The North Atlantic Ocean hosts the largest volume of global subtropical mode waters (STMWs) in the world, which serve as heat, carbon and oxygen silos in the ocean interior. STMWs are formed in the Gulf Stream region where thermal fronts are pervasive and result in feedback with the atmosphere. However, their roles in STMW formation have been overlooked. Using eddy-resolving global climate simulations, we find that suppressing local frontal-scale ocean-to-atmosphere (FOA) feedback leads to STMW formation being reduced almost by half. This is because FOA feedback enlarges STMW outcropping, attributable to the mixed layer deepening associated with cumulative excessive latent heat loss due to higher wind speeds and greater air-sea humidity contrast driven by the Gulf Stream fronts. Such enhanced heat loss overshadows the stronger restratification induced by vertical eddies and turbulent heat transport, making STMW colder and heavier. With more realistic representation of FOA feedback, the eddy-present/rich coupled global climate models reproduce the observed STMWs much better than the eddy-free ones. Such improvement in STMW production cannot be achieved, even with the oceanic resolution solely refined but without coupling to the overlying atmosphere in oceanic general circulation models. Our findings highlight the need to resolve FOA feedback to ameliorate the common severe underestimation of STMW and associated heat and carbon uptakes in earth system models. Frontal-scale ocean-to-atmosphere feedback determines the formation of subtropical mode water in the North Atlantic. Subtropical mode waters (STMWs) are upper-ocean voluminous water masses characterized by vertically homogeneous temperature and salinity, and originate from the wintertime deep mixed layer on the warm flank of the western boundary current systems . In the Given the importance of STMW with regard to memorizing climate variations and regulating ocean biogeochemical cycles, the physics governing its formation and destruction has received much attention. Traditionally, it has been considered that the bowl shape of STMW south of the Gulf Stream is constructed by wintertime intense convective mixing and eroded by diapycnal mixing . The basHigh-resolution ocean models provide some insight into the Ekman-driven convection induced by winds blowing in the downstream direction of oceanic thermal fronts ,20, the To quantify the contribution of frontal-scale ocean-to-atmosphere (FOA) feedback to STMW production, a set of twin eddy-resolving global climate simulations were conducted using the Community Earth System Model .The reliability of the CESM simulations in capturing STMW, characterized by its low potential vorticity (PV) within the pycnocline, was first verified by comparing vertical profile of PV with three observation-based data sets . AccordiTRL Fig. . The inc−2 between CTRL and FILT , which is partly replenished by vertical eddy heat transport and turbulent vertical mixing . The heat transport convergence by the mean flows (mfQ) and the lateral eddy heat flux (eddyhQ) are found to have negligible contributions. The increased vertical eddy and turbulent heat transport is a likely consequence of the ageostrophic secondary circulation associated with turbulent thermal wind balance due to the strong surface cooling in the presence of FOA feedback [The cooling STMW core layer implies a change in the upper-ocean heat content in the presence of FOA feedback. To shed light on the role of surface forcing and internal oceanic processes, we performed the upper-ocean heat content budget analysis based on the twin CESM simulations  is almost double that in FILT (10.5 Sv), indicating the much more intense air-sea buoyancy exchange on rather short time scales during STMW formation in the presence of FOA feedback Fig. . Such hiA natural question then arises as to what the relative importance of different components of air-sea buoyancy flux is to the increased FR in the presence of FOA feedback. Those components include surface net heat flux, net freshwater flux and Ekman flux driven by wind-induced cross-front advection of density. Clearly, the wintertime-mean STMW formation map by the air-sea buoyancy flux is attributable to that by surface net heat flux, with both being confined to the recirculation gyre region south of the Gulf Stream . The conWe decomposed the LHF-induced FR difference between CTRL and FILT into the direct contribution from LHF difference and the indirect contribution from STMW outcrop area difference  reveals that surface outcrops in late winter (February–March) and the injection of low PV of STMW into the ocean interior are closely associated with the seasonal deepening of the mixed layer . As exper = –0.77, p < 0.001; Fig. −2 increase in the accumulated latent heat release within two months precedes the occurrence of ∼23 m MLD increase in late winter. Hence, the deeper mixed layer in CTRL than FILT is attributable to the cumulative excessive ocean latent heat release driven by FOA feedback. Further decomposition  at standard horizontal resolutions (∼250 km atmosphere and 100 km ocean) are biased towards lower production ,37. Thesr = –0.71, p < 0.02), indicating that modeling more realistic FOA feedback is crucial to alleviating the common bias of a too-small STMW volume in CGCMs at standard CMIP resolutions, and lending further support to our CESM experimental findings.Critically, the total volumes of STMWs in the eddy-free configurations of six CGCMs are 2.3–6.6 Svy, on average, only one fifth of the observational mean (16.3 Svy) Fig. . The totCollectively, our study demonstrates that the feedback of sharp surface thermal fronts, shaped by the Gulf Stream, to the overlying atmosphere  is essential for STMW formation as it transforms plenty of lighter water masses into STMW through the cumulative extensive latent heat loss and the resultant increased surface outcropping. The enhanced surface heat release into the atmosphere is mainly caused by higher surface wind speed and sharper air-sea humidity contrast driven by the Gulf Stream fronts, and leads to the STMW-related upper-ocean cooling, which is partly compensated by the increased vertical eddy and turbulent heat transport. According to the annually integrated volume budget, the dispersion of STMW is also slightly increased in the presence of FOA feedback, maybe due to the increased lateral transportation by the strengthened Gulf Stream extension current . The mesRecent studies have pointed out changes in large-scale atmospheric circulation under different SST resolutions ,41, whicWe also demonstrate that the eddy-present and eddy-rich CGCMs reproduce more realistic spatial distributions and total volumes of STMWs compared to their low-resolution eddy-free counterparts and OGCMs, due to stronger FOA feedback intensity within the STMW formation region as the model resolution becomes finer. Resolving FOA feedback, therefore, is of paramount importance in reducing the severe underestimation of STMW in most models participating in CMIPs, and would improve representation of STMW’s climatic and biogeochemical impacts. This could be achieved by a coordinated increase in oceanic and atmospheric resolutions or by parameterization of SST front-driven winds in coarse-resolution models ,43. The Detailed descriptions of methods are available in the nwad133_Supplemental_FileClick here for additional data file.


