In Australia, the peer review process for competitive funding is usually conducted by a peer review group in conjunction with prior assessment from external assessors. This process is quite mysterious to those outside it. The purpose of this research was to throw light on grant review panels  through an examination of the impact of panel procedures, panel composition and panel dynamics on the decision-making in the grant review process. A further purpose was to compare experience of a simplified review process with more conventional processes used in assessing grant proposals in Australia.This project was one aspect of a larger study into the costs and benefits of a simplified peer review process. The Queensland University of Technology (QUT)-simplified process was compared with the National Health and Medical Research Council’s (NHMRC) more complex process. Grant review panellists involved in both processes were interviewed about their experience of the decision-making process that assesses the excellence of an application. All interviews were recorded and transcribed. Each transcription was de-identified and returned to the respondent for review. Final transcripts were read repeatedly and coded, and similar codes were amalgamated into categories that were used to build themes. Final themes were shared with the research team for feedback.Two major themes arose from the research: (1) assessing grant proposals and (2) factors influencing the fairness, integrity and objectivity of review. Issues such as the quality of writing in a grant proposal, comparison of the two review methods, the purpose and use of the rebuttal, assessing the financial value of funded projects, the importance of the experience of the panel membership and the role of track record and the impact of group dynamics on the review process were all discussed. The research also examined the influence of research culture on decision-making in grant review panels. One of the aims of this study was to compare a simplified review process with more conventional processes. Generally, participants were supportive of the simplified process.Transparency in the grant review process will result in better appreciation of the outcome. Despite the provision of clear guidelines for peer review, reviewing processes are likely to be subjective to the extent that different reviewers apply different rules. The peer review process will come under more scrutiny as funding for research becomes even more competitive. There is justification for further research on the process, especially of a kind that taps more deeply into the ‘black box’ of peer review. Health and medical researchers across the world submit their ideas to peer review to gain funding. Competition for research funding is intense, as success rates in most schemes are low and careers are on the line. The opinions of peer reviewers can mean the difference between success and failure in securing funding and publications . The peeIn Australia, the two most common sources of national competitive funding are the Australian Research Council (ARC) and National Health and Medical Research Council (NHMRC), and both use peer review panels to assess applications. Anecdotal evidence abounds discussing the dynamics of peer review panels and the membership of panels. Of particular interest are the factors that are considered crucial to an application’s success. Indeed, one of the advantages of being a panel member is gaining first-hand knowledge of the so-called black box , that isThis project reported here was nested within a larger study examining the costs and benefits of a simplified peer review process. A full description of the larger study is available at , but in Two seven-person expert panels reviewed a sample of the proposals in separate 1.5 day face-to-face meetings. In general, the panellists were the lead investigator for each proposal. The primary aim of the panels was to test a Queensland University of Technology (QUT)-simplified process by reviewing shortened proposals, including a nine-page research plan and two-page track record for each investigator. Each panel member was a spokesperson for five or six proposals, and they gave an opening summary of the strengths and weaknesses of the proposal based on a review they had prepared prior to the meeting.The overall aim of the research reported here was to explore the experiences of panel members while serving on grant review panels and to reflect on this experience in light of the QUT-simplified process. That is to say, we were interested in views about the impact of the panel procedures, composition and dynamics on the panel’s decision-making in the QUT-simplified process, but we also wanted to gather participants’ views on other panels, for example, NHMRC grant review panels (GRPs).To explore experiences of members while serving on grant review panels, in particular what factors were thought to determine ranking of applications—essentially what was thought to constitute a high-quality proposal—and how to deal with conflict of interest.To compare experiences of the QUT-simplified approach with other more standard panel processes. In particular, the extent to which the QUT-simplified process provides a more efficient and less demanding assessment procedure while continuing to be robust and discriminating.To observe any differences between the two panels that may reflect different research cultures and the relevance for grant assessment and appraisal. In particular, the extent to which the underlying expectations of each group may be revealed by contrast and comparison.The objectives of the study reported here were:The expert panellists generally had experience of varying degrees in (a) winning funding from NHMRC, (b) serving on NHMRC grant review panels and (c) being an external reviewer for NHMRC. Of the 16 panellists (14 panel members and 2 observers), 12 were at Professor (Academic Level E) or Associate Professor (Academic Level D).Each panel member was invited to be interviewed about their views on in the QUT-simplified process and their experiences as members of other grant assessment panels. Some respondents chose to be interviewed immediately after the QUT panel completed its assessment. Other panel members were interviewed at a later date, but within 4 weeks of the QUT panel meeting. No panel member refused to be interviewed.All interviews were conducted by two of the authors (JC and KM) and were recorded and transcribed (DH). Each transcription was de-identified and returned to the respondent for review (DH), the so-called member’s check . All finAssessing grant proposalsWhat makes a good grant proposal?Assessing grants: QUT method versus NHMRCJudging value for money: QUT method versus NHMRC‘Major players’ large share reduces capacity building2.Factors affecting the fairness, integrity and objectivity of the reviewThe importance of experience of panel membershipEnsuring a fair reviewThe role of track recordThe purpose and use of the rebuttalThe impact of the group dynamics on grant review processesHere we report on two major themes (and subthemes) that emerged from the interviews with the QUT panellists. The themes and subthemes are:We also report on what were seen to be major differences between the two panels, Basic Sciences (BS) and Public Health (PH), which we believe demonstrates cultural, or epistemological, differences between the two groups. The quotes are referenced for each panel member as either BS or PH according to the respective peer review panel.There was uniform agreement across both grant review panels that the success of a grant depended highly on the quality of the writing. The ideal was a clear and simple proposal that could be understood by someone not necessarily from that particular field;Both panels were also able to express a common expectation that the grants had to represent good science regardless of the discipline. There were, however, key differences in the panels’ opinions as to what constituted good science. The Basic Science group placed greater emphasis on ‘innovation’ and ‘novel’ proposals, while the Public Health panel allowed more flexibility and was more ready to accept a generic type of science that would be making a contribution to population health overall with some degree of translation;BS 2 ‘I think that the proposals that rank the highest… they’re stretching the boundaries of where we are in the research at the time’.PH 6 ‘All grant writing is selling and I'm not interested in how clever you are or how intellectual you can be; I just want good, solid, doable research which is going to make a difference’.For the Basic Sciences group, it was not necessary for the research to be immediately translated from the laboratory to the bed side; it was adequate if the panel could see the value of the proposal in light of its contribution to the incremental approach of Basic Science research, with each small part contributing to a larger whole of global research.One unique aspect of the assessment of grants within the QUT-simplified process was the introduction of a parallel scoring system. In the NHMRC, process grants are scored from 1 to 7. The QUT-simplified process entailed only three categories—gold (should fund), silver (could fund) or bronze (should not fund). Both panels, with almost complete consensus, believed that the simplified system vastly improved the process;BS 4 ‘the [NHMRC] seven point rating does obfuscate one’s thinking… the human species as a whole – does think in clear categories: fund, maybe fund, not fund…. it was very helpful to use that score, you know, one, two, three; gold, silver, bronze’.In addition, the overly detailed 1 to 7 NHMRC grading was often criticised;BS 8 ‘Oh, I think both systems have good things and bad things. So 1 to 7 is stupid because of human nature. Unless you hate someone, why would you give out a 1?’However, there was also some suggestion that, in a similar way to the NHMRC, this three-tiered ranking process left a large number of grants in the ‘middle ground’;PH 4 ‘Most of the grants that are brilliant, the fallout is brilliant and most of the crap falls out as crap and then, as we discussed, over time you’ve got this grey area where it’s a bit of a lottery’.A number of participants suggested that to address this, some levelling of silver into two categories was warranted;PH 3 ‘I think that it [QUT system] is great, that’s a much better system. I would like to see a 2A and a 2B, like, you know, polished silver and tarnished silver or something along those lines’.However, there was a high degree of acceptance of a simplified system with only one dissenting opinion, reported;BS 6 ‘Well, it comes down to a head counting exercise with how many – what proportion of the people are giving it a gold score as opposed to a silver or a bronze? It’s lost a resolution’.Another key omission in the formulation of the applications for the QUT-simplified process was project budgets. In addition to this, the concept of ‘value for money’ was introduced into the interviews for the panel members to consider. There was significant divergence of opinion with most of the Basic Science panel feeling that if the science was worth funding, then it should be funded regardless of the budget and that value for money should not be given any consideration;BS 2 ‘Yeah, I don’t really take the funding into account; it’s a separate entity. …if we decide that we’re going to fund high quality science we should fund the science