporal sulcus and supramarginal gyrus as well as with reduced surface area of the middle temporal lobe. Participants reporting both childhood neglect and abuse had a lower cortical thickness in the inferior parietal lobe, middle temporal lobe, and precuneus compared to participants not exposed to CM. In males only, regardless of diagnosis, CM severity was associated with higher cortical thickness of the rostral anterior cingulate cortex. Finally, a significant interaction between CM and age in predicting thickness was seen across several prefrontal, temporal, and temporo-parietal regions.
Severity and type of CM may impact cortical thickness and surface area. Importantly, CM may influence age-dependent brain maturation, particularly in regions related to the default mode network, perception, and theory of mind.
Cougar Mountain Cave is located in Oregon's Fort Rock Basin. In 1958, avocationalist John Cowles excavated most of the cave's deposits and recovered abundant fiber, lithic, wood, and osseous artifacts. A crew from the University of California, Davis returned to the site in 1966 to evaluate the potential for further research, collecting additional lithic and fiber artifacts from disturbed deposits and in situ charcoal from apparently undisturbed deposits. Because Cowles took few notes or photographs, the Cougar Mountain Cave collection—most of which is housed at the Favell Museum in Klamath Falls, Oregon—has largely gone unstudied even though it contains diagnostic artifacts spanning the Holocene and, potentially, the terminal Pleistocene. We recently submitted charcoal and basketry from the site for radiocarbon dating, providing the first reliable sense of when Cougar Mountain Cave was first occupied. Our results indicate at least a Younger Dryas age for initial occupation. The directly dated basketry has provided new information about the age ranges and spatial distributions of diagnostic textile types in the northwestern Great Basin.
In vitro techniques have been developed to facilitate the measurement of nutritional variability amongst food. Many kinetic studies have utilized the modified Tilley and Terry technique, with long-term incubations carried out in Erlenmeyer flasks. These are inefficient in utilizing incubator space for large scale studies. However substitution of Erlenmeyer flasks with tubes as fermentation units leaves the system prone to ‘bridging’, the formation of dense mats of forage particles by entrapped gas, above the level of the media in a fermentation unit. The objective of experiment 1 was to establish an effective incubation technique to eliminate the random variation caused by bridging.
Purpose: A peripherally inserted central catheter (PICC) is a useful option in providing secure venous access, which enables patients to be discharged earlier with the provision of home care. The objective was to identify the costs associated with having a PICC from a societal perspective, and to identify factors that are associated with total PICC costs.
Methods: Data were obtained from a retrospective cohort of 469 hospitalized pediatric patients with PICCs inserted. Both direct and indirect costs were estimated from a societal perspective. Insertion costs, complication costs, nurse and physician assessment costs, inpatient ward costs, catheter removal costs, home care costs, travel costs, and the cost associated with productivity losses incurred by parents were included in this study.
Results: Based on catheter dwell time, the median total cost associated with a PICC per patient per day (including inpatient hospital costs) was $3,133.5 ($2,210.7–$9,627.0) in 2017 Canadian dollars ($1.00USD = $1.25CAD in 2017). The adjusted mean cost per patient per day was $2,648.2 ($2,402.4–$2,920.4). Excluding inpatient ward costs, the median total and adjusted costs per patient per day were $198.8 ($91.8–$2,475.8) and $362.7($341.0–$386.0), respectively. Younger age, occurrence of complications, more catheter dwell days, wards with more intensive care, and the absence of home care were significant factors associated with higher total PICC costs.
Conclusions: This study has demonstrated the costs associated with PICCs. This information may be helpful for healthcare providers to understand PICC related cost in children and resource implications.
Body composition of animals may change (a) in response to treatments or (b) as they grow older. Studies on (a) generally model each component of composition separately, without the constraint that predicted components sum to 1 (e.g. Keane et al 1990). Allometric regression is widely used in studies of growth and differentiation (change in component proportions). This frequently involves estimating the parameters of a linear relation
between the logarithm of weight of an organ or part (Wi) and the logarithm of the weight of the whole animal (w). Sometimes the relation is between an organ and a part of the animal that contains the organ as a subcomponent. A similar difficulty as in (a) arises here also. The allometric regression equations can be recast to give predictive models for the composition of the animal at different weights. In this form the model is
Trauma code activation is initiated by emergency physicians using physiological and anatomical criteria, mechanism of injury, and patient demographic factors. Our objective was to identify factors associated with delayed trauma team activation.
We assessed consecutive cases from a regional trauma database from January 2008 to March 2014. We defined a delay in trauma code activation as a time greater than 30 minutes from the time of arrival. We conducted univariate analysis for factors potentially influencing trauma team activation, and we subsequently used multiple logistic regression analysis models for delayed activation in relation to mortality, length of stay, and time to operative management.
Patients totalling 846 were included for our analysis; 4.1% (35/846) of trauma codes were activated after 30 minutes. Mean age was 40.8 years in the early group versus 49.2 in the delayed group (p=0.01). Patients were over age 70 years in 7.6% in the early activation group versus 17.1% in the delayed group (p=0.04). There was no significant difference in sex, type of injury, injury severity, or time from injury between the two groups. There was no significant difference in mortality, median length of stay, or median time to operative management.
Delayed activation is linked with increasing age with no clear link to increased mortality. Given the severe injuries in the delayed cohort that required activation of the trauma team, further emphasis on the older trauma patient and interventions to recognize this vulnerable population should be made.
