Adalimumab for Treating Moderate-to-Severe Hidradenitis Suppurativa: An Evidence Review Group Perspective of a NICE Single Technology Appraisal

As part of its single technology appraisal (STA) process, the UK National Institute for Health and Care Excellence (NICE) invited the manufacturer of adalimumab (AbbVie) to submit evidence on the clinical effectiveness and cost effectiveness of adalimumab for the treatment of moderate-to-severe hidradenitis suppurativa (HS). The appraisal assessed adalimumab as monotherapy in adult patients with an inadequate response to conventional systemic HS therapy. The School of Health and Related Research Technology Appraisal Group was commissioned to act as the independent Evidence Review Group (ERG). The ERG produced a critical review of the evidence for the clinical effectiveness and cost effectiveness of the technology based on the company’s submission to NICE. The evidence was mainly derived from three randomised controlled trials comparing adalimumab with placebo in adults with moderate-to-severe HS. The clinical-effectiveness review found that significantly more patients achieved a clinical response in the adalimumab groups than in the control groups but that the treatment effect varied between trials and there was uncertainty regarding its impact on a range of other relevant outcomes as well as long-term efficacy. The company’s submitted Markov model assessed the incremental cost effectiveness of adalimumab versus standard care for the treatment of HS from the perspective of the UK NHS and Personal Social Services (PSS) over a lifetime horizon. The original submitted model, including a patient access scheme (PAS), suggested that the incremental cost-effectiveness ratio (ICER) for adalimumab versus standard care was expected to be £16,162 per quality-adjusted life-year (QALY) gained. Following a critique of the model, the ERG’s preferred base case, which corrected programming errors and structural problems surrounding discontinuation rules and incorporated a lower unit cost for HS surgery, resulted in a probabilistic ICER of £29,725 per QALY gained. Based on additional analyses undertaken by the company and the ERG following the publication of the appraisal consultation document (ACD), the Appraisal Committee concluded that the maximum possible ICER for adalimumab compared with supportive care was between £28,500 and £33,200 per QALY gained but was likely to be lower. The Appraisal Committee recommended adalimumab (with the PAS) for the treatment of active moderate-to-severe HS in adults whose disease has not responded to conventional systemic therapy

Phase transitions in biological membranes

Native membranes of biological cells display melting transitions of their lipids at a temperature of 10-20 degrees below body temperature. Such transitions can be observed in various bacterial cells, in nerves, in cancer cells, but also in lung surfactant. It seems as if the presence of transitions slightly below physiological temperature is a generic property of most cells. They are important because they influence many physical properties of the membranes. At the transition temperature, membranes display a larger permeability that is accompanied by ion-channel-like phenomena even in the complete absence of proteins. Membranes are softer, which implies that phenomena such as endocytosis and exocytosis are facilitated. Mechanical signal propagation phenomena related to nerve pulses are strongly enhanced. The position of transitions can be affected by changes in temperature, pressure, pH and salt concentration or by the presence of anesthetics. Thus, even at physiological temperature, these transitions are of relevance. There position and thereby the physical properties of the membrane can be controlled by changes in the intensive thermodynamic variables. Here, we review some of the experimental findings and the thermodynamics that describes the control of the membrane function.Comment: 23 pages, 15 figure

Individual differences in explicit and implicit visuomotor learning and working memory capacity

The theoretical basis for the association between high working memory capacity (WMC) and enhanced visuomotor adaptation is unknown. Visuomotor adaptation involves interplay between explicit and implicit systems. We examined whether the positive association between adaptation and WMC is specific to the explicit component of adaptation. Experiment 1 replicated the positive correlation between WMC and adaptation, but revealed this was specific to the explicit component of adaptation, and apparently driven by a sub-group of participants who did not show any explicit adaptation in the correct direction. A negative correlation was observed between WMC and implicit learning. Experiments 2 and 3 showed that when the task restricted the development of an explicit strategy, high WMC was no longer associated with enhanced adaptation. This work reveals that the benefit of high WMC is specifically linked to an individual’s capacity to use an explicit strategy. It also reveals an important contribution of individual differences in determining how adaptation is performed

Complement is activated in progressive multiple sclerosis cortical grey matter lesions

The symptoms of multiple sclerosis (MS) are caused by damage to myelin and nerve cells in the brain and spinal cord. Inflammation is tightly linked with neurodegeneration, and it is the accumulation of neurodegeneration that underlies increasing neurological disability in progressive MS. Determining pathological mechanisms at play in MS grey matter is therefore a key to our understanding of disease progression

Effect of promoter architecture on the cell-to-cell variability in gene expression

According to recent experimental evidence, the architecture of a promoter, defined as the number, strength and regulatory role of the operators that control the promoter, plays a major role in determining the level of cell-to-cell variability in gene expression. These quantitative experiments call for a corresponding modeling effort that addresses the question of how changes in promoter architecture affect noise in gene expression in a systematic rather than case-by-case fashion. In this article, we make such a systematic investigation, based on a simple microscopic model of gene regulation that incorporates stochastic effects. In particular, we show how operator strength and operator multiplicity affect this variability. We examine different modes of transcription factor binding to complex promoters (cooperative, independent, simultaneous) and how each of these affects the level of variability in transcription product from cell-to-cell. We propose that direct comparison between in vivo single-cell experiments and theoretical predictions for the moments of the probability distribution of mRNA number per cell can discriminate between different kinetic models of gene regulation.Comment: 35 pages, 6 figures, Submitte