and not cut the budgets so that they can only do half the experiments’.BS 8 ‘So if we start putting a value on top of this kind of judgment, how do you judge your research, you know? How much is it worth? It’s stupid. It’s worth nothing and millions of dollars’.In the instances when the Basic Science group considered budget, it was only in terms of whether or not the science was valid and there was a sense of responsibility to use the available funding wisely;BS 6 ‘[I] think you have to be – unless the potential outcomes were commensurate with the expenditure I think it doesn’t make common sense and it wouldn’t be responsible to be advocating public monies to be spent – it’s not as if there’s a surplus of money so why would we pour money into an idea that can’t justify that then because there’s no shortage of alternative destinations for that money’.Within the Public Health panel, although there was clear acknowledgement that the science is judged first, there was majority reasoning that the budget could play a role in achieving funding; thus, its absence was felt to hinder their decision-making. This panel also largely felt that in health research, ‘value for money’ is an important consideration;PH 4 ‘And everybody kept asking […] for the budget, you know “it would really help me to see the budget. Is this a million dollars, in which case it’s bullshit, or is it $10k in which case we should definitely support it as a pilot?” …I know that the budget isn’t supposed to influence your decision making but it does, even if subliminally’.One aspect of this particular theme in which both groups reached consensus, however, was the difficulty that can be experienced in achieving grant success for a study with a very large budget;PH 3 ‘I understand that at some point it’s important to consider that but I wouldn’t like to be in the situation where we say “okay, so this grant’s pretty good but it’s a million dollars. This grant’s not so good and it’s only $200,000; let’s fund that  one”. I don’t think that that’s appropriate, or if we think that this is important we should be funding it, but I think in general people do feel quite nervous about really big budgets.’There seemed to be agreement in the Basic Sciences panel that most grant writers manipulated the budget to some extent in anticipation of the NHMRC either viewing a smaller budget favourably or conversely the applicant increasing the budget in anticipation of an NHMRC reduction;BS 4 ‘Downgrading your budget is a common fault. Upgrading your budget is also a common fault and that’s done by the more experienced players in the field who’ve long since come to the realisation well, you know, NHMRC will cut you back anyway almost certainly so you inflate your budget a bit’.BS 5 ‘You know, you put something in there that’s not going to break the project that they can easily cut off. Everyone talks about that unofficially, yes’.There was some agreement, most notably amongst the Basic Sciences panel, that a larger organisation with a strong track record and with ‘major players’ on their teams attracted the lion’s share of the funding which in turn, they acknowledged, disadvantaged early career researchers;.BS 3 ‘They have an enormous amount of awe of these people, right, and so even in the normal GRP they get a really easy run because everybody thinks they’re there, they must be fantastic and I suppose what I think is if that’s the case why have a GRP? Just give them the money’PH 4 ‘As I say, it’s basically just going to be the spinners that are going to do better and I’d rather make that decision myself … there is negativity about the fact that you cannot - in a system structured to support that type of activity, you cannot then support brilliant, innovative young minds who aren’t necessarily affiliated with the right group, haven’t got the ten publications, don’t know enough people who know people on the review panel for their fantastic stuff to get up’.It was also discussed that being a panel member could confer a certain advantage in terms of an individual’s grant success and a number of participants spoke very highly of being involved in a panel for mentoring, career growth and the ability to produce a higher quality grant.One of the most serious and repeated criticisms from panellists in this study was of the NHMRC process where the conflict of interest regulations almost always ensure that the vital expert opinion, required to ensure an adequate and fair peer review, has left the room;BS 7 ‘we have had anecdotes where every single expert in the country has to leave the room, even for minor things’.A number of respondents felt that if you were working in a highly specialised field and ‘your’ expert left the room the inability of the panel to then extrapolate the key points in the grant was something that almost inevitably resulted in the grant faring badly;PH 8 ‘The people who excused themselves were the people with the discipline background and to exclude them from the review of these particular papers really didn’t do the grants any service at all because those people who knew that area were not there’.In contrast to the criticism of this overly rigorous process, the two panels both subsequently questioned the continued usefulness of the NHMRC soliciting an external review, its actual legitimacy and the reviews’ potential impact on grant success. It was thought that as procuring the reviews is no longer the responsibility of the spokesperson to complement their own assessment, this has significantly reduced their usefulness;PH 4 ‘I think it’s the primary spokesperson’s synthesis that really carries most weight and the [external] reviewer’s comments are used only rarely to say, you know “how can you say that when the Nobel Prize winner said it was brilliant?” or vice versa. So they are useful but the impost on the reviewers to write them and the second spokesperson to interpret them and report back on them while everybody’s going to sleep at the table, particularly when some people do it line by line, it is not worth the effort’.There is also some suspicion that an ‘expert’ review can be reasonably hard to obtain and the quality that is expected in these circumstances cannot always be relied on;BS 4 ‘I’ve never been convinced in recent years about external reviews, largely because I know NHMRC has got a lot of difficulty getting people to write external review’.PH 6 ‘The only experience I have got of external reviews is in the real thing and they are - if external reviews correlate with the primary spokesperson’s opinion, then they are normally included; but if they are against the primary spokesperson’s opinion, they are normally discarded’.Both the conflict of interest regulation and the external reviews are a process designed to ensure that the grant receives a fair review. However, across both groups, there was a subtle but consistent suggestion that one person, with a carefully crafted sentence, could decide the fate of a grant and that the conflict of interest and external review designed to avoid this occurring often fails to do so. The related concepts of ‘sinking a grant’, ‘gaming the score’ and conversations ‘off the record’ will be further explored as subthemes later in this section.When discussing the role of a spokesperson, the respondents articulated that this is a responsibility they take very seriously. The QUT process mirrored the NHMRC process in the allocation of grants to each panel member, including the chair, for which the member was then expected to present to the group a synopsis of the key points in the grant including aspects that could be improved, or aspects that were considered exceptionally good;BS 2 ‘if you’re the primary spokesperson and you don’t know the answer to a question it’s kind of your fault. You don’t have to know the answer to every question but you have to be on top of what’s contained in the grant’.Across both groups, despite the notion that the grant review process would be equitable, was a strong sense of being an ‘advocate’ for a grant which highlights the importance of allocating the correct grant to the most appropriate spokesperson;BS 5 ‘I guess those few grants that I really liked I did defend and push quite strongly. Yes, I did feel like an advocate’.BS 8 ‘So that’s a problem that everyone has, I think, that when we don’t know what to do with it, we just put them in the big grey bag of the four or five-points grants; and then everybody rallies behind the spokesperson and that’s when you can push or kill a grant’.The panel members spoke of sometimes undertaking extra research in their role of spokesperson to understand the grant more fully and to ensure that they gave each one a fair representation. Without doubt, both panels as a whole were guided by the spokesperson’s report into making a decision regarding the grant, deferring to them as the person that held the most information about the likely success of the proposal;BS 3 ‘In many ways it’s a bit of a myth that of the six or seven reviewers around the table you get six or seven independent scores. You don’t because your scores will be influenced, you will bow to superior knowledge for the spokesperson who really knows what they’re talking about on a given grant’.This process, as a result, makes the role of the spokesperson absolutely vital. There were at times, however, suggestions that if, for various reasons, the spokesperson did not take the role of the grant advocate, it then had little chance of a successful outcome;BS 1 ‘The downside is if the primary spokesperson is tepid the grant’s got almost no chance of succeeding, right, because you’re looking for reasons to sink the grant and straight 5s [scores] is just a death knell. The grant’s dead, dead in the water’.PH 6 ‘Well, it’s clearly critical. I felt very much it was about setting the expectations about this grant and if the spokesperson didn't like it, it is highly likely that everyone else would feel the most permission to go in hard and pick it to pieces’.On some occasions, the spokesperson did highlight their lack of expertise on grants allocated to them in the QUT-simplified process, but most agreed this was due to the nature of the QUT configuration and was unlikely to occur on a NHMRC panel given the vital role that the spokesperson plays in the presentation of the grant;PH 1 ‘I mean quite frankly I don’t think I was an expert in any of the six proposals [QUT simplified process] to which I was a spokesperson’.BS 3 ‘That extrapolates into quite a thorny issue inasmuch as that if you haven’t got in-depth expertise in a particular proposal for which you are primary spokesperson’.There was consensus in the groups that the NHMRC process is supposed to be regulated to ensure that the panel configuration will have the expertise to counter the effects of a spokesperson with limited expertise, which is then supported with a secondary spokesperson. This theme is explored next.A key point made during this research is that the panel must be selected to ensure a broad range of experiences and also contain significant expertise. Some discussions of the NHMRC process within the Basic Sciences group suggested that the grant applicants at times felt the panel composition could have been improved in terms of level of expertise. This panel subsequently discussed at length the highly selective nature of the grants that would be reviewed during the NHMRC process—in which there is a immunology panel, a biochemistry panel etc.