The Alternative Complement Pathway in IgA Nephropathy: A Podcast for Advanced Practice Providers

00:00:00: You are listening to an

00:00:02: AIDIS

00:00:02: Journal

00:00:03: podcast.

00:00:05: Hi everyone, my name is Anja Rastogi.

00:00:07: I'm a nephrologist and pharmacologist based out of Los Angeles with special interest in rare diseases including IgNephropathy or IGAN.

00:00:17: The topic on the podcast today is that role of the alternative complement pathway in IgNaphropathie for APPs advanced practice providers.

00:00:27: This podcast article is being hosted in advances and therapy, And it's been supported by Novartis Pharmaceutical Corporation.

00:00:36: With that I would like to welcome and introduce my two esteemed APPs Yasin Kadi who was physician assistant and Yelena Magai Who is a nurse practitioner.

00:00:48: Welcome both of you.

00:00:50: Hello, everyone.

00:00:51: My name is Yelena Magai and I'm an nurse practitioner in Lafayette Louisiana at work with the Oschner Health System.

00:00:57: We've been working in nephrology for about the past ten years And I split my time between our chronic kidney disease clinic and vein patient Nephrologist service.

00:01:10: I've

00:01:19: been practicing for almost six years and i'm lucky to practice at a multi-specialty clinic in endocrinology, nephrology and lipidology.I do both inpatient and outpatient practice.

00:01:34: this multi specialty work that I do allows me to take any more comprehensive management in IGAN.

00:01:41: Thank you so much for joining us.

00:01:43: So with that the objectives of today's podcast are to summarize the epidemiology, pathogenesis, pathology and clinical features of IGAN.

00:01:52: To discuss the importance of the alternative pathway in IGAN And finally to review the clinical implications Of Alternative Pathway Overactivation In IGAN.

00:02:03: Now let us talk about its Epidemiology.

00:02:06: It is most common primary GN, glomanophritis worldwide caused by a deposition of immune complexes containing galactose-diviscent IgA one in the kidney and more specifically in the misangium of the kidney.

00:02:20: As of today ,the only way we can diagnose i genephropathy is via kidney biopsy.

00:02:26: The estimated global incidence is about two point five cases per hundred thousand people And it contributes to the global burden of CKD or chronic kidney disease with up to fifty percent of patients progressing through kidney failure within ten-to-twenty years.

00:02:42: Now I'll hand over the scene.

00:02:44: Now that Dr Astogi has given our nice introduction regarding IGAN, i want focus on how this disease presents in real clinical practice.

00:02:54: one of biggest challenges is that the presentation's quite variable.

00:02:59: some patients may only have asymptomatic microscopic hematuria sometimes with low-grade proteinuria found incidentally.

00:03:08: Others present later, with more established chronic kidney disease and at the severe end of the spectrum.

00:03:15: some can present with rapidly progressive lomerular nephritis.

00:03:21: so it's really not a one patterned disease and has broad clinical range.

00:03:26: in adults The most common presentation is asymptomatic hematuria with varying degrees of proteinuria whereas in children and younger patients, gross hematurias often found the time for an upper respiratory infection or gastrointestinal infection.

00:03:42: And this synfergitic pattern's important because it hints at the mucosal immune dysregulation that sits upstream in terms of disease pathophysiology.

00:03:52: Another key point is that hematurria and proteinuria are not specific to IGN.

00:03:56: They can be seen in many kidney pathology.

00:03:59: So while it may raise suspicion, It does not establish diagnosis.

00:04:03: as Dr.

00:04:04: Astogi mentioned biopsy is the gold standard for diagnosis and risk assessment.

00:04:10: Great so you've seen.

00:04:11: I just wanted to highlight that You said Ig nephropathy tends to be asymptomatic or very subtle in majority of patients?

00:04:18: But i think That's something important keep in mind.

00:04:21: So now I would like to invite Yelena, to speak on the clinical features of IgNephropathy.

00:04:27: Thank you Dr Astogi!

00:04:28: As Dr Astogi and Yusin already mentioned presentation for IgNaphthy can be a little bit vague.

00:04:34: so in order to confirm diagnosis we do need kidney biopsy performed On.

00:04:40: Biopsy were specifically looking for predominant or codominant IgA deposits in the glomeruli which are identified using immunofluorescence staining.

00:04:50: These changes are illustrated in Figure One.

