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Survivors of paediatric intracranial tumours are at increased risk of psychosocial, neuro-developmental, and functional impairment. This study aimed to evaluate long-term health-related quality-of-life (HRQOL) outcomes in patients with benign paediatric brain tumours treated curatively with surgical resection alone.This was a cross-sectional study of patients with benign paediatric intracranial tumours managed with surgery alone between 2000 and 2015. Eligible patients with a minimum of 5-years follow-up after surgery were identified. Validated health-related quality of life (HRQOL) questionnaires were administered: SF-36, QLQ-BN20, QLQ-C30 and PedsQL™.Twenty-three patients participated (median age at surgery 13 years; range 1-18; 12 male). The most common diagnosis was pilocytic astrocytoma (n = 15). Median time from surgery to participation was 11 years(range 6-19). Fourteen patients achieved A-level qualifications and two obtained an undergraduate degree. Twelve patients were employed, eight were studying and three were unemployed or volunteering. HRQOL outcomes demonstrated significant limitation from social functioning (p = 0.03) and cognitive functioning (p = 0.023) compared to the general population. Patients also experienced higher rates of loss of appetite (p = 0.009) and nausea and vomiting (p = 0.031). Ten patients were under transitional teenager and young-adult (TYA) clinic follow-up. TYA patients achieved higher levels of education (p = 0.014), were more likely to hold a driver's license (p = 0.041) compared to patients not followed-up through these services.Childhood brain-tumour survivors have a greater risk of developing psychological, neuro-cognitive and physical impairment. Early comprehensive assessment, specialist healthcare and TYA services are vital to support these patients.

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In two recent cases, one in the USA and the other in the UK, courts have considered conscientious objection claims made by cake bakers who objected to providing a cake for the celebration/advocacy of same-sex marriage. I will argue that the issue in these cases is not the reasonable balance between the individual’s religious interests and the interests or rights of others in the community but is instead whether the individual’s religiously based objection should be viewed as an expression of personal religious conscience or as a (religiously grounded) civic position or action that falls outside the scope of religious freedom protection. In determining whether a conscientious objection should be viewed as a personal/spiritual matter or instead as a civic/political position, two factors are relevant. The first is whether the individual is being required to perform the particular act (to which she/he objects) because she/he holds a special position not held by others. The other factor is the relative remoteness/proximity of the act that the objector is required to perform from the act that she/he considers to be inherently immoral. The more remote the legally required action, the more likely we are to regard the objection as a political position.

The term “conscience” is used in two different ways in discussions about religious freedom. Sometimes, conscience is contrasted with religion. Freedom of conscience, in contrast to freedom of religion, is concerned with the protection of fundamental beliefs or commitments that are not part of a religious or spiritual system.1 Together, freedom of conscience and freedom of religion protect the individual’s most fundamental moral beliefs or commitments.2 Other times, though, the term “conscience” refers to a particular kind of accommodation claim. In most religious accommodation cases, an individual or group seeks to be exempted from a law that prevents them from engaging in a religious practice — for example, from wearing religious dress or keeping religious holidays. In conscientious objection cases, how- ever, the individual asks to be exempted from a law that requires them to perform an act that they regard as immoral or sinful. In many of these cases the claimant asks to be excused from performing an act that is not itself immoral, but supports or facilitates what they see as the immoral action of others, and so makes them complicit in this immorality. In this comment I will focus on this second use of the term conscience, and more particularly the conscientious objection claim made by some medical practitioners in Ontario to the requirement that they provide an effective referral to another doctor when they are unwilling, for moral or religious reasons, to perform a particular medical procedure(...) 1 The term “freedom of conscience” was once used interchangeably with freedom of religion to refer to an individual’s freedom to hold beliefs that were spiritual or moral in At this earlier time the moral beliefs of most individuals were rooted in a religious system. Freedom of conscience, though, is now viewed as an alternative to, or extension of, freedom of religion.2 However, as I have argued elsewhere, the conscience part of section 2(a) is seldom raised before the courts and may have very little practical See Richard Moon, “Conscience in the Image of Religion” in John Adenitire, ed, Religious Beliefs and Conscientious Exemptions in a Liberal State (Oxford: Hart, 2019) 73.

