Combination of both models enables prediction of transcriptional patterns for the whole population. In summary, the resulting model is not only able to anticipate the experimentally observed short-term and long-term transcriptional response, it further allows envision of altered protein levels. Our model shows that locally induced stress responses propagate throughout the bioreactor, resulting in temporal, and spatial population heterogeneity. Stress induced transcriptional response leads to a new population steady-state shortly after imposing fluctuating substrate conditions. In contrast, the protein levels take more than 10 h to achieve steady-state conditions.Rapidly changing concentrations of substrates frequently occur during large-scale microbial cultivations. These changing conditions, caused by large mixing times, result in a heterogeneous population distribution. Here, we present a powerful and efficient modeling approach to predict the influence of varying substrate levels on the transcriptional and translational response of the cell. This approach consists of two parts, a single-cell model to describe transcription and translation for an exemplary operon ( Large-scale industrial bioprocesses make use of reactors ranging from 100 to 800 m³ reaction volume. For aerobic processes, stirred tank reactors are still preferred, albeit alternative setups such as airlift reactors may be attractive if reactor sizes exceed the volume of about 500 m³. All reactors have in common that gradients of substrates, dissolved gases and pH occur, which are the consequence of poor mixing conditions  Short-term transcript dynamics observed in the PFR must be predicted, (ii) long-term transcript responses of the whole population should be mirrored, and (iii) the different time-scales of transcriptional and translational dynamics have to be reflected, too. This study will outline that every constraint is properly met by a simple mechanistic model.For the sake of simplicity, transcriptional dynamics of the tryptophan operon were chosen as an illustrative example. It has been shown by Simen et al.  that the-1 (5 mL min-1). The well-mixed bioreactor was simulated by using the steady-state condition in STR without the PFR (SS0). After characterization of SS0 the PFR was connected and a fraction of cells cycled through the PFR loop. No additional feed was added into the PFR. Therefore, the cells shift from nitrogen limitation to starvation along the PFR. The experimental design allows the observation of the transcriptional responses along the PFR (short-term) and over the process time in the STR (long-term). The system characteristics and cultivation conditions were published in Löffler et al. (-1).Oscillating substrate availability was simulated in a stirred-tank-reactor (STR) plug-flow-reactor (PFR) scale-down approach. Figure r et al. . Residen0 with a growth rate of 0.2 h-1 in the STR, the STR-PFR setup splits growth rates individually in the two compartments. Whereas, the total growth rate of the STR-PFR system is still 0.2 h-1, no growth can be expected inside PFR when the nutrient is completely consumed. Accordingly, PFR can be subdivided into a first part considering still growing cells and a subsequent part characterized by no growth. Because the total system runs with the dilution rate of 0.2 h-1, STR growth rates must be increased accordingly to compensate missing cell growth in the PFR. Calculation of growth rates in the STR can be performed based on the residence time distributed average growth rate that is set equal to the dilution rate. For the sake of simplicity and because nutrient starvation occurred very rapid in PFR, no growth was assumed to be existent in the total PFR compartment. Therefore, the average growth rate can be split into two different growth rates for each compartment (Equation 1).Compared to SSGSE90743.Samples for transcriptome analysis were taken at 25 and 120 min as well as at 28 h after installing the substrate gradient. Transcript measurements are published in Simen et al.  and are x describes the relative position of nucleotides inside the operon starting with the first mRNA encoding nucleotide of the operon sequence. RNAP movement is based on the elongation rate x between two subsequent polymerases. The following criteria were considered for RNAP motion:For the agent based transcription-translation model, DNA and mRNA templates are discretized in nucleotides, defining a 1D lattice. Movement of RNA polymerases (RNAPs) is treated according to Equation (2). Here, t is in the interval of possible induction (tind).- The first elongation step is treated as the initiation step and can only occur if - The minimum distance Δx between two subsequent RNAPs is fulfilled.i with length xi.For each passed nucleotide on the DNA sequence, the respective nucleotide in the mRNA sequence is transcribed. The resulting mRNA strand yi, j of a ribosome j on mRNA strand i is a function of yj−1. The number of ribosomes that translate a gene g . These brackets return 1 if the term inside is true and 0 if the term is false.The number of ribosomes acting on a single mRNA g can be calculated as the sum of all ribosomes acting on all mRNA strands that have passed the final nucleotide The amount of synthesized proteins per cell from the single-cell model  The trp operon leads to a polycistronic mRNA  and proteins.We used the -1  are treated as equally fast and their elongation rate was taken from the RNAP elongation rate reported by Chen et al.  and set trpA was reached divide, setting all transcriptional and translational programs on default (no initiation of transcription or translation in the corresponding daughter cell)i were definedThe following probability functions α1is used, indicating that a cell leaves the STR and enters the PFR again. Washout of cells (event 2) was treated equally with the dilution rate as flux value (α2). The probability for cell division (α3) is based on the set dilution rate D and the cell number 0. Return of cells from the PFR compartment was fixed to occur after τPFR passed. Cells that are washed out by event (2) are deleted from the system and newly born cells from event (3) are treated as default daughter cells without any transcriptional deflection.For modeling event (1), the rate αi is calculated, based on Equation (14). r1 and r2 are uniformly distributed random variables in the interval .The reaction system was numerically solved by applying Gillespie's stochastic simulation algorithm  is treated as generation of a new default cell without any additional mRNA and protein content without altering the mother cell.E. coli, simulated with a STR-PFR system, induce repeated on/off switching of several hundred genes. Among them, the frequent activation of the tryptophan operon could be observed  before the cells again reentered the PFR.The simulation of transcriptional dynamics during a single PFR passage was achieved using the single-cell model with the parameters listed in Table trpL encodes the leader peptide, translation modeling was simply focused on trpEDCBA. First, TrpE proteins were produced while the cells passed the PFR compartment. Downstream proteins were translated after the cells reentered the STR. Consequently, the majority of translation happened in STR. Protein formation is delayed and multiplexed compared to mRNA production. Accordingly, dynamics of protein courses are less steep than those of transcript levels. The latter are characterized by fast transcription and fast mRNA degradation that finally lead to sharp peaks of transcript contents. Protein degradation is slower by orders of magnitude. Consequently, only moderate pool dynamics and even protein accumulation was observed after PFR-STR transits.Based on the single-cell model, translation of mRNA was simulated as depicted in Figure trp operon. Subsequent translation enabled the formation of 80 TrpED, 100 TrpC, and 200 TrpBA copies  simulated protein levels are smaller than those reported for the given growth rate of 0.2 h-1. Accordingly, the simplifying assumption to neglect protein degradation for simulating STR-PFR dynamics is validated as half-lives of 1.1 h fairly exceed cycling times of about 500 s (about 0.12 h).Because the individual degradation constants for the -1. As such, not only short-term transcript dynamics could be elucidated by sampling the PFR but also long-term adaptation of the whole population by studying transcript patterns in STR during the adaptation period of 28 h after PFR connection.As indicated in Löffler et al.  and SimeFor simulation studies, the cell and the process model were linked predicting a stable distribution of 7526 ± 68 tracked cells in the STR (75.0 ± 0.68%) and 2513 ± 47 simulated cells in the PFR (25.0 ± 0.47%). Accordingly, the simulated cell population matched well with the volumetric setup comprising 74.7 vol% in the STR and 25.3 vol% in the PFR.Neglecting the residence time distribution in the STR indicates that cells in the STR are always induced as shown in Figure trp operon while passaging through the PFR. Notably, measured transcript dynamics were very similar so that measurements taken after 25, 120 min and 28 h were cumulated and indicated by a common variance. According to the modeling constraints, mRNA production started after 30 s which is in good agreement with experimental observations for trpL and for trpE. Synthesis of further downstream genes trpDCBA was neither predicted nor measured.Figure trpL mRNA which was hardly detected in the PFR, confirming the simulation.The long-term adaptation of the population was simulated for the exemplary time points of 25 and 120 min as well as for 28 h (see Figure trpA transcription was considered. Protein formation of TrpA disregarded putative degradation and simply considered continuous cell drain under steady-state conditions. Figure To compare the dynamics of transcript and protein adaptation toward new steady-states, both species were simulated. For transcript studies, the average trp operon as an example because its polycistronic mRNA consisting of five structural genes and a leader peptide was repeatedly transcribed envisaging ammonia limitation (Simen et al., The transcriptional dynamics observed in the STR-PFR experiments of Löffler et al.  and in pComparing the experimental observations of transcript dynamics with modeling predictions, high agreement between simulations and experimental data can be observed Figure . The quatrp genes were known. Simulation studies of Figure Protein