00:04:52: In adults, current guidelines recommend a kidney biopsy patients with pertinurea of about half a gram per day.

00:04:58: This is the new change for KDGO-MTG.

00:05:03: In a situation where IgA nephropathy is possible diagnosis and there no contraindications to procedure.

00:05:09: In children ,the threshold is different.

00:05:12: Guidelines recommend considering IgA Nephropathy When hematuria is accompanied by persistent pertinuria.

00:05:19: A protein to creatinine ratio is your point two milligrams per milligram or twenty milligrams per millimole, that lasts for about three weeks.

00:05:28: As long as serum C-III levels are normal and there's no evidence of a lower urinary tract cause or systemic disease.

00:05:35: In those cases biopsies should be used to confirm the diagnosis.

00:05:39: Another important role of kidney biopsy it provides histologic information.

00:05:43: also helps us guide prognosis.

00:05:45: The biopsy findings can be scored using the Oxford MEST-C classification, which feeds into that international IGNephropathy prediction tool.

00:05:55: Those tools help clinicians estimate disease progression risk and guide management decisions.

00:06:01: Despite how important kidney bioppsy is for diagnosis and for risk assessment it may still underutilized in clinical practice.

00:06:09: And there are several reasons.

00:06:11: Some providers may have limited training or familiarity with biopsy indications, or interpretation.

00:06:17: Others maybe concerned about procedural risks or question whether the bioppsy results will meaningfully change management.

00:06:24: and in some cases clinicians may simply feel less comfortable discussing the risks and benefits of a kidney biopysy with patients And that can make decision process even more challenging.

00:06:34: Thank you Marina.

00:06:35: now A question to both of you.

00:06:37: The K-deco guidelines, as you've mentioned has changed the threshold for biopsy.

00:06:42: We normally biopsied about one gram.

00:06:44: so my questions are with a new guideline that came out in September last year have your practices changed?

00:06:52: Absolutely!

00:06:53: Especially if my pre test probability is high For any glomerular disease especially for iJ nephropathy I am much more likely to send the patient for biopsy provided there are no contraindications, especially since I have backing from guidelines now.

00:07:10: Wonderful!

00:07:11: And Yasim?

00:07:11: How about you?

00:07:12: Down here in Orange County we've always been a bit more aggressive in terms of screening early and trying to diagnose earlier.

00:07:19: The demographic in Orange county has both Caucasian and Asian individuals... ...the latter which unfortunately due to socioeconomic or social determinants of health often had limited access care And possibly those patients' clinicians are maybe less inclined to biopsy.

00:07:37: When we get those kind of referrals, We're quite aggressive.

00:07:40: Yes

00:07:41: Thank you Yasin and I will bring up another barrier that would be social-economic.

00:07:45: These very important things.

00:07:47: now Yasin will continue with pathogenesis.

00:07:50: It's best understood through what is commonly known as the multi hit model.

00:07:55: The first hit is increased production of galactose deficient IgA one, and this is an abnormally-glycosylated form of IGA One.

00:08:04: And patients with IGAN often have elevated circulating levels of it.

00:08:10: more importantly...this abnormality appears to be inheritable partly at least....and some unaffected family members can also have elevated levels which tells us that this first hit is important but not sufficient enough.

00:08:27: presentation of the disease.

00:08:30: Second hit, formation of autoantibodies directed against those abnormal glycans.

00:08:37: The third hit is formulation of circulating immune complexes.

00:08:41: These complexes contain galactose deficient IgA-I anti-glycan autoanobodies and sometimes C-III.

00:08:50: The fourth hit Is misangio deposition Of these complexes which leads to downstream activation of inflammatory and proliferative signaling pathways which include the alternative and lectin-compliant pathways, which lead to damage.

00:09:06: And eventually fibrosis.

00:09:08: IGAN is not just a disease of IgA deposition.

00:09:11: it's a multifactorial multi step autoimmune process that involves IgA one production, auto antibody formation, misangial injury.

00:09:21: complement activation.

00:09:25: Great you're seeing and I just want to highlight the alternative complement pathway.

00:09:30: And we'll be doing a much deeper dive later in.

00:09:32: So you've seen.

00:09:33: it will continue with the risk factors for disease progression.

00:09:37: For me, The most important question is not Just who has IGAN but Who's Most likely To progress?