A commitment to freedom of expression means that an individual must be free to speak to others and to hear what others may say, without interference from the state. It is said that the answer to bad or erroneous speech is not censorship, but rather more and better speech. Importantly the listener, and not the speaker, is seen as responsible (as an independent agent) for his or her actions, including harmful actions, whether these actions occur because he or she agrees or disagrees with the speaker’s message.

AIMS Survivors of paediatric intracranial malignancies are at increased risk of psychosocial, neuro-developmental and functional impairment, important measures of patients’ well-being. This study aimed to evaluate long-term quality of life outcomes (QOL) in patients with benign paediatric brain tumours treated curatively with surgical resection alone. METHOD Cross-sectional cohort study of benign paediatric intracranial tumours managed with surgery alone between 2000-2015. Validated QOL questionnaires were administered: SF-36, QLQ-BN20, QLQ-C30 and PedsQLTM. RESULTS Twenty-three patients participated (median age at surgery 13 years; range 1-18), twelve were male. The most common diagnosis was pilocytic astrocytoma (n=15). Median time from surgery to participation was 11 years (range 6-19). Fourteen patients achieved A-level qualifications and two obtained an undergraduate degree. Twelve patients were employed, eight were studying and three were unemployed or volunteering. Twelve patients were currently driving. QOL outcomes demonstrated significant limitation from social functioning (p=0.03) and cognitive functioning (p=0.023) compared to the general population norms. Patients also experienced increased loss of appetite (p=0.009) and symptoms of nausea and vomiting (p=0.031). Ten patients were under transitional teenager and young-adult (TYA) clinic follow-up. TYA patients achieved higher levels of education (p=0.014), were more likely to hold a driver’s license (p=0.041) and had improved physical functioning (p=0.005) compared to patients not transitioned through these services. CONCLUSION Childhood brain-tumour survivors are particularly vulnerable and at greater risk of developing psychological, neuro-cognitive, socialisation and physical development challenges. Early identification, comprehensive assessment and specialist TYA cancer healthcare input are vital to support these patients and improve their quality of life.

AIMS This study aimed to describe our institutional use of a commercially available mixed reality viewer within a multi-disciplinary planning workflow for awake craniotomy surgery and to report an assessment of its usability. METHOD Three Tesla MRI scans, including 32-direction diffusion tensor sequences, were reconstructed with BrainLab Elements auto-segmentation software. Magic Leap mixed reality viewer headsets were registered to a shared virtual viewing space to display image reconstructions. System Usability Scale was used to assess the usability of the mixed reality system. RESULTS The awake craniotomy planning workflow utilises the mixed reality viewer to facilitate a stepwise discussion through four progressive anatomical layers; skin, cerebral cortex, subcortical white matter tracts and tumour with surrounding vasculature. At each stage relevant members of the multi-disciplinary team reviewed key operative considerations, including patient positioning, cortical and subcortical speech mapping protocols and surgical approaches to the tumour. The mixed reality system was used in 10 consecutive awake craniotomy procedures over a 5-month period. Ten participants (2 Anaesthetists, 5 Neurosurgical trainees, 2 Speech therapists, 1 Neuropsychologist) completed System Usability Scale assessments, reporting a mean score of 71.5. Feedback highlighted the benefit of being able to rehearse important steps in the procedure, including patient positioning and anaesthetic access and visualising the testing protocol for cortical and subcortical speech mapping. CONCLUSION This study supports the use of mixed reality for multi-disciplinary planning for awake craniotomy surgery, with an acceptable degree of interface usability. We highlight the need to consider the requirements of non-technical, non-neurosurgical team members when involving mixed reality activities.

BACKGROUND There are many questions that remain unanswered regarding outcomes following cranioplasty including the timing of cranioplasty following craniectomy as well as the material used. OBJECTIVE To establish and evaluate 30-d outcomes for all cranial reconstruction procedures in the United Kingdom (UK) and Ireland through a prospective multicenter cohort study. METHODS Patients undergoing cranioplasty insertion or revision between June 1, 2019 and November 30, 2019 in 25 neurosurgical units were included. Data collected include demographics, craniectomy date and indication, cranioplasty material and date, and 30-d outcome. RESULTS In total, 313 operations were included, consisting of 255 new cranioplasty insertions and 58 revisions. Of the new insertions, the most common indications for craniectomy were traumatic brain injury (n = 110, 43%), cerebral infarct (n = 38, 15%), and aneurysmal subarachnoid hemorrhage (n = 30, 12%). The most common material was titanium (n = 163, 64%). Median time to cranioplasty was 244 d (interquartile range 144-385), with 37 new insertions (15%) within or equal to 90 d. In 30-d follow-up, there were no mortalities. There were 14 readmissions, with 10 patients sustaining a wound infection within 30 d (4%). Of the 58 revisions, the most common reason was due to infection (n = 33, 59%) and skin breakdown (n = 13, 23%). In 41 (71%) cases, the plate was removed during the revision surgery. CONCLUSION This study is the largest prospective study of cranioplasty representing the first results from the UK Cranial Reconstruction Registry, a first national registry focused on cranioplasty with the potential to address outstanding research questions for this procedure.