—and the rigour in which the panel members needed to be drawn together to ensure the grants received a fair hearing;BS 2 ‘Yeah I think if panels are constructed well – and I can’t remember, we might have had three people speaking who had read the grants in depth so that means that three people really put their time and effort into that grant and if you’ve got the right breadth around the table then really good discussions happen and when that happens then the grants do really well’.If at any point during the QUT process a member of the Basic Sciences panel thought that they lacked the experience to appropriately judge the grant, they said so emphatically and deferred to the judgement of the spokesperson. Most also reflected on taking this action during a NHMRC process;BS 2 ‘I have been on panels where there was a grant that I said I wouldn’t provide a score for because I would just be making something up that was consistent with what the lead person’s score was. And while I trust that person I’m not just trying to balance out the scoring. I didn’t know the area at all. Even if I’d read for a week on it I still wouldn’t have known too much about it and so there was no reasonable way in which I could provide a score that would be meaningful’.In contrast, the Public Health panel discussed a different approach to reviewing grants outside of their expertise during this process. They spoke of the panel being capable of reviewing a wider range of grants, including those that they would consider outside of their field. This difference perhaps is driven by the very different research paradigms with the very exact nature of Basic Science, and the more ‘broad-church’ approach seen in Public Health research.PH 8 ‘Oh, hell, yes. Some were just so hard. Some of them, I didn't understand. I simply did not understand what they were looking at. And that was something I did learn from the other panel members. They were able to go directly to the science. So they were able to go directly to “let’s have a look at exactly what they want to do. Forget about all the background stuff for the moment. Let’s just look at the methods and look at what they want to do and how they want do it and what their outcomes are going to be.” So they were really clever’.The potential for a single panel member to effectively influence the group into negatively viewing a grant was discussed within both panels. This occurred noticeably more so in the Basic Sciences panel, and although there is acknowledgement that the conflict of interest regulation is designed to avoid this occurring, the respondents clearly feel that it is not always successful in doing so;BS 2 ‘I think you can load words and I think some people [in the QUT panel] did load their expression or the words that they used that really reflected that they have no enthusiasm whatsoever for the grant’.BS 4 ‘the discussion will go on and on and up and down and sideways and it just takes one little whiff of a hint that there’s something wrong with the grant, not in a major way, just something – and your score goes down’.BS 6 ‘There are people who seem to have a vindictive streak in them to try and cut other people in the field down and they don’t limit their vindictiveness necessarily to the weaklings, they go for anyone, you know’.Both panels discussed the manipulation of scores in order to counteract another panel member’s score or to influence the outcome of a particular grant. This was discussed on occasion in a fairly neutral and benign way in the Public Health panel and appeared to be in the context of ensuring a fairer outcome for a grant. But from within the Basic Sciences panel, the concept was highly repetitive, seen in the majority of the interviews often appeared to have a more serious intent;BS 1 ‘The other way to do is you game the scoring system and that’s a really interesting process that gets used a lot. So that’s a more passive/aggressive way. You know, I’ve seen chairs gratuitously try to game the scoring system to get outcomes, like saying ‘well, let’s’ – you know, briefing their panel ‘we all know there’s going to be 15 per cent of grants we want to get up. To give our grants the best possible chance when they get ranked next to other people’s grants let’s give all of those a seven and anything we don’t want to fund a three and have a bimodal distribution’ so the scores went like that; nothing in the middle’.BS 3 ‘it’ll be like “oh, wow, this is so great. We can go in there and sway everyone” and you think they won’t? They will. They absolutely will’.PH 3 ‘I suspect in some of the other panels there’s lots of game playing and strategic assessing or strategic grading to get a lot of people up … so lots of them will be funded’.Another issue that arose during the interviews regarding the stringent management of conflict of interest is that it again at times fails to be effective and simply moves the conversation out of the panel discussion held in public into another area which then creates a conversation ‘off the record’;PH 4 ‘I think everybody [at QUT panel], because they were empowered and trusted, were probably more objective than they would be at the real NHMRC panel where they’d be telling people in the coffee room ‘this guy’s a real bastard but, you know, I have to leave the room so make sure you sink it’ sort of thing’.PH 1 ‘Well, it’s a matter of meeting procedure and often, as indeed at any scientific forum, the most influential conversations occur around the water cooler or coffee urn rather than in the sort of formal structure of the discussion’.The role of track record is considered by these panels to be a very high priority when determining a successful grant from one that is not. The QUT process involved the provision of the two-page track record as prepared for the NHMRC panel (the NHMRC process includes far more details on papers and funding) and this created some mixed feelings;PH 8 ‘Track record was very important; very important to the people who had been on the panels in the past, who had been on the real NHMRC panels’.BS 8 ‘It is as good as admitting, you know. We are judging ego. It’s the most popular kid in high school that would get the best track record; it is polluting information. So I really appreciated that we did not have extra information on the candidates’.Reputation in the field is an important factor that is considered in the review of the grant. There is general agreement that most people on the grant review prefer to know the candidates, or know of them, and know what they have achieved or where they ‘sit’ in their field. When this is not the case, and this is more often seen in the Basic Sciences panel, a person-centred judgement is still made which is then based on the institution that they are with and this process overall largely disadvantages early career researchers;.BS 1 ‘On this panel people wouldn’t be familiar where the applicants would lie in their field so that was the main hurdle that I saw for – there was one grant that I had that – I had no idea where that person fitted in their field, whether at the top, middle or the bottom’.PH 3 ‘I think, based beyond the track record that you read in the grant, so you know like you’ve worked somewhere, you know those people or someone you know knows those people or you’ve just come across their name in lots of situations so you know that they’re very good’… ‘I think it can be really hard for early career researchers too and I know that, you know, they have the people support but it’s really – it’s even more competitive than project grants’BS 4 ‘Everybody knows who the worthy people really are… You all know each other and you all know who the bright ones are’.A common point also made is that the addition of co-investigators or associate investigators with easily recognisable names is a smart strategy to attract the panel’s attention and increase the potential for the grant’s success;PH 8 ‘They were big names and huge track records and their relevance for the project was really questionable. So whether the investigators thought that having those extra people on would give them more bang for their buck, I don’t know, but it was just so obvious that those people really weren’t going to play any role in the conduct of the research’.There was strong disagreement between the two panels on the value of a grant candidates’ supervision of research higher degree students. The vast majority of those in Basic Sciences considered this information irrelevant to the consideration of the grant; however, the Public Health panel members viewed this role as positive and considered it an essential part of a researcher obligation to contribute to supporting future researchers and capacity building;BS 3 ‘For a project grant it’s completely irrelevant. It’s just a way of buffing their track record’.PH 1 ‘I think that’s terribly important in the people scheme. You know, we want to support fellows, research fellows, senior research fellows who are training the next generation of researchers. Possibly a little bit less important in project grants but, you know, as a researcher and somebody who’s committed to building capacity it’s something that I like to see. If it’s a tossup on track record I will tend to favour the people who have made that investment in training the next generation of researchers’.The formulation of the QUT panels omitted the opportunity for the applications to be externally reviewed and the related opportunity for rebuttal. This omission was explored in the interviews and there was a clear consensus in the Basic Science panel that the opportunity for rebuttal is useful in terms of refining your grant and trying to gain the confidence of the spokesperson;BS 6 ‘it’s crucial that the applicant has the opportunity to rebut absolute nonsense’.However, the general tone of both groups, and in particular the Public Health panel, suggested that most respondents believe that rebuttal rarely influences the spokesperson or the panel into a revision of their assessment and is perhaps more useful for the next round of submissions;BS 5 ‘Would it [rebuttal] have changed any grant outcomes? I hear ‘no’ and I’ve just done my rebuttal [for the NHMRC process] and I don’t think it’s going to make any difference after spending a week on it. I mean it actually is a really good process to do yourself because you’re addressing what people might ask about your work but – and it’ll make your next grant submission better - but change of grant from not funded to funded, I don’t think it does’.PH 1 ‘For the vast majority of the grants I don’t think it would have had any influence’.Both the Basic Sciences and the Public Health panel members agree with a number of key principles regarding the role of the chairperson. Unanimously, respondents felt that a strong chair was needed to ensure that the group kept on task and dealt with the proposals fairly;PH 4 ‘I think it’s a good chair who will make sure that the opportunity to say things is equal, particularly where you’ve got a difference in experience, gender, academic status and all of those things, you know better than I do, will influence who says what first. I had good chairs and I can remember them facilitating the process and improving the fairness of the scoring by quietening down openly vocal panel members and, again it’s around the table technique, and say “okay, thank you, we’ve heard from you now let’s hear from two more people before we go to scoring” and those sorts of techniques’.Most agreed that the