P = 0.06, I2 = 0%). However, T-cell specific antibody induction significantly reduced the risk of cytomegalovirus infection , HCV recurrence , DM  and hypertension . Trial sequential analysis for acute rejection showed that the cumulative z-curve did not cross the Trial sequential boundary and the required information size was not reached. T-cell specific antibody induction compared to corticosteroid induction seems to significantly reduce opportunistic infections including cytomegalovirus infection and HCV recurrence and metabolic complications including DM and hypertension. However, given the insufficient study power, low quality of evidence, and heterogeneous immunosuppressive regimens, our results should be cautiously appreciated.Corticosteroids remain the mainstay of immunosuppression for liver transplant recipients despite several serious complications including infection, hepatitis C virus (HCV) recurrence, diabetes mellitus (DM), and hypertension. We attempted to compare the safety and efficacy of T-cell specific antibody induction with complete corticosteroid avoidance. We searched MEDLINE, EMBASE, and Cochrane central library. Randomized controlled trials comparing T-cell specific antibody induction with corticosteroid induction immunosuppression were included. Our primary outcome was the incidence of biopsy-proven acute rejection. Eleven trials involving 1683 patients were included. The incidence of acute rejection was not significantly different between the antibody and steroid induction groups (risk ratio [RR] 0.85, 95% confidence interval [CI] 0.72, 1.01,  However, treatment with corticosteroids is associated with an increased risk of infection, diabetes mellitus (DM), obesity, and hypertension3. Thus, early withdrawal or complete avoidance of corticosteroids by adding another induction immunosuppressive agent such as T-cell specific antibody has been investigated5. However, whether corticosteroid minimization provides clear benefits remains unclear3.Corticosteroids and calcineurin inhibitors remain a mainstay of immunosuppression in liver transplantation6. Induction immunosuppression using T-cell specific antibodies is now available and is used in approximately one-third of liver transplant recipients during the past decade7. T-cell specific antibodies used for induction immunosuppression include interleukin-2 receptor antagonists , monoclonal antibodies specific for the CD3 receptor (muromonab-CD3) or the CD52 surface protein , and polyclonal antibodies (rabbit or horse anti-thymocyte globulin (ATG))6.T-cell specific antibody induction has been investigated to minimize corticosteroids in liver transplant recipients11. However, two meta-analyses included trials with different concomitant immunosuppression9, and one meta-analysis included non-randomized studies11. The previous meta-analysis including only randomized controlled trials with identical concomitant immunosuppression other than antibody and steroid showed that T-cell specific antibody induction significantly reduced DM and cytomegalovirus infection10. However, the quality of evidence was low for both outcomes due to the high risk of bias and imprecision10. Also, while trial sequential analysis (TSA) for diabetes mellitus revealed a significant benefit of T-cell antibody, TSA for cytomegalovirus infection did not. TSA for both outcomes showed that sufficient study power has not been reached10. Furthermore, as the included studies are heterogeneous in study protocols, higher quality evidence with additional randomized trials is required.Four meta-analyses have been published regarding the use of T-cell specific antibody induction for complete avoidance of corticosteroidsIn this updated meta-analysis, we sought to compare the safety and efficacy of T-cell specific antibodies with corticosteroid induction in liver transplantation. We also performed subgroup analysis for different classes and types of antibodies and TSA to evaluate whether any class or drug type has a significant benefit over others.12. The meta-analysis results were reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statements13.Our analysis protocol was registered on PROSPERO (registration number: CRD42022368664). We did not make any deviations from our pre-registered protocol. This meta-analysis was performed according to the Cochrane Handbook for Systematic Reviews of InterventionsWe searched EMBASE, MEDLINE, and the Cochrane Database of Systematic Reviews until October 22, 2022 from inception. We combined search terms for liver transplantation and T-cell specific antibodies. The search strategy of Medline was (Transplant* OR Graft*) AND (Liver OR Hepatic) AND . Only randomized trials written in the English language were considered.We included randomized controlled trials comparing T-cell specific antibody induction to corticosteroid induction in patients undergoing liver transplantation of all ages. Patients with other transplanted organs, previous liver transplants, and ABO-incompatible liver transplants were excluded. Other concomitant immunosuppression regimens such as calcineurin inhibitors and/or mycophenolate mofetil were allowed if received equally by all intervention groups. Randomized controlled trials were restricted to those written in the English language. Two of our authors (WSJ and WHK) independently screened for and assessed eligible trials. The software used was Review Manager . No automation tool was used in the process.Data including first author, country of origin, trial design, inclusion and exclusion criteria, sample size, induction immunosuppression regimens, maintenance immunosuppression regimens, and participant characteristics were collected by two authors (WSJ and JHK). Another author (WHK) confirmed the accuracy of collected data and any discrepancy was resolved by discussion.The primary outcome was the incidence of biopsy-proven acute rejection. The secondary outcomes were patient safety-related outcomes including all-cause mortality, graft loss including patient death, acute rejection requiring treatment, corticosteroid resistant rejection, infection, CMV infection, hepatitis C virus (HCV) recurrence, malignancy, post-transplant lymphoproliferative disorder, the total length of hospital stay; renal function related outcomes including renal failure requiring dialysis, glomerular filtration rate, serum creatinine; and metabolic complications including diabetes mellitus, hypertension, hyperlipidemia, serum cholesterol.12. These following fields were assessed: bias due to deviations from the intended interventions, bias arising from the randomization process, bias in the measurement of the outcome, bias due to missing data, and bias in the selection of the reported result. Two authors independently assessed the risk of bias in included studies. We resolved disagreements by discussion by including, if necessary, a third author.After determining all included studies, the risk of bias of included trials was assessed using the Cochrane risk-of-bias tool version 2 for randomized clinical trials14.We evaluated the quality of the evidence for each of the outcomes according to the GRADE  system. We used all five domains of GRADE: risk of bias, publication bias, indirectness, inconsistency, and imprecision12. A fixed-effects model was adopted to calculate the effect size of our outcome variables. We used the inverse variance method for continuous outcomes and the Mantel–Haenszel method for dichotomous outcomes. The effect size was reported as a pooled mean difference (MD) or risk ratio (RR) with a 95% confidence interval (CI). Forest plots were depicted for acute rejection and new-onset DM. We assessed heterogeneity by the coefficient I2. Heterogeneity was graded by predetermined thresholds for high (more than 75%), moderate (50–74%), and low (less than 49%) levels16.Analyses were conducted using Review Manager . We extracted mean and standard deviations for continuous variables. If continuous variables were reported as median and range, we assumed the mean to be equivalent to the median and estimated the standard deviation to be the range divided by fourPublication bias was evaluated by visual examination of a funnel plot. Egger’s linear regression test and Duval and Tweedie’s trim and fill test were performed to assess the publication bias using STATA version 14.0 .Meta-regression analyses were conducted including recipient age, sex ratio, laboratory MELD score, and cold ischemia time as moderators to explore potential sources of heterogeneity regarding the primary outcome (acute rejection).To evaluate whether different immunosuppression regimens have a different impact on our outcomes, subgroup analyses were performed according to (1) different classes of antibodies , (2) different formulations of the same class of antibody (basiliximab vs. daclizumab), and (3) the administration of an intraoperative corticosteroid bolus. Sensitivity analyses were conducted by analyzing our data using a random-effects model to calculate the effect size of our study outcomes.17. A cumulative meta-analysis was performed using the cumulative number of events and patients. The pooled observed effect depicts a Z curve. Two different boundaries of a conventional boundary (P < 0.05) and O’Brien–Fleming significance boundary  were drawn by TSA to determine the preference for antibody or steroid induction group or futility. These two boundaries are symmetrically depicted on both sides of preference. Required information size was calculated to report the sufficient number of participants needed to confirm the preference for the intervention group based on an assumption of 20% relative risk reduction, type I (5%), and type II (20%) errors17.A TSA was performed using TSA Viewer 18, and the outcomes of two trials were pooled in a single report19.A total of 2221 publications were identified according to our search strategy. After screening 2221 titles and abstracts, 681 duplicate studies and 1470 irrelevant studies were excluded. Finally, 11 RCTs were included after carefully reviewing the full text. Supplemental Figure 25: four trials studied basiliximab23, and six trials studied daclizumab26. Polyclonal antibodies were studied in one trial which used anti-thymocyte globulin25. The distribution of study outcomes across the included trials is shown in Supplemental Table The summarized characteristics of included studies are shown in Table The risk of bias assessment is shown in Supplemental Figure P = 0.06: Fig. 2 = 0%, P = 0.47). TSA demonstrated the cumulative z-curve of the incidence of acute rejection crossed the conventional boundary but did not cross the O’Brien-Fleming significance boundary  also revealed the lack of publication bias.Our primary outcome of the incidence of acute rejection was not significantly different between the antibody and steroid induction groups  or steroid-resistant ACR may occur more frequently than those with other liver diseases29. Therefore, it is possible that the effect of T-cell specific antibody induction with steroid avoidance or minimization on the incidence of acute rejection may differ in the subgroups with autoimmune hepatitis. It is important to consider the underlying liver disease when interpreting the results of our meta-analysis, and further studies are needed to evaluate the effect of T-cell specific antibody induction with steroid avoidance or minimization on the incidence of acute rejection across different subgroups of liver transplantation.Our enrolled population had heterogeneity regarding the underlying liver disease. It is well-known that the risk of acute rejection varies depending on the indication of liver transplantation, especially autoimmune liver disease31. Patients with autoimmune hepatitis receive corticosteroids