In most religious accommodation cases, an individual or group seeks to be exempted from a law that restricts their religious practice. The accommodation claim, though, has a slightly different form in conscientious objection cases. In these cases, an individual asks to be exempted not from a law that restricts his/her religious practice, but instead from a law that requires him/her to perform an act that he/she regards as immoral. In many of these cases the claimant asks to be excused from performing an act that is not itself “immoral” but that supports or facilitates (what she/he sees as) the immoral action of others, and so makes him/her complicit in this immorality. In recent years, the Canadian courts have dealt with a number of conscientious objection claims and, as in other jurisdictions, the number of these claims seems to be growing. The issue in these conscientious objection cases is not, as the courts sometimes say, the reasonable balance between the individual’s spiritual commitments or interests and the interests or rights of others in the community. The significant issue, in these cases, is whether the religiously-based objection should be viewed as a personal spiritual practice/commitment that should be accommodated, if this can be done without any noticeable harm others, or instead whether it should be viewed as political – as a position, on the rights and interests of other in the community, or on the rightness of the law, that should be subject to the give-and-take of ordinary political decision-making.

We identified and characterized a series of pyrazole amides as potent, selective Ca v 3.1-blockers. This series culminated with the identification of pyrazole amides 5a and 12d , with excellent potencies and/or selectivities toward the Ca v 3.2- and Ca v 3.3-channels. This compound displays poor DMPK properties, making its use difficult for in vivo applications. Nevertheless, this compound as well as analogous ones are well-suited for in vitro studies.

Background Significant safety concerns remain surrounding the use of nonsteroidal anti-inflammatory drugs (NSAIDs) following gastrointestinal surgery, leading to wide variation in their use. This study aimed to determine the safety profile of NSAIDs after major gastrointestinal surgery. Methods Consecutive patients undergoing elective or emergency abdominal surgery with a minimum one-night stay during a 3-month study period were eligible for inclusion. The administration of any NSAID within 3 days following surgery was the main independent variable. The primary outcome measure was the 30-day postoperative major complication rate, as defined by the Clavien–Dindo classification (Clavien–Dindo III–V). Propensity matching with multivariable logistic regression was used to produce odds ratios (OR) and 95 % confidence intervals. Results From 9264 patients, 23.9 % (n = 2212) received postoperative NSAIDs. The overall major complication rate was 11.5 % (n = 1067). Following propensity matching and adjustment, use of NSAIDs were not significantly associated with any increase in major complications (OR 0.90, 0.60–1.34, p = 0.560). Conclusions Early use of postoperative NSAIDs was not associated with an increase in major complications following gastrointestinal surgery.

Canada is often cited as one of the principal sources of proportionality analysis – an approach to the determination of limits on constitutional rights that has been adopted in many jurisdictions. The two-step structure of constitutional rights adjudication is built on the idea that these rights are the basic conditions of individual autonomy or liberty that must be protected from the demands of collective welfare. At the first stage of the adjudication the court determines whether the restricted activity falls within the scope of the right. At the second stage the court balances the right against the competing interest advanced by the restrictive law to determine whether the restriction is justified. Yet few of these rights fit this individual liberty model and are better understood as social or relational in character, protecting different aspects of the individual's interaction or connection with others in the community. If we recognise that most constitutional rights do not simply protect individual autonomy but instead protect different aspects of human flourishing or dignity within community then two conclusions may follow. First, there can be no single generic test for limits on rights. The form or character of ‘limitations’ on these rights may differ in significant ways. Second, the two steps of adjudication may often be difficult to separate, or the separation may seem quite artificial. Many of the issues addressed by the courts will not fit easily into the two-step structure of analysis because the ‘competing’ interests are really different dimensions of a social relationship.

