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Focal seizures begin in the epileptogenic zone (EZ), a theoretical concept that evades practical identification and definition. Recently researchers have considered the more experimentally tractable “core” to elucidate the origins and behaviors of focal seizures. This millimeter-scale core is recruited by a wavefront of hyper-excitatory activity, in which inhibitory neurons fail to fire despite supra-threshold excitation. Herein we argue that the same failure of inhibition (FoI) as in the focal core may be critical to a theoretical understanding of the EZ. In contrast, most models of neural population activity have assumed that with increasing pre-synaptic input, population activity only increases. Two population models have recently made the critical step to account for FoI, with substantial success in modeling data from focal seizures. We provide a first-principles derivation from a single neuron model to a novel population model analogous to prior models. We show that our model fits as well or better than prior ad hoc FoI models on synthetic neural input-response data. We motivate the tristability of our model: having states of rest, functional activity, and pathological seizure. By analysing the transitions between these states, we can characterize seizure susceptibility and rescuability relative to functional excitability and stability. Thus, by relating a drug’s mechanism of action to our model parameters , our model can predict not only its nuanced effect on focal seizure, but also its effect on functional activity. The balance of these two effects is a key consideration in the clinical feasibility of an anti-epileptic drug.

Penalty kicks often play a decisive role in the most prestigious international football tournaments. The present study investigated whether shooting performance of the penalty kick in football would be improved by providing specific attentional and motivational instructions. Twenty-four experienced male volunteers were asked to kick a ball at one of four targets located in a regulation-sized goal. Using a goalkeeper-independent strategy, subjects performed the penalty kicks under external focus (EF; targets in the goal), autonomy support (AS; choice of target order), combining external focus and autonomy support (EF/AS), and control conditions (C). A goalkeeper tried to save the ball during each attempt. The mean number of scored goals and kicking accuracy of goal scored were used to determine penalty kick performance. The EF/AS combination enhanced the number of goals scored compared to the C condition. No other significant differences were observed between the conditions in the number of goals scored. The EF/AS group displayed greater kicking accuracy of goals scored relative to the AS and C conditions. Also, the kicking accuracy of the EF condition was significantly better than the C condition. Additionally, the results demonstrated that the EF/AS condition resulted in fewer missed shots compared to the C condition. There were no significant differences in blocked shots between the conditions. The findings suggest that promoting an external focus of attention and autonomy support collectively may enhance penalty kick performance.

Countries across West Africa began reporting COVID-19 cases in February 2020. By March, the pandemic began disrupting activities to control and eliminate neglected tropical diseases (NTDs) as health ministries ramped up COVID-19–related policies and prevention measures. This was followed by interim guidance from the WHO in April 2020 to temporarily pause mass drug administration (MDA) and community-based surveys for NTDs. While the pandemic was quickly evolving worldwide, in most of West Africa, governments and health ministries took quick action to implement mitigation measures to slow the spread. The U.S. Agency for International Development’s (USAID) Act to End NTDs | West program (Act | West) began liaising with national NTD programs in April 2020 to pave a path toward the eventual resumption of activities. This process consisted of first collecting and analyzing COVID-19 epidemiological data, policies, and standard operating procedures across the program’s 11 countries. The program then developed an NTD activity restart matrix that compiled essential considerations to restart activities. By December 2020, all 11 countries in Act | West safely restarted MDA and certain surveys to monitor NTD prevalence or intervention impact. Preliminary results show satisfactory MDA program coverage, meaning that enough people are taking the medicine to keep countries on track toward achieving their NTD disease control and elimination goals, and community perceptions have remained positive. The purpose of this article is to share the lessons and best practices that have emerged from the adoption of strategies to limit the spread of the novel coronavirus during MDA and other program activities.

The COVID-19 pandemic has presented many issues for courts, often requiring immediate consideration and swift delivery of reasons Nevertheless, experience has taught us that, in times of crisis, heightened vigilance must be afforded to the protection of individual rights Two judgments delivered at the peak of the pandemic illuminate the fragility of rights in the face of wider societal concerns Both cases contain statements of purported principle which are legally dubious and, if left unqualified, have the potential to fundamentally dilute the protections afforded by the European Convention on Human Rights © 2020 Thomson Reuters and Contributors

