• An integrated dimensionality reduction and surrogate optimization approach for plant‐wide chemical process operation

      Savage, Thomas R.; orcid: 0000-0001-8715-8369; Almeida‐Trasvina, Fernando; del‐Rio Chanona, Ehecatl A.; orcid: 0000-0003-0274-2852; Smith, Robin; Zhang, Dondga; orcid: 0000-0001-5956-4618; email: dongda.zhang@manchester.ac.uk (John Wiley & Sons, Inc., 2021-07-02)
      Abstract: With liquefied natural gas becoming increasingly prevalent as a flexible source of energy, the design and optimization of industrial refrigeration cycles becomes even more important. In this article, we propose an integrated surrogate modeling and optimization framework to model and optimize the complex CryoMan Cascade refrigeration cycle. Dimensionality reduction techniques are used to reduce the large number of process decision variables which are subsequently supplied to an array of Gaussian processes, modeling both the process objective as well as feasibility constraints. Through iterative resampling of the rigorous model, this data‐driven surrogate is continually refined and subsequently optimized. This approach was not only able to improve on the results of directly optimizing the process flow sheet but also located the set of optimal operating conditions in only 2 h as opposed to the original 3 weeks, facilitating its use in the operational optimization and enhanced process design of large‐scale industrial chemical systems.
    • Bacteria and bioburden and healing in complex wounds: A prognostic systematic review

      Norman, Gill; orcid: 0000-0002-3972-5733; email: gill.norman@manchester.ac.uk; Shi, Chunhu; Westby, Maggie J.; orcid: 0000-0003-4273-3942; Price, Bianca L.; McBain, Andrew J.; Dumville, Jo C.; Cullum, Nicky (John Wiley & Sons, Inc., 2021-02-16)
      Abstract: The wound microbiome may play an important role in the wound healing process. We conducted the first systematic prognosis review investigating whether aspects of the wound microbiome are independent prognostic factors for the healing of complex wounds. We searched Medline, Embase, CINAHL and the Cochrane Library to February 2019. We included longitudinal studies which assessed the independent association of aspects of wound microbiome with healing of complex wounds while controlling for confounding factors. Two reviewers extracted data and assessed risk of bias and certainty of evidence using the GRADE approach. We synthesised studies narratively due to the clinical and methodological heterogeneity of included studies and sparse data. We identified 28 cohorts from 21 studies with a total of 38,604 participants, including people with diabetes and foot ulcers, open surgical wounds, venous leg ulcers and pressure ulcers. Risk of bias varied from low (2 cohorts) to high (17 cohorts); the great majority of participants were in cohorts at high risk of bias. Most evidence related to the association of baseline clinical wound infection with healing. Clinical infection at baseline may be associated with less likelihood of wound healing in foot ulcers in diabetes (HR from cohort with moderate risk of bias 0.53, 95% CI 0.33 to 0.83) or slower healing in open surgical wounds (HR 0.65, 95% CI 0.51 to 0.83); evidence in other wounds is more limited. Most other associations assessed showed no clear relationship with wound healing; evidence was limited and often sparse; and we documented gaps in the evidence. There is low certainty evidence that a diagnosis of wound infection may be prognostic of poorer healing in foot ulcers in diabetes, and some moderate certainty evidence for this in open surgical wounds. Low certainty evidence means that more research could change these findings.
    • Corneal Confocal Microscopy Identifies Parkinson's Disease with More Rapid Motor Progression