prior to transplant. The issue is whether weaning steroids after transplantation contributes to the risk of recurrent autoimmune hepatitis. A previous study of 74 patients with autoimmune liver disease reported acceptable rates of survival and acute cellular rejection without corticosteroid maintenance dose32. Another study of 66 patients showed that the association between steroid withdrawal and recurrence of autoimmune hepatitis was not significant33. However, the first reported cases of autoimmune hepatitis occurred during weaning or withdrawal of steroid or on a background of long-term calcineurin inhibitor monotherapy31. Furthermore, previous studies of steroid withdrawal did not include a separate analysis for patients with autoimmune diseases or excluded such patients because of concerns regarding acute rejection. The use of steroid avoidance or minimization in patients with autoimmune diseases should be evaluated on a case-by-case basis, given the risk of acute rejection and complications associated with steroid-free regimens. We could not provide subgroup analysis for these patients because our meta-analysis also included only a few trials with a small proportion of patients with autoimmune liver disease25.Patients undergoing liver transplantation with autoimmune diseases such as autoimmune hepatitis, biliary cirrhosis, and primary sclerosing cholangitis, there is debate regarding the benefit or concerns of steroid avoidance or minimization in the immunosuppression regimen11 and our subgroup analyses of different immunosuppressive regimens with corticosteroids. Although the required information size was not reached, the cumulative Z-curve crossed the O’Brien-Fleming boundary for benefit.Meanwhile, we found some significant benefits of antibody induction. The risk of DM was significantly decreased in the T-cell antibody induction group, which was consistent in previous meta-analyses10, while not in another previous meta-analysis8. This result was consistent in most of our subgroup analysis but there was no difference in the risk of CMV infection when basiliximab was compared to corticosteroids. For this subgroup of basiliximab, the pooled estimate was imprecise and included only two studies.The risk of CMV infection was also significantly decreased in antibody induction which was consistent in a recent meta-analysis36. The American Society of Transplantation Consensus Conference on the use of hepatitis C viremic donors in solid organ transplantation has provided guidelines on the use of HCV-positive organs for transplantation37. Although 16.9% of HCV-infected liver recipients receive liver graft from HCV-positive donors, the possible positive impact of steroid avoidance in hepatitis C viremic donors has not been studied. Furthermore, a previous meta-analysis reported different results regarding HCV recurrence10, which may be because our updated meta-analysis added a recent trial. The risk of hypertension was significantly decreased in the T-cell antibody induction group. However, some of our subgroup analyses did not show consistent results when comparing daclizumab to corticosteroids and when comparing antibody induction with an intraoperative steroid bolus to corticosteroids.Furthermore, the risk of HCV recurrence was significantly decreased in the T-cell antibody induction group. Although the required information size was not reached in TSA, the cumulative estimate crossed the trial sequential boundary for benefit. However, none of our subgroup analyses showed significant results for this outcome, which means further studies are required to interpret significant results for HCV recurrence at the subgroup levels. It should be noted that the current use of antivirals both pre and post-transplant may limit the relevance of our findings in the context of HCV recurrence31. Patients with autoimmune hepatitis receive corticosteroids prior to transplant. The issue is whether weaning steroids after transplantation contributes to the risk of recurrent autoimmune hepatitis. A previous study of 74 patients with autoimmune liver disease reported acceptable rates of survival and acute cellular rejection without corticosteroid maintenance dose32. Another study of 66 patients showed that the association between steroid withdrawal and recurrence of autoimmune hepatitis was not significant33. However, the first reported cases of autoimmune hepatitis occurred during weaning or withdrawal of steroid or on a background of long-term calcineurin inhibitor monotherapy31. Furthermore, previous studies of steroid withdrawal did not include a separate analysis for patients with autoimmune diseases or excluded such patients because of concerns regarding acute rejection. The use of steroid avoidance or minimization in patients with autoimmune diseases should be evaluated on a case-by-case basis, given the risk of acute rejection and complications associated with steroid-free regimens. We could not provide subgroup analysis for these patients because our meta-analysis also included only a few trials with a small proportion of patients with autoimmune liver disease25.In patients undergoing liver transplantation with autoimmune diseases such as autoimmune hepatitis, biliary cirrhosis, and primary sclerosing cholangitis, there is debate regarding the benefit or concerns of steroid avoidance or minimization in the immunosuppression regimen11. This was consistent in our meta-analysis regarding renal failure requiring dialysis. However, in the T-cell specific antibody group, GFR and serum creatinine levels were significantly increased. These results are conflicting with each other because antibody induction was favorable regarding an increase in GFR and steroid induction was favorable regarding the outcome of serum creatinine. Postoperative use of calcineurin inhibitor and its different trough level may act as a confounding factor and we cannot conclusively say the pure effect of immunosuppression regimen on renal function. Also, given the effect size for these outcomes does not correspond to the levels of clinical significance, the high risk of publication bias due to the small number of studies—three for each outcome—included in the analysis, and the insignificance of the most direct outcome of renal failure requiring dialysis, we believe that renal function may not be significantly different between groups.Previous meta-analyses reported no significant differences in renal function between antibody induction and corticosteroids38. Therefore, there is a potential relevance of the metabolic advantage of steroid avoidance to individuals with NASH. However, we could not find any previous study that compared the metabolic outcomes between steroid-free immunosuppression and steroid-based immunosuppression in NASH patients undergoing liver transplantation. Among our included trials, only one trial enrolled a small number of patients with NASH4, we could not perform subgroup analysis due to mixed baseline liver diseases of that study. Further studies are required to evaluate whether the benefit of metabolic outcomes by steroid-free immunosuppression is greater in patients with NASH compared to those without.Our meta-analysis results suggest that T-cell specific antibody induction with steroid avoidance or minimization could lead to a significant reduction in metabolic complications, including diabetes mellitus and hypertension when compared to corticosteroid induction. NASH patients had a higher risk of developing metabolic syndrome after liver transplantation, which can lead to long-term complications such as cardiovascular disease10. While serum cholesterol levels were significantly higher in the corticosteroid group, we deemed this difference insignificant due to the mean cholesterol levels in the corticosteroid group (about 180 mg/dL) being low enough to ignore the difference.There were no significant differences in other secondary outcomes including mortality, graft loss, acute rejection requiring treatment, corticosteroid-resistant rejection, and infection, which was consistent in the subgroups comparing different antibodies and immunosuppressive regimens with corticosteroids. Other outcomes such as adverse events, malignancy, the total length of hospital stay, and hyperlipidemia were also not significant. Two previous meta-analyses reported the same results11. However, only one meta-analysis included RCTs comparing T-cell specific antibody induction with corticosteroids with identical concomitant immunosuppressive regimens between groups10. Wang et al.8 and Goralczyk et al.11 analyzed only studies on interleukin-2 receptor antibodies. Also, Wang et al. compared studies with different immunosuppressive regimens other than antibodies and corticosteroids, making it impossible to compare the pure impact of antibody induction versus corticosteroid induction. Goralczyk et al. included non-randomized studies, decreasing the quality of evidence.Three previous meta-analyses reported the use of T-cell specific antibody induction for corticosteroid avoidance11, our study analyzed additional outcomes such as acute rejection requiring treatment, length of hospital stay, and serum cholesterol levels. We also performed an additional subgroup analysis to address the effect of omitting the intraoperative bolus dose of corticosteroids. Meta-regression analyses of our primary outcome using recipient age, sex ratio, MELD score, and cold ischemia time were also performed. Regarding secondary outcomes, we observed antibody induction reduced the risk of hypertension and serum cholesterol levels. Compared to a previous meta-analysis10, the quality of evidence for CMV infection, HCV recurrence, and DM has been increased to ‘moderate’ due to our updated analysis.Compared to previous meta-analysesOur results should be interpreted cautiously due to the following important limitations.39. Analysis including trials with daclizumab now has a limited value.Firstly, daclizumab has been withdrawn from the market after reports of autoimmune encephalitis in Europe24. Thirdly, significant heterogeneity of study protocols should also be considered. Most RCTs differed in inclusion criteria, the type and dose of antibody or corticosteroid, and the type and dose of concomitant other immunosuppressive drugs. Fourthly, the required information size was not reached for all outcomes in TSA and the O’Brien-Fleming boundary for benefit was not crossed for CMV infection and hypertension. Fifthly, we could not find means and standard deviations for recipient age, cold ischemia time, and total hospital stay in one RCT23. We used medians as means and assumed standard deviations by dividing ranges by four. This method could be used only when the distribution of our variable follows the normal distribution.Secondly, due to the high risk of bias and imprecision, the majority of our outcomes were at a ‘low’ or ‘very low’ quality of evidence. The majority of the included trials had a high risk of bias due to not blinding participants, personnel, and outcome assessorsIn conclusion, according to our updated meta-analysis, T-cell specific antibody induction appears to significantly reduce cytomegalovirus infection and HCV recurrence and metabolic complications including DM and hypertension when compared to corticosteroid induction. However, most included RCTs were assigned a high risk of bias, and the required sample size was not reached for all outcomes. Furthermore, included RCTs were heterogeneous in the immunosuppressive regimens and study protocols. Therefore, additional RCTs with high quality and adequate study power are still needed to assess the efficacy and safety of T-cell specific antibody induction for a higher quality of evidence.Supplementary Information 1.Supplementary Information 2.