Oregon's Fort Rock Cave is iconic in respect to both the archaeology of the northern Great Basin and the history of debate about when the Great Basin was colonized. In 1938, Luther Cressman recovered dozens of sagebrush bark sandals from beneath Mt. Mazama ash that were later radiocarbon dated to between 10,500 and 9350 cal B.P. In 1970, Stephen Bedwell reported finding lithic tools associated with a date of more than 15,000 cal B.P., a date dismissed as unreasonably old by most researchers. Now, with evidence of a nearly 15,000-year-old occupation at the nearby Paisley Five Mile Point Caves, we returned to Fort Rock Cave to evaluate the validity of Bedwell's claim, assess the stratigraphic integrity of remaining deposits, and determine the potential for future work at the site. Here, we report the results of additional fieldwork at Fort Rock Cave undertaken in 2015 and 2016, which supports the early Holocene occupation, but does not confirm a pre–10,500 cal B.P. human presence.
We saw in the previous chapter that one of the key roles of judicial agents of state in Australia is to render other agents of state accountable for their actions. That judicial agents are both legally empowered to do so and actually do so is a fundamental condition of the operation of the rule of law in Australia. As such, the exercise of judicial power also serves as a key mechanism in Australian public law for the protection of individual rights – particularly against any intrusion upon them by the executive government and its bureaucracy. The key means by which the judiciary calls administrative agents to account for their actions under the law is termed the judicial review of administrative action.
The judicial review of administrative action is concerned with:
• determining the lawfulness or validity of the actions of administrative agents with reference to the public law which creates, empowers, limits and regulates those agents; and
• providing an appropriate response to any unlawfulness found.
Such judicial review is a remedial mechanism in the sense that:
• it is initiated by persons whose rights or interests have been affected by purportedly unlawful administrative action; and
• it provides a remedy to those persons where unlawfulness is found.
Aronson and Groves describe the judicial review of administrative action in terms of ‘an application for a judicial remedy focused specifically on declaring the illegality of government action and on that illegality's immediate consequences’. The High Court has repeatedly pointed out, however, that providing a remedy to affected persons is not the primary rationale of judicial review. Its primary rationale is to declare and enforce the law against administrative agents who would act outside or in contravention of the law.
In Attorney-General (NSW) v Quin, Brennan J said that:
judicial review [is] invoked, and invoked beneficially, to set aside administrative acts and decisions which are unjust or otherwise inappropriate, but only when the purported exercise of power is excessive or otherwise unlawful.
In The Foundations of Australian Public Law, Anthony J. Connolly brings together the two traditionally discrete areas of constitutional and administrative law to present Australian public law as a single, integrated body. Exploring the themes of state, power and accountability in Australia, the text also makes reference to the law of international jurisdictions, where students are informed by contemporary public law theory. Particular attention is also given to the rise of global public law and the increasingly cosmopolitan nature of the subject in Australia. A comprehensive companion website complements the theory and discussion throughout the text and includes chapter summaries, further readings and discussion questions to encourage extended student learning. Written by a leader in the field, The Foundations of Australian Public Law is a key text for students looking to gain a comprehensive understanding of public law across Australia's federal, state and territory jurisdictions.
In order for a legal system to pursue effectively the realisation of its generic functions and specific social ends and values – whether politico-moral or policy-based – its private legal subjects and its public officials must, to some significant extent, comply with its laws. There are two dimensions of this compliance requirement. First, private legal subjects and public officials must have (or must be able to acquire) a reasonably clear idea of what the law actually is and how it is to apply to a given factual situation. They must be able to comply with the law, if they are so disposed. They must have a reasonably clear idea of what their respective legal rights and duties are. The second dimension of the compliance requirement is that those who do not comply – or who, more broadly, are not disposed to comply with the law – are brought to account for that non-compliance. This is to say that the law must be appropriately enforced upon its subjects, including public officials.
These particular demands of a legally governed society are served by the promulgation of a category of secondary legal rules (rules of public law) which we termed in Chapter 1, ‘rules of adjudication’. Such rules provide for:
• the authoritative identification of the operative law in the society – including the authoritative interpretation of the meaning of legal texts such as constitutions, statutes and regulations; and
• the authoritative resolution of disputes arising under that law – including disputes or questions as to whether there has been compliance by an agent with relevant law.
These rules perform their role by creating, empowering, regulating and calling to account adjudicative agents of state (magistrates, judges, courts, and the like) whose role is to authoritatively identify both the content and the application of the law in the course of authoritatively settling disputes concerning the legal rights and obligations of law's subjects, both private and public.
We saw in Chapter 1 that although the generic functions of law and state in maintaining social order and security, coordinating social agents, and creating formal social roles and responsibilities are common to all legal systems and states, different states and their legal systems may be oriented towards the pursuit of quite different social ends and values. The most important set of ends and values a state and its legal system are oriented towards comprises the political morality of that state and legal system. The political morality of a state is the set of fundamental ends and values concerned with how the people in the society should be treated and how the society as a whole should ultimately operate. It reflects the kind of social governance arrangements considered most desirable by law's beneficiaries. It embodies a conception not only of the kind of society law's beneficiaries think ought to be sought after but also the kind of state most conducive to the realisation and maintenance of such a society, as well as the way the pursuit of that ideal by the state should be carried out.
An important point here is that the fundamental politico-moral values of a state generally serve or otherwise reflect its fundamental politico-moral ends. So, for example, one fundamental political end of a state might be the realisation of a society in which all members are treated with equal respect – including by the state itself. The political end here is the establishment of a state which treats all its subjects optimally and equally with respect, and which ensures that its subjects treat each other likewise. However, a state whose present-day actions and ongoing dealings with its subjects were not, at least, guided by the principle or value that those subjects should be accorded an optimal and equal degree of respect by state agents would not be effective in realising that fundamental and longer-term end. The pursuit of the fundamental end in question demands a present and ongoing compliance with the value here.
Thus, within a political morality, the distinction between ends and values may not be readily discernible. In the case just mentioned, the end and the value in question are virtually identical in their content.