A significant restructuring of the healthcare services has taken place since the declaration of the coronavirus disease 2019 (COVID‐19) pandemic, with elective surgery put on hold to concentrate intensive care resources to treat COVID‐19 as well as to protect patients who are waiting for relatively low risk surgery from exposure to potentially infected hospital environment.Multicentre study, with 19 participating centers, to define the impact of the pandemic on the provision of aortovascular services and patients' outcomes after having adapted the thresholds for intervention to guarantee access to treatment for emergency and urgent conditions. Retrospective analysis of prospectively collected data, including all patients with aortovascular conditions admitted for surgical or conservative treatment from the 1st March to the 20th May 2020.A total of 189 patients were analyzed, and 182 underwent surgery. Diagnosis included: aneurysm (45%), acute aortic syndrome (44%), pseudoaneurysm (4%), aortic valve endocarditis (4%), and other (3%). Timing for surgery was: emergency (40%), urgent (34%), or elective (26%). In‐hospital mortality was 12%. Thirteen patients were diagnosed with COVID‐19 during the peri‐operative period, and this subgroup was not associated with a higher mortality.There was a significant change in service provision for aortovascular patients in the UK. Although the emergency and urgent surgical activity were maintained, elective treatment was minimal during early months of the pandemic.The preoperative COVID‐19 screening protocol, combined with self‐isolation and shielding, contributed to the low incidence of COVID‐19 in our series and a mortality similar to that of pre‐pandemic outcomes. CTcomputed tomographyNHSNational Health ServicePEARSpersonalized external aortic root supportPPEpersonal protective equipmentUKUnited Kingdom1Severe acute respiratory syndrome coronavirus 2, the virus that causes coronavirus disease 2019 (COVID‐19), was first described a as cluster of cases of pneumonia at Wuhan (China) on the 31 December 2019.An extensive restructuring of the healthcare services has taken place due to the need for reallocation of intensive care resources to treat patients with COVID‐19. In the United Kingdom (UK) elective surgery was put on hold during the early months of the pandemic to concentrate resources on acute services as well as to protect surgical patients from exposure to potentially infected hospital environments.At the beginning of the lockdown in the UK, we redefined the current guidelines for treatment of aortovascular pathologies and adapted the thresholds for intervention to the current service provision.2Retrospective analysis of prospectively collected data from all patients who were admitted with aortovascular pathologies  during the early months of the pandemic (1 of March to 20 May 2020) in the 19 participating centers from the UK.The participating centers, grouped by regions, are: London—Barts Heart Centre, Royal Brompton and Harefield Hospitals, and Hammersmith Hospital; Southeast—Royal Sussex County Hospital (Brighton), University Hospital Southampton, and John Radcliffe Hospital (Oxford); West Midlands—Queen Elizabeth Hospital (Birmingham), University Hospital Coventry, and Royal Stoke University Hospital; East Midlands—Glenfield Hospital (Leicester); Northwest—Liverpool Heart and Chest Hospital and Blackpool Victoria Hospital; Yorkshire and Humberside—Sheffield Teaching Hospital and Castle Hill Hospital (Hull); Northeast—Freeman Hospital (Newcastle) and James Cook University Hospital (Middlesbrough), Scotland—Royal Infirmary of Edinburgh and Aberdeen Royal Infirmary, and Northern Ireland—Royal Victoria Hospital (Belfast).This centers represent 66% of the aortic units in the country, including the largest specialized aortic centers, and cover most of the geographical areas.The other 15 aortic units declined to participate in the study for different reasons including inability to provide emergency surgey cover during the COVID‐19, insufficient resources to collect the data and/or individual preferences.Details about preoperative demographics and risk factors, operative details, and postoperative complications were obtained from National Cardiac Databases of the individual centers. A detailed analysis of the COVID‐19 screening peri‐operatively and its effect on decision making and timing of the treatment were also analyzed.p values when comparing different groups according timing for surgery (χ2 test).The anonymized patient data from individual centers were transferred securely to St. Bartholomew's Hospital for data cleaning and analysis. Data analysis was performed with SPSS version 25, including descriptive analysis of numeric (mean and range) and categorical values  as well as Ethical approval was obtained from each participating center after acceptance of the study protocol at the recruiting center . Individual patient consent was waived due the anonymised nature of the data.2.1A protocol to treat aortovascular pathologies was created at Barts Heart Centre on the 25 March 2020 and endorsed by the UK Aortic Surgery group and the Society of Cardiothoracic Surgery for Great Britain and Ireland (SCTS).The protocol defines the cohort of aortovascular patients eligible for referral and treatment during the COVID‐19 pandemic, triaged in several categories depending on the level of urgency at time of referral/presentation.Level 1: Elective—asymptomatic patients with indications for routine surgery should be added to an elective waiting list and be reviewed regularly with the plan to treat when the COVID‐19 pandemic resolves.Level 2: Urgent—the revised agreed thresholds for intervention during the COVID‐19 pandemic, after the appropriate screening, included: large aneurysms , patients with new or persistent chest/back pain and other urgent conditions such as pseudoaneurysms, mycotic aneurysms and aortic graft infections.Level 3: Emergency—patients with acute aortic syndromes  and ruptured aneurysms of any anatomical location should be accepted and operated at the earliest opportunity, including out‐of‐hours, due to the increased risk of mortality while waiting.2.2On the 26 March 2020 a preoperative screening protocol for detection of SAVR‐CoV‐2 virus was intorudces at St. Bartholomew's Hospital after multidisciplinary review of available evidence an Public Health Guidance analysis.It included a combination of two negative nasophayngeal swabs for polymerase change raction for ribonucleic acid (PCR‐RNA) analysis, a noncontrast computed tomography (CT) thorax to assess changes in the lung parenchyma suggestive of COVID‐19 disease and analysis of the lactate dehydrogenase levels and lymphocyte counts.These results were not awaited in emergency situations Patients who tested positive in the preoperative screening posed a challenge and were managed in isolation within highly‐specialized clinical areas, monitoring their symptoms while waiting for the COVID‐19 infection to resolve, if and when time permitting.Irrespective of the patients COVID‐19 status, the surgical procedures and postoperative care in intensive therapy unit (ITU) environments were performed using universal measures of personal protective equipment (PPE).3A total of 182 patients with aortovascular pathologies were operated from 1 March to 20 May 2020 in the 19 participating centers.Mean age was 63 years (range 26–83 years), 33% of the patients were female and the mean EuroScore II was 9.6 (range 0.9–61.2). The details of preoperative risk factors are listed in Table The aortovascular pathologies mandating admission during the pandemic period were: aneurysm , aortic dissection , intramural hematoma , penetrating aortic ulcer , pseudoaneurysm , aortic valve endocarditis , and other .Timing for surgical intervention was considered as emergency , urgent , or elective .n = 31, mean size 44 mm (range 31–86 mm); ascending aorta ; aortic arch ; descending thoracic aorta , and thoracoabdominal aorta .Anatomical location of the aneurysms and the mean aortic diameters were as follows: aortic root (n = 61), acute DeBakey II (n = 5), acute DeBakey III (n = 5), chronic DeBakey I (n = 1), and chronic DeBakey III (n = 3).The acute aortic syndromes were categorized depending on antomical presentation and chronicity as follow: acute BeBakey I (n = 55), valve‐sparing root replacement (n = 11), aortic root plasty (n = 5), personalized external aortic root support (PEARS) procedure (n = 1), aortic valve and ascending aorta replacement (n = 41), isolated ascending aorta replacement (n = 29), arch replacement (n = 24), frozen elephant trunk repair (n = 9), descending thoracic aorta replacement (n = 13), thoraco‐abdominal aorta replacement (n = 4), and endovascular procedures (n = 6).The type of surgical procedures performed were: aortic root replacement (n = 11), multiorgan failure (n = 5), neurological (n = 3), mesenteric ischemia (n = 2), and other (n = 1).Overall in‐hospital mortality was 12.1% (22 patients), with a 5.5% rate of intra‐operative deaths (10 patients). Causes of death were listed as followed: Cardiac related (Postoperative complications included reintubation (4.4%) and tracheostomy (7.1%), postoperative stroke (8.8%), and need for hemofiltration (8.8%). Mean intubation and ventilation time was 2.9 days (30 min–53 days) and mean length of ITU stay was 4.7 days . Other postoperative complications such as stroke, renal failure and haemofiltration and sternal wound infection were also significantly higher in the emergency group  and comorbidities rather than COVID‐19 disease (only patient had CT changes suggestive of COVID‐19). The surgical turn down rate was 2.6% and mortality in this group was 60%.Three patients with a type A aortic dissection died due to aortic rupture before surgery could be offered .One patient presented with uncomplicated acute DeBakey III aortic dissection and did not require surgical treatment. He was diagnosed of COVID‐19 during the hospital admission but did not develop any symptoms or respiratory complications.3.2Preoperative COVID‐19 status was unknown in 135 patients (74.1%), either because it was not performed (most of the regions were not performing routine tests before the 25th March) or because the results were not awaited due the critical emergency nature of the diagnosis.Forty three patients (24.7%) were confirmed COVID‐19 negative before their operation and four patients (2.2%) were diagnosed of COVID‐19 during the preoprative period and their operation delayed until they became swab negative.Preoperative CT chest for assessment of COVID‐19‐related changes in the lung parenchyma was only available in 86 patients (47.2%). Only two patients showed suggestive changes of COVID‐19 in the CT, and in one of them they were already present in the preoperative CT but the severity of his aortic condition overweighted the risk of developing COVID‐19 related complications and surgical indication was made.3.3A total of 13 patients were diagnosed of COVID‐19 disease in the peri‐operative period (7.1%).Seven patients (3.8%) were diagnosed in the postoperative period (mean postoperative