A 24-year-old female presented to the emergency department with swelling of the forehead and oculus sinister. A soft, compressible glabellar swelling with proptosis of the oculus sinister was noted on clinical examination. Cerebral angiography revealed a left medial orbital wall arteriovenous fistula with feeders from the left internal maxillary artery, left superficial temporal artery, and left ophthalmic artery. During the cerebral angiography, a diffuse intracranial venous anomaly and left basal ganglia arteriovenous malformations were also noted. A diagnosis of Wyburn-Mason syndrome was made, and the patient underwent catheter embolization of the orbital arteriovenous fistula. After glue embolization of the left external carotid artery feeders, the patient experienced a 50% reduction in glabellar swelling in the immediate postoperative period. Glue embolization of the left ophthalmic artery feeder was planned after six months during the follow-up period. Wyburn-Mason syndrome (WMS) is a congenital, non-heritable condition characterized by widespread vascular anomalies such as arteriovenous malformations (AVM), arteriovenous fistulas (AVF), and angiomas. The phakomatoses in WMS primarily affect the face, eyes, retina, and brain, with unilateral presentation being more common. WMS is caused by a primitive vascular mesoderm disorder that affects the eyes and mesencephalon. A developmental defect before the seventh week of gestation causes the primitive undifferentiated vascular tissue to persist, resulting in widespread vascular anomalies . WMS hasA 24-year-old female presented with complaints of forehead swelling since birth and gradually progressive oculus sinister (OS) swelling for the previous six months. The patient also had one episode of a generalized tonic-clonic seizure one month back. The clinical examination revealed a 3 x 3 cm soft, non-tender, compressive swelling over the glabella with proptosis of the OS Figure .Auscultation revealed a bruit over the glabellar swelling, and a fundoscopic examination of the OS revealed dilated and tortuous vessels with the normal disc. The patient had a visual acuity of 6/6 and no sensory-motor deficits. In the digital subtraction angiographic suite, a diagnostic cerebral angiography was performed via the femoral route, suspecting a vascular anomaly. Selective angiography of the left external carotid artery (ECA) revealed an AVF in the left medial orbital wall with feeders from the left internal maxillary artery (IMA), left superficial temporal artery (STA), and draining into an anomalous dilated deep vein Figure .Selective angiography of the left internal carotid artery (ICA) revealed an ophthalmic artery feeder supplying the left orbital AVF, as well as diffuse nidus in the left basal ganglia suggestive of AVM Figure .The left basal ganglia AVM had multiple feeders from the M2 and M3 segments of the middle cerebral artery, with venous drainage into the straight sinus via an anomalous deep vein. During the venous phase of cerebral angiography, diffuse developmental venous anomalies were also observed Figure .The patient was diagnosed as a case of WMS and selective embolization of the orbital AVF's arterial feeders was planned under general anesthesia, as absolute patient immobility was needed during the procedure. The general anesthesia was induced with 100 mg of intravenous propofol followed by paralysis with 25 mg atracurium. Intravenous fentanyl (100 mcg) was administered to suppress the exaggerated hemodynamic response before tracheal intubation. The 7F right femoral introducer sheath was placed using the Seldinger technique following general endotracheal anesthesia. Intravenous unfractionated heparin (80U/kg) was given to achieve an activated clotting time (ACT) of 250-300. A 5F guiding catheter was introduced coaxially through the femoral introducer sheath and was placed in the left distal ECA. A 1.9F microcatheter with a microwire was inserted into the left IMA, and the feeders were embolized with 1.5 ml of the liquid embolic agent  dissolved in 1.5 ml of dimethyl sulfoxide (DMSO). Following the embolization of the left IMA feeders, the microcatheter was navigated into the left STA, and the feeders were embolized with the liquid embolic agent. A check angiography revealed complete occlusion of the left IMA and STA feeders. Because of technical difficulties in the cannulation of the left ophthalmic artery, the corresponding feeders were not embolized. After ensuring a normal ACT value, the microcatheter with microwire, guiding catheter, and femoral introducer sheath were removed. A compressive bandage was applied to the femoral puncture site after adequate manual compression. After ensuring adequate hemostasis of the femoral puncture site, the general anesthesia was reversed, and the trachea was extubated. The patient was neurologically intact and had a partial reduction in glabellar swelling in the immediate postoperative period. The patient was counseled for glue embolization of the left ophthalmic artery feeder during the second sitting of the follow-up period and was discharged from the hospital.Wyburn Mason syndrome, also known as cervicofacial arteriovenous metameric syndrome type-2, is a developmental disorder characterized by multiple arteriovenous anomalies that primarily affect the face and brain. Cerebrofacial arteriovenous metameric syndrome (CAMS) is an arteriovenous malformation phenotypic classification system. The hypothalamus, olfactory tract, and corpus callosum are the primary targets of CAMS-1. The maxilla, cheek, cortex, diencephalon, optic nerve, and retina are involved in CAMS-2 (WMS), whereas the mandible, temporal bone, and cerebellum are involved in CAMS-3 . An asymWMS is a rare congenital disorder that can cause life-threatening bleeding due to widespread vascular malformations and necessitates a multidisciplinary approach. Asymptomatic vascular malformations should be monitored, and only symptomatic patients should be treated. Endovascular catheter embolization is less invasive and has fewer complications than other treatment options.


Segmental fusion operations assume paramount significance for individuals afflicted by full layers of annulus tears as they avert the perils of rapid disc degeneration and segmental instability. Structures with high signal intensity in the T2-weighted MRI can predict potential damage to the injured segment. Since local structures are shortly related biomechanically, this may be an effective predictor for annulus tears.A retrospective analysis of the clinical data of 57 patients afflicted by cervical injuries and subjected to single-segment ACDF has been performed in this study. The surgeon performed intraoperative exploration to assess the integration status of the annulus. The signal intensity of the prevertebral space, nucleus, and injured vertebral bodies were judged in the T2-weighted imaging data. Regression analyses identified independent predictors for annulus tears, and the area under the receiver operating characteristic curve (AUC) was computed to evaluate the predictive performance of potential independent predictors.The occurrence of nucleus high intensity was significantly higher among individuals with annulus tears, and the nucleus high intensity was deemed an independent predictor for determining the presence of intraoperative visible annulus tears in patients with cervical injuries. AUC for nucleus high intensity was calculated as 0.717, with a corresponding p-value less than 0.05.In the realm of diagnosing annulus tears in injured cervical patients, nucleus high intensity in the T2-weighted MRI emerges as a promising predictive factor. Notably, this applies specifically to patients devoid of fracture and visible annulus tears in their MRI scans. Such positive outcomes should be regarded as prospective indications for ACDF. Spinal trauma, a condition frequently encountered in clinical practice, presents a complex array of challenges. Internal fixation procedures become imperative to restore segmental stability in patients with spinal fractures , 2. It iThe existing array of imaging-based examination techniques, while extensively employed, fails to precisely diagnose annulus tears in patients who have suffered cervical injuries. Although dynamic X-ray radiography accurately detects segmental instability , 9, we mInjured patients with spinal and joint afflictions typically undergo MRI scans as part of routine clinical practice. The T2-weighted imaging data within these scans reveal high intensity signals that accurately pinpoint local damage –16. NotaTo substantiate this hypothesis, we conducted an in-depth review of clinical data on patients who underwent single segmental anterior cervical discectomy and fusion (ACDF). Through comprehensive analysis of patients' demographic and imaging data, we endeavored to determine the reliability of these indicators in diagnosing annulus tears identified intraoperatively. By identifying this topic, our findings carry theoretical implications for selecting surgical indications in cervical injured patients. To our knowledge, this study represents the first of its kind to illuminate this subject matter.Obtaining ethical approval from the ethics committees of our hospital served as the foundation for this study. Informed consent was waived due to the retrospective nature of the study , 20. A rThe ACDF operation for all enrolled patients was conducted by a senior spine surgeon , 22. TheWithin the T2-weighted imaging data, the signal intensity of various components served as a pivotal determinant. Since normal vertebral bodies typically exhibit low signals in T2-weighted imaging data, any vertebral bodies displaying heightened signal intensity were deemed indicative of injury. However, this particular definition method cannot be applied to judge nucleus damage since the normal nucleus tends to exhibit a high signal in this specific imaging sequence. Consequently, to ascertain the status of the nucleus—determining whether it exhibited an anomalously high signal intensity or not—a comparison was drawn between the signal intensity of the injured nucleus and that of adjacent segments. If the signal intensity of the nucleus appeared visibly higher than its neighboring segments, it was classified as injured , 24. In Under the expert guidance of a skilled statistician, the statistical analyses were diligently conducted using IBM SPSS 23.0 software. As a preliminary step, a normality test was performed to assess the distribution of continuous variables, such as patients' age and body mass index (BMI). Once it was established that these variables adhered to normality, they were expressed as mean ± standard deviation , 27. On To compare the presence of demographic and MRI-based parameters between patients with and without annulus tears, distinct statistical methods were employed. Continuous variables were subjected to independent-sample Student's t-tests, while binary variables underwent chi-squared tests , 30. SubDuring the designated period for clinical data collection, a comprehensive total of 122 patients underwent cervical surgery at our department to address cervical trauma. Among them, 47 patients were afflicted with either vertebral or posterior column fractures, while 11 patients had previously undergone cervical MRI examinations at other medical facilities. Notably, one patient received a diagnosis of metastatic tumors, another patient had a history of prior cervical operations, and two patients underwent multisegmental anterior cervical discectomy and fusion (ACDF) procedures. Consequently, a carefully selected cohort of 57 cervical injury patients  who underwent single-level ACDF surgery, with an average age of 54.81 ± 11.17 years, were enrolled for this study. Upon analyzing the demographic data, no significant differences were observed between patients with and without annulus tears. The inter- and intraobserver reliability of measuring MRI-based parameters exhibited an acceptable level of agreement, and detailed kappa values, illustrating this reliability, are provided in Table Regarding the disparities in MRI-based parameters, it was discovered that the incidence rate of nucleus high intensity was 60% among patients with annulus tears, whereas it stood at 16.67% for patients without annulus tears. Consequently, the occurrence of nucleus high intensity was significantly