chair provided their expert opinion in exactly the same way as any other panel member if the grant came from within their area of expertise, which would, of course, influence the outcome of the grant but no more so than if any other expert were to present a highly valid judgement;PH 3 ‘I think [pronoun]There were no respondents that felt the chair unduly influenced the outcomes of any grants, although there were some suggestions that this had occurred in the past prior to the more recent adaptation of a ‘technical chair’ in some cases rather than an expert from the field;BS 6 ‘The first one I was on I don’t remember anyone being admonished but that didn’t mean that I didn’t think the system wasn’t – in other words I don’t think the chairperson was doing his job and that there were people who were very adversarial against projects that they didn’t like and conversely very advocating of ones they liked and it was extremely irritating’.BS 2 ‘And for NHMRC, the chairs they appoint now, typically – well in many cases they don’t really know the science, that’s kind of how they appoint them’.The process of appointing a strong technical or administrational chair seems to have been very well accepted by the respondents with significant past experiences of the NHMRC process.During the QUT research process, there was considerable personal conflict experienced by some panel members of the Basic Sciences group and there was consensus that personal conflict has a quite significant impact on the group dynamic as a whole and can directly influence the grading given to grants.BS 5 ‘I mean it felt like it [conflict] affected it. Okay, so I think there were certainly a couple of personalities [in the QUT process] that were very strong on whether they liked a grant or not and I think when there was any – a strong debate about that between the strong personalities it was kind of – you could feel the group – well, I could feel the group siding with one or the other and you think ‘are you siding with a personality or the grant?’.It is during this process that the role of the chair becomes vital in moderating this effect;BS 6 ‘Yeah, I think in a regular GRP panel the chairperson would have been a bit more forthright in telling them to pull their head in – “bag it” - sort of got the message ‘don’t keep on flogging the horse’. Yeah there were some very strong people or people with very strong ideas’.In direct contrast, the Public Health panel members all spoke highly of the group dynamic and the collegial atmosphere and clearly highlighted how this supportive environment enabled those less experienced or perhaps less confident members to present their views in an arena that made them feel safe to do so and in turn this presented the impression that the grants actually did receive a fair and considered peer review;PH 8 ‘I think it was a very collegial panel. I certainly felt very supported. I felt confident to be able to express my views without feeling that someone was going to shout me down; though they did a couple of times, but that was alright. It was part of the process and it was really well done’.Another aspect of group dynamic that was observed to be highly influential in relation to the discussion of a grant is the role that one person can take if they are seen by the group as being the expert in the room on a given topic;BS 5 ‘Yeah, well, there was at least – there was one grant that I quite liked but [name]This facet of the group dynamic was largely viewed by both panels as being a positive attribute of a panel discussion and something that is seen as enhancing the peer review of a grant. This point is made quite strikingly by one participant when discussing how this specific dynamic plays out in a review panel under usual circumstances and by highlighting how this then becomes rather dysfunctional due to the personal conflict in the room;BS 3 ‘I suppose the other thing is that generally within our panel people recognise each other’s expertise and they respect other people’s expertise and people who don’t know anything about the area, don’t work in it, are not permitted to basically lay down the rules about what’s going to go on in a discipline they don’t work in, and that happened a lot in this committee’.A key difference between the NHMRC process and the QUT process was panel size. The standard NHMRC panel formulation of 12 people was reduced for this research project to 7, and this was met with some concern by both panels. Specifically, although both agreed that the smaller panel size has some appeal and allowed for a more informal collegial discussion and the grants were discussed in a much speedier fashion;PH 4 ‘you could actually go around the table without taking all day, which is just not possible on the full panel’.Some interviewees felt that a smaller panel used in the QUT-simplified process allowed some of the more dominant personalities to take over the group and have an undue influence on the grant outcomes;PH 3 ‘There’s some people who are really harsh about some things and some people who are very generous about some things but that’s just part of the nature and the larger the group size the more likely you are to have someone who was potentially influential, but the larger the group the less that will have an impact because it’s the dilution effect’.Importantly, a number of members from both groups felt that the smaller panel size impacted on the breadth of expertise within the panel particularly when, as discussed previously, the experts left the room due to a conflict of interest;PH 1 ‘In broader areas you’ve usually got enough expertise when you’ve got a panel of 10 or 12 people’.Overall, the smaller panel size was poorly accepted with most respondents being more supportive of a larger panel;BS 1 ‘I probably would have had a slightly bigger panel so you had more opportunity for debate’.In summary, the QUT GRP process had a number of important variations to the standard NHMRC process. The panel size was smaller, and the chair of the Basic Sciences group was ‘technical’ rather than an expert in the field. There were no rebuttals, external reviews or secondary spokesperson. The grading of the grants for the QUT process took a three-tier-only approach, the conflict of interest rules were relaxed to a large extent, and no budget was provided. Although there was some agreement on certain principles across both panels, on the whole, the approaches taken to grant assessment were remarkably dissimilar.This project allowed us to examine any major differences of the perspectives of the panellist in terms of their research culture. We use the term ‘research culture’ to loosely describe the ways in which researchers give priorities to particular aspects of research. While we are careful not to over extend our findings in this section, it was clear that there were overall traits that emerged in each panel’s dynamics.For example, it was noticed that the Basic Sciences panel dynamics overall was at times combative and the language used tended to be blunt in particular the expressions of ‘pushing’ ‘killing’ and ‘sinking’ a grant. The panel expressed the value of a clear well-written grant but with the caveat that it be exclusive to one particular field which would then be expected to be reviewed only by experts from within that field. Emphasis was placed on the incremental value of basic science research with each proposal representing a small part of a ‘big picture’ and there was no need to have a proposal that could be immediately translational. The most striking aspects of a grant proposal for the Basic Sciences panel were novelty and innovation. The panel felt it was unnecessary to demonstrate value for money with more emphasis being placed on the likely contribution to the field and a strong sense of funding the person. With regard to the grading system, the panel overall felt that the QUT process was very similar to the NHMRC, with obviously outstanding proposals and clearly inadequate ones, both representing an easy decision, but both grading systems doing little to ease the decision-making for the grants finding themselves in the middle ground. Conflict of interest was highly contentious with a high degree of agreement that the regulation was absolutely essential and yet fundamentally flawed in terms of losing the required expertise from the room and still failing to adequately address the role of a personal agenda in promoting grant success.The formulation of an experienced and appropriate panel remained a priority for all respondents particularly the matching of the required expertise to the very specific fields to which the grant would be applied and the panel size for this project was felt to be too small. In addition, the role of the spokesperson was seen as a significant responsibility given that the panel if unfamiliar with the field would follow the spokesperson. The role of track record for the Basic Sciences panel was considered to be vitally important, and the grant review was undertaken with a very ‘person centred approach’, judging as important criteria the contribution to the field that the applicant had made previously. Well-known large research teams were highly valued, and there was a strong bias to publications in specific journals that were considered to be the most eminent in the specific field. The group dynamic was reported at times to be combative, and most respondents admitted to the ability of a certain amount of ego and personal agenda to play a role in the eventual result for a grant application.BS 1 ‘Yeah I think the biggest – you know, probably the tightest predictor of future success is your capacity to have done it before and part of that is what you’re looking for are people that can not only do the science but have the backbone and stamina to be able to write it up, get through the grant – the paper review process and get something published; that’s not a trivial thing’.In contrast, the Public Health panel members commented on the high degree of collegiality within the panel and the respectfully supportive group dynamic. While there were some members recognised by others as being the clear experts, this was considered in a deferential way and not seen as something to be contested. This panel also deferred to the spokesperson for a decision on grants with which they were unfamiliar and this level of expertise was appreciated by the group. However, the spokesperson’s perspective on each grant appeared to be given full consideration rather than an automatic acceptance as absolute. This facet of the group dynamic was described as vitally important with regards to the configuration of a grant review panel which ideally would include one or two very experienced researchers in balance with more ‘early career researchers’ capable of providing a more contemporary or innovative perspective. Importantly, the distinction was made that the environment within the room needs to be one that allows a perhaps more inexperienced panel member to feel as though their contribution will be considered and valued. Both panels felt the QUT panel size was too small and the conflict of interest regulations were seen as problematic when the expert leaves the room; however, the PH panel tended to take a more relaxed approach to conflict of interest issues for the grant review process, with some degree of success.In contrast to the Basic Science panel, for the Public Health panel, the lack of a budget was disconcerting and the members