formation was assumed to start immediately after mRNA transcription. Unlike mRNA degradation, no distinct decay kinetics for the trpL and trpE are fully transcribed in PFR whereas the transcription of the rest of the operon continued in the STR. Subsequently, most of the stress induced cellular burden occurred after a time-delay in the well-mixed STR compartment and not immediately in the PFR, the origin of the trigger. As a consequence, the population in the STR is very heterogeneous, consisting of cells in different transcription and translation states. Some cells should be still propagating the PFR induced stress response, whereas others may have completed the same. Moreover, given that the STR and the PFR compartments do not physically exist in large-scale bioreactors, cells are expected to co-exist next to each other while circulating around. Similar studies have already be performed investigating the lifelines of fluctuating cells (Haringa et al., One of the key findings of the STR-PFR studies of Löffler et al.  and Simein silico scale-up design, simulating large-scale performance of the cells ab initio.The ensemble model used in this study succeeded to predict experimental observations of long- and short-term transcriptional dynamics with high precision and without parameter adjustments. As such, the approach demonstrated its fundamental suitability for predicting large-scale population heterogeneity as a consequence of local stress triggers. Accordingly, likewise modeling approaches open the door for an This study illustrates that locally induced stress responses are propagated into different regions of the bioreactor thereby creating temporal and spatial inhomogeneity of the population. Notably, cellular reactions do happen on different time scales: Whereas transcriptional responses require <10 min, translational changes may continue for more than 10 h to reach new steady-states. Additionally, metabolic responses may occur which are likely to precede the transcriptional reaction. The hierarchical sequence of regulatory responses is overlaid with dynamics of mass transfer, mixing and process control which make it necessary to track individual cell responses properly for predicting large-scale performance of the total culture.AN performed the modeling, designed the study, and prepared the manuscript. ML and JS performed the experiments and prepared the manuscript. RT designed the study and prepared the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Our Mission and Our GoalsDear Colleagues,Euroasian Gastroenterological Association (EGA) was established on 1996 centered in Ankara, Turkey. Euroasian Gastroenterological Association and our journal are doing very well and getting scientific popularity in the Euroasian Countries year by year. From that day the association has founded many events, including 14 International Congresses in 12 different countries and three Single Topic Conferences (STC) in Europe and Asia.Euroasian Congresses of Gastroenterology and Surgery: 1997 Baku — Azerbaijan 1998 Almati — Kazakhstan 1999 Antalya — Turkey 2000 Tashkent — Uzbekistan 2001 Bishkek — Krygyzhstan 2003 Baku — Azerbaijan 2004 Ankara — Turkey 2005 Tbilisi — Georgia 2006 Baku — Azerbaijan 2007 Isfahan — Iran 2008 Baku — Azerbaijan 2011 Baku — Azerbaijan STC 2013 Yalta, Cremea — Ukraine 2013 Baku — Azerbaijan STC 2014 Ljubljana — Slovenia 2014 Magosa — Northern Cyprus STC 2015 Bucharest — RomaniaThe official journal of EGA, Euroasian Journal of Hepato-Gastroenterology (EJOHG) is growing rapidly with great efforts by editor-in-chief Hasan Ozkan, co-editor-in-chief Sheikh Mohammad Fazle Akbar, executive editor Mamun-Al-Mahtab, although it was launched only 5 years ago. Euroasian Journal of Hepato-Gastroenterology has began its publishing life in 2011 and it is being published and distributed regularly two times a year. With the big support from our colleagues from Asia and Europe, our journal is continuing its publishing life. In June 2015, we have applied to join the PubMed index which you will be informed about the results. Scientific level of EJOHG has been improving progressively year-by-year with increased number of submitted original articles and review articles.I have faith that in the coming years our association will grow stronger and will take role in more active affairs. Your support is very important for us. Together, I believe that we can establish a powerful platform and scientific zone in the Eurasia and our dream will come true. Finally, I would like to thank to executive committee, editorial board members and all of my colleagues once again for their valuable support.Hasan ÖzkanProfessor, President of Euroasian Gastroenterological AssociationEditor-in-Chief of EJOHG


Community Eye Health Journal has on its readers and the patients they serve.Thirty years and 100 issues call for celebration and reflection. In this article, the editors and the journal team do both, while the current editor considers the impact the Community Eye Health Journal  is something I will never forget.My interview for the position as editor of the Journal itself hadn't moved quite as far up in the world, however: my interview took place in the basement, headquarters of ICEH's education activities.The International Centre for Eye Health (ICEH) had moved up in the world – away from the somewhat cramped quarters near Moorfields Hospital from which Dr Murray McGavin published the first issue in 1988, to the lofty heights of the London School of Hygiene and Tropical Medicine's Bedford Square offices in a beautiful three-storey house overlooking a city garden. Perhaps the Having arrived from South Africa just one month earlier, I had no inkling that I would be spending the next eleven years of my life as editor of this hugely respected journal; working first in that basement and later at the School's Keppel Street building, just around the corner from the house where anaesthesia (chloroform) was first used.At the interview, Clare Gilbert, Daksha Patel and IAPB CEO Dick Porter subjected me to very thorough but friendly grilling, and I was delighted when the phone call came to say the job was mine: not only would I be working with wonderful colleagues, but I would be contributing to eye health in my own country, even though I now lived so far away.Of course, I had assumed that my years of experience in journalism, editing and science writing had impressed the panel – only to find out later that it was my enthusiasm for previous editor Victoria Francis's beautiful woodcut panels that had clinched the deal!Founding editorJournal to meet the needs of eye care workers in low-income countries first came to me. I recall a ward round in NOOR Eye Institute in Kabul, where patients with severe ocular injuries often came late for eye care. Landmines caused horrific injuries, including blindness. Little did I appreciate then that, 10 years later, Issue 24 would be the first publication worldwide to focus on the blinding effects of landmines.It was while working in Afghanistan that thoughts of an Eye After returning to Scotland in the mid-1980s, Dr Jock Anderson and Professor Barrie R Jones asked me to join them in the newly established International Centre for Eye Health, then based at Moorfields Eye Hospital in London. I shared my vision of a journal for eye workers in low-income countries with them, and later with Professor Gordon Johnson.Journal over the last 30 years and, without them, the Journal would not have been possible. Thank you.Together with Gordon, we secured funding from CBM, Sightsavers and Coca-Cola in London. CBM and Sightsavers have remained faithful supporters of the Journal for 15 years, from Issue 1 to 47. When I stepped down, I handed over to the extremely capable health educator Victoria Francis. Our current editor, Elmien Wolvaardt Ellison, joined in 2007 and is continuing this important work.It was my privilege to be the editor of the I am extremely grateful to the many people who joined in the work: the Editorial Boards; the Regional Advisers; colleagues at the International Centre for Eye Health – Professors Gordon Johnson, Allen Foster, Clare Gilbert and Darwin Minassian – who provided advice and opinion. Particular mention is due to Sue Stevens, our Nurse Consultant, whose immense practical contribution and commitment over many years kept us on course as a primary health care publication. I also offer a special word of thanks to Anita Shah, our Editorial Assistant and Administrator. Anita has lasted the pace and coped with different bosses … admirably! Well done, Anita. The emphasis has rightly been on teamwork. So many other names could and should have been mentioned. But, for all involved, Thank you!’Journal and to see it continuing to support and inform eye care workers around the world. May the Community Eye Health Journal continue to fulfil its important function of informing eye care workers in low and middle income settings as they work to prevent and treat blindness worldwide!I'm so grateful to have been given the opportunity to start the Just three months later, I was sent back to my home town of Durban for the inaugural World Congress on Refractive Error; my task was to gather ideas and authors for our upcoming issue on that theme. There, for the first time, I discovered how lucky I was to see well despite having high myopia: there are millions of people worldwide cannot not work or read because they do not have a pair of spectacles. A real eye opener. I also started to meet, for the first but not the last time, the many leading lights in international eye health who would be encouraging and supporting me in this work for many years to come, whether by answering questions, writing or reviewing articles, or providing images. I am deeply indebted to all of you.the Journal is an important tool for the improvement of global eye care.When I started in 2007, the world of international eye health was completely unfamiliar. In fact, to my great embarassment, it was a month or two before I got the better of that pesky extra ‘h’ in ophthalmology! But this did have its advantages: every issue and topic was – and still often is – new to me. I have relished the challenge of learning more about eye health with every issue we produce. For me, the best part is discovering – and then sharing – the ‘why’, and the ‘what needs to change’: why should this issue or theme matter to our readers and their patients? What do we want readers to do about it? And what information do we need to provide