higher among individuals with annulus tears. Conversely, the incidence rates of high intensity in the prevertebral space and injured vertebral bodies exhibited no significant discrepancies between patients with and without annulus tears. Notably, the rate of vertebral body high intensity was even insignificantly higher among patients without annulus tears. Furthermore, the incidence rate of observable annulus tears in the T2-weighted MRI scans reached 37.78% among patients with annulus tears, a figure significantly surpassing that of patients without annulus tears. None of the patients without annulus tears displayed any signals indicative of annulus tears in the MRI imaging data , it was deemed an independent predictor for determining the presence of intraoperative visible annulus tears in patients with cervical injuries.To further evaluate the predictive value of nucleus high intensity, an ROC curve analysis was performed. The area under the curve (AUC) for nucleus high intensity was calculated as 0.717, with a corresponding p-value less than 0.05 (p = 0.022). In contrast, the AUC values for prevertebral space high intensity and vertebral body high intensity were determined as 0.547 and 0.641, respectively, with p-values exceeding 0.05. Detailed data pertaining to these analyses can be found in Tables The significance of the annulus, composed of multiple layers of fibers, has been extensively discussed in existing literature due to its biomechanical role in bearing tensile stress and maintaining segmental stability , 35. InfRecently, a fiber tracking technique based on functional MRI examination has been proposed as an alternative method to predict annulus integration status . HoweverMotivated by the biomechanical integration of local structures and the correlation between T2-weighted high intensity and acute injury , 23, 24,It is worth noting that this study lacks a control group receiving conservative treatment, and ACDF was performed on some patients without annulus tears. Dynamic radiography is strictly prohibited for patients with cervical spinal trauma to prevent severe consequences, making the evaluation of segmental stability or instability in MRI an indirect process. Considering that misdiagnosis of segmental instability can lead to significant prognostic deterioration, broader indications for ACDF have been chosen for patients with irregular signal intensity in T2-weighted MRI. Furthermore, injury is the primary cause of disc degeneration and segmental instability in medium to long-term follow-up periods. Therefore, even in patients without observable full-layer annulus tears, ACDF may still be an effective treatment strategy for cervical-injured patients to establish segmental stability and mitigate potential disc degeneration and segmental instability risks.While the main clinical significance of this study lies in presenting MRI-based parameters for more precise assessment of surgical indications in cervical-injured patients, there is a need to further investigate the prognosis of conservative treatment in patients without high nucleus intensity and observable annulus tears. In future studies, we will select this treatment strategy and report clinical follow-up results to reconfirm the conclusions drawn in this study and determine the effectiveness of conservative treatment in patients without observable full-layer annulus tears.Admittedly, this study has inherent limitations. To validate the current results, larger sample sizes are necessary for verification. Additionally, the judgment of "high nucleus intensity" relies solely on the surgeon's subjective observation. Although intra- and interobserver reliability have been assessed through kappa analysis, a more objectively quantitative parameter should be developed to accurately evaluate the nucleus's signal intensity. Moreover, statistical analysis methods used in this study were commonly selected in the same type of studies , 20, 28.In summary, the annulus's biomechanical significance and its relation to inflammation and clinical symptoms have been well-documented. Diagnosing annulus tears in injured cervical patients using conventional imaging methods is challenging, and alternative techniques require further validation and wider availability. In this study, we propose that high intensity in local structures, particularly the nucleus, can serve as a potential predictor for annulus tears. The findings support the recommendation of routine assessment of nucleus signal intensity in injured cervical patients and consideration of high nucleus intensity as an indication for ACDF. However, future research with larger sample sizes and more objective quantitative parameters is warranted to validate these conclusions and improve the precision of annulus tear prediction in clinical practice.In the realm of diagnosing annulus tears in injured cervical patients, nucleus high intensity in the T2-weighted MRI emerges as a promising predictive factor. Notably, this applies specifically to patients devoid of fracture and visible annulus tears in their MRI scans. Such positive outcomes should be regarded as prospective indications for interbody fusion surgeries, as they hold the potential to mitigate the dangers of segmental instability and expeditious disc degeneration commonly associated with this particular patient cohort.


IntroductionLower extremity injuries represent about 15% of all emergency room visits in the United States, with ankle injuries accounting for 20% of these. Surgical site infections resulting from ankle reconstructive surgery can result in severe complications, including amputation. Depending on the procedure performed, surgical site infections of ankle reconstructive surgery can occur at a rate as high as 14%. A synthetic hybrid-scale fiber matrix with an engineered design resembling a native human extracellular matrix could be utilized to augment these difficult surgical procedures.Materials and methodsA retrospective review of 10 patients who underwent orthopedic reconstructive surgeries of lower extremity injuries that were augmented with the synthetic hybrid-scale fiber matrix between October 2021 and February 2022 was conducted.ResultsInjuries included Achilles ruptures, bimalleolar and trimalleolar ankle fractures, ankle arthrodesis, and injuries of various other etiologies. All surgical wounds achieved complete closure and patients went on to fully recover. The average time to wound closure was 12.6 days after an average of 1.2 applications of the synthetic hybrid-scale fiber matrix. Post-reconstruction, two patients went on to have complications unrelated to the synthetic hybrid-scale fiber matrix, which then went on to heal uneventfully.ConclusionsThe positive results seen with the retrospective case series indicated that the synthetic hybrid-scale fiber matrix can promote healing and should be considered as an option in at-risk lower extremity reconstructive procedures. Lower extremity injuries represent about 15% of all emergency room visits in the United States . SurgicaAugmentation of these procedures utilizing acellular matrices has been explored in prior studies . These mGiven these complications, novel technology is needed in order to mitigate the risk of postoperative wound complications. This is critically important in high-risk patient populations or procedures where incision placement involves angiosomes with a precarious or tenuous blood supply. A synthetic hybrid-scale fiber matrix, similar in both size and structure to native human extracellular matrix, has shown promise in treating surgical wounds and chronic ulcers, with healing rates seen ranging from 75% to 96% -12. The A retrospective review of patients who underwent orthopedic surgery for a lower extremity injury in which the synthetic hybrid-scale fiber matrix was utilized was conducted via a review of patient charts. Patients who received at least one application of the synthetic hybrid-scale fiber matrix at Dallas Orthopedic and Shoulder Institute in Sunnyvale, Texas between October 2021 and February 2022 to augment a lower extremity orthopedic procedure were included in this study. In each case, the patient underwent radiographic examination to determine the extent and etiology of the injury. Upon diagnosis, each patient was taken to the operating room for the clinically indicated reconstructive surgery.Use of the synthetic hybrid-scale fiber matrix in the reconstructive procedure was determined by the surgeon based on the etiology of the injury and prior patient history. Patients with a prior history of surgical site infection or dehiscence, procedures with a high risk of dehiscence, and those with skin injury or necrosis following trauma were selected for use of the hybrid-scale fiber matrix. In each case, the synthetic hybrid-scale fiber matrix was applied to the surgical wound bed to protect hardware in the case of dehiscence, or it was placed over the wound bed to allow for re-epithelization over the open wounds resulting from prior surgical dehiscence or trauma. The synthetic hybrid-scale fiber matrix was secured within the wound bed using resorbable sutures. Surgical wounds were then sutured closed with either non-resorbable sutures or staples and dressed using nonadherent petroleum-impregnated dressings soaked in betadine, 4 x 4 gauze, cotton undercast padding, and an elastic 6” bandage with clips. All patients were instructed to wear a splint for offloading and stabilization.A total of 10 patients were included in this retrospective case series. All 10 patients treated with the synthetic hybrid-scale fiber matrix during orthopedic reconstruction surgeries went on to fully heal. The average patient age was 52. The patients included in this study also had multiple co-morbidities including diabetes mellitus, obesity, aortic stenosis, cervical cancer, hypertension, hyperlipidemia, neuropathy, cellulitis, osteoporosis, and autoimmune disease.Injuries included an Achilles rupture 10%), bimalleolar and trimalleolar ankle fractures (40%), ankle arthrodesis (10%), a heel wound (10%) a dorsal foot wound (10%) a pressure injury (10%), and an adult acquired flatfoot deformity (AAFD) revision (10%). All the wounds resulting from surgery achieved complete closure. Six wounds were closed at the time of surgery, and four wounds went on to heal after surgery. The average time to wound closure was 12.6 days after an average of 1.2 applications of the synthetic hybrid-scale fiber matrix , the synthetic hybrid-scale fiber matrix prevented the exposure of hardware and bone. After these two wounds underwent an I&D procedure, they too went on to heal uneventfully. The results seen in this retrospective case series are comparable to those seen within this patient population. The incidence of surgical site infection in ankle fractures treated by ORIF is roughly 7.19% . There aNew surgical methods are needed to meet the needs of patients with known risk factors. The synthetic hybrid-scale fiber matrix is engineered to allow for cellular infiltration, re-vascularization, and differentiation . Given tSeveral previous studies have assessed the use of the synthetic hybrid-scale fiber matrix in the treatment of lower extremity surgical procedures. A separate retrospective case series of 12 patients who underwent peroneal tendon repairs augmented by the synthetic hybrid-scale fiber matrix was conducted at a single site . The patThere are limitations with this retrospective case series. This was a small retrospective study conducted by a single investigator at a single site. As with all retrospective studies, this study is subject to design flaws such as availability of medical records and recall bias . In addiOrthopedic surgical repairs of the leg and ankle are not without risk, especially in patients with multiple comorbidities or those with a history of poor wound healing. New modalities are needed to mitigate risk amongst this population. A synthetic hybrid-scale fiber matrix may provide an option for improving wound healing.This retrospective case series demonstrates successful application of the synthetic hybrid-scale fiber matrix in the setting of orthopedic surgical repair. The results observed indicate that the synthetic hybrid-scale fiber matrix could be utilized to promote healing and may be considered as a treatment option in at risk reconstructive procedures of the lower extremity.


