1 00:00:07,960 --> 00:00:12,070 Welcome to our second episode of Gut Instincts, G.I. Research Updates, 2 00:00:12,070 --> 00:00:17,380 bringing you the latest research in gastroenterology and hepatology straight to your smartphone. 3 00:00:17,380 --> 00:00:25,450 I'm Fitz. I'm a clinical lecturer in gastroenterology at Oxford with an interest in mucosal immunology and nutrition. 4 00:00:25,450 --> 00:00:31,000 And I'm Tamsin Cargill. I'm a gastroenterology registrar and D students in Oxford. 5 00:00:31,000 --> 00:00:41,720 Interested in hepatology, viral tests and vaccine development. The gastro literature can seem very overwhelming. 6 00:00:41,720 --> 00:00:47,990 There's just so many P papers coming out, and so we started this podcast to bring you some of the G.I. related highlights 7 00:00:47,990 --> 00:00:52,040 that have come out recently and discuss why we think they're interesting. 8 00:00:52,040 --> 00:00:58,670 So each episode, we're going to try and talk through to cracking primary research papers in a bit of detail. 9 00:00:58,670 --> 00:01:03,560 One will be clinical and one translational. And we'll give you our take on the research. 10 00:01:03,560 --> 00:01:12,290 And we're also going to bring you our super speedy five in five section where we'll try and summarise the key points of five papers in five minutes. 11 00:01:12,290 --> 00:01:17,030 Last week it took us eleven minutes, but five and 11 just doesn't have the same ring to it. 12 00:01:17,030 --> 00:01:21,080 So we're going to stick with the same name and just ignore the time. 13 00:01:21,080 --> 00:01:26,270 Disclaimer alert. Clearly nothing in this podcast constitutes medical advice. 14 00:01:26,270 --> 00:01:30,860 So if you're a patient, you should consult your medical practitioner about your medical management. 15 00:01:30,860 --> 00:01:36,590 And for doctors, I'm sure you wouldn't base your medical management solely on what a couple of people told you on a podcast. 16 00:01:36,590 --> 00:01:42,560 Now, thank you to our army of listeners for tuning into our first episode and giving us some feedback. 17 00:01:42,560 --> 00:01:51,920 All all 20 of you. You are the best. We hugely appreciate your thoughts of how we can improve this podcast and your listening and learning experience. 18 00:01:51,920 --> 00:01:58,520 So please let us know what you think. Write us a glowing review on whatever platform your streaming us through. 19 00:01:58,520 --> 00:02:14,670 Connects with us via Twitter at G.I. Update. Or you can email us at Gut Instinct podcast or one word at G Mail dot com. 20 00:02:14,670 --> 00:02:23,430 Right. Last week, I did the clinical paper terms, and I think you've got something clinical and sort of bile flavoured for us this week. 21 00:02:23,430 --> 00:02:28,020 Yes. So firstly, before I start, I just wanted to say upfront, 22 00:02:28,020 --> 00:02:35,340 I realised there were two pretty important trials published last week in the New England Journal of Medicine. 23 00:02:35,340 --> 00:02:40,560 These will get a mention or more than mention in a previous in future episodes to come. 24 00:02:40,560 --> 00:02:45,440 But today, I'm going to focus on some different papers. 25 00:02:45,440 --> 00:02:51,630 Two linked papers that focus on the treatment of refractory societies in psoriasis. 26 00:02:51,630 --> 00:02:56,670 So both papers report the outcomes from the reduce study trial. 27 00:02:56,670 --> 00:03:00,750 And that stands for repeated drainage of untreatable psoriasis, 28 00:03:00,750 --> 00:03:09,210 which compared long time abdominal drains with large volume paracentesis for the treatment of refractory societies due to psoriasis. 29 00:03:09,210 --> 00:03:14,400 So the first paper was actually published last year in July in AT&T. 30 00:03:14,400 --> 00:03:23,310 And that covers the quantitative outcomes of the trial. And the second paper, which is the one I saw that caught my eye, 31 00:03:23,310 --> 00:03:29,340 was published online ahead of print in December 2020 in the Journal of Pain and Symptom Management. 32 00:03:29,340 --> 00:03:34,210 And that covers the qualitative outcomes of the trial. 33 00:03:34,210 --> 00:03:40,380 So so this trial addresses an important but understudied area of end stage liver disease, 34 00:03:40,380 --> 00:03:47,070 which is palliative interventions specific for some of the symptoms of end stage liver disease. 35 00:03:47,070 --> 00:03:51,330 And everyone who's listening to this podcast will know that. 36 00:03:51,330 --> 00:03:58,740 Deaths from end stage liver disease have increased massively over the past 40 years or so. 37 00:03:58,740 --> 00:04:06,180 And one of the predominant symptoms experienced by individuals with end stages of the disease is refractory societies. 38 00:04:06,180 --> 00:04:16,380 So this is where somebody has a side to ease, but they are intolerant to or unresponsive to diabetics. 39 00:04:16,380 --> 00:04:27,010 And so they need an alternative form of management and to relieve the symptoms from that sort of large volume of sightings. 40 00:04:27,010 --> 00:04:31,320 And what's the scale of this of this problem, Tamsen? 41 00:04:31,320 --> 00:04:39,000 Unsurprisingly, it's pretty massive. So it's the most common reason for hospital admission in people with end stage liver disease. 42 00:04:39,000 --> 00:04:45,330 So any clinician up and down the country will have seen patients with this issue. 43 00:04:45,330 --> 00:04:56,410 It's prognostically a very bad sign. So median transplant free survival in individuals with refractory societies is only six months. 44 00:04:56,410 --> 00:05:01,860 But despite this, most people don't receive optimal palliative care. 45 00:05:01,860 --> 00:05:12,120 So we know that nearly 70 percent of deaths in cirrhosis with a sightings occurred in hospital, of which 97 percent followed an emergency. 46 00:05:12,120 --> 00:05:23,250 So on the planned hospital admission. And that is an indicator in of itself because because these hospital admissions were unplanned, 47 00:05:23,250 --> 00:05:28,260 the patients didn't necessarily choose to die in hospital. 48 00:05:28,260 --> 00:05:36,090 So most refractory societies in England is managed by large volume, paracentesis in hospital. 49 00:05:36,090 --> 00:05:41,220 And the scale of this is huge as well. So this is reported in Lancet. 50 00:05:41,220 --> 00:05:51,660 Gastric happened 2018, nearly 14000 cirrhosis related deaths between 2013 and 2015. 51 00:05:51,660 --> 00:05:58,950 That's nearly a third required. Large volume paracentesis in the last year of life at least once. 52 00:05:58,950 --> 00:06:06,870 So although although the evidence suggests that most people have refractory societies are managed by large volume, paracentesis. 53 00:06:06,870 --> 00:06:11,670 There is an alternative and that is a long term abdominal drain. 54 00:06:11,670 --> 00:06:19,260 And basically what these are a tunnel drains inserted under local anaesthetic and the patient goes home with them in situ. 55 00:06:19,260 --> 00:06:27,510 And then caregivers or community nurses drain one to two litres of fluid up to three times a week at home. 56 00:06:27,510 --> 00:06:35,520 And many people might be and might have seen these used sort of plural drains used in a similar way, 57 00:06:35,520 --> 00:06:44,400 long temporal drains where people have long term infusions that again need draining. 58 00:06:44,400 --> 00:06:48,710 And this this enables them to be managed at home. 59 00:06:48,710 --> 00:06:56,780 Now, in the U.K., several thousand long term abdominal drains are inserted every year for malignant societies. 60 00:06:56,780 --> 00:07:02,690 And in this setting, sort of low complication rates have been reported. 61 00:07:02,690 --> 00:07:08,990 However, they're not really routinely used for refractory sites. He's due to end stage liver disease. 62 00:07:08,990 --> 00:07:14,480 And this, I think, is due to the potential risk of peritonitis. 63 00:07:14,480 --> 00:07:20,750 But there's no previous research into the use in end stage liver disease. 64 00:07:20,750 --> 00:07:29,600 So anecdotally, these drains are used in the setting of refractory societies for for some patients in stage liver disease. 65 00:07:29,600 --> 00:07:36,110 But you say that there's not very much of that in the sense of sort of randomised controlled trials previously of using this technique. 66 00:07:36,110 --> 00:07:45,590 Exactly. Sorry, there's no large scale trials of this. And the evidence that is published would suggest that actually most refractory societies 67 00:07:45,590 --> 00:07:49,640 is actually managed by large weren't fully paracentesis rather than these drains. 68 00:07:49,640 --> 00:07:56,730 So clearly, if they are being used anecdotally, it's not due to trial. 69 00:07:56,730 --> 00:08:00,200 Not it's not due to evidence based trial based data. Yeah. 70 00:08:00,200 --> 00:08:01,880 It sort of goes against so much of the, you know, 71 00:08:01,880 --> 00:08:10,040 the sort of the teaching we get that these drains must be removed after six hours and that the risk of the risk of infection is is so great. 72 00:08:10,040 --> 00:08:15,710 Exactly. So this was a trial that's on answering a pretty important question, really. 73 00:08:15,710 --> 00:08:20,570 So reduce it was a non-flying at 12 week feasibility, randomised controlled trial. 74 00:08:20,570 --> 00:08:29,300 And it compared long term abdominal drains to large volume, paracentesis in individuals of cirrhosis and refractory societies. 75 00:08:29,300 --> 00:08:35,150 And this was conducted across five hospitals and and that resuscitated community 76 00:08:35,150 --> 00:08:41,930 settings in the south of England between September 2015 and September 2018. 77 00:08:41,930 --> 00:08:48,020 So because this was a feasibility study, it wasn't blinded and it didn't have a primary outcome prespecified. 78 00:08:48,020 --> 00:08:54,080 But the authors did predefine some study success criteria. 79 00:08:54,080 --> 00:09:03,080 And initially, you might think. But if they don't have a primary outcome, criteria of perhaps this trial isn't good quality. 