Day 11 (range 2–24). Of them only one required prolonged mechanical ventilation but there was no associated mortality.Four patients (2.2%) were diagnosed during the preoperative screening and their operations were delayed until COVID test confirmed negative (mean delay 9 days [range 2–13 days]). None of these patients developed any COVID‐19 related complications.One patient had signs of COVID‐19 lung disease on the preoperative CT scan despite being asymptomatic and swab negative. He required reintubation and ventilation 7 days after surgery due chest infection and died of respiratory failure.The last patient, mentioned earlier, was treated conservatively for acute DeBakey III aortic dissection and did not develop any COVID‐19 related complications.3.4There was a clear temporal and regional variation on the delivery of aortovascular services.The reduction of surgical activity was noticeable coinciding with the start of the lockdown in the UK on the 23th March, and reflected the interruption of elective surgery in London after the second week of the pandemic. Similarly, the number of elective operations decreased significantly in the rest of the regions in UK. However, from weeks 5 to 7 onwards some elective activities restarting slowly in certain regions , while in the majority of areas the elective activity was completely stopped during the first months of the pandemic Figure .The number of urgent and emergency operations has been slowly increasing weekly, reaching a plateau by Week 9 (end of April). The regions providing the largest nonelective activity were London, North West and South East Figures  and 2.Other regions such as West Midlands have seen their aortovascular activity almost interrupted due to a more strict restructuring of services coinciding with a higher incidence of COVID‐19 patients in the areas covered Figure .The London region lead the provision of services due to the creation of the Pan London Emergency Cardiac Surgery Service, that concentrated all the surgical activity for the region into two of the service delivery centers (Barts Heart Centre and Brompton and Harefield NHS Trust) designed as COVID‐19 free‐environments Figure .The majority of regions have managed to maintain the emergency activity when compared with the pre‐pandemic period, as obtained by comparing the acute aortic syndromes treated in the equivalent months last year prior the pandemic Table . Mortali4In the UK, like in the rest of the world, the COVID‐19 Pandemic affected the healthcare service provision significantly. The National Health Service (NHS) was re‐organized across all countries in UK with the guidance of the Public Health England and the Central Government. Private healthcare providers were also included in the overall provision of service across every regions.There was a clear reduction on the surgical activity in all units coinciding with the start of the lockdown on the 23th March, reaching the lowest activity by the third week of the lockdown to increase slowly afterwards, mainly due to the protection of the emergency services.Elective aortovascular surgical activity discontinued almost completely after the lockdown status was declared and it has only been restarted very slowly in certain regions of the UK towards the end of April 2020, while in the majority of the regions has been completely stopped Figure .The opposite effect has been seen with the emergency services; the combined urgent and emergency activity decreased coinciding with the lockdown announcement but increased progressively during each week of April Figure .The reduction of elective surgery, which came to halt in most of the regions, is explained by the restructuration of the healthcare systems, preserving the critical care capacity to attend COVID‐19 patients who would require respiratory and multiorgan support, as well a reallocation staff to those clinical areas.Also, the increased anxiety of the general public after the declaration of the lockdown, led to a significant reduction of attendance to the hospitals, including the emergency services.Compared with the prepandemic period national data for aortovascular procedures, it seems that the service provision for emergency aortovascular conditions has been protected during the early period of the COVID‐19 pandemic and similar outcomes to pre‐pandemic times have been achievedOverall, the majority of individual centers have been able to maintain similar activity for emergency procedures compared with the prepandemic period, although certain regions more affected by the COVID‐19 disease  have seen their ability to provide aortovascular cover canceled due to reallocation of the intensive care areas to treat respiratory patients Figure ; Table 3The impact of not treating aortic diseases has been already reported and a risk of increased 6 months mortality has been recognized.The preoperative COVID‐19 screening protocol,With this strategy, we have observed a low in‐hospital surgical mortality even for those who were diagnosed of COVID‐19 during the peri‐operative period.The fact that the majority of patients have been isolating at home during the lockdown period and have been shielded in the hospital only in contact with staff wearing full PPE measures, might have contributed to the low rate of COVID‐19 infection compared with other surgical series. Therefore, this finding of favorable outcomes following aortic surgery during early months of pandemic with appropriate screening protocol and postoperative care with staff wearing full PPE, supports the continuing service provision in subsequent weaves of pandemic. The knowledge of outcomes would be invaluable in consenting patients for surgery during the rest of the pandemic.5The service provision for aortovascular pathologies has changed during the early months of the pandemic while maintaining urgent and emergency activity.The preoperative COVID‐19 screening protocol, combined with self‐isolation and shielding, contributed to the low incidence of COVID‐19 in our series. Outcomes of surgery for aortovascular patients during this period are comparable with pre‐pandemic national benchmarked results. These results support continuing surgery for this patient group during the recovery phase or future waves of the COVID‐19 pandemic.This study is registered as service evaluation project and therefore need for ethical approval was not requiredAll the authors declare that there are no conflict of interests.


Sci., 2021, DOI: 10.1039/D1SC02413B.Correction for ‘Suppressing carboxylate nucleophilicity with inorganic salts enables selective electrocarboxylation without sacrificial anodes’ by Nathan Corbin  We regret that there was a minor error in the structure of the benzyl chloride in The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers.


We report on two patients with stasis symptoms, including vomiting and nausea that were caused by deformity, stenosis, and decreased gastric peristalsis associated with artificial ulcers after endoscopic submucosal dissection (ESD). In both cases, the symptoms remained unresolved despite repetitive endoscopic balloon dilation (EBD). Therefore, laparoscopic gastrojejunostomy was performed. Soon after the procedure, their food intake was improved. Laparoscopic gastrojejunostomy can be an option for the treatment of gastric outlet obstruction induced by a large field of gastric ESD that is refractory to EBD. Artificial ulcers associated with endoscopic submucosal dissection (ESD) of large gastric epithelial neoplasms can lead to stenosis and deformity. A wide resection area that comprises more than three‐quarters of the circumference is a significant risk factor for post‐ESD stenosis in both the cardia and antrum. Endoscopic balloon dilation (EBD) is the standard approach for post‐ESD stenosis management.Gastrojejunostomy is the standard palliative approach for gastric outlet obstruction (GOO) caused by malignancies such as gastric and pancreatic cancers. Laparoscopic gastrojejunostomy (Lap‐GJ) can achieve early recovery of bowel movement and resumption of oral feeding.All participants provided written informed consent, and the Tonan Hospital Institutional Review Board (IRB) granted permission to review the patients’ records (IRB number: 498). The study was conducted according to the principles of the Declaration of Helsinki.An 83‐year‐old male underwent esophagogastroduodenoscopy (EGD) as part of an investigation for epigastric pain, which revealed six tumors in the gastric body and antrum. Since the six tumors were spread across a large field Figure , total gAn 83‐year‐old female had previously undergone ESD for gastric cancer that extended from the lesser curvature to the anterior wall of the antrum; curative resection had been achieved. The large field of artificial ulcer, which comprised three‐quarters of the antrum, resulted in a post‐ESD deformity Figure  and b. TESD is generally applied for treating gastric epithelial neoplasms with low metastatic risk, regardless of their size.⁶ However, wide resection of the gastric epithelium in the antrum or cardia can result in stenosis and deformity, and ESD that reaches three‐quarters of the circumference is reportedly a significant risk factor for developing post‐ESD stenosis.Local steroid injection into artificial ulcers caused by ESD might prevent gastric deformities and stenosis in patients with gastric epithelial neoplasms; however, these findings were only based on small cohorts.Peristaltic dysfunction is also reported as a cause of GOO. Peristaltic dysfunction is speculated to be caused by injury of Latarjet's branch of the vagal nerve during ESD in the lesser curvature of the upper stomach.Although EBD is effective in treating post‐ESD stenosis, stasis symptoms caused by gastric deformity and decreased gastric peristalsis may be intractable. There are some reports about noninvasive GOO avoidance methods such as polaprezinc administration, but there is insufficient evidence to support its use. Therefore, surgical intervention is necessary for GOO that does not improve even after repetitive EBD. Elderly patients are easily enfeebled by poor food intake; therefore, shortening the stasis symptom period is essential for them. In addition, frequent vomiting related to intractable GOO will cause aspiration pneumonia, which may increase mortality in elderly patients. Lap‐GJ can achieve early recovery of bowel movement and resumption of oral feeding.⁵ Lap‐GJ is less invasive than distal gastrectomy, and successfully ameliorated stasis symptoms in our cases. Lap‐GJ may promote early discharge and a stable life at home, leading to good clinical outcomes for elderly patients. A drawback of Lap‐GJ is that deformity and stenosis of the preserved stomach remains. It may lead to poor examination and missed diagnosis of metachronous gastric cancer, which sometimes occurs after ESD over a long‐term period; hence, Lap‐GJ may not be recommended for younger patients.In conclusion, Lap‐GJ can be an option for the treatment of post‐ESD GOO refractory of EBD, especially in elderly patients.The authors declare that there is no conflict of interest.None.