The enhanced-view totally extraperitoneal (eTEP) technique, an endoscopically performed Rives-Stoppa method, has been used extensively for ventral hernia repairs. However, in this technique, the necessity of posterior rectus sheath re-approximation and mesh fixation remains unclear. There are a few reports of post-eTEP interparietal hernias (IHs) occurring because of dehiscence of the re-approximated posterior rectus sheath; however, IH secondary to mesh migration is rare. Herein, we report a rare case of IH due to mesh migration after eTEP repair for an incisional hernia.A 70-year-old man underwent eTEP repair for an incisional hernia using a self-gripping mesh without mesh fixation and posterior rectus sheath re-approximation one year previously, developed an IH. An elective laparoscopic surgery revealed an orifice to the retrorectus space as though the IH sac between the retrorectus muscle and the posterior layer including the bilateral posterior rectus sheaths, peritoneum, and mesh. We placed eight transmural sutures with 0 nylon thread and closed the orifice. The patient was then discharged on postoperative day two and was asymptomatic at 24 months without evidence of ventral hernia recurrence.We consider that strenuous activity and deep bending may cause mesh migration or dislocation. If that occurs in the early post-eTEP period without posterior rectus sheaths closure, the vulnerable peritoneal area will be exposed, which consider to be an IH orifice.Even after using the self-gripping mesh in eTEP repair, mesh fixation remains the best option to prevent postoperative complications, including IH. •The eTEP technique is used extensively for ventral hernia repairs.•However, the necessity of posterior rectus sheath re-approximation remains unclear.•We report a rare case of IH due to mesh migration after a previous eTEP repair.•The patient was asymptomatic at 24 months without ventral hernia recurrence after IH repair.•Mesh fixation remains optimal for preventing postoperative complications. This 2A 70-year-old man underwent laparoscopic ventral hernia repair with the eTEP technique for an incisional hernia after laparoscopic cholecystectomy . During Abdominal computed tomography (CT) was taken during the follow-up visit one year after the surgery. It demonstrated herniation of the large bowel into the space between the rectus muscle and the posterior layer . We suspThere were no postoperative complications, and the patient was discharged on postoperative day two. No hernia recurrence, including IH, occurred after 24 months of follow-up .Fig. 5Ab3IHs are defined as protrusions of intra-abdominal contents within the layers of the abdominal wall, which rarely occur as postoperative complications ,11. OnlyRadu et al. reported that mesh fixation was unnecessary because the retromuscular space was restricted, resulting in a low possibility of mesh migration . Further4Although the necessity of mesh fixation in eTEP repair remains controversial, we consider that mesh fixation, even after using the self-gripping mesh, in a few points along the abdominal wall is one option to prevent the incidence of IH in the early post-eTEP period.Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.No ethical approval was necessary because case reports are exempted from ethical approval in our institution, Kobe City Medical Center West Hosipital, Hyogo, Japan.This study did not receive any funding.Shusaku Honma contributed to the study concept, data collection, writing the paper. Shusaku Honma and Kana Ishikawa performed the surgery. Takashi Takashima and Tatsuhi Ushikubo followed up the patient. Takahisa Suzuki and Sanae Nakajima contributed to writing the paper.Shusaku Honma is the guarantor of this work.Not required for this report.All authors declare that they have no competing interests.


Fibrosis has emerged as one of the main pathophysiological common end-point in organ failure. Maladaptive tissue remodeling and fibrosis are typical responses to injury which leads to distorted architecture, pathologic signaling, and extracellular matrix (ECM) remodeling leading ultimately to organ dysfunction . Tissue Leifheit-Nestler et al.; Eitner et al.). Dr. Haffner’s group identified that FGF23 expression increased in cardiac fibroblasts and endothelial cells following pressure-induced cardiac hypertrophy and not in cardiac myocytes . However, Cre-Flox mediated deletion of FGF23 in myocytes resulted in worsening of cardiac function followed by transverse aortic constriction (TAC) induced cardiac insult . The protective role of FGF23 on cardiac function was also demonstrated by Dr. Leifheit-Nestler’s group by utilization of adeno-associated virus (AAV) expressing murine Fgf23 system. They demonstrated that even though FGF23 is elevated in chronic kidney disease (CKD) and is associated with left ventricular hypertrophy (LVH) in CKD, it is not cardiotoxic and does not induce LVH in healthy mice . These studies emphasized the fact that increased expression of a protein does not always translates into its pathological role in tissue pathology. Increased expression of FGF23 could be a protective compensatory mechanism to tackle the insult .In this Research Topic, our focus was to highlight studies that primarily addressed the factors involved in modulating fibrosis in cardiac repair as well as other tissue pathologies including chronic kidney diseases, keloids, type II diabetes and glaucoma. Both Drs. Haffner and Leifheit-Nestler’s groups have indicated the significance of FGF23 in cardiac and kidney pathologies . This is the first comprehensive study to perform site-specific collagen post-translational modification map of zebrafish heart. Since zebrafish have a unique capability to regenerate the heart following injury, this study will be instrumental in decoding extracellular-matrix remodeling and identifying potential therapeutic targets for the mammalian post-injury fibrotic response.Using Zebrafish as a model, Dr. Basak’s group teased out the mechanism of cardiac ECM remodeling. Collagen molecules are the major players in post-injury cardiac remodeling. Additionally, post-translational modifications including hydroxylation of proline, lysine, and glycosylation of lysine have been shown to be critical in modulating physiological as well as disease-related extracellular-matrix interaction with its cellular microenvironment . Complementing this study, Dr. Xu’s group emphasized the role of circular RNA in keloid pathophysiology and identified hsa_circ_0006867 as a biomarker of keloids .Fibrosis is not an organ-specific response. It is a physiological as well as pathological response following any kind of tissue injury as well pathological condition. Keloids is a fibroproliferative cutaneous disease with limited diagnostic indicators for early screening and prevention. Lu et al. identified IL6 and IL11 as key inflammatory cytokines that may promote fibrosis-induced islet dysfunction . This in silico analysis was confirmed in an obese rat animal model. The effect of high glucose levels in inducing inflammation and subsequently fibrosis and islet dysfunction is an important avenue of research and should get more attention in diabetes research.Another interesting study published in the Research Topic was the gene ontology analyses of human islets derived from type 2 diabetes mellitus patients. In addition to high glucose-induced activation of extracellular matrix pro-fibrotic proteins, Liu et al.). Through bioinformatics supported by mechanistic studies, Liu et al. identified RhoA/ROCK-YAP/TAZ axis as having a crucial role in modulating the fibrotic activity of dexamethasone-treated human trabecular meshwork cells .Fibrotic activity in the human trabecular meshwork (HTM) cells can be one major factor that promotes high intraocular pressure leading to glaucoma (Tissue fibrosis is a complex process that involves the interplay between multiple cell types including fibroblasts, immune cells, and endothelial cells. Fibrosis accompanies wound healing where it drives the failure of many organs. However, post-injury repair through fibrosis also ensures organ integrity making it harder to target. Understanding the molecular mechanisms regulating post-injury fibrotic healing is crucial in addressing unchecked fibrosis without interfering with the healing process. After decades of research, fibrosis research is still in its infancy to understand this inevitable pathological post-injury outcome. In this Research Topic, we have published some molecular targets in a wide range of tissues that should be further investigated and may provide a significant clue in tipping the balance towards regenerative healing instead of fibrosis.