A series of dihydropyrazole derivatives was developed as potent, selective, and brain-penetrating T-type calcium channel blockers. An optimized derivative, compound 6c, was advanced to in vivo studies, where it demonstrated efficacy in the WAG/Rij rat model of generalized nonconvulsive, absence-like epilepsy. Compound 6c was not efficacious in the basolateral amygdala kindling rat model of temporal lobe epilepsy, and it led to prolongation of the PR interval in ECG recordings in rodents.

A commitment to free speech means protecting speech for reasons that are independent of the truth or merit of its content. This commitment, though, depends on certain assumptions or conditions – most notably that individuals are capable of making reasoned and independent judgments and have access to different opinions and reliable factual information. These conditions, of course, never hold perfectly, but they now seem to be eroding at a rapid pace. The character of public speech has changed in the internet era: how we speak to one another and how we experience that speech. Audiences have become more fragmented. Disinformation and conspiracy theories seem to spread easily and widely, so that distortion and deceit rather than direct censorship may now be the most significant threat to public discourse. There is little common ground in the community on factual matters or the reliability of different sources of information, which has made it difficult, even impossible, to discuss issues and to agree or compromise on public policy. Those who hold competing positions seem rarely to engage with one another and, when they do, their engagement is often combative. A growing number of people feel they should not be expected to hear speech with which they disagree, or which is critical of their views. The spaces or platforms in which public speech occurs have become increasingly privatized and therefore outside the scope of the constitutional right to freedom of expression. What future does the right to free speech have in this changing communication environment?

This paper examines the recent Supreme Court of Canada judgment in LSBC v. TWU, in which the court upheld the decision of the BC law society not to accredit a law program proposed by an Evangelical Christian university. The paper argues that the task for the courts in this and other religious freedom cases is not to balance competing civic and religious interests but is instead to mark the boundary between the spheres of civic and spiritual life. More particularly, in this case, the issue was whether TWU (in applying to operate an accredited law program) should be viewed as a private religious institution that is free to govern itself according to its own norms, or whether, because its actions directly impact outsiders to the religious group, it should be viewed as performing a public role and therefore subject to non-discrimination and other civic norms. The different judgments in the case begin with different assumptions about the public/private character of TWU (or at least its proposed law program) and so never really address the key issue and never really engage with each other. The paper argues that because admission to law school continues to be a significant barrier to entry into the legal profession in Canada, TWU’s admission decisions will have an impact on non-members. The law society, therefore, was justified in requiring TWU to conform to non-discrimination norms as a condition of accreditation.

Pierre Trudeau’s deep personal commitment to Catholicism was largely unknown to Canadians during his tenure as Prime Minister. Indeed, his religious commitment did not play an obvious role in his political life. Trudeau’s version of Catholicism, ‘personalism’, emphasized the personal – interior – spiritual commitment of the individual and the necessity of the separation of religion and politics. He stressed the importance of individual liberty in matters of faith but also the personal responsibility of the individual to serve others and work towards a more just society. Trudeau was opposed to the recognition of an official religion, and indeed to any form of state promotion of a particular religious belief system. He rejected the assumption that political community or social solidarity required a shared (and public) commitment to a particular faith or culture. His promotion of multiculturalism stemmed from his belief that national identity or political membership should not be based on a shared ethnicity that would necessarily include some and exclude others. His championing of the Charter of Rights rested on the view that citizenship should be grounded instead on a shared commitment to the protection of individual and democratic rights. Trudeau was a committed believer and a secular politician, who sought to separate his public action and private conscience. In a sense then he embodied the separation of religion and politics – of church and state – that is central to the contemporary conception of religious freedom. In this chapter, I want to explore the challenge of separating personal or communal spiritual life from civic life which Trudeau had to navigate, throughout his political career.

In Mouvement laique v Saguenay the Supreme Court of Canada held that the recitation of a prayer at the opening of a municipal council’s public meeting breached ‘the state’s duty of neutrality’ in matters of religion. The comment discusses some of the difficulties or challenges raised by the Court's commitment to religious neutrality.