appeared to have a keen sense of ensuring a viable project with a tangible outcome be funded. The broader collegial nature of the Public Health panel also meant that the grant review process itself specifically addressed the grant’s potential contribution to the field and there was at no time acknowledgement of the person being funded rather than the grant. When track record did come under consideration, it was in a more comprehensive way, and although publications were acknowledged as important, equally so was the person’s overall career achievements. This grant review panel very clearly articulated assessing the quality of the grant first and foremost, and although track record was their second consideration, it was not necessarily dependent on a citation index. There was certainly some acknowledgement of the disadvantage that can be experienced by early career researchers when the playing field is not level which was expressed quite frankly in the Basic Sciences panel.PH 6 ‘So a lot of that Canberra process I think is people - you know, they feel it’s an honour to serve on this group, and so they have to justify their existence and also show to their peers how wise and clever and smart they are. So a lot of the comments and feedback - and they are not actually about the grant, they are about the individual giving them – “look how widely read I am. You know, I am attacking this grant because I am so clever”, and I think that’s an issue. Whereas our group was just, “Come on, let’s get to the bottom of this. Is there any good or not?” We were a lot less formal and our agenda was a healthier one’.The research reported here was based on a qualitative approach using in-depth interviews with a relatively small number of respondents. While this approach was entirely suited to the methodology required for research of this kind, the limitations are well recognised. For example, we would not claim that the results of this research can be generalised to all participants taking part in grant review processes. We do believe, however, that the consensus between many of our respondents on a number of points we have discussed gives us comfort to believe that our findings capture beliefs, opinions and decision-making processes that are shared beyond this particular project.We believe that our research provides a valuable ‘lens’ into an area that has previously been neglected. While the field of commentary on the peer review process is vast . The emphasis on these attributes raises questions about the extent to which early career researchers in the application process may be disadvantage by virtue of them not being able to have published in quantities likely to impress panels, or to have existing papers cited by others. In other words, a preoccupation with current interpretations of track record in the GRP process is likely to favour senior researchers. While it is true that fellowship funding is available for early career researchers outside of main NHMRC and ARC project schemes , these lThe simplified reviewing process in which the panellists took part omitted a number of features often included in conventional processes. This provided an opportunity for respondents to comment on whether this compromised the rigour of the simplified process. For example, the lack of a rebuttal allowed respondents to consider the merits of the rebuttal. Both groups believed that the rebuttal was unlikely to influence the decision of the primary spokesperson. And, given that the views of the primary spokesperson were considered to be crucial in the success of a proposal, the rebuttal—as an opportunity to further develop the proposal—may be redundant. However, where external assessments are obtained, the opportunity for applicant response or rebuttal is required under Administrative Law provisions to ensure procedural fairness. Another key omission in the simplified review process was budget. While budget was not considered a major issue for the Basic Science panellists, the Public Health panellists saw it to be crucial, especially in terms of value for money. This may reflect a greater belief in fields of public health that health interventions and services need to be not just effective but also cost effective. The increasing appearance of a health economics component on many public health grant proposals is further evidence of this.One of the most striking outcomes of this research was the discussion by both groups of the problems with proposals getting a ‘fair review’, and with that, the central role played by the primary spokesperson. In the views of many participants, the peer review process of the GRP was hampered because grants were not always reviewed by ‘peers’. This results from GRP members often having conflicts of interest with applications and therefore not able to be part of the appraisal process. Many members spoke of panel experiences where primary spokespeople were clearly not expert in the field of the proposal. But without the confidence of expertise, a primary spokesperson is unlikely to award an application a high score, thereby ‘sinking’ or ‘killing’ it. Members talked about how they and others elevated their score to compensate for this possibility. This and other ways of ‘gaming the score’ were considered inevitable.One of the aims of this study was to compare a simplified review process with more conventional processes. In general, participants were supportive of the simplified process. In particular, they liked the more nuanced definition of ‘conflict’ adopted by the simplified review—allowing conflicts to be rated high, medium and low and with this, various degrees of distance from the review process . Another feature of the simplified review process was awarding proposals a grade of gold (should fund), silver (could fund) and bronze (should not fund) instead of the NHMRC 1 to 7 rating. The extent to which the simplified process removed the grey middle ground was, however, a point of discussion. One suggestion was expanding from three categories to four by including a silver A or silver B grading.Our comparison of research cultures raises a number of important issues. Cultural homogeneity within a GRP is likely to create the same criteria of the judgement of so-called excellence . HoweverHow Professors Think, Lamont [In her book , Lamont  states ‘, Lamont . We beli


Fluid resuscitation continues to be recommended as the first-line resuscitative therapy for all patients with severe sepsis and septic shock. The current acceptance of the therapy is based in part on long history and familiarity with its use in the resuscitation of other forms of shock, as well as on an incomplete and incorrect understanding of the pathophysiology of sepsis. Recently, the safety of intravenous fluids in patients with sepsis has been called into question with both prospective and observational data suggesting improved outcomes with less fluid or no fluid. The current evidence for the continued use of fluid resuscitation for sepsis remains contentious with no prospective evidence demonstrating benefit to fluid resuscitation as a therapy in isolation. This article reviews the historical and physiological rationale for the introduction of fluid resuscitation as treatment for sepsis and highlights a number of significant concerns based on current experimental and clinical evidence. The research agenda should focus on the development of hyperdynamic animal sepsis models which more closely mimic human sepsis and on experimental and clinical studies designed to evaluate minimal or no fluid strategies in the resuscitation phase of sepsis. Sepsis is a significant global health problem. The worldwide incidence of sepsis is increasing, with current estimates between 20 and 30 million cases annually –5. The mFluid resuscitation remains the most enduring of sepsis treatments predating even antibiotics. Its beginnings date to the European cholera epidemic of the 1830s, where it was first used to replace the losses associated with cholera diarrhoea . In modeUnfortunately, there is no agreed uniform definition of fluid resuscitation in the literature. Fluid administration is not necessarily the same as fluid resuscitation. It is important to differentiate between fluid substitution and volume substitution in intensive care patients, a distinction that has not always been appreciated sufficiently in the design of fluid studies . For theThe following article reviews the rationale for the introduction of fluid resuscitation as treatment for sepsis and highlights a number of significant concerns based on current experimental and clinical evidence.R. Hermann was a German chemist working in Moscow during the second cholera pandemic in 1830. He proposed injecting water into the circulation to replace lost fluid after observing haemoconcentration in cholera patients. His clinician colleague Jaehnichen subsequently injected a cholera patient intravenously with 6 oz. of water, which resulted in a notable improvement in the patient’s pulse. However, the patient died 2 h later , 15. WheFluid resuscitation was re-discovered some 30 years later as a treatment for severe haemorrhage. In 1864, Goltz was the first to suggest that loss of intravascular volume rather than a loss of oxygen carrying capacity might be the central mechanism of death in haemorrhagic shock . This waThe development of a new paradigm for the condition “shock” accompanied the expansion of the use of intravenous fluids. Prior to the nineteenth century, “shock” remained a concept without a clear definition , 24. It The ability to measure cardiac output fundamentally changed the paradigm of shock again. The increased understanding of circulatory pathophysiology allowed the differentiation and description of shock by Blalock into the different subtypes recognisable today . The subThe case for tissue hypoperfusion in hyperdynamic sepsis was based on the occurrence of an increased lactate, oliguria and delivery-dependent oxygen consumption, with each finding attributed to occur due to inadequate blood flow. It was then assumed that fluid resuscitation would produce clinically relevant improvements in cardiac output able to reverse pathological tissue hypoperfusion. This example of linear clinical reasoning based on physiology is likely to be overly simplistic, and each element can be challenged by current evidence.ATPase activity has been demonstrated to be a significant contributor to the lactate of sepsis in both human and animal models [ATPase [Tissue hypoperfusion leading to tissue hypoxia was thought to be the dominant mechanism accounting for the increased lactate seen in sepsis , 40, 41.l models , 48. Micl models , 43, 48.The production and clearance of lactate during sepsis is a complex, nonlinear and still poorly understood process. The current evidence suggests that elevated blood lactate level during sepsis is not a reliable indicator of tissue hypoxia .Oliguria in patients with sepsis is widely regarded as a surrogate for renal tissue hypoperfusion and often used as a trigger for fluid resuscitation. There is, however, little direct clinical evidence of renal hypoperfusion during sepsis. While the available clinical observational data are limited in both size and quality, where accurate estimates of renal blood flow in sepsis have been reported blood flow has been demonstrated to be markedly increased . ExperimMore importantly, clinical studies both in sepsis and in other conditions such as burns have shown that fluid