80 00:09:03,080 --> 00:09:10,940 But actually, because it's a feasibility trial, the success criteria that they set were actually really practical. 81 00:09:10,940 --> 00:09:16,940 So the first one was that they wanted to see whether the attrition was above 50 percent. 82 00:09:16,940 --> 00:09:23,780 And you hope it wasn't that? Actually, this group of people are really sick and they've got a median survival of six months. 83 00:09:23,780 --> 00:09:27,200 So if you're recruiting to a study such as this, 84 00:09:27,200 --> 00:09:33,290 quite a few people are going to potentially die before the end of follow up and therefore, attrition rates are going to be high. 85 00:09:33,290 --> 00:09:38,900 Not necessarily because people are dropping out, but because people are dying. 86 00:09:38,900 --> 00:09:43,220 So that's the first one. And then they used erm I'll discuss these later. 87 00:09:43,220 --> 00:09:47,800 They used a lot of questionnaires and interviews to assess some of the, 88 00:09:47,800 --> 00:09:56,600 some different outcomes from the trial and that might not be able to be assessed in a quantitative way. 89 00:09:56,600 --> 00:10:03,800 And they wanted to see whether the completion rate of those questionnaires and interviews was over 80 percent. 90 00:10:03,800 --> 00:10:10,100 They also wanted the long term drain group to spend under 50 percent of time in 91 00:10:10,100 --> 00:10:15,380 hospital related to their societies compared to the large volume paracentesis group, 92 00:10:15,380 --> 00:10:21,260 because that was really the aim of putting in the long term drain so they wouldn't spend as much time in hospital. 93 00:10:21,260 --> 00:10:34,040 And the last success criteria was that the long term drains would be removed in under 10 percent of participants in that arm. 94 00:10:34,040 --> 00:10:45,290 So the inclusion criteria were fracturing societies requiring over one large volume piracy, 76 per month, at least twice parch recruitment. 95 00:10:45,290 --> 00:10:50,570 And the participants were randomised one to one using computer generated algorithm. 96 00:10:50,570 --> 00:10:52,610 But it wasn't blinded. 97 00:10:52,610 --> 00:11:03,410 So the intervention was a rocket drain under local anaesthetic, and that was inserted by an intervention radiologist or or trained to hepatologist, 98 00:11:03,410 --> 00:11:11,130 and then guidance was given to the participants and community nurses and jeepneys about how to manage and the drainage of that. 99 00:11:11,130 --> 00:11:17,780 And they drained once two units of society, two to three times a week, usually a trial nurse coming in to do that. 100 00:11:17,780 --> 00:11:25,610 And a district nurse and no control necessary. And no albumen was given during the drainage. 101 00:11:25,610 --> 00:11:33,950 And all participants were given Cipro, 500 milligrams once a day for the duration of the trial and invite the intervention in the control group. 102 00:11:33,950 --> 00:11:47,510 The control group had usual care, which was day unit or hospital admission as required for large volume, paracentesis with albumin cover plus. 103 00:11:47,510 --> 00:11:57,920 So they calculated the sample size based on the fact that they would probably have a really high attrition rate, as we've discussed already. 104 00:11:57,920 --> 00:12:03,290 So they aim to have 12 per group, so 24 per group based on a 50 percent attrition rate. 105 00:12:03,290 --> 00:12:11,850 And in the end, thirty six were randomised, so 19 in the large volume, paracentesis group and 17 in the long term acidic drink group. 106 00:12:11,850 --> 00:12:17,900 So the results of the trial. And so the baseline characteristics were relatively balanced. 107 00:12:17,900 --> 00:12:28,670 The other thing to say about these patients, of course, is that out of 36 of them, thirty five had a contra indication for tips. 108 00:12:28,670 --> 00:12:34,400 And one of them had been offered tips but declined it. 109 00:12:34,400 --> 00:12:38,960 So for the quantitative outcomes, the study success criteria were met. 110 00:12:38,960 --> 00:12:46,910 So attrition was under 50 percent. Fifteen of the thirty six didn't make it to the last study visits. 111 00:12:46,910 --> 00:12:51,830 80 percent of these were due to death and 20 percent due to withdrawal. 112 00:12:51,830 --> 00:12:57,230 The completion rate of question is very high. It's between 79 and 97 percent. 113 00:12:57,230 --> 00:13:01,410 And they were done longitudinally, so that's pretty good. 114 00:13:01,410 --> 00:13:12,110 Long term drain ditch group spent under 50 percent of the time in hospital due to their S.A.S. compared to the large volume paracentesis group. 115 00:13:12,110 --> 00:13:20,960 So data was available for 15 of 17 of the long term Pacific during group. 116 00:13:20,960 --> 00:13:26,710 And out of those 15 people, five of them required extra drainage in hospital. 117 00:13:26,710 --> 00:13:31,850 So 10 of them were managed in the community with their long term ascetic drain 118 00:13:31,850 --> 00:13:35,710 without any need to be coming back to hospital for further paracentesis. 119 00:13:35,710 --> 00:13:43,220 But five of them did have to come back. And they those five require a total of 13 further drains in hospital, 120 00:13:43,220 --> 00:13:49,930 some of which which the emissions were due to other reasons, and they just drained them in hospital anyway. 121 00:13:49,930 --> 00:14:00,760 But comparing that to the large volume, paracentesis group, all of them obviously required further drainage in hospital. 122 00:14:00,760 --> 00:14:06,890 And that was a total of 69 further drains, which is actually when it's written down like that. 123 00:14:06,890 --> 00:14:13,250 Quite a lot. And long term drain removal and only one drain was removed in the long term acidic drain group. 124 00:14:13,250 --> 00:14:22,580 And that was because the participant pulled out accidently after it was inserted sort of the next day and they elected not to reinsert it. 125 00:14:22,580 --> 00:14:26,660 Those are pretty impressive outcomes from from this trial. 126 00:14:26,660 --> 00:14:36,410 So. So there's 10 of these patients who, as we said, are refractory to refractory to medications of contraindications for tips and not suitable 127 00:14:36,410 --> 00:14:43,010 for transplantation who were managed in the community and didn't need any large volume. 128 00:14:43,010 --> 00:14:44,270 Paracentesis. 129 00:14:44,270 --> 00:14:57,140 And overall was at about an 80 percent reduction in the number of drains, the large volume person disease needed over again in the long term group. 130 00:14:57,140 --> 00:15:01,730 That's that's that's pretty, pretty harmless. Yeah. 131 00:15:01,730 --> 00:15:08,160 No, it is. I agree. The other things that they looked at quite a lot of other outcomes as well. 132 00:15:08,160 --> 00:15:10,100 The other outcome of sort of interest, 133 00:15:10,100 --> 00:15:19,160 I guess was peritonitis with the theoretical risk that the long term acidic drain might lead to increased risk of peritonitis. 134 00:15:19,160 --> 00:15:25,250 But they found, obviously, it's a small study and know who was power properly for this, but only one out of the 17. 135 00:15:25,250 --> 00:15:35,440 So six percent in the long term acidic drain group compared to 11 percent in the large volume, paracentesis group and developed peritonitis. 136 00:15:35,440 --> 00:15:41,100 And just to say also with the with the diagnosis of peritonitis, they're pragmatic about that, 137 00:15:41,100 --> 00:15:48,230 as we would be in real life, i.e. they they weren't routinely culturing the acidic fluid they were literally doing. 138 00:15:48,230 --> 00:15:52,630 That's only if they were symptomatic with pain, fever, decompensation. 139 00:15:52,630 --> 00:15:59,830 Westing renal failure, and then they did a tap and were there any other adverse events in either of the groups? 140 00:15:59,830 --> 00:16:02,680 Were there were no serious adverse events in either group. 141 00:16:02,680 --> 00:16:14,200 The main adverse event of having the long term acidic drain was either mild leakage or cellulitis, which was all self limiting. 142 00:16:14,200 --> 00:16:25,540 In seven out of 17 of the participants in that group vs. two of the participants had bleeding or leakage in the large volume, paracentesis group. 143 00:16:25,540 --> 00:16:28,600 And it will come out a little bit more in the qualitative data. 144 00:16:28,600 --> 00:16:34,150 But the cellulitis and leakage if if you're at home, is obviously a bit of a different issue, too. 145 00:16:34,150 --> 00:16:37,900 When youre in hospital and you've got people sort it out. 146 00:16:37,900 --> 00:16:45,190 So it wasn't a massive problem, but it was a complication that was relatively common. 147 00:16:45,190 --> 00:16:50,590 The other thing that they analysed and which was pretty impressive were the cost differences. 148 00:16:50,590 --> 00:16:55,450 And they calculated this based on various aspects. 149 00:16:55,450 --> 00:17:01,390 And they did try include staff costs and care costs. 150 00:17:01,390 --> 00:17:05,680 And they found that the in the long term abdominal drain group, 151 00:17:05,680 --> 00:17:15,910 the costs were much lower of the magnitude of sort of 300 pounds vs. a hundred pounds in the large volume, paracentesis group. 152 00:17:15,910 --> 00:17:27,490 So overall, in this feasibility study, the the long term abdominal drains are associated with fewer drains, few admissions to attendances to hospital, 153 00:17:27,490 --> 00:17:36,550 similar rates of sort of severe complications as in peritonitis and lower health care costs, pretty re driven by fewer attendances to hospital. 154 00:17:36,550 --> 00:17:40,030 So you said at the start about qualitative work that they've also done. 155 00:17:40,030 --> 00:17:46,540 And I guess that's really the crux of the matter here, because these patients on here at the end of their lives, 156 00:17:46,540 --> 00:17:51,310 and it's really about the quality of their lives and the outcomes that matter to them. 157 00:17:51,310 --> 00:17:59,530 Yeah, exactly. So when I realise anecdotally that qualitative work has a bit of a bad rep in some circles and certainly 158 00:17:59,530 --> 00:18:04,480 it's discussed less by clinicians when we're considering the evidence base for an intervention. 