COVID-19 is a highly contagious infection with no proven treatment. Approximately 2.5% of patients need mechanical ventilation while their body fights the infection.1 Once COVID-19 patients reach the point of critical illness where ventilation is necessary, they tend to deteriorate quickly. During the pandemic, patients with other conditions may also present at the hospital needing emergency ventilation. But ventilation of a COVID-19 patient can last for 2–3 weeks. Accordingly, if all ventilators are in use, there will not be time for patients to ‘queue up’ to wait for those who arrived earlier to recover. Those who need a ventilator will die if they do not receive access to one quickly. Many nations now face the prospect that they failed to prepare appropriately for this foreseen risk of pandemic (another issue worthy of legal analysis) and that their populations will need far more ventilators than the health service can supply. For many weeks, the UK has been anticipating a surge of COVID-19 infections that could leave patients queuing in hospitals for ICU care. Luckily, social distancing has ‘flattened the curve’ and this problem might not arise. There is still a degree of risk, however, and other countries will not be so lucky. At some point, during this pandemic or the next, all countries will need to answer hard questions about whether and when scarce ICU resources (such as ventilators, beds and staff) should be either withheld or withdrawn from certain groups of patients solely for the purpose of providing them to others. Attempts to answer these questions can be found in a wide range of ICU triage protocols and ethical guidance documents, many of which embrace the foundational principle of ‘save the most lives’. Unfortunately, this worthwhile goal has generated many suggestions that could violate the law. This article identifies …

Brick-manufacturing is an intensive water-consuming industry that requires a sustainable and integrated water management strategy to reduce reliance on freshwater consumption. This study aims to develop a rigorous analytical tool based on water footprint principles and water pinch analysis techniques that can be used to manage and optimise water consumption. By performing thorough water audits, the water consumption footprint (the sum of blue and green water footprints) and the theoretical water pollution footprint (grey water footprint) were quantified. The total water consumption footprint of a brick is determined as 2.02 L, of which blue water is identified as 1.71 L (84.8%) and green water as 0.31 L (15.2%). The theoretical grey water footprint of a brick was found to be 1.3 L, a value that would have been higher if in-situ wastewater treatment had not been operated before effluent discharge. In order to reduce the water footprint of a brick, water pinch analysis techniques were applied for the brick-manufacturing processes. Two water recovery schemes were explored, i.e. direct re-use/recycle and water regeneration. For the former, water targeting was first carried out using the material recovery pinch diagram. Next, an algebraic technique was utilised for the targeting of water regeneration, where an interception unit is used to partially purify the water sources for further re-use/recycle. The network that fulfils the water flow rate targets was then designed using the nearest neighbour algorithm. The calculation indicates that direct re-use/recycle scheme reduces with the standard water consumption footprint reduced only by 15.6%. Water regeneration scheme, on the other hand improved the current value (which relies on an unsystematic water regeneration scheme) by 56.4%. The analysis clearly shows that the water consumption footprint of a brick is improved when the brick-manufacturing industry operates sustainable water management strategies. This study, a first of its kind, demonstrates that integration of water pinch analysis coupled with water footprint concepts, provides a robust and effective tool for the manufacturing industries that aim for sustainable water consumption.

At some point during this pandemic or next, all countries will need to answer hard questions about whether and when scarce ICU resources (such as ventilators, beds and staff) should be either withheld or withdrawn from certain groups of patients solely for the purpose of providing them to others. Attempts to answer these hard questions can be found in ICU triage protocols and ethical guidance documents, many of which embrace the foundational principle of ‘save the most lives’. Unfortunately, this worthwhile goal has generated many suggestions that could violate the law. This article identifies 10 ways in which the withholding or withdrawal of a clinically indicated ventilator might violate a patient’s rights, along with recommendations on how to avoid doing so. While our analysis is based on UK law, its lessons are relevant for other countries with similar legal systems. If the issues we identify are not addressed, doctors may act unlawfully. Worse, patients may die unlawfully.

THE appeal in R. (on the application of SG) (previously JS) v Secretary of State for Work and Pensions (Child Poverty Action Group and another intervening) [2015] UKSC 16 concerned a challenge to the cap on welfare benefits, one of the measures introduced as part of the Government's austerity-driven economic and social policy. The “benefit cap” operates to limit the amount of welfare benefits that can be received by non-working households, to the equivalent net median earnings of a working household. The Welfare Reform Act 2012 contains provisions allowing the Secretary of State to make regulations providing for a “benefit cap” scheme. It is implemented through the Benefit Cap (Housing Benefit) Regulations 2012 and operates by a reduction in housing benefit once a specified maximum amount is reached. Benefits covered by the cap include housing benefit, child benefit, and child tax credit. Once the cap is reached, no account is taken of the number of children in the family. The lawfulness of the Act itself was not challenged. The appellants’ argument was that the implementation of the scheme was discriminatory and contrary to the Human Rights Act 1998.

IN a groundbreaking decision, the Supreme Court of Canada in Carter v Canada (Attorney General) 2015 SCC 5 has declared the criminal law measures prohibiting the provision of assistance in dying unconstitutional. In doing so, the Supreme Court unanimously overruled its previous decision (Rodriguez v British Columbia (Attorney-General) [1993] 3 S.C.R. 519) upholding the blanket prohibition on assisted suicide.