to make this possible? In that sense, Coming to each theme without specialist knowledge has also helped to ensure that everything we publish is clear to all our readers, many of whom have English as an additional language. It is hard work for everyone involved, and our authors, reviewers and consulting editors have been wonderfully patient with the endless rounds of revisions. We always get there in the end!What keeps me going is the appreciation I have for every single one of our readers who work, often in the most difficult of circumstances, to prevent blindness and improve the eye health of people in their communities. It is a joy to support them in this work.Journal meant to our readers. We repeated her survey, with minor changes, in 2010. I was deeply touched by the lovely things readers said then too. However, it was this comment, from an optometrist in Nigeria, that made the biggest impact. He wrote: “Without this journal, I am in utter darkness.” This image has stayed with me ever since, reminding me how much our readers rely on the Journal to support them and guide their way.Thanks to the excellent readership survey Victoria had conducted in 2005, it was clear to me how much the the Journal.”A few years later, Daniel Etya'ale, another leading light in international eye care, put it into context for me. “When you get to the end of the road somewhere in the middle of Africa,” he said, “and then walk another few hours into the bush, there you will find a clinic with a single ophthalmic nurse who only had her study notes from 20 years ago – until she received Editor 2004–2007My first issue was SICS – Small Incision Cataract Surgery.“Why start me off with such a technical topic?”Allen Foster: “Because if it were too easy you would run away!”I was the first non-ophthalmologist editor and I remember my gratitude to the editorial committee for their guidance during lively editorial meetings and email exchanges.Coming from an education, social research and health communication background, I saw my role, at that point in the Journal's life, to review and enhance the way it communicated with its readers. It was important that we were reaching the right people with the right information presented in the clearest way possible. My first task was a content analysis of past issues to review topics and relevance to different levels of eye care workers in diverse geographical settings. We also conducted a reader survey to solicit reader views, particularly how CEHJ influenced attitudes and practice. This, along with dialogue with regional consultants, informed the changes.The Journal's ‘face lift’ targeted content and design. The Cochrane Eyes and Vision Group contributed a section on “Evidence-based Ophthalmology” and a new “Exchange” section encouraged readers to share inspiring experiences. For the restyle, I worked with talented designer Lance Bellers to maximise space within the 16 pages and modernise layouts leading to the now familiar design starting with issue 51. We tried to make it more visual, using my illustrations as design elements and info-graphics and included ready-to-use education materials, as requested in the reader survey.Revisiting the 14 issues I worked on, I am reminded of the facilitative relationships with authors – all of them practitioners who made time in very busy lives to share their knowledge and experience. I remember too the fruitful collaborations for the Indian edition and the French translation.www.cehjournal.org. I remember with some shame my scepticism, sticking stubbornly to the argument that many readers would be hard pressed to have a working computer let alone internet access. Comparing Internet World Stats between 2004 and 2017 leads me to eat my hat; Sally's vision was well founded: Africa up from 1% – 31%, Asia up from 7% to 46%, Middle East 7% to 59%, Latin America and the Caribbean 9% up to 61%.Around this time, the online version was gaining momentum with Sally Parsley delivering improvements in My least favorite aspect of the job was meticulous proofreading to ensure correctness and consistency. To make my life easier, and with a thought for my successor, a small team  made a tedious task fun as we created the Author Guidelines and Style Sheet.Four years after taking on the editorship, it was time to hand over the baton. My last issue was Research and Training Programmes, a topic close to my heart, and I was delighted to include 20 summaries of Community Eye Health MSc dissertations, demonstrating the close relationship between training offered at the LSHTM and the Journal as a vehicle for providing distance learning to readers across over 180 countries.Handing over to Elmien and the continuity of the Editorial Committee, I felt confident that the important role of the CEHJ was in safe hands.admin@cehjournal.orgIs there anything you would like us to cover in a future issue? Send questions and suggestions to Journal inspires and enables positive changes in readers' approach to patients and eye disease. We have encouraged readers to communicate better with patients and their families, to actively include women and people with disabilities in their services, and to collaborate with colleagues in other departments to address emerging diseases such as diabetic retinopathy, glaucoma and retinopathy of prematurity. More than anything else, we have promoted the importance of the eye health team: people with different skills and qualifications, working together to improve eye health.The Journal is very much a team effort too. I am very lucky to work with ICEH's inspirational co-directors, Allen Foster and Clare Gilbert; and with the wonderful Nick Astbury (advisor), Anita Shah , Lance Bellers (designer), and online team Astrid Leck and Miyo Hanazawa. Thank you for everything you do, every day, to ensure that the journal is helpful, beautiful and reaches everyone who needs it.Producing the I would also like to express my heartfelt thanks to our two previous editors, Murray McGavin and Victoria Francis. I am standing on the shoulders of giants.It is an honour to be here at this important milestone. Here is to another 100 issues! Our readers are at the centre of all our editorial decisions about themes and articles. Readers send feedback throughout the year, and we actively invite readers' input regarding future themes and topics by conducting reader surveys every five years.Our most recent survey was conducted by mobile phone. A total of 89 readers from 27 countries were interviewed by then intern Nnamdi Nwuba. Readers were selected to represent the different occupations in eye care: mid-level personnel , ophthalmologists, optometrists and managers/others. They worked in government (57%), the private sector (23%), and non-governmental organisations (17%).Journal, and nearly two-thirds shared their copy with colleagues. Exactly half of those interviewed used the pictures to explain eye conditions to patients, and 39% relied on the Journal when teaching eye health professionals, both formally and informally.Three-quarters reported reading either ‘all of’ or ‘most of’ the Journal is a source of education and offers an opportunity to connect with the wider world, especially in remote areasThe The information is relevant and useful, particularly in low-income settingsJournal builds confidence and inspires readers to learn and do more; the international perspective is part of this.The The appreciation for the journal was overwhelming. The following themes emerged very strongly:of the Journal, e.g. the fact that it covers a different theme in-depth in each issue and that it has regular sections such as the editorial article, the quizzes, the announcement section and so on. Readers felt the Journal was easy to understand and helpful for teaching others.Other comments focused on the format Editorial administratorCommunity Eye Health Journal in 1988. I was appointed as his secretary in 1997 and joined Ann Naughton and Sue Stevens to complete the small team responsible for the production of the Journal.Dr Murray McGavin, founded the As Editorial Administrator, my overall purpose is to ensure the smooth running of the Journal's production, from planning meetings through to proofreading, printing and distribution. The Journal has a circulation of about 20,000 .I manage the database and help to increase subscriptions through promotion of the Journal at external events and through correspondence with subscribers. Such direct contact with our readers and authors is a particularly enjoyable part of my role; I am also the first point of contact for many of them.Coordination of the production schedule involves liaising with editors of other language editions, the designer, the printers, and the website manager. I also manage the article submission and review process of unsolicited research articles and correspond with authors, reviewers and the Editor. All unsolicited articles are sent to two reviewers who are experts in the relevant field of ophthalmology. All comments received are passed back to the authors for the necessary changes to be made. If the article is rejected, feedback is offered with encouragement for future submission, as appropriate.Community Eye Health Journal production team and play a part in the promotion of eye health and prevention of blindness worldwide.It is a huge privilege to be part of ICEH, especially the To subscribe, contact Anita onadmin@cehjournal.orgthe Journal changed the way you work or do your job?” 83% of the respondents said ‘yes’. Change was experienced in many different areas, including clinical and patient care, in readers themselves, and in public health eye care and planning. Here are some examples.Readers were asked: “Has anything you've read or seen in Cataract surgeon, ZambiaI used the advice on the management of bacterial conjunctivitis and the management of corneal ulcers. I have since changed my choice of antibiotics. Optometrist, NigeriaIt helps practically with going into the community. For example, I wasn't well practised with a Schiotz Tonometer, but I followed step-by-step what you mentioned and it helped me all the way! We now have protocols in place for ophthalmic assistants. It has helped with human resource training. Also, the Journal Ophthalmologist, Kenyahas been useful for the care of ophthalmic instruments. Eye care coordinator/manager, The GambiaWe used to focus only on cataracts and glaucoma. Now we can do refractive error and low vision during outreach in the community. We have improved our training