Morton's neuroma is an entrapment neuropathy of the third common plantar digital nerve, caused by the deep transverse metatarsal ligament (DTML). Minimally invasive or percutaneous surgery is a very common procedure, but surgical effectivity of this technique remains controversial. The goal of our study was to prove the effectiveness and safety of a new ultrasound‐guided technique for DTML‐release in a cadaver model.The DTML was visualized in 10 fresh frozen donated body to science‐feet  using an US device . Consecutively, minimally invasive ultrasound‐guided surgery was performed. Exclusion criteria of the donated bodies to science were previous history of forefoot surgery and space occupying mass lesions. The complete release of the ligament was achieved in all specimens without damage of any important anatomical structures as proven by anatomical dissection.The results of this study indicate that our novel approach of an ultrasound‐guided release of the DTML is safer and more effective compared to blind techniques. The DTML could reliably be visualized and securely cut through a dorsal, minimally invasive surgical incision of only 2 mm. The latter in particular, helps to avoid too much splaying of the toes . The DTML is a mostly transverse band embedded in the plantar metatarsophalangeal joint capsule complex, which is composed of four parts connecting all heads of the metatarsal bones and heads of phalanges to form a functional unit.Dorsally to the DTML a synovial bursa  can be found that protects both metatarsal heads and the tendons of the interosseous muscles from fraying. Sandwiched between the ligament and the plantar fat body  , which belong to the Body Donation Centre.The individuals had given their written informed consent for their use for scientific purpose prior to death. According to National Law, scientific institutions  are entitled to receive the body after death mainly by means of a specific legacy, which is a special form of last will and testament. No bequests are accepted without the donor having registered their legacy and been given appropriate information upon which to make a decision based upon written informed consent (policy of ethics); therefore, an ethics committee approval was not necessary , a scalpel for minimally invasive surgery with a beaver 64 blade, and a buttoned probe.2.1After US‐visualization of the DTML (Step I), we performed a landmark‐based, minimally invasive US‐guided surgical approach in all specimens (Step II), followed by anatomical dissections of the third intermetatarsal space (Step III) evaluating the effectiveness and safety of surgical release of the DTML.2.1.1To avoid alteration of the clarity of the US image due to preprocedural local anesthesia bolus in such small probe girth we recommend a proximal anesthesia procedure  or at tarsal‐metatarsal joint level.° to identify the ligament spanning between the plantar plates, and the position of the neurovascular bundle in its typical location , the step was repeated.Prior to anatomical dissection, a retractor was inserted dorsally by enlargement of the initial incision in order to verify a widening of the intermetatarsal space under fluoroscopy Figure .2.1.3An anatomical dissection of all 10 ft was finally made to verify a complete release of the DTML and to proof if no adjacent anatomical structures were injured, respectively: extensor expansion, interosseous muscles, lumbrical muscle, the collateral ligaments, plantar plate, vessels and nerves. For that, the widened incision for placing the first retractor as mentioned above, a further extension was done longitudinally, and another retractor inserted. Fat and connective tissue were removed carefully until we could visualize all important structures and the complete release of the DTML, respectively Figures .3(Figure In all 10 ft, the DTML was successfully identified with US in two planes. Figure . With thFigure . The US‐Figure  This “whThe mean length of the incision necessary for our surgical approach was just 2 mm and thus the procedure may be defined as “ultra‐minimally invasive surgery” (Fernandez‐Gibello et al., Complete release of the DTML was confirmed in all 10 ft without any injury of crucial adjacent structures.4In the current anatomical study, we describe a new, landmark‐based minimally invasive ultrasound‐guided surgical release of the DTML. The latter accounts for the majority of cases with compression of the third common digital nerve within its respective intermetatarsal space, leading to Morton's neuroma (Larson et al., In podiatric surgery, minimally invasive blind approaches are common and, at least in short‐term, overall good outcomes regarding pain reduction were communicated (de Oliveira et al., Apart from interventional techniques, alternative nonsurgical options like manipulation and/or mobilization exist (Matthews et al., On the other hand, both neurolysis and neurectomy have shown good and similar results in pain relief after Morton's neuroma procedures (Lu et al., 5Our new ultrasound‐guided, minimally invasive surgical approach for treatment of Morton's neuroma seems to be a safer and more effective technique in the release of the DTML as compared to previously reported blind techniques. The DTML shows the same and constant US‐features as any other true ligament in the human body. This enables its reliable visualization, which is fundamental to a safe, US‐guided transection that avoids injury to adjacent anatomical structures.The authors have nothing to declare, no conflict of interest.


I2: 64%). Men on GnRH antagonists showed increased risk of acute myocardial infarction  and arrhythmia  compared to GnRH agonists. Having a history of CVD was found to be an effect modifier for the associations with some CVD subtypes. Overall, we did not observe a difference in risk of overall CVD when comparing GnRH antagonists with agonists—though for some subtypes of CVD we noted an increased risk with antagonists. Further studies are required to address potential confounding caused by unadjusted variables such as severity of CVD history and PCa stage.Observational studies in prostate cancer (PCa) have shown an increased risk of cardiovascular disease (CVD) following gonadotropin‐releasing hormone (GnRH) agonists, whereas randomised‐controlled trials have shown no associations. Compared to GnRH agonists, GnRH antagonists have shown less atherosclerotic effects in preclinical models. We used real‐world data from five countries to investigate CVD risk following GnRH agonists and antagonists in PCa men. Data sources included cancer registries, primary and secondary healthcare databases. CVD event was defined as an incident or fatal CVD. Multivariable Cox proportional hazard models estimated hazard ratios (HRs) and 95% confidence intervals (CIs), which were pooled using random‐effects meta‐analysis. Stratified analyses were conducted by history of CVD and age (75 years). A total of 48 757 men were on GnRH agonists and 2144 on GnRH antagonists. There was no difference in risk of any CVD for men on GnRH antagonists and agonists  agonists has been associated with an increased risk of cardiovascular disease (CVD). Preclinical studies have indicated that newer GnRH antagonists may cause fewer atherosclerotic effects than GnRH agonists. In this meta‐analysis of prostate cancer studies, however, the authors found little benefit of GnRH antagonists over GnRH agonists, in terms of CVD risk. If anything, men taking GnRH antagonists may have an increased risk of acute myocardial infarction and arrhythmia compared to GnRH agonists. Further studies are warranted. ADTandrogen deprivation therapyAMIacute myocardial infarctionBCRBelgian Cancer RegistryBMIbody mass indexCIconfidence intervalCVDcardiovascular diseaseFDAFood and Drug AdministrationFSHfollicle‐stimulating hormoneGnRHgonadotropin‐releasing HormoneHFheart failureHRhazard ratioICDInternational Classification of DiseasesIHDischaemic heart diseaseNHSSNational Health Service ScotlandPCaprostate cancerPMSINational Hospital‐discharge Summaries database systemPRONOUNCEA Trial Comparing Cardiovascular Safety of Degarelix vs Leuprolide in Patients with Advanced Prostate Cancer and Cardiovascular DiseasePSAprostate‐specific antigenRCTrandomised‐controlled trialROBINS‐IRisk of Bias in Non‐Randomised Studies of InterventionsSASstatistical analysis softwareSESsocio‐economic statusSNIIRAMSystème National d'Informations Inter‐Régimes de l'Assurance MaladieSTATAstatistics and dataTHINThe Health Improvement Network1In 2010, the United States Food and Drug Administration (FDA) issued a requisite for gonadotropin‐releasing hormone (GnRH) agonists, a main form of androgen deprivation therapy (ADT) for locally advanced and metastatic prostate cancer (PCa), to carry a safety warning on the drug labels after several observational studies,Phase II and phase III studies showed no difference in terms of efficacy and baseline testosterone levels in men receiving GnRH antagonists for 1 year compared to men receiving various GnRH agonists for their PCa.ClinicalTrials.gov identifier: NCT02663908) is recruiting to compare the risk of fatal or nonfatal CVD in 900 men with PCa receiving GnRH agonist or antagonist as primary treatment.A phase III RCT , acute myocardial infarction (AMI), arrhythmia, heart failure (HF) and stroke.22.1This observational study combined data from five countries to investigate the association between GnRH agonists or antagonist (degarelix) and risk of CVD in men with PCa. All men with PCa prescribed or dispensed GnRH agonists or GnRH antagonists were included in the study. A detailed study protocol aimed to minimise heterogeneity in terms of data collection across countries by outlining exact codes for extraction of all study variables is published elsewhere.Data from the United Kingdom's The Health Improvement Network (THIN) database (excluding Scotland)2.2Exposure was defined as a prescription or dispensation of GnRH agonists or GnRH antagonists. We included all men with locally advanced or metastatic PCa  CVD. Six specific CVD outcomes were explored: any CVD , IHD (ICD‐10: I20‐I25), AMI (ICD‐10: I21), arrhythmia (ICD‐10: I44‐I49), HF  and stroke . In Belgium, ICD‐9 equivalent codes were used in cases where no ICD‐10 classification was available. In the United Kingdom, the THIN database made use of already published readcodes instead of ICD codes .2.4In addition to age, we obtained information on the following covariates to better understand data heterogeneity across countries: follow‐up time, year of PCa diagnosis, stage of PCa, total Gleason score, prostate‐specific antigen (PSA), any prior PCa treatment, type of ADT, ADT specifics, history of CVD indicator and number of previous CVD events Table . Additio2.5I2 statistic was calculated to determine the proportion of variation in the estimates due to heterogeneity. To assess the effect of heterogeneity, we then performed a sensitivity analysis excluding the United Kingdom as the data were collected using readcodes—as compared to ICD codes in Scotland, Belgium, the Netherlands and France. We also conducted stratified analyses by history of CVD indicator and age (<75 and ≥75 years). An age of 75 years was used as a cut‐off point in the study because the mean age was 73 or 74 years. Moreover, men above 75 years may be more likely to present with very advanced disease and this difference was accounted for by the analysis.We conducted a two‐stage analysis: firstly, we obtained country‐specific hazard ratios (HRs) from Cox proportional hazards models using age as a timescale to assess heterogeneity in each country, and secondly, we conducted a meta‐analysis. The Cox models included stratified analysis (history of CVD indicator and age at cut‐off point of 75 years) from each country with age as a timescale. The country‐specific HRs from Stage 1 were then combined in a random‐effects meta‐analytic model assessing the risk of any CVD and CVD subtypes comparing men on GnRH agonists with men on GnRH antagonists. The A further sensitivity analysis was also conducted to exclude men who may have been on GnRH agonists or GnRH antagonists for less than 3 months to eliminate short‐term neoadjuvant or adjuvant use.All country‐specific analyses were conducted using different SAS versions