We identified and characterized a series of pyrazole amides as potent, selective Ca

Despite the availability of numerous antiepileptic drugs, 20-30% of epileptic patients are pharmacoresistant with seizures not appropriately controlled. Consequently, new strategies to address this unmet medical need are required. T-type calcium channels play a key role in neuronal excitability and burst firing, and selective triple T-type calcium channel blockers could offer a new way to treat various CNS disorders, in particular epilepsy. Herein we describe the identification of new 1,4-benzodiazepines as brain penetrant and selective triple T-type calcium channel blockers. From racemic hit 4, optimization work led to the preparation of pyridodiazepine 31c with improved physicochemical properties, solubility, and metabolic stability. The racemic mixture was separated by chiral preparative HPLC, and the resulting lead compound (3R,5S)-31c showed promising efficacy in the WAG/Rij-rat model of generalized nonconvulsive absence-like epilepsy.

The Canadian courts initially described section 2(a) of the Canadian Charter of Rights and Freedoms [Charter], freedom of conscience and religion, as the liberty to hold, and live in accordance with, spiritual or other fundamental beliefs without state interference [Big M 1985].1 Freedom of religion, understood as a liberty, precludes the state from compelling an individual to engage in a religious practice and from restricting his/her religious practice without a legitimate public reason. In later judgments, however, there has been a shift in the courts’ description of the interest protected by the freedom, from liberty to equality. According to the courts, the freedom does not simply prohibit state coercion in matters of religion or conscience; it requires also that the state treat religious belief-systems or communities in an equal or even-handed manner. The state must not support or prefer the religious practices of one religious group over those of another (religion or religious contest should be excluded from politics), and it must not restrict the practices of a religious group, unless this is necessary to protect a compelling public interest (religion should be insulated from politics). The requirement of state neutrality was most recently and clearly affirmed in the unanimous judgment of the Supreme Court of Canada in Mouvement laique v. Saguenay: “[A] duty of religious neutrality on the state… results from an evolving interpretation of freedom of conscience and religion” [Mouvement laique 2015: para. 71].

Many recent hate speech cases in Canada, Europe, and elsewhere involve religion either as the source of views that are alleged to be hateful or as the target of such views and sometimes, of course, as both the source and target of these views. This chapter explores the difference religion makes to the application of hate speech laws – when it is the target of this speech. The ‘religious’ hate speech cases are difficult for the same reason that all hate speech cases are difficult. There is significant disagreement in the community about whether, or to what extent, the restriction of hate speech can be reconciled with the public commitment to freedom of expression. There is, however, another reason why hate speech cases involving religion are so difficult, which stems from our complex conception of religious adherence or membership – as both a personal commitment and a cultural identity. The chapter focuses on anti-Muslim speech in Canada.

The question of whether a province can require civil marriage commissioners to perform same sex marriages, over their religious objections, has been addressed by the Canadian courts in a series of cases. In each of these cases the issue is framed by the courts as a contest between religious freedom and sexual orientation equality that must be resolved through the balancing of these competing interests. And in each of these cases the court strikes the balance in favour of sexual orientation equality, determining that the equality rights of same-sex couples outweighs the religious freedom of marriage commissioners. Despite what they say, the courts in these cases do not balance or trade-off religious freedom and sexual orientation equality, but instead give complete priority to the latter. A refusal by a marriage commissioner to perform a same-sex civil marriage ceremony is viewed by the courts as the cause of harm or injury to the couple (an act of discrimination) and not simply as a competing claim. I will argue that there is no balancing in these cases because there is no freedom of religion interest to be balanced against the right to sexual orientation equality. The marriage commissioner’s freedom of religion lacks substance not, or not simply, because the commissioner is a public official, or because the interference with his/her religious beliefs is indirect or partial. Rather the religious objection of the marriage commissioner falls outside the scope of freedom of religion under section 2(a) of the Canadian Charter of Rights and Freedoms [the Charter], because it involves a belief about how others in the community should behave and be treated. A marriage commissioner has no claim to be exempted from the duties of his or her position on the basis of such a belief.

We report here the discovery and pharmacological characterization of N-(1-benzyl-1H-pyrazol-3-yl)-2-phenylacetamide derivatives as potent, selective, brain-penetrating T-type calcium channel blockers. Optimization focused mainly on solubility, brain penetration, and the search for an aminopyrazole metabolite that would be negative in an Ames test. This resulted in the preparation and complete characterization of compound 66b (ACT-709478), which has been selected as a clinical candidate.