159 00:18:04,480 --> 00:18:06,400 I think that's often true. 160 00:18:06,400 --> 00:18:14,890 But I did want to spend a bit of time on this past study to just explore, in my view, how it complements and enriches the overall study findings. 161 00:18:14,890 --> 00:18:20,410 Qualitative studies really have a different aim and emphasis to quantitative work because they're very, 162 00:18:20,410 --> 00:18:24,190 very good for answering particular sorts of questions. 163 00:18:24,190 --> 00:18:32,590 So they're good at understanding some of the behavioural factors around an intervention and the perceptions of the care receivers and caregivers. 164 00:18:32,590 --> 00:18:37,870 And that's especially important in the setting of palliative and palliative intervention. 165 00:18:37,870 --> 00:18:43,390 So the methods of a qualitative study can also be critically appraise, just like a quantitative study. 166 00:18:43,390 --> 00:18:52,800 So I'm going to attempt to do that here. What they specifically aimed to do was contrast the perceptions of the care pathways between 167 00:18:52,800 --> 00:18:58,960 long term ascetic drain at home compared with large volume paracentesis in hospital. 168 00:18:58,960 --> 00:19:07,960 The aim wasn't to find a representative voice, but a range in spectrum of voices, because really it needs to be able to inform future trials. 169 00:19:07,960 --> 00:19:12,730 And the key, the information implementation of future services. 170 00:19:12,730 --> 00:19:17,780 So the authors aim to recruit 20 people to the qualitative arm. 171 00:19:17,780 --> 00:19:22,930 It was only carried out two out of five of the sites where they were recruiting. 172 00:19:22,930 --> 00:19:29,020 And they chose that for practical reason because most of the patients were recruited at those two sites. 173 00:19:29,020 --> 00:19:33,580 So there were twenty seven patients recruited at these sites and 21 were invited to participate. 174 00:19:33,580 --> 00:19:39,250 The six weren't approached as they were dying quite rapidly. 175 00:19:39,250 --> 00:19:43,720 Originally, the authors also aimed to conduct several interviews of peoples to try and 176 00:19:43,720 --> 00:19:48,430 understand how people's perceptions of the intervention changed across time. 177 00:19:48,430 --> 00:19:56,800 But unfortunately, they were unable to do to sort of put in this longitudinal element, mostly because people died. 178 00:19:56,800 --> 00:20:07,030 The full interview soon. In the end, they did a single qualitative interview lasting about 30 minutes over the telephone in 14 patients. 179 00:20:07,030 --> 00:20:13,720 Six in the long term acidic drain and eight in the large volume, paracentesis arm. 180 00:20:13,720 --> 00:20:18,910 And in addition, a qualitative test telephone interview lasting about 44 minutes was conducted. 181 00:20:18,910 --> 00:20:26,680 Eight nurses. So it sounds like they they had a lot of problems with with with their method or that 182 00:20:26,680 --> 00:20:31,810 they sort of planned method for the qualitative elements of this of this study. 183 00:20:31,810 --> 00:20:42,100 Do you think that the methods as has actually performed, as opposed to what they originally intended onto the questions that that they set? 184 00:20:42,100 --> 00:20:49,900 Yes. If the aim of the qualitative work was to discover the full range inspection of perceptions, 185 00:20:49,900 --> 00:20:56,500 this study might fall short because the recruitment was opportunity to date rather than purposeful. 186 00:20:56,500 --> 00:21:01,390 So this means that the views and experiences of those not recruited. 187 00:21:01,390 --> 00:21:11,560 So, for example, those who were dying rapidly, who weren't invited to participate or indeed those that were invited to participate, 188 00:21:11,560 --> 00:21:15,550 said yes, but then died before they were able to participate. 189 00:21:15,550 --> 00:21:23,800 And also the views of those at the sites that were away from the central sites were less recruitment was happening. 190 00:21:23,800 --> 00:21:26,980 They weren't approached for recruitment either. 191 00:21:26,980 --> 00:21:35,590 So we're missing some of the voices there that might have had quite different experiences in a peripheral site away from 192 00:21:35,590 --> 00:21:42,310 the centre with different services or people that are dying much more rapidly and more aggressive cause of disease. 193 00:21:42,310 --> 00:21:47,890 They might have quite different opinions to the people whose data was actually collected in the end. 194 00:21:47,890 --> 00:21:51,600 And I think it is important to think about that. Remember that. 195 00:21:51,600 --> 00:21:55,590 Yeah. Particularly people who are deteriorating rapidly. 196 00:21:55,590 --> 00:21:59,800 May. Yes, exactly. See the benefits of a long term drain. 197 00:21:59,800 --> 00:22:08,560 But I guess because this is a feasibility study, they they've set out to do something and found that it wasn't practicable in a bigger trial. 198 00:22:08,560 --> 00:22:13,960 They can probably account for this now because they know some of the barriers that they're going to face. 199 00:22:13,960 --> 00:22:19,930 They could employ a purposeful recruitment strategy to ensure that some of these voices are heard. 200 00:22:19,930 --> 00:22:26,770 OK. So how how did the interviewers carry out these interviews to achieve this study aims? 201 00:22:26,770 --> 00:22:32,410 So the aim was to sort of contrast and explore the perceptions of the care pathways. 202 00:22:32,410 --> 00:22:37,870 And to do this, the interview is used a schedule and a topic guide to prompt the steering of the questioning. 203 00:22:37,870 --> 00:22:43,540 So they don't say this explicitly in the text, but I think it's a form of semi structured interviewing. 204 00:22:43,540 --> 00:22:54,660 So that enables the topics that the interviewers and the researchers think are important to be coverage. 205 00:22:54,660 --> 00:22:59,470 And it also allows in-depth exploration of topics or new topics that might come up 206 00:22:59,470 --> 00:23:05,890 during the course of the interview that the researchers didn't know about a primary. 207 00:23:05,890 --> 00:23:12,860 And they used to sort of make this interview topic schedule. 208 00:23:12,860 --> 00:23:17,590 They they based it on something called the Dixon Woods theoretical model of health care access. 209 00:23:17,590 --> 00:23:25,270 And basically, this theory is just saying the stages of the journey as you go through health, as you access health care. 210 00:23:25,270 --> 00:23:34,060 So, A, recognising you need to seek care. I've got societies I need it drained to identifying the right service to do that. 211 00:23:34,060 --> 00:23:44,270 Three, getting there for the permeability of the surface, i.e., how easy or difficult is it to use and find the adjudication by professionals? 212 00:23:44,270 --> 00:23:52,180 So I go to my GP and say I need to drain my GP says no, you don't sort of thing those kind of barriers. 213 00:23:52,180 --> 00:23:57,110 So it tried to explore all of those arms of access and care. 214 00:23:57,110 --> 00:23:59,470 And so I think that's that was reasonable. 215 00:23:59,470 --> 00:24:07,180 And I think they could have considered other ways of developing the scheduled topic guide because they didn't involve stakeholders, 216 00:24:07,180 --> 00:24:14,080 i.e., the patient's caregivers and nurses in its iterative development. 217 00:24:14,080 --> 00:24:19,390 But it was a practical study, and I think they can use the results from the quality for analysis of this study 218 00:24:19,390 --> 00:24:23,170 to inform further qualitative work and update their topic guide and things. 219 00:24:23,170 --> 00:24:29,200 And I think overall, you know, the topics they were interested in were covered. 220 00:24:29,200 --> 00:24:34,900 So what were the key outcomes from the interviews? 221 00:24:34,900 --> 00:24:41,020 Overall, they found that the long term sediq drain was acceptable to patients that received it, 222 00:24:41,020 --> 00:24:46,960 and it reduced or removed many of the negative factors that they attributed and associated 223 00:24:46,960 --> 00:24:53,620 with going to hospital regularly for the long term at large for the paracentesis. 224 00:24:53,620 --> 00:25:00,820 And they felt that it actually transformed the care pathway and transformed the care they received. 225 00:25:00,820 --> 00:25:12,640 So a patient's experience of large volume paracentesis was kind of difficult negotiation, often between speaking to their GP, 226 00:25:12,640 --> 00:25:19,930 ringing the local AMMU or whatever the arrangement was to get them in for a drain and sometimes in different places. 227 00:25:19,930 --> 00:25:24,940 That was. That was easier than in other places. And there's potential for conflict there. 228 00:25:24,940 --> 00:25:33,760 And then it's obviously there are several steps in accessing drainage that can be difficult, i.e., getting their booking, transport, parking, 229 00:25:33,760 --> 00:25:39,340 paying for parking and then getting reassessed by the doctor in the hospital, 230 00:25:39,340 --> 00:25:47,860 waiting and waiting and waiting and waiting and then having the procedure and then waiting. 231 00:25:47,860 --> 00:25:54,550 Whereas they found that with the long term hypothetic drain, it was easier. 232 00:25:54,550 --> 00:26:00,400 It was nicer. They didn't have to do one of those approachable ways, various every time they need to drain. 233 00:26:00,400 --> 00:26:07,720 And the other thing that was added was they liked you know, there was somebody coming in three times a week. 234 00:26:07,720 --> 00:26:13,270 And so that's a point of contact for emotional support and reassurance in case of crisis. 