in Belgium (9.4) and France (9.4) and statistics and data (STATA) versions in the United Kingdom (14C), Scotland (14) and the Netherlands (14C). The meta‐analysis was conducted using STATA version 14C.3Table Socio‐demographic factors were only available in the United Kingdom and high missing numbers for BMI, SES, smoking status and civil status resulted in an exclusion of these variables from the analytical models. Moreover, clinical characteristics of PCa were also not uniformly available in all countries. We reported these variables for descriptive purposes and no further analyses were conducted using these variables.I2 = 64%). However, men with PCa on GnRH antagonists had an increased risk of developing AMI  and arrhythmia  compared to men on GnRH agonists. An increased risk was observed for any CVD  compared to those on GnRH agonists.Table I2 = 0%) and arrhythmia . No remarkable differences in results were observed when excluding the United Kingdom . Even though we have accounted for history of CVD by history of CVD indicator stratified analysis, we may have selected a population with underlying CVD risk leading to an increased risk of CVD in men on GnRH antagonists observed in our study. Moreover, we only accounted for history of CVD indicator 12 months prior to GnRH initiation due to data unavailability, which may also have limited the number of CVD events in both arms of the study. The generic history of CVD indicator variable may have led to a loss of granularity in terms of assessment of history of CVD. This may have contributed to confounding by indication in our study due to the inability to adjust for precise history and severity of prevalent CVD. Moreover, men with more advanced stage PCa who are given more aggressive forms of PCa treatments may already have had elevated CVD risks due to their disease stage and treatments. By not accounting for PCa stage in our study, we may have missed some of the information indicative of treatment history and potential increased CVD risks.Our findings showing an increased risk of CVD subtypes in men on GnRH antagonists compared to GnRH agonists contradicts prior literature showing an increased CVD risk among men using the GnRH agonists compared to GnRH antagonists.In our methodological protocol, we used the Risk of Bias in Non‐Randomised Studies of Interventions (ROBINS‐I) tool to assess our study design, which emphasised three main forms of biases: misclassification of study variables, channelling or indication and unmeasured confounding.In this large prospective cohort study, we found it difficult to fully homogenise study variables . A largeHeterogeneity in data sources at the point of the data capture process may also reflect the results of our study. Neither healthcare records nor claims databases have research as a primary intention at point of data capture. Although claims databases reflect diagnosis codes recorded to justify medical prescriptions and procedures, electronic healthcare records reflect data captured to support clinical care that may not represent a complete medical history.Results for some subtypes of CVD were limited due to the data sources that they were obtained from. For example, the acute nature of AMI means that it is usually recorded in an acute hospital setting.A key strength of our study was the use of data from five countries that made study results applicable to the general PCa population. Moreover, the use of different types of databases  also ensured the inclusion of rare, adverse events that may not have been identified in an RCT. However, our study also highlighted the challenges involved of using real‐world data. Although the potential for real‐world data is large in the healthcare setting, differences in data sources need supervised reconfiguration of data for real‐world data to achieve its full potential. The way forward for researchers using real‐world data is to combine and analyse “big data” from databases from various institutions into a single platform through projects such as the GetReal Initiative5Our study across five countries provided little support for a difference in risk of any CVD between GnRH antagonists compared to GnRH agonists, but there was some evidence of increased risk of certain CVD subtypes. Since our results are based on real‐world data, they may be more applicable to the general PCa population who are on hormonal treatment. However, the potential for indication bias in our study needs to be addressed through RCTs, such as the PRONOUNCE trial.JGK is an employee of the PHARMO Institute for Drug Outcomes Research, which is an independent research institute that performs financially supported studies for government and related healthcare authorities and pharmaceutical companies. The other authors declare that there is no conflict of interest.The views expressed in this article are the author(s) own and not that of any particular institution or funder.Ethical approval was obtained for all data used in the study from relevant ethical committees and healthcare authorities in the five countries.AppendixS1: Supporting InformationClick here for additional data file.


JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.Currently, the cell of origin for osteosarcoma or other primary skeletal tumors is largely unknown. Recent reports identifying specific cell types comprising bone now newly enable investigation of this topic. Specifically, CXC motif chemokine 12 (CXCL12)‐abundant reticular (CAR) cells are a specific skeletal stromal cell type that orchestrate the bone marrow microenvironment through cross‐talk with hematopoietic and endothelial cells and a likely candidate cell of origin for at least a subset of primary skeletal tumors. Here, we analyze osteosarcomas via immunohistochemistry for known markers of CAR cells such as leptin receptor (LEPR), B‐cell factor 3 (EBF3), CXCL12, and platelet‐derived growth factor receptor alpha (PDGFRA). A large proportion of high‐grade tumors expressed LEPR, PDGFRA, and EBF3 but not CXCL12. These data raise the hypothesis that CAR cells are the cell of origin of this osteoblastic osteosarcoma subset, a finding with implications for the cellular oncogenesis of primary osteosarcoma and the development of effective targeted therapies. © 2021 The Authors.  Although precision medicine–targeted agents and immunotherapies have aided in the treatment of other cancers, the standard of care for osteosarcoma is still limited to combination chemotherapy and surgical resection, approaches that date back to the 1980s. Identifying the lineage of cells responsible for osteosarcomas will be a critical step toward elucidating the mechanism of oncogenesis and developing effective, targeted therapies that are based on this underlying biology.Osteosarcoma accounts for approximately 1% of all cancer cases in the United States, making it the most common primary malignant bone tumor.1, 2 Recent work identifies that skeletal stem cells and progenitors are not a monolithic group but rather include several distinct cell types, each of which have different signature locations, functions, and transcriptional profiles. These discrete sets of skeletal progenitors include CXC chemokine ligand (CXCL)12‐abundant reticular (CAR) cells. CAR cells are specialized, long‐lived skeletal cells that regulate the bone marrow hematopoietic niche through the expression of cytokines and growth factors. CAR cells are defined by their expression of leptin receptor (LEPR), Cxcl12, and early B‐cell factor 3 (EBF3). PDGFRA is expressed by CAR cells but also other populations as well. In addition to orchestrating the bone marrow niche, these cells have the capacity to move from a largely quiescent basal state to differentiate into osteoblasts, especially in response to skeletal injury. The signature cytokine of CAR cells is CXCL12, which binds CXCR4 and activates signaling cascades involved in cell proliferation, migration, and secretion. This CXCL12/CXCR4 axis directs leukocyte trafficking and hematopoietic homeostasis. Osteosarcomas downregulate CXCL12, compromising leukocyte trafficking and allowing for tumor growth and metastasis. Accordingly, strong expression of CXCL12 in osteosarcoma is associated with favorable prognosis.The human skeleton serves to protect vital organs throughout the body while serving an equally important role for hematopoiesis and mineral storage. Skeletal stem cells are responsible for differentiating into osteoblasts, adipocytes, and chondrocytes and are largely sufficient to recruit and organize the other cell types participating in the bone microenvironment.6, 7In this study, we sought to generate insight into whether cellular subsets of primary skeletal osteosarcoma express markers of skeletal stem or progenitor populations by staining a panel of tumors via immunohistochemistry for the defining markers of selected skeletal stem and progenitor lineages.22.1This study was approved by the Institutional Review Board of Memorial Sloan‐Kettering (MSKCC) and done in accordance with the U.S. Common Rule. A total of 16 osteosarcoma samples were taken from patients treated at MSKCC between 2000 and 2020. Diagnosis of osteosarcoma was confirmed by sarcoma pathologists, with the total set of specimens including nine high‐grade osteosarcomas and seven low‐grade parosteal osteosarcoma. Non‐cancerous bone from a clavicle fracture was utilized as a control for all stains and analyses.2.2 Commercially available antibodies were used for immunohistochemical (IHC) analysis: LEPR , PDGFRA , EBF3 , CXCL12 . Slides were analyzed using light microscopy and were graded using a negative (−), positive (+/++), strongly positive (+++) system.Human osteosarcoma samples were fixed in 10% neutral‐buffered formalin. Samples were processed via routine decalcification. Sectioning and staining  were performed by the Center for Translational Pathology at Weill Cornell using a previously published methodology.17 Com2.3Mann–Whitney test was conducted to compare high‐grade and low‐grade osteosarcomas following semiquantitative scoring for IHC signal intensity. Statistical analysis was performed using GraphPad Prism 8 .3Fifteen cases of primary osteosarcoma were analyzed for established markers associated with CAR cells  and subdivided into low‐grade parosteal (7/16) or high‐grade intramedullary (9/16) tumors . Expression of this set of CAR cell–associated markers appeared to largely co‐occur, as LEPR, PDGFRA, and EBF3 showed a high degree of co‐occurrence in every LEPR‐positive case except one displaying only co‐occurrence of EBF3.Immunohistochemistry for LEPR revealed a high propensity (8/9) for high‐grade osteosarcomas to be LEPR+, whereas low‐grade tumors displayed a lower rate of LEPR positivity 2/7) . PDGFRA clavicle fracture staining highlighted diffusely positive signal from stromal cells adjacent to bone matrix  cells have been characterized as a quiescent population of perivascular stromal cells that first emerge sometime during adolescence and contribute to adult bone formation. Either in response to injury or aging, these cells differentiate into osteoblasts or adipocytes.12 CAR however, important limitations must be acknowledged. Observational immunohistochemistry is unable to assign lineage status, and many tumors display an aberrant gain of expression in the markers not present in the physiologic cell of origin. Thus, it is also possible that the marker expression observed here instead reflects aberrant induction of a CAR cell‐like gene expression program in a non‐CAR cell lineage skeletal cell. This latter possibility would also be potentially important as convergent induction of such a gene expression program across tumors may indicate a selective advantage conferred by this gene expression program.In this study, we show the abundant expression of the CAR cell–associated surface marker LEPR, and the characteristic transcription factor associated with CAR cells, EBF3, in a subset of human osteosarcoma samples. The expression of these markers raises the possibility of a CAR cell lineage origin for these tumors;12 how LEPR has not yet been described as a marker of osteosarcoma despite a growing body of literature showing the importance of these cells in human and murine bone. Although this study solely focuses on