resuscitation based on oliguria often has minimal to no effect on urine output and fails to reduce renal dysfunction –56.The observation that oxygen consumption can be increased by increasing oxygen delivery in patients with sepsis is often referred to as “delivery-dependent oxygen consumption” , 41. ItsFluid resuscitation exerts its potentially therapeutic effect by increasing the stressed volume of the circulation leading to increased venous return and cardiac output . RecentlThe effect of vasopressors, increasing the stressed volume in the venous circulation, has been relatively overlooked until recently. In patients admitted to intensive care with septic shock, temporary reductions in noradrenaline infusion dose produced corresponding reductions in mean systemic filling pressure and cardiac output . This suThese studies highlight that interventions other than fluid resuscitation could be applied to manipulate haemodynamic variables such as cardiac output in sepsis. The comparative effectiveness of these therapies remains unclear.Several experimental studies in animals have investigated both the effectiveness of fluid resuscitation in improving the septic shock state and its effect on sepsis mortality.In animal models of septic shock, fluid resuscitation resulted in modest improvements in a number of physiological variables. The most consistent finding from large animal models of sepsis is that of a short-term improvement in cardiac output associated with fluid resuscitation, with the effect dissipating rapidly after the termination of infusion –74. SimiThere are several small and large animal models that demonstrate improvements in mortality with fluid resuscitation. For example, in murine models of both caecal ligation and puncture and endotoxemia, fluid resuscitation has consistently been shown to improve mortality when compared to no treatment and to provide additive benefit to both antibiotics and corticosteroids –79. SimiThe key problem with these animal studies, as briefly mentioned earlier, is the paucity of models that mirror the clinical presentation of sepsis in humans. The response to both sepsis and endotoxaemia in humans is different to commonly used murine, ovine and porcine models . The domDespite its widespread use, the clinical evidence supporting fluid resuscitation in sepsis remains conflicted. Prior to 2001, its use hinged on physiological justification and a long history of use, as there were no randomised controlled trials (RCTs) that tested fluid resuscitation as an intervention for septic shock. The landmark study of early goal-directed therapy (EGDT) by Rivers et al. and the subsequent single-centre and multicentre follow-up RCTs in China were the first prospective studies suggesting benefit of the use of fluids in septic shock –86. ThesThe observational data on the effects of fluid resuscitation in sepsis are conflicting, with studies suggesting equivocal, beneficial and negative effects on mortality.In one study in 2796 patients across 77 intensive care units to determine the effectiveness of surviving sepsis guidelines recommended therapies, regression modelling showed that fluid challenge for hypotension or elevated lactate had no association with outcome  . HoweverConversely, a conservative fluid strategy may improve patient outcomes, as was shown in the “fluids and catheters treatment trial” (FACTT) . In thisConsidering the dose–effect relationship and side effects of fluids, fluid therapy should be regarded like other drug therapy with specific indications and tailored recommendations for the timing, type and dose of fluid. Based on this, a conceptual model with four phases of intravenous fluid therapy was recently proposed, which include resuscitation, optimisation, stabilisation and evacuation (ROSE) . SpecifiTo provide a definitive answer to the crucial question what the true effect of fluid administration in the resuscitation phase of human sepsis is, we need high-level evidence from RCTs that compare fluid resuscitation versus no fluid resuscitation. This approach requires clinical equipoise between these two treatment arms, and therefore perhaps a shift in the way clinicians consider fluid resuscitation. Currently, the only randomised controlled trial of fluid resuscitation in sepsis is the “fluid expansion as supportive therapy trial” (FEAST) . The invFluid resuscitation is recommended and widely used as the first-line resuscitative therapy for all patients presenting with septic shock. This practice seems mainly based on historical beliefs and an incomplete or incorrect understanding of the pathophysiology of sepsis.Viewed as a whole, the bench-to-bedside evidence supporting fluid resuscitation as treatment for sepsis remains remarkably weak and highly conflicting. In addition, the indiscriminate use of fluid resuscitation, specifically beyond the initial resuscitation phase, has the potential to cause significant harm.Although absence of evidence does not equal evidence of absence, one could argue there is an urgent need for better evidence. The research agenda should focus on the development of hyperdynamic animal sepsis models which more closely mimic human sepsis and on experimental and clinical studies designed to evaluate minimal or no fluid strategies in the resuscitation phase of sepsis.The recent history of intensive care medicine has taught us that overly aggressive attempts to “normalise physiology”, focusing on numbers, may be harmful. Perhaps the most important contribution towards improved outcomes of intensive care patients has been the removal of ineffective and potentially harmful treatments. Until proven otherwise, fluid resuscitation for sepsis fits that description.


Varicella zoster virus (VZV) infects the face and can result in chronic, debilitating pain. The mechanism for this pain is unknown and current treatment is often not effective, thus investigations into the pain pathway become vital. Pain itself is multidimensional, consisting of sensory and affective experiences. One of the primary brain substrates for transmitting sensory signals in the face is the ventral posterior medial/posterior lateral thalamus (VPM/VPL). In addition, the anterior cingulate cortex (ACC) has been shown to be vital in the affective experience of pain, so investigating both of these areas in freely behaving animals was completed to address the role of the brain in VZV-induced pain. Our lab has developed a place escape avoidance paradigm (PEAP) to measure VZV-induced affective pain in the orofacial region of the rat. Using this assay as a measure of the affective pain experience a significant response was observed after VZV injection into the whisker pad and after VZV infusion into the trigeminal ganglion. Local field potentials (LFPs) are the summed electrical current from a group of neurons. LFP in both the VPM/VPL and ACC was attenuated in VZV injected rats after inhibition of neuronal activity. This inhibition of VPM/VPL neurons was accomplished using a designer receptor exclusively activated by a designer drug (DREADD). Immunostaining showed that cells within the VPM/VPL expressed thalamic glutamatergic vesicle transporter-2, NeuN and DREADD suggesting inhibition occurred primarily in excitable neurons. From these results we conclude: (1) that VZV associated pain does not involve a mechanism exclusive to the peripheral nerve terminals, and (2) can be controlled, in part, by excitatory neurons within the VPM/VPL that potentially modulate the affective experience by altering activity in the ACC. Varicella zoster virus (VZV) causes chickenpox and shingles resulting in acute and chronic pain. VZV infects cutaneous innervating axons, then transports to the neuronal cell body to undergo replication and later viral latency. During the latency period the VZV DNA remains in sensory ganglia, but there is little to no virus production. In a third of VZV infected individuals VZV reactivates, typically after age 50, to cause herpes zoster . HZ is debilitating and painful, with up to 90% of patients seeking pain alleviating medication  show no improvement  modulated VZV-induced nociception  was used to measure VZV-induced affective pain in the orofacial region of the rat. Pain measurements were completed after VZV injection of the trigeminal ganglion. VPV Local field potentials (LFPs) were measured in the VPM/VPL and ACC of awake rats after modulating neuronal activity in the VPM/VPL with a designer receptor exclusively activated by a designer drug (DREADD). Immunostaining was completed to identify the cell type controlled by the DREADD constructs. These studies were completed to determine a role for the central nervous system in VZV-induced affective pain in an awake animal.ad libitum. After a 4 day acclimation period experiments were carried out in accordance with the NIH regulations on animal use.This study was approved by the Texas A&M University College of Dentistry Institutional Animal Care and Use Committee. Male (280–300 g) Sprague-Dawley rats from Envigo  were kept on a 14:10 light/dark cycle. The rats were given food and water 4 pfu of VZV  or an equivalent amount of control (MeWo) cells; there were 11 animals in the control group and 17 animals in the VZV treatment group. Technical note: VZV is unstable and must be administered within MeWo cells that produce the virus particles. A behavioral affective pain assay was then completed for 2 weeks.Three experiments were completed in total Table . In ExpeIn Experiment 2, the VPM/VPL of 18 rats was infused with a neuronal silencer adeno-associated virus (AAV8-DREADD) and then a week later the whisker pad was injected with 100,000 pfu of VZV or control (4–5 rats per treatment group). Behavioral affective pain assays were completed, with and without activation of the DREADD, for 3 weeks in these animals.In Experiment 3, the VPM/VPL of 28 rats (7 rats per treatment group) was infused with AAV8 that resulted in the transduction of the neuronal silencer DREADD construct. Recording electrodes were implanted in the VPM/VPL and ACC. A week later the whisker pad was injected with 100,000 pfu of VZV. LFP recording in awake animals was completed once a week for 3 weeks, after which time the rats were sacrificed and tissues collected for molecular studies. Three rats were randomly chosen out of the control groups and four rats out of the VZV treated groups for perfusion and immunostaining, the remaining tissues were fresh frozen for future molecular analysis. The recording backpack restricts movement and significantly effects behavior (data not shown), thus behavioral measurements were not completed in Experiment 3 but were completed in Experiment 2 where the animals were treated the same but did not have electrophysiological recording. Experiments using VZV were completed under using Biosafety level II approved protocols.4 pfu/ganglion) or MeWo cells (control). A Stoelting  stereotaxic syringe pump system was used to infuse at a rate of 0.05 microliters per minute. The infusion needle was left in place 5 min before removing.The rats were anesthetized with 2% isoflurane and an air flow of 2 liter per minute. Stereotaxic  infusions of VZV were performed  at coordinates AP = 1.5 mm from Bregma, 2.0 mm from midline and 11.2 mm from the top of the skull. These coordinates correspond to neurons of the trigeminal ganglion that innervate the V1 and V2 branch of the trigeminal nerve .12 pfu/ml AAV8 at a rate of 20 nanoliters per minute. After infusion the needle was