      Lim, Sze Hway; email: szehway.lim@postgrad.manchester.ac.uk; Ferdousi, Maryam; Kalteniece, Alise; Mahfoud, Ziyad R.; Petropoulos, Ioannis N.; Malik, Rayaz A.; Kobylecki, Christopher; orcid: 0000-0002-7797-0756; Silverdale, Monty; orcid: 0000-0002-3295-6897 (John Wiley & Sons, Inc., 2021-04-07)
      ABSTRACT: Background: Corneal confocal microscopy (CCM) is a noninvasive, reproducible ophthalmic technique to quantify corneal small nerve fiber degeneration. CCM demonstrates small nerve fiber damage in Parkinson's disease (PD), but its role as a longitudinal biomarker of PD progression has not been explored. Objective: The aim of this study was to assess corneal nerve morphology using CCM in relation to disease progression in PD. Methods: Sixty‐four participants with PD were assessed at baseline and at 12‐month follow‐up. Participants underwent CCM with automated corneal nerve quantification and assessment of Movement Disorder Society Unified Parkinson's Disease Rating Scale, Hoehn and Yahr stage, and Montreal Cognitive Assessment. Results: Corneal nerve fiber density (CNFD), corneal nerve branch density, corneal nerve fiber length, corneal total branch density, and corneal nerve fiber area were significantly lower in participants with PD compared with healthy control subjects. Worsening of Movement Disorder Society Unified Parkinson's Disease Rating Scale part III score over 12 months was significantly greater in participants with a CNFD in the lowest compared with the highest quartile at baseline (mean difference: 6.0; 95% CI: 1.0–10.9; P = 0.019). There were no significant changes in CNFD, corneal nerve branch density, corneal nerve fiber length, corneal total branch density, corneal nerve fiber area, or corneal nerve fiber width between baseline and 12‐month follow‐up. Conclusions: CCM identifies neurodegeneration in patients with PD, especially those who show the greatest progression in neurological disability. CCM may be a useful tool to help enrich clinical trials with those likely to exhibit more rapid progression and reduce required sample size and cost of studies. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society
    • High dose genistein in Sanfilippo syndrome: A randomised controlled trial

      Ghosh, Arunabha; Rust, Stewart; Langford‐Smith, Kia; Weisberg, Daniel; Canal, Maria; Breen, Catherine; Hepburn, Michelle; Tylee, Karen; Vaz, Frédéric M.; Vail, Andy; et al. (John Wiley & Sons, Inc., 2021-06-13)
      Abstract: The aim of this study was to evaluate the efficacy of high dose genistein aglycone in Sanfilippo syndrome (mucopolysaccharidosis type III). High doses of genistein aglycone have been shown to correct neuropathology and hyperactive behaviour in mice, but efficacy in humans is uncertain. This was a single centre, double‐blinded, randomised, placebo‐controlled study with open‐label extension phase. Randomised participants received either 160 mg/kg/day genistein aglycone or placebo for 12 months; subsequently all participants received genistein for 12 months. The primary outcome measure was the change in heparan sulfate concentration in cerebrospinal fluid (CSF), with secondary outcome measures including heparan sulfate in plasma and urine, total glycosaminoglycans in urine, cognitive and adaptive behaviour scores, quality of life measures and actigraphy. Twenty‐one participants were randomised and 20 completed the placebo‐controlled phase. After 12 months of treatment, the CSF heparan sulfate concentration was 5.5% lower in the genistein group (adjusted for baseline values), but this was not statistically significant (P = .26), and CSF heparan sulfate increased in both groups during the open‐label extension phase. Reduction of urinary glycosaminoglycans was significantly greater in the genistein group (32.1% lower than placebo after 12 months, P = .0495). Other biochemical and clinical parameters showed no significant differences between groups. High dose genistein aglycone (160 mg/kg/day) was not associated with clinically meaningful reductions in CSF heparan sulfate and no evidence of clinical efficacy was detected. However, there was a statistically significant reduction in urine glycosaminoglycans. These data do not support the use of genistein aglycone therapy in mucopolysaccharidosis type III. High dose genistein aglycone does not lead to clinically meaningful reductions in biomarkers or improvement in neuropsychological outcomes in mucopolysaccharidosis type III.
    • Marginal habitats provide unexpected survival benefits to the alpine marmot

      Ferrari, Caterina; orcid: 0000-0002-6316-9706; email: caterina.ferrari@unito.it; email: caterinaww@gmail.com; Zanet, Stefania; orcid: 0000-0002-7543-399X; Rolando, Antonio; orcid: 0000-0002-3432-1780; Bertolino, Sandro; orcid: 0000-0002-1063-8281; Bassano, Bruno; von Hardenberg, Achaz (John Wiley & Sons, Inc., 2022-01-06)
      Abstract: Age‐specific survival trajectories can vary significantly among wild populations. Identifying the environmental conditions associated with such variability is of primary importance to understand the dynamics of free‐ranging populations. In this study, we investigated survival variations among alpine marmot (Marmota marmota) families living in areas with opposite environmental characteristics: the typical habitat of the species (alpine meadow) and a marginal area bordering the forest. We used data collected during an 11‐year study in the Gran Paradiso National Park (Italy) and performed a Bayesian survival trajectory analysis on marked individuals. Furthermore, we investigated, at a territorial level, the relationships among demographic parameters and habitat variables by using a path analysis approach. Contrary to our expectations, for most of the marmot's lifespan, survival rate was higher in the marginal site closer to the forest and with lower visibility than in the alpine meadow site. Path analysis indicated that the number of families living close to each other negatively affected the stability of the dominant couple, which in turn affected both juvenile survival and reproduction. Given the lower number of neighboring families which inhabited the marginal site and the potentially different predation pressure by the most effective predator in the area (Aquila chrysaetos), our results suggest that species adapted to live in open habitats may benefit from living in a marginal habitat. This study highlights the importance of habitats bordering the forest in the conservation of alpine marmots.
    • Multivariate statistical data analysis of cell‐free protein synthesis toward monitoring and control