immunohistochemistry of these tumors, the persistence of these lineage‐defining markers in a subset of osteosarcoma suggests that this subset of osteosarcoma may be derived from transformation of CAR cells. This suggests that sorting premalignant CAR cells, especially in patients with an increased risk of osteosarcoma, will be important to identify molecular, cytologic, or histologic CAR cell precursor lesions and therefore provide further evidence regarding the cell of origin for these tumors.Genetic studies using inducible and conditional knockout alleles in mice provide evidence both that EBF3 is a defining marker for CAR cells and that EBF3 is required for CAR cell function.18 LEPNotably, CXCL12 expression did not here track together with the expression of the other CAR cell–associated markers LEPR and EBF3. Likewise, while a subset of osteosarcoma here expresses CAR cell–associated markers, they have lost many other features of CAR cells, such as their typical reticular morphology and pattern of distribution throughout the marrow. These alterations in cellular morphology and distribution may reflect transformation induced changes and emphasize that while these tumors express some CAR cell–associated markers, they lack many CAR cell defining features. It has also been suggested that the CXCL12/CXCR4 axis serves a key role in the progression and metastasis of osteosarcomas and other cancers. Primary osteosarcoma tumors have also been shown to downregulate CXCL12 expression through an epigenetic mechanism to escape the bone and metastasize to other tissues. This emphasizes that evaluation of a broader signature of CAR cell–associated markers beyond staining for CXCL12 itself is necessary for the immunophenotyping of human primary skeletal tumors. The findings here also raise the issue that future studies on the prognostic significance of CXCL12 expression in osteosarcoma may need to deconvolute the possibility that CXCL12 may be associated with a distinct subset of disease derived from CAR cells from the impact of varying levels of CXCL12 expression. It will be important in future extensions of this work to evaluate whether these markers are retained in metastases.The etiology for CXCL12 expression not tracking with the expression of other CAR cell–associated markers is unclear, but literature in other tumor types suggests that loss of CXCL12 may confer a selective advantage. Aoki and colleagues found that CAR cells from patients with high leukemic burden expressed reduced levels of CXCL12 relative to patients with low leukemic burden.11 It  However, as an important limitation of the specimen cohort studied here, low tumor grade and periosteal anatomic location co‐occurred, making it not possible to disentangle the effects of these parameters on the rate of positivity for CAR cell–associated markers.The anatomic localization of these discrete skeletal stem and progenitor cell populations is critical to their function and can serve as a framework for analyzing osteosarcoma subsets. Our data show that low‐grade parosteal tumors were mostly CXCL12 negative, supporting the understanding that CAR cells reside in the perivascular niche of central marrow compartment. Although a small subset of LEPR cells have been reported to be periosteal stem/progenitor cells in the outer layer of the periosteum, the general lack of LEPR expression in low‐grade parosteal tumors suggests that there may be another periosteal progenitor population driving oncogenesis.24 How Our data add to literature showing that PDGFRA is coexpressed on LEPR cells and suggests that targeting PDGFRA may be of particular interest in this subset of disease. Additionally, a previous study identified a PDGFRA‐amplified subset of osteosarcoma, raising the possibility that markers such as LEPR or EBF3 will have utility in identifying the PDGFRA‐amplified subset of osteosarcoma for therapeutic targeting. Pharmacologic targeting of the LEPR pathway is also a potentially attractive therapeutic strategy for this subset of osteosarcoma.Improvement in prognosis and development of new treatments for osteosarcoma have plateaued over the past 30 years. A previous study showed that conditional deletion of PDGFRA in LEPR+ stromal cell cells and treatment with imatinib in a murine model of primary myelofibrosis suppressed LEPR+ cell expansion and ameliorated bone marrow fibrosis.25 Our Both further elucidation of the markers of these subsets of skeletal stem cells and application of these markers to human primary skeletal tumor specimens will be needed to extend the results here to identify neoplastic counterparts for other skeletal cell types. In addition to enabling further clinical study of this LEPR+ subset of osteosarcoma, it should be noted that each of these cell types, including LEPR+ cells, have one or more cre lines that allow for conditionally targeting these cells in a murine preclinical model. Knowledge of the specific cell of origin for these tumors would enable the development of novel preclinical models targeted to each of these specific lineages, thereby allowing for investigation of the differences in oncogenesis and therapeutic response as driven by the biology of these distinct lineages.Perhaps most importantly, these findings suggest that a broader cell of origin–based nosology for primary skeletal tumors is possible and that other skeletal progenitor populations, including cathepsin K (CTSK)‐lineage periosteal stem cells and parathyroid hormone‐related protein (PTHrP)‐positive growth plate resident stem cells, may each have characteristic associated neoplasms.8, 9Authors have no conflicts of interest5https://publons.com/publon/10.1002/jbm4.10596.The peer review history for this article is available at


As the global population ages, the issue of abdominal aortic aneurysm continues to grow. With the evolution of new devices and refined operative technique, aneurysm treatment via endovascular aortic repair is becoming increasingly favourable. This, however, is not without drawbacks, where regular surveillance is paramount to long‐term success and detection of post‐procedure complications. Of these complications, endoleak is the most notable and poses the greatest risk of potential future aortic rupture. The purpose of this review paper is to discuss the armada of imaging modalities used in the detection and evaluation of endoleak and their varying usefulness. Plain abdominal X‐ray is a cost‐effective tool in detecting gross graft abnormalities such as stent migration or deformity (kinking or fracture). Though it may raise suspicion for endoleak, X‐ray does not allow accurate classification of endoleak type when used alone. Duplex ultrasonography quantifies both aortic anatomy and real time flow dynamics. Most screening programmes are conducted using two‐dimensional ultrasound. Unfortunately, observer and equipment variability may lead to surveillance discrepancies—but reduced when utilising a dedicated vascular sonography laboratory. Contrast enhanced ultrasonography is a promising alternative to computed tomography, though still is emerging. Computed tomography angiography certainly has disadvantages —however, it provides near‐real surgical dimensions and highlights graft complications and concomitant disease (such as neighbouring infection). With widespread availability and short scan time, it certainly remains valuable in surveillance. Magnetic resonance angiography has a similar sensitivity to computed tomography (minus the radiation), however is plagued by movement and metal artefact. Other novel modalities in endoleak surveillance include four‐dimensional ultrasound, multiplanar intra‐operative probes, nuclear medicine and wall stress analysis. As the global population ages, the issue of abdominal aortic aneurysm continues to grow. Endovascular aortic repair has helped stem this issue, but from it arises the challenge of managing endoleak. We review the armada of imaging modalities available for the detection and evaluation of endoleak. It is well documented that the prevalence of abdominal aortic aneurysm (AAA) certainly increases per decade of life and is additionally four to six times more common in men.A disadvantage, however, of the endovascular technique is the need for regular monitoring and strictly orchestrated follow‐up. This is the case given the potential immediate and delayed procedure specific complications of endovascular repair, including endoleak, aneurysm rupture, graft limb occlusion and graft migration. These complications account for a reintervention rate that increases by as much as 11–12% each year for at least the first three post‐operative years.There are several imaging modalities available for post‐EVAR surveillance, some of which include plain film radiographs, duplex and colour duplex ultrasonography (DUS or CDUS), contrast enhanced sonography (CEUS), computed tomographic angiography (CTA) and magnetic resonance angiography (MRA). This brief review aims to discuss them in regard to their role in endoleak detection and surveillance only. Endoleaks are classified anatomically, based on the location of the leak.Plain abdominal radiography is a simple and cost‐effective adjunctive tool in the surveillance of EVAR patients, provided patient‐positioning and image capture techniques are protocol driven.Colour duplex ultrasonography (CDUS) combines standard brightness‐mode (B‐mode) imaging with Doppler ultrasound and a colour overlay to provide information on the anatomical features of the aorta and the stent‐graft, as well as dynamic flow information in real time. Repair guidelines and most population screening programmes are currently based on 2D CDUS.Ultrasound has been rivalled with CTA, which has long been considered the gold standard for EVAR surveillance, extensively in the medical literature. Compared with CTA, DUS appears to be troubled by a high inter‐ and occasionally intra‐observer variability;Compared with protocol‐based CTA, CDUS consistently has a lower sensitivity. A meta‐analysis of 31 studies suggested a sensitivity of 74%,While CDUS has a positive predictive value as low as 42%,Colour duplex ultrasonography deserves a spotlight for several other reasons. In the subset of type I and type III endoleaks, CDUS has a sensitivity and specificity of 83% and 100%, respectively.Surveillance is important for identifying the need for reintervention. It is generally agreed that type I and type III endoleaks warrant early intervention but there is no consensus on the treatment of type II endoleaks, unless aneurysm sac expansion is noted over time. DUS has been shown to be equivalent to CTA for measuring aneurysm size and detecting sac expansion.Beyond the numbers, CDUS has a number of limitations. The quality of the image is always potentially compromised by obesity, arterial wall calcification, bowel gas, ascites, abdominal wall hernias and subcutaneous emphysema.Contrast‐enhanced ultrasonography (CEUS) works the same way as standard colour duplex ultrasonography but employs the use of an intravenous contrast agent. Current approved agents include perfluorocarbon and sulphur hexafluoride which are administered as microbubbles.The contrast agent itself has an extremely low adverse effect profile. The microbubbles gradually embolize to the lungs where they are destroyed and it is safe for use in renal impairment.Like DUS, CEUS has been compared with CTA in the medical literature as a potential replacement for CTA surveillance. CEUS has a reported sensitivity of 93% to 99% and a specificity of 100% for identifying endoleak post‐EVAR.Combining DUS with an intravenous contrast appears to increase the sensitivity of the test and decrease the inter‐observer variability, particularly when combined with 3D rendering software and multiplanar probes.This imaging modality is limited by the same patient factors as DUS and is less accessible and slightly more expensive because it is a specialised test and contrast administration requires personnel, training and protocol change. While a lot of the literature on CEUS is emerging from Europe, CEUS is not routinely being used for EVAR surveillance in Australia, to our knowledge. It does still remain a promising alternative to CTA and does provide flow dynamic information that CTA does not.Computed tomography