00:09:44: The Important modifiable Factors are protein area and hypertension.

00:09:48: Persistent Protein Area Is the strongest marker of ongoing glomerular injury.

00:09:53: Reducing protein area is associated with better outcomes.

00:09:57: Blood pressure control is equally foundational, other contributors include decreased kidney function or lower EGFR at presentation use of tobacco and obesity.

00:10:08: so progression is not just driven by one's immunology it's also shaped by hemodynamic and what is a hot topic today metabolic stress layered on top of the immune pathology.

00:10:20: The non-modifiable factors are older age diagnosis male sex.

00:10:25: Ethnicity is also a factor, the highest incidence of IGAN as reported in Asia followed by Europe and lowest in Africa.

00:10:34: Asian patients have been found to have poor renal outcomes compared to their Caucasian counterparts.

00:10:40: In a study in the US those with an known race The majority of patients with IGAN were Caucasian eight percent were African American And similar number where Asian.

00:10:52: So all ethnic backgrounds are at risk.

00:10:55: Great,

00:10:56: thank you so much for your scene!

00:10:58: The twenty-twenty five KDEGO guidelines settle all for proteinuria and how has that impacted your practice as well?

00:11:05: And what is

00:11:07: the goal?

00:11:18: a prognostic marker and also marker of disease activity.

00:11:24: We know that lower degree of pernure is associated with better long-term prognosis.

00:11:30: Great, I'm sure you've seen your practice has changed the same way too.

00:11:33: That's

00:11:34: correct

00:11:35: All right.

00:11:35: so now we'll move into treatment management of IG nephropathy based on most current guidelines from KDGOL.

00:11:43: So Elina

00:11:44: Thank You Dr Astogeng.

00:11:46: One of the most important things to understand about iJ nephropathy is that there's currently no cure.

00:11:52: Because of this, the main goal for therapy is really focused on slowing disease progression and preventing kidney failure.

00:11:59: According to the KDGOOD-II-V guidelines one key treatment target is reducing prachneuria.

00:12:05: As we have mentioned earlier We want bring prachnea down to less than zero point five grams per day And if possible even below zero point three grams a day because lower levels of spartanuria are associated with much better prognosis over time.

00:12:20: Another important point is that the treatment landscape for hygiene and ferropathy is evolving very quickly, as in new clinical trials and new therapies become available.

00:12:29: our approach to management continues to change.

00:12:31: Figure three outlines a treatment algorithm then combines recommendations from the KDGOOD-M-O-N-T-W-I-V guidelines along with the new FDA approved therapies.

00:12:43: Any patient that is at risk for disease progression per-risk stratification can begin simultaneous IgA nephropathy specific intervention along with the foundational interventions.

00:12:55: Foundational interventions include optimizing blood pressure and cardiorenal risks, By introducing lifestyle or dietary modifications, starting the patient on RIS blockers like ACE and ARB therapies as guilty to inhibitors.

00:13:13: Or in the Thelon antagonists, IGA specific interventions include reducing formation of immune complexes containing galactose deficient IgA-I And reducing immune complex and complement mediated kidney injury and inflammation.

00:13:29: Those treatments include delayed release butycinide systemic glucocorticoids complement inhibitors, and April targeting agents.

00:13:37: In specific populations we can also utilize mycophenolate hydrochloroquine, tonsillectomy MRA And clinical trial enrollment.

00:13:48: One challenge that we still face in IgA nephropathy is that We don't yet have validated biomarkers That can help us match specific patients with specific treatments.

00:13:57: As more therapies become available this becomes increasingly important.

00:14:01: So identifying reliable biomarkers to guide treatment decisions is really considered a major priority for future research in IgA nephropathy.

00:14:09: Yelena, thank you so much for this presentation.

00:14:11: on the management I want to point out the foundational intervention and the IgA Nehropathy specific intervention.

00:14:19: that's basically the immune drivers of nephron loss.

00:14:22: they both should be started simultaneously And we need to separate those two big buckets.

00:14:26: i think that was one of the highlights from these K-deco guidelines.

00:14:30: Now, let's go over the complement system.

00:14:33: The complement system plays a key role in both innate and adaptive immunity as well as inflammatory responses.

00:14:40: Our body has the complement systems to fight injuries.

00:14:44: It is when these systems are over-activated or inappropriately activated that we have problems.