Transcatheter aortic valve replacement (TAVR) is a minimally invasive therapeutic procedure with a consistent, linear increase in the number of implantations worldwide. Recently, TAVR has been rapidly expanding into lower-risk populations. Sporadic cases of late prosthesis-related Stanford type A dissection have been documented in self-expanding, as well as balloon-expandable TAVR valves, manifested primarily as acute aortic syndrome. We present the case of a 76-year-old male, who experienced refractory in-hospital cardiac arrest with non-shockable rhythm due to the obstruction of coronary flow caused by aortic dissection type A, with entry directly adjacent to the aortic prosthesis according to autopsy. The patient died despite the engagement of extracorporeal cardiopulmonary resuscitation. Aortic dissection developed one year after a transfemoral TAVR procedure using an Edwards SAPIEN 3 29 mm self-expanding valve. TAVR-associated late aortic dissection type A represents a rare, life-threatening condition with various clinical manifestations. The risk factors have not been well described and the differential diagnosis may be challenging. As the number of TAVR recipients and their life expectancy is increasing, we may face this complication more often in future. Transcatheter aortic valve replacement (TAVR) is an evolving, minimally invasive procedure indicated in severe degenerative aortic stenosis, with a consistent increase in the number of implantations in developed countries . Thoraci2, with a history of an uncomplicated transfemoral TAVR procedure for combined degenerative aortic valve disease  12 months prior was admitted to the ophthalmology department for cataract surgery. The Edwards SAPIEN 3 29 mm valve  was used. The patient was former cigarette smoker, with a history of arterial hypertension, diabetes mellitus type 2, permanent atrial fibrillation, chronic obstructive pulmonary disease with mild airflow obstruction, who experienced severe bilateral community-acquired pneumonia of unknown origin 5 months prior, which required 7 days of mechanical ventilation.A 76-year-old Caucasian male, body mass index 39 kg/mThe previous TAVR procedure was followed by improvement in clinical manifestations . Examination by a cardiologist, that preceded cataract surgery by three days, documented favorable clinical status, persistent atrial fibrillation, heart rate roughly 70 bpm, and systemic arterial pressure 115/70 mmHg. According to transthoracic echocardiography, there were no signs of TAVR prosthesis malfunction . The left ventricle was non-dilated, with mild concentric hypertrophy and an ejection fraction of 50%. Aortic root diameter was 41 mm, and ascending aorta diameter 46 mm.The day of cataract surgery, after premedication , the patient manifested with sudden onset dyspnea accompanied by hypoxemia and elevated systemic arterial pressure (190/120 mmHg). The patient’s status was evaluated as emergent hypertensive crisis with cardiogenic pulmonary edema and was referred to the emergency department. On standard 12-lead electrocardiogram, atrial fibrillation and chronic left bundle branch block were observed . The patThe present report describes a case of late Stanford type A TAD related to prior transfemoral TAVR, which presented as refractory in-hospital cardiac arrest with non-shockable rhythm due to coronary arteries obstruction.Although not entirely clear, upon thorough review of the sequence of clinical signs, along with autopsy findings, we can declare with a high level of certainty that the cause of cardiac arrest was obstruction of the coronary arteries due to TAD. Acute aortic syndrome was likely triggered by increased arterial blood pressure due to stress response preceding ophthalmological intervention, but we cannot entirely exclude that the hypertensive reaction was a secondary response to TAD. The reason that the false aortic lumen was not apparent initially following cardiac arrest may be explained by sufficient VA-ECMO flow via the outflow cannula inserted into the true lumen and the absence of intrinsic left ventricular pulsatility during ongoing electromechanical dissociation. The intimal flap became apparent at the moment when adequate VA-ECMO flow could not be maintained due to relative hypovolemia.The extreme dynamics of laboratory markers of myocardial necrosis support the hypothesis that the occlusion of, in particular, the left main coronary artery was the lethal mechanism, despite the fact that typical macroscopic signs of myocardial necrosis had not entirely developed on transverse sections of the heart at autopsy due to the short time period. Unresponsiveness to initial therapy of cardiogenic pulmonary edema implies that TAD developed spontaneously and not as a traumatic consequence of cardiopulmonary resuscitation. Nevertheless, chest compression-related aortic injuries should be taken into consideration in cardiac arrest survivors, especially after prolonged mechanical resuscitation and extracorporeal cardiopulmonary resuscitation, which are increasingly used . To the In 2010, Gerber et al. reported two cases of delayed TAD following TAVR by several days . More reIn the present case, the patient did not complain of any thoracic pain before circulatory collapse. We may hypothesize that the interval from initial intimal tearing to cardiac arrest due to left main coronary artery obstruction was too short to allow the patient to develop any symptoms or he was not able to provide any meaningful subjective input due to acute respiratory failure. Nevertheless, on 12-lead electrocardiogram obtained immediately before cardiac arrest, in the terrain of the left bundle branch block, we observed some acute ischemic changes suggestive of left main or left anterior descending coronary artery hypoperfusion .As coronary artery disease is the main cause of cardiac arrest in adults, we considered performing coronary angiography. Taking into account minimal atherosclerotic lesions observed during coronary angiography preceding the TAVR procedure 14 months prior, non-shockable initial rhythm and transport difficulties due to hemodynamic instability, we elected to not proceed with urgent selective coronary angiography. We emphasize that cardiac catheterization would have likely revealed the cause of cardiac arrest. Computed tomography may have also uncovered the diagnosis earlier. Despite the fact that we considered and actively searched for TAD, we did not perform computed tomography angiography as the patient was hemodynamically unstable and the suspicion for TAD was reduced by negative findings on repeated transesophageal echocardiography. Nevertheless, in the present case, an earlier diagnosis would likely not have changed the unfavorable outcome of the patient.Predisposing factors and triggers of late TAD after TAVR have not extensively been described as cases are scarce. They may differ from the risk factors of TAD after surgical aortic valve replacement, where perioperative manipulation or clamping may also affect the integrity of the ascending aortic wall . We may Late Stanford type A TAD with associated sudden cardiac death represents an unusual clinical event in patients who underwent prior TAVR. As the number of TAVR recipients is increasing and the method spreads to younger populations, we should consider this disorder in the differential diagnosis in the context of any sudden unexplained change in clinical status and we should proactively exclude this complication, even in the absence of typical clinical manifestations and indirect echocardiographic signs of acute aortic syndrome. Cardiopulmonary resuscitation-induced aortic injuries should be considered in the differential diagnosis.