has developed rapidly over the past decade, and newer machines with greater precision are slowly improving the industry by lowering the radiation doses patients need to be exposed to. The radiation dose from a CTA may be enough to provoke cancer in as many as 1 in 2000 people,Beyond the radiation dose, the scan generally requires the use of an iodine‐based contrast. Though current literature suggests that there is no risk to renal function for intravenous iodinated contrast, the anecdotal experience of nephropathies post‐contrast remains a strong perception in the endovascular surgical community. Despite saline and sodium bicarbonate pre‐hydration protocols, post‐CTA nephropathy may affect up to 12% of patients receiving the scan, and 7% in those with no prior predisposing kidney disease.Despite these drawbacks, CTA does have a number of valuable qualities which have certainly contributed to its popularity for EVAR surveillance. Of all the available imaging modalities, CTA provides images and aortic dimensions closest to real surgical specimens. Other modalities particularly standard DUS tend to slightly underestimate the aortic diameter.The scan time itself is relatively short – an initial non‐contrast phase can be done rapidly, an arterial phase is generally performed 30 sec after injection of intravenous contrast, and delayed phases occur at between 80 and 300 sec post‐contrast.In a meta‐analysis, with CEUS as the comparator, CTA performed with a sensitivity of 70% and a specificity of 98%.The cost of one CTA scan has been cautiously estimated at around 500 Euro.Based on this information, some authors advocate for a limited non‐contrast CT to identify sac enlargement, and given a then high suspicion for endoleak, proceed to a contrast enhanced CT scan.Like CTA, MRA is generally performed in multiple stages. Most protocols begin with an axial T1‐weighted gradient echo image, followed by phases before and after intravenous gadolinium administration. MRA has a similar sensitivity to CTA and even outperforms it regarding the detection of type II endoleaks in nitinol EVARs specificallyThis imaging modality is perhaps plagued the most by movement and metal artefact out of all the modalities discussed so far. While nitinol stent grafts and platinum coils are easily visualised and cause little artefactual disturbance, elgiloy  and nickel alloy stents cause blurring from movement, and stainless steel can cause significant artefact and may even fracture or dislocate during the scan.Three‐dimensional DUS and CEUS are emerging as useful and accurate imaging modalities. They may well be an acceptable replacement for CTA in the close future and would minimise the burden of contrast complications and radiation while potentially decreasing the cost of surveillance. These technologies are not available everywhere and will have a learning curve, so any transition from CTA will have to be a slow one. Four‐dimensional modalities have also been described, but this description relates to those modalities being able to produce three‐dimensional images that are dynamic and can be viewed across an interval of time.Regarding nuclear medical imaging modalities, there is limited evidence that they can be accurately and effectively used in detecting and classifying endoleaks after EVAR, and some evidence suggesting that their accuracy is not yet comparable with CTA.Aneurysm size does not appear to be the sole indicator of rupture risk. Many large aneurysms do not rupture, and some small ones do. The fate of the large or growing remaining sac post‐EVAR has not been studied for obvious ethical concerns, where an aneurysm with a endoleak confers a risk of ongoing sac pressurisation and therefore AAA rupture risk. With this in mind, it is conceivable that surveillance modalities will target different endpoints in the future. Wall stress is one such candidate, and wall stress analysis is now possible (in a limited capacity) with CT scanning – where high‐resolution images can detect intramural stranding and local wall movement defects.Innovation has led to an armada of endoleak surveillance imaging tools, where the global literature pits one modality against another, and describes a number of modalities that simply are not available everywhere. Regardless, surveillance plans need to be tailored to the individual patient. Endoleaks will likely continue to be a problem until there are significant changes or advances in stent‐graft technology. The timing intervals appear to be largely agreed on, with surveillance scans planned at 1 and 12 months, and often another scan at 6 months.


Actually, liquid–liquid phase separation provides a simple but smart mechanism for the cell to control the spatial localization and processing of molecules, without relying on membrane boundaries. This Special ‘In the Limelight’ section, entitled ‘Membraneless organelles’, consists of three review articles, each focused on a particular aspect. The first article deals with assembly of coacervates as mediated by polyproline II helices, as well as with condensate stability. The second article addresses the formation of protein–nucleic acid coacervates by prion‐like proteins and their link to human diseases. Finally, the last article focuses on mitochondrial cytochrome  c translocation into the nucleus after DNA damage. This Special ‘In the Limelight’ section consists of three review articles on aspects related to membraneless organelles. The first article deals with coacervate assembly as mediated by polyproline II helices, the second addresses the formation of protein–nucleic acid coacervates by prion‐like proteins, and the last article focuses on mitochondrial cytochrome  MLOsmembraneless organellesPPIIpolyproline IIHow do cells enable internal spatiotemporal control of complex biochemical reactions? They have partly solved this question by creating compartments, or organelles, that allow distinct chemical environments. Most of these compartments are surrounded by membranes . It is thus easy to understand how such membrane‐bound compartments cohabit and work in the cells. On the contrary, many other compartments  lack membranes, making their coexistence inside cells harder to explain. Such membraneless organelles (MLOs) remain separated in the cell by avoiding mixture of their components with the surroundings. The following questions soon arise: ‘Are there molecules transported in and out of MLOs?’ and ‘How fast must the diffusion of the components within MLOs be to guarantee efficient chemical reactions?’.Recent experimental evidence has shown that many MLOs are liquid droplets formed by phase separation, thereby allowing MLO components to be rapidly concentrated in a concrete place in the cell. The transient assembly of liquid drops is driven by (a) multivalent weak interactions between signalling domains repetitively included in proteins and RNA and (b) substantial conformational heterogeneities of intrinsically disordered regions. In the case of cell pathology and devastating aggregation diseases, liquid–liquid demixing can eventually result in metastable condensates of intracellular matter, such as glass/hydrogels or amyloid‐like fibres, that undergo liquid–solid phase transitions , 2. Undec into the nucleus after DNA damage, where the hemeprotein inhibits the nucleosome assembly/disassembly activity of histone chaperones by binding to their acidic disordered regions [The three review articles in this Special ‘In the Limelight’ section, entitled ‘Membraneless organelles’, are focussed on how such nonequilibrium events in living cells control intracellular phase behaviour. It is noteworthy that different types of biomolecular condensates do not generally combine to form larger microdroplets, thereby suggesting that each of them uses a distinct class of attractive interactions. Within this frame, Laurents and coworkers discuss in the first article whether polyproline II (PPII) helices mediate the assembly of coacervates, as well as if the condensate stability is influenced by either the number of PPII helical tracts or the tandem PPII‐binding domains . The pot regions . Such inWe would like to thank all of the authors for their excellent contributions to this ‘In the Limelight’ section and hope the provided insights into this fascinating field will be of interest to all of our readership.The authors declare no conflict of interest.


A battery of tests from the Cambridge Neuropsychological Test Automated Battery (CANTAB) and 48 channel functional near‐infrared spectroscopy (fNIRS) measurements were performed before and after 24 hr of SD. Network metrics were obtained by graph theoretical analysis using the fNIRS records in resting state and during finger‐tapping sessions. During task, SD resulted in a significantly smaller decrease in the number and strength of functional connections (characterizing FC) in the frontal cortex. Changes in the global connection strengths correlated with decreased performance in the paired association learning test. These results indicate a global impact of SD on functional brain networks in the frontal lobes.Sleep deprivation (SD) is known to be associated with decreased cognitive performance; however, the underlying mechanisms are poorly understood. As interactions between distinct brain regions depend on mental state, functional brain networks established by these connections typically show a reorganization during task. Hence, analysis of functional connectivity (FC) could reveal the task‐related change in the examined frontal brain networks. Our objective was to assess the impact of SD on static FC in the prefrontal and motor cortices and find whether changes in FC correlate with changes in neuropsychological scores. Healthy young male individuals ( To assess the impact of sleep deprivation on static functional connectivity in the frontal lobe, functional near‐infrared spectroscopy and graph theoretical analysis were utilized before and after 24 hr sleep deprivation in healthy young male participants. Deprivation of sleep resulted in a significantly smaller task‐related decrease in the number of functional connections that correlated with decreased performance in the paired association learning test. These results indicate the global impact of sleep deprivation on functional brain networks in the frontal lobes. Importantly, studying task modulations of brain connectivity is essential. Changes in FC can be detected using functional near‐infrared spectroscopy (fNIRS). The advantage of fNIRS lies in its ability to directly capture local changes in cerebral hemodynamics by continuously monitoring concentrations of oxygenated and deoxygenated hemoglobin in the cerebral cortex  were recruited for this study. None of the volunteers reported smoking, drug abuse, excessive alcohol consumption, and relevant medical history including neurological, psychiatric diseases, or any other significant condition . All participants had a college degree. The study protocol was approved by the Institutional Review Board of the University of Oklahoma Health Sciences Center, and all participants provided a written informed consent prior to participation in the study.Subjects were asked to record their sleeping pattern using a personal diary log for 7 days prior to sleep deprivation. The sleep quality was characterized by self‐judgment in terms of approximate time of falling asleep, the time it took to fall asleep, number of awakenings at night, the time of final wake‐up in the morning, any condition during these days that could affect sleep , amount of consumed alcoholic and caffeinated beverages, and average sleepiness on a scale 1–10. All participating subjects were requested to maintain a sleep duration of no less than 7 uninterrupted hours of sleep daily over the course of 7 days. Baseline measures were acquired from all subjects 3–5 days before the scheduled date of SD. On the day of sleep deprivation, subjects arrived at the testing facility where they stayed awake until the following morning, when the final assessments were performed. Subjects were asked not to consume any substances affecting cognitive performance (caffeinated beverages) for at least 24 hr prior to measurements. We measured blood pressure before and after SD, and other basal physiological