00:14:51: They're comprised of three pathways The classical pathway, the lectin pathway And alternative pathway.

00:14:58: In IGNephopathy, the deposition of immune complexes containing galactose deficient IgA-I leads to overactivation both in alternative and lactane complement pathways leading to gluminal injury or inflammation.

00:15:14: However, the alternative pathway is a particular importance as it's responsible for upto eighty percent of implement activity.

00:15:22: So let us go through this alternative pathway.

00:15:25: C-three is common to all pathways and it can undergo hydrolysis by a process with what we call tick over.

00:15:32: And this c three which has hydrolyzed now, can bind or interact with factor B .And the factor b is broken down by factor D into BA and BB.

00:15:44: so BA separates but the BB stays attached through the factors c three that's Hydrolyzed ,or even the c three be formed from other pathways.

00:15:54: B, BB is what we call the C-III convertase of the alternative pathway.

00:16:00: An enzyme that converts C-II into C- IIIa and C-iiB.

00:16:05: there are also regulators that will make sure that there's no overactivation.

00:16:10: There is a factor H And it's also a factor HR The factor H related protein That actually works on the factor H. Now as this more c-IIIb informed It attaches to the convertase and now we have C-B, Bb.

00:16:26: This is the c-V convertase And this acts on complement V and it's broken down into CvA and CvB.

00:16:35: Then starts to mac the membrane attack complex that actually puts these poles on foreign microbes and destroys them.

00:16:43: So this is the alternative complement pathway.

00:16:45: as I mentioned in IGNF property It is overactive.

00:16:51: Now What is the evidence of over-activation of the alternative pathway in IgA nephropathy?

00:16:56: I would break down this evidence into three big buckets.

00:17:00: Histological Evidence, then Genetic Evidence and then Serum Evidence.

00:17:05: So let's go with a histological evidence.

00:17:07: The Miss Angel co-deposition of C-III and IgA which more than ninety percent of kidney biopsies correlates to disease severity and progression.

00:17:17: Co-depositions can be seen with any type of complement activation, but here the feature is deposition of properdin.

00:17:26: Properdin stabilizes the C-III convertase of the alternative pathway.

00:17:31: Proprinidine is a unique activator on the alternate pathway and it's found in seventy five to hundred percent of patients.

00:17:38: now factor H It's negative regulator of the alternate pathways And its found in thirty two ninety percent of IGN cases.

00:17:47: Finally, the glomerular deposition of factor H-related protein five a positive regulator of the alternate pathway is associated with progressive disease.

00:17:57: So this what we find on biopsy, the histological evidence.

00:18:01: What is genetic evidence?

00:18:03: Factor H-rated gene deletions confer protection against IgA nephropathy development.

00:18:09: and finally the serum evidence.

00:18:12: high IgA C-III ratio is associated with poor kidney survival in patients, and high serum levels of factor H related protein V has been associated with more severe histological diagnosis.

00:18:25: Now what are the clinical implications for alternative pathway activation in IGNF property?

00:18:31: Yasin will throw light on this topic.

00:18:35: I firmly believe that there's a gap between what we know mechanistically and what we actually do in practice.

00:18:45: We have strong evidence that the alternative complement pathway plays a real role in disease progression, these immune complexes don't just sit in the mesangium they activate complement and that amplifies inflammation and furthers glomerular injury.

00:19:01: but clinically unfortunately we're not measuring any of that And there's no routine way to assess this pathway activity In our patients...we are NOT using it to guide care.

00:19:12: Right now, we don't have any validated diagnostics in terms of urine or serum biomarkers for eye gain.

00:19:18: That's where things need to evolve.

00:19:20: Biomarkers that detect disease earlier help us understand which pathways are active and therefore would predict in some way which treatment will be best for this patient.

00:19:32: This becomes especially relevant in terms the evolving exciting therapeutic landscape and how these emerging treatments are going to be fitting into real-world, real time clinical decision making.

00:19:44: Thank you Asin.

00:19:45: we really do need more biomarkers not just diagnostic but also prognostic and also therapeutic.

00:19:51: in the future will be getting a lot of this information that all These things are being incorporated in trials now.

00:19:58: The landscape of IGN aphropathy is really evolving very rapidly And the guidelines that came out last year in September to some extent, might be a bit outdated already.

00:20:09: It's very rapidly evolving landscape and we have lot of drugs that has gone through the FDA approval either exorbitant or full.