PCSK9) and glucagon-like peptide 1 (GLP1) have yielded among the most promising therapeutics to treat cardiovascular disease and obesity, respectively4. A major obstacle in the characterization of such soluble factors is that defining their tissues and pathways of action requires extensive experimental testing in cells and animal models. Recently, studies have shown that secreted proteins mediating inter-tissue signaling could be identified by “brute-force” surveys of all genes within RNA-sequencing measures across tissues within a population9. Expanding on this intuition, we reasoned that parallel strategies could be used to understand how individual genes mediate signaling across metabolic tissues through correlative analyses of gene variation between individuals. Thus, comparison of quantitative levels of gene expression relationships between organs in a population could aid in understanding cross-organ signaling. Here, we surveyed gene-gene correlation structure across 18 metabolic tissues in 310 human individuals and 7 tissues in 103 diverse strains of mice fed a normal chow or HFHS diet. Variation of genes such as FGF21, ADIPOQ, GCG and IL6 showed enrichments which recapitulate experimental observations. Further, similar analyses were applied to explore both within-tissue signaling mechanisms (liver PCSK9) as well as genes encoding enzymes producing metabolites (adipose PNPLA2), where inter-individual correlation structure aligned with known roles for these critical metabolic pathways. Examination of sex hormone receptor correlations in mice highlighted the difference of tissue-specific variation in relationships with metabolic traits. We refer to this resource as Gene-Derived Correlations Across Tissues (GD-CAT) where all tools and data are built into a web portal enabling users to perform these analyses without a single line of code (gdcat.org). This resource enables querying of any gene in any tissue to find correlated patterns of genes, cell types, pathways and network architectures across metabolic organs.Inter-organ communication is a vital process to maintain physiologic homeostasis, and its dysregulation contributes to many human diseases. Beginning with the discovery of insulin over a century ago, characterization of molecules responsible for signal between tissues has required careful and elegant experimentation where these observations have been integral to deciphering physiology and disease. Given that circulating bioactive factors are stable in serum, occur naturally, and are easily assayed from blood, they present obvious focal molecules for therapeutic intervention and biomarker development. For example, physiologic dissection of the actions of soluble proteins such as proprotein convertase subtilisin/kexin type 9  subjects between the ages of 20–79. Data from the HMDP consisted of 96 diverse mouse strains fed a normal chow (5 tissues) or high-fat/high-sucrose diet (7 tissues) as well as carefully characterized clinical traits 16. Initially, users select a given species, followed by reported sex or diet (mouse) which loads the specified environment. Subsequent downstream analyses are then implemented accordingly from a specific gene in a given tissue.. This selection prompts individual gene correlations across all other gene-tissue combinations using biweight midcorrelation17. From these charts, users are able to select a given tissue, where gene set enrichment analysis testing using clusterprofiler18 and enrichR 19 are applied to the correlated set of genes to determine the positively (activated) and negatively (suppressed) pathways which occur in each tissue. In addition to general queries of gene ~ gene correlation structure, comparison of expression changes are also visualized between age groups as well as reported sexes. In addition, we included the top cell-type abundance correlations with each gene. To compute cell abundance estimates from the same individuals, we used single-nucleus RNA-seq available from GTEx20 and applied cellular deconvolution methods to the bulk RNA-seq21  which localizes to lipid droplets and breaks down triglycerides for oxidation or mobilization as free fatty acids for peripheral tissues31. Variation in expression of PNPLA2 showed highly significant enrichments with beta oxidation pathways in adipose tissue , estrogen receptor alpha (Esr1) or estrogen receptor beta (Esr2) and binned the top 10 phenotypes which were correlated. These analyses were segregated based on where sex hormones were expressed (either liver or adipose tissue) or dietary regiment of the ~100 strains . This analysis demonstrated the difference in relationships between tissue location of sex hormone receptor and dietary context with metabolic traits. For example, expression of Ar in adipose tissue among HMDP mice fed a HFHS diet was negatively correlated with fat mass and body weight traits, whereas expression in liver oppositely correlated with the same traits in a positive direction  also present appeal in refining some causal mechanisms. Correlation between molecular and phenotypic variables can occur for a variety of reasons, not just between their individual relationships, but often more broadly, from a variety of complex genetic and environmental factors. Further, many correlations tend to be dominated by genes expressed within the same organ. This could be due to the fact that, within-tissue correlations could capture both the pathways regulating expression of a gene, as well as potential consequences of changes in expression/function, and distinguishing between the two presents a significant challenge. For example, a GD-CAT query of insulin (INS) expression in pancreas shows exclusive enrichments in pancreas and corresponding pathway terms reflect regulatory mechanisms such as secretion and ion transport (XIST), in liver no significant correlations appear. This is due to the fact that the gene operates in a sex-dependent manner, where females are significantly less represented in GTEx and liver exists as a sparser tissue compared to others  and can be difficult in arriving at a “ground truth” for parameter selection. We note that the WGCNA package is also implemented in these analyses, but solely to perform gene-focused correlations using biweight midcorrelation to limit outlier inflation. While the midweight bicorrelation approach to calculate correlations could also be replaced with more sophisticated models, one consideration would be a concern of overfitting models and thus, biasing outcomes.The queries provided in GD-CAT use fairly simple linear models to infer organ-organ signaling; however, more sophisticated methods can also be applied in an informative fashion. For example, Koplev et al generated co-expression modules from 9 tissues in the STARNET dataset, where construction of a massive Bayesian network uncovered interactions between correlated modules44. In addition, Jadhav and colleagues adopted a machine learning approach to mine published literature for relationships between hormones and genes45. Further, association mapping of plasma proteomics data has been extensively applied and intersection with genome-wide association disease loci has offered intriguing potential disease mechanisms47. Another common application to single-cell sequencing data is to search for overrepresentation of known ligand-receptor pairs between cell types48. These and additional applications to explore tissue communication/coordination present unique strengths and caveats, depending on the specific usage desired. Regardless of methods used to decipher, one important limitation to consider in all these analyses is the nature of underlying data. For example, our evaluation of GTEx data structure suggested that important organs such as spleen and kidney were insufficient due to availability in matching expression data between individuals. Further, GTEx sample vary as to the collection times, sample processing times and other important parameters such as cause of death. Mouse population data such as the HMDP or BxD cohorts offer appeal in these regards, as environmental conditions and collection times are easily fixed. Regardless, careful consideration of how data was generated and normalized are fundamental to interpreting results.In another notable example MultiCens was developed as a tool to uncover communication between genes and tissues and applied to suggest central processes which exist in multi-layered data relevant for Alzheimer’s diseaseFGF21, GCG and PCSK9. These approaches are further suggested to be applicable to mechanisms of metabolite signaling, as evident by pan-tissue investigation of adipose PNPLA2. Exploration of hybrid mouse diversity panel data highlighted the diverse phenotype correlations depending on tissue and diet for sex hormone receptors. To facilitate widespread access and use of this transcript isoform-centric analysis of inter-individual correlations, a full suite of analyses such as those performed here can be performed from a lab-hosted server (gdcat.org) or in isolation from a shiny app or docker image.In sum we demonstrate that adopting a gene-centric approach to surveying correlation structure of transcripts across organs and individuals can inform mechanism of coordination between metabolic tissues. Initially, we queried several well-established and key mediators of physiologic homeostasis, such as https://github.com/mingqizh/GD-CAT or within the associated docker image. In addition, access to the GD-CAT web tool is also available through the web portal gdcat.org. This portal was created to provide a user-friendly interface for accessing and using the GD-CAT tool without the need to download or install any software or packages. Users can simply visit the website, process data and start using the tool. Corresponding tutorial and the other resources were made available to facilitate the utilization of the web tool on GitHub. The interface and server of the web were built and linked based on the shiny package using R (v. 4.2.0). Shiny package provides a powerful tool for building interactive web applications using R, allowing for fast and flexible development of custom applications with minimal coding required.All analyses, datasets and scripts used to generate the associated web tool (GD-CAT) can be accessed via: https://github.com/itamburi/gtex-app-kegg-pathways. Briefly, to interrogate broad tissue correlation structure, the number of genes which passed each biweight midcorrelation pvalue cutoff are shown normalized to the total number of genes corresponding to that pathway term. Pathways were selected by accessing all available GO annotations for all genes using the Universal Protein Resource49 and subletting genes where a given term is listed. To determine which tissues show the most co-correlation across genes and organs, KEGG terms shown were selected and each corresponding gene-tissue combinations were correlated. Tissues were then binned by the number of significant correlations which occurring both within and across organs among each selected KEGG pathway at indication correlation pvalues. Rank-ordering on the figure was shown by chemokine signaling at P<0.01 and each term was compared to a randomly sampled set of genes corresponding to the same number contained in each pathway.Detailed scripts and analyses for pathway-specific investigations across tissues in 10. These raw data can also be readily accessed from the associated R-based walkthrough: https://github.com/Leandromvelez/myokine-signaling. Briefly, these data were filtered to retain genes which were detected across tissues where individuals were required to show counts > 0 across all data. Given that our goal was to look across tissues at enrichments, this was done to limit spurious influence of genes only expressed in specific tissues in specific individuals. Hybrid mouse diversity panel data was collected from previously described studies34 and inter-individual differences were compared at the strain-level to maximize possible comparisons between historical data.All human data used in this study can be immediately accessed via web tool or docker to facilitate analysis. Metabolic tissue data was accessed through GTEx V8 downloads portal on August 18, 2021 and previously described17. We note that while the WGCNA package was used to calculate coefficients and corresponding students pvalues, this generalized framework does not utilize any module generation. Associated qvalue adjustments were applied using the Benjamini-Hochberg FDR from the R package “stats”. These BH adjustments, as opposed to standard qvalue adjustments, were selected given their efficiency in CPU usage on the hosted server.biweight midcorrelation coefficients and corresponding p-values within and across tissues were generated using WGCNA bicorandpvalue functionPathway enrichments were generated using gene set enrichment analyses available from the r package clusterprofiler. Specifically, the bicor coefficients were used as the rank-weight of each gene and enrichment tests performed by permuting against the human or mouse reference transcriptome. Terms used for the enrichment analyses were derived from Gene Ontology  which were accessed using the R package enrichR. For this analysis and on the available app, input genes were determined at indicated qvalue threshold.https://github.com/cvan859/deconvolution. Briefly, sn-RNA-seq data was accessed from the Human cell atlas20 for matching organ datasets with metabolic tissues. From these data, 4 deconvolution methods were applied using ADAPTS21 where DeconRNA-Seq22 was selected for its ability to capture the abundances of the most cell types across tissues such as liver heart and skeletal muscle (17.All scripts and deconvolution data produced is available at: l muscle –3. The fSupplement 1