parameters obtained in this cohort have been reported . The system was equipped with 16 sources  emitting light at two different wavelengths (760 and 850 nm) and 16 photodetectors  defining 48 channels. A 128‐port Easycap (Easycap GmbH) was mounted over the head covering the area of the international 10–10 system. Optode localization was guaranteed by aligning the line between Fpz and Iz ports on the headcap with the midsagittal plane and aligning the optode in the Fpz position of the cap with Fpz on the participant's head. Average source–detector distance was 3 cm, and the variability of the distance between optodes was limited by setting up the cap with custom‐made spacers, provided by the manufacturer. This setup of optodes was capable of probing the PFC, dorsolateral PFC, and also the medial motor cortex which was confirmed by the projection of channel position to the cortical surface within the Montreal Neurological Institute coordinate space  were acquired in a quiet and darkened room, while the subjects were seated in a comfortable armchair. Changes in cerebral hemodynamics were captured during a one‐minute resting state followed by a finger‐tapping task Figure . In brie2.3The measured fNIRS signal comprises not only components associated with functional brain activation but also systemic physiological processes with characteristic frequencies. The majority of these oscillations originate from heart pulsation, breathing, and autonomic nervous system functions which contribute to scalp hemodynamics . Since the obtained matrices are symmetric, all approaches allow for reconstructing undirected graphs, reflecting the linear statistical interdependence between the examined brain regions.We determined the functional brain networks using preprocessed HbT time series, as described in Ref. , the clustering coefficient (C), and the global efficiency (E). These parameters can be calculated for each node  and for the whole network as an average across the nodes; the weighted parameter is denoted by a left superscript W.In the next step, we defined the graph theoretical parameters both for binary and weighted undirected networks  or average node degree (binary networks) is the simple functional connectivity parameter:Local weighted density is a fraction of connection strength to the maximal connection strength for each node and it is the average of the corresponding edge weights. For node ik is the degree of node i, hence C reflects how the neighboring nodes in the network form connected groups. Therefore, C is a measure of functional segregation for the whole network.We also computed the binary global clustering coefficient, which expresses the average probability that a link exists between two nodes if there is another node in the graph, which is connected to both. In other words, it is equal to the average of local clustering coefficient according toijd is the shortest path between nodes i and j of a binary network. Efficiency captures functional integration by describing the effectiveness of information transfer between distinct nodes of the given network.By definition, the architecture of a functional network is more efficient if the average shortest path length between all pairs of nodes is smaller . To reveal any sensorimotor deficits or lack of comprehension, the testing began with the Motor Screening Task (MOT). After successful completion of MOT, the following domains of cognitive functions were examined in this study: attention and psychomotor speed , spatial working memory (SWM test), visual memory, short‐term recognition, and visual information matching . All participants performed tests uninterrupted using the touchscreen 10.5” iOS tablet device running the CANTAB application.2.6s = 0.05 (significance level). The effect of sleep state and stimulus was assessed with the aid of a two‐way repeated‐measures analysis of variance (ANOVA) where sleep state had two levels  and task state had seven levels . Difference of means was considered significant in case of p < .05 confirmed by using Dunnett's post hoc test which used values obtained in resting state as controls to the compare with task states. All statistical tests were performed with TIBCO Statistica 13.4.Data preprocessing and analyses were carried out using custom scripts written by the authors in Matlab . Functions for calculating the graph theoretical parameters were obtained from the Brain Connectivity Toolbox , and Dunnett's test confirmed significant differences. Two‐way repeated‐measures ANOVA also revealed a significant effect of the interaction between sleep state and stimulus levels on D for most of the post hoc rest versus task comparisons. Since spurious connections were omitted from characterizing surrogate thresholded networks, task state was characterized by less significant links between the monitored brain regions. Apparently, task‐related changes of D were smaller after SD in comparison with the preceding state. Comparing the average of weighted density (connection strength) also revealed the statistically significant effect of the interaction between sleep and task (p = .012).Contrarily, when we examined surrogate thresholded networks, a marked decrease in connectivity Figure  was founD in subsequent analyses.In order to evaluate functional segregation and functional integration of different networks, it was necessary to apply cost thresholding. Thus, the same number of functional connections enabled a comparison of the global clustering coefficient and global efficiency. Although these results also depend on the chosen cost value, the global parameters of functional connectivity obtained for cost‐thresholded networks are calculated and shown after summing these parameters across networks determined at different cost values between 10% and 85% similarly to Racz et al. . StatistWDloc are depicted in Figure WDloc in particular, albeit none of such channel‐wise effects reached the level of significance due to the moderate between‐subjects concordance . In spite of these noticeable patterns of local functional connectivity changes, none of these effects could be localized.We evaluated the effect of task and sleep state on functional connectivity also at the local level by comparing connection strengths in surrogate thresholded networks; the overall changes of 3.3WD and in neuropsychological scores obtained by CANTAB tests  First Attempt Memory score, a measure of executive function. A clear difference between task‐related change of connection strength before and after SD was observed in participants whose second PAL score showed a decrease compared to that achieved during the first visit. Since the low number of subjects did not permit assessing brain–behavior correlation at a local level, we only evaluated the influence of global network metrics on cognitive performance.To evaluate the association between the difference (∆) in s Figure , we defi4In this study, we tested the novel hypothesis that deprivation of sleep does affect functional brain networks in the frontal lobe captured by fNIRS. We confirmed that sleep deprivation significantly alters task‐related changes in functional connectivity. In essence, the observed global network response in the sleep‐deprived state is featured by significantly less decrease in the average number of functional connections. We also found a significant negative correlation between changes in PAL score and task‐related alteration of global connection strength.Brain networks of the frontal lobe were reconstructed using temporal correlation of simultaneously recorded fNIRS signal, a broadly utilized approach to investigate functional organization underlying mental processes  in these affected brain regions. Though we used CBSI‐treated hemoglobin signals for FC calculations . The increase in task‐related changes in global connection strength showed a significant anticorrelation with PAL score  and sustained attention (RVPA), but it did not significantly affect other cognitive domains examined by the CANTAB test battery  , further longitudinal studies are needed. We propose that fNIRS‐based approaches are ideally suited for this task.The study protocol was approved by the Institutional Review Board of the University of Oklahoma Health Sciences Center and was conducted in compliance with the Helsinki Declaration.Written informed consent was obtained from all subjects prior to participation.Not applicable.Not applicable.The authors declare that they have no competing interests.https://publons.com/publon/10.1002/brb3.2135.The peer review history for this article is available at


This study aimed to investigate the demographic, clinical, and epidemiological statistics of Japanese patients attending a designated outpatient clinic for COVID‐19 in Sapporo, Japan, and contrast the clinical and epidemiological features between those with and without mild COVID‐19. A total of 27 (8.6%) of 315 patients were diagnosed with COVID‐19. They had higher proportions of myalgia, direct contact with a confirmed COVID‐19 patient, and attendance of social gatherings in close confines. We believe that our study makes a significant contribution to the literature because it provides a clinical picture of mild COVID‐19 in the Japanese population, which has not been studied extensively. It can also assist in optimizing the local preventive measures to reduce the transmission of COVID‐19. The primary outcome was the diagnosis of COVID‐19, as confirmed by the real‐time reverse transcription‐polymerase chain reaction assay with nasal or pharyngeal swab specimens. Exposure variables are described in Table 3A total of 315 patients visited the Teine Keijinkai Medical Center Infection Triage Clinic and underwent RT‐PCR tests, and COVID‐19 was diagnosed in 27 patients (8.6%). Compared to patients without COVID‐19, infected patients had a significantly higher percentage of having myalgia (37% vs. 17%); the infected patients were also more likely to have had direct contact with other COVID‐19 patients in the previous two weeks (93% vs. 18%). They were more likely to have participated in social gatherings in the previous two weeks (37% vs. 13%). Other clinical manifestations  were comparable between the two groups. Among COVID‐19 patients, one patient required oxygen administration and the same patient was hospitalized for COVID‐19–associated pneumonia, treated successfully with dexamethasone without any sequelae. Other 26 patients did not require oxygen therapy and were instructed recuperation at home for seven to fourteen days. These 26 patients were returned to the daily life without the development of COVID‐19–associated pneumonia.4Our finding that patients with COVID‐19 had a significantly higher proportion of direct contact with confirmed COVID‐19 cases and participation in social gatherings in the two weeks before presenting at the clinic was consistent with previous studies.This study has several limitations. First, our study has selection bias because this study was conducted in an outpatient clinic, and therefore, we may have missed patients with severe symptoms. Indeed, we had only one patient who required hospitalization for this disease. Second, there is a possibility of recall bias because information about symptoms two weeks before the clinic visit relied on a self‐reported questionnaire. Third, antigen testing using saliva or nasopharyngeal swabs was not used for COVID‐19 diagnosis because the test had not been introduced at our institution at the time of data collection. Undoubtedly, more effort should be made to continue capturing a comprehensive clinical picture of COVID‐19 patients in Japan. Nonetheless, our findings may be applicable to other clinical settings, such as emergency room, where performing a focused history taking is the cornerstone of diagnosis and treatment.5In conclusion, to our knowledge, this is the first report describing the clinico‐epidemiological characteristics of patients attending a specialized outpatient clinic for COVID‐19. More studies from Japan will be needed to contribute to the growing volume of clinical evidence and elucidate the complete clinical spectrum of the disease in the Japanese population.The authors have stated explicitly that there are no conflicts of interest in connection with this article.