235 00:26:13,270 --> 00:26:18,540 And some of the other things that they might be some of the other symptoms they might be experiencing, 236 00:26:18,540 --> 00:26:22,480 can they've got an irregular advocate who's seeing them every day. 237 00:26:22,480 --> 00:26:24,790 And I think they found that really helpful. 238 00:26:24,790 --> 00:26:33,760 That's really interesting because that's not a I guess, a specific intended outcome of large volume, paracentesis versus long term drain. 239 00:26:33,760 --> 00:26:35,930 But actually, when you phrase it like that, 240 00:26:35,930 --> 00:26:46,110 in developing that relationship with a regular regular caregiver and and having that kind of reassurance and emotional support, 241 00:26:46,110 --> 00:26:55,640 that that person who's sort of sharing the journey with you as part of the I guess, the package of of having a long term drain, 242 00:26:55,640 --> 00:27:00,730 you can see how that could be hugely beneficial for patients at the end of their lives. 243 00:27:00,730 --> 00:27:09,430 Yes, indeed. So so I think can the quality of outcomes of this feasibility study were actually some of the most important? 244 00:27:09,430 --> 00:27:17,750 And it'll be interesting to see going forward what's larger trials of this intervention will find. 245 00:27:17,750 --> 00:27:25,220 So so, Tamzin, based on these results, do you think there's a case for changing your practise, 246 00:27:25,220 --> 00:27:33,260 or do you think that this is really the start of the evidence base needed to change kind of routine clinical care for these patients? 247 00:27:33,260 --> 00:27:41,100 That's a very good question. I think that if a service was available to me locally, 248 00:27:41,100 --> 00:27:48,450 a provision for certain individual patients that I thought might really benefit from this intervention. 249 00:27:48,450 --> 00:27:55,400 And I think it's a really good option. But overall, I think this is the start of an evidence base. 250 00:27:55,400 --> 00:28:01,700 And because and this kind of intervention actually isn't just taking a pill. 251 00:28:01,700 --> 00:28:06,890 It relies on a whole network of services and people. 252 00:28:06,890 --> 00:28:10,580 It's something that can't be done overnight. 253 00:28:10,580 --> 00:28:18,150 Really, it needs buy in from the organisation. And that probably does need more evidence. 254 00:28:18,150 --> 00:28:26,240 Also, there's a sort of another argument about this in that there is really good evidence from a very large, 255 00:28:26,240 --> 00:28:29,380 pretty recent observational study in England. 256 00:28:29,380 --> 00:28:35,870 Good quality observational study that attending planned large volume paracentesis was the factor that was associated with 257 00:28:35,870 --> 00:28:43,670 the lower number of inpatient days and a lower probability of dying after an unplanned mission with end stage liver disease. 258 00:28:43,670 --> 00:28:51,080 Should we actually be concentrating on providing planned large volume, paracentesis more broadly? 259 00:28:51,080 --> 00:28:58,520 Okay, so there's a there's a balance there that maybe there's there's room for improvement in how we deliver large volume paracentesis to these 260 00:28:58,520 --> 00:29:08,690 patients and the kind of reactive model where we're waiting for people to have this symptoms and be flagged up and often be delayed because of, 261 00:29:08,690 --> 00:29:15,350 you know, bear bed issues and space on day case and all of the things that get in the way. 262 00:29:15,350 --> 00:29:18,770 Actually, that model of care is a suboptimal. 263 00:29:18,770 --> 00:29:28,490 And actually, if we can provide really good, large volume, paracentesis care, then that's probably the best comparator in a larger study. 264 00:29:28,490 --> 00:29:37,250 Yeah, potentially. You know, if some of these barriers that patients talked about in the qualitative study could be circumnavigated by a really good, 265 00:29:37,250 --> 00:29:42,020 dedicated, large volume, paracentesis service. Great. 266 00:29:42,020 --> 00:29:45,220 Well, I think this is fantastic food for thought. 267 00:29:45,220 --> 00:29:53,180 And I also think it's a really impressive for the researchers for taking on a topic that's so difficult. 268 00:29:53,180 --> 00:29:59,820 End stage liver disease. Palliative care, these kind of complex interventions. 269 00:29:59,820 --> 00:30:04,760 And I think it's you know, it's really important area to to to deal with. 270 00:30:04,760 --> 00:30:08,270 But it's it's it's really challenging from a research point of view. 271 00:30:08,270 --> 00:30:18,790 So, you know, sort of full credit to them for for taking this out. Absolutely. 272 00:30:18,790 --> 00:30:24,760 So what have you got for me today? It's something totally different terms. 273 00:30:24,760 --> 00:30:34,660 Something. Yeah, a million miles away from excited. We are going back to sort of single cell, single cell transcripts, homing methods. 274 00:30:34,660 --> 00:30:42,520 Back to back to the lab, our favourite. So this is a paper that's from a group based here in Oxford. 275 00:30:42,520 --> 00:30:49,360 The lead authors are David Forkan and Corbitt Agony and son of a CETA and call Patrick. 276 00:30:49,360 --> 00:30:53,560 And they're all based in Allison Simmons lab here in Oxford. 277 00:30:53,560 --> 00:31:02,410 Now, I haven't just picked this work because of its Oxford connexion or because we know some of the authors and they're generally delightful people. 278 00:31:02,410 --> 00:31:06,700 But it's because I think that this really is an astounding piece of work and something 279 00:31:06,700 --> 00:31:12,910 that's gonna be a really important and powerful resource for researchers for years to come. 280 00:31:12,910 --> 00:31:15,100 This group, Professor Simmons, his group, 281 00:31:15,100 --> 00:31:24,370 have been real pioneers in the use of single cell RNA sequencing to understand intestinal cell types and their role in disease. 282 00:31:24,370 --> 00:31:31,960 And in previous papers published in both Nature and Cell, they've described novel cell types, both in the colon, 283 00:31:31,960 --> 00:31:40,240 including a subtype of epithelial cell, the best for reptilian cell, and identifying different subtypes or fibroblasts. 284 00:31:40,240 --> 00:31:45,640 And they've explored their differential roles in the context of inflammatory bowel disease. 285 00:31:45,640 --> 00:31:53,800 Now, this work, which is sort of under the broad umbrella of the Human Cell Atlas project, is taking a very different perspective, 286 00:31:53,800 --> 00:31:59,740 which is looking at the development of the human foetal intestine over time and applying some 287 00:31:59,740 --> 00:32:05,980 of those same intestinal single cell sequencing approaches that they've used previously. 288 00:32:05,980 --> 00:32:12,300 And then combining them with a very cool novel technique called spatial transcripts mix call. 289 00:32:12,300 --> 00:32:17,290 This sounds like a massive piece of work. What is spatial transcriptase mix? 290 00:32:17,290 --> 00:32:20,650 I've not heard of that one before. An extremely good question. 291 00:32:20,650 --> 00:32:27,880 And I'll I'll talk I'll talk a bit about the detail of of both of the methods that they've used to. 292 00:32:27,880 --> 00:32:33,730 They've used to characterise the development of these cell types within the human gut. 293 00:32:33,730 --> 00:32:40,480 So what they're trying to do is create this kind of long detuned, not atlas of the developing human gut. 294 00:32:40,480 --> 00:32:44,680 So they're looking at sort of several different dimensions, a first time. 295 00:32:44,680 --> 00:32:55,300 So weeks post conception, looking at the different cell types that are there, but also looking at where they are range to both along the gut. 296 00:32:55,300 --> 00:33:02,440 So for Gartin hind gut or small intestine, large intestine, but also where they are in the gut. 297 00:33:02,440 --> 00:33:10,120 Are they in the epithelium, the lamen appropriate or in deeper and deeper layers, to kind of answer your question? 298 00:33:10,120 --> 00:33:14,200 The scale and technical complexity of this work is is pretty mind blowing. 299 00:33:14,200 --> 00:33:18,650 So it's worth definitely spending a couple of minutes talking about just the skin, 300 00:33:18,650 --> 00:33:23,300 the scale and technical complexity of this work and the two key methods used. 301 00:33:23,300 --> 00:33:29,020 So we talked last episode a little bit about single cell RNA sequencing. 302 00:33:29,020 --> 00:33:37,750 In this in this study, they've performed this approach on human foetal intestinal tissue from different locations and gestational ages. 303 00:33:37,750 --> 00:33:41,290 They analysed 77 samples in all. 304 00:33:41,290 --> 00:33:46,870 That's a lot. And as someone who's done some single cell RNA sequencing. 305 00:33:46,870 --> 00:33:54,810 And you have to. That's a lot of stuff. That's a scary number of samples. 306 00:33:54,810 --> 00:33:56,920 Quite an expensive number of samples. Yeah. 307 00:33:56,920 --> 00:34:05,830 So we mentioned RNA sequencing in the last episode, which is an unbiased method for looking at all the genes that are being transcribed in a sample. 308 00:34:05,830 --> 00:34:11,950 And we're normally thinking about a sort of a bulk sample or blood sample or a piece of tissue, 309 00:34:11,950 --> 00:34:16,270 and we extract all the RNA from all the cells in that sample. 310 00:34:16,270 --> 00:34:19,090 We process it and then we get an idea of, you know, 311 00:34:19,090 --> 00:34:26,920 maybe comparing health and disease and what what RNA transcripts are up or down regulated in disease. 312 00:34:26,920 --> 00:34:33,010 This is single cell RNA sequencing. And that really just does the procedure in miniature. 