programme. We get people from East Africa now, not just West Africa (as we did before). It is a very comprehensive journal! Ophthalmic nurse, NigeriaI always wanted to go into the community. It informs me about things to do in the community. Gives me courage to do things. It enables me to assess myself and my ability. I find joy in reading things through and practically performing them. Makes me proud to be an ophthalmic nurse. Even when the doctor is not available, I can feel confident. Professor/educator, BangladeshIt's had a complete effect on my work. I take ideas from the Journal and use it to revise my work. It directs me to do good things. When I read it, it makes me a better person – better in thinking, better in performing. Ophthalmologist, NigeriaThe thoroughness seen in the Journal motivates me to implement changes in my own practice. According to the World Bank Development IndicatorsGraphic designerJournal together. That was issue 51 and I'm still here – making it a round 50 issues for me and a perfect 100 for the Journal since its inception.I think I may have said something like “I'll just help a bit on one or two,” to Victoria when we first discussed how best to piece the I was working as freelance graphic designer for Sightsavers at the time. When asked if I'd be interested in branching out to work on a project at the International Centre of Eye Health, of course I said yes.Focus on Africa magazine at the BBC World Service – and so my role with the Journal is to lend my experience of presenting stories and information in an accessible way to a wide range of readers. The Journal is sometimes quite specialist and technical, so it is important that the design makes everything clear and easy to follow. Then everyone can get as much as possible from its pages; whether for their own education, to train others, or to explain eye conditions to patients.My background is largely reports and magazines – including 20 years on The idea that it is used and appreciated by the readership is very important to me and and it has been a privilege to play a part in its evolution. Elmien has brought her keen journalistic approach to each of her issues since Victoria handed over the baton and it has also been a pleasure for me to design the French edition of the Journal with Paddy Ricard, who works tirelessly to reach the Francophone readership across the world.In the most recent refresh of both the English and French editions, we have kept in mind the ever-more important online aspect and hopefully the structure lends itself to transferring to the web after each printed edition has come off the press.Journal helps make this happen – long may it continue.The high point? In 2005, I was fortunate to travel in Africa and visit eye care projects in Tanzania and Ethiopia. The look of glee on an elderly woman's face as her bandage was removed after a cataract operation was priceless. The


ILs containing phenylalanine and methionine were synthesized and deposited on zirconia. Intermolecular interactions driving IL deposition on zirconia were studied using X-ray photoelectron spectroscopy (XPS). Anti-biofilm activity and cell compatibility were evaluated in vitro after one and seven days, and wear performance was tested using a pin-on-disk apparatus. ILs were observed to form strong hydrogen bonds with zirconia. IL containing phenylalanine formed a stable film on the surface after one and seven days in phosphate-buffered saline (PBS) and artificial saliva and showed excellent anti-biofilm properties against Streptococcussalivarius and Streptococcussanguinis. Compatibility with gingival fibroblasts and pre-osteoblasts was maintained, and conditions for growth and differentiation were preserved. A significantly lower coefficient of friction and wear volume loss were observed for IL-coated surfaces as compared to non-coated substrates. Overall, zirconia is an emerging alternative to titanium in dental implants systems, and this study provides additional evidence of the materials’ behavior and IL coatings as a potential surface treatment technology for improvement of its properties.In the present work, dicationic imidazolium-based ionic liquids (ILs) were investigated as multi-functional coatings on a zirconia (ZrO One of the attractive aspects of zirconia for oral implants is its ivory, tooth-like color. Additionally, the material’s mechanical and chemical properties, such as high fracture toughness, flexural strength and resilience, and high corrosion stability, make it a good choice for dental implant systems [Commercially pure titanium (cpTi) has been the material of choice for oral implants during the last few decades due to their biocompatibility, corrosion resistance, and good mechanical properties, resulting in high survival rates of 90.9%–97.7% 15 years post-implantation . However systems ,9,10. Fu systems ,12,13. I systems . In a re systems .Porhyromonas gingivalis has been implicated as a major reason for dental implant failure and estimated to affect 15%–56% of all dental implants [For long-term success of a dental implant system, it is necessary for the implant surface to achieve integration with soft and bone tissues, which will ensure sealing and functional integration. Furthermore, it has been discussed in the literature that soft tissue seal formation around an implant neck is critical to provide a barrier against bacterial penetration toward the bone . Despiteimplants . Despiteimplants ,27,28,29Given that zirconia is a relatively new alternative material for the design of osseointegrative implant bodies or screws of two-piece dental implant systems, few studies have reported the biological and physico-chemical behavior of this material under circumstances relevant to the oral environment . LikewisAlthough several approaches have been proposed for the surface modification of osseointegrative implants, many of which are applicable to zirconia, there is still a need to provide multi-functionalities to an implant surface with a single surface treatment. Recently, dicationic imidazolium-based ionic liquid (IL) coatings were developed for dental implant applications. These IL coatings were functionalized to promote surfaces with antimicrobial activity, corrosion protection, and improved lubrication ,31,32,33Based on our previous results, two ILs with the same dicationic moiety and phenylalanine and methionine as anions were selected and investigated on zirconia substrates ,31,32. TIL coatings were deposited on the surface of zirconia to investigate their adsorption and deposition profile. XPS  and release profile studies were carried out to understand intermolecular interactions between IL and zirconia and coating stability, respectively. The hypothesis was that the carboxylate and amino groups of ILs would interact with zirconium (Zr) and oxygen (O) in the substrate. It was expected that a change in the chemical environment surrounding the constituent elements would be seen due to this interaction.Binding energies (BEs) were used to assess the chemical interaction of ILs before and after the adsorption process on the investigated surfaces. Shifts found in these BEs that were greater than the measurement error of the equipment (±0.1 eV) were designated as a change in the chemical environment of the constituent atoms on the material’s surface.5/2 peak is discussed. XPS data for pure IL1 and IL2 are referenced based on our previous study [According to previous studies, it was observed that the cationic moiety in the ILs can interact with negatively-charged sites, and the anionic moiety can interact with positively-charged sites ,36. To dus study . Spectraus study ,38. The Beginning with the C 1s spectra, aliphatic carbon was the primary peak component previously detected at 285.0 eV for pure IL1 and IL2 . As for 2), which is in accordance with values reported in the literature for zirconia surfaces [For non-coated control zirconia, the primary O 1s peak at 530.8 ± 0.1 eV corresponded to O comprising zirconium oxide  and cationic (Nc) moieties of IL exhibited separate peaks at distinct BEs. Per our previous study, pure IL1 exhibited Na and Nc peaks at 399.1 eV and 401.8 eV, respectively [a and Nc. The former new peak represented a shift to higher BE of Na due to hydrogen bond formation between the amine of the anionic moiety and oxygen atoms present in zirconia. Likewise, a shift to higher BE of Nc can be attributed to this interaction as decreased charge neutralization by the IL anion is hypothesized to cause the IL cation (and thus Nc) to become more positive [Although the O 1s spectra suggested interaction between IL and zirconia surfaces, the N 1s spectra  was evenectively . After cpositive . Howeverpositive . Furtherpositive . Moreove2 can act as an acidic site and accept electrons [In addition to the elements comprising IL, Zr comprising zirconia surfaces also exhibited increased BE values after deposition of IL on its surface. This shift in BE from 183.0 ± 0.1 eV to 183.7 ± 0.2 eV for IL1 coated zirconia and 183.9 ± 0.0 eV for IL2-coated zirconia corroborated that hydrogen bond formation occurred between oxygen in IL anion and Zr atoms on zirconia. Like titanium, zirconium in the metal oxide of ZrOlectrons . Furtherlectrons . OverallIn this study, IL coating release in aqueous media was investigated after one and seven days of immersion to evaluate the stability of the IL coating during the time frame in which initial healing occurs post-implantation. Phosphate-buffered saline (PBS) and artificial saliva were chosen to simulate relevant physiological conditions.p < 0.05), which was also previously observed for IL1 coatings on titanium surfaces [p > 0.05). surfaces . Similarp > 0.05) increased when compared to the results obtained for one day of immersion in both media. These results corroborated trends seen in our previous study on IL-coated titanium surfaces [p > 0.05), suggesting that IL2 had a lower affinity for the zirconia surface than for titanium ones.After seven days, the percentage of IL1 released in PBS and saliva relative to the initial amount of IL coated was 41.9% ± 8.3% and 8.7% ± 1.9%, respectively, and for IL2, it was 64.4% ± 8.7% and 59.9% ± 19.5%, respectively. Even after seven days of immersion in PBS and saliva, the results showed that IL release was not significantly . In contrast, IL2 resulted in significant reduction in cell viability (80.8%) when compared to control zirconia (p < 0.05). After seven days, both IL1 (82.2%) and IL2-coated (90.1%) zirconia specimens