A high frequency of coronary artery disease (CAD) is reported in patients with severe aortic valve stenosis (AS) who undergo transcatheter aortic valve implantation (TAVI). However, the optimal management of CAD in these patients remains unknown.We hypothesis that AS patients with TAVI complicated by CAD have poor prognosis. His study evaluates the prognoses of patients with CAD and severe AS after TAVI.We divided 186 patients with severe AS undergoing TAVI into three groups: those with CAD involving the left main coronary (LM) or proximal left anterior descending artery (LAD) lesion (the CAD[LADp] group), those with CAD not involving the LM or a LAD proximal lesion (the CAD[non‐LADp] group), and those without CAD (Non‐CAD group). Clinical outcomes were compared among the three groups.The CAD[LADp] group showed a higher incidence of major adverse cardiovascular and cerebrovascular events (MACCEs) and all‐cause mortality than the other two groups . Even after adjustment for STS score and percutaneous coronary intervention (PCI) before TAVI, CAD[LADp] remained associated with MACCE and all‐cause mortality. However, PCI for an LM or LAD proximal lesion pre‐TAVI did not reduce the risk of these outcomes.CAD with an LM or LAD proximal lesion is a strong independent predictor of mid‐term MACCEs and all‐cause mortality in patients with severe AS treated with TAVI. PCI before TAVI did not influence the outcomes. We analyzed the cases of the series of 199 consecutive symptomatic patients with severe AS who were treated with TAVI at St. Marianna University School of Medicine, Kawasaki, Japan since January 2016. All patients' cases and options were discussed by our cardiology team for appropriate adaptation. Before undergoing the TAVI, the patients were examined by coronary angiography (CAG) or coronary computed tomography angiography (CTA). We excluded 13 patients who underwent coronary artery bypass grafting (CABG) . Informed consent was acquired in the form of opt‐out on the website.n = 13) was comprised of the patients in whom CAD (as defined below) was detected in the LM or proximal LAD (five and six segments in American Heart Association [AHA] classification) by CAG or CTA. The CAD[non‐LADp] group (n = 65) was the patients in whom CAD was detected at sites other than the LM and proximal LAD by CAG or CTA. The non‐CAD group (n = 108) was the patients in whom CAD was not detected by CAG or CTA. CAD was defined as >75% stenosis of ≥1 major branch on CAG/CTA or 50% stenosis only in the LM based on the AHA classification derived from the visual assessment of CAG or CTA results. The angiographic assessment of CAD was based on the consensus of three experienced cardiologists. If PCI had been performed previously and there was no re‐stenosis at the time of coronary screening, the patient was assigned to the non‐CAD group. When deciding whether to perform PCI for the patients with CAD, we took into consideration the ischemic burden, the technical complexity, the risk of in‐stent restenosis, and the patient's general condition . PCI for CAD detected by this coronary screening was basically implemented before TAVI as an independent hospitalization.We divided the 186 remaining patients into the following three groups. The CAD[LADp] group  or anticoagulant therapy . Procedural anticoagulation was achieved by heparinization, and the target activated clotting time was 250–300 msec. We used two TAVI systems: the Medtronic CoreValve™ or Evolut R™/PRO™  and the Edwards SAPIEN XT™/3™ . The choice of valve type was discussed by a heart team conference made up of cardiologists, cardiac surgeons, anesthesiologists, nurses, and clinical engineers. Balloon expandable valves were generally chosen for CAD patients indicated for PCI, so that the coronary artery could be easily accessed after TAVI. However, consideration was also made for factors other than the coronary artery itself  in order to make a comprehensive decision. All patients were initially screened for a transfemoral approach. In cases in which transfemoral access was not possible, the patients were evaluated for alternative access sites in the following order of preference: subclavian arteries, left ventricular apex, ascending aorta.The PCI procedure was initiated following the administration of unfractionated heparin (100 IU/kg) into the peripheral vein. The decision to choose either a drug‐eluting stent or a drug‐coated balloon was left to the operators' discretion. The patients generally continued dual antiplatelet therapy for 1 year after the PCI.2.3The primary outcome was the major adverse cardiovascular and cerebrovascular events (MACCEs) defined as non‐lethal myocardial infarction, unstable angina pectoris, heart failure requiring hospitalization, stroke, and cardiovascular death. The secondary outcome was all‐cause mortality.2.4SD) or as frequencies (percentages). We used the chi‐squared test, an analysis of variance, and the Kruskal‐Wallis test to examine differences among three groups, and we performed a Kaplan–Meier analysis and a multivariate Cox regression analysis to examine changes over time to the endpoints. Bonferroni corrected post‐hoc tests were conducted to determine where these differences occurred. A two‐tailed p value <.05 was considered significant.All statistical analyses were carried out with SPSS/Windows, ver. 22.0 . Data are presented as the mean . The CAD[LADp] and CAD[non‐LADp] groups had significantly higher rates of a history of angina pectoris compared to the non‐CAD group . The CAD[non‐LADp] group had a significantly higher rate of antiplatelet drug use on admission and at discharge than the non‐CAD group . The CAD[LADp] group had significantly higher SYNTAX scores than the CAD[non‐LADp] group .During the follow‐up period, the total number of MACCEs was 30 and the total number of deaths was 17 Table . The resThe univariate analysis demonstrated that CAD in an LM or LAD proximal lesion was significantly associated with increased incidences of MACCEs  and an increased incidence of all‐cause mortality . Even after adjustment for the STS score and the performance of a PCI before TAVI, CAD involving an LM or LAD proximal lesion remained associated with increased incidences of MACCEs  and all‐cause mortality . PCI involving an LM or LAD proximal lesion before TAVI did not have a significant impact on MACCEs  or all‐cause mortality  Table .4The main findings of this study were as follows. (1) The prevalence of CAD in patients with severe AS treated by TAVI was 42%. (2) The CAD[LADp] group had a higher incidence of MACCE and a higher incidence of all‐cause mortality than the other two patient groups. (3) The multivariate Cox regression adjusted for the STS score and the performance of a PCI before TAVI revealed that CAD involving an LM or LAD lesion was independently associated with increased rates of MACCEs and all‐cause mortality. (4) PCI before TAVI did not affect the patients' outcomes.In this series of patients with severe AS, the prevalence of CAD was 42%. In previous TAVI studies the prevalences of CAD ranged from 11%The impact of coexisting CAD on clinical outcomes in TAVI patients is very controversial. Dewey et al. reported that coexisting CAD negatively influenced procedural outcomes and long‐term survival in TAVI patients.We also found that the performance of a PCI before the TAVI did not influence the incidence of MACCEs or all‐cause mortality in the multivariate Cox regression analysis. A previous report showed that there was no difference in 2‐year mortality between PCI plus TAVI and only TAVI.On the other hand, it is reported that the reduction in ischemic burden achieved by PCI reduces the risk for death or myocardial infarction. A COURAGE trial nuclear substudy suggested that a treatment target of more than 5% ischemia reduction is suitable for adding PCI to OMT.Finally, the timing of PCI is a different issue. In their review, Cao et al. included the timing of PCI in a flowchart of the strategy of CAD management in TAVI patients.5This study has some limitations. It was a single‐center exploratory research and the sample size  was relatively small. The prognosis of the patients undergoing TAVI was relatively favorable, with 17 all‐cause deaths and 30 MACCEs during the follow‐up period. Further studies with a large sample size are warranted to validate the prognostic significance of patients with CAD after TAVI. Further research with large number of patients with proximal LAD disease is needed. However, the standardized TAVI procedure and the reliable follow‐up of the patients could help counteract these limits. In addition, because this was a retrospective analysis, there may have been selection bias. Although we minimized the risk of selection bias by performing a multivariate Cox regression analysis, there is a possibility of inconclusive results. There was also the limitation of defining CAD by visual assessments of CAG or CTA findings. PCIs guided by physiological assessments using FFR or iFR might have led to other results.6A lesion in the LM and a LAD proximal lesion are both a strong independent prognostic factor for patients with severe AS treated with a TAVI, and the performance of a PCI before the TAVI did not influence the present patients' mid‐term MACCEs or all‐cause mortality. For AS patients who undergo a TAVI and are complicated by CAD involving an LM or LAD proximal lesion, more intensive management may be necessary to improve clinical outcomes.The authors declared no potential conflict of interest.Appendix S1: Supporting informationClick here for additional data file.


Subcutaneous panniculitis‐like T‐cell lymphoma is a rare and highly malignant extra‐nodal lymphoma. It has a wide range of clinical presentations  and should be considered in the differential diagnosis of systemic lupus erythematosus, especially in children. Subcutaneous panniculitis‐like T‐cell lymphoma is a rare and highly malignant extra‐nodal lymphoma. It has a wide‐range of clinical presentations  and should be considered in the differential diagnosis of systemic lupus erythematous, especially in children. Biopsy and pathological evaluation is essential for a definite diagnosis. To our knowledge, there have been no reported cases of SPTCL with periorbital swelling. We report a very rare case of SPTCL complicated by severe periorbital swelling in a young girl.Subcutaneous panniculitis‐like T‐cell lymphoma (SPTCL) is a peripheral T‐cell lymphoma derived from a mature cytotoxic T cell. SPTCL accounts for less than 1% of non‐Hodgkin lymphomas (NHLs).2A previously healthy ten‐year‐old girl was referred to our hospital due to a right periorbital swelling, weakness, and high‐grade fever. She had developed the swelling about one week before admission Figure  and had On evaluation she had leukopenia, lymphopenia, and mildly elevated inflammatory markers. Ultrasound of the lesion showed extensive edema of the soft tissue in the face and upper neck, particularly in the superficial subcutaneous tissue. Magnetic resonance imaging (MRI) revealed cellulitis without any fluid collection or lymphadenitis in the subcutaneous area of the bilateral cheek and submandibular regions. Evaluation with metaiodobenzylguanidine (MIBG) scintigraphy was negative. Bone marrow evaluation was normal, and there was no evidence of inflammatory involvement. Finally, the patient underwent an excisional buccal biopsy Figure . The res3Panniculitis is the inflammation of the subcutaneous fat. Histopathologically, panniculitis mostly affects the lobules or septa regardless of vascular involvement.Most patients with PTCL that undergo treatment will either not achieve remission or experience relapse.4We report a young girl who presented with fever, facial swelling, and painless ulcerative lesions as well as a hemophagocytic syndrome. She was diagnosed with SPTCL and showed good response to chemotherapy.The authors declare no conflict of interests.All authors passed four criteria for authorship contribution based on recommendations of the International Committee of Medical Journal Editors. All authors had equal contribution to this study. All authors have read and approved the final manuscript.This study was conducted following the principles of the World Medical Association Declaration of Helsinki.Written informed consent was obtained from the patient's parents for the publication of this case report and any accompanying images.