313 00:34:33,010 --> 00:34:36,610 And here we're looking at the level of single cells, 314 00:34:36,610 --> 00:34:44,500 which is technically challenging in terms of both how to generate the data and then also how to analyse it and interpret it. 315 00:34:44,500 --> 00:34:52,420 But the real power of it is that it allows us to understand different subsets of cells, different types of cells, 316 00:34:52,420 --> 00:34:57,100 but also different transcriptional states of different cell types, 317 00:34:57,100 --> 00:35:04,690 and how those gene expression profiles change in different conditions, ILIT diseases or locations. 318 00:35:04,690 --> 00:35:09,280 And so in this world, they have they've created this atlas. 319 00:35:09,280 --> 00:35:17,910 Looking at the transcriptional profiles of over seventy five thousand cells over this really important window in development where. 320 00:35:17,910 --> 00:35:23,790 We're really all of the important structures, and so one of the gut develop, 321 00:35:23,790 --> 00:35:32,310 including the development of the crypt of villus access and the colonisation of the guts by different immune cell populations. 322 00:35:32,310 --> 00:35:40,620 And they describe an astounding 101 different cell states, not necessarily all different cell types. 323 00:35:40,620 --> 00:35:42,840 Some of them will be a particular cell type, 324 00:35:42,840 --> 00:35:51,370 but expressing a different sort of pattern and set of of genes because they're they're doing something slightly different in the tissue at that time. 325 00:35:51,370 --> 00:35:57,630 But 101 different cell states, and that includes epithelial cells and fibroblasts, 326 00:35:57,630 --> 00:36:05,430 but also endothelial cells and Perry sites and neural cells involved in in the gut. 327 00:36:05,430 --> 00:36:12,690 Muscular, muscular cells, meesa, thallium. And all of the immune cell populations. 328 00:36:12,690 --> 00:36:16,250 And then if that wasn't enough. If that wasn't enough. 329 00:36:16,250 --> 00:36:23,220 They then go on to use this novel technique that you've asked about called spatial transcripts, OMX. 330 00:36:23,220 --> 00:36:31,230 And this is to look at the localisation of genes expressed within the anatomy of the developing gut. 331 00:36:31,230 --> 00:36:36,540 So what they've done is they've used a very cool technique called called visión, 332 00:36:36,540 --> 00:36:41,670 where you can look at the gene expression within each area of a section of tissue. 333 00:36:41,670 --> 00:36:46,140 So effectively, they've sliced some thin, a thin section of tissue. 334 00:36:46,140 --> 00:36:52,890 And then you can take individual spots within that tissue and you can see what genes are being transcribed in that place. 335 00:36:52,890 --> 00:36:57,570 And then using basically magic, but very clever bioinformatics analysis. 336 00:36:57,570 --> 00:37:06,750 You can take your single cell RNA, see that you've used before to identify all the different cell populations and then integrate it with 337 00:37:06,750 --> 00:37:12,990 your spatial data and say what kind of cells are likely to be a different places in the tissue. 338 00:37:12,990 --> 00:37:16,830 So it really is. It really is truly, truly astounding. 339 00:37:16,830 --> 00:37:23,730 Wow. I just want to say wow, because this is so much work and it's a really cool. 340 00:37:23,730 --> 00:37:32,400 And so huge. It really is. You're right. This is going to be analysed for a year or used for years and years by scientists. 341 00:37:32,400 --> 00:37:35,460 So what did they found using these amazing techniques? 342 00:37:35,460 --> 00:37:42,720 I mean, in truth, I guess it's not really possible to scratch the surface within within a show, within a podcast. 343 00:37:42,720 --> 00:37:47,520 This paper is huge. And I mean, it is ridiculous in a good way. 344 00:37:47,520 --> 00:37:54,630 There is so much there and it's really relevant. Pretty much every cell type and process in the human guts that you can probably imagine 345 00:37:54,630 --> 00:37:59,640 will highlight a few particular cool things that this work sheds some light light on. 346 00:37:59,640 --> 00:38:09,960 First, I think the temporal relax aspect. So having having samples from foetal guts at different weeks post conception shows the development 347 00:38:09,960 --> 00:38:15,810 over time of the intestinal epithelial compartments in a way that's not really been done before. 348 00:38:15,810 --> 00:38:25,000 So it even it really early time points in gestational development even before the development of what we'd recognise is as crypts and Vili's. 349 00:38:25,000 --> 00:38:32,250 So the crit develops access. You can see differences in gene expression in the small and large intestine epithelial cells. 350 00:38:32,250 --> 00:38:37,290 So they're even even way before we've even got a villus in sight. 351 00:38:37,290 --> 00:38:42,090 The small and large intestine are different in terms of their gene expression. 352 00:38:42,090 --> 00:38:48,990 So, for instance, the small intestine expresses a molecule called CCL 25, 353 00:38:48,990 --> 00:38:57,600 which is the ligand for a chemokine receptor called CCI nine, which is involved in immune cell homing to the developing gut. 354 00:38:57,600 --> 00:39:02,970 We can see the developments have some really interesting cell types later on in gestation. 355 00:39:02,970 --> 00:39:06,630 So want one that I've been thinking about recently are intra endocrine cells. 356 00:39:06,630 --> 00:39:13,890 So these are the sensory and secretory cells that you find in the epithelium in both the small and large Vall. 357 00:39:13,890 --> 00:39:20,190 And they they sense luminal contents and then responds by releasing gut hormones, 358 00:39:20,190 --> 00:39:27,330 which we are increasingly recognising have have a really important role in metabolic responses to nutrition. 359 00:39:27,330 --> 00:39:36,870 And we can also start to infer potential interactions between the developing enteric nervous system and the secretary cells. 360 00:39:36,870 --> 00:39:46,230 And I think it shows this this really early interaction between those kind of neuro and neural and hormonal systems in the control of gut function. 361 00:39:46,230 --> 00:39:52,050 The second thing this this this paper talks about in a bit of depth is the development of that cryptid villus structure, 362 00:39:52,050 --> 00:40:00,050 which they look at one of the subsets of these Mease and Kime or cells, the the s to fibroblast that they've described before. 363 00:40:00,050 --> 00:40:05,460 And they show that they have a role in both supporting and maintaining the epithelium creped. 364 00:40:05,460 --> 00:40:11,880 And this work particularly shows that those those same cells are associated with the development of villus structures. 365 00:40:11,880 --> 00:40:17,360 Right. Right at the start of the Krypto Villus actually axis developments and that they differ. 366 00:40:17,360 --> 00:40:20,600 Gain between the small and large intestine. 367 00:40:20,600 --> 00:40:27,770 Again, suggesting that these cells are involved in this distinct structure, distinct structures of the smaller large intestine. 368 00:40:27,770 --> 00:40:34,060 And then it goes on and then just, you know, briefly discusses the development of gut associated lymphoid tissue, 369 00:40:34,060 --> 00:40:40,670 the colonisation of immune cell populations and and the importance of the the stroma around. 370 00:40:40,670 --> 00:40:46,220 Gutt associated lymphoid tissues to the fibroblasts and how they help with its development. 371 00:40:46,220 --> 00:40:52,050 So, you know, not much not covering anything. Shall I? 372 00:40:52,050 --> 00:40:55,370 And then, you know, and then just as the sort of the cherry on the cake, 373 00:40:55,370 --> 00:41:04,610 the group used this data to unpick the potential cellular basis for a variety of congenital intestinal disorders. 374 00:41:04,610 --> 00:41:09,020 So trying to work out which cells might be involved in those disorders. 375 00:41:09,020 --> 00:41:15,170 So such as Hirsch Broom's intestinal mount mal rotation and on Fallas SEAL. 376 00:41:15,170 --> 00:41:20,510 And I think this last bit really shows the power of this work because I think this 377 00:41:20,510 --> 00:41:27,380 paper's real impact is not in necessarily the findings and the conclusions of the paper, 378 00:41:27,380 --> 00:41:34,850 but in its in its role as just really an unparalleled resource to ask specific questions about gut 379 00:41:34,850 --> 00:41:41,270 development related to particular genes or cell types or processes that you're interested in. 380 00:41:41,270 --> 00:41:49,340 And the great thing is that you don't have to be a hard core coder with it, with a deep love of art or python to go and have a look for yourself, 381 00:41:49,340 --> 00:41:58,370 because the group have put together a really nice graphical user interface, which you can access on the Web and you can look at the gene expression. 382 00:41:58,370 --> 00:42:05,660 And so the single cell, but also the spatial transcriptase mix and look at gene regulatory networks and 383 00:42:05,660 --> 00:42:10,910 receptor ligands interactions for whatever your your chosen gene of choice is. 384 00:42:10,910 --> 00:42:14,630 And we'll share share the link to that in the show notes. 385 00:42:14,630 --> 00:42:18,920 Amazing. Thank you. That sounds like a really impressive paper. 386 00:42:18,920 --> 00:42:23,810 You also mentioned Human Cell Atlas. Is this integrated within that? 387 00:42:23,810 --> 00:42:28,040 So I think it's part of this human cell atlas. Yes, Altium. 388 00:42:28,040 --> 00:42:33,140 So this is a sort of an international an international consortium of different 389 00:42:33,140 --> 00:42:39,470 funders and research groups who are supporting the use of single cell sequencing 390 00:42:39,470 --> 00:42:45,650 approaches in health and in disease for the whole of the human body and the sort 391 00:42:45,650 --> 00:42:52,070 of the broad aims to make an atlas of the human body within health and disease. 392 00:42:52,070 --> 00:42:57,410 I think it's probably going to be more like, you know, hundreds of hundreds of atlas's more more like a well, 393 00:42:57,410 --> 00:43:01,700 like a geography map room than it will be a single atlas. 