Autism as a disorder of neural information processing: directions for research and targets for therapy

The broad variation in phenotypes and severities within autism spectrum disorders suggests the involvement of multiple predisposing factors, interacting in complex ways with normal developmental courses and gradients. Identification of these factors, and the common developmental path into which theyfeed, is hampered bythe large degrees of convergence from causal factors to altered brain development, and divergence from abnormal brain development into altered cognition and behaviour. Genetic, neurochemical, neuroimaging and behavioural findings on autism, as well as studies of normal development and of genetic syndromes that share symptoms with autism, offer hypotheses as to the nature of causal factors and their possible effects on the structure and dynamics of neural systems. Such alterations in neural properties may in turn perturb activity-dependent development, giving rise to a complex behavioural syndrome many steps removed from the root causes. Animal models based on genetic, neurochemical, neurophysiological, and behavioural manipulations offer the possibility of exploring these developmental processes in detail, as do human studies addressing endophenotypes beyond the diagnosis itself

Community health workers in rural India: analysing the opportunities and challenges Accredited Social Health Activists (ASHAs) face in realising their multiple roles

Background: Globally, there is increasing interest in community health worker’s (CHW) performance; however, there are gaps in the evidence with respect to CHWs’ role in community participation and empowerment. Accredited Social Health Activists (ASHAs), whose roles include social activism, are the key cadre in India’s CHW programme which is designed to improve maternal and child health. In a diverse country like India, there is a need to understand how the ASHA programme operates in different underserved Indian contexts, such as rural Manipur. Methods: We undertook qualitative research to explore stakeholders’ perceptions and experiences of the ASHA scheme in strengthening maternal health and uncover the opportunities and challenges ASHAs face in realising their multiple roles in rural Manipur, India. Data was collected through in-depth interviews (n = 18) and focus group discussions (n = 3 FGDs, 18 participants). Participants included ASHAs, key stakeholders and community members. They were purposively sampled based on remoteness of villages and primary health centres to capture diverse and relevant constituencies, as we believed experiences of ASHAs can be shaped by remoteness. Data were analysed using the thematic framework approach. Results: Findings suggested that ASHAs are mostly understood as link workers. ASHA’s ability to address the immediate needs of rural and marginalised communities meant that they were valued as service providers. The programme is perceived to be beneficial as it improves awareness and behaviour change towards maternal care. However, there are a number of challenges; the selection of ASHAs is influenced by power structures and poor community sensitisation of the ASHA programme presents a major risk to success and sustainability. The primary health centres which ASHAs link to are ill-equipped. Thus, ASHAs experience adverse consequences in their ability to inspire trust and credibility in the community. Small and irregular monetary incentives demotivate ASHAs. Finally, ASHAs had limited knowledge about their role as an ‘activist’ and how to realise this. Conclusions: ASHAs are valued for their contribution towards maternal health education and for their ability to provide basic biomedical care, but their role as social activists is much less visible as envisioned in the ASHA operational guideline. Access by ASHAs to fair monetary incentives commensurate with effort coupled with the poor functionality of the health system are critical elements limiting the role of ASHAs both within the health system and within communities in rural Manipur

Two-Nucleon Momentum Distributions Measured in 3He(e,e'pp)n

We have measured the 3He(e,e'pp)n reaction at 2.2 GeV over a wide kinematic range. The kinetic energy distribution for `fast' nucleons (p > 250 MeV/c) peaks where two nucleons each have 20% or less, and the third nucleon has most of the transferred energy. These fast pp and pn pairs are back-to-back with little momentum along the three-momentum transfer, indicating that they are spectators. Experimental and theoretical evidence indicates that we have measured distorted two-nucleon momentum distributions by striking the third nucleon and detecting the spectator correlated pair.Comment: 6 pages, 5 figures, submitted to PR

Contrasting impacts of heat stress on violent and nonviolent robbery in Beijing, China

Previous studies investigating the relation between heat stress and crime incidents often focus on violent crimes. In this study, the impacts of heat stress on two types of robbery (violent and nonviolent) in China are compared using crime statistics collected in Beijing and heat stress indices that consider the combined effects of temperature and humidity. The results indicate that the abrupt change in the trend of robbery rates is affected by the 2008 Beijing Olympic Games. The nonviolent robbery rates have a more pronounced seasonality and are better correlated with heat stress at daily scales, especially during the period from 2009 to 2014 when no trend exists. The results also demonstrate that both violent and nonviolent robbery rates significantly increase with heat stress in spring. The nonviolent robbery rates also significantly increase with heat stress in summer. The influence of heat stress on violent robbery rate is more complicated and nonlinear

Performance of the CMS Cathode Strip Chambers with Cosmic Rays

The Cathode Strip Chambers (CSCs) constitute the primary muon tracking device in the CMS endcaps. Their performance has been evaluated using data taken during a cosmic ray run in fall 2008. Measured noise levels are low, with the number of noisy channels well below 1%. Coordinate resolution was measured for all types of chambers, and fall in the range 47 microns to 243 microns. The efficiencies for local charged track triggers, for hit and for segments reconstruction were measured, and are above 99%. The timing resolution per layer is approximately 5 ns