00:20:16: And there are lots of drugs in trials so will expect more.

00:20:21: But let go over those approved.

00:20:23: Let start with the first one Neficon which is delayed release formulation of corticosteroid butanide and its target B cells within the ileum to reduce galactose deficient IgA-I production, which is the autoantigen in IgNephropathy.

00:20:40: The second drug is Cib Penlemap, a blocker of APROM, which has proliferous inducing ligand.

00:20:46: April is a cytokine that belongs to TNF superfamily and it mediates antibody class switching into mature B cells as well as plasma cell survival SIB panel map reduces the production of galactose deficient IgA-I molecule.

00:21:01: So these are immunosuppressive medications, but I would call them immune modulators and more targeted.

00:21:07: SPAR-Centen is a dual endothelin type A and angiotensin two type one receptor antagonist which targets hemodynamic inflammatory and fibrotic processes through simultaneous blockade.

00:21:22: Atrocentin is a selective endothelium type A receptor antagonist with hemodynamic, anti-inflammatory and antifibrative effects through reduction of intradermal pressure, misangial activation ,and porocyte and tripler injury.

00:21:38: And the last one is Iptacopen .

00:21:40: The alternative complement pathway factor B inhibitor which reduces overactivation on the alternate pathways and targets subsequent inflammatory processes.

00:21:49: So these are five drugs that are currently approved by FDA.

00:21:54: Now, we have mentioned the KDO.

00:21:56: practice guidelines came out in September of last year several times and I would strongly urge to recommend everybody who is listening pull up those guidelines and look at them.

00:22:08: They had a significant impact on their diagnostic criteria And also therapeutic goals.

00:22:13: But keep in mind, it does not include all recent progopuvos.

00:22:18: The treatment algorithms will need frequent updates and also communication to the providers that updates have been

00:22:25: done.".

00:22:26: So building on that once we consider like Dr Ostogi says-the dynamic expanding therapeutic landscape I think next question becomes who are actually treating?

00:22:39: And why?

00:22:40: because IgA nephropathy is not a uniform disease.

00:22:43: Like we discussed, it's heterogeneous.

00:22:46: identifying the subset of patients where complement and the alternative pathway that's driving the diseases very important—that's where hopefully biomarkers will come in.

00:22:57: This could come from biopsy-based approach which would come from validated compliment staining patterns or novel noninvasive approach functional complement assays which would allow you to assess this pathway in real time.

00:23:16: Once we do that, We can move from the blunt and tools To targeted therapy And That's how I actually unlocked a value of complement inhibition In my opinion.

00:23:26: So The tool that we currently have is the kidney biopsy But...we cannot proceed with either diagnosis or treatment if were not utilizing the tools.

00:23:37: So, the important point is that we need to encourage more appropriate use of kidney biopsy in clinical practice.

00:23:44: There are several ways where we can help move into that direction.

00:23:47: First off course education and we can achieve this through creating targeted initiatives That can help providers better understand when a kidney biopsies indicated How to interpret histopathology And how those findings actually impact clinical decision making.

00:24:03: Second is to develop clear clinical protocols, especially for providers that are new to practice.

00:24:09: If we have clear evidence-based biopsy protocols for suspected IgNuphropathy it can help standardize our care.

00:24:16: Those protocols can outline things like risk stratification appropriate patient selection and how bioppsy results should be integrated into treatment.

00:24:25: Of course another component is multi-disciplinary collaboration.

00:24:29: When nephrologist, pathologist and advanced practice providers work closely together you can significantly improve confidence in both biopsy decision-making And interpretation of your results which ultimately leads to better patient care.

00:24:43: Finally patients center communication is of course essential.

00:24:46: Providers need to feel comfortable with having clear balanced conversations With patients about the risks and benefits of kidney biopcy as well As any alternatives if we incorporate shared decision-making.

00:24:59: This ensures that these choices align with each of the patient's values, preferences and overall goals.

00:25:23: communication with the pathologist is very important.

00:25:27: So let me ask you, Yelena how often do you actually speak to your pathologist?

00:25:32: Every single time every time we have a preliminary result the pathologists reaches out to the ordering provider which is me whenever I order kidney biopsies.

00:25:42: so that's very helpful with aligning the biopsy findings from the pathologist's point of view to clinical presentation.