left in place for 5 min and then removed. Using these coordinates and injection procedure the modified acetylcholine Gi protein-coupled receptor was expressed primarily in the VPM, VPL with a smaller amount of expression in the reticular (Rt) thalamic nuclei, as well as, the zona incerta (ZI) of Sprague-Dawley rats -mCherry  or vehicle. The hM4D(Gi) gene was an engineered acetylcholine Gi-protein coupled receptor that inhibits neuronal firing when bound by clozapine-n-oxide  were implanted into the right VPM/VPL or right ACC. Thalamic coordinates were 3.6 mm posterior of Bregma, 3.0 mm from midline at a depth of 6.0 mm. The second recording electrode was placed in the ACC at coordinates 1.0 mm posterior from Bregma, 0.7 mm lateral of midline at a depth 3.1 mm at a 26° angle. The recording electrodes were cemented with acrylic to jewelers screws attached to the skull. Histology was performed after sacrifice to verify that electrode placement was correct.The rats received an intraperitoneal injection of 1 mg/kg CNO dissolved in 0.9% saline or an injection of 0.9% saline in a 0.5 ml volume 30 min before testing. The rats were tested once a week for 3 weeks.Because the magnitude of the behavioral response in the PEAP test has been shown to be greater than the thermal and mechanical response after VZV injection, all testing in this study was completed using the PEAP test  anesthetized with 2% isoflurane and fitted with a backpack containing the LFP customized wireless recording module  within the recording microcontroller module. Signals were transmitted by a receiver on a USB dongle to a laptop using customized software. The signals were saved as data in a text file and imported as a raw waveform at a sampling rate of 4096 Hz .In Experiment 3, the animals were anesthetized with 100 mg/kg ketamine and 10 mg/kg xylazine the animals were first perfused with 9% sucrose and then with 4% paraformaldehyde in 1× PBS, pH 7.4. Fixed tissues were stored in 25% sucrose, frozen, cryo-sectioned and the 20 μm sections placed on Histobond slides .The tissue was then blocked with a PBS solution containing 5% normal goat serum and 0.3% Triton-X 100 for 2 h at room temperature. The slides were incubated in primary antibody or the dilution buffer overnight at 4°C. Primary antibodies consisted of the mouse monoclonal NeuN antibody at a 1:250 dilution , or the mouse monoclonal vesicular glutamate transporter 2 (VGLUT2) antibody  at a 1:150 dilution. Primary antibodies were diluted in PBS containing 5% BSA and 0.3% Triton X-100. After rinsing three times in PBS with 0.3% Triton X-100 for a total of 45 min, slides were placed for 2 h in secondary antibody. Secondary antibodies (1:500 dilution) included goat anti-mouse Alexa 488 conjugate . After rinsing the slides three times in PBS for a total of 45 min, the slides were mounted with Fluoromount-G mounting medium containing Hoechst 33342 stain . The fluorescent signal was imaged using a Nikon fluorescent microscope and NIS-Elements imaging software and a Photometrics CoolSnap K4 CCD camera.In Experiment 3, cellular quantitation was completed by a blinded reviewer. Three rats were randomly chosen out of the control groups and four rats out of the VZV treated groups and the remaining tissues were frozen fresh for other molecular studies not included in this manuscript. Cell counts were completed on 20 μm coronal sections. The AAV8 injection site was the center point from which sections were selected. Every other section was selected for staining. Typically three sections were counted for each animal. The slides were analyzed using ImageJ software, the average background for the slides within a treatment group was subtracted from the image and a fluorescent signal associated with a cell nucleus was counted as a positive cell.2 circular field adjacent to the injection site. On each section two randomly selected fields near the tip of the injection site was counted. Counts were completed within the ventral thalamic nuclei including the VMP, VPL and Rt thalamic nuclei . Counts were also completed in the ZI .Counts were completed for the number of AAV8, NeuN or VGLUT2 positive cells within a 0.5 mmCell counts from the two fields on each section were then averaged. This average count for the three sections was averaged for each animal. Values were given as a mean and standard error of the mean (SEM) representing an average of the values for the three or four animals in each treatment group.loglog and for the precision parameter was log. The responses were modified by applying the following transformation (y (n − 1) + 0.5)/n, where y is a response and n is the total number of observations (=54). This “shrunk” the range of responses to the open (0.0 1.0) interval required by the model  and/or drug  and the dependent variables were the power values and cell counts. Data was analyzed for normality and homogeneity . For the PEAP assay the fraction of time each animal spent on the light side of the testing chamber during the 30 min testing period was analyzed using a Generalized Linear Model (GLM) regression with response variable (the time fraction) modeled by the Beta distribution parametrized by the location and precision parameters. This approach allowed us to account for the bounded nature of the response variable from 0.0 to 1.0, while employing the flexibility of the GLM. The precision parameter of the beta distribution was explicitly modeled in addition to the location parameter because the variance of the responses was expected to change with change in the mean response . Link function for the location parameter was F = 60.6, p < 0.0001, Figure F = 14.9, p < 0.001, Figure Injection of the V1/V2 region of the trigeminal ganglion Figures  resultedA significant VZV effect was measured 1 Figure , 2 Figu and 3 F, weeks aInfusion of AAV8 resulted in mCherry expression in the VPM/VPL Figure . The virThe response to CNO was not significant in the absence of DREADD .p-values for the location parameter submodel are presented in Table df = 3) and a p-value < 2.2E-16.Parameter estimates, their standard errors, z test statistic values and associated z test statistic value and associated p-value for the precision parameter submodel are presented in Table Parameter estimate, its standard error, F = 3.89, p = 0.05, n = 7). VZV also increased VPM/VPL activity at the gamma frequencies in week 1  = 4.18, p = 0.05). A significant interaction between virus and drug (CNO) treatment was observed in week 1  = 5.10, p = 0.03). Post hoc analysis demonstrated VZV significantly increased gamma frequency activity and CNO treatment decreased this response  = 3.7, p = 0.05, n = 7). An interaction between virus and drug was not observed  = 2.86, p = 0.10) in the ACC during week 2. Post hoc analysis indicated VZV treatment significantly increased theta activity and CNO treatment prevented this increased activity  in coherence, with the control condition having a higher level of waveform coherence (0.85 ± 0.03) vs. the period of Von Frey testing (0.64 ± 0.05). Note the strong coherence between the VPM/VPL and ACC waveforms in the control condition during the second week. In the final week the coherence between the raw trace waveforms was 0.75. In this week there was also a significant difference (p = 0.003) in the coherence of the ACC and VPM with the control condition (0.83 ± 0.03) once again being more correlated than during Von Frey testing (0.67 ± 0.03).For the first week of testing, the mean correlation between VPM/VPL and ACC waveforms was 0.58 Figure . There w2 field was not significantly different between the treatment groups  = 0.94, p = 0.42, n = 3 control groups, n = 4 VZV groups) or between the different nuclei   = 0.32, p = 0.72). No significant interaction between treatment and location was observed  = 0.25, p = 0.95). The Gi construct with a fluorescent tag (mcherry) was observed in cells positive for the neuronal marker NeuN  = 36.66, p < 0.0001) than the Rt or ZI  = 0.33, p = 0.80) and no interaction between treatment and location of the cells  = 0.35, p = 0.90).Thalamic neurons were transduced with the Gi construct after injecting the VPM/VPL with AAV as indicated by the mCherry signal Figure . Followi Figures . Cell coI Figure . There wF = 27.56, p < 0.0001). Treatment had no effect on the number of AAV transduced cells that stained for VGLUT2  = 0.08, p = 0.96) nor was there a significant interaction between treatment and the location of the cells  = 0.06, p = 0.99). The data show a majority of the mCherry positive cells  were VGLUT2 positive excitatory neurons  and the ACC has an important role in the affective pain response we studied activity in the ACC (LaBuda and Fuchs, Inflammatory and visceral pain has been associated with changes in the low frequency band of the ACC, consistent with our observation that the theta frequency band significantly increased upon VZV treatment (Wang J. et al., Although less than 30% of the neurons adjacent to the recording electrode in the VPM/VPL were AAV infected, inhibition of the LFP was nearly complete after administration of CNO. The robust LFP response would be expected if the region near the tip of the electrode had nearly complete AAV infection resulting in expression of CNO controlled Gi activation. Our data indicated less than 30% of the cells were AAV infected. The cell counts completed in this study included the region very near the recording electrode tip but counts did include regions extending from the recording electrode tip and would potentially include regions of reduced infection. We did not count the percentage of infected cells vs. distance from the injection site and have not tested this idea directly but it is possible that the method of the cell counting resulted in a lower than expected infection rate. Alternatively, if electrically active cells preferentially became infected with AAV this would result in a low percentage of infectivity but a highly effective suppression of the LFP.Approximately two-thirds of the virus infected cells contained the excitatory glutamatergic marker VGLUT2. Glutamate is a key signaling molecule in the thalamic region, relaying pain from periphery (Bhave et al., This is the second study to look at the role of specific brain regions in VZV-induced pain. In the first study GABA neurons in the reticular thalamic region were shown to modulate VZV pain (Stinson et al., In conclusion, we have a rat model that allows study of VZV disease mechanisms resulting in pain within the orofacial region. Our results suggest the mechanism for VZV affective pain is not restricted to the peripheral nerve terminals, but involves thalamic excitatory neurons. Importantly, attenuation of excitatory neuronal activity in the thalamus resulted in an attenuation of electrical activity in the ACC, which was associated with a reduction in affective pain. This association is consistent with the idea that excitatory neurons within the VPM/VPL modulate effective aspects of VZV-induced affective pain by altering activity in the ACC.PRKramer, PRKinchington, YBP, JS and LLB contributed in the design of the experiments and analysis of the data as well as contributing to the drafting and editing of the manuscript. JS, CS and MBY collected data, performed experiments and analyzed the data for this study. MU performed data analysis and contributed to writing 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. The reviewer VG-S and handling Editor declared their shared affiliation.