      Duran‐Villalobos, Carlos A.; orcid: 0000-0002-5350-761X; email: carlos.duran@manchester.ac.uk; Ogonah, Olotu; Melinek, Beatrice; Bracewell, Daniel G.; Hallam, Trevor; Lennox, Barry (John Wiley & Sons, Inc., 2021-03-23)
      Abstract: The optimization and control of cell free protein synthesis (CFPS) presents an ongoing challenge due to the complex synergies and nonlinearities that cannot be fully explained in first principle models. This article explores the use of multivariate statistical tools for analyzing data sets collected from the CFPS of Cereulide monoclonal antibodies. During the collection of these data sets, several of the process parameters were modified to investigate their effect on the end‐point product (yield). Through the application of principal component analysis and partial least squares (PLS), important correlations in the process could be identified. For example, yield had a positive correlation with pH and NH3 and a negative correlation with CO2 and dissolved oxygen. It was also found that PLS was able to provide a long‐term prediction of product yield. The presented work illustrates that multivariate statistical techniques provide important insights that can help support the operation and control of CFPS processes.
    • Predicting new protein conformations from molecular dynamics simulation conformational landscapes and machine learning

      Jin, Yiming; Johannissen, Linus O.; email: linus.johannissen@manchester.ac.uk; Hay, Sam; orcid: 0000-0003-3274-0938; email: sam.hay@manchester.ac.uk (John Wiley & Sons, Inc., 2021-03-03)
      Abstract: Molecular dynamics (MD) simulations are a popular method of studying protein structure and function, but are unable to reliably sample all relevant conformational space in reasonable computational timescales. A range of enhanced sampling methods are available that can improve conformational sampling, but these do not offer a complete solution. We present here a proof‐of‐principle method of combining MD simulation with machine learning to explore protein conformational space. An autoencoder is used to map snapshots from MD simulations onto a user‐defined conformational landscape defined by principal components analysis or specific structural features, and we show that we can predict, with useful accuracy, conformations that are not present in the training data. This method offers a new approach to the prediction of new low energy/physically realistic structures of conformationally dynamic proteins and allows an alternative approach to enhanced sampling of MD simulations.
    • Recurrent KCNT2 missense variants affecting p.Arg190 result in a recognizable phenotype

      Jackson, Adam; orcid: 0000-0002-3674-3960; email: adam.jackson-5@postgrad.manchester.ac.uk; Banka, Siddharth; orcid: 0000-0002-8527-2210; Stewart, Helen; orcid: 0000-0002-1196-3000; Genomics England Research Consortium; Robinson, Hannah; Lovell, Simon; Clayton‐Smith, Jill (John Wiley & Sons, Inc., 2021-06-01)
      Abstract: KCNT2 variants resulting in substitutions affecting the Arg190 residue have been shown to cause epileptic encephalopathy and a recognizable facial gestalt. We report two additional individuals with intellectual disability, dysmorphic features, hypertrichosis, macrocephaly and the same de novo KCNT2 missense variants affecting the Arg190 residue as previously described. Notably, neither patient has epilepsy. Homology modeling of these missense variants revealed that they are likely to disrupt the stabilization of a closed channel conformation of KCNT2 resulting in a constitutively open state. This is the first report of pathogenic variants in KCNT2 causing a developmental phenotype without epilepsy.
    • Reid Bryson: The crisis climatologist