resulted in lower cell viability than control zirconia; however, these viability values were not statistically different than the control (p > 0.05). For pre-osteoblast cells, IL2-coated zirconia resulted in similar cell viability (92.7%) as control zirconia (100%) after one day, whereas IL1-coated zirconia displayed significantly lower viability values (82.2%) relative to control zirconia (p < 0.05). After seven days, viability values obtained for IL1-coated (87%) and IL2-coated (94.4%) specimens were similar to control zirconia and no significant differences were observed between them (p > 0.05).To better understand the cytocompatibility of IL-coated zirconia, cell viability was evaluated with human gingival fibroblasts (HGF-1) and mouse pre-osteoblasts (MC3T3-E1) after exposure to IL-coated and non-coated control zirconia specimens, and the results are summarized in Per ISO 10993-5:2009 standard, which assesses cell viability on the surface of biomaterials, a more than 30% of reduction in cell viability is considered a cytotoxic effect. Since cell viabilities obtained for all IL-coated specimens were above 80% across both cell lines, the IL coatings can be considered non-cytotoxic. Furthermore, the trends observed in these results correlated with the release profile of IL1-coated and IL2-coated zirconia in PBS as discussed previously. That is, IL coating was observed to have lower average viability for fibroblasts and pre-osteoblasts after one day of exposure relative to non-coated specimens. However, cell viability in general was observed to increase and recover after seven days. It can be assumed that since a high concentration of IL1 and IL2 was released after the first day of immersion in this medium, lower viability would be expected for IL-coated zirconia after one day. However, IL release did not significantly increase between one and seven days based on the release profile, implying that IL coating became stable after one day and therefore could not release substantially more IL. Furthermore, cell culture medium was changed every 48 h, thereby removing the initial amount of IL released. As a result, mammalian cells would be exposed to lower amounts of IL in the surrounding media, thereby lessening the cytotoxic effect of ILs and allowing for increased cell viability by the seven-day time point.In our previous study, IL1-coated titanium specimens showed more than 70% cell viability for both MC3T3-E1 pre-osteoblasts and HGF-1 fibroblasts after seven days, which was similar to the results found for IL1-coated zirconia . Interesp > 0.05). However, due to the low ALP values, this data are not relevant. The ALP staining results for the surfaces of control, IL1-coated, and IL2-coated zirconia after seven days are shown in The differentiation of pre-osteoblasts on IL-coated and non-coated control zirconia were determined by their alkaline phosphatase (ALP) activity, and the results are summarized in S. salivarius and S. sanguinis for one and seven days in culture broth containing brain heart infusion (BHI) and saliva, and the results are summarized in S. salivarius (5.5 ± 0.2) and S. sanguinis (4.3 ± 0.4) as compared to control zirconia  after one day (p < 0.05). The surfaces of specimens coated with IL1 were found to be almost devoid of bacteria (below the limit of detection) for both S. salivarius (0.0 ± 0.0) and S. sanguinis (0.0 ± 0.0), with significant reduction in relation to control zirconia  (p < 0.05). However, IL2-coated zirconia specimens did not exhibit anti-biofilm activity and had similar bacterial load as control zirconia. Bacterial count (log CFU/mL) in immersion fluid of IL2-coated specimens for S. salivarius (6.1 ± 0.4) and S. sanguinis (6.3 ± 0.2) was found to be similar to control zirconia  (p > 0.05). Similarly, no significant difference was found between the S. salivarius (5.2 ± 0.2) and S. sanguinis (4.0 ± 0.1) loads on IL2-coated zirconia in relation to control zirconia  (p > 0.05). These results correlated with the release profile for IL coating previously discussed. For IL1, the amount of coating released was only 4.9% ± 0.5% after 1 day of immersion in saliva. However, this still led to the decrease in CFU/mL measured in the immersion fluid and maintained no bacteria (below detection limit) on the zirconia substrate. In contrast, this behavior was not observed for IL2 coating despite its release profile demonstrating that IL2 was present on both surface and in immersion media.Anti-biofilm activity of IL1-coated and IL2-coated zirconia was tested against S. salivarius (2.7 ± 0.5) and S. sanguinis (4.4 ± 0.3) as compared to control zirconia  (p < 0.05). Again, the surface of IL1-coated specimens showed absence of bacterial colonies and significantly lower bacteria count for S. salivarius (0.0 ± 0.0) and S. sanguinis (0.0 ± 0.0) after seven days in relation to control zirconia  (p < 0.05). Correlating these results with the coating release profile, 8.7% ± 1.9% of IL1 was released in saliva from zirconia surface after seven days. Since the amount released was still relatively low, it helped to maintain the antimicrobial activity both in fluid and on the surface. However, like the one-day results, IL2-coated zirconia specimens exhibited a similar number of bacterial colonies as the control zirconia after seven days (p > 0.05). This behavior has been seen in our previous work, and it is assumed that the absence of antimicrobial activity of IL2 may be attributed to the formation of crystals between the IL molecules and compounds found in the artificial saliva. The crystallization was suggested to inactivate the IL molecules and therefore inhibit the antimicrobial activity of IL2 [After seven days of immersion, the anti-biofilm activity of IL1-coated zirconia was still retained, which resulted in significantly lower count of bacteria (log CFU/mL) in the immersion fluid of y of IL2 .Despite few studies suggesting lower bacterial load on zirconia surfaces in physiological conditions relative to titanium, a number of other studies have demonstrated similar bacterial adherence and biofilm formation on titanium and zirconia surfaces ,45. TherTo investigate the effect of the two ILs on the tribological behavior of zirconia, wear tests were performed using experimental conditions that represented worst-case scenarios for the implant experiencing stresses during insertion, mastication, and micromotion ,47. Coefp < 0.05). Wear volume loss for IL1-coated zirconia was significantly lower than control zirconia specimens (p < 0.05). IL2-coated zirconia also exhibited lower wear volume loss as compared to the control. However, this reduction was not significantly different (p > 0.05).IL coatings were found to be stable throughout testing and able to reduce friction between the two surfaces in contact . A signiThe results showed that both IL compositions resulted in a significant reduction in COF compared to control specimens. This reduction can be attributed to the presence of long alkyl chains in both IL structures. As discussed in the literature, longer alkyl chains help to form more stable layers on titanium surfaces, which in turn lead to lower wear loss ,49. AlsoRegarding lubricant film stability, ILs formed a stable layer on zirconia surfaces. COF values for IL1-coated and IL2-coated zirconia were found to be stable throughout test indicating hydrodynamic lubrication between the stainless steel ball and zirconia specimens . As seenp < 0.05). Moreover, the total wear volume loss for IL-coated specimens can mainly be attributed to wear generation from the stainless steel ball and not the zirconia specimen. That is, the appearance of relative large wear track width observed for the wear scars on zirconia was due to superficial scratching by the stainless steel ball as minimal indentation was visible on its surface. Furthermore, the presence of the regions within the wear scar that appeared to be pristine and similar to regions of the surface adjacent to the wear scar indicated that minimal damage had occurred on the zirconia surface. As stainless steel is less wear-resistant than zirconia, the circular contact area between the ball and specimen became increasingly larger, allowing for more superficial damage on the zirconia surface. In the context of dental implant systems, frictional forces applied during insertion of an implant, mechanical stresses, and micromotion are factors contributing to early implant loss by hampering the surface stability of the implant during the initial phases after implantation [As seen in antation . LubricaDespite the multi-functional behavior imparted by IL1 coating on zirconia surface, some limitations of the present study need to be addressed. Although IL1 demonstrated coating stability due to a stable release profile being observed in PBS and artificial saliva after seven days, this testing was performed under stagnant conditions and with the immersion media not being replaced periodically, thereby possibly mitigating further release of the IL from the coating due to reaching dynamic equilibrium. During evaluation of mammalian cell activity, media was changed every 48 h, removing IL initially released into the cell culture medium. This reduction in exposure to IL, although necessary to assess recovery of pre-osteoblasts and gingival fibroblasts by the seven-day time point, did not allow for evaluation of growth under continuous seven-day exposure to IL. Future studies will overcome these limitations by evaluating the IL release profile, antimicrobial activity, and mammalian cell growth under fluid-flow conditions to better mimic fluid movement in the oral cavity while allowing for continuous release and exposure to IL.1H nuclear magnetic resonance spectroscopy (NMR) , and the data found were in accordance with the literature [1,10-Bis(3-methylimidazolium-1-yl)decane diphenylalanine (IL1) and 1,10-bis(3-methylimidazolium-1-yl)decane dimethionine (IL2) were synthesized following protocols discussed in our previous studies ,32. Bothterature . The che2) ceramic rods partially stabilized with 3% magnesium oxide (MgO) were obtained . The rods were cut into disks with 0.95 cm diameter and 0.45 cm height using a precision cutter equipped with a diamond blade  and were subsequently mounted for polishing using epoxy resin. Mounted specimens were polished using an automated polishing head  and plate  by applying a set force of 90 psi at a speed of 200 rpm for 5 min per step, excluding the last step, which ran at 100 rpm. The polishing procedure included 30 µm polycrystalline diamond solution, 6 µm polycrystalline diamond solution, 1 µm polycrystalline diamond solution, and 40% colloidal silica solution in sequential steps. The polished specimens were then removed from the resin molds and cleaned by ultrasonicating in acetone, deionized water, and ethanol for 15 min each before drying in an oven at 60 °C for 48 h. To coat IL on the zirconia substrates, 0.011 mM ethanolic solutions of IL1 and IL2 were prepared. Five microliters of the coating solution was pipetted onto specimens 10 times at an interval of 15 min. The coated specimens were then dried in an oven at 60 °C for 48 h. Three coated and three non-coated samples were tested in each of the following experiments.Wear-resistant zirconia  was used to analyze the surface elemental composition and interaction between IL coating and zirconia surface, and ultraviolet-visible (UV-Vis) spectroscopy  was used to study the IL release from the coated specimens.