394 00:43:01,700 --> 00:43:05,410 I think this makes a fantastic contribution to that. 395 00:43:05,410 --> 00:43:15,280 Yeah. Amazing. Thank you very much, Fits. That was a brilliant paper. 396 00:43:15,280 --> 00:43:22,440 So now we'll move on to our five in five section and we'll we'll try and invite trouble. 397 00:43:22,440 --> 00:43:29,050 We are definitely not going to manager in five. I've just had a leg papers, and I think we're both going to go off on one a bale manager. 398 00:43:29,050 --> 00:43:32,940 I don't know about you, Tamsin, but there's just so many interesting things everywhere. I know. 399 00:43:32,940 --> 00:43:38,080 I know. I've really, really struggled. I came up with about. We could have done about 20 papers. 400 00:43:38,080 --> 00:43:44,410 Yeah, I guess we know so. And I think this probably tells us we should do the podcast more often better. 401 00:43:44,410 --> 00:43:53,020 So to start with, I've got a good one which actually kind of riffs off the last paper because whereas talking about entero endocrine cells. 402 00:43:53,020 --> 00:43:57,610 So this is the results of a trial in the New England Journal of Medicine 403 00:43:57,610 --> 00:44:03,460 entitled Once Weekly Semigloss Glue Tined in Adults with Overweight or Obesity. 404 00:44:03,460 --> 00:44:10,990 This is, I think, a really exciting trial of a pharmacological intervention in obesity that seems to work really well. 405 00:44:10,990 --> 00:44:18,520 So obesity and its associated complications of metabolic syndrome and diabetes is really one 406 00:44:18,520 --> 00:44:24,080 of the great global health challenges of our time and non pharmacological intervention. 407 00:44:24,080 --> 00:44:35,110 Alton's of diet and exercise are broadly ineffective, and the current armamentarium of of drug interventions is also pretty limited, 408 00:44:35,110 --> 00:44:40,090 both in terms of its efficacy and side effect profiles. 409 00:44:40,090 --> 00:44:44,860 And there is a real unmet need for drug treatments for those with obesity. 410 00:44:44,860 --> 00:44:54,370 Smugly side is a glucagon like receptor one or JLP one analogue, which is licenced for treatment of Type two diabetes. 411 00:44:54,370 --> 00:45:00,760 And previous trials have noted that individuals with diabetes who are given this drug often lost weight. 412 00:45:00,760 --> 00:45:08,560 Now JLP one is one of these peptide hormones released from entero endocrine cells in the small intestine after meals. 413 00:45:08,560 --> 00:45:14,980 And it's got a number of functions, including inducing insulin secretion, delaying gastric emptying. 414 00:45:14,980 --> 00:45:21,040 And importantly, it seems to to signal to induce the sensation of SIST satiety. 415 00:45:21,040 --> 00:45:32,710 So this is a multicenter international phase three trial of nearly 2000 patients, either with obesity or who are overweight with complications. 416 00:45:32,710 --> 00:45:41,200 And importantly, none of them had diabetes and they were randomised two to one to receive either weekly a glue tide or placebo. 417 00:45:41,200 --> 00:45:48,070 And it was a nice, long trial. They looked over 68 weeks and the primary end point was the percentage of weight loss 418 00:45:48,070 --> 00:45:52,390 and particularly the proportion achieving greater than five percent weight loss. 419 00:45:52,390 --> 00:46:00,370 That's been shown in previous trials and observational data sets to be associated with improved cardiovascular outcomes in this trial. 420 00:46:00,370 --> 00:46:10,330 The average age was around 46. The average weight of participants was about 105, five kilos with a BMI of 38. 421 00:46:10,330 --> 00:46:17,440 So on the intention to treat analysis, individuals getting semigloss height lost fourteen point nine percent of their 422 00:46:17,440 --> 00:46:23,230 body weight compared to a weight loss of just two percent in the placebo arm. 423 00:46:23,230 --> 00:46:31,090 So importantly, 86 percent of those taking Samma glue tide lost five percent body weight or more. 424 00:46:31,090 --> 00:46:36,130 But really amazingly, 51 percent lost fifteen percent body weight. 425 00:46:36,130 --> 00:46:40,120 So that's that's really enormous changes in in body weight. 426 00:46:40,120 --> 00:46:46,450 And. And they showed showed that that's associated with a number of other physical and biochemical improvements. 427 00:46:46,450 --> 00:46:56,130 So rate reduction in visceral fat mass and then consequent improvements in blood pressure, HBK one, see lipids and so on. 428 00:46:56,130 --> 00:46:59,110 All improved and also people felt better. 429 00:46:59,110 --> 00:47:08,980 So those global improvements in quality of life indices similarly tied, as has been shown in previous studies, is associated with some side effects. 430 00:47:08,980 --> 00:47:15,280 The most common are gallstone disease and pancreatitis, probably secondary to the same gallstones. 431 00:47:15,280 --> 00:47:24,730 And we see that both with other JLP one analogues, but also with individuals with profound weight loss from any from any method. 432 00:47:24,730 --> 00:47:29,380 So overall, seven glew tide is more efficacious than weight loss. 433 00:47:29,380 --> 00:47:36,340 That's been seen with other anti obesity therapies, and it really has great efficacy at generating that five percent weight loss, 434 00:47:36,340 --> 00:47:40,570 which is the widely used criterion for successful treatments. 435 00:47:40,570 --> 00:47:44,770 So SOUNDS was about 10 minutes just on one paper, but it's pretty breakthrough. 436 00:47:44,770 --> 00:47:48,610 That's actually that's a pretty important study. It's mine now. 437 00:47:48,610 --> 00:47:58,270 Okay. Right. What if what have you got for. For me, Tamzin, first paper is a success story for primary biliary cholangitis. 438 00:47:58,270 --> 00:48:02,620 Last week I presented a negative trial. This week, it's a positive trial. 439 00:48:02,620 --> 00:48:13,790 So this was Thich Hippocrates for each tribe raising Colon Geography's and which was a double blind randomised placebo controlled trial published in. 440 00:48:13,790 --> 00:48:19,730 Gastroenterology in the March 20 21 print edition, pruritus, as we know, is often, 441 00:48:19,730 --> 00:48:25,890 quite often a really very difficult problem and an intractable problem, often in allostatic liver disease. 442 00:48:25,890 --> 00:48:34,130 And there are various drugs recommended by current guidelines, say co-star Mean Fromson Naltrexone centrally. 443 00:48:34,130 --> 00:48:39,960 But these often have limited efficacy, and with some they have limiting side effects. 444 00:48:39,960 --> 00:48:46,310 Benza fib rate plus ursu oxy coated passage has been shown previously to be useful to 445 00:48:46,310 --> 00:48:51,530 initiate complete biochemical response in some PBS patients that are resistant to us alone. 446 00:48:51,530 --> 00:48:59,090 And they noticed that as well as the bike health improvement in these studies, which also improved in the groups receiving better hip rage. 447 00:48:59,090 --> 00:49:04,940 But it hasn't been assessed for the treatment of H in the wider spectrum of Callisto's eclipses, including PCV, 448 00:49:04,940 --> 00:49:09,740 also encompassing PSC and secondary SKERRIES and cholangitis, 449 00:49:09,740 --> 00:49:18,440 and also in a wider group of patients who maybe do respond by chemically to orthodox killik acid alone. 450 00:49:18,440 --> 00:49:27,950 So this trial randomised adults with PGC, PSC and SASE with moderate to severe itch to benefit BRAIT or placebo and the 451 00:49:27,950 --> 00:49:33,050 quantified moderate or severe itch by a visual analogue scale of zero to 10. 452 00:49:33,050 --> 00:49:42,020 So any antipathetic drugs that they were on except for Calista are mean or topical agents like menthol creams and things. 453 00:49:42,020 --> 00:49:47,360 And so we continued. But other ones were stopped. So rifampicin, naloxone search. 454 00:49:47,360 --> 00:49:55,730 The primary endpoint was a 50 percent or more reduction in the H intensity on the vast school day 21. 455 00:49:55,730 --> 00:50:04,140 This study, like the other study that I reported recently in the last podcast about PPC and it was difficult to recruit to. 456 00:50:04,140 --> 00:50:08,710 So they recruited seventy four participants in total. 457 00:50:08,710 --> 00:50:14,250 So 38 were randomised to Benza for breach and 36 to placebo. 458 00:50:14,250 --> 00:50:18,920 And most of them were either PPC or PSC patients. 459 00:50:18,920 --> 00:50:26,700 Only two of them had secondary sclerosing cholangitis. The median vascular in each group at baseline was seven for each and in each group, 460 00:50:26,700 --> 00:50:34,700 80 percent of the participants were also taking ESA jokes Kotick acid and four percent in each were taking care storming. 461 00:50:34,700 --> 00:50:36,800 As I said, slow recruitment. 462 00:50:36,800 --> 00:50:45,350 They planned to recruit over one year, but they ended up stopping the trial at three years, even though they hadn't met their recruitment target. 463 00:50:45,350 --> 00:50:52,010 But they did meet their pre calculated power because they had a lower dropout rate than they expected primary outcome, 464 00:50:52,010 --> 00:50:57,530 which was the 50 percent reduction in the visual alino score at 21 each. 465 00:50:57,530 --> 00:51:04,790 Forty five percent of the benefit rate group reached that primary outcome versus 11 percent of the placebo group. 466 00:51:04,790 --> 00:51:12,890 So that translates into a median visual annual score in the beneficiary group of seven day zero compared to four a day. 467 00:51:12,890 --> 00:51:21,980 Twenty one. There were no serious adverse events seren creating an increased by three percent from baseline and with benefit bright treatment. 468 00:51:21,980 --> 00:51:29,000 The median change of craton didn't actually differ between two groups. So though this was a short trial, only three weeks of therapy. 469 00:51:29,000 --> 00:51:35,270 This is a good news story for paratus treatment and should really inform practise going forward. 