      Naylor, Robert Luke; orcid: 0000-0002-9585-9939; email: robert.naylor-4@postgrad.manchester.ac.uk (John Wiley & Sons, Inc., 2021-10-25)
      Abstract: Reid Allen Bryson (1920–2008) was a forceful orator who consistently fought against institutional pressures to get his messages out to the public. In the 1960s, Bryson was a leader in the wider academic turn toward politically charged interdisciplinarianism. To the dismay of many of his colleagues, he publicly made climatological prognoses in the 1970s, becoming a significant figure in the media landscape. He was not swayed by the arguments for global warming, even as the framing became the recognized face of climate change in the late 1980s. By examining the controversies that Bryson instigated and the currents that he swam against, we can see the wider community crystallizing and promoting positions that may have previously gone unstated. In addition, Bryson's personal contribution to the rise of climate discourse has been underexplored in the historical literature. Bryson was instrumental in bringing climate onto the political radar during the World Food Crisis of 1973, shocking both the US and Canadian political establishments into paying more attention to the issue. Bryson's narrative linking climate change to both food supply and a series of climate anomalies in the 1970s remained predominant in the first World Climate Conference of 1979. Bryson also helped break a seal on climatologists speaking directly to the media, leading to unprecedented climate discourse in the 1970s and giving climate change a springboard to become one of the defining issues of the 21st century. This article is categorized under: Climate, History, Society, Culture > Thought Leaders
    • Solidarity under duress: Defending state vigilantism

      Viehoff, Juri; orcid: 0000-0002-5763-0279; email: juri.viehoff@manchester.ac.uk (John Wiley & Sons, Inc., 2021-09-06)
      Abstract: May European Union (EU) member states, in the pursuit of enforcing the norms of ‘EU justice’, unilaterally adopt harmful policies that are ordinarily impermissible in the course of voluntary cooperation amongst democratic states? Though conditions of permissible vigilantism are strict and only rarely met, there are some basic EU duties the compliance with which each individual member state is permitted to enforce unilaterally. Such measures are sometimes permissible even if European community law says otherwise: to the extent that European law prevents states from enforcing these duties, it lacks authority.
    • The emotional face of anorexia nervosa: The neural correlates of emotional processing

      Halls, Daniel; orcid: 0000-0002-5372-3179; Leslie, Monica; Leppanen, Jenni; Sedgewick, Felicity; Surguladze, Simon; Fonville, Leon; Lang, Katie; Simic, Mima; Nicholls, Dasha; Williams, Steven; et al. (John Wiley & Sons, Inc., 2021-03-19)
      Abstract: Social–emotional processing difficulties have been reported in Anorexia Nervosa (AN), yet the neural correlates remain unclear. Previous neuroimaging work is sparse and has not used functional connectivity paradigms to more fully explore the neural correlates of emotional difficulties. Fifty‐seven acutely unwell AN (AAN) women, 60 weight‐recovered AN (WR) women and 69 healthy control (HC) women categorised the gender of a series of emotional faces while undergoing Functional Magnetic Resonance Imaging. The mean age of the AAN group was 19.40 (2.83), WR 18.37 (3.59) and HC 19.37 (3.36). A whole brain and psychophysical interaction connectivity approach was used. Parameter estimates from significant clusters were extracted and correlated with clinical symptoms. Whilst no group level differences in whole brain activation were demonstrated, significant group level functional connectivity differences emerged. WR participants showed increased connectivity between the bilateral occipital face area and the cingulate, precentral gyri, superior, middle, medial and inferior frontal gyri compared to AAN and HC when viewing happy valenced faces. Eating disorder symptoms and parameter estimates were positively correlated. Our findings characterise the neural basis of social–emotional processing in a large sample of individuals with AN.
    • Using process data to generate an optimal control policy via apprenticeship and reinforcement learning

      Mowbray, Max; orcid: 0000-0003-1398-0469; email: max.mowbray@manchester.ac.uk; Smith, Robin; email: robin.smith@manchester.ac.uk; Del Rio‐Chanona, Ehecatl A.; email: a.del-rio-chanona@imperial.ac.uk; Zhang, Dongda; orcid: 0000-0001-5956-4618; email: dongda.zhang@manchester.ac.uk (John Wiley & Sons, Inc., 2021-05-15)
      Abstract: Reinforcement learning (RL) is a data‐driven approach to synthesizing an optimal control policy. A barrier to wide implementation of RL‐based controllers is its data‐hungry nature during online training and its inability to extract useful information from human operator and historical process operation data. Here, we present a two‐step framework to resolve this challenge. First, we employ apprenticeship learning via inverse RL to analyze historical process data for synchronous identification of a reward function and parameterization of the control policy. This is conducted offline. Second, the parameterization is improved online efficiently under the ongoing process via RL within only a few iterations. Significant advantages of this framework include to allow for the hot‐start of RL algorithms for process optimal control, and robust abstraction of existing controllers and control knowledge from data. The framework is demonstrated on three case studies, showing its potential for chemical process control.