−8 torr, and the survey spectra were obtained using a pass energy of 187.850 eV and 0.8 eV step size. The high-resolution spectra were acquired using a pass energy of 23.5 eV and step size of 0.2 eV.One non-coated control and IL-coated zirconia specimen for each IL were analyzed on three different areas per specimen using X-ray photoelectron spectroscopy  X-ray Photoelectron Spectrometer, . A monochromatic Al Kα source of 1486.6 eV was used, and the measurements were taken at an angle of 45° with respect to the surface of the specimen. The pressure in the analysis chamber was kept below 10n = 3) were each immersed in 1 mL of 1X phosphate-buffered saline  or Fusayama/Meyer artificial saliva , separately in 24-well plates. The plates were maintained at 37 °C for one day and seven days. After one and seven days, absorbance was recorded from the 2 µL aliquots obtained from each well using an ultraviolet-visible (UV-Vis) spectrophotometer . The corresponding IL concentration in the immersion media was determined using previously established calibration curves for IL1 and IL2 in PBS and artificial saliva [To study IL coating release into the immersion media, non-coated, IL1-coated, and IL2-coated zirconia  and Streptococcus salivarius , were chosen to evaluate the anti-biofilm activity of IL-coated zirconia specimens against early bacterial colonizers. The bacterial strains were streaked on BHI agar plates and then incubated in microaerophilic atmosphere at 37 °C. The bacterial inoculation was incubated and then diluted with 1.9:0.1 ratio of artificial saliva/BHI with a concentration of 105 colony-forming units per ml (CFU/mL). For the one-day test, control and IL-coated zirconia specimens (n = 3) were immersed for 24 h in cell-density-normalized bacterial culture. Thereafter, the specimens were taken out and washed three times gently with buffer to remove non-adherent bacterial cells. The specimens were then vortexed vigorously in buffer, and the surface of the specimens was scraped with the help of a sterile spatula to remove any bacteria attached to the surface. The bacterial growth in immersion media and on specimen surface was then quantified in CFU/mL by plating serial dilutions of the immersion fluid and buffer solution on BHI agar plates. To evaluate the long-term antimicrobial activity of IL coatings, non-coated and IL-coated zirconia specimens (n = 3) were immersed in artificial saliva/BHI medium for six days. On the seventh day, bacterial inoculation, removal of bacterial biofilm, and quantification of bacterial growth in the immersion and specimen surface were performed as described above for one-day testing.Two Human gingival fibroblasts (HGF-1), murine pre-osteoblast cells (MC3T3-E1), Dulbecco’s modified eagle medium, alpha minimum essential medium, and trypsin were obtained from the American Type Culture Collection. Agar and BHI were purchased from Fisher Scientific.2 in a humid environment. Control and IL-coated zirconia (n = 3) were then placed individually in six-well plates with seeding density of 350,000 cells per well for one-day tests and 100,000 cells per well for seven-day tests. These cell densities were chosen to ensure the full confluency of cells and hence detect differences in cell proliferation at specific time points of the study [To understand and evaluate host cell integration on IL-coated zirconia, cell culture tests were performed in vitro using six-well plates for one and seven days. Human gingival fibroblasts (HGF-1) and murine pre-osteoblast cells (MC3T3-E1) of the fifth to seventh passages were used for this study. The cells were cultured in Dulbecco’s modified eagle medium with 10% fetal bovine serum and alpha minimum essential medium with 10% bovine serum, respectively, at 37 °C and 5% COhe study ,32. The Cell viability for fibroblasts and osteoblasts after being exposed to control zirconia and IL-coated zirconia for one and seven days was evaluated using MTT -2,5-diphenyltetrazolium bromide) assay, as described in detail in our previous study . Cells aALP expression was evaluated in two ways, as described in detail in our previous study . A colorThe wear behavior of IL-coated zirconia in comparison to non-coated specimens was evaluated in artificial saliva maintained at 37 °C. A continuous sliding motion using a modified pin-on-disk apparatus mounted on a hybrid rheometer  was used to perform wear testing. The method employed followed procedures described in ASTM G99-05 and ASTM G133-05.A stainless steel ball (12.7 mm) was fixed in a modified ball specimen holder consisting of a semi-spherical fluid compartment as shown in R = Radius of the wear track formed on zirconia specimen.r = Diameter of the spherical pin.d = Width of the wear track on zirconia specimen or the diameter of the wear scar on the ball.h = Wear depth of the flat wear scar on the ball.After wear testing, the specimens were cleaned with acetone to remove wear debris generated during testing and observed with optical microscopy. The average width of wear scars was measured from six different points located on the circular wear scar using optical microscopy. The wear volume loss was then calculated using Equations (1)–(3) below defined in ASTM G99-05, which are applicable to a disk and spherical pin sliding against each other under elastic deformation conditions.p-values ≤ 0.05.Statistical significance between non-coated and IL-coated zirconia was determined for parameters used to assess coating stability, mammalian cell cytotoxicity, anti-microbial activity, and lubricant behavior. One-way analysis of variance (ANOVA) and post-hoc Tukey tests were performed using Origin Pro 8 software , and the between-group means were deemed significantly different for S. sanguinis and S. salivarius on both the surface of zirconia and the surrounding immersion media, while IL2 coating exhibited bacterial loads similar to those of non-coated control zirconia. Evaluation of the anti-biofilm mechanism of these IL-coatings as well as the interaction between IL and zirconia surface after long-term bacterial cell incubation will be investigated in future studies. As a lubricant, both IL1 and IL2 demonstrated excellent wear performance for zirconia substrates, resulting in sustained decreases in coefficient of friction and wear volume loss generated. Within the limitations of this study, IL1 demonstrated the best performance as a multi-functional coating for zirconia surfaces by providing antimicrobial activity and lubrication as well as maintaining a suitable environment for host cell attachment, proliferation, and differentiation.In conclusion, dicationic imidazolium-based IL coatings containing phenylalanine (IL1) and methionine (IL2) were found to interact with zirconia surfaces based on XPS analysis, which resulted in a shift to higher BE values for all elements comprising IL and zirconia. Similarly, both IL1 and IL2 coatings were found to be stable after one and seven days of immersion in either PBS or artificial saliva. However, IL1 coating demonstrated greater film stability in saliva as compared to IL2. Both IL1 and IL2 coatings on zirconia were deemed to be non-cytotoxic to both HGF-1 fibroblasts and MC3T3-E1 pre-osteoblasts after one and seven days of exposure. On the other hand, only IL1 coating demonstrated anti-biofilm activity against early-colonizing


Croatian Medical Journal (CMJ) was in 2009 (The last time we wrote for the  in 2009  and 2011In December 2017, we were invited to celebrate the CMJ’s 25th anniversary and to see how it sails on. What impressed us most was that the journal has the best people for the job: the editorial team has some old members, who have been with the journal almost from its beginning and who can provide continuity and editorial wisdom, and new young editors, who can take on the challenge of the rapidly developing world of scientific communication and editing.The silver anniversary was also a time to remind us all why we had started the journal  – to havDuring the five years after we had left, CMJ continued to publish good science, kept its bibliometric indices at the same high levels, and trained new editors. Is this enough? We would like to repeat our challenge to the CMJ’s new editor-in-chief and his team , only thCMJ has a great potential for such change. Even during our editorship, the journal moved from topics related to social aspects of medicine, including the consequences of natural and man-made disasters such as war , toward Regardless of its future, the focus of the journal should always include its responsibility to the society, just as social responsibility is at the core of the Europe’s Horizon 2020 program . We shou