470 00:51:35,270 --> 00:51:42,860 And we'd need some longitudinal data on efficacy and safety because it was only a three week trial. 471 00:51:42,860 --> 00:51:50,050 That's fantastic news. And I'm with 45 percent achieving the primary outcome. 472 00:51:50,050 --> 00:51:53,750 I mean, that's sort of number needed to treat of two. 473 00:51:53,750 --> 00:51:58,700 That's massive given how challenging the symptom is in the clinic. 474 00:51:58,700 --> 00:52:03,110 While I totally agree with you that the longer term data is always needed. 475 00:52:03,110 --> 00:52:10,940 You know, this is a class of drugs that we've been prescribing for, well, decades and have got a great deal of long term safety data on it. 476 00:52:10,940 --> 00:52:17,950 So, you know, it's it's one of the you know, the real benefits of sort of repurposing these drugs or extending the licence for these drugs is there. 477 00:52:17,950 --> 00:52:23,600 You know, we've already got quite a lot of experience in using them. 478 00:52:23,600 --> 00:52:27,200 Yeah. That's fantastic. That's for sure. So if you got another one for me. 479 00:52:27,200 --> 00:52:34,010 Yes. I've got something different for you. Everyone's favourite topic, pharmacokinetics. 480 00:52:34,010 --> 00:52:39,830 Just what you're always after full on on a podcast. But I think this is relevant and I think this is important. 481 00:52:39,830 --> 00:52:42,050 It's going slightly niche. 482 00:52:42,050 --> 00:52:52,160 So this is this was in a peaty recently, a few weeks ago, flagged up by by a friend on Twitter, of course, where I love everything nice. 483 00:52:52,160 --> 00:52:57,950 And the title of this is Maternal Thyer Pureeing Metabolism during pregnancy in 484 00:52:57,950 --> 00:53:03,920 IBD and clearance of thigh appearing metabolites and outcomes in exposed neonates. 485 00:53:03,920 --> 00:53:09,530 This is from a group in Australia, the Piccolos Study Group. 486 00:53:09,530 --> 00:53:13,720 Pregnant and breastfeeding women often get a pretty poor deal when it comes to. 487 00:53:13,720 --> 00:53:17,230 Clinical trials, particularly clinical trials of therapeutics, 488 00:53:17,230 --> 00:53:22,840 and I think they're the current example that people are talking about our our kuvin vaccines 489 00:53:22,840 --> 00:53:26,620 and the fact that they were excluded from all of the trials and now everyone's going, 490 00:53:26,620 --> 00:53:33,520 well, oh, we don't have any data. And it's it's yes, ordinarily frustrating for, you know, 491 00:53:33,520 --> 00:53:40,720 50 percent of the population who can potentially become pregnant to be excluded from from these trials. 492 00:53:40,720 --> 00:53:43,240 It's very frustrating in IBD. 493 00:53:43,240 --> 00:53:52,570 Pregnancy is a worrying time for women affected because of considerable concerns and justifiable concerns about drug risks, 494 00:53:52,570 --> 00:54:00,730 as well as the dangers of active disease. And, you know, our general approach is that the importance is to maintain disease control, 495 00:54:00,730 --> 00:54:09,280 as that seems to be the greatest risk to pregnancy outcomes, as well as to avoid obvious sort of known two antigens like like methotrexate. 496 00:54:09,280 --> 00:54:19,030 However, there are real questions that remain about some of the agents that we use regularly, particularly about their pharmacokinetics in pregnancy, 497 00:54:19,030 --> 00:54:26,470 as well as the transfer of those agents to the newborn and whether that bit beyond the sort of the teratogenic things that we worry about, 498 00:54:26,470 --> 00:54:32,320 concerns about immunosuppression and potential vaccine efficacy in the newborn. 499 00:54:32,320 --> 00:54:40,150 So this this study group, the picolo group which stands for pregnancy and Crohn's and colitis, observations, levels and outcomes, 500 00:54:40,150 --> 00:54:46,570 have been looking at these factors with Thyer periods in a cohort of patients 501 00:54:46,570 --> 00:54:52,360 in Australia THOI appearing so captive Puritan and the Prodrug ASIO Pareene 502 00:54:52,360 --> 00:54:56,680 are generally considered safe in pregnancy and they are commonly used maintenance 503 00:54:56,680 --> 00:55:04,000 therapies in IBD either prescribed alone or alongside anti TMF therapy. 504 00:55:04,000 --> 00:55:13,330 Thyer periods are metabolised in the liver into the therapeutically active molecule, which is Thyer body nucleotides, or 60 GM. 505 00:55:13,330 --> 00:55:21,190 The adequate levels of which are associated with disease control and excessive levels are associated with myelosuppression. 506 00:55:21,190 --> 00:55:31,440 However, on that sort of metabolic pathway, you can get sort of hyper methylation or shunting of the of MoCap Superior metabolites, 507 00:55:31,440 --> 00:55:40,960 and that can lead to the accumulation of six mith AAMA caps a period or six MMP, which at high levels is associated with hepatic toxicity. 508 00:55:40,960 --> 00:55:48,760 Now both of these metabolites can be detected in serum masses and on the basis of which we dose titrate. 509 00:55:48,760 --> 00:55:58,420 However, it's unclear how pregnancy affects those metabolic pathways and therefore what how those levels change in pregnancy. 510 00:55:58,420 --> 00:56:06,580 There have been some previous studies that have suggested that it's six TGA levels may may drop during pregnancy and 511 00:56:06,580 --> 00:56:15,070 there have been previous associations with severe neonatal anaemia at or raised liver enzymes with Thyer periods. 512 00:56:15,070 --> 00:56:20,080 So in this cohort of 40 or pregnant women, the levels were measured before, 513 00:56:20,080 --> 00:56:25,690 during and after pregnancy and where possible levels were also taken from the newborn, 514 00:56:25,690 --> 00:56:30,880 both at the time of delivery from cord blood, but also six weeks postpartum, 515 00:56:30,880 --> 00:56:36,340 which is sort of an important time because that's when the first round of vaccinations are given. 516 00:56:36,340 --> 00:56:44,560 So the first finding of note is that this study has confirmed that six TGA levels fall during pregnancy 517 00:56:44,560 --> 00:56:50,140 and they seem to be lowest in the second trimester compared to either pre or post pregnancy levels. 518 00:56:50,140 --> 00:56:58,390 And the differences were pretty marks. So the median level in this cohort in the second trimester was was one hundred and seventy nine, 519 00:56:58,390 --> 00:57:06,370 which is well below the therapeutic range compared to a median of three to three post-partum. 520 00:57:06,370 --> 00:57:14,320 In contrast, the levels of six MMP that sort of the toxic metabolites generated by shunting 521 00:57:14,320 --> 00:57:18,910 increased during pregnancy and they had the highest in the second trimester, 522 00:57:18,910 --> 00:57:27,610 suggesting that that drop a six TGA levels, while it might be partly due to increased volume of distribution or other effects, 523 00:57:27,610 --> 00:57:32,980 is partly due to alterations in shunting during pregnancy. 524 00:57:32,980 --> 00:57:37,810 From a clinical point of view, the reassuring part was that in this in this cohort, 525 00:57:37,810 --> 00:57:45,340 the reduced levels of six TGA in the second trimester didn't seem to be associated with an increased risk of flare. 526 00:57:45,340 --> 00:57:52,030 Now, the second part of this, which I think is really important when we're sort of thinking about sort of counselling, 527 00:57:52,030 --> 00:57:59,170 counselling patients, is what the what they've done when looking at cord blood and blood tests in the near NAIT. 528 00:57:59,170 --> 00:58:07,060 So 60 Jaén was detected in cord blood at birth, generally at considerably lower levels than in the maternal circulation, 529 00:58:07,060 --> 00:58:13,690 although the two did correlate as as you would expect. Now, reassuringly, both 60 gen and six. 530 00:58:13,690 --> 00:58:19,460 We were undetectable in all of the infants tested six weeks postpartum, 531 00:58:19,460 --> 00:58:24,410 so the these metabolites are cleared relatively quickly after delivery because 532 00:58:24,410 --> 00:58:29,730 of the previous study that had flagged up this risk of postpartum anaemia. 533 00:58:29,730 --> 00:58:41,600 They look specifically at haematological and biochemical changes in the neonatal and they didn't see any cases of severe postpartum anaemia, 534 00:58:41,600 --> 00:58:50,120 which was reassuring. However, 80 percent of the children had some some either biochemical or haematological abnormality, 535 00:58:50,120 --> 00:58:57,680 either with mildly elevated liver biochemistry or thrombosis like Tice's. 536 00:58:57,680 --> 00:59:02,250 And both of those seemed to result resolve over the next few months. 537 00:59:02,250 --> 00:59:06,590 Now, it's important to recognise that this is not a study that has a controller. 538 00:59:06,590 --> 00:59:14,300 There weren't individuals who didn't have IBD or who didn't have the Iberians or weren't receiving type hearings as a comparative. 539 00:59:14,300 --> 00:59:22,450 So it's hard to clearly link these particular biochemical or haematological changes to the drug necessarily. 540 00:59:22,450 --> 00:59:24,860 It may be that, you know, potentially, 541 00:59:24,860 --> 00:59:33,860 particularly the thrombus I ptosis maybe due to some subclinical inflammation of the underlying inflammatory bowel disease or another factor. 542 00:59:33,860 --> 00:59:34,280 But overall, 543 00:59:34,280 --> 00:59:45,050 I think this is an important study flagging up some issues with alterations in the pharmaco pharmacokinetics of five periods in pregnancy. 544 00:59:45,050 --> 00:59:52,670 And also, I think providing sort of this sort of the clearest evidence of of of what happens in the near late for those. 545 00:59:52,670 --> 00:59:58,070 And it's a great use of real world data to inform us sort of a challenging, 546 00:59:58,070 --> 01:00:03,140 challenging aspect of practise in a historically pretty understudied patient group. 