Hydroxypropyl methylcellulose (HPMC) is a biopolymer that is biodegradable, environmentally friendly, and bio-friendly. Owing to its unique chemical structure, HPMC can reduce the coefficient of friction (COF) and frictional wear and thus possesses excellent lubrication properties. HPMC has good dissolvability in specific solvents. The present research focuses on the reversible dissolution reaction subsequent to the film formation of HPMC, with a view to the healing and lubrication properties of thin films. Raman spectroscopy was used to test the film-forming properties of HPMC and the dissolution characteristics of various solvents. In this study, the solvents were water, methanol, ethanol, and acetone. The results showed that the HPMC film had the highest dissolvability in water. The ball-on-disk wear test was used to analyze the lubrication properties of HPMC, and the results showed that HPMC had the same COF and lubrication properties as the original film after being subjected to the water healing treatment. The HPMC film can be reused, recycled, and refilled, making it an ideal lubricant for next-generation ecotribology. The concept “reduce, reuse and recycle” is exercised through ecodesign and sustainable manufacturing. Sustainable manufacturing refers to minimizing or eliminating adverse environmental effects during the product manufacturing process, while also saving energy and conserving the earth’s resources. In this research, we aim to demonstrate that the incorporation of a biopolymer (HPMC), as a green lubricant, can reduce not only friction and wear, but also the use of petroleum. Hence, the adverse environmental effects associated with the use of petrochemical products are mitigated. Sustainable manufacturing has two directions of development in manufacturing procedures. The first direction of development is to reduce or even eliminate the use of cutting fluid. Therefore, minimum quantity lubrication (MQL) and dry film lubrication have attracted increasing attention in recent years. Rapid progress has been made in MQL technologies. In particular, some lubrication materials with MQL and adhesiveness can be directly sprayed on the locations that need to be lubricated, thus preventing the use of large quantities of lubricating fluid in conventional cutting manufacturing processes. Moreover, nanofluidic properties are used to strengthen the effects of MQL ,2,3. OthThe second direction of development is to use green lubricants  made of natural materials; in addition to reducing the use of petroleum oil, this method enables the materials to be reused and recycled. Examples of such oils include natural vegetable oil ,13, ricePrevious research points out that HPMC is a biopolymer material with several potential applications, especially as a lubricant. However, there are few references available for the use of HPMC as a lubricant, especially with regard to self-healing. This is the first study to include the use of a healing agent with HPMC materials to induce self-healing. The present study investigated the self-healing property of dry films of biopolymer materials with the aims of reducing frictional wear, providing good lubrication properties, decreasing material consumption, and attaining the goals of reusing and recycling in sustainable manufacturing.First, 100 mL ethanol was heated to 60 °C, and 30 mL water was added to the ethanol; then, 5 g HPMC powder  was added to the solution and stirred with an electromagnetic heating stirrer until the HPMC was completely dissolved in the solution. Subsequently, a micropipette was used to aspirate 150 μL of the solution and to drip the solution onto the silicon substrate. The HPMC-coated silicon substrate was then left to stand for 1 h in an environment with a temperature of 25 ± 2 °C and a relative humidity (RH) of 60% ± 5%.Film properties such as the morphology and surface characteristics were analyzed by scanning electron microscopy  and energy-dispersive X-ray spectroscopy .The degradation properties of the thin films were investigated using by Raman spectroscopy .This study investigated the lubrication properties and anti-wear behavior of HPMC with a ball-on-disk tribometer . For testing, a ball is fixed on a stationary holder, and the bottom disk is rotated at a specified speed. The tribology tests were performed in ambient air at ambient temperatures with a sliding speed variation of 0.01 m/s and a loading variation of 2 N. All friction and wear tests were conducted at a rotation radius of 2 mm. The steel balls were composed of AISI 52100 with a hardness of 61 HRC. The tested HPMC coating was prepared on a silicon substrate and mounted onto the bottom disk of the tribometer. The friction force on the motion of the disk was recorded by connecting a load cell to the rotating disk. The friction coefficient was measured for further analysis of the lubrication and anti-wear properties. The friction experiments were repeated to ensure the reproducibility of the results.After the HPMC film was subjected to the wear test, a micropipette was used to drip deionized water, methanol, ethanol (95%), and acetone solutions onto the worn test strips. The test strips were held under atmospheric pressure and ambient temperature for 10 min, and the repair status of the wear scar was observed before proceeding to the next stage of the frictional wear test. In the healing process, only the solvent was dripped onto the surface of the test strip, and in the refilling process, the HPMC solution was directly dripped onto the surface of the test strip.A 3D scanner  was used for scratch analysis. VK analysis was used to combine the information acquired by charge-coupled device (CCD) photography with the laser intensity information acquired by the laser component to produce color image data for the specimen. In the present experiment, a 3D scanner was used to observe the cross-sectional profile of the surface of the HPMC film and the width and depth of the wear scar.First, HPMC was dripped onto the Si substrate (top processes shown in 56H108O30). −1 are from C–O stretching, O–H bending, C–H stretching and O–H stretching, respectively[pectively. The eviFilm thickness is a key parameter in film preparation. As shown in −1) were used as the judgment criteria [Because of the material properties, the HPMC powder could be completely dissolved in mixed solutions in which the alcohol: water ratio ranged from 20% to 100%. A completely transparent solution was generated. In this study, the HPMC film was directly soaked in four types of common solutions , and Raman spectroscopy was used to measure the dissolution of the HPMC film in the different solutions. criteria ,36. WhenAfter the film was subjected to 2000 cycles of frictional wear, water and methanol were dripped onto its surface, and then the film was allowed to sit for 10 min. The lubrication properties of the HPMC film were correlated to the generation and development of a transfer layer. During frictional wear, the transfer layer and thin film were consumed because of the wear behavior. After the film underwent frictional wear for a certain length of time, the film thickness decreased , therebyThe excellent lubricating properties of HPMC were demonstrated. The thickness of the HPMC thin film has a large effect on its lubrication characteristics. Here, the optimal thickness was 50 μm. Different healing agents have different abilities to induce self-healing in HPMC. Among them, water performs as the best healing agent when compared to methanol, ethanol, and acetone. The lubricating characteristics of HPMC before and after self-repair are equivalent when the appropriate thickness is used. In this study, self-repair could occur at least twice without affecting the lubrication qualities of the thin film. Furthermore, the refill process did not affect the lubricating characteristics of the thin film. HPMC possesses good lubricating and self-healing properties; therefore, it is very suitable to serve as a green lubricant for sustainable manufacturing.