To describe the management of a serious adverse event in a patient undergoing penetrating keratoplasty (PK).A 68-year-old man underwent PK for an aphakic bullous keratopathy following previous complicated cataract surgery. He had no past history of herpetic disease. Storage of the corneoscleral disc in the transport bottle precluded microscopic examination. After placement of the trephined donor cornea on the open eye of the recipient, a large dendritiform geographic ulcer was noted on the donor cornea. A replacement cornea was used after changing potentially contaminated instruments. Intravenous antiviral treatment was commenced intraoperatively to reduce the risk of infection to the central nervous system. Postoperatively, oral and topical antiviral treatment was commenced and 6 months following surgery the patient developed a geographic corneal ulcer at the graft host interface.Containers to transport corneoscleral discs should enable microscopic examination by the surgeon prior to use. High dose systemic antivirals may reduce the risk of herpetic disease involving the posterior segment of the eye and neuroretina in the aphakic eye and spread to the central nervous system. Herpes simplex keratitis (HSK) is one of the major causes of corneal inflammation and corneal blindness, rated just second to trauma in most developed countries –3. Clini2 with mild polymegethism and pleomorphism. A 8.5 mm Hessberg–Barron trephine was used to prepare the donor cornea and a 8 mm trephine for the recipient. After placement of the donor onto the aphakic eye a large dendritic-geographic epithelial ulcer was noted . Postoperatively, the patient was commenced on systemic and local antiviral therapy for 1 week  and local antibiotic treatment (chloramphenicol four times a day). Topical steroids were withheld for 48 h. At 1 week the graft was clear and had re-epithelialized. Long term prophylactic acyclovir 400 mg twice a day was commenced but 6 months later the patient developed a geographic corneal ulcer involving the graft-host interface Fig.  with kerThe potential transmission of HSV-1 from donor to host has been recognized by clinical and laboratory studies –14. ViraWe describe a case of clinically suspected HSK in the donor cornea and subsequently in the recipient. Biswas et al.  describe


We developed a novel technique to create drainage holes for skin grafts simply and safely using a beaker, a rubber band, and gauze, which are easily obtained in the operating room.What data have been reported on the prevention of hematoma development in skin grafts?What problems exist in the conventional method of creating a drainage hole in skin grafts?What is the technique presented here for the creation of a drainage hole?What are the merits of the present technique?-2,3,6-Skin grafts can be partially or completely unsuccessful for various reasons. The most common reason for graft failure is hematoma formation between the skin graft and the wound bed, obstructing graft nutrition and revascularization.1A surgical knife and a needle may be used conventionally to create a drainage hole in a skin graft in cases in which meshing is not appropriate due to cosmetic reasons. This method is often applied to full-thickness skin grafts using a metal or wooden plate as a desk pad  and 2. HThe technique presented here for creating a drainage hole is shown in The present technique has various merits. First, it is simple and safe, and a single surgeon can create the drainage holes certainly involving all layers of the skin graft. Second, the instruments necessary to perform this technique are used daily in the operating room; therefore, it is cost-effective. Even if the gauze is worn with many holes, it can be rapidly exchanged with a new gauze. In addition, even if the skin graft is large, drainage holes can be created evenly and wholly by shifting the graft, and drainage holes can be created more easily by creating tension in the skin graft at the margin of the beaker with the surgeon's finger.We have applied the present technique in our daily practice for graft operations and consider it useful for simple and safe creation of drainage holes, particularly for thick skin grafts.


The kurtosis-based indexes are usually used to identify the optimal resonant frequency band. However, kurtosis can only describe the strength of transient impulses, which cannot differentiate impulse noises and repetitive transient impulses cyclically generated in bearing vibration signals. As a result, it may lead to inaccurate results in identifying resonant frequency bands, in demodulating fault features and hence in fault diagnosis. In view of those drawbacks, this manuscript redefines the correlated kurtosis based on kurtosis and auto-correlative function, puts forward an improved correlated kurtosis based on squared envelope spectrum of bearing vibration signals. Meanwhile, this manuscript proposes an optimal resonant band demodulation method, which can adaptively determine the optimal resonant frequency band and accurately demodulate transient fault features of rolling bearings, by combining the complex Morlet wavelet filter and the Particle Swarm Optimization algorithm. Analysis of both simulation data and experimental data reveal that the improved correlated kurtosis can effectively remedy the drawbacks of kurtosis-based indexes and the proposed optimal resonant band demodulation is more accurate in identifying the optimal central frequencies and bandwidth of resonant bands. Improved fault diagnosis results in experiment verified the validity and advantage of the proposed method over the traditional kurtosis-based indexes. Rolling bearings are one of the most common but the most vulnerable parts in rotating mechanical systems. In order to ensure uninterrupted operation and avoid unexpected failures, research attention has been focused on the extraction of weak fault features of rolling bearings which constitute a key factor to condition monitoring and fault diagnosis of rotating mechanical systems . BearingAntoni ,4 put foIn view of these deficiencies, Wang  proposedThe aforementioned review of related studies indicates that the identification quality of resonant frequency bands depends on the construction of criterion used to detect transient features and on the construction of a band-pass filter used to segment the frequency band. Among them, the construction of criteria used to detect transient features is the key factor to determine the quality of identified resonant frequency bands.Taking advantage of the periodical features of transient impulses, McDonald et al.  proposedTo address these issues, the manuscript redefines the correlated kurtosis, on the basis of kurtosis and auto-correlative function, and puts forward an improved correlated kurtosis based on the squared envelope spectrum of rolling bearing vibration signals. Meanwhile, this manuscript proposes an optimal resonant frequency band demodulation by combining the complex Morlet wavelet band-pass filter and the Particle Swarm Optimization algorithm, which can adaptively identify the optimal resonant frequency bands and demodulate transient features of rolling bearings.The rest of the manuscript is organized as follows: the related theoretical background is presented in j is the imaginary number, h and l are respectively the upper and lower cut-off frequency of the band-pass filter As we know, kurtosis can represent the characteristics of signals around their mean value and characterize the strength of transient impulses. Given a zero mean signals, kurtosis can be defined as the ratio among the fourth central moment of the signal to the squared second central moment of the signal . Given aThen the kurtosis can be expressed as:Taking a step further, the corresponding transient impulses can lead to an instantaneous energy fluctuation in vibration signals when a rolling bearing catches local faults. The squared envelope signal can represent the instantaneous energy fluctuation of the signal . Given aSubstituting Equation (5) into Equation (1), a new expression of kurtosis can be expressed as:As we know, the resonant frequency band filtered signal contains prominent repetitive transient fault impulses when a rolling bearing records local faults. Those repetitive transient fault impulses can lead to instantaneous energy fluctuations in the filtered signal and amplify the normalized variance in Equation (6). As a result, the resonant frequency band filtered signals usually have a high kurtosis value, and resonant frequency band demodulation based on kurtosis citation can be effective in detecting transient fault impulses and diagnosing faults of rolling bearings, such as the fast kurtogram. However, the vibration signals of rolling bearings always contain many other components, which may be useless for bearing diagnosis, such as discrete impulsive noises. Discrete impulsive noises also can give rise to an instantaneous energy fluctuation of signals. The filtered signal, which may not contain repetitive transient impulses but rather contain discrete impulsive noises, can also have a high kurtosis value. As a result, the kurtosis can only characterize the strength of impulses, but it cannot effectively differentiate impulsive noise and repetitive transient fault impulses. As a result, the kurtosis may lead to the inaccurate identification results of resonant bands, the unsatisfactory demodulation results of fault features and the misleading fault diagnosis results of rolling bearings.Thanks to the superiority of kurtosis in characterizing transient impulses, it has been widely used in fault diagnosis of rolling bearings . HoweverT is the periodicity of impulses, nth element of the filtered signal The CK of zero-mean filtered signal ucted as :(7)CK and (8) into Equation (2), a new expression of the kurtosis can be obtained as:m equals to zero. And m equals to zero.As the auto-correlative function of the filtered signal T, the auto-correlative function T, and The auto-correlative function can be used to detect hidden periodicity of signals. If the periodicity of a finite length signal N is the length of the filtered signal, T the periodicity of transient impulses, m equals to T, and m equals to zero.Enlightened by the characteristic of auto-correlation function and combining Equation (9), the authors redefine the correlated kurtosis as the ratio between N as its correction factor and the other is that the computation of the redefined correlated kurtosis moves T points of the signal to right, instead of to left. Moreover, inheriting characteristics of auto-correlative function and kurtosis, the correlated kurtosis redefined in this manuscript can not only reduce impacts of impulsive noises and uncorrelated transient impulses on the detection of repetitive transient fault impulses, but also overcome the drawbacks of the kurtosis-based indexes. As a result, the redefined correlated kurtosis can be a potential substitution criterion for kurtosis-based indexes in detecting repetitive transient fault features.In comparison with the correlated kurtosis proposed by McDonald in Equation (7), the redefined correlated kurtosis in Equation (10) has two distinctions. One is that the redefined correlated kurtosis utilizes signal length kth spectrum line of SES, and Unlike the kurtosis, the correlated kurtosis both in Equations (7) and (10) is defined on