00:25:50: Then we can discuss, order specific staining or further testing if needed.

00:25:54: so those conversations have been very important.

00:25:57: You've seen how about you?

00:25:58: Unfortunately the hospital system has a contract with another lab and let us just say things are bit more challenging to even discuss in an ideal world where real life limitations happen.

00:26:14: There might be challenges for us across the country, and I think that key thing is to keep on trying to communicate.

00:26:44: to provide some concluding remarks on today's presentation.

00:26:46: and what does it mean really?

00:26:52: ten

00:26:56: to twenty years after diagnosis.

00:27:16: Because the clinical presentation can be so variable, kidney biopsy still remains essential for making a definitive diagnosis and helping us understand a patient's individual risk of progression.

00:27:28: For my pathophysiologist standpoint The multi-hit model helps explain how this disease develops.

00:27:34: Abherent IgA production leads into formation of immune complexes that deposit in the glomeruli triggering inflammation and kidney injury.

00:27:43: An important part of this process is over-activation of the alternative complement pathway which can further amplify damage that happens in a kidney.

00:27:51: As we look ahead, several developments are likely to improve how care for patients with IgN property.

00:27:58: One major priority is develop reliable noninvasive biomarkers that could help us with earlier diagnosis and better disease monitoring.

00:28:06: We also need to move towards early detection more personalized risk prediction and better tools to monitor complement activity.

00:28:15: And that could help us guide treatment decisions more precisely.

00:28:19: At the same time, new complement targeted therapies are beginning to enter clinical practice.

00:28:24: They offer treatment options that go beyond traditional supportive care and immunosuppression.

00:28:29: Equally important is strengthening how we use the tools that we already have.

00:28:34: That includes greater utilization of kidney biopsy improved provider education the development of clear clinical protocols and strong collaboration between nephrologists, pathologists and advanced care providers.

00:28:46: Ultimately by combining better diagnostics targeted therapies and biopsy guided clinical decision-making we can move beyond one size fits all care in towards more personalized treatment strategies to improve outcomes and quality of life for every single patient that lives with IG nephropathy.

00:29:03: Thanks Elena on the whole team based approach.

00:29:06: Dr.

00:29:07: Oztogi, thank you because I never thought about it like that.

00:29:09: The pathologist is a huge part of the team.

00:29:13: Obviously nephrologists lead the way.

00:29:16: i believe that physician assistants and nurse practitioners can contribute.

00:29:21: They can spend a little bit more time convincing the patient in A slow controlled empowered Way to go ahead And go forward with just basic diagnostics at twenty four hour urine protein a biopsy which many Of my patients i see do not have And the patient's family is also very important.

00:29:39: Moving towards a therapeutic landscape.

00:29:41: like Yelena and Dr.

00:29:42: Rastogi mentioned, The IGN Therapeutic Landscape Is Constantly Involving.

00:29:48: So there s a need for novel biomarkers to provide personalized treatment guidance.

00:29:54: For example We Need To Identify Which Patients Would Benefit From Compliment Inhibition.

00:30:00: It s not A One Person Job.

00:30:02: it s Not A One Mechanism Disease.

00:30:06: It's about aligning the right team, optimizing the right diagnostics and delivering the most precise treatment algorithm to the patient.

00:30:15: That is how we move forward.

00:30:17: Wonderful!

00:30:18: And I think Yasin mentioned that, Yelena definitely implied it was not just about patients' centric care but person-centric care... ...and at end as a pharmacologist i will say The most expensive drug is one you never took.

00:30:32: If the patients don't take their medication, it won't work no matter how good the medication is.

00:30:37: And I think that's where The education piece that was re-emphasized Is very critical.

00:30:42: we need to spend time with a patient.

00:30:43: We need to tell them what's important going over even the biopsy results Whatever they level of understanding is the outcomes That might happen if you don't intervene.

00:30:52: all those things are important if we're able To really implement the guideline directed medical therapy.

00:30:58: So with that, we're going to conclude this podcast.

00:31:01: I really hope you found it useful.

00:31:02: We went over IG Nephropathy and the role of Alternative Complement Pathway And also the clinical manifestations in how do we actually manage this overactivation?

00:31:15: Thank You very much for joining today!

00:31:30: For a full list of declarations, including funding and author disclosure

00:31:34: statements and copyright information

00:31:36: please visit the

00:31:37: article page on The Journal website.