547 01:00:03,140 --> 01:00:10,070 That was very interesting and actually leads to many, many more questions, I think, that we don't really have time to go into right now. 548 01:00:10,070 --> 01:00:16,040 But yes, and kind of also begs the question, do we need to do more of this? 549 01:00:16,040 --> 01:00:21,110 And so my next one moving on is another liver one. 550 01:00:21,110 --> 01:00:28,430 And it's about Willson's disease. And I thought I'd do this paper in support of the recent Rare Diseases Day. 551 01:00:28,430 --> 01:00:33,680 So this was published in Gastroenterology in February 2021. 552 01:00:33,680 --> 01:00:41,090 And it's entitled Direct Measurement of ATP seven V Peptides is highly effective in the diagnosis of Willson's Disease. 553 01:00:41,090 --> 01:00:44,990 So I didn't know much about Wilson's disease. To be honest. 554 01:00:44,990 --> 01:00:53,990 But before I read this paper. But apparently it relies on the combination of clinical and biochemical features for diagnosis. 555 01:00:53,990 --> 01:00:58,790 And so current practise guidelines recommend the use of the Leipzig school. 556 01:00:58,790 --> 01:01:02,200 And basically this combines things like the presence of Kaisa Flash. 557 01:01:02,200 --> 01:01:05,960 It rings some biochemical things like lonesome plasma. 558 01:01:05,960 --> 01:01:12,740 And in the presence or absence of known genetic mutations to adapt to guide the diagnosis. 559 01:01:12,740 --> 01:01:20,720 But what I didn't really appreciate about the diagnosis of Wilson's disease is it's actually can be quite challenging. 560 01:01:20,720 --> 01:01:27,950 So low, Sarena, plasma levels alone aren't enough to diagnose or refute Wilson's disease. 561 01:01:27,950 --> 01:01:36,380 And the gene that is involved in Wilson's disease is the ATP 70 gene sequencing. 562 01:01:36,380 --> 01:01:42,470 It can be helpful and you can find some sort of no mutations should be held for the diagnosis. 563 01:01:42,470 --> 01:01:50,240 But actually, there are lots of single nucleotide polymorphisms and also variants of unknown significance within that gene. 564 01:01:50,240 --> 01:01:53,750 So you don't always get a clear answer. In this study, 565 01:01:53,750 --> 01:02:01,940 the authors set out to measure ATP 70 peptide directly from dried blood spots using a mass spectrometry 566 01:02:01,940 --> 01:02:07,160 technique that's modified cheeze monoclonal antibodies to target the protein of interest. 567 01:02:07,160 --> 01:02:15,170 And this allows very small quantities to be detected. So they establish and will range by testing 150 healthy control samples. 568 01:02:15,170 --> 01:02:25,580 And then they took blood samples from patients with known Willson's disease, diagnosed Wilson to these 216 patients and forty eight obligate carriers. 569 01:02:25,580 --> 01:02:31,940 So these were family members of patients with heterozygous variants in the eighty seven Beijing. 570 01:02:31,940 --> 01:02:38,660 So they found that the signature peptide levels in patients and the patients dried blood 571 01:02:38,660 --> 01:02:47,780 spots were below Cut-Off in 90 percent of samples for both 80 p 70 one zero five six, 572 01:02:47,780 --> 01:02:55,400 which contains the most common Willson's disease causing mutation and ATP seven B eight eight seven. 573 01:02:55,400 --> 01:03:03,140 And they used the presence or absence of these to work out how good this test was. 574 01:03:03,140 --> 01:03:09,380 The receiver operating curve analysis generated a really pretty good area under the curve of nought point nine eight. 575 01:03:09,380 --> 01:03:13,040 Using these parameters, the peptide analysis of the. 576 01:03:13,040 --> 01:03:17,350 T.P seventy eight, eight, seven was found to have very high sensitivity. 577 01:03:17,350 --> 01:03:23,260 Ninety one percent and a specificity of ninety eight percent with high and positive and 578 01:03:23,260 --> 01:03:28,220 negative predictive values and an impatience that are a bit more difficult to diagnose. 579 01:03:28,220 --> 01:03:38,410 So with normal cerrillo plasma concentrations, there are only 16 of these in the cohort, but 87 percent of them were deficient in this protein. 580 01:03:38,410 --> 01:03:45,440 So it would have been diagnosed with this test and in patients without clear genetic results. 581 01:03:45,440 --> 01:03:51,310 94 percent were deficient and therefore would have been diagnosed with this test. 582 01:03:51,310 --> 01:03:59,620 So obviously this needs separate validation in other cohorts, but it's pretty exciting because this might represent an off biomarker. 583 01:03:59,620 --> 01:04:05,280 That might be a really helpful development in diagnosing Willson's disease. 584 01:04:05,280 --> 01:04:12,460 And the last paper I wanted to cover published in Lancet Gastro Hepp in the January 21 21 print issue, 585 01:04:12,460 --> 01:04:19,070 and it's entitled Redefining Fatty Delivered These Fatty Liver Disease and International Patient Perspective. 586 01:04:19,070 --> 01:04:27,460 Briefly, this concerns the proposed change in nomenclature of NAFLD so non-alcoholic fatty liver 587 01:04:27,460 --> 01:04:33,320 disease to Mathilde's metabolic dysfunction associated fatty to live liver disease. 588 01:04:33,320 --> 01:04:38,020 And I'm a bit reluctant to admit that I wasn't aware of this proposed change before now, 589 01:04:38,020 --> 01:04:47,960 even though it's been talked about quite a lot in the literature of the lost last six months and the proposed name change from NAFLD to Mathilde's, 590 01:04:47,960 --> 01:04:55,210 the full details can be found in the May 20-20 print issue of gastroenterology and also the July 2020 print issue of the Journal of Hepatology. 591 01:04:55,210 --> 01:04:56,930 You know, put links on the nights, 592 01:04:56,930 --> 01:05:07,120 but basically it was an international experts consensus statement which called for the change of name from Nettle's to Mathilde. 593 01:05:07,120 --> 01:05:09,670 They wanted to do this for several reasons. One, 594 01:05:09,670 --> 01:05:18,580 because they wanted to move away from the NAFLD versus Nashed dichotomy of okay versus bad liver disease 595 01:05:18,580 --> 01:05:25,900 and move towards a grading the liver disease severity on the grade of activity in fibrosis stage. 596 01:05:25,900 --> 01:05:31,240 And also they wanted to move towards diagnostic criteria that have a focus on 597 01:05:31,240 --> 01:05:36,460 positive presence of things rather than the absence of alcohol consumption. 598 01:05:36,460 --> 01:05:44,500 NAFLD is to logically the presence of statuses in over five percent of hepatocytes in the absence of significant, 599 01:05:44,500 --> 01:05:48,190 ongoing or recent alcohol consumption and other men cause of liver disease. 600 01:05:48,190 --> 01:05:50,560 That's the accepted definition now. 601 01:05:50,560 --> 01:06:01,210 But the proposed algorithm for Mathilde's is about icks decisis in an adult and that Seada detected by imaging biomarkers on bludge histology. 602 01:06:01,210 --> 01:06:09,970 And if the individual is overweight or obese, they've got muffled or if they've got type two diabetes, 603 01:06:09,970 --> 01:06:14,920 they've got muffled or if they are lean or normal weight. 604 01:06:14,920 --> 01:06:23,110 But they also have the presence of at least two metabolic risk abnormalities, such as blood pressure, high blood pressure, high triglycerides, etc. 605 01:06:23,110 --> 01:06:31,180 Then they were also diagnosed with Mathilde. There's been quite a lot of discussion since this has been proposed in the literature and the authors, 606 01:06:31,180 --> 01:06:33,820 when they did propose it, acknowledged they need to. 607 01:06:33,820 --> 01:06:41,380 This would need validation and prospective studies to assess its utility in clinical practise, especially with the proposed new diagnostic criteria. 608 01:06:41,380 --> 01:06:48,100 The article and I want to talk about and is actually the patient's perspective on this. 609 01:06:48,100 --> 01:07:00,070 So it outlines the patient groups, representative groups, and are in support of this change of name from NAFLD to Mathilde and for many reasons. 610 01:07:00,070 --> 01:07:07,360 But in particular, they perceive that Mathilde has less stigma attached to it as a term that Nuffield. 611 01:07:07,360 --> 01:07:12,940 So as I wasn't aware of this, I'd really encourage people to have a read of this and some of the other 612 01:07:12,940 --> 01:07:18,100 editorials that have been published on the consequences of this proposed change. 613 01:07:18,100 --> 01:07:24,330 And that's the five and five slash five and 10, we should call it five and fifty five. 614 01:07:24,330 --> 01:07:32,410 And but like it, I think we I think we might be able to manage that and that last year the last articles are, you know, 615 01:07:32,410 --> 01:07:43,880 it's really interesting until pretty I haven't read those and I will I will now go and have a look at some of those. 616 01:07:43,880 --> 01:07:49,550 Excellent. Well, we seem to have got to the end of this was his had been a particularly long episode of our podcast. 617 01:07:49,550 --> 01:07:58,010 I'm looking forward to our next episode because as we've said, it's been it's been a bumper bumper crop of papers in the last few weeks. 618 01:07:58,010 --> 01:08:01,850 And I think we've pretty much got the line up for the next episode sorted. 619 01:08:01,850 --> 01:08:09,410 We'll be talking a lot about Albumen and Turley Pressin in liver disease and in her of renal syndrome. 620 01:08:09,410 --> 01:08:16,510 I'm also going to talk about the battle between Kitto and plant based diets for for weight loss 621 01:08:16,510 --> 01:08:21,770 and and probably something about enteral nutrition in the context of acute severe colitis. 622 01:08:21,770 --> 01:08:29,960 So, yeah, lots to lots. Tune in for next time. So that brings us to the end of this episode of Gut Instinct. 623 01:08:29,960 --> 01:08:35,030 Please let us know what you think and leave us a review or get in touch on Twitter. 624 01:08:35,030 --> 01:08:40,210 Actually, update Dr. Greenmail at Gut Instinct cast. 625 01:08:40,210 --> 01:08:58,627 That's Gene and Lucy.