the basis of periodic signals. However, according to cyclostationary analysis, bearing vibration signals have typically some second-order cyclostationary characteristics, repetitive transient fault features of bearing vibration signals are not periodic, but rather cyclostationary, which means the instantaneous energy fluctuates rather than their waveform being periodic . As a reh and l are upper and lower cut-off frequency of band-pass filter It can be seen from Equation (11) that the fault feature frequency Comparing Equation (10) with Equation (12), one can learn that Equation (12) is the implementation of Equation (10) on SES. The improved correlated kurtosis can approach a higher value when the SES of filtered signal contains higher peak values of the fault feature frequency, more harmonics, and wider filtered bandwidth. On the contrary, the improved correlated kurtosis approaches an especially small value when the SES contains lower peak values of the fault feature frequency, less harmonics, and narrower filtered bandwidth, or even doesn’t contain any fault feature frequency, nor its harmonics. As a result, it also can overcome the drawbacks of the kurtosis-based indexes.Y1:Signal δ(20) and its length equals to 40.a unit-impulse function Y2:Signal δ(20), δ(40) and δ(60), its length equals to 80.a Dirac comb function composed by unit-impulse functions Y3:Signal δ(20), δ(40), δ(60), δ(80) and δ(100), its length equals to 120.a Dirac comb function composed by unit-impulse functions Y4:Signal a sine function and its length equals to 200.Y5:Signal a Gaussian noise function and its length equals to 200.In previous subsections, the authors have redefined the correlated kurtosis and proposed an improved correlated kurtosis based on SES. In order to verify the superiority of the redefined correlated kurtosis and the improved correlated kurtosis against the kurtosis, spectral kurtosis and the correlated kurtosis originated by McDonald, several discrete testing signals, shown in As is mentioned in references ,13, a DiAs the kurtosis, the original correlated kurtosis and the redefined correlated kurtosis are all defined in the time domain, in order to compare their performances in detecting repetitive transient impulses, firstly, treating testing signals in Y1, Y2 and Y3 calculated by the kurtosis have the same value, even if Y1, Y2 and Y3 contain different quantities of repetitive transient impulses. As a result, the kurtosis in the time domain cannot differentiate a single impulse and a series of repetitive impulses, the latter of which is usually believed to be more helpful in fault diagnosis. The result of Y2 calculated by the correlated kurtosis originated by McDonald is larger than other signals, especially larger than Y3, which is the optimal repetitive impulses with more obvious periodicity than Y2. Such is the case, the correlated kurtosis originated by McDonald might fail in identifying the optimal filtered signal which contains more repetitive impulses. Finally, the result of Y3 calculated by the redefined correlated kurtosis is larger than other signals. Thus, the redefined correlated kurtosis claims the superiority over other methods in identifying the optimal filtered signal which contains more repetitive impulses.From Y1, Y2 and Y3 in Y1, Y2 and Y3 calculated by spectral kurtosis and the improved correlated kurtosis are shown in As a Dirac comb has the same structure in both time domain and SES, treating testing signals As is mentioned above, the redefined correlated kurtosis can detect the optimal repetitive transient impulses in time domain and the improved correlated kurtosis can detect the optimal repetitive impulsive harmonics in SES. Consequently, the performance comparison can verify the superiority of the redefined correlated kurtosis and the improved correlated kurtosis.The resonant frequency band demodulation is an effective method for extracting fault features and diagnosing faults of rolling bearings, and the key factor of resonant frequency band demodulation is to accurately identify the central frequency and the bandwith of the optimal resonant frequency band. However, the identification quality of resonant band depends on the construction of criterion used in detecting transient features and on the construction of band-pass filter used in segmenting frequency band.Firstly, as is demonstrated in previous subsections, the improved correlated kurtosis on the basis of SES can not only reduce the impacts of impulse noises in detecting repetitive transient fault features, but also can remedy the drawbacks of the kurtosis-based indexes. Thus, the improved correlated kurtosis can be a substitution criterion for kurtosis-based indexes in detecting repetitive transient fault features.α is the envelope factor and Secondly, the complex Morlet wavelet is a kind of band-pass filter. Its wavelet function contains exponential attenuation components, which correspond with transient characteristics of rolling bearing faults. The wavelet function of complex Morlet wavelet essed as ,24,25,26β, and it equals to the frequency range between the upper cut-off frequency and lower cut-off frequency, which correspond with the Taking normalized central frequency y domain , as showThen the complex Morlet wavelet filtered signal can be expressed as:Finally, an optimal resonant band demodulation method, by combining the improved correlated kurtosis and the complex Morlet wavelet filter, is proposed for the purpose of diagnosing faults of rolling bearings in this manuscript. Coupled with the Particle Swarm Optimization algorithm, the proposed method can adaptively identify the optimal resonant bands and demodulate transient features of rolling bearings.(1)Calculating the fault feature frequency according to the geometric parameters of the rolling bearing and operation conditions of the mechanical system.(2)Determining the searching range of the resonant bandwidth. As the band-pass filtered bandwidth should be greater than three times of the fault feature frequency, the searching range of the resonant bandwidth can be set as (3)Determining the searching range of the resonant central frequency. As the filtered range of the Morlet wavelet filter is (4)Initializing the Particle Swarm Optimization algorithm. The dimension of the particle swarm is set as 2, the size of the particle swarm is set as 30. The initial particle swarm can be achieved in line with the searching settings in step (2) and step (3).(5)Performing SES analysis on the initial particle swarm, calculating their values of the improved correlated kurtosis and achieving the individual maximum and global maximum.(6)Updating speed and location of the particle swarm iteratively until the maximum iterations. Achieving the optimal resonant central frequency (7)Setting the central frequency of the optimal complex Morlet wavelet filter as (8)Performing the SES of the optimal resonant band filtered signal and diagnosing faults of rolling bearings.The flowchart of the proposed method is shown in T is the average period of impulse series; T and set to 100 Hz; i-th impulse and C is the damping coefficient which equals to 900; D is the damping coefficient of the impulsive noise which equals to 600; A numerical simulation model of rolling bearing vibration is used to construct bearing failure simulation signals to verify the validity of the proposed method. The numerical simulation model is expressed as follows:In line with Equation (16), a simulation signal is generated as is shown in Firstly, utilizing the proposed optimal resonant band demodulation method to analyze the simulation signal, which is shown in Constructing the complex Morlet wavelet filter based on the optimal resonant frequency band parameters, the filtered simulation signal both in time domain and in frequency domain are shown in To compare the improved correlated kurtosis with kurtosis and spectral kurtosis, the kurtosis and spectral kurtosis of squared envelope signal are used to substitute the improved correlated kurtosis, respectively. According the same algorithm flow in One can learn from One can learn from As mentioned in this subsection, kurtosis can only characterize the strength of transient impulses, it cannot differentiate impulse noises and repetitive transient impulses, the SES of the filtered signal in Vibration data from the Case Western Reserve University (CWRU) Bearing Data Center are utilized to verify the validity of the proposed method. The bearing test rig of CWRU  is shownIn line with the algorithm flow in One can learn from Analysis results of IR007-0 and IR021-3 are shown in One can learn from As is mentioned above, the proposed optimal resonant frequency band demodulation based on the improved correlated kurtosis can steady identify the optimal resonant bands, clearly demodulate fault feature frequencies and their harmonics, and effectively diagnose rolling bearing faults. Comparison analysis with kurtosis and spectral kurtosis have verified the superiority of the improved correlated kurtosis.As to the drawbacks of kurtosis in detecting repetitive transient impulses and diagnosing rolling bearing faults, this manuscript firstly redefines correlated kurtosis based on auto-correlation function and the kurtosis. Then, it proposes an improved correlated kurtosis on the basis of squared envelope spectrum, which has been proved more effective in detecting repetitive transient impulses. Regarding the improved correlated kurtosis, it can not only characterize the strength of repetitive transient impulses, but also feature the cyclical occurrence of repetitive transient impulses, that is, the improved correlated kurtosis is effective in differentiating impulsive noises and repetitive transient impulses, and in reducing the noise impact on the detection of repetitive transient impulses as opposed to kurtosis-based indexes. Finally, this manuscript puts forward an optimal resonant band demodulation method based on improved correlated kurtosis by combining complex Morlet wavelet filter and the Particle Swarm Optimization algorithm. Analysis of both simulation signals and CWRU data demonstrate that, the proposed optimal demodulation method based on the improved correlated kurtosis can be more robust in identifying resonant frequency bands of rolling bearings and more accurate in demodulating transient fault features of rolling bearing. Analysis of data from experiment verify the validity and advantage of the proposed method over traditional kurtosis-based indexes.