During thymopoiesis, a unique program of gene expression promotes the development of CD4 regulatory T (T reg) cells. Although Foxp3 maintains a pattern of gene expression necessary for T reg cell function, other transcription factors are emerging as important determinants of T reg cell development. We show that the NF-kappaB transcription factor c-Rel is highly expressed in thymic T reg cells and that in c-rel(-/-) mice, thymic T reg cell numbers are markedly reduced as a result of a T cell-intrinsic defect that is manifest during thymocyte development. Although c-Rel is not essential for TGF-beta conversion of peripheral CD4(+)CD25(-) T cells into CD4(+)Foxp3(+) cells, it is required for optimal homeostatic expansion of peripheral T reg cells. Despite a lower number of peripheral T reg cells in c-rel(-/-) mice, the residual peripheral c-rel(-/-) T reg cells express normal levels of Foxp3, display a pattern of cell surface markers and gene expression similar to those of wild-type T reg cells, and effectively suppress effector T cell function in culture and in vivo. Collectively, our results indicate that c-Rel is important for both the thymic development and peripheral homeostatic proliferation of T reg cells.

Private organizations are deeply entrenched in fulfi lling the responsibilities of government through the provision of public services. In this context, we must question the conceptual coherence of drawing sharp distinctions between public and private functions. In YL v Birmingham City Council, however, the House of Lords had to determine which of the various functions contracted out by public authorities retain their public character for the purposes of the United Kingdom’s Human Rights Act 1998. This article analyzes the complex public/private division set up by the Human Rights Act and argues that the decision of the House of Lords has led to a gap in human rights protection and has weakened public accountability. Public functions and services traditionally carried out by public entities have been transferred increasingly to the private sector. 1 In the United Kingdom, policies such as privatization, outsourcing, and public/private projects under the Private Finance Initiative 2 have altered dramatically the way in which public services are delivered. Although these policies cover a variety of activities and varying arrangements, they typically share three features: the transfer of public functions, with the associated delivery risk, to private entities; the use of market-style competition to select the supplier; and a shift in the measurement of performance — from a concern with process to the achievements of outputs. “ Internal markets ” have been introduced into the provision of such fundamental public services as health and education, organized around a separation between “ purchasers ” and “ providers ” and governed by sophisticated commercial contracts. 3 Prisons and immigration centers are managed by

only against public authorities.2 The issue of whether a body is a public authority has proved highly controversial. The hiving-off of many traditional governmental functions through policies such as privatisation, outsourcing and projects under the Private Finanace Initiative (PFI) has led to a blurring of the traditionally understood publicprivate distinction.3 The changed nature in the way that public services are delivered has led to sharply divergent views among the judiciary about which functions are those of a public nature for the purposes of the Human Rights Act. This is evident in the YL judgment itself: a split decision, with two dissenting judgements.4 The division in the House reflects different understandings of the operation of the Human Rights Act, the public-private distinction and, perhaps more fundamentally, competing ideological stances. The decision also suggests that the ghost of Dicey still haunts the development of public law in our legal tradition. Dicey's premise that the Rule of Law admits of no separation between public and private law and that all people were subject to the ordinary laws of the realm inhibited the development of public law.5 The first inkling of change occurred during the 1960's.6 Influenced no doubt by EC and human rights law, gradually the judiciary began to establish substantive public law rules and principles. It is ironic that just as public law became more established and effective in the control of government power, the state began to shrink and the pattern of government to change. The transformation of the delivery of public services poses a serious threat to public law values, to ensuring public accountability and to the

Background Multiple autoimmune syndrome (MAS), an extreme phenotype of autoimmune disorders, is a very well suited trait to tackle genomic variants of these conditions. Whole exome sequencing (WES) is a widely used strategy for detection of protein coding and splicing variants associated with inherited diseases. Methods The DNA of eight patients affected by MAS [all of whom presenting with Sjögren’s syndrome (SS)], four patients affected by SS alone and 38 unaffected individuals, were subject to WES. Filters to identify novel and rare functional (pathogenic–deleterious) homozygous and/or compound heterozygous variants in these patients and controls were applied. Bioinformatics tools such as the Human gene connectome as well as pathway and network analysis were applied to test overrepresentation of genes harbouring these variants in critical pathways and networks involved in autoimmunity. Results Eleven novel and rare functional variants were identified in cases but not in controls, harboured in: MACF1, KIAA0754, DUSP12, ICA1, CELA1, LRP1/STAT6, GRIN3B, ANKLE1, TMEM161A, and FKRP. These were subsequently subject to network analysis and their functional relatedness to genes already associated with autoimmunity was evaluated. Notably, the LRP1/STAT6 novel mutation was homozygous in one MAS affected patient and heterozygous in another. LRP1/STAT6 disclosed the strongest plausibility for autoimmunity. LRP1/STAT6 are involved in extracellular and intracellular anti-inflammatory pathways that play key roles in maintaining the homeostasis of the immune system. Further; networks, pathways, and interaction analyses showed that LRP1 is functionally related to the HLA-B and IL10 genes and it has a substantial impact within immunological pathways and/or reaction to bacterial and other foreign proteins (phagocytosis, regulation of phospholipase A2 activity, negative regulation of apoptosis and response to lipopolysaccharides). Further, ICA1 and STAT6 were also closely related to AIRE and IRF5, two very well known autoimmunity genes. Conclusions Novel and rare exonic mutations that may account for autoimmunity were identified. Among those, the LRP1/STAT6 novel mutation has the strongest case for being categorised as potentially causative of MAS given the presence of intriguing patterns of functional interaction with other major genes shaping autoimmunity. Electronic supplementary material The online version of this article (doi:10.1186/s12967-015-0525-x) contains supplementary material, which is available to authorized users.

THE right not to be subjected to torture or to inhuman or degrading treatment or punishment is guaranteed in absolute terms in Article 3 of the ECHR. This article imposes on a State both a negative and a positive obligation. In recent months, the House of Lords has considered cases raising both obligations pursuant to Article 3. This paper will examine first the nature of Article 3 and these obligations, second the jurisprudence of the European Court of Human Rights on the issue of State responsibility, and finally the recent decisions of the House of Lords in R. (on the application of Adam, Limbuela and Tesema) v. Secretary of State for the Home Department

The dramatic terrorist attacks in the United States in September 2001 all too clearly illustrated the threat posed by international terrorism. Understandably, politicians are provoked into taking tough measures to protect their citizens from terrorist enemies. In times of danger the civil liberties implications of such measures can easily play second fiddle to security needs. Indeed, we need look no further in our jurisprudence than the discredited majority decision in Liversidge v. Anderson [1942] A.C. 206. Recently, Lord Woolf has warned that “the mistakes which have been made in the past, in relation to internment of aliens at the outbreak of war, should not be forgotten” (A v. Secretary of State for the Home Department [2002] EWCA Civ 1502 at para. [9]).

In R. (Bancoult) v. Secretary of State for Foreign and Commonwealth Affairs [2001] 2 W.L.R. 1219 a former resident of the British Indian Ocean Territory (“BIOT”) successfully challenged the lawfulness of banishment from his own country.

The Labour government has quickly acted on its election promise to introduce a bill of rights into domestic law. The Human Rights Act 1998 partially incorporates the European Convention on Human Rights (ECHR) into United Kingdom law. This legislation is part of a wider constitutional package including devolved government for Scotland and Wales and reform of the House of Lords. The government’s programme is intended to modernise and indeed transform the British constitutional structure. According to the government, the Human Rights Act will bring rights home. Individuals will be able to argue for their Convention rights in the United Kingdom’s own courts and tribunals and judges will be able to adjudicate directly on Convention issues. All new laws will be carefully scrutinised to ensure compatibility with Convention rights.

The Labour government has quickly acted on its election promise to introduce a bill of rights into domestic law. The Human Rights Act 1998 partially incorporates the European Convention on Human Rights (ECHR) into United Kingdom law. This legislation is part of a wider constitutional package including devolved government for Scotland and Wales and reform of the House of Lords. The government’s programme is intended to modernise and indeed transform the British constitutional structure. According to the government, the Human Rights Act will bring rights home. Individuals will be able to argue for their Convention rights in the United Kingdom’s own courts and tribunals and judges will be able to adjudicate directly on Convention issues. All new laws will be carefully scrutinised to ensure compatibility with Convention rights.

Although those sentenced to life imprisonment have no right to release, a life sentence rarely involves imprisonment for the remainder of a convicted offender's natural life. Life prisoners may hope for early release on the so-called “life-licence”, whereby they remain liable to be recalled to prison for the rest of their lives.

Disrupted sleep is considered a patient outcome sensitive to oncology nursing care and can lead to a variety of physical and psychologic dysfunctions, such as insomnia, chronic pain, respiratory distress, obesity, stress, and anxiety. Although sleep disturbances have been studied in recipients of hematopoietic stem cell transplantations (HSCTs), these studies have not examined the acute phase of transplantation. The current study aimed to identify the level of sleep disturbance in this patient population, identify factors contributing to decreased ability to sleep for hospitalized recipients of HSCT, and compare the differences in sleep disturbance between age, gender, type of transplantation, and initial stem cell transplantation versus readmission for transplantation-associated complications. Among the 69 patients studied, 26% reported clinical insomnia, as measured by the Insomnia Severity Index, and 74% had some degree of insomnia. Patient characteristics were not significantly associated with insomnia scores. Patients reported bathroom use as the most frequent reason for sleep disruption (85%). These findings suggest that sleep disturbances are common in hospitalized patients undergoing HSCT, and strategies to reduce disruptions are needed to improve patient outcomes.